TW201040174A - 4-amino-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one derivatives - Google Patents

Abstract

The invention provides compounds of Formula (Ia) or pharmaceutically acceptable salts thereof, as well as the preparation, compositions and uses thereof, where R1, R2, R3, and m are defined as described above.

Description

201040174 6. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to 4-amino-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one derivatives, which include Pharmaceutical composition, and their use. [Prior Art] 0 It is estimated that there are about 34 million and 61 million people in the United States who are obese, and in most developing worlds, this incidence is increasing every year.丨%. Obesity increases the likelihood of all causes of death by 20%, and more specifically, increases mortality from coronary artery disease and stroke by 25 percent and 10%, respectively. The main priority for anti-obesity treatment is to reduce food intake and/or hyperlipidemia. Because it has been suggested that hyperlipidemia induces insulin resistance, molecules developed to prevent triglyceride accumulation not only reduce obesity, but also have the additional effect of reducing insulin resistance, which is caused by Q to cause diabetes. A main cause. The therapeutic activity of the leptin agonist shows its potential to reduce food intake and reverse insulin resistance under detailed examination; however, its potential may be affected by alizarin resistance (obesity traits).醯Kyethase A: Dimercaptoglycerol thiol transferase 1 (DGAT-1) is one of two DGAT enzymes known to catalyze the final step in the synthesis of mammalian triglycerides and closely affects obesity and insulin resistance. Enzymes that occur. Mice lacking DGAT-1 are resistant to eating-induced obesity via a mechanism involving increased energy expenditure. Researchers in the United States have now demonstrated that these mice have reduced levels of tissue triglyceride and increased sensitivity to pancreatic -5 - 201040174 ally and leptin. Importantly, the lack of DGAT-1 protects the yellow rat (a severe leptin resistance model) against insulin resistance and obesity. Thus 'DGAT-1 represents a useful target for the treatment of insulin and leptin resistance and thus for the treatment of human obesity and diabetes. Chen, H. C. et al. J Clin Invest, 109 (8), 1 049-5 5 (2002). Although studies have shown that DGAT-1 inhibition can be used to treat obesity and diabetes, 'but still have therapeutic metabolic disorders (eg, obesity, type 2 diabetes, and insulin resistance syndrome (also known as "metabolic syndrome" There is a need for a DGAT-1 inhibitor of the efficacy of )). SUMMARY OF THE INVENTION The compounds of the present invention include those represented by the formula (la):

Or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, (C^Ca)alkoxy, halo-substituted (C!-C2)alkyl, halo substituted (C!-C2) Alkoxy or alkyl; R2 is independently halogen, hydrazine H, (C, -C4) alkyl, cyano, (C3-C6) cycloalkyl or (CrD alkoxy; R3 is ammonia, (C1) -C2) a hospital base, (C1-C2) alkoxy or - 0-(Ci-C2)alkyl-(C 〖-C 2 )alkoxy; and m is 0, 1, 2 or 3. The invention In another aspect is a pharmaceutical composition comprising: (1 -6 - 201040174) a compound of the invention and (2) a pharmaceutically acceptable excipient, diluent or carrier. The composition may comprise a therapeutically effective amount The compound of the invention may also contain at least one additional pharmaceutical agent, such as an anti-obesity agent and/or an anti-diabetic agent. Another aspect of the invention provides a method for treating an animal by inhibiting DGAT-1 A method of modulating a disease, disorder or condition, the method comprising the step of administering a therapeutically effective amount of a compound of the invention (or a pharmaceutical composition thereof) to an animal in need of such treatment, such as a human. Diseases, symptoms and/or conditions regulated by DGAT-1 include, for example, obesity (including weight control or weight maintenance), type 2 diabetes, diabetic nephropathy, insulin resistance syndrome, hyperglycemia, hyperinsulinemia, high Lipidemia, impaired glucose tolerance, hypertension, and reduced blood glucose levels. The compounds of the invention may be administered in combination with other pharmaceutical agents, particularly including the anti-obesity agents and anti-diabetic agents described herein below. The combination therapy can be administered as follows: (a) a single pharmaceutical composition comprising a compound of the present invention, at least one additional pharmaceutical agent described herein, and a pharmaceutically acceptable excipient, diluent or carrier. Or (b) two separate pharmaceutical compositions comprising (i) a first composition comprising a compound of the invention and a pharmaceutically acceptable excipient, diluent or carrier, and (Π) A second composition comprising at least one additional pharmaceutical agent described herein and a pharmaceutically acceptable excipient, diluent or carrier. The pharmaceutical compositions can be administered simultaneously or sequentially and in any order. It is to be understood that the following description of the invention and the appended claims are intended to be construed as The detailed description of the exemplary embodiments and the examples included herein are also more readily understood. It should be understood that the invention is not limited to the specific synthetic methods that can be modified. It should also be understood that the terms used herein are merely illustrative of specific examples. The purpose is not intended to be limiting, and the plural and singular are considered to be interchangeable, except for the representation of numbers. The headings in this document are for the reader only to speed up the review. These headings should not be construed as limiting in any way. this invention. In the context of this specification and the claims that follow, reference is made to a number of terms that are defined in the following sense: "a" as used in the specification herein, may mean one or more. The word "a 〃 or "an" as used in the scope of the patent application herein, when used in conjunction with the word *comprising ,, may mean one or more than one. As used herein, "another" can mean at least a second or more. The term ''about' refers to a relative term that refers to the approximate 値 plus or minus 10% of the nominal 値, in one particular case, plus or minus 5%, in another specific case, plus Or minus 2%. In the field of the present disclosure, this approximate level is appropriate unless it is specifically stated that a more stringent range is required. The term "alkyl oxime" as used herein refers to a hydrocarbon of the formula CnH2n+1 201040174. The alkane group may be straight or branched. For example, the term A(C^-Ce)alkyl" refers to a monovalent 'linear or branched aliphatic group containing from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) Base, n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3 , 3-dimethylpropyl, hexyl, 2-methylpentyl and the like). Similarly, the alkyl moiety (i.e., the alkyl moiety) of the alkoxy group has the same definition as described above. " Halo-substituted alkane-based " or " halo-substituted alkoxy hydrazine refers to an alkyl or alkoxy group substituted with one or more halogen atoms (e.g., fluoromethyl, difluoro) Methyl, trifluoromethyl, perfluoroethyl, 1,1-difluoroethyl and the like). The term "cycloalkyl" refers to a non-aromatic ring which is fully hydrogenated and which may exist as a monocyclic, bicyclic or helical ring. The carbon ring is typically a 3- to 6-membered ring unless otherwise indicated. For example, cycloalkyl groups include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like. ^Halogen or "halo" means a chlorine, fluorine, iodine or bromine atom. Q Therapeutic effective amount " means that the amount of the compound of the invention is used to (i) treat or prevent a particular disease, condition or condition, (π) to alleviate, ameliorate or eliminate one or more of the particular diseases, symptoms or conditions. Or (Hi) prevents or delays the onset of one or more of the particular diseases, conditions or conditions described herein. The term "animal" refers to human (male or female), companion animals (e.g., dogs, cats, and horses), food-derived animals, zoo animals, aquatic animals, birds, and other similar animal species. a Edible animal 〃 means food-derived animals such as cattle, pigs, sheep and poultry. 201040174 The word "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients (including the formulation) and/or the mammal to be treated therewith. The term '"treating, treat or treatment" includes both preventive (i.e., preventive) and debilitating treatments. The term "modulated or modulated" (modulated (s)) as used herein refers to the inhibition of dimercaptoglycerol-purine transferase 1 (DGAT-1) enzyme with a compound of the invention, unless otherwise Instructions. The term 'mediated or mediating (media) ( s )) as used herein refers to (i) treating or preventing a particular disease, symptom or condition by inhibiting DGAT-1 enzyme, (Π) reducing or modifying #或消除表示一个一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一种一个一个一个一个一个一个一个一个一个一个一个一个一个一个一个一个一个一个一个一个一个The term "compounds of the invention" (or compounds or simple ''compounds'" or 'compounds' (unless otherwise specifically identified) refer to the classes of compounds included in this application, such as included in the formula Intermediates of compounds and compounds, as well as salts, all stereoisomers (including non-image isomers and mirror image isomers), tautomers, conformational isomers and isotopically labeled compounds. Hydrates and solvates of the compounds are considered to be part of the invention wherein the compounds are each associated with water or a solvent. The term "salt" and "pharmaceutically acceptable salts mean none of the compounds - 10-201040174 Machines and organic salts. These salts can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the compound with a suitable organic or inorganic acid or base and separating the salt thus formed. Representative salts include hydrobromide, hydrochloride, hydroiodide, sulfate, hydrogen sulfate, nitrate, acetate, trifluoroacetate, oxalate, benzene. Besylate ), palmitate, pamoate, malonate, stearate, laurate, malate, borate, benzoate, lactate, phosphate, 0 hexafluorophosphate , besylate, tosylate, formate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, Portuguese Sugar heptanoate, lactobionate and lauryl sulfonate and the like. These salts may include cations mainly composed of alkali metals and alkaline earth metals such as sodium, lithium 'potassium, calcium, magnesium and the like. And non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like See, for example, Berge et al., J. Pharm. S ci., 6 6, Q 1_ 1 9 (1 977 ). In one specific example, the compound class is represented by the formula (lb):

(lb) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or ((^-(:2)alkyl; R2 is hydrogen, halogen, OH, (CVCU) alkyl or (CzCO alkoxy; -11 - 201040174 R3 is hydrogen, (CrD alkyl or (CrC^) alkoxy. In one embodiment, R1 is hydrogen or methyl and R3 is hydrogen, methyl or methoxy. In another embodiment, The compound class is represented by formula (II):

Or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen and R2 is selected from the group consisting of hydrogen, halogen, hydrazine, (Κ4) alkyl or (Ci-Q) alkoxy. In another embodiment, the compound is represented by formula (III):

Or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen and R2 is hydrogen, halogen, OH, alkyl or (CrC^)alkoxy. In another embodiment, the compound is represented by formula (IV): -12- 201040174

OH (IV) or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen and R2 is hydrogen, halogen, alkyl or (C丨-c2) alkoxy. 0 The present invention also includes solvates and hydrates of the compounds of the present invention. The term "solvate" refers to a molecular complex of a compound of the invention, including its pharmaceutically acceptable salts, with one or more solvent molecules. These solvent molecules are those commonly used in medical practice and are known to be harmless to the recipient, such as water, ethanol, ethylene glycol and the like. The term "hydrate hydrate refers to a complex in which the solvent molecule is water. The solvate and/or hydrate may be present in crystalline form. Other solvents may be used as intermediate solvates for the preparation of more desirable solvates, such as methanol, methyl tert-butyl ether, ethyl acetate, Q methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1, 4-butynediol and the like. The compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention and mixtures thereof (including racemic mixtures) are intended to form part of the invention, unless otherwise indicated. Additionally, the invention encompasses all geometric and positional isomers. For example, if a compound of the invention is incorporated into a double bond or a fused ring, both cis and trans and mixtures are embraced within the scope of the invention. -13- 201040174 Non-imagewise isomerization mixtures can be separated into their individual non-image isomers based on their physicochemical differences, such as by chromatography and/or fractional crystallization, by methods well known to those skilled in the art. effect. Separation of the mirror image isomers can be converted to a non-image mirror isomerization mixture by reacting the mirror image isomerization mixture with a suitable optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher decyl chloride. The non-image isomers are separated and the individual non-image isomers are converted (eg, hydrolyzed) to the corresponding pure mirror image isomers. Some of the compounds of the invention may also be a limiting atropisomer (e.g., substituted biaryl) and are considered to be part of the present invention. The mirror image isomers can also be separated by using a chiral HP LC column. Alternatively, a particular stereoisomer can be obtained by using an optically active starting material; by asymmetric synthesis of an optically active reagent, substrate, catalyst or solvent; or by stereoisomerism The product is synthesized by asymmetric transformation to another stereoisomer. It is also possible that the intermediates and compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer 〃 or '', tautomeric form 〃 refers to structural isomers of different energies that are mutually transformable via a low energy barrier. For example, proton tautomers (also known as proton-isomorphic tautomers) include interconversions via proton transfer, such as isomerization with keto-enol and imine-enamine. A specific example of a proton tautomer is the imidazole moiety, wherein protons can migrate between the two ring nitrogens. Valence tautomers include interconversions that are recombined by some bonding electrons. Certain compounds of the invention may exist in different stable conformational forms, -14-201040174. These forms are separable. Torsional asymmetry due to limited rotation around an asymmetric single bond (e.g., due to steric hindrance or ring strain) may allow for separation of different conformational isomers. The invention also encompasses isotopically-labeled compounds of the invention which are identical to those recited herein, but in fact one or more atoms are replaced by atoms having a different atomic mass or mass number than found in nature. Examples of isotopes which may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2h, 3H ' nC ' 13C ' 14C ' 13N ' 15N ' 150 ' 170 ' , 80 ' 31P ' 32P , 35s ' 18F , 123I , 125I and 36C1 . Certain isotopically-labeled compounds of the invention (e.g., those labeled with 3H and 14c) are useful for compound and/or substrate distribution assays. Deuterated (ie, 3H) and carbon-14 (ie, 14C) isotopes can be used because they are easy to prepare and detectable. Furthermore, substitution with heavier isotopes such as deuterium (ie, 2H) can provide certain therapeutic advantages (eg, increase in vivo half-life or reduce dosage requirements) that are caused by greater metabolic stability, and thus are available. In some environments. The positron radioisotopes (such as 15〇, 13n, "c and 18f) are used for the study of positron emission tomography (PET) to check the occupancy of the substrate. Isotopically labeled compounds of the invention can generally be prepared by substituting an isotope-labeled reagent for a reagent that is not isotope-labeled in accordance with procedures similar to those disclosed in the Schemes and/or Examples herein. Certain compounds of the invention may exist in more than one crystal form (commonly referred to as t polymorph). Polymorphs can be prepared by crystallization under various conditions -15-201040174, for example recrystallization using different solvents or different solvent mixtures; crystallization at different temperatures; and/or from very fast to very very high during crystallization Various cooling modes for slow cooling. Polymorphs can also be obtained by heating or melting the compound of the invention followed by gradual or rapid cooling. The presence of the polymorph can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other techniques. In general, the compounds of the invention may be prepared by methods known in the art, in particular in combination with the knowledge of those skilled in the art. While other reagents 'starting materials, intermediate compounds or methods can be used in the practice or testing, the broad methods used to prepare the compounds of the present invention are exemplified by the following description, preparation and reaction schemes. Other preparation methods are described in the experimental paragraphs. The methods disclosed herein, including those recited in the scheme, the preparation and the examples, are intended to be illustrative, and are not intended to be construed as limiting the invention in any way. The starting materials are generally commercially available, It is readily prepared, for example, by Aldrich Chemicals (Milwaukee, WI) or by methods well known to those skilled in the art (for example, widely described in Louis F. Fies er an d Mary F ieser, Reagents for Organic Syn sis, v. 1-19, Wiley, New Yc 丨rk ( 1967-1999 ed •), or Beilsteins Handbuch der orj ganischen Chemi e, 4, Aufl. ed . Springer- Verl ag, Berlin including appendices (also via the Beilstein online database) Obtained in the method). -16- 201040174 Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the invention. While specific starting materials and reagents are described in the Scheme and discussed below, other starting materials and reagents can be readily substituted to provide various derivatives and/or reaction conditions. In addition, many of the compounds produced in the following manner can be further modified in accordance with the present disclosure using conventional chemistry well known to those skilled in the art. The compounds of the invention can be synthesized by synthetic routes, including those well known in the art of chemistry, particularly in accordance with the teachings set forth herein. The starting materials are typically available from commercial sources, such as Aldrich Chemicals (Milwaukee, WI) or readily prepared using methods well known to those skilled in the art (e.g., widely described in Louis F. Fieser and Mary Fieser, Reagents for Organic). Synthesis, v. 1-19, Wiley, New York (1 967- 1 999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, A u fl. ed. Springer-Verlag, Berlin 'includes appendix (also via the The Beilstein online database was obtained by the method of Q in the system). For illustrative purposes, the reaction schemes described below provide possible pathways for the synthesis of the classes of compounds of the invention and important intermediates. For a more detailed description of the individual reaction steps, see the example paragraphs below. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the Scheme and discussed below, other starting materials and reagents can be readily substituted to provide various derivatives and/or reaction conditions. In addition, many of the compounds prepared in the following manner can be further modified in accordance with the present disclosure using conventional chemistry well known to those skilled in the art -17-201040174. In the preparation of the compounds of the invention, it may be desirable to protect the distal functionality of the intermediate species (e.g., 'primary or secondary amines). The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation process. Suitable amine-protecting groups (NH-Pg) include ethenyl, trifluoroethenyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethoxy Carbonyl (Fmoc). The need for such protection is easily determined by those skilled in the art. For a broad description of protecting groups and their use, see τ·W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,. New York, 1991 o Scheme I can be used to provide compounds of the formula (Π) General procedure -18- 201040174

