TW201102372A - Indane analogs and use as pharmaceutical agents and process of making - Google Patents

Abstract

This invention relates to novel indane analogues that are useful in the treatment of diseases and disorders such as treating and/or preventing diabetes and related disorders such as Syndrome X, impaired glucose tolerance, impaired fasting glucose, and hyperinsulinemia obesity, atherosclerotic disease, dyslipidemia, and related disorders such as hypertriglyceridemia, low HDL cholesterol, and hypercholesteremia, cardiovascular disease, cerebrovascular disease, psoriasis, or Alzheimer's disease. The invention also relates to intermediates useful in preparation of indane acetic derivatives and to methods of preparation.

Description

201102372 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention is generally directed to the use of a scorpion analog and its pharmaceutical composition for medical treatment. [Prior Art] π-type diabetes is a common form of diabetes, and 95% of patients with hyperglycemia experience this type of disease. In m-type urinary disease, there are some defects in the presence of parotid gland (4) and the presence of lycopene secretion. And the tissue is less sensitive to 姨 素. Symptoms and consequences of this form of diabetes include frequent urination, genital tract, blurred vision, frequent wound infection and slow healing, diabetic nerve damage, retinopathy, microvascular and macrovascular damage, and heart disease and kidney disease. The resistance of 姨 素 对 to metabolism is a key feature of TYPE 2 diabetes. Insulin resistance is characterized by impaired glucose uptake and utilization in insulin-sensitive target organs (such as fat cells and bone musculature) and glucose output. Inhibition of damage. Functional insulin deficiency 'peripheral insulin resistance and insulin inhibition of hepatic glucose output produce fasting hyperglycemia. Pancreatic p cells compensate for insulin resistance by secreting more insulin. , 'The field cell can't maintain this southern insulin output, and finally the glucose-induced insulin cleavage decline' leads to impaired glucose homeostasis and subsequent development of dominant diabetes: high insulin* disease is also associated with lycopene resistance, high triglyceride Hypertension, low m-duration, monthly g protein (HDL) cholesterol, and low-density lipoprotein (LDL) blood-increasing concentrations are associated with insulin resistance and hyperinsulinemia and such metabolic disorders such as 0 is called "symptoms" And is associated with increased risk of hypertension and coronary artery I48833.doc 201102372. Obesity is an excessive accumulation of adipose tissue. Excessive adipose tissue is associated with the development of severe medical conditions such as π-diabetes, hypertension, coronary artery disease, hyperlipidemia, obesity, and certain malignant diseases. Adipocytes can also affect glucose homeostasis by producing tumor necrosis factor a (TNFa) and other molecules. Atherosclerosis is known to be caused by a variety of factors such as hypertension, diabetes, low HDL levels, and high LDL levels. Atherosclerosis-related diseases include cardiovascular disease, coronary heart disease (CHD), cerebrovascular disease, and peripheral vascular disease. Coronary heart disease includes CHD death, myocardial infarction, and coronary revascularization. Cerebrovascular diseases include ischemic stroke or hemorrhagic stroke and transient ischemic attack. Psoriasis is a chronic, genetically affected 'relieving skin disease. It is estimated that bovine skin affects 1% to 3% of the world's population. The skin lesions of psoriasis are repeated. There are several types of psoriasis, including plaques, pustules, spots, and nine variants. The disease can occur in two different age ranges. The peak disease peak between the ages of 15 and 35 is the most frequent and frequent, and is related to the history of sputum. The peak incidence of advanced disease manifestations (type 2) occurs between the age of Η and 60 years old. Tian Hao, the available treatment of plaque psoriasis is incorporated into the use of emollients, dehorned shell coal tar, enphenol, medium to strong corticosteroids and ealpotriene. The efficacy of all such treatments is variable. However, these/oral therapies do not prevent frequent recurrence of the disease, and they all exhibit varying degrees of side effects. In some cases, systemic treatment has been used in patients with psoriasis who have a significant impact on the body, society, or economy and who do not respond to topical treatment. To date, the choice has been limited to phototherapy or systemic drug therapy. In general, systemic therapy has used phototherapy with ultraviolet B radiation, photochemotherapy with methoxsalen and ultraviolet A phototherapy (puVA), methotrexate, and Qudi vinegar (deduction (4) celestial (4), king's body, corticosteroids and cyclosporine (Cycl〇Sp〇rine). However, these systemic treatments each have indefinite effects and undesirable side effects. Alzheimer's Disease ("ADj" is the main cause of Alzheimer's disease worldwide. From the age of 65 until the age of 85, the incidence of the disease has steadily increased. In 2 years, there are an estimated 26,6 million people worldwide. Zehmer's disease. Determining that AD is a protein folding abnormality caused by the accumulation of Αρ&τ protein in abnormal folds in the brain. The plaque consists of a small peptide of 39-43 amino acids in length (called β-amyloid peptide, Also written as A_beta peptide or genus. The β-amyloid peptide is a fragment from a larger protein called a starch-like precursor protein (ΑΡΡ), a transmembrane protein that penetrates the neuronal membrane. Αρρ is involved in the nerve. Meta growth, survival and post-injury repair In Alzheimer's disease, ΑΡΡ is separated into smaller fragments by proteolysis of the enzyme. One of these fragments produces fibrils of β-amyloid peptides, which form a mass that is deposited on the outside of the neuron in a poorly-performing structure. (10) is a spot.) (4) The unstoppable decline in cognitive function is accompanied by a general behavioral change, which leads to the inability of the patient to take care of themselves in the society, resulting in the need for caregivers and home care and elderly nursing home attendants. There is no universally satisfactory treatment for Alzheimer's disease. There are some drugs for the treatment of these diseases, but still need 148833.doc 201102372 New drugs for safe and effective treatment of diseases. The present invention relates to a compound of formula I,

Wherein R is an alkyl group; R is Η, COOH, -C(,_0Ri, c3 c8 cycloalkyl, Ci_C6 alkyl, CVC6 alkenyl or Cl_c0 alkoxy, wherein R^C1_C6 alkyl, and the The cycloalkyl, sulfhydryl or fluorenyl group may be optionally substituted with or a plurality of groups selected from the group consisting of: I, methylenedioxyphenyl and phenyl, /, 2, 4 fluorene oxide The phenyl or phenyl group may be optionally substituted by R6; is a fluorenyl halide or a Ci-C6 alkyl group, wherein the alkyl group may optionally be substituted with one or more aryl groups selected from the group consisting of: a pendant oxy group (0X0) and fluorine, or a Cs-M aryl group, a C3_M heterocyclic ring or a c^4 heteroaryl group, wherein the aryl group, heterocyclic ring or heteroaryl group may be optionally substituted by one or more r6; Is H Cl-C6 alkyl or phenyl, wherein the alkyl or phenyl group may be substituted by a plurality of R6; 'X is 〇 or S; R is c5-14 aryl, C3 i4 heterocyclic ring or Cs &quot a heteroaryl group, wherein the aryl group, 148833.doc 201102372 heterocyclic or heteroaryl group is substituted by one or more R7, and the side gas R5 is η, i group or cva group, wherein the alkyl group is visible Substituent; R is halo' CF3, c丨-C6 a base wherein the alkyl group may be optionally substituted with a pendant oxy group or a hydroxy group; or optionally a fluorine substituted ring <6 alkoxy group; R7 is selected from the group consisting of: (a) thiol, (b) CVC6 An oxy group, wherein one or more of the alkoxy groups are (10) (9), and (c) - oxime-protecting groups; (4) - 0-C(=0)-Rh 'where r, Ci_C6 alkyl or C5•" An aryl group, wherein the aryl or aryl group may be optionally substituted with _ or a plurality of groups selected from the group consisting of: ghrelin, hydroxy, -SH, decylamine, carboxylic acid, CN, C& a thiol group, a 4-aryl group, and a C5"heteroaryl group; and a parallax, wherein Rc and Rd are independently hydrogen or a Ci_C6 alkyl group; (e) -〇-C(-0)-R11' wherein Rl" ·Claws and wherein ^ and ^ are independently gas or C!-C6 leuco; or pharmaceutically acceptable salts, esters, prodrugs, stereoisomers, diastereomers, enantiomers thereof a compound or a racemate. In some embodiments, the compound of formula j is a meglumine salt, a salt or a salt thereof. In one embodiment, for a compound of formula 1, the ruler is 11, and R1 is H. ί is H, R3 is c丨-C: 6 alkyl, \ is 〇 and ruler 4 is one or more R7 Diphenylene' wherein R7 is selected from the group consisting of (4) hydroxy, (8) c〆 alkoxy, and alkoxy- or a plurality of 11 is 2H(D), and (4)_〇_cH: 148833.doc 201102372

