WO2016040078A1 - Substituted phenyl imidazolyl piperidyl compounds as p70s6k1 inhibitors - Google Patents

Abstract

The present invention relates to novel substituted phenyl imidazolyl piperidyl compounds that inhibit activity ofP70S6KI, pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat physiological disorders, such as dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/ or hypertriglyceridemia.

Description

SUBSTITUTED PHENYL IMIDAZOLYL PIPERIDYL COMPOUNDS AS

P70S6K1 INHIBITORS

The present invention relates to novel substituted phenyl imidazolyl piperidyl compounds that inhibit activity of 70kDa ribosomal protein S6 kinase 1 (P70S6K1), pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat physiological disorders such as dyslipidemia, preferably

hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia.

Dyslipidemia is an imbalance (either too high or too low) of lipids (cholesterol and/or triglyceride in the bloodstream. Hyperlipidemia is a heterogeneous group of disorders characterized by an excess of lipids in the bloodstream. These lipids include cholesterol, phospholipids, and triglycerides. Lipids are transported in the blood as large 'lipoproteins'. Hypercholesterolemia is a disorder characterized by an excess of cholesterol in the bloodstream. Hypertriglyceridemia is a disorder characterized by an excess of triglyceride in the bloodstream.

Lipoproteins are divided into five major classes, based on density: chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low- density lipoproteins (LDL), and high-density lipoproteins (HDL). Most triglycerides are transported in chylomicrons or VLDL, and most cholesterol is carried in LDL and HDL.

The liver plays a central role in regulation of lipid metabolism. Circulating levels of lipids, low density lipoprotein cholesterol (LDL-C) and triglycerides are governed by two main mechanisms, production and clearance. Statins block an enzyme the body needs to produce cholesterol in the liver. In addition, reduction in intracellular cholesterol levels leads to increased expression of LDL receptor in the liver via a feedback mechanism. As a result, LDL-C clearance is increased, thereby lowering blood LDL cholesterol ("bad" cholesterol) levels.

Statins can help lower the risk of heart attack, stroke, and death in people who are at high risk of a heart attack or stroke. Statins may be taken alone or taken with other cholesterol medicines such as ezetamibe, fibric acid derivatives, bile acid sequestrants, or nicotinic acid. Statins may also be combined with other types of medicines into one pill.

Despite the success of statins in cardiovascular disease management, there is significant residual cardiovascular risk. Further strategies to lower LDL-C levels effectively and safely are being actively sought. Fibrates are used as single agents and in combination therapy in many forms of hyperlipidemia, usually with statins. Fibrates appear to reduce insulin resistance when dyslipidemia is associated with other features of the metabolic syndrome (hypertension and diabetes mellitus type 2). They are therefore used in treating many forms of hyperlipidemias. Most fibrates can cause mild stomach upset and myopathy. Since fibrates increase the cholesterol content of bile, they also increase the risk for gallstones. Furthermore, when they are used in combination with statins, fibrates cause an increased risk of rhabdomyolysis (idiosyncratic destruction of muscle tissue), leading to renal failure.

The 70kDa ribosomal protein S6 kinase 1 (P70S6K1) is a member of the AGC subfamily of serine/threonine protein kinases. It is a downstream effector of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. An array of stimuli, including growth factors, cytokines and nutrients has been reported to activate this enzyme. Studies over the past decade have also uncovered a number of P70S6K1 substrates, revealing multiple levels at which P70S6K1 regulates cell physiology. In particular, P70S6K1 is thought to be an important regulator of lipid and energy metabolism. Sterol responsive element binding proteins SREBPlc and SREBP2 are master regulators that control transcription of genes involved in de novo fatty acid synthesis, de novo sterol synthesis, as well as lipoprotein metabolism. Recent evidence suggests P70S6K1 regulates lipid homeostasis via promoting processing and activation of both SREBPlc and SREBP2. Chronic activation of P70S6K1 also leads to feedback inhibition of insulin receptor substrate 1 (IRS1), hence inhibiting insulin signaling. Dysregulation of P70S6K1 activity has been linked to a number of pathologies, including dyslipidemia, obesity, diabetes, aging, and cancer. Thus, inhibition of P70S6K1 appears to be a promising approach for the treatment of these metabolic diseases.

It may also be desirable to minimize the inhibitory activity of the P70S6K1 inhibitor on AKT activity in patients with dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia. AKT comprises three closely related isoforms AKT1, AKT2 and AKT3. All are members of the AGC family of serine/threonine kinases who share sequence homology with P70S6K1. AKT isoforms play important roles in regulation of lipid and glucose metabolism, cell proliferation and survival, angiogenesis and vascular homeostasis. Hence AKT isoforms appear to be important anti-targets for dyslipidemia and cardiovascular indications.

Furthermore, in diabetic patients who are in need of treatment for hyperlipidemia, it may also be desirable to combine a compound that inhibits P70S6K1 activity with a glucose lowering agent, in as much as such a combination could potentially decrease cardiovascular risk. In this patient population it is desirable to lower glucose while decreasing cardiovascular risk.

WO2005/117909 and WO2006/046024 disclose P70S6K1 inhibitors.

WO2008/140947 discloses 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-l-methyl-lH- imidazol-2-yl] -piperidin- 1 -yl} - 1 H-pyrazolo [3,4-^pyrimidine 4-methylbenzenesulfonate, which was originally developed for oncology indications. It was surprisingly found to produce significant reduction in blood levels of LDL-C, triglyceride, and total cholesterol after repeat dosing in humans.

Compounds which inhibit P70S6K1 may be an effective treatment for dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia. Compounds that inhibit P70S6K1 in the liver in a dose dependent manner are desired for the treatment of dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia. Compounds that inhibit P70S6K1 which have low brain exposure when chronically administered may be desired for the treatment of dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia. Compounds that inhibit P70S6K1 with low inhibitory activity on AKT in patients with dyslipidemia, preferably

hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia are desired.

