Substituted heterocyclic ethers and their use in CNS disorders

The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating CNS disorders.

BACKGROUND OF THE INVENTION

Tachykinins are a group of naturally occurring peptides found widely distributed throughout mammals, both within the central nervous system and in the peripheral nervous and circulatory systems. The three known mammalian tachykinins are Neurokinin-1 (NK-1, substance P), Neurokinin A, and Neurokinin B. These compounds act as neurotransmitters and immunomodulators and may contribute to the pathophysiology of a wide variety of human diseases.

Selective serotonin reuptake inhibitors (SSRI's) have proven to be effective in treating depression, but have the disadvantages of delayed onset of antidepressant activity, limited efficacy, and significant side effects. See Novel strategies for pharmacotherapy of depression, K. A. Maubach, N. M. J. Rupniak, M. S. Kramer, and R. G. Hill, Current Opinion in Chemical Biology 1999, 3, 491-499. Selective serotonin reuptake inhibitors (SSRIs) in combination with other agents can be useful for the treatment of depression and other disorders and combination SERT/NK1 compounds should also be useful for these conditions. For example, the combination of SSRIs with dopamine reuptake inhibitors such bupropion and modafanil have shown clinical benefit relative to SSRIs alone, primarily due to superior side effect profiles (Bodkin et al, 1997, J Clin Psychiatry, 58: 137-145; Kennedy et al, 2002, J Clin Psychiatry, 63:181-186). Additionally, the combination of SSRIs with 5-HT1A antagonists such as pindolol have shown improved clinical response relative to SSRIs alone (Artigas F et al, 1994, Arch Gen Psychiatry 51:248-251; Blier P and Bergeron R, 1995, J Clin Psychopharmacol 15:217-222). Finally, combining SSRIs with antipsychotics, such as fluoxetine plus olanzapine, has provided superior profiles in certain depressed populations including psychotic depression and bipolar depression (Corya et al, 2003, J Clin Psychiatry, 64:1349-1356; Rothschild et al, 2004, J Clin Psychopharmacol, 24:365-373).

NK-1 antagonists are believed to modulate 5-HT function via noradrenergic pathways and have been shown to attenuate presynaptic 5-HT1Areceptor function. NK-1 antagonists offer an alternative approach for treating depression in patients that respond poorly to the SSRI's and other available drugs and the combination of serotonin reuptake inhibition with NK-1 antagonism may lead to new classes of drugs with improved characteristics.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I and related compound and compositions including pharmaceutically acceptable salts and their use in treating CNS disorders related to levels of tachykinins or serotonin or both.

One aspect of the invention are compounds of Formula I

Another aspect of the invention is a compound of formula I whereR1is hydrogen or alkyl;R2is hydrogen or alkylR3is hydrogen or alkyl;Ar1is phenyl or pyridinyl and is substituted with 0-3 substituents selected from the group consisting of halo, alkyl, haloalkyl, and cyano;Ar2is indolyl, indazolyl, benzimidazolyl, or benzotriazolyl and is substituted with 0-3 substituents selected from the group consisting of halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, pyrrolidinyl, piperidinyl, piperazinyl, (alkyl)piperazinyl, morpholinyl, thiomorpholinyl, and Ar3; andAr3is phenyl substituted with 0-3 substituents selected from the group consisting of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and cyano;
or a pharmaceutically acceptable salt thereof.

Another aspect of the invention are compounds of Formula I where R1is hydrogen.

Another aspect of the invention are compounds of Formula I where R1is methyl.

Another aspect of the invention are compounds of Formula I where R2and R3are hydrogen.

Another aspect of the invention are compounds of Formula I where R2is methyl and R3is hydrogen.

Another aspect of the invention are compounds of Formula I where Ar1is phenyl.

Another aspect of the invention are compounds of Formula I where Ar1is monohalophenyl.

Another aspect of the invention are compounds of Formula I where Ar1is p-fluorophenyl.

Another aspect of the invention is a compound of formula I where Ar2is indazolyl, benzimidazolyl, or benzotriazolyl and is substituted with 0-3 substituents selected from the group consisting of halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, pyrrolidinyl, piperidinyl, piperazinyl, (alkyl)piperazinyl, morpholinyl, thiomorpholinyl, and Ar3.

Another aspect of the invention is a compound of formula I where Ar2is indazolyl and is substituted with 0-3 substituents selected from the group consisting of halo, alkyl, cycloalkyl, (cycloalkyl)alkyl, haloalkyl, cyanoalkyl, hydroxy, alkoxy, haloalkoxy, cyano, amino, alkylamino, dialkylamino, pyrrolidinyl, piperidinyl, piperazinyl, (alkyl)piperazinyl, morpholinyl, thiomorpholinyl, and Ar3.

Any scope of a substituent, including R1, R2, R3, Ar1, Ar2, and Ar3, can be used independently with the scope of any other instance of a substituent.

Unless specified otherwise, these terms have the following meanings. “Alkyl” means a straight or branched alkyl group composed of 1 to 6 carbons. “Alkenyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 7 carbons. “Hydroxyalkyl,” “alkoxy” and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl. “Aryl” includes carbocyclic and heterocyclic aromatic substituents. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some Formula I compounds have tautomeric forms, for example, the tautomeric moieties shown below. The invention includes all tautomeric forms of the compounds.

Some Formula I compounds contain at least one asymmetric carbon atom, an example of which is shown below. The invention includes all stereoisomeric forms of the compounds, both mixtures and separated isomers. Mixtures of stereoisomers can be separated into individual isomers by methods known in the art.

Compounds of Formula I can be made according to methods known in the art and those illustrated in the schemes below and in the specific embodiments section. The compounds can be made by reasonable variations known in the art. The variables describing general structural formulas and features in the synthetic schemes are distinct from and should not be confused with the variables in the claims or the rest of the specification. These variables are meant only to illustrate how to make some of the compounds of this invention. For this section, a benzene ring with an H in the middle can represent a phenyl or heteroaryl moiety, for example pyridinyl or pyrimidinyl.

Biological Methods

NK-1 Binding assay. Crude membrane suspensions were prepared for the NK1 and SERT radioligand binding assays from U373 cells or recombinant HEK-293 cells expressing hSERT, respectively. Cells were harvested from T-175 flasks as follows. The medium is removed from the flasks and the cells rinsed with HBSS without Ca and without Mg. The cells are then incubated for 5-10 minutes in 10 mM Tris-Cl, pH 7.5, 5 mM EDTA before the cells are lifted with a combination of pipetting and scraping, as needed. To prepare membranes, the cell suspension is collected into centrifuge bottles and homogenized for 30 seconds with a Polytron homogenizer. The suspension is centrifuged for 30 min@32,000×g, 4° C., then the supernatant is decanted and the pellet resuspended and homogenized in 50 mM Tris-Cl, pH 7.5, 1 mM EDTA for 10 seconds. The suspension is then centrifuged again for 30 min@32,000×g, 4° C. The supernatant is decanted and the pellet resuspended in 50 mM Tris-Cl, pH 7.5, 1 mM EDTA and briefly homogenized. A Bradford assay (Bio-rad) is performed and the membrane preparation diluted to 2 mg/ml with 50 mM Tris-Cl, pH 7.5, 1 mM EDTA. Aliquots are prepared, and then frozen and stored at −80° C.

NK1 radioligand binding assay. Compounds are dissolved in 100% DMSO at a concentration 100× the desired highest assay concentration, serially diluted 1:3 in 100% DMSO, and 0.6 ul/well of each solution is dispensed to a Nunc polypropylene, round bottom, 384 well plate. 100% inhibition is defined with 0.6 ul/well of 1 mM L-733,060 (Sigma L-137) dissolved in DMSO. 30 ul/well of a 2×U373 membrane preparation (267 ug/ml in 100 mM Tris-Cl, pH 7.5, 6 mM MgCl2, 0.2% (v/v) Sigma mammalian protease inhibitor cocktail (Sigma P-8340), and 4 ug/ml chymostatin, Sigma C-7268) and 30 ul/well of a 2× radioligand solution (400 pM [125I]Substance P (Perkin ElmerNEX-190) in 1% (w/v) BSA (Sigma A-2153), 0.1 mg/ml bacitracin, Sigma B-0125) are added to the well and the reaction incubated for 1 hour at room temperature. The contents of the assay plate are then transferred to a Millipore MultiscreenHTSGF/B filter plate which has been pretreated with 0.5% PEI for at least one hour. The plate is vacuum filtered and washed with 7 washes of 100 ul/well of 20 mM Tris-Cl, pH 7.5, 0.5% (w/v) BSA chilled to 4° C. The filtration and washing is completed in less than 90 s. The plates are air-dried overnight, 12 ul/well of MicroScint scintillation fluid added, and the plates counted in a Trilux.