Ph, wherein the phenyl group may be optionally substituted with (: 1-(6 alkoxy; and R5 is hydrazine, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound has the following structure:

Another aspect of the invention provides a process for the preparation of a compound of formula la, which comprises dealkylating a compound of formula B to obtain a compound of formula la

COOR

COOR wherein R is HSCVCe alkyl for formula B and formula la; 148833.doc 201102372

Ri is hydrazine, COOH, _C(=0)-0R, C3-C8 cycloalkyl, CJ-C6 alkyl, c2-c6 alkenyl or CVC6 alkoxy, wherein R, Cl-C6 alkyl, and The alkyl, cycloalkyl, alkenyl or alkoxy group may be optionally substituted with one or more groups selected from the group consisting of fluorine, methylenedioxyphenyl and phenyl, wherein the anthracene dioxide The phenyl or phenyl group may be optionally substituted by R6; R2 is hydrazine, halo or CrG alkyl, wherein the alkyl group may optionally be substituted with one or more groups selected from the group consisting of: Cl-C6 alkoxylate a base, a pendant oxy group and a fluorine, or R 2 is a C 5 -C 14 aryl group, a C 3 -C 14 heterocyclic ring or a c 5 -C 14 heteroaryl group, wherein the hydroxy group and the heteroaryl group are optionally and independently passed through one or more R6 is substituted; R is hydrazine, Ci-C6 alkyl or phenyl, wherein the alkyl or phenyl group is optionally substituted with one or more R6; X is 0 or S; R is C"C6 alkoxy , R5 is hydrazine, halo or Cl_C6 alkyl, wherein the alkyl group is optionally substituted with a pendant oxy group; and R6 is halo, CF3, optionally substituted by a pendant oxy or hydroxy group, or optionally Fluorine substituted hydrazine-decyloxy. Ming another aspect, there is provided a method of preparing a compound b. The other method comprises Compound A dealkylation

Obtained compound B J48833.doc 201102372

C〇〇Rc wherein Rc is hydrogen or C"C6 alkyl. In another embodiment, in the method of preparing compound B, has the following structure

A h3co

<r-C〇〇H and Compound B has the following structure

COOH Further, a method of the present invention provides a method for preparing a compound hydrazine comprising a method of breaking an ether bond of O-CH^Ph of compound C.

Wherein Re is hydrogen or an alkyl group. Compound c In some embodiments, for the preparation of Compound D 148833.doc . ι〇. 201102372 has the following structure phH2C〇

,,CO〇H, the following structure

And Compound D has a pharmaceutical composition according to another aspect of the invention which provides a compound described herein. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable cutting agent. In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional therapeutic agents. Another aspect of the invention relates to methods of treating and/or preventing: diabetes and related conditions, such as syndrome X, abnormal glucose tolerance, abnormal fasting blood glucose and sputum gastrinemia; obesity; atherosclerosis Sclerosis, dyslipidemia and related disorders such as hypertriglyceridemia, low HDL cholesterol and hypercholesterolemia; heart and blood disease; and cerebral tube disease 0 Another aspect of the invention provides for the treatment and/or prevention of psoriasis And/or methods of Alzheimer's disease. The subject matter of the present invention will be understood by reading the following detailed description of the drawings and embodiments. [Embodiment] A. Definition: 148833.doc • II· 201102372 The term "halo" means F, Cl, Br or I. The term "CrC6 alkyl" means a straight or branched chain saturated hydrocarbon carbon chain having from 1 to about 6 carbon atoms, respectively. Examples of such groups include methyl, ethyl, isopropyl, t-butyl, pentyl, n-hexyl and the like. The term "Cs-C6 alkenyl" means a straight or branched chain unsaturated hydrocarbon carbon chain having from 2 to about 6 carbon atoms. Examples of such groups include ethenyl, allyl, isopropenyl, 2-butenyl, 3-ethyl-2-butenyl, 4-hexenyl and the like. The term "CrC: 6 haloalkyl" means a fluorenyl-fluorenyl group substituted with 1 to 3 halogen atoms or substituted with fluorine up to the degree of perfluoro. Examples of such groups include trifluoromethyl, tetrafluoroethyl, 1,2-dichloropropyl, 5-bromopentyl, 6-iodohexyl and the like. The terms "Cs-C6 cycloalkyl" and cycloalkyl" mean a saturated carbocyclic ring system having from 3 to about 6 carbon atoms or from 3 to about 8 carbon atoms, respectively. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "CrC6 fluorenyl" means an alkyl group attached at a carbon atom of a carbonyl group. The group is attached to the remainder of the molecule at the carbonyl group bearing a carbon atom. Examples of such groups include ethenyl, propyl fluorenyl, n-butyl fluorenyl, 2-methylpentenyl and the like. The term "CrC6 alkoxy" means a straight or branched chain saturated carbon group having from 1 to about 6 c atoms which is bonded to a ruthenium atom. A ruthenium atom is the point of attachment of an alkoxy substituent to the rest of the molecule. Such groups include (but 148833.doc 12 201102372 not limited to) methoxy, ethoxy, n-propoxy, isopropoxy and the like. The term "qc: 6 sulfanyl" means having from { to about 6 (: a straight or branched chain saturated carbon group of an atom, the carbon group being bonded to the s atom. The s atom based substituent and the rest of the molecule The group includes, for example, a methylthio group, a propylthio group, a hexylthio group, and the like. The term "CrC6 tooth alkoxy" means further substitution or passage via c to 3 halogen atoms on c. Fluorine is further substituted until the degree of perfluorination c _ c6 alkoxy. The term "CrC8 cycloalkoxy" means a c3_Cg cycloalkyl group attached to a ruthenium atom. The 0 atom is the point of attachment of the cycloalkoxy group to the rest of the molecule. The term "phenoxy" means a phenyl group attached to the ο atom. The atom is the point of attachment of the phenoxy group to the rest of the molecule. The term "6-membered heteroaryl ring" means having up to 5 carbon atoms and at most A 6-membered monocyclic heteroaryl ring group of a specified number of N atoms. 6 members of hetero-based, thiol, fluorenyl, oxime, trisyl and its like. The term "5 or 6 members" "Heterocycle" means a 5- or 6-membered ring containing from 1 to 5 c atoms and up to a specified number of N, oxime and S atoms, and may be aromatic or partially Saturated or fully saturated. Unless otherwise stated, the term "optionally substituted" means that the modified moiety may have from 1 to a maximum number of substituents, as long as the substitutions believed to be chemically feasible in the art are considered That is, each substituent may be substituted for any deuterium atom on the modified moiety, as long as the permutation method is chemically feasible and chemically stable. For example, 'if two substituents are each passed through each 14S833.doc -13- 201102372 A compound in which a substituent hetero atom is bonded to a single c atom is a chemically labile compound. Another example of a chemically labile compound is an enol ether compound formed by an alkoxy group bonded to an unsaturated carbon of an olefin. When two or more substituents are present on any moiety, each substituent is selected independently of the other substituent 'so the substituents may be the same or different. When a 5- or 6-membered heterocycle is attached as a substituent to the rest of the molecule When it becomes a group, an example of a 5- or 6-membered heteroaryl ring is a furyl group, a pyrrolyl group, a stilbene group, a pyrazolyl group, a thiol group, an imidazolyl group, an oxazolyl group. An oxazolyl group, an isothiazolyl group, a triazolyl group, a thiadiazolyl group, an oxadiazolyl group, a pyridyl group, a guanidino group, a pyridazinyl group, a triazinyl group and the like. Partially unsaturated 5 members Examples of the 6-membered heterocyclic group include dihydropyrano, pyrrolinyl, pyrazolinyl, imidazolinyl, bis-xanthyl, and the like. Saturated 5 or 6 The m2 of the ring group is a bite group, a tetrahydro(tetra)yl group, a benzyl group, a morphine group, a tetrahydrofuranyl group, a tetrahydrogen group, a thiophene group, a (tetra) group and the like. The connection point of the group may be Any available L atom of $ is attached to the rest of the molecule. When 5 or 6 = heterocyclic ring is attached to the other ring contained in the rest of the molecule, a bicyclic ring is formed. These 5 and 6-heterocyclic rings are slightly combined. Examples of the ring include a mercapto group (fUr), a pyrido, a piper, a thieno, and the like. The fused point is at any available face of the heterocycle and the parent molecule. As used herein, as used herein (eg, dogs, cats, horses 'bovines, sheep, individuals (including male and female individuals, individuals) mean mammalian goats, monkeys, etc.), and especially humans and including newborns , infant, master 148833.doc • 14· 201102372 juvenile, youth, adult and elderly individuals, and in addition to various races and races 'including (but not limited to) whites, blacks, Asians, American Indians and Hispanics). "Treatment" as used herein refers to the reversal, alleviation, alleviation or alleviation of progression of a condition or disease as described herein or (4) a condition or disease. As used herein, prophylaxis refers to the elimination or reduction of the incidence or onset of a condition or disease as described herein as compared to the situation occurring without the use of measures. As used herein, "effective amount" means an effective period of time when the symptoms of a disease or disease are alleviated as recorded by clinical testing and evaluation, patient observation, and/or the like, which may further indicate biological activity or chemistry. The dose at which the activity reaches a detectable change. The detectable change can be detected and/or further quantified by a person skilled in the relevant mechanism or method. In addition, an "effective amount" can mean an amount used to maintain a desired physiological state (i.e., to alleviate or prevent a significant deterioration of a related condition and/or to promote a modified related condition). "Effective amount" may further mean a therapeutically effective amount. B. Compounds The present invention encompasses compounds of formula I,