The desired starting material (SM-1-1) can be prepared as described in Compound 56, U.S. Application No. 2004/0209871, or by a similar procedure. The starting material (SM-1-2), such as ethyl 3-aminopropionate wherein R1 is hydrazine, can be purchased from commercial sources. The compound wherein Rl is a methyl group (i.e., ethyl 3-aminobutyrate) can also be purchased from a commercial source as a racemic mixture or, if necessary, a single mirror image isomer. -19- 201040174 Two starting materials can be used at elevated temperatures (for example, about 8 ° C to about 13 ° C) in palladium (or copper) catalysts, weak bases (eg, cesium carbonate) and plant second rings. The haptenyl-2',4',6'.triisopropylbiphenyl (x_pH〇s) is coupled together in an inert environment to form an intermediate (IN_丨_i). The cyanoacetic acid is then added via a guanamine coupling reaction to the secondary amine group of the intermediate (m-oxime), which uses procedures well known to those skilled in the art (eg, in an activator such as N, N'-di In the presence of propyl carbodiimide (Die) and a mild base such as 4-dimethylaminopyridine (d MAP ) and in a suitable solvent (such as acetonitrile (ACN)), An intermediate (IN-1-2) is formed. Formation of the indoleamine (IN-1-3) can be achieved by treatment with a base such as 1,8-diazabicycloundec-7-ene (DBU) in methanol. The cyclization reaction is carried out at elevated temperature. The methylation of the indoleamine intermediate can be achieved by the addition of oxaloin chloride in the presence of dichloromethane (DCM) and dimethyl hydrazine (DMSO) and followed by the addition of methanol. The resulting methoxyindanamine intermediate (IN-1 -4 ) can then be reacted with cyanamide in the presence of sodium methoxide and methanol to provide the corresponding aminonitrile intermediate (IN-1-5). The second cyclization reaction is carried out by treatment with a strong mineral acid (e.g., sulfuric acid) in a protic solvent (e.g., methanol (MeOH)) to form an aminopyrimidine intermediate (IN-1-6). This reaction can be carried out at elevated temperatures. The aminopyrimidine intermediate (IN-1-6) is a mixture of cis- and trans-isomers which can be chromatographed using procedures well known to those skilled in the art. The corresponding carboxylic acid (formula ruthenium compound) is formed by a strong base such as potassium hydroxide (KOH) or in the presence of water and one or more polar solvents (for example, Me Ο Η and tetrahydrofuran (THF)) Sodium hydroxide ( -20- 201040174

NaOH)) is achieved by treatment. Scheme II summarizes the general procedures that can be used to provide compounds of formula III. (R2)m

SM-2-1

Scheme π desired starting material (SM-2-1) (such as 4-iodoaniline, ie wherein R2 is Η) and (SM-2-2) (such as ethyl acrylate, ie where R1 is Η, and Ethyl crotonate, i.e., wherein R1 is a methyl group, is commercially available. Substituted 4-iodoaniline (i.e., wherein R2 is, for example, fluoro, chloro or -21 - 40,040, 174 methyl) may also be purchased from commercial sources or it is well known in the art to use two starting materials in an acid (e.g., acetic acid). ) together to form an intermediate (IN-2-1). Subsequent addition of the cyanamide coupling reaction to the secondary amine of the intermediate (IN-2-1) is carried out by procedures well known to those skilled in the art, for example, in living oxime, Ν'-diisopropylcarbodiimide (DIC) Or 2-(7-azatriazol-1-yl)-1,1,3,3-tetramethylurea gun hexafluorophosphate (and a mild base (such as 4-dimethylaminopyridine (DMΑΡ)) Cyanide is added to the corresponding cyanamide intermediate (IN-2-2) in a suitable solvent such as acetonitrile (ACN). The indoleamine can be formed by a suitable solvent such as ethanol (EtOH) such as ethanol. By sodium (EtONa) treatment, the indoleamine intermediate (IN-2-4) is methylated by the alkylation of diazomethane (TMS-diazomethane). The addition of acetamidine to the methoxyl The corresponding aminopyrimidine (IN-2-5).1 hex-3-enyl)acetate methyl ester and aminopyrimidine intermediate (boron reagent obtained by IN-2) (for example, 2- (4- (4,4,5,5-tetraoxaborolan-2-yl)cyclohex-3-methyl ester) are coupled together, and the coupling is carried out using those procedures which are well known. The coupling reaction can occur in palladium catalyst (eg phosphine) palladium (Pd (PP) Under the presence of h3) 4) and a weak base (for example, carbonic acid) and hydrogenfuran (THF) in a suitable solvent or solvent mixture, the intermediate coupling (IN-2-6) is used to obtain the presence of a lower coupling. Acetic acid via a sulfhydryl group, which is in the presence of a hydrazine (such as hetero-1 Η-benzo HATU)) and acetic acid, in the form of bismuth -2-3)) with a base (addition of trimethyl hydrazine to provide methoxy In the base decylamine, ί 2 (cyclo-5) is known as the keto-1,3,2-dienyl) acetic acid, 肆 (triphenyl hydrazine (Cs2C03 (for example, tetra. olefin system - 22- 201040174

Reduction by hydrogenation, for example, treatment with hydrogen (H2) in the presence of a catalyst such as palladium hydroxide on carbon (Pd(OH)2/carbon) and in a suitable solvent such as methanol. The resulting cyclohexane intermediate (IN-2-7) is a mixture of cis- and trans-isomers which can be chromatographed using procedures well known to those skilled in the art. The corresponding carboxylic acid (compound of formula III) is formed by a strong base such as potassium hydroxide (KOH) or in the presence of water and one or more polar solvents such as methanol (MeOH) and tetrahydrofuran (THF). This is achieved by treatment with sodium hydroxide (NaOH). Scheme Ila describes alternative procedures that can be used to prepare compounds of formula II and III.

Process Ha In Scheme Ila, the methoxy decylamine intermediate is treated as desired in the presence of a base (eg, diisopropylethylamine (DIPEA)) and in a suitable solvent (eg, methanol). (IN-1-4) is supplied to the corresponding aminopyrimidine, which can be converted into a compound of the formula or III using the above method. Scheme III summarizes the general procedures used to prepare the compounds of Formula IV. -23- 201040174

The compound of the formula m formula ιν can usually be derived from the intermediate compound class (IN5). The aminonitrile intermediate was treated with H C1 in dioxane at elevated temperature to supply the corresponding chloroaminopyrimidine intermediate (ΙΝ-3-1). Treatment of the chloroaminopyrimidine intermediate in the presence of Pd(ΟΗ) 2/carbon and in a suitable solvent (eg, ethyl acetate (EtO Ac )), followed by addition in a suitable solvent or solvent mixture ( For example, an oxidizing agent of dichloromethane (DCM) and acetonitrile (ACN) (for example, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)) to give a dehalogenated aminopyrimidine (ΙΝ-3- 2 ). With a strong base (for example, hydroxide

Aminopyrimidine is treated with potassium (Κ0Η)), water, and one or more solvents (eg, THF or Me〇H) to provide a compound of formula IV. The compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention and mixtures thereof (including racemic mixtures) are intended to form part of the invention, unless otherwise indicated. In addition, the present invention -24-201040174 contains all geometric and positional isomers. For example, if a compound of the invention is incorporated into a double bond or a fused ring, both cis and trans and mixtures are embraced within the scope of the invention. The mixture of non-imagewise isomers can be separated into their individual non-imaged isomers, such as by chromatography and/or fractional crystallization, based on their physicochemical differences, in a manner well known to those skilled in the art. Separation of the mirror image isomers can be converted to a mixture of non-imagewise isomers by reacting a mixture of mirror image isomers with a suitable optically active compound 0 (eg, a chiral auxiliary such as a chiral alcohol or Mosher mercapto chloride). The non-image isomers are separated and the individual non-image isomers are converted (eg, hydrolyzed) to the corresponding pure mirror image isomers. Some of the compounds of the invention may also be restricted conformational isomers (e.g., substituted biaryls) and are considered to be part of the present invention. The mirror image isomers can also be separated by using a chiral HPLC column. Alternatively, a particular stereoisomer can be obtained by using an optically active starting material; by using an asymmetric synthesis of an optically active reagent, substrate, catalyst or solvent. The symmetric transformation method is converted into another stereoisomer and synthesized. It is also possible that the intermediates and compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term "tautomer" or A tautomer form refers to structural isomers of different energies that are mutually transformable via a low energy barrier. For example, proton tautomers (also known as proton-isomorphic tautomers) include interconversions via proton transfer, such as isomerization with keto-enol and imine-enamine. A specific example of a proton tautomer is the imi-25-201040174 azole moiety, in which protons can migrate between two ring nitrogens. Valence tautomers include interconversions that are recombined by some bonding electrons. Certain compounds of the invention may exist in different stable conformational forms' such forms are separable. Torsional asymmetry due to limited rotation around the asymmetric single bond (e.g., due to steric hindrance or ring strain) may allow for separation of different conformational isomers. The invention also encompasses isotopically-labeled compounds of the invention which are identical to those recited herein, but in fact one or more atoms are replaced by atoms having a different atomic mass or mass number than found in nature. Examples of isotopes which may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3 Η, 11 C, 13 C, 14 C, 13 N, respectively. , 15 N, 15 Ο, 17 0, 18 Ο, 31P, 32 ]>, 35S, 18F, 123J, 125j and 36C1. Certain isotopically-labeled compounds of the invention (e.g., those labeled with 3H and 14c) are useful for compound and/or substrate distribution assays. Deuterated (ie, 3H) and carbon-14 (ie, 14C) isotopes can be used because they are easy to prepare and detectable. Furthermore, substitution with heavier isotopes such as deuterium, ie 2H, may afford certain therapeutic advantages resulting from greater metabolic stability (eg, increase in vivo half-life or reduce dosage requirements), and thus may be used for some Environment. The positron radioisotopes (such as 15 〇, 13n, nc, and 18f) are used for positron emission tomography (PET) investigations to check the occupancy of the substrate. Isotopically labeled compounds of the invention can generally be prepared by substituting an isotope-labeled reagent for a non-isotopically labeled reagent in accordance with procedures similar to those disclosed in the Schemes and/or Examples -26-201040174 herein. Certain compounds of the invention may exist in more than one crystal form (commonly referred to as ~polymorphs). Polymorphs can be prepared by crystallization under various conditions, such as recrystallization using different solvents or different solvent mixtures; crystallization at different temperatures; and/or cooling from very fast to very slow during crystallization. Various cooling modes. Polymorphs can also be obtained by heating or melting the compound of the invention followed by gradual or rapid cooling. ¢) The presence of polymorphs can be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other techniques. The compounds of the invention are useful in the treatment of diseases, conditions and/or conditions modulated by inhibition of DGAT-1; thus, another embodiment of the invention comprises a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable excipient , a pharmaceutical composition of a diluent or carrier. The compounds of the invention, including the compositions and methods used herein, can also be used in the manufacture of a medicament for use in the treatment of the treatments described herein. A typical formulation is prepared by mixing a compound of the invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents , water and similar materials. The particular carrier, diluent or excipient used will depend on the mode and purpose of the compound of the invention. Solvents are usually selected on the basis of a solvent (GRAS) that is known to the skilled artisan to be safely administered to mammals. The normally safe solvent is non-toxic water -27- 201040174 Solvents (such as water) and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., 'PEG400, PEG3 00), and the like, and mixtures thereof. The formulation may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, slip agents, processing aids, colorants, Sweeteners, perfumes, flavoring agents, and other known additives that provide a high quality appearance of the drug (i.e., a compound of the invention or a pharmaceutical composition thereof) or that facilitate the manufacture of a pharmaceutical product (i.e., a pharmaceutical agent). Formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug (i.e., a stabilized form of a compound or compound of the invention (e.g., a complex with a cyclodextrin derivative or other known complex)) is dissolved in the presence of one or more of the above-described excipients. In a suitable solvent. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to provide the patient with a quality and readily manageable product. The pharmaceutical composition (or formulation) for administration can be packaged in various ways depending on the method used to administer the drug. Typically, the article for dispensing comprises a container in which the pharmaceutical formulation in a suitable form is stored. Suitable containers are those well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cans and the like. The container may also include an anti-tampering assembly to prevent rash access to the contents of the package. In addition, the label indicating the contents of the container is stored on the container. The label may also include appropriate warnings. The invention further provides a method for treating a disease, symptom and/or condition modulated by DGAT-1 in an animal comprising a therapeutically effective amount of a compound of the invention at -28 to 201040174 or an effective amount of the invention The compound and the pharmaceutically acceptable excipient, diluent or carrier pharmaceutical composition are administered to an animal in need of such treatment. This method is particularly useful for treating diseases, conditions and/or conditions that benefit from inhibition of DGAT-1. One aspect of the invention is the treatment of obesity and obesity-related disorders (e.g., overweight, weight gain, or weight maintenance). Obesity and overweight are usually defined by body mass index (BMI), which is related to overall fat mass and estimates the risk associated with the disease. The BMI is calculated by dividing the body weight in kilograms by the square of the height meter (kg/m2). Overweight is typically defined as a BMI of 25-29.9 kg/m2, while obesity is typically defined as a BMI of 30 kg/m2. See, for example, National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC: US Department of Health and Human Services, NIH publication no. 98- 4083 (1 998 ) o Another aspect of the invention is the treatment or delay of progression or initiation of diabetes or diabetes related disorders, including type 1 diabetes (insulin dependent diabetes mellitus also known as "IDDM〃) and type 2 diabetes (non-insulin-dependent diabetes mellitus, also known as "N ID D Μ "), impaired glucose tolerance 'insulin resistance, hyperglycemia, and diabetes mellitus (such as atherosclerosis, coronary artery) Sexual heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy and retinopathy. Yet another aspect of the invention is the treatment of diabetes or obesity associated with "29 - 201040174 with the same onset' such as metabolic syndrome. Metabolic syndrome includes diseases, symptoms or conditions such as abnormal dyslipidemia, hypertension, insulin resistance, diabetes (e.g., type 2 diabetes), weight gain, coronary artery disease, and heart failure. For more detailed information on metabolic syndrome, see, for example, Zimmet, P. Z. et al., "The Μ etabolic Syndrome : Perhaps an Etiologi c Mystery but Far From a Myth-Where Dose the International Diabetes Federation Stand?, Diabetes &

