Title of Invention	INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND APO-B SECRETION
Abstract	The present invention relates to compounds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. These compounds can be useful for the prevention and treatment of various diseases, particularly atherosclerosis and its clinical sequelae, for lowering serium lipids, and related ailments. The invention further relates to pharmaceutical compositions comprising the compounds and to methods of treating diseases, such as hypertiglyceridemia, hyperchylomicronemia, atherosclerosis, obesity, and related conditions using the compounds. A method for decreasing apolipoprotein B (apo B) secretion is also provided.

Title of Invention

INHIBITORS OF MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN AND APO-B SECRETION

Abstract

The present invention relates to compounds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. These compounds can be useful for the prevention and treatment of various diseases, particularly atherosclerosis and its clinical sequelae, for lowering serium lipids, and related ailments. The invention further relates to pharmaceutical compositions comprising the compounds and to methods of treating diseases, such as hypertiglyceridemia, hyperchylomicronemia, atherosclerosis, obesity, and related conditions using the compounds. A method for decreasing apolipoprotein B (apo B) secretion is also provided.

Full Text	INHIBITORS OF MICROSOMAJL TRIGLYCERIDE TRANSFER PROTEIN AND APO-B SECRETION CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. provisional patent application nos. 60/672,778, filed April 19,2005, and 60/755,390, filed December 30, 2005. The contents of each of these applications are incorporated herein by reference in their entireties. FIELD OF THE INVENTION The present invention relates to compotmds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoproteia B (Apo B) secretion. These compotmds can be useful for the prevention and treatment of various diseases, particularly atherosclerosis and its clinical sequelae, for lowering serum lipids, and related ailments. The invention further relates to pharmaceutical compositions comprising the compounds and to methods of treating diseases, such as hypertriglyceridemia, hyperchylomicronemia, atherosclerosis, obesity, and related conditions using the compounds. A method for decreasing apoHpoproteia B (apo B) secretion is also provided. BACKGROUND OF THE INVENTION J/ficrosomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride, cholesteryl ester, and phosphoUpids, MTP has been identified as an agent that may be involved in the assembly of Apo B-containing lipoproteins and biomolecules that contribute to the formation of atherosclCTotic lesions. Compounds that can inhibit MTP and/or inhibit Apo B secretion can be useful in the treatment of atherosclerosis and related diseases (see, e.g., U.S. Patent No. 5,919,795, incorporated herein by reference). These compounds are also useful in the treating diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels are reduced. Examples of tbese diseases or conditions include hypertriglyceridania, hypercholesterolemia, pancreatits, and obesity; and hyperchylomicronemia and hyperhpidemla associated with pancreatitis, obesity, and diabetes. Therefore, th^e is a need for compounds that inhibit MTP that are effective in treating diseases or conditions, such as atherosclerosis and related diseases, and/or can provide an effective lowering of serum apo B in mammals or humans. SUMMARY OF THE INVENTION In one aspect, the present invention provides compounds of Formula I: wherein Ri is alkyl (optionally substituted, e.g., with one to three substituents, e.g., halogen, amino, or alkoxy groups), R4R5NC(0)CH2, cycloalkyl, heterocyclyl, or heterocyclylalkyl; Xi is a direct bond, 0, S, -N(R6)-, C(0)NR6, or N(R6)C(0); X2 is O, -N(R^)-, or S; X3 is a direct bond, O, -N(R6)-, -CH2-, arylene, or S; R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyl, alkylcaibonyL, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, -OH, aDcoxy, aryloxy, -SH, tfaioalkyl, thioaryl, or NR4R5; R4 and Rs are, independently for each occurrence, H, alkyl, cycloaDcyl, heterocyclyl, arjd, heteroaryl, heteroalkyl, aralkyl^ aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl; Re is, independently for each occurrence, H or alkyl; misO or 1; and n is an integer fiom 0 to 3; provided that if m is 0, X3 is a direct bond or CH2; or apharmaceutically acceptable salt, solvate, ester or hydrate thereof. In certain preferred embodiments, Xi is 0. In certain preferred embodiments, Ri is alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferred embodiments, Ri and Xi taken together form a moiety selected from the group consisting of: and Xi taken together fonn CH3-O-. In c^ain prefeared embodiments, m is 1. In certain preferred embodimeatSa when m is 1, X3 is O or NH. In certain preferred ranbodiments, n is 0,1 or 2. In certain preferred embodim^its, R3 is aryl, more preferably unsubstituted or substituted phenyl. In other preferred embodiments, R3 is cycloallcyl, heterocyclyl, heteroaryi, or allcoxy. In certain preferred embodiments, the moiety In another embodimmt, the invention provides compomids reptesented by Formula II: and pharmaceutically acceptable salts, esters, isom^ aad hydrates thereof. In one embodiment, the present invention is drawn to a pharmaceutical composition comprising a compound of Formula I or n and a pharmaceutically acceptable carrier. The compounds of Fomiula I or II, or a composition comprising a conapound of Formula I or n, can be used for treating a variety of diseases or conditions including, but not limited to, hypertri^yceridemia, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hyperchylomicroneiDia, hyperlipidemia, and diabetes. Furthermore, a method for treating or preventing such a disease or condition, such as atherosclerosis and related conditions, in a subject (e.g., a mammal including a human), is provided'in accordance with the present invention. The method comprises administering to a subject (e.g., a mammal iacluding a human) in need of such a treatment, an effective amount of a compound of Formula I or II, such that the disease or condition is treated or prevented. The present invention also provides a method of decreasing apo B secretion in a subject (e.g., a mammal or a human), comprising administering to said subject a compound of Formula I or n, or a phannaceutical composition comprising a compound of Formula I or II, in an amount sufficient to decrease the levels or amount of secretion of apo B in the subject. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a depiction of the proton NMR of a MTP inhibitor of the present invention (compound 6). Figi2re 2 is a depiction of the mass spectrum of a MTP inhibitor of the present invention (compound 6). Figure 3 is a depiction of the proton NMR of a MTP inhibitor of the present invention (compound 15). Figure 4 is a depiction of the ^^Carbon-NMR of a MTP inhibitor of the present invention (compound 15). Figure 5 is a depiction of the mass spectrum of a MTP inhibitor of the present invention (compound 15). DETAILED DESCRIPTION In one aspect, the present invention provides compounds. In one embodiment, the compounds are represented by Formula I: whCT'ein Ri is alkyi (optionally substituted, e.g., with one to teee substituents, e,g., halogen, amino, or alkoxy groups), R4R5NC(0)CH2, cycloaUcyl, beterocyclyl, or beterocyclylalkyl; Xi is a direct bond, O, S, -NCRe)-, C(0)NR6, orN(R6)C(0); X2 is O, -N(R6>, or S; X3 is a direct bond, O, -N(R^)-, -CH2", arylene, or S; R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaxyl, heteroalkyl, aralkyl, alkylcarbonyl, alkoxycarbonyL, arylcarbonyl, aryloxycarbonyl, -OH, alkoxy, aryloxy, -SH, thioalkyl, thioaryl, orNR4R5; R4 and R5 are, indepeodently for each occurrence, H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyl, aminocarbonyl, alkylcaibonyl, aJkoxycaibonyl, arylcarbonyl, or aryloxycarbonyl; R^ is, indq>endently for each occurrence, H or alkyl; m is 0 or 1; and n is an integer frova 0 to 3; provided that if m is 0, X3 is a direct bond or CH2; or a pharmaceutically acceptable salt, solvate, ester or hydrate thereof III certain preferred raabodiments, Xi is O. In certain preferred anbodiments, Ri is alkyl, more preferably methyl. In certain preferred embodim^its, Ri and Xi taken together foim a moiety selected from the group consisting of; and Xi taken togetiaer form CH3-O-. In certain preferred embodiments, m is 1. In certain preferred embodiments, when m is 1, X3 is O or NH. In certain preferred embodiments, n is 0,1 or 2. In certain preferred embodiments, R3 is aryl, more preferably unsubstituted or substituted pbCTiyi- In other preferred embodiments, R3 is cycloalkyl, heterocyclyl, heteroaryl, or alkoxy. la cratain prefeaxed embodiments, the moiety in which Ar is optionally substituted aryl or optionally substituted heteroaryl; Cy is optionally substituted cycloaDcyl or optionally substituted heterocyclyl; Alk is optionally substituted alkyl; n is 0-3; and p is 1-3. In certain preferred embodiments, n is 0 or 1. In certain preferred embodiments, Ar is optionally substituted phenyl or optionally substituted furan-2-yl; Cy is optionally substituted cyclopropyl or tetrahydrofuran-2-yl; and Alk is methyl, ethyl, or isopropyl. and phaxmaceutically acceptable salts, esters, isomers, or hydrate thereof. In certain preferred CTabodiments, Ru is —OCH3. In certain preferred embodiments, Rn is not H. Among the more preferred compoirnds of Foimnla I and/or II of the present invention are the following compounds: and pharmaceutically acceptable salts, estars, isomer and hydrates thereof. As tised hCTein, tiie term '"alkyl" means a saturated straight chain or branched non-cyclic hydrocarboii typically having from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-. hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2- methylbutyl, 3-methylbutyl, Z-methylpeat^d, 3-methy]pentyl, 4-methylpentyl, 2- methylhexyl, 3-methylhexyl, 4-metiiylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3- dimethylpentyl, 2, 4-dunethylpentyl, 2, 3-dimethylhex>d, 2,4-dimethylhKcyl, 2, 5-dimetiiylhexyl, 2,2-dimethylpentyl, 2, 2-dimethylhexyl, 3, 3-dimethylpCTityl, 3, 3-dimethylh^yl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethyIhexyl, 3- ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl- 4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-mefhyl-3-ethylhexyl, 2-methyl-4- ethylhexyl, 2,2-diethylpeaityl, 3, 3-diethylhexyl, 2, 2-diethylhexyl, 3,3-diethylhexyl and the like. Alkyl groi5>s included in compounds of this invention may be optionally substituted with one or more substituents (preferably one to three substituents), such as amino OSIH2), Ci-Ce alkylamiuo, CrQ, dialiylamino, arylamino, diarylamino, heterocyclylamino, (Ci-Cg al3cyl)caxbanyl2mino, Ci-Ce alkoxy, Cj-Ce alkylthio, 0x0, =S, halo (includiug F, CI, Br, and I), nitro, hydroxyl, cyano, aiyl, heteroaryl, aryloxy, arylthio, caibocyclyl, carbocyclyloxy, carbocyclylthio, caibocyclylamino, het^ocyclyl, heterocyclyloxy, heterocyclyltiiio, and the like. Lower alkyls (having from 1 to 6 carbon atoms in the alkyl chain) are typically preferred for the compounds of this iavention. The term "cycloalkyr, as used herein, refers to a cyclic alkyl group having from 3 to 10 carbon atoms ia the ring, more preferably 3-6 carbon atoms to the riag. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopeatyl, and cyclohexyl. Cycloalkyls maybe substituted by one or more substituents (e.g., one to three substituents) as described above for alkyl groups. As used herein, the term "heterocycle" or '"heterocyclyl" means a monocyclic or polycyclic heterocyclic ring (typically having 3- to 14-members) which is either a saturated ring or a unsaturated non-aromatic ring. A 3-membered heterocycle can contain up to 3 heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 to about 8 heteroatoms. Each hetCToatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulibr, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomoipholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyiindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to tiiose of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl maybe optionally substituted with one or more substituents, e.g., one to three substituents (including without limitation a halogen atom, an aDcyl radical, or aryl radical). Only stable isomers of such substituted heterocyclic groups are contemplated in this definition. Heterocyclyl groups can be substituted or unsubstituted. As used herein, the term an "aromatic ring" or "aiyl" means a monocychc or polycycHc-aromatic ring or ring radical comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacraiyl, fluorenyl, indenyl, azulenyl, and naphtiiyl, as well as benzo-fiised carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyL An aryl group can be unsubstituted or, optionally, substituted with one or more substituents, e.g., one to three substituents (including without limitation aDcyl (preferably, lower aBcyl or alkyl substituted with one or more halo), hydroxy, alkoxy preferably, lower alkoxy), alkylthio, cyano, halo, amino, and nitro. In certain embodiments, fee aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms. As used herein, the term "heteroaromatic" or "heteroaryl" means a monocyclic or polycychc heteroaromatic ring (or radical thereof) comprising carbon atom ring members and one or more heteroatom ring members (such as, for example, oxygen, sulfur or nitrogen). Typically, the heteroaromatic ring has from 5 to about 14 ring members in which at least 1 ring member is a heteroatom selected from oxygen, sulfur and nitrogra.. In another embodimCTt, the heteroaromatic ring is a 5- or 6- membered ring and may contain from 1 to about 4 heteroatoms. In another embodiment, the heteroaromatic ring system has a 7 to 14 ring members and may contaxQ from 1 to about 7 heteroatoms. Representative heteroaryls include pyridyl, ftuyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, mdoUzdnyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazmyl, pjoimidiayl, pyrazinyl, triazmyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoqnniolyl, inda2X)lyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, ben^imidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl, pynolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl or b^izo(b)thienyl and the hke. These heteroaryl groups may be optionally substituted with one or more substituents, e.g., one to three substituents as described for aryl groups. As used herein, the term "halogen" or "halo" means -F, -CI, -Br or -I. The term "alkylene," as used herein, refers to an alkyl group that has two points of attachment to two moieties (e.g., {-CH2-}, -{CH2CH2"}, , etc., wherein the brackets indicate the points of attaclnnent). Alkylene groups may be nnsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described for alkyl groups. Exemplary alkylene groups include methylene, ethylene, and propylene. The term "arylene," as used herein, refers to an aryl or heteroaryl group that has two points of attachment to two moieties. Arylene groups may be unsubstituted or optionally substituted with one or more substituCTits, e.g., 1-3 substituents as described for aUcyl groups. Exemplary arylene groups include phenyH,2-diyl, pheayl-13-diyl, andpheaayl-l,4-diyl-; thiazol-2,4-diyl, and the like. The tenn "aralkyl", as used hereiu, refers to an aryl group that is attached to another moiety via an alkylene liaker. Aralkyl groups may be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described for altyl groups. The torn "heterocyclylalkyl," as used herdn, refers to a heterocycljd group tiiat is attached to another moiety via an alkyleae linker. Heterocyclylalkyl groups may be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described for alkyl groups. The term "alkylcarbonyl," as used herein, refers to the group -C{0)-aIkyl. The alkyl portion of the alkylcarbonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 13 substituents as described above for alkyl groups. The term "alkoxycaxbonyl," as used herein, refers to the group -C(0)-0-aIkyL The alkyl portion of the alkoxycaibonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups. The term "arylcaibonyl," as used herein, refers to the group -C(0)"aryl or-C(O)-heteroaryl. The aryl or heteroaryl portion of the axylcarbonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for aUcyl groups. The term "aryloxycarbonyl," as used herein, refers to the group -C(0)-0-aryl OT-C(0)-O-heteroaryL The aryl or heteroaryl portion of the aryloxycarbonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups. The term "aminocarbonyl," as used herein, refers to the groups -C(0)-l The term "alkoxy," as used herein, refers to the group -O-alkyl. The alkyl portion of the alkoxy moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups. The term "aryloxy," as used herein, refers to the grou^j -0-aryI or-Oheteroaryl. The aryl or heteroaryl portion of the aryloxy moiety can be unsubstitated or optionally substituted with one or more substiturats, e.g., 1-3 substitumts as described above for alkyl gror5)S. The term "thioalkoxy," as used herein, refers to tiie group -S-aUcyl The alkyl portion of the thioalkoxy moiety can be unsubstitated or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups. The term "thioaryloxy," as used herein, refers to tiie group -S-aryl or -S-heteroaryl. The aryl or heteroaryl portion of the thioaryloxy moiety canbe unsubstitated or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I or II and a phaimaceutically acceptable carrier. The compounds of Formula I or n or compositions comprising the compounds of Formula I or H can be used for treating a variety of diseases or conditions includingj but not limited to, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridCTcda, hyperhpidemia, and diabetes. Furthermore, a method for treating such a disease or condition, such as atiierosclerosis and related conditions, in a mammal or a human, is provided in accordance with the present invention. The method comprises administering to a subject (e.g., a mammal, including a human) in need of such a treatment an effective amount of a compound of Formula I or II, or a pharmaceutical composition comprising an effective amount of a compound of Formula I or II, such that the disease or condition is treated. In certain embodiments, the compound is administered in an amount sufficient to decrease the secretion of apoUpoprotein B. The present invention also provides for a method of decreasing ^o B secretion in a mammal or human, comprising administering to a mammal or a human of a compound of Formula I or H, or a pharmaceutical composition comprising a compound of Formula I or II, in an amount sufficient to decrease the levels or amount of secretion of apo B. The invention further provides a pharmaceutical composition suitable for the treatment of conditions including hypertriglyceridemia, atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hyperchylomicronemia, hyperlipidemia, and diabetes, comprising a compound of Formula I or 11 as hereinbefore defined, and a pharmaceutically acceptable carrier. The compounds of this invention inhibit or decrease apo B secretion, likely by the inhibition of MTF, although it may be possible that other mechanisms are involved as well. The compounds are useful in any of the diseases or conditions in which apo B, serum cholesterol. and/or triglyceride levels are elevated. Accordingly, the invention further provides a metiiod of treating a condition selected from hypextri^yceridemia, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hyperchylomicronsmia, hyperlipidemia, and diabetes, comprising administering to a mammal, especially a human, in need of such treatmrat an amoimt of a compound of Fonmila I or H as defined above sufficient to decrease tiie secretion of apolipoproteinB. The t^m "treating" as used herein includes preventative as well as disease remitative treatment The invention further provides a method of decreasing apo B secretion in a mammal, especially a human, comprising administering to said mammal an apo B"(secTetion) decreasing amoimt of a compound of Formula I or n as defined above. The invention also provides kits for treatment or prevention of diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated. Accordingly, the invention finther provides provides kits for treatment or prevention of a condition selected from -hypertriglyceridemia, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hyperchylomicronemias hyperlipidemia, and diabetes. In one embodiment, the kit includes an effective amount of a compound of this invention (e.g., a compound of Formula I or Formula 11) in unit dosage form, together with instructions for administering the compound to a subject sufimng from or susceptible to diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated (including witiiout limitation hypertriglyceridemia, atherosclerosis, pancreatitLs, obesity, hypercholesteremia, hyperchylomicronemia, hyperlipidemia, and diabetes), preferably wherein the effective amount of compound is less than 1000 mg (more preferably less than 500 mg) of the con:q)Ound, In preferred embodiments, the kit comprises a sterile container whidi contains the compound; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container form known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holdiag medicaments. The instructions will generally include information about the use of the compound for treatment or prevention of diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated (including without limitation hypertriglyceridemia, atherosclerosis, pancreatitis, obesity, hypercholestK:^niia, hyperchylomicronemia, hyperlipidemia, and diabetes); in preferred embodiments, the instructions include at least one of the following: description of the compound; dosage schedule and administration for treatment of diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated; € precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container. In another aspect, the presait invention provides intamediate compounds that are useful for the synthesis of the MTP inhibitor compounds of the invention. Examples of such intermediate cornpounds include compounds of structure 20, in which Ri and Xi have the meanings described in connection with Formula I or U, and R7 is selected from the group consisting of OH, 0-Cat (in which Cat is a cation (e.g., a proton, a metal cation such as sodium, lithium, potassium, calcium, ammonium, and the like)), a Ci - Ce alkoxy group, and a leaving group (including a halogen such as chloride or bromide, a tosylate or mesylate, a pentafhiorophenol, and ttie like). In a preferred embodiment of a compoimd of stracture 20, Ri together wiQi Xi forms a CH3O groiq), and R7=OH. The present invention also provides iutermediates useful in the preparation of compounds of Formula I or Formula n. A preferred intermediate compound of the present invention is described by structure 2 shown below. It will be appreciated by those skilled in the art that certain compounds of Formula I or n may contain an asymmetrically substituted carbon atom and accordingly may exist in, and be isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encon^passes any racemic, optically^active, polymoiphic or stereoisomeric form, or mixtures Hi&reof, which form possesses pToperties useful in tiie treatment of atherosclerosis, obesity, and the other conditions noted herein, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to detennine efiScacy for the treatment of the conditions noted herein by the standard tests described heremafter. The chemist of ordinary skill will recognize that certain combinations of substitueats or moieties hsted in this inv^ition define compoimds which will be less stable under physiological conditions (e.g., those containing amTn^l or acetal linkages). Accordingly, such compounds are less preferred. ■ The present invention furtha: provides a method of forming the compomids of Formula I or U of the present invention by a synthetic process. Compounds of Formula I or H can also be made by processes which include processes known in the chennical arts for the production of similar compounds. Such processes for the manufacture of a compound of Formula I or II as defined above are provided as further features of the invention and are illustrated by the procedures discussed below. ConvKitional methods and/or techniques of purification and separation known to those skilled in tiie art can be xised to isolate the compounds of this invention. Such techniques include aU types of chromatography (HPLC, column chromatography using common adsorbents such as silica geL and thin layer chromatography), recrystallization, and differential (i.e., Hquid-hquid) extraction techniques. The compounds hereui forai cationic salts such as acid addition salts and the expression "pharmaceutically-acceptable salts" is intended to define but not be hmited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, benzoate, ascorbate, lactate, pamoate, tartrate, methauesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. For many compounds polyaddition salts are feasible. The acid addition salts of the compounds of the present invention are readily prepared by reacting the base forms with the appropriate acid. "When the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogCTi form of a tribasic acid (e.g., the dihydrogeai phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However, w:hen such salts as the sulfate, the hemisuccinate, the hydrogKi phosphate or the phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base and the acid axe usually combined in a co-solveot from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent In certain embodiments, the term "phaimaceutically acceptable salt," as used herein, can refer to a salt prepared from a compound of Formula I or n having an acidic functional group, such as a carboxyhc acid functional group, and apharmaceulically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such ELS sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substitated mono-, di-, or trialkylaraines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyefhyl)- amine, 2-hydroxy-tCTt-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower altyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)- amine/or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like, A representative general synthetic route for the MTP inhibitor compounds of Formula I or n of the present invention is exemplified in Scheme 1, which shows the synthesis of compound 6. The individual reaction steps involved in the synthetic process are subsequently described in greater detail (see Examples 1-7). Qfz OTf 0 N^^='5>'^\-^ 74% Me^ H 4 l!