148833.doc •15· 201102372 where R is Η or C “C6 炫; R1 is Η, COOH, —C(=〇)_ORi, C3_C8. cycloalkyl, Ci C^ group, (VC6 alkenyl or C丨) a C6 alkoxy group, wherein the alkyl group, and the alkyl group, % alkyl group, alkenyl group or alkoxy group may be optionally substituted with one or more groups selected from the group consisting of fluorine, methylenedioxy a phenyl group and a phenyl group, wherein the methylenedioxyphenyl group or a phenyl group is optionally substituted by R6; R is an anthracene, a halogen group or a C-C6 alkyl group, wherein the alkyl group may be subjected to one or the other Substituted from a group consisting of: (^_(:6 alkoxyoxy and I, or R is c^4 aryl, C3-u heterocycle or c5 i4 heteroaryl, wherein The aryl, heterocyclic or heteroaryl group may be optionally substituted with one or more R6; R is hydrazine, CrC6 alkyl or stupid, wherein the alkyl or phenyl group may be optionally substituted with one or more R6; Or S; R is cs_M aryl, C:3·丨4 heterocyclic or C5 μheteroaryl, wherein the aryl, heterocyclic or heteroaryl is substituted by one or more R 7 and R is deuterium, halo or a C,-C6 alkyl group, wherein the alkyl group may be optionally substituted with a pendant thiol group; 〆R is halo; CF3; Ci-C6 alkyl, wherein the alkyl group may be optionally substituted with a pendant oxy 7 or a thiol group; or a ci C6 alkoxy group optionally substituted by fluorine; R7 is selected from the group consisting of Group (a) hydroxy, (b) C-C6 alkoxy, wherein one or more H of the alkoxy group is 2H(D), and 148833.doc -16 · 201102372 (c) -Ο-protecting group (4)-0-C(=0)-R", wherein r, Ci_c6, or c5." aryl, wherein the alkyl or aryl group may optionally be - or a plurality of groups selected from the group consisting of The group replaces .ii, thiol, _SH, decylamine, acid retardation, CN, Ci_C6 alkyl, CA thiol, c6_14 aryl and c5 "heteroaryl; and arbitrarily, and wherein Rc and Rd are independently Hydrogen or (^-C; 6 alkyl; (4) _〇-C(=〇)-Rin, wherein Rii, -NReRf and wherein Re and Rf are independently hydrogen or 0^-(:6 alkyl; or its medicinal An acceptable salt, ester, prodrug, stereoisomer, diastereomer, enantiomer or racemate. In some embodiments, the compound is an alkali metal salt, a group of basic nitrogen. In some embodiments, the compound of formula j is a meglumine salt thereof, Salts, magnesium salts, ammonium, potassium or sodium salt. In another embodiment the real drag,〗 compound having the structure of formula

As used herein, in the formula I, the term "anthracene protecting group" refers to an oxygen-containing S-energy group such as a mesogenic group which is temporarily blocked by k to allow the reaction to proceed selectively at another reaction site in the polyfunctional compound. The protecting group can be introduced and removed during the field phase of compound synthesis using methods known to those skilled in the art. The protecting group is applied according to standard organic synthesis methods as described in the literature. 148833.doc -17- 201102372 (Theodora W Green and Peter GM Wuts (2007) /W hacker Grow/?·? 4th edition, John Wiley and

Sons' is incorporated by reference to the protecting group. Exemplary oxygen protecting groups include, but are not limited to, oxime ethers, substituted gems (eg, MOM (decyloxymethyl ether), MTM (thiol oxime ether), BOM (benzyloxymethyl ether), PMBM (p-nonyl phenoxy methoxymethyl ether)), optionally substituted diethyl ether, optionally substituted anisole, decyl ether (eg TMS (trimethyl decyl ether), TES (tri-B) Base alkyl ether), TIPS (triisopropyl decyl ether), TBDMS (t-butyl dimethyl decyl ether), trityl decyl ether, TBDPS (tertiary butyl diphenyl decyl alkyl Ether)), esters (eg, formate, acetate, benzoate (Bz), trifluoroacetate, diacetate, carbonate), cyclic condensate and ketal. In some embodiments, the -〇-protecting group is _0_CH2_Ph, wherein the phenyl group is optionally substituted with a CrC6 alkoxy group (e.g., _4-methoxybenzyl). In another embodiment, for the compound of Formula I, r7 is an ester having the structure of _〇_c(=〇)_Rn, wherein R11 is as defined in Formula I. The ester of "_〇_c( = 〇)_Rii" may be the product of the reaction of a compound of formula I wherein R? is _〇H with a suitable carboxylic acid. Any suitable carboxylic acid can be used. In some embodiments, the diacid can be an amino acid. In another embodiment the 'carboxylic acid can be a natural alpha amino acid. As used herein, the term "amino acid" refers to a compound comprising a primary amine group (-ΝΗ2) and a carboxylic acid (-COOH) group. Amino acids for use in the present invention include naturally occurring and synthetic alpha, beta, indole or s-amino acids and include, but are not limited to, the amino acids found in proteins. Exemplary amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, guanidine thione, 148833.doc -18- 201102372 phenylalanine, tryptophan, Proline, serine, threonine, cysteine, tyrosine, aspartame, glutamic acid, aspartic acid, glutamic acid, lysine, arginine and histamine acid. In some embodiments, the amino acid may be a derivative of the following: propylamine, amidino, leucine, isoleamine, amidino, amphetamine, tryptamine , guanidine thiol amide, glycine sulphate, serine acid group, lysine thiol group, cysteamine sulfhydryl group, amide amine, aspartic acid amine, acetoguanidine, aspartame Sulfhydryl, glutamine sulfhydryl, amide group, arginyl sulfhydryl, histamine sulfhydryl, β-alaninyl, β-arginyl sulfhydryl, β-leucine thiol, β-iso-araminyl thiol , amidoxime, β-phenylalanine thiol, β-tryptamine sulfhydryl, β-fluorenyl sulfhydryl sulfhydryl, β-glycosyl fluorenyl, Ρ_serotoninyl, β-threonyl, β-half Cystatamine, β-tyramine, β-aspartame, β-ammonium oxime, β-aspartate, β-glutamicin, β-amidoxime, --spermine thiol or β-histamine sulfhydryl. Further, as used herein, "amino acid" also includes derivatives of amino acids such as vinegar, and guanamine, and salts, and other derivatives, including derivatives having medicinal properties after being metabolized into an active form. . As used herein, the term "natural alpha amino acid" refers to a naturally occurring alpha amino acid comprising a carbon atom bonded to a primary amine group (-ΝΗ2), a carboxylic acid (_c〇〇H) group, side Chain and hydrogen atoms. Exemplary natural alpha amino acids include, but are not limited to, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, valine, silk Aminic acid, sulphate, cysteine, tyrosine, aspartic acid, glutamic acid, aspartic acid, glutamic acid, lysine, arginine and histidine. In one embodiment, for the formula, 11 is 11, R1 is H, R2 is 148833.doc -19- 201102372 Η, R3 is Ci-C6 alkyl, X is 0 and R4 is one or more a phenyl substituted with R7, wherein R7 is selected from the group consisting of: (a) a hydroxyl group, an alkoxy group, and one or more of the alkoxy groups are 2H(D), and (c)-0-CH2 - Ph, wherein the phenyl group may be optionally substituted with a fluorenyl-decyloxy group; and R5 is hydrazine, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound has the structure:

/COOH

Or a pharmaceutically acceptable salt thereof. In another embodiment, the compound has the structure:

148833.doc -20- 201102372

Or a pharmaceutically acceptable salt thereof. Further, in one embodiment, the compound of formula I is a meglumine (N-methyl-d-reducing glucosamine) salt, a potassium salt or a sodium salt of the following structure.