SERT radioligand binding assay. Compounds are dissolved in 100% DMSO at a concentration 100× the desired highest assay concentration, serially diluted 1:3 in 100% DMSO, and 0.4 ul/well of each solution is dispensed to a Nunc polypropylene, round bottom, 384 well plate. 100% inhibition is defined with 0.4 ul/well of 1 mM fluoxetine (Sigma F-132) dissolved in DMSO. 20 ul/well of a 2× HEK-hSERT membrane preparation (15 ug/ml in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) and 20 ul/well of a 2× radioligand solution (520 pM [125I]RTI-55 (Perkin-Elmer NEX-272) in 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5mM KCl) are added to each well and the reaction incubated for 1 hour at room temperature. The contents of the assay plate are then transferred to a Millipore MultiscreenHTs GF/B filter plate which has been pretreated with 0.5% PEI for at least one hour. The plate is vacuum filtered and washed with 7 washes of 100 ul/well of 50 mM Tris-Cl, pH 7.5, 120 mM NaCl, 5 mM KCl chilled to 4° C. The filtration and washing is completed in less than 90 s. The plates are air-dried overnight, 12 ul/well of MicroScint scintillation fluid added, and the plates counted in a Trilux.

Data analysis. The raw data are normalized to percent inhibition using control wells defining 0% (DMSO only) and 100% (selective inhibitor) inhibition which are run on each plate. Each plate is run in triplicate, and the concentration response curve thus generated is fit using the four-parameter dose response equation, Y=Bottom+(Top-Bottom)/(1+10^((LogIC50−X)*HillSlope)) in order to determine the IC50value for each compound. The radioligand concentration chosen for each assay corresponds to the Kdconcentration determined through saturation binding analysis for each assay. NK-1 and serotonin transporter binding results are shown in Table 1.

Pharmaceutical Composition and Methods of Use

The compounds of Formula I demonstrate inhibition of neurokinin-1 or serotonin reuptake or both. Inhibition of these receptors correlates with efficacy for affective disorders such as anxiety, depression, obsessive compulsive disorder, bulimia, and panic disorder. As such, the compounds of Formula I can be useful for the treatment of these disorders and other aspects of the invention are compositions and methods of using the compounds to treat these conditions and other conditions associated with aberrant levels of tachykinins or serotonin or both.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and may contain conventional exipients. A therapeutically effective amount is the amount needed to provide a meaningful patient benefit as determined by practitioners in that art. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols).

Solid compositions are normally formulated in dosage units providing from about 1 to about 1000 mg of the active ingredient per dose. Some examples of solid dosage units are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Liquid compositions are generally in a unit dosage range of 1-100 mg/mL. Some examples of liquid dosage units are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, the dosage unit will be in a unit range similar to agents of that class used clinically, for example fluoxetine.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to agents of that class used clinically, for example fluoxetine. Typically, the daily dose will be 0.01-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, should be determined by a physician using sound medical judgement.

Tachykinin and serotonin modulators are associated with depression. Accordingly, another aspect of the invention are methods for treating depressive disorders including Major Depressive Disorders (MDD), bipolar depression, unipolar depression, single or recurrent major depressive episodes, recurrent brief depression, catatonic features, melancholic features including feeding disorders, such as anorexia, weight loss, atypical features, anxious depression, or postpartum onset. Other central nervous system disorders encompassed within the term MDD include neurotic depression, post-traumatic stress disorders (PTSD) and social phobia, with early or late onset dementia of the Alzheimer's type, with depressed mood, vascular dementia with depressed mood, mood disorders and tolerance induced by drugs such as alcohol, amphetamines, cocaine, inhalants, opioids, sedatives, anxiolytics and other substances, schizoaffective disorder of the depressed type, and adjustment disorder with depressed mood.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of schizophrenic disorders. Accordingly, another aspect of the invention are methods for treating schizophrenic disorders including paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of anxiety. Accordingly, another aspect of the invention are methods for treating anxiety disorders including panic disorders, agoraphobia, phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorders, generalized anxiety disorders, acute stress disorders and mixed anxiety-depression disorders.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of cognitive disorders. Accordingly, another aspect of the invention are methods for treating cognitive disorders including dementia, and amnesia disorders. Tachykinin and serotonin modulators are also associated with the treatment or prevention of memory and cognition in healthy humans.

Tachykinin and serotonin modulators are also associated with use as analgesics. Accordingly, another aspect of the invention are methods for treating pain, including the treatment of traumatic pain such as postoperative pain, chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis, neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, various forms of headache such as migraine, acute or chronic tension headache, cluster headaches, maxillary sinus pain, cancer pain, pain of bodily origin, gastrointestinal pain, sport's injury pain, dysmennorrhoea, menstrual pain, meningitis, musculoskeletal pain, low back pain e.g. spinal stenosis, prolapsed disc, sciatica, angina, ankylosing spondyolitis, gout, burns, scar pain, itch and thalamic pain such as post stroke thalamic pain.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of sleep disorders. Accordingly, another aspect of the invention are methods for treating sleep disorders including insomnia, sleep apnea, narcolepsy, and circadian rhymic disorders.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of inflammation. Accordingly, another aspect of the invention are methods for treating inflammation, including the treatment of inflammation in asthma, influenza and chronic bronchitis, in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drug induced damage, inflammatory diseases of the skin such as herpes and eczema, inflammatory diseases of the bladder such as cystitis and urge incontinence, and eye and dental inflammation.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of allergic disorders. Accordingly, another aspect of the invention are methods for treating allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of emesis, nausea, retching and vomiting. Accordingly, another aspect of the invention are methods for treating these disorders.

Tachykinin and serotonin modulators are also associated with the treatment or prevention of premenstrual dysphoric disorder (PMDD), in chronic fatigue syndrome and multiple sclerosis. Accordingly, another aspect of the invention are methods for treating these disorders.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The following experimental procedures describe the synthesis of some Formula I compounds. Standard chemistry conventions are used in the text unless otherwise noted. The experimental encompass reasonable variations known in the art. The following HPLC conditions may be used where indicated.

1-(tert-Butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid. To a suspension of 4-phenyl-4-piperidinecarboxylic acid p-methylbenzenesulfonate (100 g, 265 mmol) and triethylamine (111 mL, 795 mmol) in tetrahydrofuran (1200 mL) was added di-tert-butyl dicarbonate (63.6 g, 291 mmol). The reaction was slowly heated to a gentle reflux and held there for 1 h. After one hour, gas evolution had ended and the reaction had become a clear solution. The reaction was cooled to room temperature and concentrated to remove most of the tetrahydrofuran. The residue was dissolved in water/diethyl ether and the aqueous made very basic by the addition of 10 M sodium hydroxide (50 mL). The aqueous was washed with diethyl ether (2×) which was discarded. The aqueous was transferred to an erlenmeyer flask and made acidic (ca. pH 5) by addition of acetic acid to give a white precipitate. The precipitate was collected by filtration and air dried overnight to give a white powder. The last traces of water were removed under high vacuum to give 78.9 g (98%).1H-NMR (CD3OD, 500 MHz) δ 10.5 (bs, 1H), 7.39 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 3.90 (bs, 2H), 3.08, (bs, 2H), 2.48 (d, J=13.4 Hz, 2H), 1.85 (m, 2H), 1.44 (s, 9H);13C NMR (126 MHz, CDCl3) δ ppm 179.6, 155.0, 141.6, 128.8, 127.6, 126.1, 79.9, 49.3, 41.7, 33.4, 28.5. Mass spec.: 328.12 (MNa)+.

1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid. tert-Butyl 4-cyano-4-(4-fluorophenyl)piperidine-1-carboxylate (0.35 g, 1.15 mmol) was dissolved in ethanol (3.0 mL) and sodium hydroxide (50% in water, 3.0 mL). The reaction mixture was then heated at reflux for 6 h. After cooling to room temperature, the mixture was concentrated in vacuo to remove most of the ethanol. The residue was poured into water/ethyl acetate. The product was extracted with water (2×) and the organics discarded. The aqueous layers were pooled together and acidified to pH 2.0 with 1 N hydrochloric acid. The resulting precipitate was filtered and dried in vacuo for several hours to afford 0.24 g (64%) as a white powder.1H-NMR (CD3OD, 500 MHz) δ 7.46-7.48 (m, 2H), 7.07-7.11 (m, 2H), 3.94-3.98 (m, 2H), 3.10 (m, 2H), 2.50-2.53 (m, 2H), 1.78-1.83 (m, 2H), 1.48 (s, 9H). Mass spec.: 346.20 (MNa)+.