^ 98% , 1^ 20% Me""" 95% /O over two steps Me •OH O The compouBds of the present invention are orally administrable and are accordingly used in combination with a phaimaceutically acceptable carrier or diluent suitable to oral dosage forms. Suitable pharmaceuticaUy-acceptable carriers include inert solid fillcErs or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described below. Thiis, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. The tablets, piUs, capsules, and the like may also contain a binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as . magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit For instance, tablets may be coated with shellac, sugar or both. A syrap or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. These active compounds may also be administered parenterally. For parenteral administration the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Solutions or suspensions of these active compoimds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrroHdone and mixtures thereof in oils as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or iatramuscxdarly. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extraiporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syingabihty exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminatnig action of microorganisnis such as bacteria and fimgi. The dose of a compound of Formula I or 11 which is administered will goaerally be varied according to principles well known in the art taldng into accoimt the severity of the condition being treated and the route of administration. In general, a compound of Formula I or n will be administered to a warm blooded animal (such as a human) so that an effective dose, usually a daily dose administered in unitary or divided portions, is received, for example a dose in the range of about 0.1 to about 15 mg/kg body weight, preferably about 1 to about 5 mg/kg body weight. The total daily dose received will generally be between 1 and 1200 mg, preferably between 5 and 800 mg. In certain preferred embodiments, a compoimd of Formula I or IT may be administered in divided doses taken with meals, e.g., three times daily, in which case each dose can be, e.g., between 5 and 500 mg. The compounds of this invention may be used in conjunction with other pharmaceutical agents, including other lipid lowering agents. Such agents include cholesterol biosynthesis inhibitors,- especially HMG CoA reductase inhibitors (such as atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, rosuvastatin, and pitivastatin (itavastatin/risivastatin)); squalene synflietase inhibitors; bile acid sequestrants such as cholestyramine; fibrates (bezafibrate, clofibrate, fenofibrate); cholesterol absorption inhibitors such as ezetimibe and pamaqueside; and niacin. A test compound is considered to be active if it is active in any of the following screens. The activity of a compound according to the invention can be assessed by measuring inhibition of apo B secretion in HepG2 cells. Activity can also be confirmed if a test compound inhibits MTP activity directly. Inhibition of MTP activity by a compound can be quantitated by observing the inhibition of transfer of radiolabeled triglyceride from donor vesicles to acceptor vesicles in the presence of soluble human MTP. The present invention is illustrated by the following Examples. However, it should be understood that the invention is not limited to the specific details of these examples. Amixture of phaiol (1.82g) andtrifluoromethaQesulfonyl (l.OSeq) anhydride in anhydrous pyridine (IM) was stirred at 0 ^C and then slowly warmed up to 15 °C overnight Water was added to the mixture, which then was extracted three times with EtjO. The organic layer was washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the crude was passed through a plug of siHca gel to afford 3.07g (98%) of the triflate (purity 98%). The triflate (1.3g) was dissolved in 25 mL of DME (0.16M) and the boronic acid (0.64g, O.Seq), K2CO3 (0.85g, L49mmol) and Pda2dppf-DCM (0.02eq) were added. The mixture was refluxed over night In the morning all the reagents were added to reach 1.05eq of boronic acid. 2.0eq of K2CO3 and 0.03eq of catalyst The mixture was heated for additional 5 hours, and then water (S.Oeq) was added. After 18 hours, the reaction mixture was diluted with Et20, and it was filtered through a sihca gel plug column and eluted with Et20. No separation of impurities from product occiuxed. The organic phase was washed wife a solution of citric acid (10%), 2Xbrine and dried over NaaSOA. The solvent was removed unda: reduced pressure. The residue was dissolved in MeOH, water was added and some precipitate was formed. The solid was collected, washed with hexanes, dissolved in DCM and crystallized again with hexanes. The solid was isolated (0.26g, pure 97.5% by HPLC) Compound 1 (0.26g) was dissolved in THF (2.0 mL) and LiOH'HzO (4.8eq) was added ru 1.0 mL of water. After stirring the mixture at room temp, MeOH was added to. have a homogenous solution. The mixture was heated at 50°C overnight The solvent was removed imder reduced pressure, the residue was dissolved in DCM and washed with IN HCl and brine. The organic phase was dried over NaaSOA and the removal of the solvent by reduced pressure afforded 0,22g (88%) of compound 2 (purity 98%). Compouad 2 (0.21 g) was suspended in DCM (3.0 mL) and the solution was cooled to 0°C. Oxalyl chloride (1.6eq) was added dropwise followed by the addition of catalytic amount of DMF. The mixture was stiired at 0°C for 30 minutes, th^ at room temperature for 1.5 hours. The solution became clear. The solvent was removed under reduced pressure. The crude was used from the next reaction without further purification. Compound 3 was dissolved in THF (2.0 nxL) and a solution of N-Boc-tetrahydroisoquinoline in 2.QmL of THF was added dropwise (some precipitate formed) followed by the addition of NEts. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the crude was purified through sihca gel column chromatography (EtOAc/Hexanes 0-30%). The product was not clean at this point The product was washed with Et20 to give (0.36g) of compound 4 (purity 99%). Example 6: Removal of Boc Protecting Group Compound 4 (O.lg) was dissolved in 4MHQ.dioxane (1.0 mL) and the solution was stirred at room temp for 2 hours. The solvent WELS removed under reduced pressure, the residue was dissolved in DCM and Et20 was added. Some precipitate formed, it was filtered and wash with Et20 to afford 60 mg (74%) of compound 5 (purity 95%). Compound 5 (0,05g) was suspended in DCM (1.5 mL) and 0-1 mL of NEts was added. The solution became homogeneous. The mixture was stirred for 12 hours at room temperature and some precipitate was formed. Et20 was added and some additional precipitate was formed. After filtration, 38 mg (57%) of compound 6 were collected (purity 99%). Example 8: Experimental Protocol for Apo-B/ApoAl Assay The following protocol is written for HepG2 cells types, hut the same or similar protocol may be used with other cell types, such as Caco-2 cells. HepG2 cells were grown in MEM Eagle's medium containing 10% fetal bovine serum with 1% penicillin/streptomycin in an incubator (5% CO2, 100% relative humidity, 37 °C). At ca, 85% confluency, the cells were treated with test compounds (0 J2 % DMSO) at appropriate conceatrations in triplicate, Aiter 24 hour iacubation witii the test compotmds, growth media were collected from each sample. Concentrations fox apo-B and apoAl were determined using ELISA. Mouse anti-human Apo-B and ApoAl antibody and Alk-phos conjugated secondary antibody (goat) was used in ELISA. Triplicate data in six half-log concentrations were used to calculate an IC50 value for each compound. Cellular Actmtv The following table (Table 1) depicts the activity of several compounds of Formula I ox n according to the present invention. Permeability was measured in a bidirectional Caco-2 assay with analysis by fluorescence and HPLC. Componnd Characterizatjon Compound 15 HPLC shows a retention time of 9.351 minutes with a Cie column and 5-95% acetonitrile gradient over 10 minutes. High resolution mass spectrometry shows an (M+Na) peak consistent with the molecular weight ^H and ^"^C NMR spectroscopy are consistent with the chemical structure. Compound 6 HPLC shows a retention time of 8.996 minutes with a C}6 column and 5-95% acetonitrile gradient over 10 minutes. High resolution mass spectrometry shows an (M+H)"" peak consistent with the molecular weight. 'H NMR spectroscopy is tonsistent with the chemical structure. Other compounds were characterized by H NMR and ^ C NMR, mass spectroscopy, and HPLC, and were consistent with analytical data. The MTP inhibitors of the invention exhibit selective inhibition activity towards HepG2-ApoBl that is associated with the VLDL lipoproteins secreted by the intestine while remaining inert towards HepG2-ApoAl, which is related-to HDL (Table 1). One desired characteristic of a compound is the combination of permeability as shown in the Caco-2 peimeability assay and cellular activity as shown in the HepG2 and Caco-2 ApoB assays. These assays indicate that the compounds of the invrntion exhibit selective permeability. Such selective permeability may result in these compounds having the ability to permeate the intestinal membrane, but not cross it, which is expected to minimize side effects. The MTP inhibitor conq>ounds of the iQvention are expected to exhibit selective activity in the intestine without exhibiting undesirable systemic exposure, when administered orally. One skilled in the art would understand that, despite the full description provided herein, the present invention can be performed within a wide and equivalent range of conditions, formulations, and other paramet^s without affecting the scope of the invention or any embodiment thereof Additional embodiments are within the scope of the appended claims. The contents of any patents, patent applications, or other references cited in this specification are hereby incorporated by reference in their entireties. What is claimed is: 1. A coir5>oimd represeated by Formula I: wherein R] is alkyl, R4R5NC(0)CH2, cycloalkyl, heteorocyclyl, or heterocyclylalkyl; Xy is a direct bond, O, S, -N(R6)-, C(0)NR6, or N(R6)C(0); . X2 is O, -N(ru)-, or S; X3 is.a direct bond, O, "N(R6)-> -CH2-, arylene, or S; R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryi, hetCToalkyl, axaDcyl, alkylcarbonyl, alkoxycarbonyl, aiylcarbonyl, aryloxycarbonyl, -OH, alkoxy, aryloxy, -SH, thioalkyl, fhioaryl, orNR4R5; R4 and R5 are, independently for each occurrence, H, alkyl, cycloaHcyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyi, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, 01 ar>ioxycarbonyl; R^ is, independraitly for each occurrence, H or alkyl; mis 0 or 1; and n is an ioteger from 0 to 3; provided that if m is 0, X3 is a direct bond or CH2; or a phaimacentically accq)table salt, solvate, ester or hydrate thereof. 2. The compound of claim 1, wherein Xj is O. 3. The compound of claim 1, wherein R1 is alkyl. 4. The compound of claim 3, wherein R1 is methyl. 5. The compound of claim 1, wherein R1 and Xi taken togetiaer form a moiety selected from the group consistiag of: 6. The compound of claim 1, wherein R1 and Xi taken together form CH3-O-. 7. The compound of claim 11, wherein R3 is xmsubstituted or substitiited phenyl. 8. The compoimd of claim 1, Wherein the moiety represents one of the following groups: 9. wherein Rn is selected from the group consisting of; and wherein R12 is selected from the group consisting of: and phaimaceutically acceptable salts, esters, isomers, and hydrates thereof. 10. The compoimd of claim 9, wherein R] 1 is —OCH3. 11. The compound of claim 9, wherein Ru is not H. 12. A pharmaceutica] composition compR1sing a componnd of any one of claims 1-11 and a phannaceutically acceptable carR1er, 13. The pharmaceutical composition of claim 12 further compR1sing an additional Hpid- loweR1ng agent 14. A method of treating or preventiag a condition selected from the group consisting of attierosclerosis, pancreatitis, obesity, hypercholesteremia, hypertR1glyceR1demia, hyperlipidemia. and diabetes, compR1sing administeR1ng to a subject in need of such treatment an effective amount of a compound of any one of claims 1-11, such tiiat the condition is treated or prevented. 15. The method of claim 14, wherein said condition is selected from atherosclerosis, pancreatitis, obesity, and diabetes. 16: The method as defined in claim 14, wherein said condition is atherosclerosis. 17. A method of decreasing apo-B secretion in a subject, compR1sing administeR1ng to said subject an apo-B secretion decreasing amount of a compound of any one of claims 1-11. 18. A kit compR1sing an effective amount of a compound of any one of claims 1 -11 in unit dosage form, together with instructions for administeR1ng the compound to a subject suffeR1ng from or susceptible to a disease or condition in which apo B, serum cholesterol, and/or tR1glyceR1de levels are elevated.