The present invention rovides a compound of the formula:

or a pharmaceutically acceptable salt thereof. The present invention also provides crystalline 2-[4-(4-fluorophenyl)-2-[l-(lH- pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l-yl]ethanol. The present invention further provides crystalline 2-[4-(4-fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4- yl)-4-piperidyl]imidazol-l-yl]ethanol characterized by the X-ray powder diffraction pattern (Cu radiation, λ=1.54060 A) comprising a peak at 19.4° with one or more of the peaks at 13.3°, 22.3°, and 21.4° (2Θ± 0.2°).

The present invention also provides crystalline 2-[4-(4-fluorophenyl)-2-[l-(lH- pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l -yljethanol dihydrochloride. The present invention further provides crystalline 2-[4-(4-fluorophenyl)-2-[l-(lH- pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l -yljethanol dihydrochloride characterized by the X-ray powder diffraction pattern (Cu radiation, λ=1.54060 A) comprising a peak at 24.1° with one or more of the peaks at 19.4°, 13.9°, and 27.0° (2Θ± 0.2°).

The present invention provides a method of treating dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia in a patient in need of such treatment comprising administering the patient an effective amount of a compound or salt of the present invention. Optionally this method further comprises the simultaneous, separate, or sequential administration of a lipid lowering agent or a glucose lowering agent.

The present invention also provides a pharmaceutical composition comprising a compound or salt of the present invention, and one or more pharmaceutically acceptable excipients, carriers, or diluents. Optionally, the composition further comprises a lipid lowering agent or a glucose lowering agent.

This invention also provides a compound or salt of the present invention for use in therapy. Additionally, this invention provides a compound or salt of the present invention for use in the treatment of dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia. Furthermore, this invention provides the use of a compound or a salt of the present invention in the manufacture of a medicament for treating dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or hypertriglyceridemia. Additionally, the compound or salt is optionally administered in simultaneous, separate, or sequential combination with a lipid lowering agent or a glucose lowering agent. As used herein, the term lipid lowering agent includes statins and fibrates.

As used herein, the term statin includes atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

As used herein, the term fibrate includes bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and genofibrate.

As used herein, the term glucose lowering agent includes metformin, a DPP4 inhibitor, and pioglitazone.

As used herein, the term DPP4 inhibitor includes sitagliptin, vildagliptin, saxagliptin, and linagliptin.

It will be understood by the skilled reader that the compound of the present invention is capable of forming salts. The compound of the present invention is a base, and accordingly reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al, HANDBOOK OF PHARMACEUTICAL SALTS:

PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008); S.M. Berge, et al, "Pharmaceutical Salts, " Journal of Pharmaceutical Sciences, Vol 66, No. 1 , January 1977.

The present invention may exist in crystalline form. It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. , The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature or humidity at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ± 0.2 in 2Θ will take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks (in units of ° 2Θ), typically the more prominent peaks.

The compounds of the present invention are prepared as illustrated in the

Examples below. The naming of the following Examples is done using Accelrys Draw 4.1 SP1.

Alternative names for the Examples include lH-imidazole-1 -ethanol, 4-(4- fluorophenyl)-2-[ 1 -( 1 H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-4-piperidinyl] -; 2- {4-(4- fluorophenyl)-2-[ 1 -( 1 H-pyrazolo[3 ,4-d]pyrimidin-4-yl)piperidin-4-yl] - 1 H-imidazol- 1 - yl } ethanol; 1 H-imidazole- 1 -ethanol, 4-(4-fluorophenyl)-2- [ 1 -( 1 H-pyrazolo [3,4- d]pyrimidin-4-yl)-4-piperidinyl]-, dihydrochloride; and 2-{4-(4-fluorophenyl)-2-[l-(lH- pyrazolo[3 ,4-d]pyrimidin-4-yl)piperidin-4-yl] - 1 H-imidazol- 1 -yl } ethanol dihydrochloride.

Example 1

2-[4-(4-Fluorophenyl)-2-[ 1 -(1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol- 1 - yl] ethanol

STEP 1

2-Amino- 1 -(4-fluorophenyl)ethanone hydrochloride

Add methanamine (2600 g, 18.5 mol) to a solution of 2-bromo-l-(4- fluorophenyl)ethanone (4000 g, 18.5 mol) in 35 L of ethyl acetate (EtOAc). Stir the slurry at room temperature for 16 hours. Collect the solid by filtration. Slurry the solid in ethanol (EtOH; 30 L) and add HCl (8 L, 5.4 equivalents) drop wise over 2 hours at room temperature. Stir the white slurry at room temperature for an additional two hours.

Concentrate to 10 L of solvent, filter and dry the solid under vacuum to obtain the crude title compound as a white solid (3490g, 18.5 mol, 100% yield); mass spectrum (m/z): 154(M+1-HC1).

STEP 2

tert-Butyl 4-[[2-(4-fluorophenyl)-2-oxo-ethyl]carbamoyl]piperidine-l-carboxylate

Add N-methylmorpholine (3.8 L, 33 mol) to a solution of \-tert- butoxycarbonylpiperidine-4-carboxylic acid (1900 g, 8.3 mol) in tetrahydrofuran (THF; 24 L). Cool to -10°C for 1 hour. Add isobutyl chloro formate (1.42 L, 1.26 equivalents) over 1 hour and stir the suspension for an additional 1 hour at -10°C. Add 2-amino-l-(4- fluorophenyl)ethanone hydrochloride (1750 g, 9.13 mol) and stir the suspension for 1 hour at room temperature. Quench the reaction by the addition of water (1.2 L), pour the reaction mixture into methyl tert-butyl ether (MTBE; 10 L) and 0.1M aqueous NaOH (10 L). Separate the organic phase, wash with saturated aqueous sodium chloride (10 L), dry organic phase over sodium sulfate, filter drying agent, concentrate until 2L of solvent and dry over sodium sulfate, filter, concentrate, and add petroleum ether (5 L). Collect the resulting solid by filtration and dry under vacuum to give the title compound as a white solid (2220 g, 73% yield); mass spectrum (m/z): 387(M+Na). STEP 3