7-Methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-5-carbaldehyde. The title compound was prepared according to the literature procedure (Luo, J. Org. Chem. 2006, 5392).

7-Bromo-5-(trifluoromethyl)-1H-indazole. To a suspension of 2-bromo-6-methyl-4-(trifluoromethyl)aniline (1 1.3 g, 44.5 mmol) in hydrochloric acid (8 M, 40 mL, 320 mmol) at −10° C. was added a solution of sodium nitrite (3.22 g, 46.7 mmol) in water (ca. 10 mL) dropwise. After 10 min, the resulting solution was neutralized by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (5.01 mL, 44.5 mmol) in ethanol (100 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (25 mL) and transferred to a solution of potassium tert-butoxide (39.9 g, 356 mmol) in dimethylsulfoxide (250 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid to give a precipitate. After 30 min, the resulting solid was collected by filtration and air dried on the filter overnight to give 10.1 g (86%) as a tan solid.1H-NMR (CDCl3, 500 MHz) δ 8.24 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 2.83 (bs, 1H);13C-NMR (CDCl3, 126 MHz) δ 140.7, 136.3, 125.8 (q, J=2.9 Hz), 124.9 (q, J=33 Hz), 123.8 (q, J=273 Hz), 123.2, 118.4 (q, J=3.8 Hz), 104.1.

(3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methanol 3-Bromo-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (400 mg, 0.95 mmol) was suspended in ethanol (5 mL), cooled to 0° C., and treated sodium borohydride (18 mg, 0.47 mmol) in one portion. Cooling was removed and the reaction stirred at room temperature for 1 h. The reaction was cooled to 0° C. and treated with saturated aqueous ammonium chloride. The reaction was concentrated to remove most of the ethanol and diluted with ethyl acetate. The layers were separated and the organic layer washed with brine (2×), dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel afforded 220 mg (55%) as a light yellow oil.1H-NMR (CDCl3, 300 MHz) δ 7.86 (s, 1H), 7.61 (s, 1H), 5.86 (s, 2H), 5.02 (s, 2H), 3.51-3.56 (m, 2H), 0.79-0.85 (m, 2H), 0.09 (s, 9H). Mass spec.: 448.82 (MNa)+.

tert-Butyl 4-(((3-methyl-5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. tert-Butyl 4-phenyl-4-(((5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (97 mg, 0.16 mmol) was dissolved in dry tetrahydrofuran (3 mL) and stirred at room temperature for 15 min. The stirred mixture was cooled to −78° C. and treated with a solution of tert-butyllithium (1.7 M in pentane, 190 μL, 0.33 mmol). The reaction was gradually warmed to −20° C. over 1 h, cooled to −78° C. and treated with iodomethane (10 μL, 0.19 mmol). The reaction was warmed to 0° C. over several hours then treated with saturated ammonium chloride. The reaction was diluted with ethyl acetate. The layers were separated and the organic layer washed with brine (2×), dried over sodium sulfate, filtered and concentrated to afford 100 mg (quant.) as a clear oil. LC/MS (HPLC method 1): tR=3.70 min, 634.26(MH)+.

7-Bromo-5-chloro-1H-indazole. 2-Bromo-4-chloro-6-methylaniline (13.2 g, 59.90 mmol) was suspended in 24% hydrochloric acid (40 mL). The stirred mixture was cooled to 0° C. and treated with sodium nitrite (4.54 g, 65.90 mmol) in water (10 mL), dropwise over 30 min. The mixture was then buffered to ca. pH 5 with sodium acetate. This mixture was kept at 0° C. and added in portions to a stirred solution of 2-methyl-2-propanethiol (6.8 mL, 59.9 mmol) in ethanol (40 mL) at 0° C. over 30 min. After the addition, the mixture was stirred at 0° C. for 30 min then transferred to crushed ice, and extracted with ethyl acetate (2×). The organics were pooled together, washed with brine (2×), dried over sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in dimethyl sulfoxide (50 mL) and transferred to a solution of potassium tert-butoxide (53.7 g, 479 mmol) in dimethyl sulfoxide (200 mL) at 0° C. via cannula. The ice-bath was removed and stirring continued for 30 min. The reaction was then poured into a mixture of crushed ice (400 mL) and 10% hydrochloric acid (200 mL) to give a precipitate which was collected by filtration. The resulting solid was triturated with hexanes to afford 7.5 g (54%) as a brown powder.1H-NMR (CDCl3, 300 MHz) δ 7.97 (s, 1H), 7.60 (s, 1H), 7.44 (s, 1H). Mass spec.: 232.90 (MH)+.

5-Chloro-1H-indazole-7-carbaldehyde. 7-Bromo-5-chloro-1H-indazole (0.44 g, 1.90 mmol) and sodium hydride were combined in tetrahydrofuran (5 mL) at 0° C. After 15 min, cooling was removed and the mixture stirred at room temperature for 20 min. The stirred mixture was cooled to −78° C. and treated with a solution of tert-butyllithium in pentane (1.7 M, 2.4 mL, 3.99 mmol) over several minutes. The mixture was allowed to gradually warm to −20° C. over 1 h, re-cooled to −78° C. and treated with dimethylformamide (220 μL, 2.85 mmol). The reaction was warmed to 0° C. over several hours, then treated with saturated ammonium chloride. The reaction was diluted with ethyl acetate. The layers were separated. The organic layer was washed with brine (2×), dried over sodium sulfate, filtered and concentrated to afford 0.3 g (87%) as a white powder. LC/MS (HPLC method 1): tR=1.88 min, 181.02(MH)+.

(±)-tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. (±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (75 mg, 0. 113 mmol), cyclopropyl boronic acid (20 mg, 0.34 mmol), and tetrakis(triphenylphosphine) palladium(0) (13. 1 mg, 0.011 mmol) were combined in dry tetrahydrofuran (2 mL) followed by addition of 0.58 mL of a 1 N aqueous potassium hydroxide solution in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate and washed with water and brine, concentrated and purified by flash chromatography on silica gel (20% EtOAc/Hex) to afford 70.5 mg (100%) as an oil. LC/MS (HPLC method 2): tR=3.738 min, 624.24(MH)+.

(±)-tert-Butyl 4-((1-(5-cyclopropyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. (±)-tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(70.5 mg, 0. 113 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature overnight. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 40.5 mg of (±)-5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-2H-indazole (91%). The crude amine (40.5 mg, 0. 103 mmol) in dichloromethane (2 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (44.9 mg, 0.206 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (1%→30% EtOAc/Hex) to give 30 mg (59%) as oil. LC/MS (HPLC method 3): tR=3.15 min, 494.12(MH)+.

(±)-5-Cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole. (±)-tert-Butyl 4-((1-(5-cyclopropyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (30 mg, 0.061 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 2 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 21.8 mg (91%). LC/MS (HPLC method 3): tR=2.235 min, 394.10(MH)+.

(±)-tert-Butyl 4-((1-(5-cyano-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. (±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (75 mg, 0. 113 mmol), tetrakis(triphenylphosphine) palladium(0) (13.1 mg, 0.011 mmol) and cyanozinc (20.7 mg, 0.226 mmol) were combined in dry N,N-dimethylformamide (2 mL) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate and washed with water and brine, concentrated and purified by flash chromatography on silica gel (20% EtOAc/Hex) to afford 21 mg (30.5%) as an oil. LC/MS (HPLC method 2): tR=3.265 min, 609.18(MH)+.

(±)-7-(-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole-5-carbonitrile. (±)-tert-Butyl 4-((1-(5-cyano-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (21 mg, 0.034 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 13.5 mg (quant.). LC/MS (HPLC method 3): tR=1.717 min, 379.09(MH)+.

(±)-7-(1-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)ethyl)-5-methyl-1H-indazole. (±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-methyl-1H-indazol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (35 mg, 0.075 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 2 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 24 mg (87%). LC/MS (HPLC method 3): tR=2.658 min, 368.38(MH)+.