148833.doc -21 · 201102372 or a pharmaceutically acceptable salt thereof. In one embodiment, for the compound of Formula I, R2 is selected from the group consisting of phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiol, stagnation, ° ratio α sits on the base, is different from evil. Sitting on the base 'iso-β sitting base, three-degree sitting base, σ evil two α sitting base, ° plug two. Sit-base, four-degree sitting base, °-bite base, ° ratio ° bite base, 0 bottom bite base, tetrahydrogen bottom base, tetrahydrosulfur bucky base, pie base and morphine base, which can be seen The situation is replaced by one or more R6 as defined herein. In one embodiment, for the compound of Formula I, R4 is selected from the group consisting of phenyl, naphthyl, and. Fraunyl, ° thiophene, ° ratio σ group, tetrahydro 0-folyl group, ° ratio '^ σ base. More than 17 Liner, tetrahydro-septyl, ° ° ° sit, ° plug 0 sit base, ρ m ° sit. It is more basic than β, and it is different from β. Plug α sitting base, three π sitting base, ° evil two. Sitting base, 嗟 two α sitting base, four. Sitting group, D is more than a decidyl group, a bottom biting group, a tetrahydro 0 thiol group, a tetrahydrothiopyranyl group, a σ dense bite group. Than Qin, darzinyl, ruthenium, morphinyl, benzofuranyl, dihydrobenzofuranyl, benzothienyl, dihydrobenzo. Queenyl, fluorenyl, indolinyl, oxime, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzo Oxecyclopentenyl, quinolyl, isoquinolinyl, π quinalinyl, quinoxazolinyl, dihydrobenzoalpha-pyridyl, dihydrobenzothiopyranyl and 1,4-benzodioxanyl, which may each be substituted with one or more R7 as defined herein. In one embodiment, for the compound of Formula I, Rule 7 is an alkoxy group wherein one or more of the alkoxy groups are 2H (D). The deuterated substituted compound can be used as a medical treatment as described below. In addition, deuterated substituted compounds can also be used as biomarkers for pharmacological studies of compounds. For example, 148833.doc -22- 201102372 The biological availability and quantification of compounds can be determined by using an aerosolized compound to measure the amount of a compound in serum using mass spectrometry. When the alkyl, cycloalkyl, and alkenyloxy groups are substituted by a gas, they may be substituted at any available carbon atom - or a plurality of fluorine atoms until the full extent. When the alkyl substituent is traced by a wire, it is replaced by an oxygen atom of a double bond, which forms a carbonyl group with the attached carbon - (C = 0) - when any part is described as When substituted, it may have one or more of the indicated substituents, which may be located at any available position on the moiety. When two or more substituents are present on any moiety, each substituent may be defined independently of any other substituent and thus may be the same or different. The term "optionally substituted" means that the modified moiety may be substituted with an unsubstituted or determined substituent. R can be attached to the 4 or 5 position of the heterocyclic moiety of the compound of formula I (i.e., at any available carbon atom) and thus the remainder of the molecule will be attached at the remaining available carbon atoms. - Examples of compounds which illustrate the invention but are not intended to limit the invention in any way include the following:

[S] 148833.doc •23- 201102372

_—COOH

Or a pharmaceutically acceptable salt thereof. Salts of the compounds of formula I can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Similarly, when the compound of formula I contains a carboxylic acid moiety (e.g., R = H), the salt of the compound of formula I can be prepared by reacting it separately with a suitable inorganic or organic base and isolating the salt thus formed. The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the invention (see, for example, Berge et al., J. Pharm. Sci. 66: 1-19, 1977). 148833.doc • 24· 201102372 Representative salts of the compounds of formula i include the conventional non-toxic salts and quaternary ammonium salts formed, for example, by mineral or inorganic or organic or organic bases by methods well known in the art. For example, such acid addition salts include acetates, adipates, alginate, ascorbate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, Citrate, camphorate, camphor sulfonate, cinnamate, cyclopentane propionate, digluconate, eleven alkyl sulfate, ethyl citrate, antibutanate, Glucose heptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, itaconate, Lactate, maleate, mandelate, methanesulfonate, 2-naphthoate, nicotinic acid, nitrate, oxalate, pamoate, pectate, Persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, undecane Acid salts and the like. Salts include, for example, alkali metal salts such as potassium and sodium salts; alkaline earth metal salts such as about salts and magnesium salts; and organic salts such as dicyclohexylamine and N-methyl-D-reduced glucosamine . Further, the basic nitrogen-containing group in the conjugate base can be quaternized by the following four groups: a calcined dentate such as a Gy alkyl group, such as a fluorenyl group, an ethyl group, a propyl group, and a butyl group. Compound, bromide and telluride, sulfuric acid, sulphuric acid, such as dimethyl sulphate, diethyl sulphate and dibutyl sulphate; and diamyl sulphate; c ** Q_4G alkyl halide, such as fluorenyl, eleven Chlorides, desertifications and breaks of base, tetradecyl and octadecyl; or aralkyl toothings such as phenylhydrazine bromide and phenethyl evolution. In some embodiments, the salt is an alkali metal salt, such as a sodium or potassium salt or an adduct of a nitrogenous base, such as meglumine (N-methyl), which may be attached to 148833.doc -25-201102372. Heart-reducing glucosamine salt. The ester of the formula I according to the invention is a non-toxic, pharmaceutically acceptable ester such as an alkyl ester such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentose. Other esters such as oxime ester or stupid _Cl_C5 alkyl ester can be used. The compound of formula J can be esterified by a variety of conventional procedures, including reacting an appropriate anhydride, carboxylic acid or acid chloride with an alcohol group of a compound of formula I. A suitable anhydride can be reacted with the alcohol in the presence of the test to promote deuteration such as 1,8-bis[dimethylamino]naphthalene or anthracene, hydrazine-dimethylaminol. A suitable carboxylic acid can be used in conjunction with an alcohol in a dehydrating agent such as dicyclohexylcarbodiimide, 1-[3-dimethylaminopropyl]-3-ethylcarbodiimide, or used to drive the reaction by removing water. The other water-soluble dehydrating agent and, in some cases, the brewing catalyst are reacted. Esterification can also be carried out using the appropriate carboxylic acid in the presence of trifluoroacetic anhydride and, optionally, pyridine or in the presence of N,N-carbonyldiimivir and pyridyl. The reaction of the acid chloride with the alcohol can be carried out using a deuteration catalyst such as 4-DMAP or pyridine. Those skilled in the art will readily be aware of ways to successfully carry out these and other methods of esterifying alcohols. Furthermore, a sensitive or reactive group on a compound of formula I may require protection and removal of the protecting group during any of the above methods of forming an ester. Protecting groups can generally be added and removed by well-known methods known in the art (see, for example, T. w. Greene and P.G.M. Wuts, Gr〇« 外ζ·„