tert-Butyl 4- [4-(4-fluorophenyl)- 1 H-imidazol-2-yl]piperidine- 1 -carboxylate

Add tert-butyl 4- [ [2-(4-fluorophenyl)-2-oxo-ethyl]carbamoyl]piperidine- 1 - carboxylate (2900 g, 8 mol) to N-methylpyrrolidone (NMP; 14.5 L, 5 mL/g). Heat the white slurry at 130°C and add ammonium acetate (8600 g, 14 equivalents, 112 mol) in 4 portions over 6 hours. Stir the mixture at 130°C for an additional 10 hours. Cool to room temperature, add MTBE (15 L), and wash with 4M aqueous NaOH (35 L). Separate the organic phase and wash with water (20 L), dry over sodium sulfate, filter and evaporate to a solid. Dissolve the solid in EtOAc (20 L), dry over sodium sulfate, filter, concentrate the filtrate until 2 L of solvent remains, filter the resulting solid and dry under vacuum to give the title compound as a white solid (1484g, 54% yield); mass spectrum (m/z):

346(M+1).

STEP 4

tert-Butyl 4-[4-(4-fluorophenyl)-l-(2-tetrahydropyran-2-yloxyethyl)imidazol-2- yljpiperidine- 1 -carboxylate

F

In a 2 L round bottom flask with magnetic stirrer, add 2-(2- chloroethoxy)tetrahydro-2H-pyran (29.5 mL, 0.200 mol, 1.5 equivalents) to a solution of tert-butyl 4-(4-(4-fluorophenyl)-lH-imidazol-2-yl)piperidine-l -carboxylate (46.0 g, 0.133 mol, 1 equivalent) in dimethyl sulfoxide (DMSO; 460 mL) and KOH pellets (22.4 g, 0.400 mol, 3 equivalents) and heat the mixture at 60°C for 18 hours. Add additional 2-(2- chloroethoxy)tetrahydro-2H-pyran (10 mL, 0.067 mol, 0.5 equivalents) and continue heating at 60°C for an additional 20 hours. Cool to room temperature and pour the reaction mixture onto ice/water (1.0 L) and extract with EtOAc (2 x 250 mL). Combine the organic layers, wash with water (2 x 750 mL) and saturated aqueous sodium chloride (500 mL), dry over sodium sulphate, filter, and concentrate to an orange oil. Triturate the residue with 1:1 diethyl ether (Et₂0)/heptane (250 mL), filter the solids and dry under vacuum to give the title compound (47.0 g, 75% yield) as a cream solid; mass spectrum (m/z): 474(M+1).

STEP 5

2-[4-(4-Fluorophenyl)-2-(4-piperidyl)imidazol-l-yl]ethanol dihydrochloride F

Add a solution of 5.0 N HC1 in isopropyl alcohol (IPA, 265 mL) to a suspension of tert-butyl 4-[4-(4-fluorophenyl)-l -(2-tetrahydropyran-2-yloxyethyl)imidazol-2- yl]piperidine-l-carboxylate (100 g, 211 mmol, 1 equivalent) in IPA (1063 mL) and stir at room temperature overnight. Collect the solid by filtration, wash with IPA/Et₂0 (1 : 1 , 530 mL), and dry under vacuum at 40°C. Triturate the dry product successively in 1 : 1 Et₂0/IPA (530 mL), then twice in IPA (530 mL). Filter the solid and dry under vacuum to give the title compound as a white solid, (67 g, 90% yield); mass spectrum (m/z): 290(M+1-2HC1).

STEP 6

2-[4-(4-Fluorophenyl)-2-[ 1 -(1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol- 1 - yljethanol

In a 5 L, 3 neck round bottom flask fitted with an overhead stirrer, add triethylamine (497 mL, 3.56 mol) to a suspension of 2-(4-(4-fluorophenyl)-2-(piperidin-4- yl)-lH-imidazol-l-yl)ethanol dihydrochloride (323 g, 0.89 mol) and 4-chloro-lH- pyrazolo[3,4-d]pyrimidine (138 g, 1.02 equivalents) in IPA (2.58 L). Heat the mixture to 70°C under nitrogen atmosphere and hold for 1 hour. Add water (323 mL) and cool the mixture to 20°C and collect the solid by filtration. Wash the solid with IPA (1 L) and Et₂0 (1 L) and dry under vacuum at 40°C overnight. Add DMSO (1 L) to the solid and heat to 80°C to dissolve. Add water (300 mL), cool the solution to room temperature and filter. Wash the collected solid with water (2 L) and slurry in IPA (2 L). Filter the slurry and wash the collected solid with IPA (2 L) and dry the solid at 60°C until a constant weight is observed to yield the title compound as a pale yellow solid (247 g, 68% yield); mass spectrum (m/z): 408(M+1).

Example 1A

Crystalline 2- [4-(4-Fluorophenyl)-2- [ 1 -(1 H-pyrazolo [3,4-d]pyrimidin-4-yl)-4- piperidyl] imidazol- 1 -yl] ethanol