Full Text

INHIBITORS OF MICROSOMAJL TRIGLYCERIDE TRANSFER
PROTEIN AND APO-B SECRETION
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. provisional patent application nos. 60/672,778, filed April 19,2005, and 60/755,390, filed December 30, 2005. The contents of each of these applications are incorporated herein by reference in their entireties.
FIELD OF THE INVENTION
The present invention relates to compotmds which are inhibitors of microsomal triglyceride transfer protein and/or apolipoproteia B (Apo B) secretion. These compotmds can be useful for the prevention and treatment of various diseases, particularly atherosclerosis and its clinical sequelae, for lowering serum lipids, and related ailments. The invention further relates to pharmaceutical compositions comprising the compounds and to methods of treating diseases, such as hypertriglyceridemia, hyperchylomicronemia, atherosclerosis, obesity, and related conditions using the compounds. A method for decreasing apoHpoproteia B (apo B) secretion is also provided.
BACKGROUND OF THE INVENTION J/ficrosomal triglyceride transfer protein (MTP) catalyzes the transport of triglyceride, cholesteryl ester, and phosphoUpids, MTP has been identified as an agent that may be involved in the assembly of Apo B-containing lipoproteins and biomolecules that contribute to the formation of atherosclCTotic lesions. Compounds that can inhibit MTP and/or inhibit Apo B secretion can be useful in the treatment of atherosclerosis and related diseases (see, e.g., U.S. Patent No. 5,919,795, incorporated herein by reference). These compounds are also useful in the treating diseases or conditions in which, by inhibiting MTP and/or Apo B secretion, serum cholesterol and triglyceride levels are reduced. Examples of tbese diseases or conditions include hypertriglyceridania, hypercholesterolemia, pancreatits, and obesity; and hyperchylomicronemia and hyperhpidemla associated with pancreatitis, obesity, and diabetes.
Therefore, th^e is a need for compounds that inhibit MTP that are effective in treating diseases or conditions, such as atherosclerosis and related diseases, and/or can provide an effective lowering of serum apo B in mammals or humans.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds of Formula I:

wherein
Ri is alkyl (optionally substituted, e.g., with one to three substituents, e.g., halogen, amino, or alkoxy groups), R4R5NC(0)CH2, cycloalkyl, heterocyclyl, or heterocyclylalkyl;
Xi is a direct bond, 0, S, -N(R6)-, C(0)NR6, or N(R6)C(0);
X2 is O, -N(R^)-, or S;
X3 is a direct bond, O, -N(R6)-, -CH2-, arylene, or S;
R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyl, alkylcaibonyL, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, -OH, aDcoxy, aryloxy, -SH, tfaioalkyl, thioaryl, or NR4R5;
R4 and Rs are, independently for each occurrence, H, alkyl, cycloaDcyl, heterocyclyl, arjd, heteroaryl, heteroalkyl, aralkyl^ aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, or aryloxycarbonyl;
Re is, independently for each occurrence, H or alkyl;
misO or 1; and
n is an integer fiom 0 to 3;
provided that if m is 0, X3 is a direct bond or CH2; or apharmaceutically acceptable salt, solvate, ester or hydrate thereof.
In certain preferred embodiments, Xi is 0. In certain preferred embodiments, Ri is alkyl, more preferably methyl, ethyl, or isopropyl. In certain preferred embodiments, Ri and Xi taken together form a moiety selected from the group consisting of:

and Xi taken together fonn CH3-O-.
In c^ain prefeared embodiments, m is 1. In certain preferred embodimeatSa when m is 1, X3 is O or NH. In certain preferred ranbodiments, n is 0,1 or 2. In certain preferred embodim^its, R3 is aryl, more preferably unsubstituted or substituted phenyl. In other preferred embodiments, R3 is cycloallcyl, heterocyclyl, heteroaryi, or allcoxy. In certain preferred embodiments, the moiety

In another embodimmt, the invention provides compomids reptesented by Formula II:

and pharmaceutically acceptable salts, esters, isom^ aad hydrates thereof.
In one embodiment, the present invention is drawn to a pharmaceutical composition comprising a compound of Formula I or n and a pharmaceutically acceptable carrier.
The compounds of Fomiula I or II, or a composition comprising a conapound of Formula I or n, can be used for treating a variety of diseases or conditions including, but not limited to, hypertri^yceridemia, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hyperchylomicroneiDia, hyperlipidemia, and diabetes.
Furthermore, a method for treating or preventing such a disease or condition, such as atherosclerosis and related conditions, in a subject (e.g., a mammal including a human), is provided'in accordance with the present invention. The method comprises administering to a subject (e.g., a mammal iacluding a human) in need of such a treatment, an effective amount of a compound of Formula I or II, such that the disease or condition is treated or prevented.
The present invention also provides a method of decreasing apo B secretion in a subject (e.g., a mammal or a human), comprising administering to said subject a compound of Formula I or n, or a phannaceutical composition comprising a compound of Formula I or II, in an amount sufficient to decrease the levels or amount of secretion of apo B in the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a depiction of the proton NMR of a MTP inhibitor of the present invention (compound 6).
Figi2re 2 is a depiction of the mass spectrum of a MTP inhibitor of the present invention (compound 6).
Figure 3 is a depiction of the proton NMR of a MTP inhibitor of the present invention (compound 15).
Figure 4 is a depiction of the ^^Carbon-NMR of a MTP inhibitor of the present invention (compound 15).
Figure 5 is a depiction of the mass spectrum of a MTP inhibitor of the present invention (compound 15).

DETAILED DESCRIPTION
In one aspect, the present invention provides compounds. In one embodiment, the compounds are represented by Formula I:

whCT'ein
Ri is alkyi (optionally substituted, e.g., with one to teee substituents, e,g., halogen, amino, or alkoxy groups), R4R5NC(0)CH2, cycloaUcyl, beterocyclyl, or beterocyclylalkyl;
Xi is a direct bond, O, S, -NCRe)-, C(0)NR6, orN(R6)C(0);
X2 is O, -N(R6>, or S;
X3 is a direct bond, O, -N(R^)-, -CH2", arylene, or S;
R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaxyl, heteroalkyl, aralkyl, alkylcarbonyl, alkoxycarbonyL, arylcarbonyl, aryloxycarbonyl, -OH, alkoxy, aryloxy, -SH, thioalkyl, thioaryl, orNR4R5;
R4 and R5 are, indepeodently for each occurrence, H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyl, aminocarbonyl, alkylcaibonyl, aJkoxycaibonyl, arylcarbonyl, or aryloxycarbonyl;
R^ is, indq>endently for each occurrence, H or alkyl;
m is 0 or 1; and
n is an integer frova 0 to 3;
provided that if m is 0, X3 is a direct bond or CH2; or a pharmaceutically acceptable salt, solvate, ester or hydrate thereof
III certain preferred raabodiments, Xi is O. In certain preferred anbodiments, Ri is alkyl, more preferably methyl. In certain preferred embodim^its, Ri and Xi taken together foim a moiety selected from the group consisting of;

and Xi taken togetiaer form CH3-O-.
In certain preferred embodiments, m is 1. In certain preferred embodiments, when m is 1, X3 is O or NH. In certain preferred embodiments, n is 0,1 or 2. In certain preferred embodiments, R3 is aryl, more preferably unsubstituted or substituted pbCTiyi- In other preferred embodiments, R3 is cycloalkyl, heterocyclyl, heteroaryl, or alkoxy. la cratain prefeaxed embodiments, the moiety

in which Ar is optionally substituted aryl or optionally substituted heteroaryl; Cy is optionally substituted cycloaDcyl or optionally substituted heterocyclyl; Alk is optionally substituted alkyl; n is 0-3; and p is 1-3. In certain preferred embodiments, n is 0 or 1. In certain preferred embodiments, Ar is optionally substituted phenyl or optionally substituted furan-2-yl; Cy is optionally substituted cyclopropyl or tetrahydrofuran-2-yl; and Alk is methyl, ethyl, or isopropyl.

and phaxmaceutically acceptable salts, esters, isomers, or hydrate thereof.
In certain preferred CTabodiments, Ru is —OCH3. In certain preferred embodiments, Rn is not H.
Among the more preferred compoirnds of Foimnla I and/or II of the present invention are the following compounds:

and pharmaceutically acceptable salts, estars, isomer and hydrates thereof.
As tised hCTein, tiie term '"alkyl" means a saturated straight chain or branched non-cyclic hydrocarboii typically having from 1 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-. hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2- methylbutyl, 3-methylbutyl, Z-methylpeat^d, 3-methy]pentyl, 4-methylpentyl, 2- methylhexyl, 3-methylhexyl, 4-metiiylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3- dimethylpentyl, 2, 4-dunethylpentyl, 2, 3-dimethylhex>d, 2,4-dimethylhKcyl, 2, 5-dimetiiylhexyl, 2,2-dimethylpentyl, 2, 2-dimethylhexyl, 3, 3-dimethylpCTityl, 3, 3-dimethylh^yl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethyIhexyl, 3- ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl- 4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-mefhyl-3-ethylhexyl, 2-methyl-4- ethylhexyl, 2,2-diethylpeaityl, 3, 3-diethylhexyl, 2, 2-diethylhexyl, 3,3-diethylhexyl and the like. Alkyl groi5>s included in