(±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-morpholino-1H-indazol-7-yl)ethoxy)methyl)piperidine-1-carboxylate. (±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-morpholino-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (44 mg, 0.066 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 30.5 mg of (±)-4-(7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-2H-indazole-5-yl)morpholino (quant.). The crude amine (30.5 mg, 0.07 mmol) in dichloromethane (2 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (30.4 mg, 0.139 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (30% EtOAc/Hex) to give 32 mg (85%) as oil. LC/MS (HPLC method 3): tR=1.592 min, 539.44(MH)+.

(±)-4-7-(-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole-5-yl)morpholino. (±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-morpholino-1H-indazol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (32 mg, 0.059 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 2 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 24.2 mg (93%). LC/MS (HPLC method 3): tR=1.752 min, 439.10(MH)+.

(±)-tert-Butyl 4-((1-(5-(dimethylamino)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. (±)-tert-Butyl 4-((1-(5-dimethylamino-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (206 mg, 0.329 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 3.5 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 124 mg of (±)-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-N,N-dimethyl-2H-indazol-5-amine (95%). The crude amine (124 mg, 0.313 mmol) in dichloromethane (2.7 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (137 mg, 0.625 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (18%→45% EtOAc/Hex) to give 138 mg (89%) as clear oil. LC/MS (HPLC method 3): tR=2.816 min, 497.50(MH)+.

(±)-7-(1-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)ethyl)-N,N-dimethyl-1H-indazol-5-amine. (±)-tert-Butyl 4-((1-(5-(dimethylamino)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (138 mg, 0.278 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 7.5 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 101 mg (92%). LC/MS (HPLC method 3): tR=1.133 min, 397.42(MH)+.

7-Bromo-5-methoxy-1H-indazole. To a suspension of 2-bromo-4-methoxy-6-methylaniline hydrobromide (18.5 g, 62.3 mmol) in hydrochloric acid (8 M, 56 mL, 448 mmol) at 0° C. was added a solution of sodium nitrite (4.51 g, 65.4 mmol) in water (ca. 14 mL) drop wise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (7.02 mL, 62.3 mmol) in ethanol (140 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (35 mL) and transferred to a solution of potassium tert-butoxide (55.9 g, 498 mmol) in dimethylsulfoxide (350 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Preparative HPLC gave 10.1 g (86%) as a tan solid.1H-NMR (CDCl3, 300 MHz) δ 8.05 (s, 1H), 7.24 (m, 1H), 7.04 (m, 1H), 3.82 (s, 3H); Mass spec.: 226.95 (MH)+.

5-Methoxy-1H-indazole-7-carbaldehyde. To a solution of 7-bromo-5-methoxy-1H-indazole (1.32 g, 5.81 mmol) in tetrahydrofuran (27 mL) at 0° C. was added sodium hydride (0.465 g, 11.62 mmol). The ice bath was removed and stirring continued for 20 min. The solution was cooled to −78° C. and treated with tert-butyllithium (1.7 M in pentane, 6.84 mL, 11.63 mmol) dropwise. The reaction was stirred at −78° C. for 10 min, allowed to warm gradually in the dewar to −50° C., recooled to −78° C., and then treated with dimethylformamide (1.8 mL, 23.25 mmol). After 15 min, the ice bath was removed and stirring continued for 1 h. The reaction was poured onto ice/1 M hydrochloric acid (20 mL). The mixture was extracted with ethyl acetate (2×). The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.1 g of 5-methoxy-1H-indazole-7-carbaldehyde (100%) as a tan solid.1H-NMR (CDCl3, 300 MHz) δ 10.08 (s, 1H), 8.04 (s, 1H), 7.52 (s, 1H), 7.44 (m, 1H), 3.90 (s, 3H); Mass spec.: 177.09 (MH)+.

(±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-methoxy-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate. (±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (29 mg, 0.047 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 17 mg of (±)-7-(1-((4-(4-fliuorophenyl)piperidin-4-yl)methoxy)ethyl)-5-methoxy-1H-indazole (94%). The crude amine (17 mg, 0.044 mmol) in dichloromethane (1 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (19.4 mg, 0.089 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (1%→30% EtOAc/Hex) to give 20 mg (93%) as oil. LC/MS (HPLC method 3): tR=3.818 min, 484.49(MH)+.

(±)-7-(1-((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)methyl)-5-methoxy-1H-indazole. (±)-tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-methoxy-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (20 mg, 0.041 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 1.5 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (95%). LC/MS (HPLC method 3): tR=2.387 min, 384.41(MH)+.

7-Bromo-5-fluoro-1H-indazole. To a suspension of 2-bromo-4-fluoro-6-methylaniline (5 g, 24.51 mmol) in hydrochloric acid (8 M, 22 mL, 176 mmol) at 0° C. was added a solution of sodium nitrite (1.78 g, 25.7 mmol) in water (ca. 5.5 mL) dropwise. After 10 min, the resulting solution was neutralized (pH 4-5) by addition of solid sodium acetate. The resulting solution was added to a solution of 2-methyl-2-propanethiol (2.76 mL, 24.5 mmol) in ethanol (57 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. The resulting mixture was poured onto ice and the resulting mixture was extracted into diethyl ether (2×). The ethereal was washed with water, then brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in dimethylsulfoxide (14 mL) and transferred to a solution of potassium tert-butoxide (22 g, 196 mmol) in dimethylsulfoxide (140 mL) in a cool water bath (ca. 10° C.) via canula. The bath was removed and stirring continued for 30 min. The reaction mixture was poured onto ice/concentrated hydrochloric acid. The resulting mixture was extracted with dichloromethane (2×), washed with water (3×), then brine, dried over magnesium sulfate and concentrated. Prep HPLC gave 1.66 g (31.5%) as a pale solid. LC/MS (HPLC method 3): tR=2.337 min, 215.01(MH)+.

5-Fluoro-1H-indazole-7-carbaldehyde. To a solution of 7-bromo-5-fluoro-1H-indazole (1.66 g, 7.72 mmol) in tetrahydrofuran (35 mL) at 0° C. was added sodium hydride (0.618 g, 15.4 mmol). The ice bath was removed and stirring continued for 20 min. The solution was cooled to -78° C. and treated with tert-butyllithium (1.7 M in pentane, 9.08 mL, 15.4 mmol) dropwise. The reaction was stirred at −78° C. for 10 min, allowed to warm gradually in the dewar to −50° C., recooled to −78° C., and then treated with dimethylformamide (2.39 mL, 30.9 mmol). After 15 min, the ice bath was removed and stirring continued for 1 h. The reaction was poured onto ice/I M hydrochloric acid (26.5 mL). The mixture was extracted with ethyl acetate (2×). The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.42 g of 5-fluoro-1H-indazole-7-carbaldehyde (quant.) as a light yellow solid. LC/MS (HPLC method 3): tR=1.39 min, 165.17(MH)+.

(±)-5-Fluoro-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)methyl)-1H-indazole. (±)-tert-Butyl 4-((1-(5-fluoro-1H-indazol-7-yl)ethoxy)methyl) 4-(4-fluorophenyl)piperidine-1-carboxylate (94 mg, 0.199 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 5.5 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 64 mg (86%). LC/MS (HPLC method 3): tR=2.478 min, 372.37(MH)−.

(±)-tert-Butyl 4-((1-(5-bromo-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. (±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(380 mg, 0.573 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 6 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 200 mg of (±)-5-bromo-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-2H-indazole (81%). The crude amine (200 mg, 0.463 mmol) in dichloromethane (4 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (202 mg, 0.925 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (1%→30% EtOAc/Hex) to give 200 mg (81%) as clear oil. LC/MS (HPLC method 3): tR=4.046 min, 532.27(MH)+.

Enantiomer B of tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. Enantiomer B of tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (105 mg, 0.158 mmol), cyclopropyl boronic acid (40.8 mg, 0.475 mmol), and tetrakis(triphenylphosphine) palladium(0) (18.3 mg, 0.016 mmol) were combined in dry tetrahydrofuran (3 mL) followed by addition of 0.56 mL of a 1 N potassium hydroxide aqueous solution in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 100° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate and washed with water and brine, concentrated and purified by flash chromatography on silica gel (20% EtOAc/Hex) to afford 46 mg (46.5%). LC/MS (HPLC method 2): tR=4.431 min, 624.63(MH)+.

