WO2014081995A1

WO2014081995A1 - Novel compounds as diacylglycerol acyltransferase inhibitors

Info

Publication number: WO2014081995A1
Application number: PCT/US2013/071378
Authority: WO
Inventors: Mui Cheung; Raghuram S. TANGIRALA
Original assignee: GlaxoSmithKline LLC
Current assignee: GlaxoSmithKline LLC
Priority date: 2012-11-23
Filing date: 2013-11-22
Publication date: 2014-05-30
Anticipated expiration: 2015-05-23

Abstract

This invention relates to novel compounds which are inhibitors of acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT-1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination with weight management therapies or other triglyceride lowering therapy for the prevention or treatment of diseases related to DGAT-1 dysfunction or where modulation of DGAT-1 activity may have therapeutic benefit.

Description

NOVEL COMPOUNDS AS DIACYLGLYCEROL ACYLTRANSFERASE INHIBITORS

FIELD OF INVENTION

This invention relates to novel compounds which are inhibitors of acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT-1), to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy, alone or in combination with weight management therapies or other triglyceride lowering therapy, for the prevention or treatment of diseases related to DGAT- 1 dysfunction or where modulation of DGAT- 1 activity may have therapeutic benefit including but not limited to obesity, obesity related disorders, genetic (Type 1 , Type 5 hyperlipidemia) and acquired forms of hypertriglyceridemia or hyperlipoproteinemia- related disorders, caused by but not limited to lipodystrophy, hypothyroidism, medications (beta blockers, thiazides, estrogen, glucocorticoids, transplant) and other factors (pregnancy, alcohol intake), hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, cardiovascular outcomes, angina, excess hair growth (including syndromes associated with hirsutism), nephrotic syndrome, fibrosis such as mycocardial, renal and liver fibrosis, hepatitis C virus infection and acne or other skin disorders.

BACKGROUND OF THE INVENTION

Obesity is a medical condition that is reaching epidemic proportions among humans in a number of countries throughout the world. It is a condition that is also associated with or induces other diseases or conditions that disrupt life activities and lifestyles. Obesity is recognized as a serious risk factor for other diseases and conditions such as diabetes, hypertension, and arteriosclerosis. It is also known that increased body weight due to obesity can place a burden on joints, such as knee joints, causing arthritis, pain, and stiffness.

Because overeating and obesity have become such a problem in the general population, many individuals are now interested in losing weight, reducing weight, and maintaining a healthy body weight and desirable lifestyle. One approach to treating obesity is to reduce food intake and/or hyperlipidemia. It has been suggested that molecules which are developed to prevent the accumulation of triglyceride would not only reduce obesity but also have the additional beneficial effect of reducing insulin resistance, a primary factor contributing to the development of diabetes.

Acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT-1) is one of two known DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis. DGAT-1 is an enzyme that is implicated in the development of both diabetes and insulin resistance. Studies of DGAT-1 deficient mice show that DGAT- 1 deficiency protects against insulin resistance and obesity, see Chen, H.C. et al., J Clin Invest., 109(8), 1049-1055 (2002). Therefore, inhibitors of DGAT-1 should be useful for the treatment of metabolic disorders, e.g. obesity, Type 2 diabetes, and insulin resistance syndrome (or metabolic syndrome) and other associated or related diseases and conditions. SUMMARY OF THE INVENTION

This invention relates to compounds of Formula (I):

wherein:

X is CH₂, C=0, or NR¹;

Y is CR²R³, C=0, or NR ; wherein when X is CH₂, Y is CR²R³, when X is C=0, Y is CR²R³ or NR¹, and when X is NR¹, Y is CR²R³ or C=0;

R¹ is hydrogen or (Ci-C₄)alkyl;

R² is hydrogen or -C(R⁵)₂R⁴;

R³ is hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, hydroxyl, or (Ci-C₄)alkoxy;

R⁴ is -CH₂C(0)OH or -C(0)OR⁶;

each R⁵ is independently hydrogen or -CH₃; and

R⁶ is hydrogen, (C C₄)alkyl, halo(Ci-C₄)alkyl, phenyl, or 5- or 6-membered heteroaryl; or a pharmaceutically acceptable salt thereof.

This invention also relates to a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient.

This invention also relates to a method of treating obesity comprising administering to a human in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

DETAIL DESCRIPTION OF THE INVENTION

This invention relates to compounds of the Formula (I) as defined above.

In another embodiment, this invention also relates to compounds of Formula (II):

wherein R³ is hydrogen, (C C₄)alkyl, halo(Ci-C₄)alkyl, hydroxyl, or (C C₄)alkoxy; or a pharmaceutically acceptable salt thereof. In another ormula (III),

wherein R is hydrogen, (Ci-Cz alkyl, halo(Ci-C4)alkyl, hydroxyl, or (Ci-Cz alkoxy; or a pharmaceutically acceptable salt thereof.