Endocrinology, 7 (2), (2005); and Alberti, Κ·G. et al., "The Metabolic Syndrome-A New Worldwide Definition", Lancet, 366, 1059-62 (2005). Administration of a compound of the invention provides at least one cardiovascular disease risk factor (p < 0.05), such as a decrease in blood leptin, C, when compared to a vehicle control group that does not contain a drug. - Reactive protein (CRP) and / or cholesterol. Administration of the compounds of the invention also provides a statistically significant reduction in glucose serum levels (P< 〇.〇5). In still another aspect of the invention, the symptom to be treated is impaired glucose tolerance, hyperglycemia, diabetes mellitus (such as glycocatalytic, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, and diabetes) Myocardial disease), anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, abnormal dyslipidemia, mixed abnormal dyslipidemia, high triglyceride Hemorrhagic, nonalcoholic fatty liver disease 'atherosclerosis' arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, myocardial disease, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, local Ischemia, lack of -30- 201040174 blood reperfusion injury, aneurysm, restenosis, vascular stenosis, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, cancer, stomach cancer, esophageal cancer, pancreatic cancer, care Adenocarcinoma, kidney cancer, bladder cancer, cervical cancer, urethral cancer, sputum cancer and ovarian cancer. The invention also relates to a method of treatment for the treatment of mammals, including humans, wherein the compounds of the invention are administered as part of a suitable dosage regimen designed to benefit. The amount of 0, the dose per dose, and the interval between doses of each compound depend on the compound of the present invention, the type of pharmaceutical composition to be used, the nature of the condition to be treated, and the severity of the symptoms. The invention also provides a method comprising blending a therapeutically effective amount of a compound or a salt thereof with at least one pharmaceutically acceptable excipient. Compositions include those having a form suitable for oral, enteral use and which can be used to treat diabetes and sputum compositions as described above which can be formulated for any route known in the art such as subcutaneous, inhalation, oral, topical , non-intestines and so on. The compositions are any form known in the art including, but not limited to, capsules, powders, granules, lozenges or liquid preparations such as oral enteric solutions or suspensions. Tablets and capsules for oral administration. The unit dosage form may contain conventional excipients such as binding agents such as syrup, aminatin, sorbitol, gum arabic or polyvinylpyrrolidone; for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or Symptoms, solid, colon, liver cancer, the above-mentioned symptoms to obtain the therapeutic dose system to be used for the treatment of the medically available medical group or non-related symptoms, the species may have) tablets, or sterile Appearance and labrador, chelating agent, amine acid; pressure -31 - 201040174 tablet lubricant 'such as magnesium stearate, talc, polyethylene glycol or vermiculite; disintegrating agent 'such as potato starch; or acceptable A humectant such as sodium lauryl sulfate. The tablets may be coated according to methods well known in the ordinary pharmaceutical practice. Oral liquid preparations may be presented, for example, in the form of an aqueous or oily suspension, solution, emulsion, syrup or elixir' or may be presented as a dry product reconstituted with water or other suitable vehicle before use. These liquid preparations may contain customary additives such as suspending agents such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, hydroxymethylcellulose, aluminum stearate or hydrogenated edible fats. An emulsifier such as lecithin, sorbitan monooleate or gum arabic; a non-aqueous vehicle (which may include an edible oil), such as almond oil, an oily ester such as glycerol 'propylene glycol or ethanol; a preservative, For example, methyl or propyl p-hydroxybenzoate or sorbic acid; and, if necessary, conventional flavoring or coloring agents. Fluid unit dosage forms for parenteral administration are prepared using a compound and a sterile vehicle, preferably water. The compound may be suspended or dissolved in a vehicle or other suitable solvent' depending on the vehicle and concentration employed. In preparing the solution, the compound can be dissolved in water for injection and sterilized by filtration prior to filling into a suitable vial or vial and sealing. Agents such as local anesthetics, preservatives, and buffering agents are preferably dissolved in the vehicle. The composition can be frozen after filling into a vial and removing water under vacuum to enhance stability. The anhydrous lyophilized powder is then sealed in a vial and supplied to the accompanying vial for water for injection, and the liquid is reconstituted prior to use. The parenteral suspension is prepared substantially in the same manner except that the compound is dissolved in the vehicle instead of being dissolved and the sterilization is not filtered. Compound -32- 201040174 The substance can be sterilized by being exposed to the epoxy plant before being suspended in a sterile vehicle. The surfactant or wetting agent is preferably included in the composition to promote uniform distribution of the compound. The composition may contain, for example, from about 0.1% by weight to about 99% by weight of the active material, depending on the method of administration. When the composition comprises a unit dose, the unit contains, for example, from about 0.1 to 900 mg of the active ingredient, more typically from 1 mg to 25 mg, or 0 or 0.01 mg in a single or divided dose. /kg/day to 30 mg/kg/day, such as 〇.〇1 mg/kg/day to 5 mg/kg/day of active compound. The compounds of the invention may be formulated for administration in any convenient manner similar to the use of other anti-diabetic agents in human or veterinary medicine. These methods are known in the art and have been summarized above. For a more detailed discussion of the preparation of such formulations, the reader's attention is directed to the 2nd edition of Remington's Pharmaceutical Sciences o Q of the University of Science and Technology (U niversity of the Science) η P hi 1 ade I phia. In formulations for sustained release, controlled release, and delayed release, such forms are also well known to those skilled in the art. The compounds of the invention may also be used in combination with other pharmaceutical agents for the treatment of the diseases, conditions and/or conditions described herein. Accordingly, the present invention also provides a method of treatment comprising administering a compound of the present invention in combination with other pharmaceutical agents. Suitable pharmaceutical agents which can be used in combination with the compounds of the present invention include anti-obesity agents (including appetite suppressants), anti-diabetic agents, anti-hyperglycemic agents, lipid lowering agents, and antihypertensive agents. -33- 201040174 Suitable anti-diabetic agents include acetyl-CoA carboxylase-2 (ACC-2) inhibitors, phosphodiesterase (PDE)-10 inhibitors, sulfonium urea (eg, Aitoma serrata) (acetohexamide), chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, 葛美琵莱_ Glimepiride ), gliclazide, glip_entide, gliquidone, glisolamide, tolazamide and tolbutamide, Meg Meglitinide, alpha-source enzyme inhibitors (eg, tendamistat, trestatin, and AL-3 68 8 ), glucoside hydrolase inhibitors (eg, Aka) Acarbose ), 〇:-glucosidase inhibitors (eg, adiposine, camiglibose, emigliate, miglitol, bud Voglibose, pradimicin -Q and Shabostatin (s Albostatin)), PPARr agonist (eg, ba 1 ag 1 ita ζ ο ne ), ciglitazone, darglitazone, englitazone , Isaglitazone, pioglitazone, rosiglitazone, and troglitazone 'PPARa/χ agonist (eg, CLX-0940, GW) - 1 53 6. GW- 1 929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-2 1 9994), double eyes (for example, metformin), Glycoglycan peptide 1 (G LP -1 ) agonist (eg -34- 201040174, exendin-3 and Ididine-4), protein tyrosine phosphatase-IB (PTP- 1B) Inhibitors (for example, trodusquemine, hyrtiosal extract, and Drug Discovery Today, 1 2 ( 9/ 1 0 ), 3 73 - 38 1 by Zhang, S. et al. Compounds disclosed in 2007), SIRT-1 inhibitors (eg, reservatrol) 'dipeptidyl peptidase IV (DP P -1V ) inhibitors (eg, sitagliptin, dimension (Q vildagliptin, alogliptin and saxagliptin), insulin secretion promoter, fatty acid oxidation inhibitor, A2 antagonist, c-jun amine-terminal kinase (JNK) inhibition Agents, insulin, pseudo-insulin, glycogen phosphorylase inhibitors, VPAC2 receptor agonists and glucokinase activators. Exemplary anti-diabetic agents are mefofloxacin and DPP-IV inhibitors (e.g., sitagartin, vildagrin, alogrene, and saskatchewan). Suitable anti-obesity agents include 11Θ-hydroxysteroid dehydrogenase-1 (11〇/3-HSD type 1) inhibitor, stearin-CoA desaturase-1 (SCD-1) inhibitor, MCR-4 Agonists, cholecystokinin_A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic, /3 3 adrenergic agonists, dopamine Agent (such as bromocriptine) 'melanocyte stimulating hormone analog, 5HT2c agonist, melanin aggregation hormone antagonist, leptin (〇B protein), leptin analog, leptin agonist , galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin (orlistat), appetite suppressants (such as scorpion agonist -35- 201040174), nerves Peptide-Y antagonists (eg, ΝΡΥY5 antagonists), ΡΥΥ3-36 (including analogs thereof), thyroxine agents, dehydroepiandrosterone or analogs thereof, glucocorticoid agonists or antagonists , orexin antagonist, glucagon peptide-1 agonist, ciliary neurotrophic factor (such as from Regene) Ron Pharmaceuticals, Inc., Tarrytown, NY and Procter & Gamble Company, Cincinnati, AxokineTM, OH, humanuti-related protein (AGRP) inhibitors, ghrelin antagonists, tissues Amine 3 antagonist or inverse agonist, neuromodulin (neur 〇medin) U agonist, MTP/ApoB inhibits Qiqi (eg, intestinal selective sputum inhibitors, such as dirlotapide), Opiate antagonists, alixin antagonists and analogs. Exemplary anti-obesity agents for use in the combination of the invention include intestinal selective MTP inhibitors (e.g., dirlotapide, mitratapide, Implita (implitapide), R56918 (CAS No. 403987) and CAS No. 9 1 354 1 -47-6 ), CCKa agonists (for example, in PCT Publication No. WO 2005/1 1 6034 or N-Benzyl-2-[4-(1H-indol-3-ylmethyl)-5-one-1-phenyl- 4 as described in US Publication No. 2005-0267 1 00 A1 ,5-dihydro-2,3,6,10b-tetraaza-benzo[e]mol-6-yl]-N-isopropyl-acetamide), 5HT2C agonist ( For example, lorcaserin (Lorcaserin), MCR4 agonist (for example, the compounds described in US 6,8 1 8,6 5 8), lipase inhibitors (for example, celestatin (cetilistat) )), PYY3-36 (as used herein, "ΡΥΥ3-3〆 includes analogs such as peglated -36- 201040174 PYY3-36' such as those published in US 2006/01 7850 1 Said), opioid antagonists (eg, naltrexone), estrone (CAS No. 180003-17-2), obinipitide (TM3033 8 ), pralitre ( Praminintide) (symlin®), tesofensine (NS2330), leptin, liraglutide, pomoket, orlistat, exenatide (byetta®) , AOD-9604 (CAS No. 0 22 1 23 1 -1 0-3 ) and Hibu found. The compounds of the invention and combination therapies can be administered in conjunction with exercise and sensible dieting. Specific examples of the invention are exemplified by the following examples. However, it is to be understood that the specific embodiments of the invention are not limited to the specific details of the examples, and other variations of these examples will be apparent to those skilled in the art. [Embodiment] 〇 Unless otherwise indicated, 'starting materials are usually taken from commercial sources' such as Aldrich Chemicals Co. (Milwaukee, WI),

Lancaster Synthesis, Inc. ( Windham, NH ) . Acros

Organics ( Fairlawn, NJ) > Maybridge Chemical Company, Ltd. ( Cornwall, England ) > Tyger Scientific ( Princeton, NJ ) and AstraZeneca Pharmaceuticals ( London, England ) General Experimental Procedure - 37- 201040174 NMR Spectroscopy at Room Temperature The proton was 40 〇mHz and was recorded on a Varian UnityTM 400 (taken from Varian Inc., Palo Alto, CA). The chemical shift is expressed in parts per million (<5) relative to the residual solvent as an internal reference. The peak shape is expressed as follows: s, singlet; d, doublet; dd, doublet of doublet; t, triplet; q, four peaks; m, multiplet, · bs, broad singlet; 2s, two Single peak. Atmospheric pressure chemical ionization mass spectrometry (APCI) was obtained on a FisonsTM Platform II spectrometer (carrier gas: acetonitrile; taken from Micromass Ltd., Manchester, UK). Chemical ionization mass spectrometry (CI) was obtained on a Hewlett-PackardTM 5 9 89 instrument (ammonia ionization, PBMS: taken from Hewlett-Packard Company, Palo Alto, CA). Electrospray ionization mass spectrometry (ES) was obtained on a WatersTM ZMD instrument (carrier gas: acetonitrile; taken from Waters Corp., Milford, USA). High resolution mass spectrometry (HRMS) was obtained on a AgilentTM Model 6210 using time-of-flight methods. When indicating the strength of chlorine- or bromide-containing ions, the expected intensity ratio (about 3:1 for ions containing 35C1/37C1 and about 1:1 for ions containing 79Bf/8 hr) is observed and only low-mass ions are provided. Strength of. In some examples, only representative 1 Η NMR peaks are provided. The optical rotation was determined on a PerkinElmerTM 241 polarimeter (taken from PerkinElmer Inc., Wellesley, MA) using the sodium D line (λ = 5 89 nm) at the indicated temperature and with the following [ct]D s *, concentration (c = g / 100 ml) and solvent to record.