Organic Synthesis; Wiley: New York, (1999)) ° Depending on the position and nature of the various substituents, the compound of formula j may contain one or more asymmetric centers. Asymmetric carbon atoms can be (phantom or illusory 148833.doc -26- 201102372 二i-dimers are isomers having a two-absolute configuration that produces a more desirable biological activity. In some cases Asymmetry may also exist due to the square 疋轺 限 关 ❹ 两 两 。 。 。 。 。 。 。 。 。 因而 因而 因而 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称 不对称Substituents may exist in z or five form. All isomers (including enantiomers and diastereomers) that are expected to exist due to asymmetric center or rotation limitation are isolated, purely or partially purified. Isomers or racemic mixture forms thereof are included in the present invention. Standard techniques known in the art encompass purification of such isomers and separation of the isomer mixtures can be carried out by this Standard techniques known in the art are achieved. C. Synthesis The specific method to be used in the preparation of the compounds of the invention depends on the particular compound desired, and the choice of the specific X moiety and the possible specific substituents at each position on the molecule are Invention special ^ The route followed by the preparation of the compounds functions. The average person readily discerns their factors. In general, the compounds of the invention can be prepared by standard techniques known in the art and analogous methods known per se. An exemplary synthetic method is shown in the general reaction scheme. A compound of formula A (Formula I, wherein the ruthenium is an octadecylaryl group and the aryl radical is substituted with a 6 alkoxy group or a hydrazine protecting group) can be cooked Prepared according to methods described in the literature by modifications known to those skilled in the art. For example, the compound of formula A can be prepared according to the method described in U.S. Patent No. 6,828,335, the disclosure of which is incorporated herein by reference. 27· 148833.doc 201102372 A compound of formula A may be first subjected to dealkylation or removal of a protecting group to obtain a compound of formula B. Subsequently, a compound of formula B may be reacted with a suitable acid to obtain an ester of formula C. The compound of formula B may also be suitably employed. Reagent reaction to obtain a compound of formula D, wherein 114 <1 is a -hydrazine-protecting group. For example, formula B can be alkylated to obtain a compound of formula D, wherein R4dSCl_C6 alkoxy, optionally alkoxy One or more of the oximes are D. Alternatively, the compound of formula b can be subjected to other suitable reaction conditions to obtain other analogs. For example, as in the general reaction scheme, the hydrazine compound can be reacted with a compound containing an isocyanate group. A urethane analog of the hydrazine compound. The compound of formula I can be prepared according to methods known to those skilled in the art, wherein R is (^-(6 alkoxy and one or more η alkoxy groups) 2H(D). For example, it can be prepared by using a suitable deuteration starting material or a deuterated intermediate according to the method described herein (for example, Example 5). 148833.doc 28- 201102372 General Reaction Process

COOR aryl, wherein R" is defined in Formula I Formula D 114 (1 is a 0 protecting group R5 R<c represents other analogs, such as -0-C(=0)-Ra as defined in claim 1

Formula E Another aspect of the invention provides a process for the preparation of a compound of formula la which comprises dealkylating a compound of formula B to obtain a compound of formula la 148833.doc

COOR

B -29- 201102372

Wherein R is 11 or (1:1-(:6 alkyl; R1 is oxime, COOH, -C(=0)-〇R', c3-C8 cycloalkyl, CVC6 alkyl for formula B and formula la , CrC6 alkenyl or Ci-C: 6 alkoxy, wherein R is a Cl-c6 fluorenyl group, and the alkyl, cycloalkyl, alkenyl or alkoxy group may optionally consist of one or more selected from the group consisting of Substituting groups of groups: fluorine, methylenedioxyphenyl and phenyl, wherein S-methylenedioxyphenyl or phenyl may be optionally substituted by R6; R is hydrazine, halo or c--Ce An alkyl group, wherein the alkyl group is optionally substituted with one or more groups selected from the group consisting of Ci_c6 alkoxy, pendant oxy and fluoro, or 2 R is Cs-Cm aryl, CVCm heterocycle or a C5_Ci4 heteroaryl group, wherein the aryl, heterocyclic and heteroaryl groups are optionally substituted with one or more sizing 6; R is hydrazine, C "C6 alkyl or phenyl", wherein the alkyl or phenyl group Depending on the situation and independently substituted by one or more R6; X is Ο or S;

Ra is a fluorenyl-decyloxy group, R is a fluorene, a aryl group or a aryl group, wherein the alkyl group is optionally substituted with a pendant oxy group; and R6 is a dentate group, CF3, optionally a pendant oxy group or a (iv) substituted Ci_c々 Base, or as the case may be replaced by fluorine - 匕 氧 oxygen. 148833.doc .30- 201102372 According to another aspect of the invention, a method of preparing Compound B is provided. Such methods include dealkylating compound A

Obtaining compound B

Wherein Re is hydrogen or an alkyl group. In some embodiments, in the method of preparing compound B, by using, for example, a halogenating solvent such as dichloromethane (CI^C 2) 'cCu, chloroform (CHCI3), 1, 1, 1-trichloroethane (methyl chloroform, CH3 CC1), dibromoethane (I,2-dibromoethane, BrCH2_CH2Br), chlorobromomethane (bromochloromethane, CHJrCl), methyl bromide (bromodecane) The solvent A is treated with boron dibromide (BBr3) in a solvent such as cHjr) to carry out dealkylation. Alternatively, the dealkylation can be carried out by treating the compound A with a dodecylthiol containing aluminum chloride in a solvent. In one embodiment, the method is as follows: when compound A is an ester, ^ is (: 丨_c6 alkyl. This step includes hydrolyzing compound B to obtain a compound of the following structure:

'Compound A In some embodiments, in the preparation of the compounding method 148833.doc •31· 201102372 has the following structure h3co

COOH and compound B has the following structure

COOH In another embodiment, in the method of preparing compound B, compound A has the following structure h3co

COOH and compound B has the following structure

HO

COOH In addition, one aspect of the invention provides a method of preparing Compound D. The methods include cleavage of the ether bond of 0-CH2Ph of compound C

PhH, C-0

COORc

Obtaining compound D

COORc 148833.doc -32- 201102372 where is hydrogen or c--c6 alkyl. In some embodiments, the breaking step is performed by hydrogenolysis. Hydrogenolysis can be carried out by any known method for obtaining a compound oxime by cleavage of the ether bond of 〇_CH2Ph. For example, hydrogenolysis can be carried out by treating compound c with a catalyst and hydrogen (H2) gas. Exemplary catalysts include, but are not limited to, palladium (pd)/carbon, oxyfluoride, Raney nickel, or combinations thereof. In one embodiment, the breaking step is carried out by treating compound C with boron tribromide or boron trichloride. Further, in one embodiment, the cleavage step is carried out by treating compound C with trimethyldecyl iodide. In the method of preparing the compound D, in the method of preparing the compound D, for the compound 匸 and α, when the ruthenium is 匸1丄0, the methods further include hydrolyzing the compound D to obtain a compound having the following structure.

In some embodiments, for the method of preparing a compound, compound c has the following structure

And compound D has the following structure

148833.doc • 33- 201102372 In another embodiment, for the method of preparing compound D, compound c has the following structure σ