2-Azido-3-bromo-5-chlorobenzaldehyde. To a suspension of 2-amino-3-bromo-5-chlorobenzaldehyde (3.0 g, 12.8 mmol) in a water (4 mL) and hydrochloric acid (4 mL) mixture at 0° C. was added a solution of sodium nitrite (1.1 g, 16.0 mmol) in water (ca. 2 mL) dropwise. After 30 min, the ice bath was removed and the reaction stirred at room temperature for 30 min forming a white suspension. The solids were removed by filtration. The mother liquor was cooled to 0° C. and treated with sodium azide (0.8 g, 12.8 mmol) in water (2.0 mL). The ice bath was removed and stirring was continued for 30 min. The resulting solid was collected by filtration and dried in vacuo for several hours to afford 2.6 g (76%) as a white solid.1H-NMR (CDCl3, 500 MHz) δ 10.30 (s, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H).

7-Bromo-5-chloro-2-cyclopropyl-2H-indazole. 2-Azido-3-bromo-5-chlorobenzaldehyde (1.38 g, 5.30 mmol) and cyclopropylamine (0.37 mL, 5.30 mmol) in methylene chloride (20 mL) were treated with molecular sieves (1.5 g). The reaction was stirred at room temperature for 2 h, filtered over celite and the resulting solution evaporated in vacuo. The resulting oil was suspended in toluene (15 mL) and heated at reflux for 2 h. After cooling to room temperature, the mixture was poured into ice water and extracted with diethyl ether (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (76%) as a light yellow solid.1H-NMR (CDCl3, 500 MHz) δ 8.7 (s, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 3.05-3.09 (m, 1H), 0.95-0.99 (m, 4H). Mass spec.: 273.03 (MH)+.

5-Chloro-2-cyclopropyl-2H-indazole-7-carboxylic acid. A microwave tube was charged 5-chloro-2-cyclopropyl-2H-indazole-7-carbonitrile (0.54 g, 2.5 mmol), methanol (8.0 mL) and a 4 N sodium hydroxide solution (5 mL, 20 mmol). The tube was sealed and heated at 110° C. for 3 h via microwave. After cooling to room temperature, the mixture was concentrated in vacuo to remove most of the methanol. The residue was poured into water/ethyl acetate. The product was extracted with water (2×) and the organics discarded. The aqueous layers were pooled together and acidified to pH 2.0 with 1 N hydrochloric acid. The resulting precipitate was filtered and dried in vacuo for several hours to afford 0.47 g (80%) as a white powder.1H-NMR (CD3OD, 300 MHz) δ 8.40 (s, 1H), 7.94-7.95 (m, 2H), 4.08-4.14 (m, 1H), 1.37-1.42 (m, 2H), 1.21-1.23 (m, 2H). Mass spec.: 237.16 (MH)+.

7-bromo-5-trifluoromethyl-1H-indole. The title compound was prepared according to the procedure in patent WO 2006/013048.

Enantiomers A and B of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate. (±)-tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate (derived from tert-Butyl 4-(4-fluorophenyl)-4-((1-(5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate by methylation) was subjected to chiral HPLC on a chiralcel OD-H column with a mobile phase of 95% CO2/5% ethanol/0.1% diethylamine. The early-eluting enantiomer is Enantiomer A of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate and the late-eluting enantiomer is Enantiomer B of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate.

7-(((4-(4-Fluorophenyl)piperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole. tert-Butyl 4-(4-fluorophenyl)-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (120 mg, 0.188 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted using 2M ammonia in methanol and concentrated to give 75 mg (98%) as an amorphous solid. LC/MS (HPLC method 4): tR=2.28 min, 409.15(MH)+.

5-Bromo-1H-benzo[d]imidazol-2-yl)methanol. The title compound was prepared from the corresponding phenylenediamine following literature procedure described for the synthesis of 2-hydroxymethylbenzimidazole (Philips, J. Chem. Soc. 1928, 2393).

5-(Trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methanol. The title compound was prepared from the corresponding phenylenediamine following literature procedure described for the synthesis of 2-hydroxymethylbenzimidazole (Philips, J. Chem. Soc. 1928, 2393).

5-Bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methanol and 6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methanol. A 0.1 M solution of 5-Bromo-1H-benzo[d]imidazol-2-yl)methanol (630 mg, 2.8 mmol) in dimethylformamide was stirred with 2.4 equiv of cesium carbonate and (0.3 mL, 1.2 equiv) of cyclopropylmethyl bromide at 50° C. for 19 h. At the end dimethylformamide was evaporated in vacuo. The residue was partitioned between ethyl acetate (70 mL) and water (30 mL). Organic layer was dried (sodium sulfate) and evaporated in vacuo to give 800 mg of crude product which by LC-MS was 75% pure. LC/MS (HPLC method 1): tR=2.1 min, 281(MH)+. Silica gel TLC (ethyl acetate:hexane=4: 1) revealed two major products with Rf=0.29 and 0.20, which without separation were used in the next step.

tert-Butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate. The conversion of the alcohol to chloromethyl derivative and the subsequent alkylation were done using similar procedure as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (5) and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. (6-(Trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methanol (25 mg, 0.072 mmol) was converted to chloromethyl derivative as described in the synthesis of tert-butyl 4-(((5-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate and tert-butyl 4-(((6-bromo-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate using thionyl chloride (0.030 mL, 5.7 eq) and the crude chloromethyl derivative was alkylated with tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (25.2 mg, 1.2 eq) using sodium hydride (9 equiv) in tetrahydrofuran (3 mL) at ambient temperature for 3 days. The crude product was purified by silica gel chromatography using a gradient of 10%-80% ethyl acetate in dichloromethane. Fractions containing required compound were combined and evaporated in vacuo to give tert-butyl 4-phenyl-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (25 mg) containing required product and piperidinyl alcohol reagent in the ratio of 2:3 by proton NMR. Material used without additional purification. LC/MS (HPLC method 8): tR=3.8 min, 642(MNa)+.

tert-Butyl 4-((1-(6-chloro-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)vinyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. General Note: The reaction was run in such a way as to minimize exposure to light. Reactions were run under a layer of foil to block light and the lab lights were turned off while manipulating the reaction mixtures. To a suspension of titanocenedichloride (0.560 g, 2.198 mmol) in toluene (18 mL) at 0° C. was added methyllithium (1.6 M in diethyl ether, 3.4 mL, 5.5 mmol) dropwise. The reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of 9 mL of a 6% ammonium chloride solution. The heterogeneous mixture was filtered through a course frit and added to the sep funnel. The layers were separated and the organic layer dried over magnesium sulfate. The solution was filtered and treated with (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.560 g, 0.733 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.078 mL, 0.366 mmol) and the mixture concentrated to ca. ⅓ its volume. The bath temperature was maintained at 30° C. while the reaction mixture was being concentrated. The reaction flask was flushed with a stream of nitrogen and fitted with a reflux condenser and the resulting solution was placed in an oil bath preheated to 80° C. The bath temperature was set to 80° C. and stirred at that temperature for 2 h. The reaction was diluted with ˜20 mL of hexanes to precipitate some of the titanocenes with stirring. To decompose the remaining titanocene, silica gel (excess) was added as a solid with vigorous stirring to the suspension at 0° C. The ice bath was removed and stirring continued for 15 min. The resulting suspension was filtered and the resulting pad washed with 25% ethyl acetate/n-hexane. The mother liquor was concentrated and loaded onto a silica gel column (10% ethyl acetate/n-hexane). After several volumes at 10%, the gradient was ramped to 25% ethyl acetate/n-hexane to give 470 mg (84%) as a very faint yellow solid.1H-NMR (CD3OD, 500 MHz) δ 7.36 (dd, J=8.9, 5.2 Hz, 2H), 7.19 (d, J=2.1 Hz, 1H), 7.02 (m, 2H), 6.84 (d, J=2.1 Hz, 1H), 5.24 (s, 2H), 4.59 (s, 2H), 4.43 (d, J=2.7 Hz, 1H), 4.22 (d, J=2.5 Hz, 1H), 3.78 (s, 2H), 3.69 (m, 2H), 3.54 (t, J=7.8 Hz, 2H), 3.26 (m, 2H), 2.94 (bs, 2H), 2.19 (m, 2H), 1.78 (m, 2H), 1.36 (s, 9H), 0.85 (t, J=7.9 Hz, 2H), 0.66 (t, J=7.9 Hz, 2H), −0.10 (s, 9H), −0.16 (s, 9H);13C NMR (126 MHz, CD3OD) δ ppm 163.0 (d, J=245 Hz), 158.7, 156.5 (d, J=14 Hz), 139.4 (d, J=3.8 Hz), 131.8, 130.6 (d, J=7.7 Hz), 128.3, 125.6, 125.1, 124.1, 116.3 (d, J=21 Hz), 110.7, 89.2, 81.1, 77.8, 71.6, 67.4, 66.9, 41.8, 33.2, 28.7, 18.63, 18.58, −1.29, −1.32. Mass spec.: 784.01 (MNa)+.