Column chromatography is performed in a glass column or in a Flash 40 BiotageTM column (ISC, Inc., Shelton, CT) or BiotageTM SNAP 匣KPsil with BakerTM sand (40 μm; JT Baker, Phillipsburg, NJ) -38- 201040174) or Silica Gel 50 (EM SciencesTM, Gibbstown, NJ) or with Redisep Rf silica sand (from TeledyneTM IscoTM) under low nitrogen pressure. The starting material [trans-4-[4-[[(trifluoromethyl))]oxy]phenyl]cyclohexyl]acetic acid methyl ester is as described in US Application No. 2004/020987 No. 1 This was prepared in the manner described for compound 5.6. Preparation of Important Intermediates Preparation of ethyl N-{4-[trans-4-(2-methoxy-2-oxooxyethyl)cyclohexyl]phenyl}alanine:

Methyl [trans-4-[4-[[(trifluoromethyl)sulfonyl)oxy]phenyl]cyclohexyl]acetate (13.0 g, 34·1 mmol), 3-amino Ethyl propionate (6.3 grams, 41 millimoles) was combined with a carbonic acid planer (27.8 grams, 85.4 millimoles) in a reaction vessel and suspended in toluene (230 ml). Nitrogen was bubbled through the stirred mixture for 20 minutes. Palladium(II) acetate (614 mg, 2_73 mmol), 2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (1.3 g, 2.73 mmol) and DIPEA (7.74 mL, 44.4 mmol) were added to the reaction and nitrogen-39-201040174 was bubbled through the mixture for a further 5 minutes. The vessel was capped and the mixture was stirred at +12 ° C for 20 hours. The reaction was cooled to room temperature and concentrated. Purification by chromatography (40% EtOAc: heptane cartridge) afforded N-{4-[trans-4-(2-methoxy-2-oxoethyl)cyclohexyl] Phenyl}-cold-alanine ethyl ester (6.75 g, 57% yield). *H NMR (500 MHz, CDC13): δ ppm 1.09-1.19 ( m '2 H) 1.27 (t> 3 H) 1.40- 1.53 (m> 2 H) 1.81-1-93 (m , 6 H) 2.26 ( d,2 H) 2.62(t,2 H ) 3.44 ( t » 2 H ) 3.69 (s - 3 H) 4.16 (q > 2 H) 6.60 (d - 2 H) 7.04 (d - 2 H ) . m/z = 3 4 8.5 ( M+1 ). Preparation of N-(cyanoethyl)-N- { 4-[trans-4-(2-methoxy-2-oxoethyl)cyclohexyl]phenyl}-yS-alanine ethyl ester :

Diisopropylcarbodiamine (3.16 ml, 20.4 mmol) was added dropwise to Ν-{4-[trans-4-(2-methoxy-2-sideoxy) at 〇 °C Ethyl ethyl)cyclohexyl]phenyl}alanine ethyl ester (6.75 g ' 19.43 mmol), cyanoacetic acid (1.74 g, 20·4 mmol) and DMF (1 mL) stirred mixture. The reaction was allowed to warm and stirred at room temperature for 3 days. EtOAc (200 mL) and heptane (400 mL) were added -40 - 201040174 to the mixture, then the mixture was washed with water (3x3 00 rnL). The organic phase was dried over magnesium sulfate and loaded onto silica gel. The column was eluted with a gradient from 30_90% EtOAc: heptane to give N-(cyanoethyl)-N-{4-[trans-4-(2-methoxy-2-s. Ethyl ethyl)cyclohexyl]phenyl}-/3-alanine ethyl ester (5.2 g, 64% yield). H NMR ( 500 MHz, CDC13 ) : δ ppm 1.14-1.21 ( m , 2H) , 1.21 (t, 3H) , 1.48-1.56 (m, 2H) 1.84-1.89 (m, 1H) , 1.90 - 1.96 ( m , 4H ) , 2.28 ( d, 2H), 2.50-2.57 (m, 1H) , 2_59 (t, 2H) , 3.19 ( s, 2H), 3.71 (s, 3H) , 4.02 (t, 2H) , 4.08 ( q,2H) , 7.14( d,2H) , 7.30(d,2H) » m/z = 4 1 5.5 ( M+1 ). 2-{trans-4-(4-(3-Cyano-4-hydroxy-2-oxo-5,6-dihydro-1(2H)-yl)phenyl)cyclohexyl}acetate methyl ester Preparation:

N((cyanoethyl)-N- { 4-[trans-4-(2-methoxy-2-oxoethyl)cyclohexyl]phenyl}-y3-alanine ethyl ester ( a mixture of 7.3 g, 18 mmoles and 15-diazabicyclo (5.4.0) eleven-7-ene (3.16 ml, 21.1 mmol) diluted in MeOH (138 mL) at +80 ° Heat at C for 3 hours. The reaction was concentrated and then diluted with EtOAc - 41 - EtOAc (EtOAc) (EtOAc) The mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered off and dried in vacuo <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> Methyl 6-dihydro-1(2H)-yl)phenyl)cyclohexyl}acetate (5.2 g, 80% yield). NMR (500 MHz » DMSO-d6) : δ ppm 1.08-1.19 ( m &gt; 2Η ) , 1.40-1.51 (m, 2H) &gt; 1.7 2-1.83 (m&gt; 6H) ' 2.24 ( d &gt; 2H ) &gt ; 2.44 ( t &gt; 1H ) , 2.80 (t, 2H) , 3.60 (

s,3H) ,3.77(t,2H) ,7.15(d,2H) ,7.22(d,2H )°m/z = 367.4 (Ml) ° {trans-4-[4-( 5-cyano- Preparation of 4-methoxy-6-tertiaryoxy-3,6-dihydro-1(2H)-yl)phenyl]cyclohexylindoleacetic acid methyl ester:

[Trans-4-(4-cyano-4-hydroxy-2-oxo-5,6-dihydro-1 (2H)-yl)phenyl)cyclohexyl}acetic acid methyl ester ( 245 grams, 6 65 millimoles), DCM (3.22 liters) and DMF (32.1 milliliters, 415 millimoles) were added to a 5 liter round bottom flask. Grass chloroform (106.33 ml, 1.23 mol) was slowly added to the stirred solution. During the addition, the reaction was cooled to 15 °C and maintained between 15-25 °C. The reaction was stirred at room temperature -42 - 201040174 until the reaction mixture was clear. Remove DCM and add MeOH (3.92 liters). The reaction was heated to 65 °C for an additional 12 hours until all of the chlorine intermediate had been used up. The solid was filtered off to give 2 - { trans-4-[4-(5-cyano-4-methoxy-6-oxo- 3,6-dihydro-1(2H)-yl)benzene. Methylcyclohexyl}acetate (230.0 g, 90.4% yield). *11 NMR ( 4 00 MHz > DMSO-de) δ ppm 1.03-1.18 (m , 2 Η) 1.36-1.51 (m, 2 H) 1.76 (d, J = 9.76 Hz, 5 Η) 2.21 ( d, J = 6.64 Hz, 2 H ) 2.37-2.45 ( m * 1 H ) 3.01 ( t , J = 6.83 Hz, 2 H ) 3.56 ( s,3 H ) 3.79 ( t,J = 6.83 Hz, 2 H) 4.00 (s* 3 H) 7.11-7.24 (m&gt; 4 H). m/z = 3 8 3.5 ( M+l ). (trans-4-{4-[5-cyano-4-(amino)-6-o-oxy-3,6-dihydro-1(2H)-yl]phenyl}cyclohexyl)acetic acid Preparation of methyl ester:

{trans-4-[4-(5-cyano-4-methoxy-6-oxo- 3,6-dihydro-1(2H)-yl)phenyl]cyclohexyl}acetate The ester (230 grams, 601.33 millimoles)' cyanamide (55.62 grams, 1.32 moles) and MeOH (2.66 liters) were added to a 5 liter round bottom flask. Slowly add -43- 201040174 plus sodium methoxide (107.2 grams, 1.98 moles). The reaction was allowed to stand in the chamber for 1 hour. The mixture was cooled to 10 °C. Add IN HCI (1 to pH 3) and water (1.6 liters). Remove MeOH IN HC1 (0.4 liters) in vacuo. The slurry was stirred at room temperature for 15 minutes. The filter cake was washed with water (0.5 liter) and dried to give a powder (trans-4-{4-[5-cyano-4-(cyanoamino)-6-{| 3,6-dihydrogen) Methyl 1-(2H)-yl]phenyl}cyclohexyl)acetate, 98.7% yield). This material is either uncharacterized or purified in the next reaction. {trans-4-[4-(4-Amino-2-methoxy-5-oxo-7,8-di-[4,3-d]pyrimidin-6(5H)·yl)benzene Preparation of Cyclohexyl} B: Stir under temperature. 6 liters. Add and filter off-white IJ oxy-(233.0 for methyl hydropyridine)

(trans-4-{4-[5-indole (cyanoamino)-6-o-oxy-3,6-dihydro-1(2Η)-yl]phenyl) in MeOH (400 mL) a mixture of methyl acetate (11.5 grams, 30.1 millimoles), 2-methyl (6.65 grams, 60.1 millimoles) and DIP(R) (20.1 ml, molar) was warmed to +70 °C over 20 minutes. 1 hour at +70 °C. The mixture was filtered and the obtained white solid was evaporated from EtOAc EtOAc EtOAc EtOAc The mixture was filtered. The mash was concentrated and the residue was purified by chromatography (1 20 g EtOAc EtOAc EtOAc EtOAc 2-Methoxy-5-o-oxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)phenyl]cyclohexyl}acetic acid methyl ester (4.3 g, 4 8 % yield).

*H NMR (400 MHz &gt; DMSO-d6) : δ ppm 1.03-1.18 ( m &gt; 2 H) &gt; 1.36- 1.52 ( m &gt; 2 H) 1 1.64-1.84 ( m &gt; 5 H ), 2.2 1 ( d, J = 6.83 Hz &gt; 2H ) , 2.3 8 - 2.4 5 ( m » 1 H ) -2.90 ( t, J = 6.83 Hz &gt; 2H ) , 3.57 ( s ' 3H ) , 3.79-3.8 8 ( m &gt; 5H ), 7.17-7.25 ( m, 4H ) , 7.73 ( d, J = 3.90 Hz, 1H ), 8.34 ( d, J = 4.10 Hz, 1H ). m/z = 425.5 ( M+l ). Preparation of N-(3-ethoxybut-3-enyl)-4-iodoaniline:

Ο

O EtO^^^N 4- 4-iodoaniline (50 g, 227 mmol) and ethyl acrylate (24 mL of 227 mmol) were dissolved in acetic acid (200 mL). The mixture was heated to 75 ° C for 16 hours. The reaction mixture was then concentrated and the residue was diluted with water. It was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over Na 2 SO 4 and evaporated to dry. The crude material was purified by column chromatography using hexane-EtOAc eluting solvent to afford N-(3-ethoxybut-3-enyl)-4-iodoaniline (57 g, -45 - 201040174 7 9 % yield). lH NMR (400 MHz, CDC13): δ ppm 7 · 2 4 ( m, 2 Η ) , 6.69 ( m &gt; 2H ) ' 4.13 ( q &gt; 7 = 7.2 Hz, 2H ) ' 3.64 ( m , 2 H ) , 2.57 ( m 5 2 H ) ' 1.22 (t, /=7.2 Hz' 3 H ). Preparation of ethyl 3-(2-cyano-N-(4-iodophenyl)acetamido)propionate:

Diisopropylcarbodiimide (8.6 g, 68 mmol) was at 0. (: and N-(3-ethoxybut-3-enyl)-4-iodoaniline (20 g, 62 mmol) added dropwise to DMF (100 mL) over 15 min. A stirred solution of a mixture of cyanoacetic acid (7.99 g, 94.04 mmol). The mixture was stirred at room temperature for 1 hour and diluted with a 1:1 mixture of ethyl acetate-hexanes. In addition to urea by-product, the filtrate was partitioned between diluted HCI (0.5N) and ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The crude material was used 230-400 mesh gelatin as a carrier Purification by column chromatography with 2% by weight of ethyl acetate in hexane as a solvent to give ethyl 3-(2-cyano-N-(4-iodophenyl)acetamido)propanoate (17 g, 70% yield). Re-purified on a silica gel column containing 15% EtOAc in hexane. The compound obtained after purification of the column was dissolved in a minimum amount of ether and solid after cooling. It was filtered off to give 8 g (32% yield) of ethyl 3-(2-cyano-N-(4-iodophenyl)ethylamino)propanoate. -46- 201040174 'H NMR (400 MHz, DMSO-d6): /=8.4 Hz, 2H), 6.98 (d, "7=8.4 Hz - 7=7.2 Hz, 2H), 3.96 (t, 2H) » 3.1 (t, 2H ) , 1.2 1 ( m, 3H ). Preparation of 4-hydroxy-1-(4-iodophenyl)-2-oxooxy-1,2, δ ppm 7.80 ( d &gt; 2H ) , 4.04 ( q, 8 ( s, 2H ) , 2.53 5 , 6 - tetraammonium than D -3 - meal o