In a 500 mL, round bottom flask fitted with magnetic stirring, add triethylamine (30.78 mL, 221 mmol) to a suspension of 2-(4-(4-fluorophenyl)-2-(piperidin-4-yl)-lH- imidazol-l-yl)ethanol dihydrochloride (20 g, 55.21 mmol) and 4-chloro-lH-pyrazolo[3,4- djpyrimidine (8.96 g, 57.97 mmol) in IPA (160 mL). Heat the mixture to 70 to 75°C under nitrogen atmosphere and hold for 2 hours. Cool reaction mixture to room temperature, add water (100 mL) and stir suspension for 1 hour. Collect the solid by filtration. Wash the solid with IPA (100 mL) and dry under vacuum. Add acetonitrile (180 mL) to the solid and heat to 70°C over 1 hour, filter, wash the solid with IPA, vacuum dry to obtain 17g of a pale yellow solid. Suspend a 16.0g sample of the solid in DMSO (48 mL), heat to 80°C, add water (16 mL) to the solution, allow to cool to room temperature, filter, wash with H₂0, and dry under vacuum at 50°C to obtain the title compound a pale yellow solid (14.9g, 66% yield), mass spectrum (m/z): 408(M+1), ^!H NMR (300.13 MHz, DMSO): 13.55 (s, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 7.69 (dd, J= 5.8, 8.5 Hz, 2H), 7.51 (s, 1H), 7.10 (t, J= 8.8 Hz, 2H), 5.04 (t, J= 5.2 Hz, 1H), 4.80-4.77 (m, 2H), 4.04 (t, J= 5.2 Hz, 2H), 3.71 (q, J= 5.2 Hz, 2H), 3.15-3.48 (m, 3H), 1.99 (d, J= 11.0 Hz, 2H), 1.80 (q, J= 10.9 Hz, 2H).

Example 2

Crystalline 2-[4-(4-Fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4- piperidyl] imidazol- 1 -yl] ethanol dihydrochloride

In a 5 L, 3 neck round bottom flask fitted with overhead stirrer, stir a suspension of 2-[4-(4-fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol- l-yl]ethanol (112.5 g, 0.276 mol) in a mixture of acetone (1.125 L) and water (225 mL) and heat at 55°C for 1 hour. Add concentrated HCl (37%, 58 mL, 0.690 mol) at 55°C and stir the mixture for 5 minutes. Add further acetone (1.125 L) and continue stirring at 55°C for 2 hours. Cool the mixture to 5°C, filter the solid and wash with acetone (1.00 L). Triturate the crude material in Et₂0 (1 L) for 1 hour, filter the solid and dry at 40°C under vacuum until constant weight to give the title compound (127 g, 96% yield) as a pale yellow solid; mass spectrum (m/z): 408(M+1-2HC1), 1H NMR (300.16 MHz, D₂0): 8.65 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H), 7.59-7.54 (m, 2H), 7.18-7.12 (m, 2H), 4.95-4.50 (bm, 2H), 4.35 (t, J= 4.8 Hz, 2H), 3.92 (t, J= 4.9 Hz, 2H), 3.79-3.68 (m, 1H), 3.67-3.62 (bm, 2H), 2.28 (d, J= 12.3 Hz, 2H), 2.14-2.02 (m, 2H).

Example 3

Crystalline 2- [4-(4-Fluorophenyl)-2- [ 1 -(1 H-pyrazolo [3,4-d]pyrimidin-4-yl)-4- piperidyl] imidazol- 1 -yl] ethanol dihydrochloride Place 2-[4-(4-fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4- piperidyl] imidazol- 1-yl] ethanol (754 mg) in 12 mL of 20% water in acetone. Stir this slurry on a 75°C hot plate at 500 rpm until the temperature of the slurry reaches 55°C. Add aqueous 12.1N HCl (335 μί) to the slurry to give a clear yellow solution. Slowly add acetone (10 mL) at 55°C to give a cloudy solution (12.4% water by volume) and a light yellow solid precipitate. Allow the slurry to continue stirring at 75 °C (plate temperature)/52°C (slurry temperature) for 30 minutes. Remove the sample to a 5°C refrigerator for two hours. Isolate the resulting light yellow solid by vacuum filtration to give a cake. Dry this cake in a 65°C vacuum oven overnight (809 mg, 91% yield).

XRD Patterns of the Crystalline Solids

Obtain the XRD patterns of crystalline solids on a Bruker D4 Endeavor X-ray powder diffractometer, equipped with a CuKa source λ = 1.54060 A) and a Vantec detector, operating at 35 kV and 50 mA. Scan sample between 4 and 40° in 2Θ, with a step size of 0.009° in 2Θ and a scan rate of 0.5 seconds/step, and with 0.6 mm divergence, 5.28 fixed anti-scatter, and 9.5 mm detector slits. Pack the dry powder on a quartz sample holder and obtain a smooth surface by using a glass slide. Collect the crystal form diffraction patterns at ambient temperature and relative humidity. Adjust the crystal form diffraction patterns, collected at ambient temperature and relative humidity based on NIST 675 standard peaks at 8.853 and 26.774 degrees 2-theta.

Characterize Example 1A, 2-[4-(4-fluorophenyl)-2-[l-(lH-pyrazolo[3,4- d]pyrimidin-4-yl)-4-piperidyl]imidazol-l-yl]ethanol, by an XRD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table 1 below, and in particular having peaks at 19.4° in combination with one or more of the peaks selected from the group consisting of 13.3°, 22.3°, and 21.4°; with a tolerance for the diffraction angles of 0.2 degrees.

Table 1 : X-ray Powder Diffraction Peak Positions of Crystalline 2-[4-(4-Fluorophenyl)-2- [l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l-yl]ethanol (Example 1A).

Peak Positions

Characterize Example 3, 2-[4-(4-fluorophenyl)-2-[l-(lH-pyrazolo[3,4- d]pyrimidin-4-yl)-4-piperidyl]imidazol-l-yl]ethanol dihydrochloride, by an XRD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table 2 below, and in particular having peaks at 24.1° in combination with one or more of the peaks selected from the group consisting of 19.4°, 13.9°, and 27.0°; with a tolerance for the diffraction angles of 0.2 degrees. Table 2: X-ray Powder Diffraction of Crystalline 2-[4-(4-Fluorophenyl)-2-[l-(lH- pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l-yl]ethanol dihydrochloride (Example 3).