And compound D has the following structure

D. Assessing the Biological Activity of a Compound The demonstration of the activity of a compound of the invention can be verified by in vitro, ex vivo and in vivo assays well known in the art. 1. Diabetes and related diseases and diseases For example, the following test methods can be used to verify the efficacy of pharmaceutical agents in the treatment of diseases such as diabetes X and related diseases, such as syndrome X, glucose tolerance, abnormal fasting blood glucose, and sedative Blood; or atherosclerosis and related conditions such as hypertriglyceridemia and hypercholesterolemia.腾. The compound-treated 3T3-L1 cells in which the T10-L1 cells bind to 3T3-L1 cells are seeded into c〇star flat-bottom TC at 9300 cells per well, and incubated for 1 week until they meet (eg, the cells have reached Maximum density) 2 days later. The cells were then subjected to a differentiation medium containing 0.5 μM human insulin-like growth factor (igF-1) and test compound (Dulbecco's Modified Eagle Medium (DMEM), 100 pg/ml chlorin (Penicillin). / Streptomycin, 2 mM L-drumamine 148833.doc • 34- 201102372 acid, 10% fetal bovine serum) for 2 days. After the treatment, the medium was replaced with a differentiation medium, and the cells were incubated for 4 days. The insulin receptor activity of the cells is then detected. After washing the cells with buffer, they were incubated with 0.1 nM 125I-insulin and (+/-) 100 nM unlabeled insulin and incubated for 1 hour at room temperature. The cells were then washed three times with buffer, dissolved with 1 N NaOH, and counted on a gamma counter. If a steady state is obtained, the EC50 value is determined and the maximum stimulation percentage is assessed. B. In Vivo Detection (1). Method for measuring jk sugar content db/db gas (obtained from Jackson Laboratories, Bar Harbor, ME) is bled (by eye or tail vein) and grouped according to the equivalent average sugar content. . Each time, the compound was administered orally (by gavage, in a pharmaceutically acceptable vehicle) to test the compound for 14 days. At this time, the animal was again bled through the eye or tail vein, and the blood sugar level was measured. In each case, the glucose content was measured by Glucometer Elite XL (Bayer Corporation, Elkhart, IN). (2) Method for measuring triglyceride content hApoAl mice (obtained from Jackson Laboratories, Bar Harbor, ME) were bled (by eye or tail vein) and grouped according to a comparable average serum triglyceride content. The compound was administered orally (by gavage, in a pharmaceutically acceptable vehicle) once a day for 8 days. The animal is then bled again via the eye or tail vein and serum triglyceride is determined. In each case, the triglyceride g content was measured using a Technicon Axon automated analyzer (Bayer Corporation, Tarrytown, NY). 148833.doc -35- 201102372 (3). Method for measuring HDL-cholesterol content To determine plasma HDL-cholesterol content, hApoAl mice were bled and grouped according to a comparable mean plasma HDL-cholesterol content. Mice were orally administered vehicle or test compound once daily for 7 days, and then bled again on day 8. Plasma HDL-cholesterol was analyzed using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA). (4) Method for measuring total cholesterol, HDL-cholesterol, triglyceride and glucose content In another in vivo assay, an obese monkey is bled, followed by oral administration of a vehicle or test compound once a day. Week, and then bleeding again. Serum total cholesterol, HDL-cholesterol, triglyceride S and glucose were analyzed using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, CA). Lipoprotein subclass analysis was performed by NMR spectroscopy as described by Oliver et al. (Proc. Natl. Acad. Sci. USA 98: 5306-531 1, 2001). (5). Methods for measuring the effects on cardiovascular parameters Cardiovascular parameters (such as heart rate and blood pressure) are also assessed. Vehicles or test compounds were administered orally to SHR rats once daily for 2 weeks. Blood pressure and heart rate were measured using tail sleeve compression as described by Grinsell et al. (Am. J. Hypertens. 13: 370-375, 2000). In monkeys, blood pressure and heart rate were monitored as described by Shen et al. (J. Pharmacol. Exp. Therap. 278: 1435-1443, 1996). 2 Psoriasis, Alzheimer's disease, some recent studies indicate the promotion of peroxisome proliferator-activated receptors (PPAR) 148833.doc -36- 201102372 efficacious agents may be used as potential treatment for psoriasis (see Romanowska, corpse / Enhances Keratinocyte Proliferation in Psoriasis and Induces Heparin-Binding EGF-Like, Growth Factor, J Investigative Dermatology, 128, 1 10-124, (2008) ; Ellis, Troglitazone Improves Psoriasis and Normalizes Models of Proliferative Skin Disease, Arch Dermatology, 136, 609 -616 (2000), and Bongartz, Rheumatology, Vol. 44, 2004, p. 126). PPAR agonists are also indicated for the treatment of Alzheimer's disease. (See Escribano et al., Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model, Biochemical and Biophysical Research Communications, 379, 406-410 (2009)). PPAR receptor agonist activity can be determined by conventional screening methods known to those skilled in the art. For example, the methods described in U.S. Patent Application Publication Nos. 2007/0054907, 2008/0262047, and U.S. Patent No. 7,3, 879, incorporated herein by reference. Exemplary screening tests are described below: A. Binding assays Scintillation proximity assays (SPA) can be used to test the ability of a compound to bind to hPPAR gamma, hPPAR alpha or hPPAR δ. The PPAR ligand binding domain (LBD) can be expressed in E. coli and purified in the form of a poly-His-tagged fusion protein. The LBD can then be labeled with biotin and immobilized to the streptavidin-modified scintillation proximity beads. The beads can then be combined with a constant amount of the appropriate radioactivity 148833.doc -37- 201102372 (5·{4-[2-(methyl-n-bipyridin-2-yl-amino)-ethoxy] Benzylthiazolidine-2,4-dione (J. Med. Chem. 1994, 37(23), 3977) for PPAR γ; and labeled gw 2433 (for the structure of this ligand and Synthesis 'See Brown, P. J et al. Chem. Biol. 1997 4: 9〇9_ 918) 'for ppAR α and PPAR δ); and variable concentrations of test compounds are incubated together, and after equilibration, The radioactivity combined with the beads was measured by a scintillation counter. The amount of monospecific binding as assessed by a control well containing 5 相应 of the corresponding unlabeled ligand was subtracted from each data spot. The apparent Ki value was estimated from the nonlinear least squares fit of the data for each compound tested to plot the concentration of the ligand relative to the CPM bound by the radioligand, and assuming simple competitive binding. Details of this test have been reported elsewhere (see Blanchard, S. G. et al., Anal. Biochem., 257 1 12-1 19 (1998)). Β·Functional detection method (a) Development of a cell-based functional assay to distinguish between agonists and antagonists. Agonist assay: HEK 293 cells stably expressing human melanocortin receptors were dissociated from tissue culture flasks using trypsin/EDTA solution (0.25%; Life Technologies, R0ckville, Md.) (see, eg, Yang et al., Mol-Endocrinol·, 11(3): 274-80, 1997). The cells were collected by centrifugation and resuspended in DMEM (Life Technologies, Rockville, Md_) supplemented with 1% L-glutamic acid and 0.5% fetal bovine serum. Count the cells and dilute to 4.5 x 105 / ml. The compound of the present invention was diluted in diterpenoid (DMSO) (3xlO·5 to 148833.doc -38 - 201102372 3χ10_1() Μ final concentration), and 0.05 volume of compound solution was added to 0.95 volume of cell suspension; final DMSO The concentration is 0.5 ° /. . After incubation for 5 hours at 37 ° C / 5% CO 2 , a luciferin solution (50 mM Tris, 1 mM MgCl 2 , 0.2) was added to quantify the reporter gene luciferase activity (intracellular cAMP production). % Triton-X100, 5 mM DTT, 500 μπιοίCoA, 150 μηιοί ATP, and 440 μηιοί luciferin) to dissolve the cells. Luciferase activity was measured from cell lysates using a Wallac Victor 2 luminometer. The amount of lumen production produced by the compounds of the present invention is compared to the amount of lumen produced by NDP-a-MSH (defined as 1% agonist) to obtain the relative potency of the compound. EC5Q is defined as the concentration of a compound that produces half the maximum stimulus compared to its own maximum stimulation level. (b) Melanocortin receptor whole-cell caMP accumulation assay Compound preparation: In the agonist assay, compounds were prepared as 10 mM stock solutions in 100% DMSO and NDP-aMSH (control) in 100% DMSO Prepare a stock solution of 33.3 μM. These stock solutions were serially diluted in 1% DMSO. Compound disks were further diluted 1:200 in compound dilution buffer (HBSS-092, 1 mM ascorbic acid, 1 mM guanidine, 0.6% DMSO, 0.1% BSA). The final concentration of the compound in 0.5% DMSO ranged from 1 〇 μΜ to 100 pM, and the final concentration of the control in 0.5% DMSO ranged from 33.33 nM to 0.3 pM. 20 μΐ from this plate was transferred to 4 PET 96-well plates (all assays for each receptor were double-coated). (c) Cell culture and cell stimulation: 148833.doc -39· 201102372 HEK 293 cells stably transfected with MC3R and MC4R were grown in DMEM containing 10% FBS and 1% antibiotic/antimycotic solution. On the day of the assay, the cells were removed by the enzyme-free cell dissociation solution and resuspended in cell buffer (HBSS-092, 0.1% BSA, 10 mM HEPES) at 1 xe6 cells per ml. 40 μM cells were added to each well of a PET 9-well plate containing 20 μM of the diluted compound and the control. Incubate for 20 minutes at 37° (: in a water bath. Stop the assay by adding 50 μM quenching buffer (50 mM sodium acetate, 0.25% Triton X-100) C. Radioligand binding assay in SPA buffer ( Radioligand binding assay was performed in 50 mM sodium acetate '0.1% BSA. The beads, antibodies and radioligands were diluted in SPA buffer to provide sufficient volume for each 96-well plate. Add 100 μΐ of a mixture containing 3 3.33 μΐ beads ' 33.33 μΐ antibody and 33.33 μΐ 125I-cAMP to the assay well based on 6.3 mg/ml beads and 0.65% anti-goat antibody in the final assay volume of 21 0 μΐ. Final concentration of 61 pM 125I-cAMP (containing 25 000-3 0000 CPM) After 12 hours of incubation, the plates were counted in a Wallac MicroBeta counter. Data were converted to pmol cAMP using a standard curve tested under the same conditions. The Activity Base software was used to analyze the data to generate agonist potency (EC50) and relative potency percentage data relative to NDP-aMSH. D. Transfection assays can be performed in CV-1 cells in transient transfection assays. Compound activation PPAR The ability of the type (transactivation assay) to screen for the functional potency of the compound. The previously established chimeric receptor system can be used to compare the relative transcriptional activity of the receptor subtype to the phase 148833.doc -40- 201102372 with the target gene, and It is used to prevent the activation of endogenous receptors to complicate the interpretation of the results. See WLehmann, Μ, et al, 夂 Biol·Chem” 1995 27〇: 12953_6. Rodent and human ppAR α,