NC HO

Ethyl 3-phenyl)ethylamino)propionate dissolved in 60 ml of absolute ethanol (5 g, a solution added dropwise to a new: 14.24 mmol) in ethanol at 〇 ° C . The solution was then distilled off of ethanol and the crude residue was dissolved in water. j to pH-4. The precipitate was filtered off and dried to give phenyl)-2-ylidene-1,2,5,6-tetrahydropyridine-3-indole. !H NMR (400 MHz, DMSO-d6): 7 = 8.4 Hz, 2H), 7.08 (d &gt; *7 = 8.4 Hz 2H), 2_79 (t, 2H). Preparation of 1-(4-iodophenyl)-4-methoxy-2-oxooxy-1, nitrile: (2-cyano-N-(4-iodine 12.95 ml/mole) freshly prepared NaOEt (Stirring at room temperature overnight. Treat it with 2N HCl acid [[4-hydroxy-1-(4- io) (2.9 g, 67% δ ppm 7.69 ( d 1 '2H ) &gt; 3.75 ( t &gt; 2, 5,6-tetrahydropyridine-3-47-201040174

4-Hydroxy-1-(4-iodophenyl)-2-oxoyl-1,2,5,6-tetrahydropyridine-3-carbonitrile (9 g, 26.4 mmol) dissolved in 250 mL of methanol in. An excess of diazomethane ether solution (prepared freshly from 25 equivalents of nitrosylurea (NMU)) was added to the reaction mixture at 〇 °c. The reaction was stirred at 0 ° C for 0.5 h and the methanol was removed. The crude product was washed thoroughly with water and dried to give 1-(4-iodophenyl)-4-methoxy-2-oxooxy-1,2,5,6-tetrahydropyridine-3-carbonitrile (2.9 Grams, 31% yield). ^ NMR ( 400 MHz &gt; DMSO-d6) : δ ppm 7.72 . (d, «/=8.4 Hz' 2H ) , 7.12 ( d &gt;/=8.4 Hz, 2H) , 4.03 (s, 3H ) , 3.83 ( t, 2H), 3. 〇 4 (t, 2H). Preparation of 4-amino-6-(4-iodophenyl)-2-methyl-7,8-dihydropyrido[4,3-(1]pyrimidin-5(6H)-one:

丨·&quot;-iodophenyl)_4_methoxy_2-sided oxy-^2,5,6-tetrahydropyridine.3-carbonitrile (4 〇 mg' MeOH in MeOH (1.5 liters) Mixture of 1 〇 millimolar), acetamidine hydrochloride (87 gram, 〇.8 〇 1 mmol) and diisopropylethylamine (〇 〇 4 〇 pen liter, 0.8 〇 4 摩尔) Warm from room temperature to +80 aC in Μ minutes and stir at this temperature for 丨 hours. The mixture was loaded onto a silica gel eluting with EtOAc EtOAc (EtOAc) Base-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (IN-2-5) (26 mg, 59% yield). *H NMR (400 MHz &gt; DMSO-d6) : δ ppm 8 · 1 5 ( s, 1 Η ) &gt; 7.7 4 ( m &gt; 3 Η ) * 7.17 ( d » 7=8.4 Hz &gt; 2H) , 3.88 ( m, 2H ) , 2.96 ( m, 2H ) , 2.35 ( s, 3H ). m/z = 381 ( M+l ). 2-(4-(4-(4-Amino-2-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzene) Preparation of methyl)cyclohex-3-enyl)acetate:

Add hydrazine (triphenylphosphine) palladium (0) (13 mg, 0. 011 mmol) and carbonic acid (105 mg, 0.316 mmol) to THF in THF (2 mL) -6-(4-iodophenyl)-2-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6Η)-one (1 〇〇 mg, 0.263 mmol) And methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)acetate (73.7 mg , 0.263 millimolar) in solution. The reaction mixture was stirred at reflux for 16 hours. The reaction mixture was then cooled 'diluted with EtOAc, washed with water and brine, then -49- 201040174

The MgS04 was dried and concentrated. The crude material was purified by chromatography (1 2 g EtOAc EtOAc EtOAc EtOAc -Sideoxy-methyl 7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)cyclohex-3-enyl)acetate (82 mg, 7 7 % Yield). lH NMR ( 400 MHz, CHLOROFORM-J ) δ ppm 1.36-1.51 (m,1 Η) 1.75 (br. s·,1 Η) 1.82-1.98 (m,2 Η) 2.14 ( br. s.,1 H ) 2.32 (d, /=7.4 2 Hz, 2 H ) 2.37-2.53 (m, 5 H) 3.06 ( t, J-6.83 Hz, 2 H ) 3_67 ( s,3 H ) 3.94 ( t &gt; 7=6.83 Hz , 2 H ) 5.70 ( br. s.,1 H ) 5.97-6.1 1 (m,1 H) 7.18-7.26 (m,2 H) 7.40 (d, /=8.59 Hz, 2 H ) 8.52 ( b rs &gt ; 1 H ) m/z = 407.4 ( M+l). 2-(4-(4-(4-Amino-2-methyl-5-oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzene Preparation of methyl)cyclohexyl)acetate.

2_(4-(4-(4-Amino-2-methyl-5-oxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzene Methyl)cyclohex-3-enyl)acetate (82 mg, 0.20 mmol) was dissolved in EtOAc (EtOAc) 20% Pd(OH) 2/C (40 mg) -50- 201040174 was added to the solution. The reaction mixture was shaken at Hz for 5 〇 P si (3.4 atm) for 16 hours. The mixture was filtered through celite to remove the catalyst and concentrated to give 2-(4-(4-(amino)-2-methyl-5- </RTI> Hydrogen pyrido[4,3-(1]pyrimidin-6(511)-yl:)phenylphenyl)cyclohexyl)acetate (80 mg, 97% yield) m/z = 409.5 (M+1) 〇{trans-2--4-(4-(4-Amino-2-chloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- Preparation of methyl)phenyl)cyclohexyl}acetate:

CI

〇, cyanoguanamine (115 mg, 2.74 mmol) was added to NaH (60% solution in mineral oil, 109 mg, 2.74 mmol) in dioxane (15 mL) at room temperature. Stir the suspension. After stirring for 15 minutes, {trans-4-[4-(5-cyano-4-(cyanoamino)-6-o-oxy-3,6-dihydropyridine-1(2H)-yl) was added. Phenyl]cyclohexyl}acetic acid methyl ester (700 mg, 1.8 3 mmol) and the mixture was stirred at room temperature for 4 hours. A 4 M HCl solution (12.5 mL) in dioxane was then added and the mixture was heated to 100 ° C for 3 hours. After cooling, water (100 mL) was added and the mixture was extracted EtOAc EtOAc. The combined organics were washed with brine (50 ml), dried (MgSO4) and evaporated to give the title compound, <RTIgt; </RTI> <RTIgt; </RTI> 4--4-(4-amine-51 - 201040174 -2- chloro -5-Sideoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)cyclohexyl}acetic acid methyl ester (700 mg), which is not Characterized or purified for use in the next reaction. 2-{trans-4-(4-(4-Amino-5-sidedoxy-7,7-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl) Preparation of cyclohexyl}methyl acetate:

{trans-2--4-(4-(4-amino-2-chloro-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- Methyl)phenyl)cyclohexyl}acetate (700 mg) was dissolved in EtOAc (100 mL). Palladium hydroxide (2% by weight on carbon, 200 mg) was added thereto and the mixture was stirred under a hydrogen atmosphere of 800 P si (54.4 atm) overnight. The mixture was then filtered through celite and the filter cake was washed thoroughly with EtOAc. The filtrate was concentrated and the residue was purified by flash chromatography to afford &lt;RTI ID=0.0&gt;&gt; Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)cyclohexyl}acetic acid methyl ester 〇'H NMR (3 00 MHz, CDC13) : δ ppm 1.05- 1.22 ( m , 2H &gt; 1.40- 1 .5 5 ( m &gt; 2H ) , 1 · 8 0 -1 · 9 5 ( m,5 Η ), 2.21-2.26 ( m,2H ) , 2.40-2.50 ( m,1H ) &gt 2.5 5 -2.65 ( m,2H ) , 3.66-3.73 ( m,5H ) , 4.64 ( s,2H) &gt; 7.11- -52- 201040174 7.2 1 ( m,4H ). PREPARATION EXAMPLE EXAMPLE 1 { 4-[ 4-(4-Amino-2-methoxy-5. oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)- Preparation of 3-fluorophenyl]cyclohexyl}acetic acid

Add lithium hydroxide (4.3 mg, 0.18 mmol) to {4-[4-amino-2-methoxy- in THF/MeOH / water (2 mL, 3:2:1) 5-Phenoxy-7,8-dihydropyrido[4,3-(1]pyrimidin-6(511)-yl)-3-fluorophenyl]cyclohexyl}acetic acid methyl ester (20 mg, 0.04 5 In a solution of Q millimolar), the resulting solution was stirred at room temperature for 4 hours. 1 M HCl was added to the reaction solution to adjust the pH to about 3. 2% isopropyl alcohol in DCM was added to the reaction mixture. The organic layer was collected and dried. The solid was purified by chromatography (4 g EtOAc EtOAc EtOAc EtOAc EtOAc Oxy-5-yloxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-fluorophenyl]cyclohexyl}acetic acid (1-A) ( 8 mg, 40% yield) NMR (400 MHz &gt; MeOH-J4) δ ppm 1.09 - 1 .27 ( m , 1H) &gt; 1.42- 1.56 ( m &gt; 1H ) &gt; 1.62-1.74 ( m &gt 4H ), -53- 201040174 1.77- 1.95 ( m,2H ) , 2.20 ( d,J = 7.06 Hz,1H ) , 2.40 (d,J = 7.48 Hz,1H ) &gt; 2.46-2.56 ( m &gt; 1H ) , 2.56-2.67 (m 1H ) , 3.00 (t, J = 6.85 Hz, 2H ) , 3.8 1-3.88 ( m &gt; 2H ) 3.92 ( s, 3H ) , 6.99-7.13 ( m &gt; 2H) &gt; 7.20-7.29 ( m,lH °m/z = 429.5 (M+l). Example 2 {trans-4-[4-(4-Amino-2-methoxy-5-sideoxy-7,8-dihydropyridine) Preparation of [4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid (2-A);

Add lithium hydroxide (12.6 mg, 0.3 mmol) to {4-[4-(4-amino-2-methoxy-) in THF/MeOH/7jc (2:2: 0.3 mL) 5-Sideoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid methyl ester (14 mg, 0. 〇33 mmol) ) in the solution. The resulting solution was stirred at EtOAc (3 mL). EtOAc was evaporated. The mixture was washed with water and dried under a high vacuum of 45 ° C to give a white compound as a white solid (trans-4-[4-(4-amino-2-methoxy-5-s. 8-Dihydropyrido[-54- 201040174 4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid (6.8 mg, 50% yield). NMR (500 MHz &gt DMSO-i/e) δ ppm 1.08-1.18 ( m ,2H ) &gt; 1.3 9- 1.53 ( m &gt; 2H ) , 1.67 -1 · 8 6 ( m,6H ), 2.14 (d,2H) , 2.94(t, 2H) , 3.81-3.91 (m, 5H), 7.17-7.3 1 ( m &gt; 4H ) , 7.79 (s, lH) , 8.36 (s, lH), 1 2.05 ( s &gt; 1 H °m/z = 411.0(M+l). 0 {trans-4-(4-(4-amino-2-methoxy-5-sideoxy-7,8-dihydropyridyl) Preparation of 4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid hydrochloride (2-B): 1.0 M HCl (0.165 mL, 0.165 mmol) was added to 4-(4-(4-Amino-2_methoxy-5-sideoxy-7,8-di) a mixture of pyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid (2-A: 60 mg, 0.15 mmol) and MeOH (3 mL) Stir at room temperature. Concentrate the mixture at +35 ° C and dry in vacuum Q to give {trans-4_[4-(4-amino-2-methoxy-5-sideoxy) 7,8-Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid hydrochloride (65 mg, 100% yield). 11 1/2 = 411.0 ( M+ 1 ). {trans-4-[4-(4-Amino-2-methoxy-5-oxyl-7,8-dihydropyrido[4,3-d]pyrimidin-6 ( Preparation of 5H)-yl)phenyl]cyclohexyl}acetic acid potassium salt (2-C): {trans-4-[4-(4-amino-2-methoxy-5-sideoxy-) 7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}ethyl-55- 201040174 methyl ester (2-A: 119.0 g, 280·3 m Mole), THF (714 mL) and 1 Torr. The slurry was passed for 30 minutes. The mixture was filtered through MeOH (100 mL EtOAc). EtOAc &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&& , the obtained {trans-4-[amino-2-methoxy-5-side [j-pyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl] potassium salt ( 85 grams, 67.6% yield). lH NMR (400 MHz, DMSO-d6) δ ppm , 2 Η ) 1.28- 1.46 ( m &gt; 2 Η ) 1 .59 ( br. s. 1·87(πι,6 Η) 2.32-2.45 (m,1 Η) 2.90( , 2 Η) 3.77-3.93 ( m , 5 Η) 7.20 ( s , 4 J = 3.51 Hz, 1 Η) 8.34 ( d, J = 3.71 Hz, 1 Η (Μ +1 ). {trans Preparation of (4-amino-2-bromo-5-oxo[4,3-d]pyrimidin-6(5Η)-yl)phenyl]cyclohexyl (2-D): 1.0Μ NaOH (0.165 ml, 0.165 mM trans-4-[4-(4-amino-2-methoxy-5-oxo-7-[4,3-d]pyrimidin-6(5H)-yl) Phenyl]cyclohexyl 60 mg, 〇15 mmol) and MeOH (3 mL) allowed to stir at room temperature. The mixture was heated at +35 ° C, MeOH ( 357 (874.63 g. The cleaned hydrazine is concentrated to remove the wash. The filter cake is white acicular oxy-7,8-dihydrocyclohexyl}acetic acid 0.86-1.04 (m » 1 Η ) 1.64-:t, J = 6.73 Hz Η 7.74 ( d, ). m/z = 411.0 -7,8-dihydropyridinyl} sodium acetate salt) added to a mixture of {,8-dihydropyridin}acetic acid (2-A:, concentrated Drying in vacuum -56 - 201040174 ·{trans-4-[4-(4-Amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)- Sodium phenyl]cyclohexyl}acetate (65 mg, 1% yield) 411.0 ( Μ+L). Example 3 (trans-4-{4-[(7R)-4-amine 2-yloxy-7-methyl-5-oxooxy 0-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl]phenyl}cyclohexyl)acetic acid Preparation: NH,