Peak Positions

Differential Scanning Calorimetry (DSC)

Perform the DSC analyses on a TA Instruments DSC unit Q1000 or Q2000. Heat Example 3 in aluminum Tzero pans from 25 to 300-350 °C at 10°C/minute with a nitrogen purge of 50 mL/minute. Calibrate the DSC temperature with an indium standard, onset of 156.3-156.9°C. Crystalline 2-[4-(4-fluorophenyl)-2-[l-(lH- pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l -yljethanol dihydrochloride shows a melt/decomposition onset by DSC at 264.3°C.

The results of the following assays demonstrate that the compounds exemplified herein are useful P70S6K1 inhibitors and may be useful in treating dyslipidemia, preferably hyperlipidemia, more preferably hypercholesterolemia and/or

hypertriglyceridemia. The following assays also demonstrate that the compound of Example 2 inhibits P70S6K1 activity in a dose dependent manner in the target tissue, liver, whereas 4- {4-[4-(3-chloro-4-fluorophenyl)- 1 -ethyl- 1 H-imidazol-2-yl]piperidin- 1 - yl}-lH-pyrazolo[3,4-d]pyrimidine hydrochloride, referred to hereafter as Compound A, from WO2008/140947 does not inhibit P70S6K1 activity in a dose dependent manner in the target tissue, liver, despite similar inhibitory activity against P70S6K1 in vitro. As used herein, "IC50" refers to the concentration of an agent which produces 50% of the maximal inhibitory response possible for that agent, (relative IC50), or the concentration of an agent which produces 50% inhibition of the target enzyme activity compared to placebo control (absolute IC50). Human P70S6K1 In Vitro Enzyme Assay

This assay is used to determine the absolute IC50 value of a test compound versus human P70SK1. Perform the kinase reactions (25 μΙ_, reaction volumes) in 96-well half- area black polystyrene plates. Add adenosine triphosphate (ATP) to start the reactions. Obtain final reaction conditions of 10 mM N-2-hydroxyethylpiperazine-N'-2- ethanesulfonic acid (HEPES) pH 7.5, 0.005% TRITON™ X-100, 0.082 mM

ethyleneglycol tetraacetic acid, 1 mM dithiothreitol, 10 mM magnesium chloride, 4 μΜ PKA, PKC, MAPKAP-K1 Substrate (AnaSpec #29983-5), 25 μΜ ATP, active hP70S6Kl enzyme (Human recombinant, amino acids 1-421, T412E, N-terminal histidine-tagged), 4% DMSO and serial dilutions of compound (diluted 1 :3 from 20,000 to 1 nM). Following ATP addition, incubate the reactions at room temperature for 60 minutes and then quench with the addition of 25 μΙ_, of a BellBrook Labs Transcreener® ADP-FP Kit (#3004-10K) reagent mix. Incubate the quenched reactions for 4-16 hours, and then read in a Tecan Ultra Evolution plate reader in Fluorescence Polarization mode using polarizing filters of Ex₆₁2nm and Em₆33nm wavelength. Convert the Millipolarization (mP) raw data to μΜ ADP using a prepared ADP/ATP standard curve essentially as described in Huss, K. L., Blonigen, P. E., and Campbell, R. M. (2007) Development of a Transcreener kinase assay for protein kinase A and demonstration of concordance of data with a filter-binding assay format, Journal of Biomolecular Screening 12, 578-584. Derive the absolute IC50 value for the test compounds using percent inhibition data which is calculated using the μΜ ADP reaction data relative to on-plate controls (DMSO versus 100 mM ethylenediaminetetraacetic acid (EDTA) inhibited enzyme controls). Fit the percent inhibition and ten-point compound concentration data to a four-parameter logistic equation using ACTIVITYBASE 4.0. Example 2 is tested essentially as described above and exhibits an absolute IC₅₀ for hP70S6Kl of 0.0142 μΜ (SD=0.016, n=13). Compound A is tested essentially as described above and exhibits an absolute IC50 for hP70S6Kl of 0.037 μΜ (SDK).867, n=4). This data demonstrates that the compound of Example 2 and Compound A inhibit hP70S6Kl enzyme activity in vitro. Human AKT1 In Vitro Enzyme Assay

This assay is used to determine the absolute IC50 value of a test compound versus human AKT1. Perform the kinase reactions (25 μΕ reaction volumes) in 96-well half- area black polystyrene plates. Add adenosine triphosphate (ATP) to start the reactions. Obtain the final reaction conditions of 56 mM N-2-hydroxyethylpiperazine-N'-2- ethanesulfonic acid (HEPES) pH 7.5, 0.01% TRITON™ X-100, 0.4 mM dithiothreitol, 5 mM magnesium chloride, 30 μΜ Crosstide (AnaSpec #60209-5), 20 μΜ ATP, active hAKTl enzyme (Human recombinant, V-AKT Murine Thymoma Oncogene Homolog 1, Invitrogen #PV3599), 4% DMSO and serial dilutions of compound (diluted 1 :3 from

20,000 to 1 nM). Following ATP addition, incubate the reactions at room temperature for 60 minutes and then quench with the addition of 25 μΙ_, of a BellBrook Labs

Transcreener® ADP-FP Kit (#3004-1 OK) reagent mix. Incubate the quenched reactions for 4-16 hours, and then read in a Tecan Ultra Evolution plate reader in Fluorescence Polarization mode using polarizing filters of Ex6i2nm and Em633nm wavelength. Convert millipolarization (mP) raw data to micromolar ADP using a prepared ADP/ATP standard curve essentially as described in Huss, K. L., Blonigen, P. E., and Campbell, R. M. (2007) Development of a Transcreener kinase assay for protein kinase A and demonstration of concordance of data with a filter-binding assay format, Journal of Biomolecular

Screening 12, 578-584. Derive the absolute IC50 value for the test compound using percent inhibition data which is calculated using the μΜ ADP reaction data relative to on- plate controls (DMSO versus 100 mM EDTA inhibited enzyme controls). Fit the percent inhibition and ten-point compound concentration data to a four-parameter logistic equation using ACTrVITYBASE 4.0. Example 2 is tested essentially as described above and exhibits an absolute IC₅₀ for hAKTl of 1.44 μΜ (SD=1.75, n=5). This data demonstrates that the compound of Example 2 is approximately 100 fold less active against hAKTl enzyme in vitro as compared to hP70S6Kl enzyme.