The ligand binding domains of PPAR gamma and PPAR δ are each fused to the yeast transcriptional GAL4 DNA binding domain. Transient transfection of reporter constructs with separate expression vectors for the eight-foot chimera and three of the GAL4 DNA binding sites that drive the expression of secretory placental phosphatase (spAp) and beta-galactosidase CV-1 cells. After 16 hours, the medium was changed to DME medium supplemented with 1% fat-free fetal bovine serum and an appropriate concentration of test compound. After a further 24 hours, cell extracts were prepared and alkaline ligase and beta galactosidase activity were measured. The transfection efficiency of alkaline phosphatase activity was corrected using β-galactosidase activity as an internal standard (see, for example, Kliewer, S. Α. et al., Cell 1995 83: 813-819). Rosigiitazone (BRL 49653) can be used as a positive control for hPPAR gamma detection. The positive control in the hPPAR α assay can be 2-4-[2-(3-[4-fluorophenyl]-1-heptylureido)ethyl]-phenoxy-(2-, propylpropionic acid (WO 97/3 6579). The positive control for the PPAR δ assay can be 2-{2-f-group-4_[({4-methyl-2-{trifluoromethyl)phenyl]-1,3- Thiazol-5-yl}mercapto)thio]phenoxy}acetic acid (WO 01/00603). The EC50 can be determined in the form of a concentration at which the compound achieves 50% activation relative to the appropriate positive control. In the binding assay described above, the "activator" will typically have a pKi for the relevant PPAR of at least 6.0, preferably at least 7.0' and in the transfection assay described above, at 1〇·5. At least a 50% activation of the relevant PPAR is achieved relative to a suitably designated positive control at a concentration of ^^ or 10·5 M or less. E. Animal Model, 148833.doc • 41 201102372 (1) Alzheimer's Disease ° The present invention was tested in any animal model known to the skilled artisan. The animal model of the inferior animal includes (but is not limited to, a mouse model of Alzheimer's disease transgenic gene; aged rats; rats with entorhinal cortex-induced injury; monkeys with aged rhesus monkeys and entorhinal cortex injury). For each model, the test results were compared to the control m not treated with the compound of the present invention. It is expected that the treated animals will be shown in the various learning and memory tests, and the improvement is shown. For example, it is expected that the treated animals are observed. The brain also exhibits a large cell size, improved cell signaling, and/or activation of neuronal function (which would otherwise degenerate) compared to untreated animals. These benefits can be extended to degenerating hippocampus that treat short-term memory. The hippocampus is one of the first areas of the brain to be damaged in Alzheimer's disease. (2) Psoriasis Any animal model known to those skilled in the art can be used in the present invention. Exemplary animals (4) include (but are not limited to) Human psoriasis skin-severe combined immun〇deficient (scid) mouse transplantation model and AGR丨29 mouse model. 下# & ^ , Xing 1 below An exemplary SCID mouse model is described. 'Transplanting skin from normal human volunteers or psoriasis lesions to SCID-small skin for 3 to 5 weeks prior to administration of the compound of the invention. During this period, the thickness is corresponding to normal skin before transplantation. About 3 to 4 times of psoriasis skin maintains its phenotype (ie, increased epidermal thickness, pure reticular ridges, and T lymphocytes in the lesion). However, 'transplanted normal human skin undergoes a proliferative response during this period, The skin thickness is increased by about 2 to 3 times. After healing 148833.doc • 42· 201102372 period, the animals transplanted with normal skin or psoriasis skin are treated for 14 days by appropriate administration (such as topical administration or injection) of the compound of the present invention. At the end of the treatment period, the mice were sacrificed, and the changes in epidermal thickness of the tissues were evaluated by morphometric measurement for the skin of psoriasis lesions and normal skin, and the presence of T lymphocytes was evaluated immunohistochemically. E. Pharmaceutical composition according to the present Another aspect of the invention 'provides a pharmaceutical composition of a compound described herein. In some embodiments, a pharmaceutical The composition further comprises a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional therapeutic agents. In one embodiment, an additional therapeutic agent is used to treat or prevent Alzheimer's disease. Exemplary additional therapeutic agents include, but are not limited to, cholinesterase inhibitors (eg, tacrine, galantamine, rivastigamine or Donepezil and NMDA inhibitors (e.g., memantine). The compounds described herein can be administered in combination with one or more other drugs for the treatment or prevention of other dementias. Other drugs include non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, ibuprofen, diclofenac, indomethacin, nabumetone ), ° piroxicam, celecoxib and aspirin. Other drugs that may be combined with the compounds described herein include HMG-CoA reductase inhibitors, such as statin (eg, simvastatin 'Zokocor, atorvastatin' j (at 〇Vastatin, Lipitor), 148833.doc -43 · 201102372 rosuvastatin 'Crestin, vavastatin ( Lescol)). In some embodiments, the additional therapeutic agent is used to treat or prevent other diseases. Exemplary additional therapeutic agents include, but are not limited to, antioxidants, anti-inflammatory agents, gamma secretase inhibitors, neurotrophic agents, acetylcholinesterase inhibitors, statins> butyl statins, Αβ peptides, and anticonvulsants Beta peptide. However, in various embodiments, exemplary additional therapeutic agents include, but are not limited to: corticosteroids; vitamin D analogs; methotrexate; ciclosporin; fumarate ;adalimunag; alefecept; afalizumab; etanercept; infHximab; steroid; retinoid; Microbial compounds; anti-oxidants; anti-inflammatory compounds; salicylic acid; endothelin antagonists; immunomodulators; angiogenesis inhibitors; inhibitors of fgf, VEGF, HGF or EGF; inhibitors of EGF, FGF, Vegi^hgi^ Tyrosine kinase inhibitor; protein kinase c inhibitor; and combinations thereof. Other well-known assays based on the above tests or for determining the efficacy of the above-described conditions for treating a mammal, and by comparing the results of the known drugs for treating such conditions, can be easily The effective dose of the compound of the present invention for treating each indication is determined. The amount of active ingredient to be administered to treat such conditions may vary widely depending on the tester's factors such as: the particular compound and dosage unit employed, the dose: heart: =, the age and sex of the patient being treated' And the condition to be treated: quality and extent. I48833.doc •44- 201102372 The total amount of active ingredient to be administered can generally range from about 0.001 mg per kilogram of body weight per day to about 200 mg per kilogram of body weight per day, and preferably about 0.01 per kilogram of body weight per week. From mg to about 2 〇〇mg per kilogram of body weight per day. The unit dose may contain from about 0.05 mg to about 1500 mg of the active ingredient and may be administered one or more times daily. The daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injection, and using infusion techniques) can range from about 0_01 to about 200 mg/kg. Each rectal administration regimen can range from 0.01 to 200 mg per kg of total body weight. The transdermal concentration can be the concentration required to maintain a sputum dose of 〇〇1 to 2〇〇 mg/kg. Of course, the specific initial and sustained dosing regimen for each patient will be based on the following changes: the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age of the patient, the patient's diet, the time of administration, and the route of administration. , drug excretion rate, drug combinations and similar factors. Those skilled in the art will be able to use the conventional therapeutic test to determine the mode of treatment and the number of times the compound of the invention or its pharmaceutically acceptable salt is administered. The compounds described herein can be used to achieve the desired pharmacological effect by appropriate conditioning, and the dispensing of the desired patient. For the purposes of the present invention, a patient is a mammal in need of treatment for a particular disease (IV) disease. Accordingly, the invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound identified by the methods described herein, or a pharmaceutically acceptable salt or vinegar thereof. It is pharmaceutically acceptable in the right-hand side of the active ingredient, which is harmless, so that the concentration attributable = the relatively non-toxic benefit of the patient can damage the activity into a carrier. The pharmaceutically effective amount of the compound is the amount that produces or affects the particular condition