compounds of this invention may be optionally substituted with one or more substituents (preferably one to three substituents), such as amino OSIH2), Ci-Ce alkylamiuo, CrQ, dialiylamino, arylamino, diarylamino, heterocyclylamino, (Ci-Cg al3cyl)caxbanyl2mino, Ci-Ce alkoxy, Cj-Ce alkylthio, 0x0, =S, halo (includiug F, CI, Br, and I), nitro, hydroxyl, cyano, aiyl, heteroaryl, aryloxy, arylthio, caibocyclyl, carbocyclyloxy, carbocyclylthio, caibocyclylamino, het^ocyclyl, heterocyclyloxy, heterocyclyltiiio, and the like. Lower alkyls (having from 1 to 6 carbon atoms in the alkyl chain) are typically preferred for the compounds of this iavention.
The term "cycloalkyr, as used herein, refers to a cyclic alkyl group having from 3 to 10 carbon atoms ia the ring, more preferably 3-6 carbon atoms to the riag. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopeatyl, and cyclohexyl. Cycloalkyls maybe substituted by one or more substituents (e.g., one to three substituents) as described above for alkyl groups.
As used herein, the term "heterocycle" or '"heterocyclyl" means a monocyclic or polycyclic heterocyclic ring (typically having 3- to 14-members) which is either a saturated ring or a unsaturated non-aromatic ring. A 3-membered heterocycle can contain up to 3 heteroatoms, and a 4- to 14-membered heterocycle can contain from 1 to about 8 heteroatoms. Each hetCToatom is independently selected from nitrogen, which can be quatemized; oxygen; and sulibr, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomoipholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyiindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to tiiose of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl maybe optionally substituted with one or more substituents, e.g., one to three substituents (including without limitation a halogen atom, an aDcyl radical, or aryl radical). Only stable isomers of such substituted heterocyclic groups are contemplated in this definition. Heterocyclyl groups can be substituted or unsubstituted.
As used herein, the term an "aromatic ring" or "aiyl" means a monocychc or polycycHc-aromatic ring or ring radical comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthacraiyl, fluorenyl, indenyl, azulenyl, and naphtiiyl, as well as benzo-fiised carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyL An aryl group can be unsubstituted or, optionally, substituted with one or more substituents, e.g., one to three substituents (including without limitation aDcyl (preferably, lower aBcyl or alkyl

substituted with one or more halo), hydroxy, alkoxy preferably, lower alkoxy), alkylthio, cyano, halo, amino, and nitro. In certain embodiments, fee aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms.
As used herein, the term "heteroaromatic" or "heteroaryl" means a monocyclic or polycychc heteroaromatic ring (or radical thereof) comprising carbon atom ring members and one or more heteroatom ring members (such as, for example, oxygen, sulfur or nitrogen). Typically, the heteroaromatic ring has from 5 to about 14 ring members in which at least 1 ring member is a heteroatom selected from oxygen, sulfur and nitrogra.. In another embodimCTt, the heteroaromatic ring is a 5- or 6- membered ring and may contain from 1 to about 4 heteroatoms. In another embodiment, the heteroaromatic ring system has a 7 to 14 ring members and may contaxQ from 1 to about 7 heteroatoms. Representative heteroaryls include pyridyl, ftuyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, mdoUzdnyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazmyl, pjoimidiayl, pyrazinyl, triazmyl, triazolyl, pyridinyl, thiadiazolyl, pyrazinyl, quinolyl, isoqnniolyl, inda2X)lyl, benzoxazolyl, benzofuryl, benzothiazolyl, indolizinyl, imidazopyridinyl, isothiazolyl, tetrazolyl, ben^imidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, qunizaolinyl, purinyl, pynolo[2,3]pyrimidyl, pyrazolo[3,4]pyrimidyl or b^izo(b)thienyl and the hke. These heteroaryl groups may be optionally substituted with one or more substituents, e.g., one to three substituents as described for aryl groups.
As used herein, the term "halogen" or "halo" means -F, -CI, -Br or -I.
The term "alkylene," as used herein, refers to an alkyl group that has two points of attachment to two moieties (e.g., {-CH2-}, -{CH2CH2"},

, etc., wherein the brackets indicate the points of attaclnnent). Alkylene groups may be nnsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described for alkyl groups. Exemplary alkylene groups include methylene, ethylene, and propylene.
The term "arylene," as used herein, refers to an aryl or heteroaryl group that has two points of attachment to two moieties. Arylene groups may be unsubstituted or optionally

substituted with one or more substituCTits, e.g., 1-3 substituents as described for aUcyl groups. Exemplary arylene groups include phenyH,2-diyl, pheayl-13-diyl, andpheaayl-l,4-diyl-; thiazol-2,4-diyl, and the like.
The tenn "aralkyl", as used hereiu, refers to an aryl group that is attached to another moiety via an alkylene liaker. Aralkyl groups may be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described for altyl groups.
The torn "heterocyclylalkyl," as used herdn, refers to a heterocycljd group tiiat is attached to another moiety via an alkyleae linker. Heterocyclylalkyl groups may be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described for alkyl groups.
The term "alkylcarbonyl," as used herein, refers to the group -C{0)-aIkyl. The alkyl portion of the alkylcarbonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1*3 substituents as described above for alkyl groups.
The term "alkoxycaxbonyl," as used herein, refers to the group -C(0)-0-aIkyL The alkyl portion of the alkoxycaibonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups.
The term "arylcaibonyl," as used herein, refers to the group -C(0)"aryl or-C(O)-heteroaryl. The aryl or heteroaryl portion of the axylcarbonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for aUcyl groups.
The term "aryloxycarbonyl," as used herein, refers to the group -C(0)-0-aryl OT-C(0)-O-heteroaryL The aryl or heteroaryl portion of the aryloxycarbonyl moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups.
The term "aminocarbonyl," as used herein, refers to the groups -C(0)-l The term "alkoxy," as used herein, refers to the group -O-alkyl. The alkyl portion of the alkoxy moiety can be unsubstituted or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups.

The term "aryloxy," as used herein, refers to the grou^j -0-aryI or-Oheteroaryl. The aryl or heteroaryl portion of the aryloxy moiety can be unsubstitated or optionally substituted with one or more substiturats, e.g., 1-3 substitumts as described above for alkyl gror5)S.
The term "thioalkoxy," as used herein, refers to tiie group -S-aUcyl The alkyl portion of the thioalkoxy moiety can be unsubstitated or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl groups.
The term "thioaryloxy," as used herein, refers to tiie group -S-aryl or -S-heteroaryl. The aryl or heteroaryl portion of the thioaryloxy moiety canbe unsubstitated or optionally substituted with one or more substituents, e.g., 1-3 substituents as described above for alkyl
groups.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula I or II and a phaimaceutically acceptable carrier.
The compounds of Formula I or n or compositions comprising the compounds of Formula I or H can be used for treating a variety of diseases or conditions includingj but not limited to, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hypertriglyceridCTcda, hyperhpidemia, and diabetes.
Furthermore, a method for treating such a disease or condition, such as atiierosclerosis and related conditions, in a mammal or a human, is provided in accordance with the present invention. The method comprises administering to a subject (e.g., a mammal, including a human) in need of such a treatment an effective amount of a compound of Formula I or II, or a pharmaceutical composition comprising an effective amount of a compound of Formula I or II, such that the disease or condition is treated. In certain embodiments, the compound is administered in an amount sufficient to decrease the secretion of apoUpoprotein B.
The present invention also provides for a method of decreasing ^o B secretion in a mammal or human, comprising administering to a mammal or a human of a compound of Formula I or H, or a pharmaceutical composition comprising a compound of Formula I or II, in an amount sufficient to decrease the levels or amount of secretion of apo B.
The invention further provides a pharmaceutical composition suitable for the treatment of conditions including hypertriglyceridemia, atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hyperchylomicronemia, hyperlipidemia, and diabetes, comprising a compound of Formula I or 11 as hereinbefore defined, and a pharmaceutically acceptable carrier.
The compounds of this invention inhibit or decrease apo B secretion, likely by the inhibition of MTF, although it may be possible that other mechanisms are involved as well. The compounds are useful in any of the diseases or conditions in which apo B, serum cholesterol.

and/or triglyceride levels are elevated. Accordingly, the invention further provides a metiiod of treating a condition selected from hypextri^yceridemia, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hyperchylomicronsmia, hyperlipidemia, and diabetes, comprising administering to a mammal, especially a human, in need of such treatmrat an amoimt of a compound of Fonmila I or H as defined above sufficient to decrease tiie secretion of
apolipoproteinB.
The t^m "treating" as used herein includes preventative as well as disease remitative
treatment
The invention further provides a method of decreasing apo B secretion in a mammal, especially a human, comprising administering to said mammal an apo B"(secTetion) decreasing amoimt of a compound of Formula I or n as defined above.
The invention also provides kits for treatment or prevention of diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated. Accordingly, the invention finther provides provides kits for treatment or prevention of a condition selected from -hypertriglyceridemia, atherosclerosis, pancreatitis, obesity, hypercholesteremia, hyperchylomicronemias hyperlipidemia, and diabetes. In one embodiment, the kit includes an effective amount of a compound of this invention (e.g., a compound of Formula I or Formula 11) in unit dosage form, together with instructions for administering the compound to a subject sufimng from or susceptible to diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated (including witiiout limitation hypertriglyceridemia, atherosclerosis, pancreatitLs, obesity, hypercholesteremia, hyperchylomicronemia, hyperlipidemia, and diabetes), preferably wherein the effective amount of compound is less than 1000 mg (more preferably less than 500 mg) of the con:q)Ound,
In preferred embodiments, the kit comprises a sterile container whidi contains the compound; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister-packs, or other suitable container form known in the art. Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holdiag medicaments.
The instructions will generally include information about the use of the compound for treatment or prevention of diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated (including without limitation hypertriglyceridemia, atherosclerosis, pancreatitis, obesity, hypercholestK:^niia, hyperchylomicronemia, hyperlipidemia, and diabetes); in preferred embodiments, the instructions include at least one of the following: description of the compound; dosage schedule and administration for treatment of diseases or conditions in which apo B, serum cholesterol, and/or triglyceride levels are elevated;

€
precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references. The instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
In another aspect, the presait invention provides intamediate compounds that are useful for the synthesis of the MTP inhibitor compounds of the invention. Examples of such intermediate cornpounds include compounds of structure 20, in which Ri and Xi have the meanings described in connection with Formula I or U, and R7 is selected from the group consisting of OH, 0-Cat (in which Cat is a cation (e.g., a proton, a metal cation such as sodium, lithium, potassium, calcium, ammonium, and the like)), a Ci - Ce alkoxy group, and a leaving group (including a halogen such as chloride or bromide, a tosylate or mesylate, a pentafhiorophenol, and ttie like).