In another ormula (IV):

In another embodiment, this invention relates to compounds of Formula (I) wherein X is CH₂ or C=0 and Y is CR²R³. In another embodiment, this invention relates to compounds of Formula (I) wherein X is CH₂ and Y is CR²R³. In another embodiment, this invention relates to compounds of Formula (I) wherein X is NR¹ and Y is C=0.

In another embodiment, this invention relates to compounds of Formula (I), (II), (III), or

(IV), wherein R³ is hydrogen, (Ci-Cz alkyl, or halo(Ci-C4)alkyl. In a specific embodiment, this invention relates to compounds of Formula (I), (II), (III), or (IV), wherein R³ is hydrogen, -CH₃, -CH₂CH₃, -CH₂CF₃, or -OCH₃. This invention also relates to compounds that are exemplified in the Experimental section.

Specific compounds of this invention include:

2-(6-(7-aminopyrazolo[ 1 ,5-a]pyrimidin-6-yl)- 1 -oxo-2-(2,2,2-trifluoroethyl)- 1 ,2,3,4- tetrahydronaphthalen-2-yl)acetic acid;

or pharmaceutically acceptable salts thereof.

Other compounds that may be prepared using the methods described herein or by methods known in the art include: 2-(6-(7-aminopyrazolo[ 1 ,5-a]pyrimidin-6-yl)-2-methyl- 1 -oxo- 1 ,2,3,4- tetrahydronaphthalen-2-yl)acetic acid;

2-(6-(7-aminopyrazolo[l ,5-a]pyrimidin-6-yl)-2-ethyl- 1 -oxo- 1 ,2,3,4-tetrahydronaphthalen- 2-yl)acetic acid;

2-(6-(7-aminopyrazolo[ 1 ,5-a]pyrimidin-6-yl)-2-methoxy- 1 -oxo- 1 ,2,3,4- tetrahydronaphthalen-2-yl)acetic acid;

2-(6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)-2-(2,2,2-trifluoroethyl)- 1,2,3,4- tetrahydronaphthalen-2-yl)acetic acid;

2-(6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)-2-ethyl-l,2,3,4-tetrahydronaphthalen-2- yl)acetic acid;

2-(6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)-l,2,3,4-tetrahydronaphthalen-2-yl)acetic acid;

6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[l,5-a]pyrimidin-7-amine;

2-(6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)- 1-oxo- l,2,3,4-tetrahydronaphthalen-2- yl)acetic acid;

6-(7-aminopyrazolo[l ,5-a]pyrimidin-6-yl)-3,4-dihydronaphthalen- 1 (2H)-one;

6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)-3,4-dihydroisoquinolin-l(2H)-one;

6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)-3,4-dihydroquinolin-2(lH)-one;

6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)-2-ethyl-3,4-dihydroisoquinolin-l(2H)-one; and 6-(7-aminopyrazolo[l,5-a]pyrimidin-6-yl)-l-ethyl-3,4-dihydroquinolin-2(lH)-one;

or pharmaceutically acceptable salts thereof.

A person of ordinary skills in the art recognizes that compounds of the present invention may have alternative names when different naming software is used.

This invention also relates to compounds of Formula (I), (II), (III), (IV) or any of the exemplified compounds, or their pharmaceutically acceptable salts thereof, for use in therapy. In particular, for use in the treatment of diseases mediated by Acyl coenzyme A: diacylglycerol acyltransferase 1 (DGAT- 1 ), such as obesity, obesity related disorders, genetic (Type 1 , Type 5 hyperlipidemia) and acquired forms of hypertriglyceridemia or hyperlipoproteinemia-related disorders, hyperlipoproteinemia, chylomicronemia, dyslipidemia, non-alcoholic steatohepatitis, diabetes, insulin resistance, metabolic syndrome, cardiovascular outcomes, angina, excess hair growth (including syndromes associated with hirsutism), nephrotic syndrome, fibrosis such as mycocardial, renal and liver fibrosis, hepatitis C virus infection and acne or other skin disorders. In particular, this invention relates to compounds of Formula (I), (II), (III), (IV), or any of the exemplified compounds, or their pharmaceutically acceptable salts thereof, for use in the treatment of obesity.

This invention also relates to compounds of Formula (I), (II), (III), (IV) or any of the exemplified compounds, or their pharmaceutically acceptable salts thereof, for use as a medicament. This invention also relates to compounds of Formula (I), (II), (III), (IV), or any of the exemplified compounds, or their pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of obesity.

Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the disclosed compounds containing a basic amine or other basic functional group may be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates succinates, suberates, sebacates, fumarates, maleates, butyne- l,4-dioates, hexyne- 1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,

methoxybenzoates, phthalates, phenylacetates, phenylpropionates, phenylbutrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates mandelates, and sulfonates, such as

xylenesulfonates, methanesulfonates, propanesulfonates, naphthalene- 1 -sulfonates and naphthalene-2-sulfonates.

Salts of the disclosed compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,

dehydroabietylamine, N,N-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, choline, quinine, quinoline, and basic amino acid such as lysine and arginine.

Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention. These salts, such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.

As used herein, the term "a compound of Formula (I)" or "the compound of Formula (I)" refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline compounds. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.