Mouse P70S6K1 Whole Cell Assay in Primary Mouse Hepatocyte This assay is used to determine the relative IC50 values of a test compound against mouse cellular P70S6K1. Isolate primary mouse hepatocytes from female C57BL/6 mice using a method essentially as described in Berry, M. N., and Friend, D. S. (1969) High- yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study, The Journal of Cell Biology 43, 506-520 and Seglen, P. O. (1972) Preparation of rat liver cells. I. Effect of Ca 2+ on enzymatic dispersion of isolated, perfused liver, Experimental Cell Research 74, 450-454. Suspend cells in Williams E media (containing 10% fetal bovine serum, 2 mM Gluta-MAX-1, 50 μg/mL gentamicin solution, 2.5 μg/mL insulin, 2.5 μg/mL transferrin, 2.5 ng/mL sodium selenite, and 400 ng/mL

dexamethasone) and seed onto GIBCO collagen 1 coated 96 well plates on the first day and incubated in the 37°C, 5% C0₂ incubator. On the second day, switch the cells to DMEM/High Modified media (4500 mg/L glucose, 110 mg/L sodium pyruvate) and incubate in a 37°C, 5% C0₂ incubator. On the third day, treat cells with a 10 dose series of test compounds (starting at 80 μΜ, 1 :3 serial dilutions) in DMEM/High Modified media (4500 mg/L glucose, 110 mg/L sodium pyruvate) for 30 minutes. Add medium with 200 nM human insulin to each well and incubate for an additional 45 minutes in a 37°C, 5% C0₂ incubator. Aspirate the medium and add 50 μΐ_^ of lysis buffer

(PerkinElmer #TGRS6P2S 1 OK) to each well and place the plates in a -80°C freezer.

Determine the phosphorylation levels of S6RP by utilizing the phosphoS6RP ALPHASCREEN® SUREFIRE® kit (PerkinElmer #TGRS6P2S10K). Transfer 4 μΐ, of lysate and 5 μΐ_^ of activation buffer/reaction buffer/acceptor beads solution (PerkinElmer) to a 384 well ProxiPlate (PerkinElmer). Incubate the plate at room temperature while on a plate shaker for 2 hours. Add 6 μΐ_^ of donor beads (PerkinElmer) to each well and incubate for another 2 hours at room temperature on the plate shaker. Read the plate. Derive the relative IC50 value for each compound using percent inhibition data which is calculated using the pS6RP signal relative to on-plate controls (DMSO versus 40 μΜ control compound). Fit the percent inhibition and ten-point compound concentration data to a four-parameter logistic equation using ACTrVITYBASE 4.0.

Example 2 is tested essentially as described above and exhibits a relative IC50 for cellular mP70S6Kl of 0.234 μΜ (SD=0.107, n=4). Compound A is tested essentially as described above and exhibits a relative IC50 for cellular mP70S6Kl of 0.221 μΜ

(SD=0.0372, n=3). This data demonstrates that the compound of Example 2 and

Compound A inhibit mP70S6Kl enzyme activity in a mouse P70S6K1 whole cell assay in primary mouse hepatocyte. Human P70S6K1 Whole Cell Assay in Primary Human Hepatocyte

This assay is used to determine the relative IC50 values of a test compound against human cellular P70S6K1. Obtain primary human hepatocytes from Yecuris (Cat#20- 0003). Suspend cells in Williams E media (containing 10% fetal bovine serum, 2 mM Gluta-MAX-1, 50 μg/mL gentamicin solution, 2.5 μg/mL insulin, 2.5 μg/mL transferrin, 2.5 ng/mL sodium selenite, and 400 ng/mL dexamethasone) and seed onto GIBCO collagen 1 coated 96 well plates on the first day and incubate in a 37°C, 5% C0₂ incubator. On the second day, switch the cells to DMEM/High Modified media (4500 mg/L glucose, 110 mg/L sodium pyruvate) and incubate in a 37°C, 5% C0₂ incubator. On the third day, treat cells with a 10 dose series of test compounds (starting at 80 μΜ, 1:3 serial dilutions) in DMEM/High Modified media (4500 mg/L glucose, 110 mg/L sodium pyruvate) for 30 minutes. Add medium with 200 nM human insulin to each well and incubate for an additional 45 minutes in a 37°C, 5% C0₂ incubator. Aspirate medium and add 50 μΐ_^ of lysis buffer (PerkinElmer #TGRS6P2S10K) to each well and place the plates in a -80°C freezer.

Determine phosphorylation of S6RP by utilizing the phosphoS6RP

ALPHASCREEN® SUREFIRE® kit (PerkinElmer #TGRS6P2S10K). Transfer 4 μΐ, of lysate and 5 μΐ_^ of activation buffer/reaction buffer/acceptor beads solution (PerkinElmer) to a 384 well ProxiPlate (PerkinElmer). Incubate the plate at room temperature while on a plate shaker for 2 hours. Then add 6 μΐ_^ of donor beads (PerkinElmer) to each well and incubate for another 2 hours at room temperature on the plate shaker. Read the plate. Determine compound activities against human cellular P70S6K1 by the

Insulin_pS240/244S6RP ALPHASCREEN®, utilizing primary human hepatocytes. Derive the relative IC50 value for each compound using percent inhibition data which is calculated using the pS6RP signal relative to on-plate controls (DMSO versus 40 μΜ control compound). Fit the percent inhibition and ten-point compound concentration data to a four-parameter logistic equation using ACTrVITYBASE 4.0.