In a preferred embodiment of a compoimd of stracture 20, Ri together wiQi Xi forms a CH3O groiq), and R7=OH.
The present invention also provides iutermediates useful in the preparation of compounds of Formula I or Formula n. A preferred intermediate compound of the present invention is described by structure 2 shown below.

It will be appreciated by those skilled in the art that certain compounds of Formula I or n may contain an asymmetrically substituted carbon atom and accordingly may exist in, and be

isolated in, optically-active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encon^passes any racemic, optically^active, polymoiphic or stereoisomeric form, or mixtures Hi&reof, which form possesses pToperties useful in tiie treatment of atherosclerosis, obesity, and the other conditions noted herein, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to detennine efiScacy for the treatment of the conditions noted herein by the standard tests described heremafter.
The chemist of ordinary skill will recognize that certain combinations of substitueats or moieties hsted in this inv^ition define compoimds which will be less stable under physiological conditions (e.g., those containing amTn^l or acetal linkages). Accordingly, such compounds are less preferred.
■ The present invention furtha: provides a method of forming the compomids of Formula I or U of the present invention by a synthetic process. Compounds of Formula I or H can also be made by processes which include processes known in the chennical arts for the production of similar compounds. Such processes for the manufacture of a compound of Formula I or II as defined above are provided as further features of the invention and are illustrated by the procedures discussed below.
ConvKitional methods and/or techniques of purification and separation known to those skilled in tiie art can be xised to isolate the compounds of this invention. Such techniques include aU types of chromatography (HPLC, column chromatography using common adsorbents such as silica geL and thin layer chromatography), recrystallization, and differential (i.e., Hquid-hquid) extraction techniques.
The compounds hereui forai cationic salts such as acid addition salts and the expression "pharmaceutically-acceptable salts" is intended to define but not be hmited to such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, benzoate, ascorbate, lactate, pamoate, tartrate, methauesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. For many compounds polyaddition salts are feasible.
The acid addition salts of the compounds of the present invention are readily prepared by reacting the base forms with the appropriate acid. "When the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogCTi form of a tribasic acid

(e.g., the dihydrogeai phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However, w:hen such salts as the sulfate, the hemisuccinate, the hydrogKi phosphate or the phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base and the acid axe usually combined in a co-solveot from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent
In certain embodiments, the term "phaimaceutically acceptable salt," as used herein, can refer to a salt prepared from a compound of Formula I or n having an acidic functional group, such as a carboxyhc acid functional group, and apharmaceulically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such ELS sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substitated mono-, di-, or trialkylaraines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyefhyl)- amine, 2-hydroxy-tCTt-butylamine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower altyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)- amine/or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like,
A representative general synthetic route for the MTP inhibitor compounds of Formula I or n of the present invention is exemplified in Scheme 1, which shows the synthesis of compound 6. The individual reaction steps involved in the synthetic process are subsequently described in greater detail (see Examples 1-7).

Qfz
OTf 0
N^^='5>'^\-^ 74% Me^
H
4
l!^ 98% , 1^ 20% Me"""

95% /O
over two steps Me
•OH O

The compouBds of the present invention are orally administrable and are accordingly used in combination with a phaimaceutically acceptable carrier or diluent suitable to oral dosage forms. Suitable pharmaceuticaUy-acceptable carriers include inert solid fillcErs or diluents and sterile aqueous or organic solutions. The active compound will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described below. Thiis, for oral administration the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
The tablets, piUs, capsules, and the like may also contain a binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as . magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit For instance, tablets may be coated with shellac, sugar or both. A syrap or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
These active compounds may also be administered parenterally. For parenteral administration the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Solutions or suspensions of these active compoimds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrroHdone and mixtures thereof in oils as well as aqueous solutions of

water-soluble pharmaceutically acceptable salts of the compounds. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or iatramuscxdarly.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extraiporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syingabihty exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminatnig action of microorganisnis such as bacteria and fimgi.
The dose of a compound of Formula I or 11 which is administered will goaerally be varied according to principles well known in the art taldng into accoimt the severity of the condition being treated and the route of administration. In general, a compound of Formula I or n will be administered to a warm blooded animal (such as a human) so that an effective dose, usually a daily dose administered in unitary or divided portions, is received, for example a dose in the range of about 0.1 to about 15 mg/kg body weight, preferably about 1 to about 5 mg/kg body weight. The total daily dose received will generally be between 1 and 1200 mg, preferably between 5 and 800 mg. In certain preferred embodiments, a compoimd of Formula I or IT may be administered in divided doses taken with meals, e.g., three times daily, in which case each dose can be, e.g., between 5 and 500 mg.
The compounds of this invention may be used in conjunction with other pharmaceutical agents, including other lipid lowering agents. Such agents include cholesterol biosynthesis inhibitors,- especially HMG CoA reductase inhibitors (such as atorvastatin, pravastatin, simvastatin, lovastatin, fluvastatin, cerivastatin, rosuvastatin, and pitivastatin (itavastatin/risivastatin)); squalene synflietase inhibitors; bile acid sequestrants such as cholestyramine; fibrates (bezafibrate, clofibrate, fenofibrate); cholesterol absorption inhibitors such as ezetimibe and pamaqueside; and niacin.
A test compound is considered to be active if it is active in any of the following screens. The activity of a compound according to the invention can be assessed by measuring inhibition of apo B secretion in HepG2 cells.
Activity can also be confirmed if a test compound inhibits MTP activity directly. Inhibition of MTP activity by a compound can be quantitated by observing the inhibition of transfer of radiolabeled triglyceride from donor vesicles to acceptor vesicles in the presence of soluble human MTP.

The present invention is illustrated by the following Examples. However, it should be understood that the invention is not limited to the specific details of these examples.

Amixture of phaiol (1.82g) andtrifluoromethaQesulfonyl (l.OSeq) anhydride in anhydrous pyridine (IM) was stirred at 0 ^C and then slowly warmed up to 15 °C overnight Water was added to the mixture, which then was extracted three times with EtjO. The organic layer was washed with brine and dried over Na2S04. The solvent was removed under reduced pressure and the crude was passed through a plug of siHca gel to afford 3.07g (98%) of the triflate (purity 98%).

The triflate (1.3g) was dissolved in 25 mL of DME (0.16M) and the boronic acid (0.64g, O.Seq), K2CO3 (0.85g, L49mmol) and Pda2dppf-DCM (0.02eq) were added. The mixture was refluxed over night In the morning all the reagents were added to reach 1.05eq of boronic acid.

2.0eq of K2CO3 and 0.03eq of catalyst The mixture was heated for additional 5 hours, and then water (S.Oeq) was added. After 18 hours, the reaction mixture was diluted with Et20, and it was filtered through a sihca gel plug column and eluted with Et20. No separation of impurities from product occiuxed. The organic phase was washed wife a solution of citric acid (10%), 2Xbrine and dried over NaaSOA. The solvent was removed unda: reduced pressure. The residue was dissolved in MeOH, water was added and some precipitate was formed. The solid was collected, washed with hexanes, dissolved in DCM and crystallized again with hexanes. The solid was isolated (0.26g, pure 97.5% by HPLC)

Compound 1 (0.26g) was dissolved in THF (2.0 mL) and LiOH'HzO (4.8eq) was added ru 1.0 mL of water. After stirring the mixture at room temp, MeOH was added to. have a homogenous solution. The mixture was heated at 50°C overnight The solvent was removed imder reduced pressure, the residue was dissolved in DCM and washed with IN HCl and brine. The organic phase was dried over NaaSOA and the removal of the solvent by reduced pressure afforded 0,22g (88%) of compound 2 (purity 98%).