The title compound was used according to the procedure described in Example 1 (trans-4-{4-[(7R)-4-amino-2-methoxy-7-methyl_5_sideoxy_Q Prepared by methyl 7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]phenyl}cyclohexyl)acetate (130 mg '0.296 mmol) to give an off-white solid (65 mg '52% yield). The resulting racemic mixture was separated on a Chiralcel OJ-H column (7〇: 3〇c〇2: Me0H 'at 10 g/min) to supply trans-4-{4-[(7R) 4-amino-2-methoxy-7-methyl-5-oxo-7,8-dihydropyrido[4,3-d] oxime- 6(5H)-yl]phenyl }cyclohexyl)acetic acid (3 mg, residence time = 2_94 minutes). *H NMR ( 400 MHz - MeOH-d4) δ ppm 1.11-1.25 ( m ,5H ) ' 1.47-1 ·ό2 ( m ' 2H ) , 1 · 7 7 - 1.9 8 ( m,5 Η ), 201040174 2.20 ( d, J = 6.65 Hz, 2H), 2.53 (t, J = 12.25 Hz, 1 H ), 2.71 (dd, J = 16.62, 3.74 Hz, 1H), 3.3 8 ( dd, J = 16.82 &gt; 6.44 Hz, 1H), 3.93 (s, 3H), 4.07-4.19 ( m -1 H ) , 7.20-7.26 ( m, 2H ) , 7.2 7 - 7.3 4 ( m, 2 H ). m/z = 42 5.5 ( M+ 1 ). Example 4 (trans-4· { 4-[( 7S ) -4-amino-2-methoxy-7-methyl-5-oxo-7,8-dihydropyrido[4,3] -d]Preparation of pyrimidine-6(5H)-yl]phenyl}cyclohexyl)acetic acid:

The title compound was used according to the procedure described in Example 1 (trans _4-{4-[(7R)-4-amino-2-methoxy-7-methyl-5- pendant oxy-7 , 8 -Dihydropyrido[4,3-d]pyrimidin-6 (5H)-yl]phenyl}cyclohexyl)acetic acid methyl ester (130 mg, 0.296 mmol) to provide acid (65 mg , 52% yield). The resulting racemic mixture was separated on a Chiralcel OJ-H column (70:30 CO 2 : MeOH at 10 g/min) to afford (trans-4-{4-[(7S)-4- Amino 2-methoxy-7-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]phenyl}cyclohexyl) Acetic acid (3 mg, residence time = 3.72 minutes). -58- 201040174 NMR ( 400 MHz &gt; MeOH-£/4) δ ppm 1.11-1.25 ( m ,5H ) , 1.47- 1.62 ( m,2H ) ,1 · 7 7 - 1 . 9 8 ( m,5 H ), 2.20 ( d, J = 6.65 Hz, 2H ) , 2.53 ( t, J = 1 2 · 2 5 Η z, 1 H ) , 2.71 ( dd, J = 16.62, 3.74 Hz * 1H ) , 3.3 8 ( dd , J = 16.82, 6.44 Hz, 1H), 3.93 (s, 3H), 4.07-4.19 (m, 1H), 7.20-7.26 (m, 2H), 7.2 7 - 7.3 4 ( m, 2 H ). m/z = 425.5 ( M+1 ) 〇o Example 5 {trans-4-[4-(4-Amino-2-methoxy-5-sideoxy-7,8-dihydropyridinium) Preparation of 4,3-d]pyrimidin-6(5H)-yl)-2-methylphenyl]cyclohexylindoleacetic acid:

The title compound was used according to the procedure described in Example 2: {4-(4-amino-2-methoxy-5-oxooxy-7,8-dihydropyridino[4, Prepared by 3-d-pyridyl-6(5H)-yl)-2-methylphenyl]cyclohexyl}acetic acid methyl ester (62 mg, 0.14 mmol) to provide {trans _4_[ 4- (4-Amino-2-methoxy-5-sideoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methylphenyl]cyclohexyl }Acetic acid (33 mg, 5 5 % yield). 'H NMR ( 5 00 MHz - DMSO-i6) δ ppm 〇. 8 5- 1.3 0 ( m -59- 201040174 ,2H ) , 1.28- 1.56 ( m,2H ) &gt; 1.60-1.94 ( m &gt; 5H ) , 2.12 ( d, J = 6.65 Hz, 2H ) , 2.25 ( s, 3H ) , 2.54-2.68 ( m, 1H ) , 2 · 8 9 ( t, J = 6.6 5 Hz, 2H) &gt; 3.61-3.96 ( m &gt; 5H) , 7.07 ( s, 2H ). m/z = 42 5 · 5. ( M+1 ). Example 6 {trans-4-[4-(4-Amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H) Preparation of -yl)-2-chlorophenyl]cyclohexyl}acetic acid:

The title compound was used according to the procedure described in Example 2: {4-(4-amino-2-methoxy-5-oxooxy-7,8-dihydropyridin[4] , 3-d]pyrimidine-6(5H)-yl)-2-chlorophenyl]cyclohexyl}acetic acid methyl ester (50.5 mg, 0.11 mmol) to give {trans-4-[4- (4-Amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-chlorophenyl]cyclo Hexyl}acetic acid (8 mg, 20% yield). NMR ( 5 00 MHz &gt; DMSO-J6) δ ppm 1.01-1.19 ( m , 2H) &gt; 1.38-1.54 (m - 2H) , 1.64-1.89 (m, 5H) 2.13 (d, J = 6.65 Hz, 2H ), 2.85 ( t, J = 8.72 Hz, 1 H ), 2.9 1 ( t, J = 6.8 5 Hz, 2H ) , 3.82 ( s, 3H ) , 3.86 ( t, -60- 201040174 J = 6.65 Hz, 2H ), 7.26 (d, J = 8.3 1 Hz, 1H), 7.34-7.45 (m, 2 H ). m/z = 445.5 ( M+l). Example 7 {trans-4-[4-(4-Amino-2-methoxy-7-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine) Preparation of 6(5H)-yl)-2-fluorophenyl]cyclohexyl}acetic acid:

The title compound was used according to the procedure described in Example 1 to give the formula: </RTI> <RTIgt; </RTI> 4-[4-(4-amino-2-methoxy-7-methyl-5- </RTI> • Nitrogen D was prepared with methyl pyridine[4,3-d]pyrimidin-6(5H)-yl)-2-fluorophenyl]cyclohexyl}acetate (80 mg, 0.18 mmol) to provide { Trans-4-[4-(4-Amino-2-methoxy-7-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine-6 ( 5H)-yl)-2-fluorophenyl]cyclohexyl}acetic acid (25 mg, 32% yield). NMR (500 MHz &gt; MeOH-d4) δ ppm 1.11-1.28 ( m , 5H ) , 1.47 - 1.63 ( m, 2H ) &gt; 1.76- 1 .96 ( m &gt; 5H ), 2.20 ( d, J = 7.06 Hz, 2H ) , 2.71 ( dd, J = 17.03, 3.74 Hz , 1H) , 2.7 6- 2.89 (m, lH) &gt; 3.31-3.38 ( m &gt; 1H ), 3.92 ( s, 3H ) · 4.06 -4.18 ( m ' 1H ) , 7.00 ( dd, Jl 7.65, 8.52 Hz, 2H ) , 7.29 ( t, J-8.3 1 Hz, 1H ). -61 - 201040174 m/z = 443 · 5 ( M+1 ). Example 8 {trans-4-[4-(4-Amino-2-methoxy-5-oxooxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H) Preparation of 2-yl-2-fluorophenyl]cyclohexyl}acetic acid: NH2

The title compound was obtained from {trans-4-[4-(4-amino-2-methoxy-5-oxooxy-7,8-dihydropyridino[4] according to the procedure described in Example 1. , 3-d pyrimidine-6(5H)-yl)-2-fluorophenyl]cyclohexyl}acetic acid methyl ester (150 mg, 0.339 mmol) to provide {trans-4-[4- (4-Amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-fluorophenyl]cyclo Hexyl}acetic acid (70 mg, 36% yield). 1H NMR ( 400 MHz - DMSO-d6 ) δ ppm 1.01-1.18 ( m, 2H ) , 1.49 ( q - J = 12.19 Hz, 2H ) , 1.58-1.87 (m, 5H ) , 2.12 ( d, J = 7.06 Hz &gt; 2H ) &gt; 2.65 -2.8 0 ( m &gt; 1H ) , 2.9 1 ( t, J-6.85 Hz, 2H ) , 3 · 7 3 - 3 · 91 ( m, 5 H ), 7.06-7.21 (m , 2H) , 7.32 (t, J = 8.52 Hz, 1H), 7.82 ( d, J = 4.1 5 Hz, 1H ) , 8.30 (d, J = 4.15 Hz, 1 H ) , 12.03 (br. s., lH ) °m / z = 395.4 (M + l). -62- 201040174 Example 9 {trans-4-[4-(4-amino-2-(isopropoxy-5-yloxy-7,8-)-gas D-pyridyl[4,3-d Preparation of pyrimidine-6(5H)-yl)phenyl]cyclohexyl}acetic acid:

The HO title compound was obtained from {trans-4-[4-(4-amino-2-isopropoxy-5-sideoxy-7,8-) gas liu according to the procedure described in Example 2. Prepared by [4,3_d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid methyl ester (10·4 mg, 0.023 mmol) to provide {trans-4-[ 4 - (4-Amino-2-isopropoxy-5-sideoxy-7,8-one gas enthalpy ratio and [4,3-d] succinate-6 (5H)-yl) phenyl] ring Hexyl}acetic acid (8.5 mg, 84% yield) 〇!H NMR (500 MHz &gt; DMSO-d6) δ ppm 1.03-1.19 ( m, 2 Η) &gt; 1 .28 ( d &gt; 6H ) , 1.39-1.54 (m, 2H), 1.66- 1.87 (m, 6H), 2.14 (d, 2H), 2.90 (t, 2H) &gt; 3.85 (t, 2H) &gt; 5.13-5.24 ( m &gt; 1H ) , 7.17- 7.29 (m, 4H), 7.69 ( d, 1H) &gt; 8.33 ( d &gt; 1H ) , 12.05 ( s, 1H). m/zM 3 9 · 0 o Example 10 -63- 201040174 (trans-4-{4-[ 4 -amino-2-(2-methoxyethoxy)-5-sideoxy.yl-7 Preparation of 8-dihydropyrido[4,3-(1]pyrimidin-6(511)-yl]phenyl}cyclohexyl)acetic acid:

The title compound was obtained from (trans-4-{4-[4-amino-2-(2-methoxyethoxy)-5-sideoxy-7,8 according to the procedure described in Example 2. -Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]phenyl}cyclohexyl)acetic acid methyl ester (14.1 mg, 0.03 mmol) to provide (trans-4- {4-[4-Amino-2-(2-methoxyethoxy)-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6 ( 5H )- Benzyl}cyclohexyl)acetic acid (5 mg, 40% yield). m/z = 45 5.0 ( M+1 ). Example 1 1 {trans-4-[4-(4-Amino-2-ethoxy-5-oxooxy-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5H) Preparation of -) phenyl]cyclohexyl}acetic acid: -64- 201040174

The title compound was obtained from {trans-4-[4-(4-amino-2-ethoxy-5-oxooxy-7,8-dihydropyridino[4] according to the procedure described in Example 2. , 3-d pyrimidine-6(5H)-yl)phenyl]cyclohexyl}acetate methyl ester (11 mg €), 0.02 5 mmol) to provide {trans-4-[4-( 4-Amino-2-ethoxy-5-sideoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid (8 Mg, 80% yield). *H NMR ( 5 00 MHz &gt; DMSO-d6) δ ppm 1.07-1.19 ( m , 2H ) , 1.28 ( t,3H) &gt; 1.3 9- 1.54 ( m &gt; 2H ) &gt; 1.68- 1.85 (m, 6H) , 2.14(d,2H) , 2.91(t,2H) &gt; 3.84 (t,2H) , 4.29 ( q,2H) &gt; 7.21 -7.29 ( m &gt; 4H ) &gt; 7.73 (d, 1H ) , 8.35 ( d, 1H ) , 12.05 ( s, 1H ).

m/z = 425.0 ( M+l ). Example 1 2 {trans-4-[4-(4-Amino-2-methoxy-7-methyl-5-sidedoxy-7,8-dihydropyrido[4,3-d] Preparation of pyrimidine-6(5H)-yl)phenyl]cyclohexyl}acetic acid: -65- 201040174

The title compound was used according to the procedure described in Example 1 (trans-4-[4-(4-amino-2-methoxy-7-methyl-5- </RTI> Prepared with methyl pyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl)acetate (130 mg '0.30 mmol) to provide 2-(trans-4- [4-(4-Amino-2-methoxy-7-methyl-5-oxyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl) Phenyl]cyclohexyl}acetic acid (65 mg, 52% yield). NMR (400 MHz, METHANOL-d4) d ppm 1.08-1.28 (m« 5 H) 1.40-1.59 (m&gt; 2 H) 1.73-1.97 (m&gt; 5 H ) 2.20 ( d - J = 6.65 Hz, 2 H ) 2.49 ( t, J = 12.05 Hz, 1 H ) 2.70 ( dd, J = 16.62, 3.74 Hz, 1 H ) 3.3 0-3.3 9 ( m ' 1 H ) 3.92 (s&gt; 3 H) 4.02-4.15 (m&gt; 1 H) 7.13-7.21 (m&gt; 2 H )7.22-7.32 ( m,2 H ) .m/z = 425.5 ( M+l ) Example 1 3 2-(4-(4-(4-Amino-2-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6 (5H)) Preparation of -yl)phenyl)cyclohexyl)acetic acid: -66- 201040174