5-Chloro-1H-indazole-7-carboxylic acid. To a suspension of 7-bromo-5-chloro-1H-indazole (23.7 g, 102 mmol) in tetrahydrofuran (400 mL) at 0° C. was added sodium hydride (2.70 g, 113 mmol) in portions to control the release of hydrogen. The ice bath was removed and the reaction was stirred at room temperature for 20 min. The reaction was then cooled to −78° C. and treated with tert-butyllithium (1.7 M, 126 mL, 215 mmol) dropwise over 20 min. The reaction was allowed to gradually warm to −40° C. in the icebath over 1 h. The reaction was re-cooled to −78° C. and treated with an excess of freshly crushed pellets of dry ice. The ice bath was removed and the reaction allowed to gradually warm to room temperature. The reaction was diluted with diethyl ether, and washed with water until most of the insoluble solid was dissolved. The ethereal was washed once more with 1M sodium hydroxide, which was combined with the other aqueous layers. The ethereal was discarded. The combined aqueous washings were cooled to 0° C., and made acidic by the cautious addition of concentrated hydrochloric acid to give a precipitate. The resulting solid was collected by filtration to give the product as a light tan solid. The product was air dried overnight and then pumped under high vaccuum to remove any trace of water to give 15.9 g (79%) which was used without purification.1H-NMR (d6-DMSO, 500 MHz) δ 13.29 (bs, 1H), 8.18 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H);13C NMR (126 MHz, d6-DMSO) δ ppm 165.6, 136.5, 133.6, 128.0, 125.5, 124.8, 123.9, 115.5. Mass spec.: 196.97 (MH)+.

tert-Butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)vinyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. General Note: The reaction was run in such a way as to minimize exposure to light. Reactions were run under a layer of foil to block light and the lab lights were turned off while manipulating the reaction mixtures. To a suspension of titanocenedichloride (4.33 g, 17 mmol) in toluene (141 mL) at 0° C. was added methyllithium (1.6M in diethyl ether, 26.5 mL, 42.5 mmol) dropwise. The reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of 70 mL of a 6% ammonium chloride solution. The resulting heterogeneous mixture was vigorously stirred for 15 min at 0° C. prior to separation of the layers. The heterogeneous mixture was filtered through a course frit and added to the sep funnel. The layers were separated and the organic layer dried over magnesium sulfate. The solution was filtered and treated with (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (3.5 g, 5.7 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.61 mL, 2.8 mmol) and the mixture concentrated to ˜⅓ its volume. The bath temperature was maintained at 30° C. while reaction mixture was being concentrated. The reaction flask was flushed with a stream of nitrogen and fitted with a reflux condenser (which had also been flushed with a stream of nitrogen for some time) and the resulting solution was placed in an oil bath preheated to 80° C. The bath temperature was set to 80° C. and stirred at that temperature (start=11 AM). After 9 h, heating was discontinued and the reaction allowed to stir at room temperature overnight. The reaction was concentrated to remove ˜½ of the toluene. The reaction was diluted with 100 mL of hexanes to precipitate some of the titanocenes with stirring. To decompose the remaining titanocene, silica gel (10 g) was added as a solid with vigorous stirring to the suspension at 0° C. The ice bath was removed and stirring continued for 15 min. The resulting suspension was filtered and the resulting pad washed with 25% ethyl acetate/n-hexane. The mother liquor was concentrated and loaded onto a silica gel column (10% ethyl acetate/n-hexane). After several volumes at 10%, the gradient was ramped to 25% ethyl acetate/n-hexane to give the product with significant levels of titanocene byproducts by TLC. All of the fractions that contained product were concentrated and repurified by column chromatography (10% ethyl acetate/n-hexane→25% ethyl acetate/n-hexane) to give 3.06 g (88%) as a very faint yellow solid.1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.44 (dd, J=8.9, 5.5 Hz, 2H), 7.33 (d, J=1.8 Hz, 1H), 7.10 (dd, J=8.9, 8.5 Hz, 2H), 5.95 (d, J=2.1 Hz, 1H), 5.69 (s, 2H), 4.59 (d, J=2.1 Hz, 1H), 3.83 (s, 2H), 3.80 (bs, 2H), 3.64 (t, J=8.6 Hz, 2H), 3.10 (m, 2H), 2.31 (m, 2H), 1.99 (m, 2H), 1.45 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), −0.04 (s, 9H);13C NMR (126 MHz, CDCl3) δ ppm 161.6 (d, J=246 Hz), 155.0, 144.3, 138.21, 138.19, 128.9 (d, J=8.6 Hz), 127.8, 126.9, 124.7, 123.6, 122.4, 119.2, 115.5 (d, J=20 Hz), 90.0, 82.0, 79.6, 75.8, 67.8, 41.1, 40.2 (br), 32.5, 28.6, 17.9, −1.4. Mass spec.: 616.36 (MH)+.

Tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. Tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)-2-fluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (420 mg, 0.660 mmol) was dissolved in TBAF (1M in THF) (8.5 mL, 8.50 mmol). The flask was sealed and heated at 55° C. for 1.5 h. The reaction was cooled to room temperature and diluted with ether, washed with water then brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (30%-40% EtOAc/Hex) to give title compound (286 mg, 0.565 mmol, 86% yield) as a colorless oil. LC/MS (HPLC method 3): tR=3.78 min, 506.3(MH)+.

tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-(methylsulfonyloxy)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.236 mmol) and Et3N (0.099 mL, 0.709 mmol) in DCM (3 mL, 46.6 mmol) at 0 C was added Methanesulfonyl chloride (0.037 mL, 0.473 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0 , quenched by addition of saturated NaHCO3 and diluted with ether, the layers were separated and the ether layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by Biotage LC (30% EtOAc/Hex) to give 155 mg of title product as white foam (92% yield). LC/MS (HPLC method 3): tR=4.15 min, 712.3(MH)+.

tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2,2-difluoroethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. To a well-stirred solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (85 mg, 0.134 mmol) in dry DCM (4 ml) was slowly added DAST (0.019 ml, 0.1428 mmol). It was stirred at room temperature for 24 h. The reaction mixture was quenched with 10% sodium bicarbonate solution, the aqueous layer was extracted with dichloromethane (×2), the combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated. It was purified by Biotage LC (15-32% EtOAc/Hex) to afford 36.6 mg (42%) of title compound as clear oil. LC/MS (HPLC method 3): tR=4.28 min, 654.28(MH)+.

tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-3-(methylsulfonyloxy)propoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate. To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-3-hydroxypropoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (56 mg, 0.086 mmol) and TRIETHYLAMINE (0.036 ml, 0.259 mmol) in DCM (1.5 ml) at 0 C was added METHANESULFONYL CHLORIDE (0.013 ml, 0.173 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0 C and quenched by addition of sat'd sodium bicarbonate. The reaction was diluted with ether and the layers separated. The ethereal was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 69 mg title compound (quantitative yield). LC/MS (HPLC method 1): tR=4.42 min, 726.2(MH)+.

7-bromo-5-chloro-1H-indole-3-carbaldehyde. Phosphorus oxychloride (3.11 mL, 33.4 mmol) was added dropwise to a 0° C sample of DMF (30 mL). The reaction was stirred 30 min at 0° C., then 7-bromo-5-chloro-1H-indole (7.0 g, 30.4 mmol) in DMF (5 mL)was added and the reaction was warmed to ambient temperature and stirred 20 hours. Ice water (300 mL) was added, and the resulting thick solid was filtered. The product was detected by TLC in both filtrate and cake. Cake and filtrate were combined, and sodium hydroxide (10N) was added until most solids disappeared, then the mixture was extracted with ethyl acetate (4×100 mL). The organic layers were dried with MgSO4and evaporated to a solid that weighed 10.5 g. The residue was dissolved in 400 mL boiling ethyl acetate, the insoluble material was filtered away and the filtrate was evaporated. 7-bromo-5-chloro-1H-indole-3-carbaldehyde (6.45 g, 24.95 mmol, 82% yield) was obtained as an off-white solid.1H-NMR (CDCl3, 400 MHz) δ 9.99 (s, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.47 (d, J=2.0 Hz, 1H). LC/MS (HPLC method 4): tR=2.87 min, 257.91(MH)+.