Compouad 2 (0.21 g) was suspended in DCM (3.0 mL) and the solution was cooled to 0°C. Oxalyl chloride (1.6eq) was added dropwise followed by the addition of catalytic amount of DMF. The mixture was stiired at 0°C for 30 minutes, th^ at room temperature for 1.5 hours. The solution became clear. The solvent was removed under reduced pressure. The crude was used from the next reaction without further purification.

Compound 3 was dissolved in THF (2.0 nxL) and a solution of N-Boc-tetrahydroisoquinoline in 2.QmL of THF was added dropwise (some precipitate formed) followed by the addition of NEts. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the crude was purified through sihca gel column chromatography (EtOAc/Hexanes 0-30%). The product was not clean at this point The product was washed with Et20 to give (0.36g) of compound 4 (purity 99%).

Example 6: Removal of Boc Protecting Group

Compound 4 (O.lg) was dissolved in 4MHQ.dioxane (1.0 mL) and the solution was stirred at room temp for 2 hours. The solvent WELS removed under reduced pressure, the residue was dissolved in DCM and Et20 was added. Some precipitate formed, it was filtered and wash with Et20 to afford 60 mg (74%) of compound 5 (purity 95%).

Compound 5 (0,05g) was suspended in DCM (1.5 mL) and 0-1 mL of NEts was added. The solution became homogeneous. The mixture was stirred for 12 hours at room temperature and some precipitate was formed. Et20 was added and some additional precipitate was formed. After filtration, 38 mg (57%) of compound 6 were collected (purity 99%).
Example 8: Experimental Protocol for Apo-B/ApoAl Assay
The following protocol is written for HepG2 cells types, hut the same or similar protocol may be used with other cell types, such as Caco-2 cells.
HepG2 cells were grown in MEM Eagle's medium containing 10% fetal bovine serum with 1% penicillin/streptomycin in an incubator (5% CO2, 100% relative humidity, 37 °C). At ca, 85% confluency, the cells were treated with test compounds (0 J2 % DMSO) at appropriate

conceatrations in triplicate, Aiter 24 hour iacubation witii the test compotmds, growth media were collected from each sample. Concentrations fox apo-B and apoAl were determined using ELISA. Mouse anti-human Apo-B and ApoAl antibody and Alk-phos conjugated secondary antibody (goat) was used in ELISA. Triplicate data in six half-log concentrations were used to calculate an IC50 value for each compound.
Cellular Actmtv
The following table (Table 1) depicts the activity of several compounds of Formula I ox n according to the present invention. Permeability was measured in a bidirectional Caco-2 assay with analysis by fluorescence and HPLC.

Componnd Characterizatjon
Compound 15
HPLC shows a retention time of 9.351 minutes with a Cie column and 5-95% acetonitrile gradient over 10 minutes. High resolution mass spectrometry shows an (M+Na) peak consistent with the molecular weight ^H and ^"^C NMR spectroscopy are consistent with the chemical structure.
Compound 6
HPLC shows a retention time of 8.996 minutes with a C}6 column and 5-95% acetonitrile gradient over 10 minutes. High resolution mass spectrometry shows an (M+H)"*" peak consistent with the molecular weight. 'H NMR spectroscopy is tonsistent with the chemical structure.
Other compounds were characterized by H NMR and ^ C NMR, mass spectroscopy, and HPLC, and were consistent with analytical data.
The MTP inhibitors of the invention exhibit selective inhibition activity towards HepG2-ApoBl that is associated with the VLDL lipoproteins secreted by the intestine while remaining

inert towards HepG2-ApoAl, which is related-to HDL (Table 1). One desired characteristic of a compound is the combination of permeability as shown in the Caco-2 peimeability assay and cellular activity as shown in the HepG2 and Caco-2 ApoB assays. These assays indicate that the compounds of the invrntion exhibit selective permeability. Such selective permeability may result in these compounds having the ability to permeate the intestinal membrane, but not cross it, which is expected to minimize side effects. The MTP inhibitor conq>ounds of the iQvention are expected to exhibit selective activity in the intestine without exhibiting undesirable systemic exposure, when administered orally.
One skilled in the art would understand that, despite the full description provided herein, the present invention can be performed within a wide and equivalent range of conditions, formulations, and other paramet^s without affecting the scope of the invention or any embodiment thereof Additional embodiments are within the scope of the appended claims.
The contents of any patents, patent applications, or other references cited in this specification are hereby incorporated by reference in their entireties.

What is claimed is:
1. A coir5>oimd represeated by Formula I:

wherein
R] is alkyl, R4R5NC(0)CH2, cycloalkyl, heteorocyclyl, or heterocyclylalkyl;
Xy is a direct bond, O, S, -N(R6)-, C(0)NR6, or N(R6)C(0); . X2 is O, -N(ru)-, or S;
X3 is.a direct bond, O, "N(R6)-> -CH2-, arylene, or S;
R3 is H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryi, hetCToalkyl, axaDcyl, alkylcarbonyl, alkoxycarbonyl, aiylcarbonyl, aryloxycarbonyl, -OH, alkoxy, aryloxy, -SH, thioalkyl, fhioaryl, orNR4R5;
R4 and R5 are, independently for each occurrence, H, alkyl, cycloaHcyl, heterocyclyl, aryl, heteroaryl, heteroalkyl, aralkyi, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, 01 ar>ioxycarbonyl;
R^ is, independraitly for each occurrence, H or alkyl;
mis 0 or 1; and
n is an ioteger from 0 to 3;
provided that if m is 0, X3 is a direct bond or CH2; or a phaimacentically accq)table salt, solvate, ester or hydrate thereof.
2. The compound of claim 1, wherein Xj is O.
3. The compound of claim 1, wherein R1 is alkyl.
4. The compound of claim 3, wherein R1 is methyl.
5. The compound of claim 1, wherein R1 and Xi taken togetiaer form a moiety selected from the group consistiag of:

6. The compound of claim 1, wherein R1 and Xi taken together form CH3-O-.
7. The compound of claim 11, wherein R3 is xmsubstituted or substitiited phenyl.
8. The compoimd of claim 1, Wherein the moiety

represents one of the following groups: 9.

wherein Rn is selected from the group consisting of;

and wherein R12 is selected from the group consisting of:

and phaimaceutically acceptable salts, esters, isomers, and hydrates thereof.
10. The compoimd of claim 9, wherein R] 1 is —OCH3.
11. The compound of claim 9, wherein Ru is not H.
12. A pharmaceutica] composition compR1sing a componnd of any one of claims 1-11 and a
phannaceutically acceptable carR1er,
13. The pharmaceutical composition of claim 12 further compR1sing an additional Hpid-
loweR1ng agent
14. A method of treating or preventiag a condition selected from the group consisting of
attierosclerosis, pancreatitis, obesity, hypercholesteremia, hypertR1glyceR1demia, hyperlipidemia.

and diabetes, compR1sing administeR1ng to a subject in need of such treatment an effective amount of a compound of any one of claims 1-11, such tiiat the condition is treated or prevented.
15. The method of claim 14, wherein said condition is selected from atherosclerosis, pancreatitis, obesity, and diabetes.
16: The method as defined in claim 14, wherein said condition is atherosclerosis.
17. A method of decreasing apo-B secretion in a subject, compR1sing administeR1ng to said
subject an apo-B secretion decreasing amount of a compound of any one of claims 1-11.
18. A kit compR1sing an effective amount of a compound of any one of claims 1 -11 in unit
dosage form, together with instructions for administeR1ng the compound to a subject suffeR1ng
from or susceptible to a disease or condition in which apo B, serum cholesterol, and/or
tR1glyceR1de levels are elevated.

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Patent Number

268459

Indian Patent Application Number

5224/CHENP/2007

PG Journal Number

36/2015

Publication Date

04-Sep-2015

Grant Date

31-Aug-2015

Date of Filing

19-Nov-2007

Name of Patentee

SURFACE LOGIX, INC

Applicant Address

50 SOLDIERS FIELD PLACE BRIGHTON, MA 02135

Inventors:

#	Inventor's Name	Inventor's Address
1	CAMPBELL, A. STEWART	4 SHEEHAN CIRCLE FRAMINGHAM MA 01701
2	YANG, YINGFEI	30 STEWART TERRACE BELMONT, MA 02478
3	BARTOLOZZI, ALESSANDRA	60 COLLEGE AVENUE APT. 3, SOMERVILLE MA 02144
4	FOUDOULAKIS, HOPE	16 ANDERSON ROAD FRAMINGHAM, MA 01701
5	KIM, ENOCH	24 MARLBOROUGH STREET UNIT 2, BOSTON MA 02116
6	SWEETNAM, PAUL	47 GREGORY STREET MARBLEHEAD, MA 01945

PCT International Classification Number

A61K 31/18

PCT International Application Number

PCT/US06/15146

PCT International Filing date

2006-04-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/755,390	2005-12-30	U.S.A.
2	60/672,778	2005-04-19	U.S.A.