The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The compound of Formula (I) or a salt thereof may exist in stereoisomeric forms (e.g., it contains one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.

Likewise, it is understood that a compound or salt of Formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically/diastereomerically enriched mixtures. It is to be understood that the present invention includes all combinations and subsets of the particular groups defined hereinabove. The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H, ^UC, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I, and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H or ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon- 14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. ^UC and ¹⁸F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

DEFINITIONS

Terms are used within their accepted meanings. The following definitions are meant to clarify, but not limit, the terms defined.

As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms. The term "(Ci-C6)alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, ?-butyl, «-pentyl, isopentyl, «-hexyl and branched analogs thereof.

When the term "alkyl" is used in combination with other substituent groups, such as "halo(Ci-C₄)alkyl", the term "alkyl" is intended to encompass a divalent straight or branched-chain hydrocarbon radical, wherein the point of attachment is through the alkyl moiety.

"halo(Ci-C₄)alkyl" is intended to mean a radical having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms, which is a straight or branched-chain carbon radical. Examples of "halo(Ci-C4)alkyl" groups useful in the present invention include, but are not limited to, -CF₃ (trifluoromethyl), -CCI₃ (trichloromethyl), 1 , 1 -difluoroethyl, 2,2,2-trifluoroethyl, and

hexafluoroisopropyl.

"Alkoxy" refers to a group containing an alkyl radical, defined hereinabove, attached through an oxygen linking atom. The term "(Ci-C₄)alkoxy" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(Ci-C₄)alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, and ?-butoxy.

As used herein, "halogen" or "halo" refers to F, CI, Br, or I. "Hydroxy" or "hydroxyl" is intended to mean the radical -OH.

As used herein, "5- or 6-membered heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur.

The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different. The alternative definitions for the various groups and substituent groups of Formula (I) provided throughout the specification are intended to particularly describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this invention includes any combination of these group and substituent group definitions.

PHARMACEUTICAL COMPOSITIONS

The invention further provides a pharmaceutical composition (also referred to as pharmaceutical formulation) comprising a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and one or more excipients (also referred to as carriers and/or diluents in the pharmaceutical arts). The excipients are pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, with at least one excipient.

Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).

When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules, powders or granules, solutions or suspensions in aqueous or nonaqueous liquids, edible foams or whips, oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as a syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through a tablet machine, resulting in imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration can be

microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred for delivery of the

pharmaceutical composition.

As used herein, the term "treatment" refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.

The present invention provides a method of treatment in a mammal, especially a human, suffering from obesity, diabetes, hypertension, depression, anxiety, drug addiction, substance addiction, or a combination thereof. Such treatment comprises the step of administering a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) or a

pharmaceutically acceptable salt thereof, to said mammal, particularly a human. Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, to said mammal, particularly a human.

As used herein, the term "effective amount" means that amount of a drug or

pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.

The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of Formula (I), (II), (III), or (IV), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition. While it is possible that, for use in therapy, a therapeutically effective amount of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, may be administered as the raw chemical, it is typically presented as the active ingredient of a

pharmaceutical composition or formulation.

The precise therapeutically effective amount of a compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian. Typically, a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day. Acceptable daily dosages may be from about 0.1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of Formula (I), (II), (III), or (IV) per se. Similar dosages should be appropriate for treatment of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art.

Additionally, the present invention provides the use of a compound of the invention in combination with weight management therapies or other triglyceride lowering therapy. In particular, the present invention provides a combination of a compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof with at least one other therapeutically active agent, including another anti-obesity drug and/or an anti- diabetes drug. Such other therapeutically active agent can include, for example, metformin (Glucophage^®), CB 1 receptor antagonists, GLP- 1 agonists, opioid antagonists, and

neurotransmitter reuptake inhibitors. When a compound of the invention is employed in combination with another anti-obesity drug or anti-diabetes drug, it is to be appreciated by those skilled in the art that the dose of each compound or drug of the combination may differ from that when the drug or compound is used alone. Appropriate doses will be readily appreciated and determined by those skilled in the art. The appropriate dose of the compound of Formula (I), (II), (III), or (IV) or a pharmaceutically acceptable salt thereof, and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attending doctor or clinician. COMPOUNDS PREPARATION

Generic Synthesis Schemes

The compounds of this invention may be made by a variety of methods, including well- known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention. The synthesis of the compounds of the general Formula (I) and pharmaceutically acceptable derivatives and salts thereof may be accomplished as outlined below in Scheme 1 by those skilled in the art. In the following description, the groups are as defined above for compounds of Formula (I) unless otherwise indicated. Starting materials are commercially available or are made from commercially available materials using methods known to those skilled in the art.