The title compound was used according to the procedure described in Example 1 using 2-(4-(4-(4-amino-2-methyl-5- oxo-7,8 - one gas D ratio D and [4] , 3-d]pyrimidine-6(5H)-yl)phenyl]cyclohexyl)acetic acid methyl ester (20 mg, 0 0.049 mmol) to provide 2-(4-(4-(4-amine) Benzyl-2-methyl-5-tertiaryoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 Η)-yl)phenyl)cyclohexyl)acetic acid (19 mg, 0.04 9 millimolar. *H NMR ( 400 MHz, ETH ETH AN OL - ί/4 ) δ ppm 1.08-1.32 (m,1 Η) 1.44-1.59 (m,1 Η) 1.61-1.77 (m,4 Η )1.77-1.96 (m,3 Η) 2.20 (d, /=6.64 Hz, 2 Η) 2.43 ( s - 3 Η) 2.45-2.67 ( m &gt; 2 Η) 3.04 ( t &gt; 7=7.42 Hz &gt; 2 Η) 3.87-4.00 ( m,2 Η) 7.15-7.40 ( m,4 H) .m/z = 3 95.4 (Example 1 4 {trans -4-[ 4- ( 4-amino-2-) Preparation of 5-yloxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid-67- 201040174

The title compound was used according to the procedure described in Example 1 to give the formula: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Prepared by methyl 3-d]pyrimidin-6(5Η)-yl)phenyl]cyclohexyl}acetate (60 mg, 0.15 mmol) to provide {trans-4-[4_(4-amino)- 2-Methyl-5-o-oxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5 Η)-yl)phenyl]cyclohexyl}acetic acid (52 mg, 90% yield) rate). H NMR ( 500 MHz - DMSO-d6) δ ppm 1.08- 1.2 8 ( m , 2H ) , 1.44 - 1.64 ( m, 2H ) &gt; 1.75 - 1.97 ( m &gt; 5H ), 2.21 ( d &gt; J = 7.06 Hz, 2H) , 2.4 2 - 2 · 5 8 ( m, 4 H ) &gt; 3.18 (t, J = 6.85 Hz, 2H ) , 4.01 ( t, J = 6.85 Hz, 2H) , 7.28 (q, J = 8.5 9 Hz &gt; 4H ). m/z = 3 95.1 ( M + 1 ). Example 15 {cis-4-[4-(4-Amino-2-methyl-5-sideoxy-7,8-one gas oxime 卩疋[4,3-d]pyrimidine-6 (5H Preparation of p-phenyl)cyclohexyl}acetic acid -68- 201040174

The title compound was used according to the procedure described in Example 1 for </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Prepared by methyl 3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetate (50 毫克 mg, Ο 2 mol) to provide {cis-4-[4-(4) -amino-2-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid (40 mg, 83% yield). !H NMR (400 MHz &gt; MeOH-d4) δ ppm 1.61-1.78 (m,8H), 2.20-2.30 (m,lH), 2.39-2.47 (m,5H), 2 54-2.66 ( m,1 H ) ' 3.06 ( t &gt; J = 6 · 8 5 Hz ' 2H ) ' 3.95 ( t,j = 6.85 Hz, 2H ) , 7.28 ( dd - 4H ). m/z = 3 9 5 · 1 ( M+1 )° 实例 Example 16 {trans _4-[ 4- ( 4-amino-2,7-dimethyl-5-sideoxy-7,8 -Preparation of dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid: -69- 201040174

OH

反',,, {trans-4-[4-(4-amino-2,7-dimethyl-5-oxo-7,8-dihydropyridine) in MeOH (1.5 mL) A solution of [4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid methyl ester (25 mg, 0.059 mmol). A 2 M NaOH solution (0.75 mL) was added to the solution. The reaction was stirred for 2 days. The solvent was removed under reduced pressure and acidified with 1 citric acid. The solid was filtered off and dried in vacuo at 50 °C over 4 h. Purification of the white solid using reverse-phase preparative HP LC to afford &lt;RTI ID=0.0&gt; [4,3-d] Pyrimidine-6(511)-yl)phenyl]cyclohexyl}acetic acid (4 mg '20% yield). 1H NMR ( 4 〇〇 MHz &gt; Chloroform-d ) δ ppm 1.13-1.24 (m &gt; 2H ) , 1.26 ( d, J = 6.64 Hz ' 3H ) &gt; 1.45-1.60 ( m

, 2H ) , 1.8 3 -2.02 ( m &gt; 5H) » 2.30 ( d &gt; J = 6.83 Hz &gt; 2H ), 2.52 (br. S. '4H) , 2.84 (dd'J=16.69, 3.61 Hz, 1H ) , 3.40 ( dd 1 J= 16.79, 6.25 Hz, 1H ) , 4.08-4.1 8 ( m,1H) , 6.33 ( br. S. ' 1 H ) , 7 · 2 3 - 7 · 3 1 ( m, 2 H ) ' 8.62 ( br. s. 1 H ) ° Example 17 -70- 201040174 {trans-4-[4-(4-amino-2-ethyl-5-sideoxy-7,8- Preparation of 卩•N-Nb-indene and [4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid

The title compound was used according to the procedure outlined in Example 1 to use: &lt;RTIgt;&lt;RTIgt;&lt;/RTI&gt; 4- 4- 4- 4-amino-2-ethyl-5-sideoxy-7,8-dihydropyridin[4, Prepared by 3-D-pyrimidine-6(5H)-yl)phenyl]cyclohexyl}acetic acid methyl ester (26 mg, 0.062 mmol) to provide {trans-4-[4-(4-amino) 2-ethyl-5-o-oxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid (15 mg, 57% yield) rate). 'H NMR (500 MHz &gt; DMSO-d6) d ppm 1.08-1.14 ( m , 2 H) 1.22 (t,3 H) 1.42-1.51 (m,2 H) 1.69-1.85 (m &gt; 5 H) 2.13 (d - 2 H) 2.43-2.48 (m&gt; 1 H) 2.62 (q - 2 H) 2.97 (t&gt; 2 H) 3.88 (t&gt; 2 H) 7.21-7.32 (m&gt; 4 H) 7.73 (s&gt; 1H 8.25 (s&gt; 1H) 12.06 (s&gt; 1H). Example 1 8 {trans-4-[4-(4-Amino-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl Preparation of cyclohexyl}acetic acid: -71 - 201040174

Add lithium hydroxide solution (2.0 M solution in water, 3.36 ml) to 2-(trans-4-(4-amino-4-yloxy)- in dioxane (25 mL) a solution of methyl 7,7-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)cyclohexyl)acetate (265 mg, 0.672 mol) with a mixture at 45 ° Stir for 4 hours at C. After cooling to ambient temperature, the volume of the reaction mixture was reduced to 5 ml in vacuo and water (5 mL) was added. The solution was acidified to about pH 2-3 with 10% aqueous citric acid and the resulting precipitate was collected by filtration. The collected solid was washed with EtOAc (EtOAc m. *H NMR 1.00-1 . 15 ( m &gt; 2H ) - 1.38-1.50 (m&gt; 2H) , 1.62-1.83 (m, 5H) &gt; 2.08-2.1 3 ( m &gt; 2H ) , 2.40-2.50 | ) (m - 1H), 2.97 (t, 2H), 3.87 (t, 2H), 7.18-7.28 (m, 4H), 7_56 (bs, NH), 8_24 (bs, NH), 8.34 (s, 1H). Pharmacological Tests The practice of the invention for treating diseases modulated by inhibition of DGAT·1 can be confirmed by activity in at least one of the following modes. -72- 201040174 In vitro assay for inhibition of DGAT-1 activity Human full-length dimercaptoglycerol: thiol CoA thiol transferase 1 (DGAT-1) is expressed in Sf9 insect cells 'then it is then dissolved and crude cell membrane is prepared Part (105,000 χ 8 cell pellet) ° DGAT_1 gene is the human DGAT-1 gene described in J. Biol Chem 273: 26765 (1998) and US Pat. No. 6,100,077. The in vitro inhibition of DGAT-1 was measured using a modification of the assay described in U.S. Patent No. 0,994,956 B2, which is further described below.

The cell line was cultured as follows. Sf9 cells (20 liters) in Wave Bioreactor System 20/50P (Wave Biotec/GE

In 4 ml of insect cells (BIIC) infected with DGAT-1 baculovirus (Baculovirus) were infected in 72 hours. The crude DGAT-1 particulate system was prepared as follows. The cell pellet was washed once with ice-cold Dulbecco's phosphate buffered saline. The fine cells were collected in a tabletop centrifuge (Beckman GS-6KR) for 15 minutes, 2000 x g, 4 °C. 20 ml of ice-cold Microsome Buffer (MB) was added per 5 gram of cell pellet. The suspension was passed through a microcell mill 3 times (18K psi). The lysate was transferred to a centrifuge tube and centrifuged at 5000 xg for 20 minutes at 4 ° C (86 〇 1 ^ & 11 - Coulter, Inc., Allegra® 64R high speed refrigerated tabletop centrifuge (High-Speed Refrigerated Benchtop) Centrifuge ) , F0 6 5 0 rotor). The supernatant was transferred to an ultracentrifuge tube and centrifuged at 125,000 xg for 1 hour at 4 °C in a Beckraan Ti-45 rotor. Discard the supernatant stream -73- 201040174. The cell pellet was resuspended in 70 ml of MB with ultrasound. The mitochondrial concentrate was measured using the Bio-Rad Protein DC Protein assay. The samples were dispensed, snap frozen and stored at -8 °C. Microsome buffers for microsome preparation were prepared in a conventional manner and contained 125 mM sucrose, 3 mM imidazole, 0.2 μg/ml aprotinin, 0.2 μg/ml leupeptin and 5 mM dithiothreitol ( Cleland reagent) at pH = 7.4. DGAT-1 activity was measured in a 3 84-well format with a total assay volume of 20 μl containing Hep es buffer (50 mM » pH 7.5 ), MgCl 2 (10 mM ), bovine serum albumin ( 0.6 mg/ml), [14C] mercapto C〇A (25 μΜ '58 Ci/mole) and 1,2-dioleyl-sn-glycerol (75 μΜ) particles that have been incorporated into acetone Body (5.6 μg/ml). The inhibitor in DMSO was pre-incubated with the cell membrane before the DGAT-1 reaction was initiated by the addition of 癸醯CoA. The two control DGAT-1 responses were also co-cultured: 1) DMSO without inhibitor to measure the inhibitory effect of 0% and 2) 1 μΜ {trans-4-[4-(4-amino-2, DGAT- for the maximum inhibition of 7,7-trimethyl-7-pyrimido[4,5-b][1,4]oxan-6-yl)phenyl]cyclohexyl}acetic acid (W02004/047755) 1 reaction (&quot;blank&quot;)' which is a sample of 1% effect. The DMSO concentration in the reaction mixture was 2.5%. Inhibitors were present in 8 concentration ranges' to produce an apparent IC 5 每一 for each compound. The concentrations of the eight inhibitors used ranged from 3 μΜ to 1 nM (from high to low concentrations). The eight concentrations used are especially 3 Ι^Μ, 1 μΜ, 300 η Μ, 1 0 0 η Μ, 3 0 η Μ, 1 〇 η Μ, 3 η Μ and 1 η Μ. The reaction was allowed to continue at room temperature for 1.5 hours and then terminated by the addition of -74-201040174 20 microliters of EDT A (40 mM). The reaction mixture was then mixed by wet milling with 30 microliters of MicroscintTM-E (Perkin Elmer). Allow the flat contents to be isolated for 15 to 30 minutes before measuring 14C in a scintillation spectrometer (Walac Microbeta Trilux 1 450-030, 12 detector in top-count DPM mode). The percent inhibition of the test compound was calculated by computer using 100-((unsuppressed DMP DMSO-DMP test compound) / (uninhibited DMP DMSO). 0 Four separate assays using 4 different analytical methods The analytical method of assay 1 is the same as that of assay 4 (described above), except that 25 μg/ml of microsomes are used instead of 5 μg/ml. The analytical method of assay 2 is the same as that of assay 4 (described above). Except that the concentration of 11 inhibitors was used instead of 8 . The analytical method of assay 3 was the same as that of assay 2, except that the compounds were serially diluted in different laboratories. The exemplary embodiments of the invention described in the above examples were tested. Inhibition of DGAT-1 in the test tube of the compound, and it was found that the IC50値〇 shown in Table 1 exhibited DGAT-1 inhibition, wherein the DGAT-1 inhibition assay was performed on the compound more than once, providing a test average of the compound.値》-75- 201040174 Table 1 Example No. Compound Name Verification Method 1 Verification Method 2 Verification Method 3 Verification Method 4 1 {4-[4-(4-Amino-2-methoxy-5. Side Oxy-7 , 8-dihydropyridine [4,3-(1)pyrimidin-6(5H)-yl)-3-fluorophenyl]cyclohexylindoleacetic acid 0.0016 n=4 2-A {trans-4-[4-(4-amino) 2-methoxy-5-oxooxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid 0.00156 n=4 0.00917 n TM2 0.00359 n=2 2-B {trans-4-[4-(4_Amino-2.methoxy-5-sideoxy-7,8-dihydropyrido[4,3-d] Pyrimidine D-6(5H)-yl)phenyl]cyclohexyl}acetate hydrochloride 0.0239 0.0142 2-C {trans-4-[4-(4-amino-2-methoxy-5-) Side oxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid potassium salt 0.00663 n=2 0.0387 n=2 2-D {trans-4-[4-(4-Amino-2-methoxy-5-oxooxy-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5H) -yl)phenyl]cyclohexyl}acetic acid sodium salt 0.00429 n=3 3 (trans-4_{4_[(7R)-4-amino-2-methoxy-7-methyl-5-sideoxy) -7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]phenyl}cyclohexyl)acetic acid 0.0101 n=3 4 (trans-4-{4-[(7S) -4-amino-2-methoxy-7-methyl-5-oxyl-7,8-dihydropyrido[4,3-d] Pyridin-6(5H)-yl]phenyl}cyclohexyl)acetic acid 0.0837 n=3 5 {trans-4-[4-(4-amino-2-methoxy-5-sideoxy-7, 8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-methylphenyl]cyclohexyl}acetic acid 0.00303 n=3 6 {trans-4-[4- (4 -amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyramid-6(5H)-yl)-2-chlorophenyl]cyclohexyl }Acetic acid 0.00426 n=4 7 {trans-4-[4-(4-Amino-2-methoxy-7-methyl-5-sideoxy-7,8-dihydropyrrole 0.0165 0.0383 n= 2 -76- 201040174 并[4,3-d]pyrimidine D-6(5H)-yl)-2-ylphenyl]cyclohexyl}acetic acid 8 {trans-4-[4- (4-amine Benzyl-2-methoxy-5-tertiaryoxy-7,8-dihydrochad[4,3-d]pyrimidin-6(5H)-yl)-2-fluorophenyl]cyclohexylindoleacetic acid 0.00379 0.0144 n=4 9 {trans-4-[4-(4-Amino-2-isopropoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidine -6 (5H)-yl)phenyl]cyclohexyl}acetic acid 0.183 n=2 0.142 10 {trans-4-[4-(4-amino-2-(2-methoxyethoxy)-5 -Sideoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclo Hexyl}acetic acid 0.434 11 {trans-bucket [4_(4-amino-2-ethoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6 (5H) -yl)phenyl]cyclohexyl}acetic acid 0.0307 n=2 0.0207 12 {trans-4-[4-amino-2-methoxy-7-methyl-5-sideoxy-7, 8-—Gas ratio is determined by [4,3-d]pyrimidin-6 (5H)-yl)phenyl]cyclohexyl}acetic acid 0.00687 0.0719 n=4 13 {4-[4-(4-Amino) -2-methyl-5-o-oxy-7,8-dihydropyrido[4,3-(1]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid 0.231 n=3 14 { Trans-4-[4-(4-Amino-2-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl) Phenyl]cyclohexyl}acetic acid 0.618 n=2 15 {cis-4-[4-(4-ylanyl-2-methyl_ 5-sideoxy-7,8-dihydropyrrole[4 ,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid 0.717 n=2 16 {trans-4-[4-(4-amino-2,7-dimethyl -5-Sideoxy-7,8-dihydropyrido[4,3-d]pyrimidine-6 (5H)-yl)phenyl]cyclohexyl}acetic acid 0.412 n=2 0.252 n=4 -77 - 201040174 17 {trans-4-[4-(4-Amino-2-ethyl-5-sideoxy-7,8-dihydro Pyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid 0.598 18 {trans-4-[4-(4-amino-5-sideoxy-7, 8-Dihydro-deep-[4,3-(1)pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid 0.0140 n=2 In vivo assay for reducing glucose oral glucose tolerance The trial (&quot;〇GTT〃) has been used in humans since the 1980s (Pincus et al., Am J Med Sci 188, 782 (1 934)) and is routinely used for the diagnosis of human diabetes, although no therapeutic agents have been evaluated. The effectiveness of the patient. KK mice have been used to evaluate glitazone (Fujita et al., Diabetes, 32, 804-8 1 0 (1 983); Fujiwara et al.