Ethyl 5-bromo-1H-benzo[d]imidazole-7-carboxylate. To a suspension of crude 5-Bromo-1H-benzo[d]imidazole-7-carboxylic acid (247 mg, 0.81 mmol, 77% pure) in dichloroethane under N2with stirring was added oxalyl chloride (0.5 mL, 5.6 equiv). Added one drop of DMF as catalyst. After 10 min, the suspension was treated with another 0.5 mL of oxalyl chloride. After 2.5 h, when effervescence ceased, added another 0.5 mL portion of oxalyl chloride and 2 drops of DMF and continued the reaction for another 1.5 h. The reaction mixture was added to 50 mL of ethanol carefully. The ethanol solution was maintained at ambient temperature for 30 min. It was then evaporated in vacuo. The residue was partitioned between EtOAc (75 mL) and satd aqueous bicarbonate (100 mL). The organic layer was washed with water (50 mL), dried (Na2SO4) and evaporated in vacuo. The crude product was coevaporated with hexane (50 mL). A suspension of the residual solid in hexane (50 mL) was filtered and washed with another 20 mL more hexane to give 200 mg. The crude product itself was used for subsequent reactions.1H NMR (500 MHz, DMSO-d6) δ ppm 8.53 (s, 1 H), 8.20 (s, 1 H), 7.93 (s, 1 H), 4.45 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H). 269(MH)+.

2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)propan-2-ol and 1-(6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)ethanol. To a stirred ice cold solution of 1M methylmagnesium bromide in butylether (4.9 mL) under argon was added triethylamine (2.1 mL, 6 equiv) followed by a solution of ethyl 6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-4-carboxylate (974 mg, 2.44 mmol) in THF (5 mL). After stirring for 1 h, saturated aqueous ammonium chloride (50 mL) was added and the reaction mixture was subjected to extractive work up using EtOAc (50 mL). Organic layer was dried (Na2SO4), evaporated in vacuo. The residue was purified by SiO2chromatography using a linear gradient of EtOAc:hexane (7:93) to EtOAc (1:1) on biotage instrument on a 40M cartridge. The required ketone and the byproduct tertiary alcohol co-eluted and fractions containing the two compounds were combined and evaporated in vacuo to give 0.72 g of the mixture. Integration of the methylene singlet from the SEM residue in both compounds at δ 5.71 and δ 5.64 ppm in the proton NMR indicated that the ratio of the ketone to tertiary alcohol was 10:7. This mixture was subjected to reduction of the ketone as follows. The crude product (0.72 g) was dissolved in THF (10 mL) and treated with LiBH4 (130 mg, 6 mmol). After 5 h, the reaction mixture was cooled in ice-water bath and acetone (15 mL) was added carefully. The reaction mixture was warmed up to ambient temperature and volatiles were removed in vacuo. The residue was partitioned between EtOAc (40 mL) and water (30 mL). Organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by SiO2chromatography using a linear gradient of EtOAc:CH2Cl2(3:22) to EtOAc on biotage instrument on a 25M cartridge. Fractions containing the less polar tertiary alcohol were combined and evaporated in vacuo to give 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)propan-2-ol (308 mg, 33% yield).1H NMR (500 MHz, MeOD) δ ppm 8.24 (s, 1 H), 7.73 (d, J=1.8 Hz, 1 H), 7.59 (d, J=1.8 Hz, 1 H), 5.64 (s, 2 H), 3.58 (t, J=7.8 Hz, 2 H), 1.77 (s, 6 H), 0.90 (t, J=7.9 Hz, 2 H), −0.05 (s, 10 H). 385(MH)+. Fractions containing the more polar secondary alcohol were combined and evaporated in vacuo to give 1-(6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)ethanol (344 mg, 38% yield). 1H NMR (500 MHz, MeOD) δ ppm 8.30 (s, 1 H), 7.74 (d, J=1.8 Hz, 1 H), 7.57 (d, J=1.2 Hz, 1 H), 5.65 (s, 2 H), 5.54 (q, J=6.4 Hz, 1 H), 3.56-3.60 (m, 2 H), 1.56 (d, J=6.4 Hz, 3 H), 0.90 (t, J=7.9 Hz, 2 H), −0.05 (s, 9 H). 371(MH)+.

tert-Butyl 4-(((6-bromo-1H-benzo[d]imidazol-4-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate. The protected intermediate (121 mg, 0.192 mmol) in DMF (1.9 mL) was combined with CsF (11 equiv) and heated at 80° C. for 76 h. At the end, DMF was evaporated in vacuo. The residue was partitioned between EtOAc (20 mL) and water (10 mL), EtOAc layer dried (Na2SO4) and evaporated. The residue was purified by SiO2chromatography using ethylacetate dichloromethane gradient to afford 43 mg of pure product. LC-MS (Method 7) tR=2.5 min, 400 (MH)+.

(±)-7-(1-((4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1H-indazole-5-carbonitrile. To a suspension of (±)-5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (21.8 mg, 0.055 mmol) and sodium cyanoborohydride (17.4 mg, 0.277 mmol) in acetonitrile (1 mL) at 0° C. was added formalin (0.041 mL). The reaction was treated with 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added. The ice bath was removed and stirring continued for another hour. The reaction was diluted with diethyl ether and washed with 1 M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. It was then purified by preparative HPLC to give 7.8 mg (55.7%). LC/MS (HPLC method 3): tR=1.742 min, 393.07(MH)+.

(±)-1-(2,2-Difluoroethyl)-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-5-methyl-1H-indazole. (±)-tert-Butyl 4-((1-(1-(2,2-difluoroethyl)-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.9 mg, 0.01 mmol) and formalin (0.52 mL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by column chromatography (10% methanolic ammonia/methylene chloride) to afford 4 mg (47%) as a clear oil. LC/MS (HPLC method 1): tR=2.35 min, 446.56(MH)+.

(±)-1-(Cyclopropylmethyl)-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-5-methyl-1H-indazole. (±)-tert-Butyl 4-((1-(1-(cyclopropylmethyl)-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (7 mg, 0.01 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (4.2 mg, 0.07 mmol) and formalin (37 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 4 mg (68%). LC/MS (HPLC method 1): tR=2.49 min, 436.59(MH)+.

(±)-1-Cyclopropyl-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-5-methyl-1H-indazole. (±)-tert-Butyl 4-((1-(1-cyclopropyl-5-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (10 mg, 0.02 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (6.2 mg, 0.1 mmol) and formalin (54 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 3 mg (36%) as a clear oil. LC/MS (HPLC method 1): tR=2.46 min, 422.37(MH)+.

EXAMPLES 74 AND 75

Enantiomers A and B of 7-(1-((4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1-methyl-5-(trifluoromethyl)-1H-indole. Enantiomer A was derived from Enantiomer A of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate by reduction as for previous indole examples. Enantiomer B was derived from Enantiomer B of tert-butyl 4-(4-fluorophenyl)-4-((1-(1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)ethoxy)methyl)piperidine-1-carboxylate by the same method.

7-(((4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-1-methyl-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole. tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (17 mg, 0.033 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., treated with sodium cyanoborohydride (4.1 mg, 0.065 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to give 10.4 mg (73%) as a colorless film.1H-NMR (CDCl3, 500 MHz) δ 8.28 (s, 1H), 7.42 (s, 1H), 7.12 (m, 2H), 6.89 (m, 2H), 4.69 (s, 2H), 4.08 (s, 3H), 3.44 (s, 2H), 2.51 (m, 2H), 2.19 (s, 3H), 2.12 (m, 4H), 1.89 (m, 2H). Mass spec.: 437.14 (MH)+.

4-(((4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-2-methyl-6-(trifluoromethyl)-2H-benzo[d][1,2,3]triazole. tert-Butyl 4-(4-fluorophenyl)-4-(((2-methyl-6-(trifluoromethyl)-2H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (22 mg, 0.042 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (5.3 mg, 0.084 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to 13 mg (71%) as a colorless film.1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.32 (m, 2H), 7.30 (s, 1H), 6.99 (m, 2H), 4.80 (s, 2H), 4.51 (s, 3H), 3.53 (s, 2H), 2.57 (m, 2H), 2.21 (m, 7H), 2.00 (m, 2H). Mass spec.: 437.08 (MH)+.