Compounds of Formula (I) may be prepared as illustrated in Scheme 1. 6- Methoxytetralone A can be converted to intermediate B using glyoxalic acid followed by sulfuric acid in diglyme under heating conditions. Reduction of the olefin B in the presence of Zn in AcOH affords intermediate C the acid group of which is readily esterified to the corresponding ethyl ester D under standard conditions. Introduction of the R³ group to generate the quaternary center is achieved by treating the enolate of D with a suitable alkylating agent R³-I to afford E. Methoxy substitution on E is then unmasked to reveal the phenol upon treatment of E with aqueous HBr. Under these conditions, however, the ethyl ester also gets hydrolysed giving acid F. Methylation of the acid under acidic conditions to G followed by triflation of the phenol using trifluoromethanesulfonic anhydride and pyridine affords the intermediate H. Conversion of the triflate to the corresponding cyano group proceeds under palladium catalysed conditions in the presence of zinc cyanide at high temperature to give the cyano tetralone I.

The cyano group in I is then selectively reduced to the corresponding aldehyde in the presence of the methyl ester by treatment with Raney nickel in the presence of sodium

hypophosphite to give J. Aldehyde J is then subjected to a sequence of reduction (with sodium borohydride), bromination (under standard Appel conditions using triphenylphosphine and carbon tetrabromide) and finally cyanation (using sodium cyanide) to obtain the key intermediate cyanide M. Cyanide M is then treated with bis(dimethylamino) tert-butoxy methane (Bredereck's reagent) to afford the intermediate enamine (not shown) that then reacts with 3-aminopyrazole at high temperatures. A condensation reaction results in the formation of pyrazolo pyrimidine la, a compound of Formula (I). Subsequent hydrolysis of the ester under standard lithium hydroxide conditions provides lb, another compound of Formula (I).

Scheme 1. Reagents and conditions: a) Glyoxalic acid, H₂S0₄, diglyme, 1 10 °C; b) Zn, AcOH, 100 °C; c) MeS0₃H, EtOH, RT; d) R³-I, NaH, DMF, RT; e) Aq. HBr, 100 °C; f) MeOH, H₂S0₄, 65 °C; g) Tf₂0, CH₂C1₂, Py, RT; h) Pd(PPh₃)₄, Zn(CN)₂, DMF, 140 °C; i) Raney Ni, NaH₂P0₂.H₂0, Py-AcOH, 45 °C; j) NaBH₄, MeOH, RT; k) Ph₃P, CBr₄, DCM, RT; 1) NaCN, CH₃CN-H₂0, 60 °C; m) Bredereck's reagent, toluene, 80 °C, then 3-aminopyrazole, AcOH, CH₃CN, 80 °C; n) LiOH, EtOH-H₂0, RT.

EXPERIMENTALS

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention. Unless otherwise noted, reagents are commercially available or are prepared according to procedures in the literature. The symbols and conventions used in the descriptions of processes, schemes, and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. In the Examples:

Chemical shifts are expressed in parts per million (ppm) units. Coupling constants (J) are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).

Flash column chromatography was performed on silica gel.

The naming program used is ChemDraw^®.

Abbreviations:

Ac acetyl

ACN acetonitrile

AcOH acetic acid

Aq. aqueous

DCE dichloroethane

DCM dichloromethane

DMF dimethylformamide

DMSO dimethyl sulfoxide

ESI-MS electron spray ionisation mass spectrometry

EtOH ethanol/ethyl alcohol

g grams

h hours

m/z mass to charge ratio

MeOH methanol

mL millilitres

mmol millimoles

NMR nuclear magnetic resonance

Ph phenyl

Py pyridine

RT room temperature

?-Bu tertiary butyl

Tf trifluoromethanesulfonyl

THF tetrahydrofuran Example 1

Reagents and conditions: a) Glyoxalic acid, H₂S0₄, diglyme, 1 10 °C, 12 h; b) Zn, AcOH, 100 °C, 3 h; c) MeS0₃H, EtOH, RT, 16 h; d) CF₃CH₂I, NaH, DMF, RT, 3 h; e) Aq. HBr, 100 °C, 12 h; f) H₂S0₄, MeOH, 65 °C, 16 h; g) Tf₂0, CH₂C1₂, Py, RT, 2 h; h) Pd(PPh₃)₄, Zn(CN)₂, DMF, 140 °C, 3 h; i) Raney Ni, NaH₂P0₂.H₂0, Py-AcOH, 45 °C, 2 h; j) NaBH₄, MeOH, RT, 1 h; k) Ph₃P, CBr₄, DCM, RT, 2 h; 1) NaCN, CH₃CN-H₂0, 60 °C, 16 h; m) Bredereck's reagent, toluene, 80 °C, 4 h, then 3-amino pyrazole, AcOH, CH₃CN, 80 °C, 12 h; n) LiOH, EtOH-H₂0, RT, 12 h.