Diabetes, 37, 1549-48 (1988); Izumi et al. Biopharm

Drug Dispos., 18, 247-257 (1997)), Meifoming (Reddi et al., Diabet Metabl, 19, 44-5 1 (1993)), glucosidase inhibitors (Hamada et al., Jap Pharmacol Ther, 17, 17-28 (1 98 8 ); Matsuo et al Am J Clin Nutr., 55, 3 14S-3 1 7S (1 992 )) and additional pancreatic urea pancreatic effects (Kameda et al. Arzenim Forsch) ./Drug Res, 32,39044 (1 982); and Murl Metabl Res, Muller et al., 28, 469-487 (1 990)). KK mice are derived from the close relatives established by Kondo et al. (Kondo et al. Bull Exp Anim, 6, 107-112 (1957)) -78-201040174. Mice naturally develop a genetic form of polygenic diabetes that progresses similarly to those observed in human diabetic subjects, but does not require insulin or other agents for survival. Another aspect of the invention is directed to the use of KK mice to assess the effects of insulin secretion promoters in the context of an oral glucose tolerance test. In Vivo Assay for Food Intake 0 The following selections can be used to assess the efficacy of test compounds in inhibiting food intake in Sprague-Dawley rats after overnight fasting. Male Sprague-Dawley rats were individually housed and fed into powdered food. Keep them in a 12-hour daylight/dark cycle and receive food and water ad libitum. Animals were used to raising their premises during the week prior to testing. The test is performed during the daylight of the cycle. For food intake efficacy screening, rats were transferred to individual test cages without food and the rats were fasted overnight after the test.给 After overnight fasting, the rats were given vehicle or test compound the next morning. A known antagonist (3 mg/kg) was administered as a positive control group and the control group received a separate vehicle (no compound). Test compounds in the range of 0.1 and 100 mg/kg depending on the compound are administered. The standard vehicle is 0.5% (w/v) methylcellulose in water and the standard route of administration is oral. However, different vehicles and routes of administration may be used to conform to the various compounds as needed. Food was supplied to rats 30 minutes after dosing and the Oxymax automated food ingestion system (Columbus Instruments, Columbus, Ohio) was initiated. Individual rats' food intake was continuously recorded at 1 minute intervals during the 2-hour period -79-201040174. When needed, use an electronic scale to manually record food intake; after serving the food, weigh the food every 30 minutes up to 4 hours after serving the food. The potency of the compounds was determined by comparing the food intake profiles of the rats and vehicle treated with the compound and the standard positive control group. Various publications have been referenced throughout the application. The entire disclosure of these publications is hereby incorporated by reference in its entirety for all purposes. Those skilled in the art will recognize that various modifications and changes can be made in the present invention without departing from the spirit and scope of the invention. Other embodiments of the invention will be apparent to those skilled in the art from this disclosure. It is intended that the present invention be construed as being limited by the scope of the invention -80-

Claims (1)

201040174 VII. Patent application scope: 1. A compound of formula I a: 〇 wherein R 1 is hydrogen, (Κ 2) alkoxy, substituted by halo (Ci-Ca, halo-substituted (Ci-G) alkoxy or (G-C 2 ) alkyl; R 2 is independently Halogen, OH, (C)-C4)alkyl, cyano, cycloalkyl or ((^-(:4) alkoxy; R3 is hydrogen, alkyl, (Ci-Cz) alkoxy or - 0-) Affiliation-(C1-C2) alkoxy; and m is 0, 1, 2 or 3; hydrazine or a pharmaceutically acceptable salt thereof. 2. A compound according to the scope of claim 1 ^ Shown: ) Alkyl (C3-C6 (C!-C2 Z-port lb where (lb) -81 - 201040174 R1 is hydrogen or (CVC2)alkyl; R2 is hydrogen, halogen, OH, (Ci-C*)alkyl or (Ci-CU) alkoxy; R3 is hydrogen or (alkoxy) Or a pharmaceutically acceptable salt thereof. 3. A compound according to the first aspect of the patent application, which is represented by formula (II): Wherein R 1 is hydrogen; R 2 is hydrogen, halogen, OH, alkyl or ((^- mountain) alkoxy; and m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof. A compound of the first aspect of the patent, which is represented by the formula (111): (Hi) -82- 201040174 wherein R1 is hydrogen; R2 is hydrogen, halogen, OH, ((^-(:4)alkyl or (CrC^)alkoxy; and m is 0, 1, 2 or 3; Or a pharmaceutically acceptable salt thereof. 5. A compound according to the first aspect of the patent application, which is represented by the formula (❹ IV): Wherein R1 is hydrogen; 〇 R2 is hydrogen, halogen, (Ci-C)alkyl or (Ci-C2)alkoxy; and m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof. 6. The compound according to any one of claims 1 to 5, wherein R1 is hydrogen; R3 is selected from hydrogen, methyl or methoxy; and m is 1 〇7. From: { 4 -[ 4 -( 4 -Amino-2-methoxy-5-o-oxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl) 3-fluorophenyl]cyclohexyl}acetic acid; -83- 201040174 {trans-4-[4-(4-amino-2-methoxy-5-oxo-7,8-dihydropyridine) And [4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; {trans-4-[4-(4-amino-2-methoxy-5-sideoxy) -7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetate hydrochloride; (trans-4-{4-[ (7R) 4-amino-2-methoxy-7-methyl-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]phenyl} Cyclohexyl)acetic acid; (trans-4-{4-[(7S)-4-amino-2-methoxy-7-methyl-5-oxyl-7,8-dihydropyridinium[ 4,3-d]pyrimidine-6(5H)-yl]phenyl}cyclohexyl)acetic acid; {trans-4-[4-(4-amino-2-methoxy-5-sideoxy-) 7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-yl)-2-methylphenyl]cyclohexyl}acetic acid; {trans-4-[4-(4-amino-2-methoxy-5-sideoxy-7, 8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-chlorophenyl]cyclohexyl}acetic acid» {trans-4-[4-(4-amino-2) -methoxy-7-methyl-5-oxooxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2-fluorophenyl]cyclohexyl} Acetic acid; {trans-4-[4-(4-amino-2-methoxy-5-o-oxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H) -yl)-2-fluorophenyl]cyclohexyl}acetic acid 1 {trans-4-[4-(4-amino-2-isopropoxy-5-o-oxy-7,8-dihydropyridyl) -84- 201040174 pyridine[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; {trans-4-[4-(4-amino-2-(2- Methoxyethoxy)-5-o-oxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; {trans- 4-[ 4-(4-Amino-2-ethoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl] Cyclohexyl}acetic acid; {trans-4-[4-(4-amino-2-methoxy-7-methyl-5-sideoxy-7,8-dihydropyridinium) 4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; {4-[4-(4-amino-2-methyl-5-oxyl-7,8-) Dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; {trans-4-[4-(4-amino-2-methyl-5-) Side oxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; {cis-4-[4-(4-amino) -2-methyl-5-oxyl-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; 〇{trans-4 -[ 4-(4-Amino-2,7-dimethyl-5-oxooxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzene [cyclo]cyclohexyl}acetic acid; {trans-4-[4-(4-amino-2-ethyl-5- oxo-7,8-monoaminopurine 卩疋[4,3-d Pyrimidine-6(5H)-yl)phenyl]cyclohexyl}acetic acid; and {trans-4-[4-(4-amino-5-sidedoxy-7,8-dihydropyridin[4] , 3-d]pyrimidin-6(5H)-yl)phenyl]cyclohexyl}acetic acid; or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising (i) a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof; and (-85 - 201040174 π) pharmaceutically acceptable Excipient, diluent or carrier. 9. The composition of claim 8 wherein the compound or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount. 10. The composition according to claim 9 of the patent application, which further comprises at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent or an anti-diabetic agent. 11. The composition according to claim 10, wherein the anti-obesity agent is selected from the group consisting of dirlotapide, mitratapide, implitapide, R56918 (CAS No) 403987 ) , CAS No. 913541 -47-6 ), lorcaserin, cetistat _, ΡΥΥ3-36, naltrexone, oleoyl-estrone , obinepitide, pramlintide _'tesofensine, leptin, liraglutide, bromocriptine, orlistis He (orlistat), exenatide, AOD-9604 (CAS No. 22 1 23 1 - 1 0-3 ) or sibutramine. 1 2 · The composition according to claim 10, wherein the anti-diabetic agent is selected from the group consisting of metformin, acetohexamide, chlorpropamide, and debbie. Diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, Gliquidone, glisolamide, tolazamide, tobrahim (-86-201040174 tolbutamide), tendamistat, trestatin , acarbose (.acarbose), adiposine (adiposine), camiglibose, emiglitate, miglitol, voglibose, padi米Pradimicin.-Q, salbostatin, balaglitazone, eiglitazone, darglitazone, engglizon (◎ englitazone) , Isa Gatazon (isaglitazone), Pigta Pioglitazone, rosiglitazone, troglitazone, exendin-3, Ididine-4, trodusquemine, reservatrol , hyrtiosal extract, sitagliptin, vildagliptin, alogliptin or saxagliptin. 13. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for treating obesity and obesity-related disorders in an animal. A use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for treating or delaying the progression or onset of type 2 diabetes and a diabetes-related disorder in an animal. The use of a pharmaceutical composition according to any one of claims 8 to 12 for the manufacture of an agent for treating obesity and obesity-related disorders in an animal. 16. Use of a pharmaceutical composition of any of the inventions in the range of claims 8 to 12 for the manufacture of a type 2 diabetes and diabetes related condition for treating or delaying an animal Or the beginning of the potion. 17. Use of two separate pharmaceutical compositions for the manufacture of a medicament for treating a disease, condition or disorder modulated by DGAT-1 in a therapeutic animal, the two separate pharmaceutical compositions comprising: (i) a first composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, diluent or carrier; (U) a second composition comprising at least one additional pharmaceutical agent selected from the group consisting of an anti-obesity agent or an anti-diabetic agent, and a pharmaceutically acceptable excipient, diluent or carrier; wherein the inhibition by DGAT-1 The disease, condition or condition being modulated is selected from the group consisting of obesity, obesity-related disorders, type 2 diabetes or diabetes related disorders. 18. The use according to item 17 of the scope of the patent application, wherein the anti-obesity agent is selected from the group consisting of Delota, Miteta, Inpulita, R5 69 1 8 (CAS No. 403 98 7 ), CAS No. 913541-47-6), Lokallin, Zillistat, ΡΥΥ3·36, naltrexone, estrone, oleicidone, pralitre, tesofensine, leptin, lira Gutai, Pomok Kiosk, Orlistat, Aichna, AOD_96〇4 (CAS No. 221231-10-3) or Xibu Chaming; and the anti-diabetic agent is selected from Meifoming, Ai Tuga Shamai, Klobopai, Debini, Geblan, Ge, Zai, Geblai, Gemeilai, Ge Lazai, Ge Pantai, Ge Kuidong, Gesolamai, Tolasulfuron, tobrahim, tandamite, tristatin, acarbose 'adiposin, -88- 201040174 Cami Gebos, Amygtai, Megto, Fogo Pers , Padimisin-Q, Shabo Statin, Balaguezzon, Xige Tazong, Da Ge Ta Zong, Ngue Tazon, Isha Ge Tazon, Pigeta, Rosieta Zong, Uganda Tazon, Yidunding-3, Yisanding-4, Ugly Dukui Ming, Ruisai Faqiu, Hetiansha Extract, Sita Geting, Vida Geting, Aloji Pavilion or Shasa Geting. 19. The use according to claim 17 or 18, wherein the first composition and the second composition are administered simultaneously. 20. The use according to claim 17 or 18, wherein the first composition and the second composition are administered continuously and in any order. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment of a disease, symptom or condition modulated by inhibition of DGAT-1. -89 - 201040174 IV. Designated representative map: (1) The representative representative of the case is: None (2) The symbol of the representative figure is simple: No -3- 201040174 5. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: (la)