Example 2 is tested essentially as described above and exhibits a relative IC50 for cellular hP70S6Kl of 0.427 μΜ (SD=0.053, n=3). This data demonstrates that the compound of Example 2 inhibits hP70S6Kl enzyme activity in a human P70S6K1 whole cell assay in primary human hepatocyte. Mouse AKT Whole Cell Assay in Primary Mouse Hepatocyte

This assay is used to determine the relative IC50 values of a test compound against mouse cellular AKT. Isolate primary mouse hepatocytes from female C57BL/6 mice using a method essentially as described in Berry, M. N., and Friend, D. S. (1969) High- yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study, The Journal of Cell Biology 43, 506-520 and Seglen, P. O. (1972) Preparation of rat liver cells. I. Effect of Ca 2+ on enzymatic dispersion of isolated, perfused liver,

Experimental Cell Research 74, 450-454. Suspend in Williams E media (containing 10% fetal bovine serum, 2 mM Gluta-MAX-1, 50 μg/mL gentamicin solution, 2.5 μg/mL insulin, 2.5 μg/mL transferrin, 2.5 ng/mL sodium selenite, and 400 ng/mL

dexamethasone) and seed onto GIBCO collagen 1 coated 96 well plates on the first day and incubate in a 37°C, 5% C0₂ incubator. On the second day, switch the cells to DMEM/High Modified media (4500 mg/L glucose, 110 mg/L sodium pyruvate) and incubate in a 37°C, 5% C0₂ incubator. On the third day, treat the cells with a 10 dose series of test compound (starting at 80 μΜ, 1 :3 serial dilutions) in DMEM/High Modified media (4500 mg/L glucose, 110 mg/L sodium pyruvate) for 30 minutes. Add media with 200 nM human insulin to each well and incubate for an additional 45 minutes in a 37°C, 5% C0₂ incubator. Aspirate media and add 50 μΐ_^ of lysis buffer (Mesoscale, # RT60TX- 3) to each well and place the plates in a -80°C freezer.

Determine phosphorylation of PRAS40 by utilizing the MSD Phospo-PRAS40

(Thr246) Assay (Mesoscale #K150JZD). Transfer 25 μΐ_^ of lysate into the pre-blocked (1 hour at room temperature) Multi-Spot 96-well 4 Spot Phospho-PRAS40 (Thr246) plate (Mesoscale) and seal with an adhesive plate seal. Incubate the plate for 3 hours at room temperature with vigorous shaking (300-1000 rpm). Wash the plate 3 times with 300 μίΛνεΙΙ Tris wash buffer (Mesoscale) and add 25 μΐ. of detection antibody solution

(Mesoscale) to each well of the plate and seal again. Incubate the plate for 1 hour at room temperature with vigorous shaking (300-1000 rpm). Wash the plate 3 times with 300 μΕΛνεΙΙ Tris wash buffer (Mesoscale) and add 150 μΐ. of Read Buffer T (Mesoscale to each well of the plate and then read the plate within 5 minutes. Derive the relative IC50 value for each compound using percent inhibition data which is calculated using the pPRAS40 signal relative to on-plate controls (DMSO versus 40 μΜ control compound). Fit the percent inhibition and ten-point compound concentration data to a four-parameter logistic equation using ACTIVITYBASE 4.0.

Example 2 is tested essentially as described above and exhibits a relative IC50 for cellular mAKT of greater than 40 μΜ (n=l). This data demonstrates that the compound of Example 2 does not inhibit key anti-target (AKT) in a mouse AKT whole cell assay in primary mouse hepatocyte.

Mouse In Vivo Target Inhibition Assay for P70S6K1 Fast wild type C57BL/6NHsd male mice of 10-14 weeks of age from Harlan Laboratories by placing them in a new clean cage for 5 hours under normal light cycle. For making the dose solution add a portion of the vehicle (1%

hydroxymethylcellulose/0.25% TWEEN® 80/0.05% antifoam) (-20%) to the compound and stir to wet. Add the remainder of the vehicle to make up the appropriate volume. Apply sonication as needed to form a suitable dosing suspension or solution. Keep mixing the test articles at room temperature on a stir plate after preparation and during dosing. Following 3 hours of fasting, dose mice PO with the test article at 10 mL dose volume/kg body weight according to a dose response protocol (1.67, 5.0, 15.0 and 45.0 milligram per kilogram (mpk)). At the end of the fasting period re-feed with STAT high calorie liquid diet (PRN Pharmacal) PO at 10 mL dose volume/kg body weight. Forty- five minutes after the re-feeding euthanize the mice. Collect blood samples via cardiac puncture. Prepare plasma samples for the determination of parent compound exposure. Clamp freeze the left lateral lobe of the liver and place in polycon tube in dry ice.

In vivo target inhibition of P70S6K1 is measured utilizing Meso Scale Discovery ELISA technology to assess effects of the compound on phosphorylation of the serine240/244 site of the downstream effector S6RP (Meso Scale, Cat# K150DGD). Homogenize 25 to 40 mg of liver tissue using Lysing Matrix D tube (MP Biomedicals, Cat# 6913), Tris lysis buffer (Meso Scale) with Halt protease & phosphatase single-use inhibitor cocktail (Thermo Scientific, Cat# 78442), and a MP Biomedicals FastPrep-24. Measure the protein concentration of the homogenate and adjust to 0.8 mg/mL with complete lysis buffer (Meso Scale). Transfer 25 of lysate into a pre-blocked 96-well Phospho-S6RP (Serine240/244) plate (Meso Scale) and seal with an adhesive plate seal. Incubate the plate for 1 hour at room temperature with vigorous shaking (700 rpm). Wash the plate 3 times with 300 μΕΛνεΙΙ Tris wash buffer (Meso Scale) and add 25 μΙ_, of detection antibody solution (Meso Scale) to each well of the plate and seal again.