Procedures

2-(6-(7-Aminopyrazolo[l,5-alpyrimidin-6-yl)-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4- tetrahydronaphthalen-2-yl)acetic acid: 2-(6-Methoxy-l-oxo-3,4-dihydronaphthalen-2(lH)-ylidene)acetic acid ( A):

Glyoxalic acid (190 mL, 1.7 mol) and water (180 mL) were added to a stirred solution of 6-methoxytetralone (300 g, 1.7 mol) in diglyme (600 mL) followed by sulfuric acid (80 mL, 1.5 mol) and the reaction mixture was heated to 1 10 °C overnight. The reaction mixture was cooled to 0 °C and resulting solids were filtered off and washed with water (3 x 200 mL), dried under reduced pressure to afford the title compound (350 g, 88%) as a solid. ^lB NMR (300 MHz, DMSO-i/₆): δ 12.9 (bs, 1H), 7.9 (d, J= 8.4 Hz, 1H), 7.0 (m, 2H), 6.6 (s, 1H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (m, 2H). ESI-MS m/z: 233 (M+H)⁺.

2-(6-Methoxy-l-oxo-l, 2, 3, 4-tetrahvdronaphthalen-2-vDacetic acid (IB):

Zinc (493 g, 7.54 mol) was added to a solution of 1A (350 g, 1.51 mol) in acetic acid - water mixture (1 L + 420 mL), and stirred at 100 °C for 3 h. The reaction mixture was then filtered over celite bed, and the organic layer was removed under reduced pressure. Water (5 L) was added to the residue. The resulting solids were filtered off and dried under vacuum to afford the title compound (280 g, 77%) as a solid. H NMR (400 MHz, OMSO-d₆): δ 12.2 (bs, 1H), 7.8 (d, J= 8.4 Hz, 1H), 6.9 (m, 2H), 3.8 (s, 3H), 3.1 (m, 1H), 3.0 - 2.8 (m, 2H), 2.7 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H), 1.9 (m, 1H). ESI-MS m/z: 235 (M+H)⁺.

Ethyl 2-(6-methoxy-l-oxo-l,2,3,4-tetrahydronaphthalen-2-yl) acetate (1C):

Methanesulfonic acid (450 mL) was added to a solution of IB (250 g, 1.07 mol) in ethanol (1.5 L) and stirred at room temperature for 16 h. Ethanol was removed from the reaction mixture under reduced pressure and the residue diluted with ethyl acetate and extracted with brine solution. The organic layer dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum to afford the title compound (241 g, 81%) as a solid. H NMR (400 MHz, CDC1₃): δ 7.99 (d, J= 8.8 Hz, 1H), 6.82 (dd, J = 2.4 Hz, J₂ = 8.8 Hz, 1H), 6.68 (d, J= 2.4 Hz, 1H), 4.18 (q, J = 8.1 Hz, 2H), 3.8 (s, 3H), 3.12 - 2.85 (m, 4H), 2.39 (q, J= 9.0 Hz, 1H), 2.23 (m, 1H), 1.94 (dq, J = 4.5 Hz, J ₂ = 12.6 Hz, 1H), 1.28 (t, J= 7.5 Hz, 3H). ESI-MS m/z: 263 (M+H)⁺.

Ethyl 2-(6-methoxy-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2-yl) acetate

A solution of 1C (25 g, 95 mmol) in DMF (40 mL) was added over a period of 30 min to an ice cold solution of NaH (9.53 g, 238 mmol) in DMF (20 mL) and the mixture was stirred for 10 min. Trifluoroethyl iodide (50 g, 238 mmol) was now added, the mixture warmed to room temperature and stirred for 3 h. The reaction was then cooled back to 0 °C, excess NaH quenched with ice water and the aqueous layer was washed with ethyl acetate (2 x 200 mL). The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum to give the title compound (16.2 g, 42%) as a solid. H NMR (300 MHz, CDC1₃): δ 8.02 (d, J= 9.3 Hz, 1H), 6.85 (dd, J = 2.7 Hz, J₂ = 9.0 Hz, 1H), 6.68 (d, J= 2.7 Hz, 1H), 4.1 (q, J= 6.9 Hz, 2H), 3.86 (s, 3H), 3.05-2.9 (m, 4H), 2.6-2.4 (m, 4H), 1.23 (t, J= 6.9 Hz, 3H). ESI-MS m/z: 345 (M+H)⁺.

2-(6-Hvdroxy-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2-yl)acetic acid

Aqueous HBr (100 mL) was added to ID (10 g, 29 mmol) and the reaction mixture was refluxed overnight. The reaction mixture was then cooled to room temperature and washed with ethyl acetate (2 x 100 mL). The organic layer was dried over sodium sulfate and removed under reduced pressure to afford crude compound (8 g) as a solid, which was carried on to the next step without any further purification. ¾ NMR (400 MHz, OMSO-d₆): δ 12.4 (s, 1H), 10.4 (s, 1H), 7.76 (d, J= 8.0 Hz, 1H), 6.75 (dd, J, = 2.4 Hz, J₂ = 8.8 Hz, 1H), 6.64 (d, J= 2.4 Hz, 1H), 3.0 - 2.85 (m, 3H), 2.73 (d, J = 16.4 Hz, 1H), 2.7 - 2.61 (m, 1H), 2.48 (m, 1H), 2.38 (m, 1H), 2.1 1 (m, 1H). ESI-MS m/z: 301 (M-H)\ Ethyl 2-(6-hvdroxy-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2-yl) acetate

m:

Sulfuric acid (0.4 mL) was added to a solution of IE (5 g, 16.54 mmol) in methanol (50 mL) and the mixture was stirred at 65 °C for 16 h. Methanol was removed from reaction mixture under reduced pressure; the residue was diluted with ethyl acetate and extracted with saturated NaHC0₃ solution and brine solution. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (4.5 g, 79%) as a syrup. ^lH NMR (400 MHz, DMSO-i/₆) δ 10.43 (s, 1H), 7.77 (d, J= 8.6 Hz, 1H), 6.75 (dd, J_; = 8.7 Hz, J₂ = 2.4 Hz, 1H), 6.65 (s, 1H), 3.57 (s, 3H), 3.05 - 2.78 (m, 4H), 2.73 - 2.55 (m, 2H), 2.32 (m, 1H), 2.09 (m, 1H). ESI-MS m/z: 317 (M+H)⁺.

Ethyl 2-(l-oxo-2-(2,2,2-trifluoroethyl)-6-(trifluoromethylsulfonyloxy)-l,2,3,4- tetrahydronaphthalen-2-vD acetate (1G):

Trifluoromethanesulfonic anhydride (6.02 g, 21.34 mmol) was added to an ice cold solution of IF (4.5 g, 14.23 mmol) and pyridine (1.68 mL, 21.3 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound (5 g, 64%) as a syrup. ^lH NMR (300 MHz, CDC1₃): δ 8.16 (d, J= 8.7 Hz, 1H), 7.29 - 7.15 (m, 2H), 3.68 (s, 3H), 3.09 (t, J= 6.3 Hz, 2H), 2.98 - 2.78 (m, 2H), 2.66 (d, J= 16.5 Hz, 1H), 2.59 - 2.44 (m, 2H), 2.36 (m, 1H).

Ethyl 2-(6-cvano-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2-yl)acetate

Zn(CN)₂ (1.41 g, 12.04 mmol) and Pd(PPh₃)₄ (0.58 g, 0.5 mmol) were added to a solution of 1G (4.5 g, 10.04 mmol) in DMF (45 mL) and the mixture was degassed for 10 min. The reaction mixture was then stirred at 140 °C for 3 h and filtered through a pad of celite. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was diluted with ethyl acetate and water, concentrated in vacuo and triturated with n-pentane to afford the title compound (2.2 g, 67%) as a white solid. ^lU NMR (400 MHz, CDC1₃): δ 8.13 (d, J= 8.4 Hz, 1H), 7.6 (d, J= 8.0 Hz, 1H), 7.59 (s, 1H), 3.67 (s, 3H), 3.08 (t, J= 6.4 Hz, 2H), 2.92 (d, J= 16.0 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.67 (d, J= 16.4 Hz, 1H), 2.58 - 2.45 (m, 2H), 2.34 (m, 1H).

Ethyl 2-(6-formyl-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2-yl)acetate

Acetic acid (12 mL), sodium hypophosphite (0.49 g in 3 ml of H₂0) and then 10% Raney

Ni (0.9 g) were all sequentially added to a solution of 1H (1 g, 3.07 mmol) in pyridine (25 mL). The resultant mixture was heated at 45 °C for 2 h, cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate and washed with water (2 x 20 mL). Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 15% ethyl acetate in hexanes to afford the title compound (0.5 g,

49%) as a white solid. ^ NMR ^OO MHz, OMSO-d₆): δ 10.1 (s, 1H), 8.05 (d, J= 8.1 Hz, 1H), 7.9 (s, 1H), 7.86 (d, J= 7.8 Hz, 1H), 3.57 (s, 3H), 3.22 - 3.08 (m, 2H), 3.0 - 2.9 (m, 2H), 2.8 - 2.7 (m, 2H), 2.52 - 2.35 (m, 1H), 2.3 (m, 1H). ESI-MS m/z: 329 (M+H)⁺. Ethyl 2-(6-(hvdroxymethyl)-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2- vDacetate (1 ):

Sodium borohydride (0.0576 g, 1.523) was added in portions to an ice cold solution of II (0.5 g, 1.52 mmol) in methanol (15 mL) and the mixture was stirred at room temperature for 3 h.

The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water.

Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and triturated with n-pentane to afford the title compound (0.4 g, 66%) as a white solid. ^lU NMR (400 MHz, OMSO-d₆): δ 7.83 (d, J= 7.6 Hz, 1H), 7.32 - 7.28 (m, 2H), 5.36 (t, J= 6.0 1H), 4.55 (d, J= 5.6 Hz, 2H), 3.56 (s, 3H), 3.12 - 2.95 (m, 3H), 2.88 (d, J= 16.4 Hz, 1H), 2.75 -

2.55 (m, 2H), 2.4 - 2.35 (m, 1H), 2.15 (m, 1H). ESI-MS m/z: 331 (M+H)⁺. Ethyl 2-(6-(bromomethyl)-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2- vDacetate (IK):