4-(((4-(4-Fluorophenyl)-1-methylpiperidin-4-yl)methoxy)methyl)-1-methyl-6-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole. tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-6-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (14 mg, 0.027 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (3.4 mg, 0.054 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to give 8 mg (68%) as a colorless film.1H-NMR (CDCl3, 500 MHz) δ 7.70 (s, 1H), 7.36 (s, 1H), 7.33 (m, 2H), 6.99 (m, 2H), 5.01 (s, 2H), 4.34 (s, 3H), 3.57 (s, 2H), 2.59 (m, 2H), 2.22 (m, 7H), 2.02 (m, 2H). Mass spec.: 437.16 (MH)+.

Methyl 2-(5-chloro-1H-indazol-7-yl)-2-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)acetate trifluoroacetic acid salt. tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (20 mg) was dissolved in trifluoroacetic acid (20% in dichloromethane, 1.5 mL) and stirred for 20 min at room temperature. The reaction was concentrated and the resulting residues loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The amine was eluted with 2M ammonia in methanol and concentrated. The unprotected piperidine was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) and sodium cyanoborohydride (2.4 mg) and one drop of acetic acid. The reaction was stirred at room temperature for 1 h. The reaction was concentrated. The resulting residue was dissolved in trifluoroacetic acid (25% in dichloromethane, 2 mL), stirred for 5 min, and concentrated. The resulting residue was purified by preparative HPLC to afford the title compound.1H-NMR (CD3OD, 500 MHz) δ 8.05 (m, 1H), 7.78 (m, 1H), 7.44 (m, 2H), 7.22 (m, 0.75H), 7.13 (m, 1.8H), 7.03 (m, 0.6H), 5.34 (s, 0.3H), 5.27 (s, 0.7H), 3.69 (m, 4H), 3.47 (m, 4H), 2.55-3.00 (m, 7H), 2.00-2.55 (m, 2.5H). Mass spec.: 446.24 (MH)+.

5-Chloro-7-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one trifluoroacetic acid salt. tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (26 mg, 0.040 mmol) was dissolved in trifluoroacetic acid (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The crude piperidine was eluted with 2M ammonia in methanol and concentrated. The crude product was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) followed quickly by sodium cyanoborohydride (5.0 mg, 0.08 mmol). To this was added two small drops of acetic acid over 5 minutes. The reaction was concentrated and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The crude product was dissolved in ethanol (10 mL) and heated at reflux overnight. The reaction was concentrated and purified by preparative HPLC (28% B isocratic method, TFA/ACN) to give 10.3 mg (47%).1H-NMR (CD3OD, 500 MHz) δ 7.44 (m, 1.5H), 7.35 (m, 0.5H), 7.14 (m, 1.5H), 7.06 (m, 0.5H), 6.90-7.20 (m, 1H), 6.78 (d, J=2.1 Hz, 0.6H), 6.68 (m, 0.3H), 4.99 (m, 1H), 3.35-3.52 (m, 5H), 3.30 (d, J=9.2 Hz, 1H), 2.55-3.00 (m, 6H), 2.05 (m, 2H), 1.30-1.50 (m, 3H). Mass spec.: 432.1 (MH)+.

EXAMPLES 130 AND 131

(R)-6-bromo-1-(cyclopropylmethyl)-4-(1-((1-methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-1H-benzo[d]imidazole and (S)-6-bromo-1-(cyclopropylmethyl)-4-(1-((1-methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-1H-benzo[d]imidazole. Racemic tert-butyl 4-((1-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (34 mg, 0.053 mmol) was dissolved in DMF (0.5 mL) and to this was added CsF (133 mg, 16.6 equiv). The mixture was heated at 80° C. for ˜18 h. At the end DMF was evaporated in vacuo and the residue was subjected to extractive work up using EtOAc (30 mL), water (20 mL). Organic layer was dried (Na2SO4) and evaporated in vacuo. LC-MS analysis at this stage (HPLC method 19) indicated complete conversion to the required product [tR=1.2 min, 514(MH)+]. The crude product was dissolved in DMF (0.5 mL) and stirred with Cs2CO3(96 mg, 5.6 equiv) and cyclopropylmethylbromide (0.006 mL) for ˜18 h. DMF was evaporated and the residue was subjected to extractive work up as mentioned before. LC-MS analysis (HPLC method 7) at this stage indicated complete conversion to the required alkylation product [tR=3.2 min, 568(MH)+]. The crude alkylation product was purified by preparative HPLC (method 17). Fractions containing the required product were combined and evaporated in vacuo. The residue obtained was dissolved in HCOOH (0.3 mL,147 equiv) and formaldehyde (37%, 0.3 mL, 76 equiv) and heated at 70° C. for 18 h. At the end, after cooling to ambient temperature and diluting with MeOH to 2 mL the mixture was purified by preparative HPLC (method 18). Fractions containing the required product were evaporated in vacuo and the residue was subjected to chiral separation (SFC method 1). Fractions corresponding to peak #1 by SFC were pooled and evaporated in vacuo. The residue 5.3 mg (0.011 mmol) in MeOH (1 mL) was treated with 0.11 mL of 0.1 M succinic acid in water. Volatiles were evaporated to obtain (S)-6-bromo-1-(cyclopropylmethyl)-4-(1-((1-methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-1H-benzo[d]imidazole (IX) (6.7 mg, 0.9mol succinic acid/mol, assignment of absolute stereochemistry was tentative). 1H NMR (500 MHz, MeOD) δ ppm 8.23 (s, 1 H), 7.70 (d, J=1.8 Hz, 1 H), 7.38-7.45 (m, 4 H), 7.28-7.32 (m, 1 H), 5.05 (q, J=6.4 Hz, 1 H), 4.11 (d, J=7.0 Hz, 2 H), 2.77 (s, 1 H), 2.61 (s, 3 H), 2.53 (s, 3 H), 2.41-2.51 (m, 2 H), 2.24 (s, 1 H), 1.43 (d, J=6.4 Hz, 3 H), 1.35 (s, 1 H), 0.65-0.70 (m, 2 H), 0.44-0.49 (m, 2 H). 482(MH)+, [α]20D(MeOH)=−54.8°. Fractions corresponding to peak #2 were processed in the same manner as above to obtain the opposite enantiomer, (R)-6-bromo-1-(cyclopropylmethyl)-4-(1-((1-methyl-4-phenylpiperidin-4-yl)methoxy)ethyl)-1H-benzo[d]imidazole as succinate salt (7 mg, 0.8 mol succinic acid/mol, assignment of absolute stereochemistry was tentative). Spectral characteristics were same as the other enantiomer. [α]20D(MeOH)=+54.8°.

EXAMPLES 133 AND 134

(S)-1-(Cyclopropylmethyl)-4-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole and (R)-1-(cyclopropylmethyl)-4-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole. tert-Butyl 4-((1-(1-(cyclopropylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (174 mg, 0.302 mmol) was dissolved in HCOOH (4 ml) and HCHO (37 wt % solution in H2O, 4 ml), the reaction mixture was heated at 75° C. for 3 days. At the end volatiles were removed in vacuo. To the residue was added 20 ml sat. NaHCO3, the mixture was stirred for 30 min under ambient temperature. Then the mixture was extracted with ethyl acetate (90 mL). The organic layer was washed with sat. NaHCO3(20 mL), brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC (HPLC method 16). The fractions with required product were collected and evaporated. The residue was lypholized to give 304 mg the product as racemate from which 203 mg was purified by SFC Chiral chromatography (SFC Method 2). Fractions corresponding to peak #1 by SFC were pooled and evaporated in vacuo. The residue 54 mg was treated with exactly equivalent amount of 0.1 M succinic acid in water. The succinate salt solution was lyophilized to obtain (−)-product (63 mg, assignment of absolute stereochemistry was tentative).1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 8.06 (s, 1 H), 7.55 (s, 1 H), 7.17-7.39 (m, 3 H), 6.87-7.07 (m, 2 H), 5.11 (q, J=6.4 Hz, 1 H), 4.02 (d, J=7.0 Hz, 2 H), 3.20-3.50 (m, 2 H), 2.40-2.69 (m, 2 H), 1.90-2.28 (m, 10 H), 1.44 (d, J=6.4 Hz, 3 H), 1.18-1.38 (m, 1 H), 0.62-0.82 (m, 2 H), 0.42 (q, J=5.2 Hz, 2 H); 490.34(MH)+, [α]20D(MeOH)=−36.4°. Fractions corresponding to peak #2 were processed in the same manner as above to obtain the opposite enantiomer as succinate salt (67 mg, assignment of absolute stereochemistry was tentative). Spectral characteristics same as the other enantiomer. [α]20D(MeOH)=+35.5°.

EXAMPLES 135 AND 136

EXAMPLES 137 AND 138