Incubate the plate for 1 hour at room temperature with vigorous shaking (700 rpm). Wash the plate 3 times with 300 μΕΛνεΙΙ Tris wash buffer (Meso Scale) and add 150 μΙ_, of Read Buffer T (Meso Scale) each well of the plate and then read the plate within 5 minutes. For each study, calculate the percent inhibitions relative to the vehicle control group and perform ANOVA analysis using JMP software package for the determination of statistical significance. Plot percent inhibitions against unbound concentrations of the parent compounds in plasma with Prism software to determine the relative IC50 of each compound. A confidence interval gives an estimated range of values which is likely to include an unknown population parameter, the estimated range being calculated from a given set of sample data.

The following data in Table 3 demonstrates that the compound of Example 2 (runs 1 and 2) inhibits P70S6K1 activity in vivo in a dose dependent manner. Compound A is tested 4 times (runs 2 to 5) essentially as described above at identical doses to Example 2. In spite of similar exposure levels, Compound A did not demonstrate dose dependent inhibition of P70S6K1 activity in the liver. At the highest dose tested (45 mpk),

Compound A did not inhibit P70S6K1 activity greater than 50%.

Table 3

The data demonstrates that the compound of Example 2 inhibits P70S6K1 activity in the target tissue, liver, in a dose dependent manner whereas Compound A does not inhibit P70S6K1 activity in the target tissue, liver, despite similar activity in vitro and similar exposure levels in vivo.

The compounds of the present invention are preferably formulated as

pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (D. Troy, et al, eds., 21^st ed., Lippincott Williams & Wilkins, 2005).

The compounds of the present invention are generally effective over a wide dosage range. For example, dosages per day normally fall within the daily range of about 1 to 2000 mg/day, but could be more in the range of 20 to 800 mg/day. Additionally, dosages per day of a lipid lowering agent or a glucose lowering agent, if necessary, should typically fall within the manufacturer's recommended dosage, for example, see below. It will be understood however that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. atorvastatin: The dosage range is typically 10 to 80 mg/day.

fluvastatin: The dosage range is typically 20 mg to 80 mg/ day.

lovastatin: The dosage range is typically 10 to 80 mg/day.

pitavastatin: The dosage range is typically 1 to 4 mg/day,

pravastatin: The dosage range is typically 10 to 80 mg/day,

rosuvastatin: The dosage range is typically 5 to 40 mg/day,

simvastatin: The dosage range is typically 5 to 80 mg/day,

bezafibrate: The dosage range is typically 400 to 600 mg/day.

ciprofibrate: The dosage is typically around 100 mg/day.

clofibrate: The dosage is typically 1.5 to 2 g daily in divided doses,

gemfibrozil: The dosage is typically 1200 mg in two divided doses,

fenofibrate: The dosage is typically 40 to 160 mg/day.

metformin: For treating type 2 diabetes in adults, metformin (immediate release) usually is begun at a dose of 500 mg twice a day or 850 mg once daily. The dose is gradually increased by 500 mg weekly or 850 mg every two weeks as tolerated and based on the response of the levels of glucose in the blood. The maximum daily dose is 2550 mg given in three divided doses.

sitagliptin: The dosage is typically 100 mg/day.

vildagliptin: The dosage is typically 100 mg/day. saxagliptin: The dosage is typically 2.5 to 5 mg/day. linagliptin: The dosage is typically 5 mg/day.

pioglitazone: The dosage is typically 15 to 45 mg/day.

Claims

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof.

2. The compound or salt according to Claim 1 which is 2-[4-(4- fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l-yl]ethanol dihydrochloride.

3. The compound according to Claim 1 which is crystalline 2-[4-(4- fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l- yljethanol.

4. The compound according to either Claim 1 or Claim 3 which is crystalline 2- [4-(4-fluorophenyl)-2- [ 1 -(1 H-pyrazolo[3 ,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol- 1 - yljethanol characterized by the X-ray powder diffraction pattern (Cu radiation, λ=1.54060 A) comprising a peak at 19.4 ° with one or more of the peaks at 13.3 °, 22.3 °, and 21.4 ° (2Θ± 0.2°).

5. The compound or salt according to Claim 2 which is crystalline 2-[4-(4- fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol-l-yl]ethanol dihydrochloride.

6. The compound or salt according to any one of Claim 1, Claim 2, or Claim

5 which is crystalline 2-[4-(4-fluorophenyl)-2-[l-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)-4- piperidyl]imidazol-l -yljethanol dihydrochloride characterized by the X-ray powder diffraction pattern (Cu radiation, λ=1.54060 A) comprising a peak at 24.1 ° with one or more of the peaks at 19.4 °, 13.9 °, and 27.0 ° (2Θ± 0.2°).

7. A pharmaceutical composition according to any one of Claims 1-6 and one or more pharmaceutically acceptable excipient, carrier, or diluent.

8. A method of treating dyslipidemia in a patient in need of such treatment comprising administering the patient an effective amount of 2-[4-(4-fluorophenyl)-2-[l- (1 H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-piperidyl]imidazol- 1 -yljethanol or a

pharmaceutically acceptable salt thereof.

9. The method according to Claim 8 wherein the dyslipidemia is

hyperlipidemia.

10. The method according to Claim 8 wherein the hyperlipidemia is hypercholesterolemia.

11. The method according to Claim 9 wherein the hyperlipidemia is hypertriglyceridemia.

12. The method according to any one of Claims 8-11 wherein the salt is a dihydrochloride.

13. The method according to any one of Claims 8-11 wherein the

administration includes a lipid lowering agent or a glucose lowering agent.

14. A compound or salt according to any one of Claims 1-6 for use in therapy.

15. A compound or salt according to any one of Claims 1-6 for use in the treatment of dyslipidemia.

16. A compound or salt according to any one of Claims 1-6 for use in simultaneous, separate, or sequential combination with a lipid lowering agent or a glucose lowering agent for the treatment of dyslipidemia.

17. A compound or salt according to either Claim 15 or 16 wherein the dyslipidemia is hyperlipidemia.

18. A compound or salt for use according to Claim 17 wherein the hyperlipidemia is hypercholesterolemia.

19. A compound or salt for use according to Claim 17 wherein the hyperlipidemia is hypertriglyceridemia.