Triphenylphosphine (0.476 g, 1.81 mmol) and CBr₄ (0.6 g, 1.81 mmol) were added to an ice cold solution of 1J (0.4 g, 1.21 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and triturated with diethyl ether and n-pentane to afford the title compound (0.3 g, 54%) as a yellow solid. ¾ NMR (400 MHz, CDC1₃): δ 8.02 (d, J= 8.4 Hz, 1H), 7.35 (dd, J, = 1.2 Hz, J₂ = 7.6 Hz, 1H), 7.28 (s, 1H), 4.46 (s, 2H), 3.67 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), 2.85 (d, J= 16.0 Hz, 1H), 2.82 (m, 1H), 2.64 (d, J= 16.4 Hz, 1H), 2.56 (m, 1H), 2.43 (m, 1H), 2.32 (m, 1H). ESI-MS m/z: 393 (M+H)⁺. Ethyl 2-(6-(cvanomethyl)-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahvdronaphthalen-2- vDacetate (1L):

A solution of IK (0.3 g, 0.76 mmol) in acetonitrile (10 mL) was warmed to 40 °C and a solution of NaCN (0.0748 g, 1.526 mmol) in water (1 mL) was added over 15 minutes and the resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and triturated with diethyl ether and n-pentane to afford the title compound (0.15 g, 51 %) as an off-white solid. ¾ NMR (300 MHz, CDC1₃): δ 8.05 (d, J= 8.7 Hz, 1H), 7.30 - 7.25 (m, 2H), 3.79 (s, 2H), 3.67 (s, 3H), 3.06 (t, J= 6.3 Hz, 2H), 2.87 (d, J= 15.9 Hz, 1H), 2.82 (m, 1H), 2.68 - 2.5 (m, 2H), 2.45 (m, 1H), 2.34 (m, 1H). ESI-MS m/z: 338 (M-H)\

Ethyl 2-(6-(7-aminopyrazolo[l,5-alpyrimidin-6-yl)-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4- tetrahydronaphthalen-2-vDacetate (1M):

A solution of 1L (0.15 g, 0.44 mmol) and Bredereck's reagent (0.095 g, 0.48 mmol) in toluene (5 mL) was heated to 70 °C for 4 h. The reaction mixture was then cooled to 40 °C and acetic acid (0.63 g, 10.61 mmol) and 3-aminopyrazole (0.092 g, 1.10 mmol) in acetonitrile (1 mL) were added and stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. Separated organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography using 30% ethyl acetate in hexanes to afford the title compound (0.055 g, 29%) as an off-white solid. ESI-MS m/z: 433 (M+H)⁺.

2-(6-(7-Aminopyrazolo[l,5-alpyrimidin-6-yl)-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4- tetrahydronaphthalen-2-vDacetic acid (1):

Lithium hydroxide (0.015 g, 0.63 mmol) was added to a solution of 1M (0.055 g, 0.127 mmol) in 4 mL ethanol - water (3: 1) mixture and stirred at room temperature overnight. After the solvent was removed in vacuo the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified by addition of saturated citric acid solution until pH 5 was attained. The resulting solution was cooled to 0 °C and solids obtained were filtered off and dried under vacuum to afford the title compound (0.03 g, 55%) as a pale yellow solid. ¾ NMR (300 MHz, DMSO-i/₆): δ 12.4 (s, 1H), 8.18 (s, 1H), 8.15 (d, J= 1.8 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H),

7.74 (bs, 2H), 7.51 (m, 2H), 6.48 (d, J= 1.8 Hz, 1H), 3.10 (t, J= 6.0 Hz, 2H), 2.95 (m, 1H), 2.85 -

2.75 (m, 2H), 2.6 - 2.4 (m, 2H), 2.17 (m, 1H). ESI-MS m/z: 419 (M+H)⁺; LCMS purity: 98%.

Biological Assay Inhibition of human DGAT1 activity in vitro

Human DGAT1 was expressed in Sf9 insect cells using a baculovirus expression system. Microsomes were prepared and used as enzyme for in vitro inhibition testing in either of two formats measuring production of coenzyme A or tridecanoylglycerol product, respectively. All steps were performed at 21-23°C. All data for DGAT1 inhibition by test compounds were collected under conditions where product formation was linear with reaction time.

CPM assay: For inhibition of CoA product formation, test compounds were prepared in 100% DMSO, diluted 100-fold into assay buffer, and 10 uL added to 96-well half-area plates (Greiner 675076). An equal volume (10 uL) of 3X enzyme in buffer was added and the components incubated for 30 minutes pre -reaction incubation to allow enzyme and test compounds to attain binding equilibrium. The 3X enzyme mixture contained 30 uM {4-[4-(4-amino-7,7- dimethyl-7H-pyrimido[4,5-Z7][l,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid for fully inhibited control wells. Some assays were performed with inclusion of didecanoylglycerol in the pre- reaction incubation of test compound and enzyme. DGAT reactions (30 uL) were initiated upon addition of 10 uL of 3X substrate solution. Final reaction conditions consisted of 20 mM HEPES pH 7.5, 2 mM MgCl₂, 1 mM CHAPS, 50 uM didecanoylglycerol, 3 uM decanoyl-CoA, 1 ug/mL microsomal protein, and 1% DMSO. Following a 60 minute reaction incubation, reactions were stopped and CoA product derivatized with 30 uL of buffer containing 10 uM {4-[4-(4-amino-7,7- dimethyl-7H-pyrimido[4,5-Z7][l,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid and 50 uM 7- diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM). Fluorescence was read using Envision reader at Ex 405 nm/Em 480 nm about 30 minutes after addition of final solution.

Inhibition was normalized to controls containing DMSO or 10 uM {4-[4-(4-amino-7,7-dimethyl- 7H-pyrimido[4,5-Z7][l,4]oxazin-6-yl)phenyl]cyclohexyl} acetic acid. IC₅oS were fitted using GraphPad Prism to a sigmoidal dose response.

LE assay: For inhibition of triacylglycerol product formation, 1 1 uL reactions were run in white Polyp late-384 (PerkinElmer6007300) starting with a 30 minute pre -reaction incubation of 5 uL of 2.2X enzyme and 1 uL of 100% DMSO containing test compound or control compound, {4- [4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-Z7][l,4]oxazin-6-yl)phenyl]cyclohexyl} acetic acid. Some assays were performed with inclusion of didecanoylglycerol in the pre-reaction incubation of test compounds and enzyme. Reactions were initiated after 30 minute pre-reaction incubation via addition of 5 uL of 2.2X substrate. Final reaction conditions consisted of 50 mM HEPES pH 7.5, 2 mM MgCl₂, 1 mM CHAPS, 25 uM didecanoylglycerol, 0.5 uM decanoyl-CoA, 0.3 nCi/uL [¹⁴C]-decanoyl-CoA or 0.5 nCi/uL [³H]-decanoyl-CoA, 0.05-4 ug/mL microsomal protein, and 1% DMSO. Following 60 minute reaction incubation, reactions were stopped with 40 uL of 45% isopropanol and 50 mM sodium carbonate in water and mixed. Extraction of tridecanoylglycerol product was accomplished via addition of 30 uL Microscint-E (Perkin Elmer) and 2 hours of incubation (sealed). Plates were read on a Microbeta Microplate reader. Inhibition was normalized to controls containing DMSO or 10 uM {4-[4-(4-amino-7,7-dimethyl-7H- pyrimido[4,5-Z?][l,4]oxazin-6-yl)phenyl]cyclohexyl}acetic acid. IC₅oS were fitted using GraphPad Prism to a sigmoidal dose response.

Biological Data

Exemplified compounds of the present invention were tested in one or more DGAT assays described above and were found to be inhibitors of DGAT 1 with IC₅o < 10 μΜ. For instance, the compound of Example 1 exhibited an IC₅o of approximately 49 nM in the human DGAT1 lipid extraction (LE) assay.

Claims

Claims:

wherein:

X is CH₂, C=0, or NR¹;

Y is CR²R³, C=0, or NR¹; wherein when X is CH₂, Y is CR²R³, when X is C=0, Y is CR²R³ or NR¹, and when X is NR¹, Y is CR²R³ or C=0;

R¹ is hydrogen or (Ci-C₄)alkyl;

R² is hydrogen or -C(R⁵)₂R⁴;

R⁴ is -CH₂C(0)OH or -C(0)OR⁶;

each R⁵ is independently hydrogen or -CH₃; and

R⁶ is hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, phenyl, or 5- or 6-membered heteroaryl; or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt according to claim 1 wherein X is CH₂ or C=0 and Y is CR²R³.

3. The compound or pharmaceutically acceptable salt according to claim 1, which is represented by Formula (II):

wherein R is hydrogen, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, hydroxyl, or (Ci-C₄)alkoxy.

4. The compound or pharmaceutically acceptable salt according to claim 2, which represented by Formula (III):

5. The compound or pharmaceutically acceptable salt according to claim 2, which is represented by Formu

6. The compound or pharmaceutically acceptable salt according to any one of claims 1-5 wherein R³ is hydrogen,

or halo(Ci-C4)alkyl.

7. The compound or pharmaceutically acceptable salt according to any one of claims 1-5 wherein R³ is hydrogen, -CH₃, -CH₂CH₃, -CH₂CF₃, or -OCH₃.

8. The compound according to claim 1 which is 2-(6-(7-aminopyrazolo[l,5- a]pyrimidin-6-yl)-l-oxo-2-(2,2,2-trifluoroethyl)-l,2,3,4-tetrahydronaphthalen-2-yl)acetic acid or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to any one of claims 1-8 and a pharmaceutically acceptable excipient.

10. A method of treating obesity comprising administering to a human in need thereof an effective amount of the compound or pharmaceutically acceptable salt according to any one of claims 1-8.

1 1. The compound or pharmaceutically acceptable salt according to any one of claims 1-8 for use in therapy.

12. Use of the compound or pharmaceutically acceptable salt according to any one of claims 1-8 for the treatment of obesity.