of the 148833.doc •45-201102372. The compounds identified by the methods described herein can be administered orally, parenterally, topically or the like together with a pharmaceutically acceptable carrier in any of the effective unit dosage forms, including, for example, immediate release formulations and time release formulations. Cast. For oral administration, the compound may be formulated into a solid or liquid preparation such as a capsule, a pill, a lozenge, a dragee, a lozenge, a melt, a powder, a solution, a suspension or an emulsion, and may be formulated according to the pharmaceutical composition. It is prepared by methods known in the art. The solid unit dosage form can be a conventional hard or soft shell gelatin type capsule containing, for example, a surfactant, a lubricant, and an inert filler such as lactose, Yan sugar, ginseng and corn starch. In still other embodiments, the compounds of the present invention may be combined with the following materials: compositions of conventional binder bases such as lactose, Yan sugar and corn powder, and binders such as acacia, corn starch or gelatin. · Disintegrators that want to help break down and dissolve after the administration of tablets, such as horse bell powder, alginic acid, corn house powder and guar gum (§ and gum); to improve the (four) nature of granular tablets And anti-money riding materials (4) on the surface of ingots and punches (4) slip agents, such as talc, stearic acid or magnesium stearate, stearic acid (four) or monthly "text" wood coloring agent; and to improve the senses of tablets A quality and a flavoring agent that is more acceptable to the patient. Suitable for use in oral liquid dosage forms including diluents such as water and alcohols such as ethanol, methanol and polyethylene are added or not added pharmaceutically acceptable Surfactant, suspension!: Various other materials may be present in the form of coatings or in other forms. -r, π basket. For example, tablets, pills or polycapsules may be coated with shellac, sugar or both. 148833.doc -46- 201102372 Dispersible powder and granules An aqueous suspension is prepared which provides the active ingredient in admixture with a dispersing or wetting, suspending, and/or preserving agents. Suitable dispersing or wetting agents and suspending agents are exemplified by the above. Additional excipients may be present, such as the sweeteners, flavoring agents, and coloring agents described above. The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as liquid sarcophagus. Or vegetable oils. Suitable emulsifiers can be (1) naturally occurring gums such as acacia and tragacanth, (7) naturally occurring fats such as soy and (iv) fat, and (3) fatty acids and hexitols. Anhydride-derived vinegar or (iv) such as sorbitan mono-oil (iv), and (4) condensation products of such partial vinegar with ethylene bromide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetness. Flavoring agents and flavoring agents. Oily suspensions may be formulated by suspending the active ingredient in vegetable oils such as peanut oil, eucalyptus oil, sesame oil or coconut oil or in mineral oils such as liquid stone soil. Pure suspensions may contain Enhancing agent, Such as bee-like, solid stone or cetyl alcohol. The suspension may also contain one or more preservatives, such as (iv) phenyl ketone or propyl benzoic acid; one or more H or one or more seasonings An agent, and/or a plurality of sweeteners, such as a balance or a syrup. The syrup and the ugly agent may be combined with a sweetener such as glycerin, glycerin or sucrose - (iv). Containing a slowing agent, a flavoring-like coloring agent. Fangshu: The compound of the invention may also be in the form of a physiologically acceptable diluent and a pharmaceutical-borne primary sputum compound, parenteral (ie, subcutaneous, intravenous, intramuscular or peritoneal). The drug carrier can be a sterile liquid or liquid 148833.doc • 47- 201102372 body mixture, such as water, physiological order k. ^. physiological g saline, dextrose aqueous solution and related sugar solution; alcohol 'such as ethanol , isopropanol or cetyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol, such as 2,2-dimethyl-U•dioxol-4-methanol; ethers, such as poly (ethylene glycol) 4 〇〇; oil; fatty acid; fatty acid ester or glyceride; or acetylated fatty acid Oil esters with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents; such as gums, carbomers, thiol cellulose, hydroxypropyl methylcellulose or carboxymethyl a suspension of cellulose based; or an emulsifier and other pharmaceutical adjuvants. Illustrative oils useful in parenteral formulations of the invention are oils of petroleum, animal or synthetic origin such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil and mineral oil. . Suitable fatty acids include oleic acid, stearic acid and isostearic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty alkali metal salts, salt and triethanolamine salts, and suitable cleaning agents include cationic detergents such as dentylated dimethyldialkylammonium, _alkylpyrrolidine and alkylamine acetate; anionic Detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefins, ethers and monoglyceride sulfates and sulfosuccinates; nonionic detergents such as fatty amine oxides, fatty alcohols Indoleamine and polyoxyethylene polypropylene copolymers; and amphoteric detergents such as alkyl-β-aminopropionic acid vinegar and 2-carboyl X»米嗤琳 four-stage salt and mixtures. The parenteral compositions of the present invention typically comprise from about 5% by weight to about 25 % by weight of active ingredient in solution. Preservatives and buffers should also be used. In order to minimize or eliminate irritation at the injection site, the compositions may contain a nonionic surfactant having a hydrophilicity of from about 12 to about 17 in a hydrophilic, lipophilic balance. The amount of surfactant in the formulation ranges from about 5% by weight to about (four) percent by weight. The surfactant may be a single component having the above-mentioned hlb or a mixture of two or more components having the desired HLB. Illustrative surfactants for use in parenteral formulations are the following categories: • Polyethylene sorbitan fatty acid vinegar, such as sorbitan monooleate; and Ethylene Ethylene and hydrophobic matrices (by ring A high molecular weight adduct formed by the condensation of oxypropane with propylene glycol. The pharmaceutical composition can be in the form of a sterile injectable aqueous suspension. These suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, such as sodium methacrylate, methylcellulose, propylmethylcellulose, browning, poly Ethylene (four) _, yellow turn and Arabian; dispersant or wetting agent can be a naturally occurring fat, such as (four) fat; condensation products of epoxy burned with fatty acids, also 丨Λ @心难" house, such as polyoxyethylene hard a fatty acid ester; a condensation product of ethylene bromide with a long-chain aliphatic alcohol, such as a seven-fold ethyl octadecyl alcohol, a condensation product derived from a partial derivative derived from a fatty acid and a coenzyme, such as a fatty acid. A condensation product of polyoxyethylene sorbitan monooleate or epoxide with a partial vinegar derived from a fatty acid and an alcoholic anhydride, such as polyoxyethylene sorbitan monooleic acid. The sterile (4) preparation may also be a non-invasive injectable solution or solution in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents which can be used are, for example, Ringer's solution (Ringer, ss〇luti〇, etc.). In addition, 'sterile fixed oils are known to be used as a solvent or suspending medium. For this purpose, Any bland fixed oil may be employed, including synthetic monoglycerin 148833.doc -49- 201102372 or monoglyceride. In addition, fatty acids such as oleic acid may be used to prepare the formulation. 'The compositions of the invention may also be used in pharmaceuticals. Administration of suppository forms for rectal administration ° These compositions can be prepared by dissolving the drug with a drug that is solid at room temperature but liquid in the rectum and therefore will melt in the rectum to release the drug. Prepared by mixing. These materials are, for example, cocoa butter and another formulation used in the method of polyethylene glycol. The transdermal patches can be used to provide a continuous or discontinuous round of the present in a controlled amount. The use and use of a transdermal patch for the delivery of a pharmaceutical agent is well known in the art (see, for example, U.S. Patent No. M23,252, incorporated herein by reference). The patches can be constructed for continuous, pulsatile or delivery of the medicinal agent as needed. The construction and use of mechanical delivery devices that may or may not require the introduction of a pharmaceutical composition to a patient via a mechanical delivery device for delivery of a pharmaceutical agent are well known in the art. For example, the direct technique of directly administering a musical substance to the brain generally involves placing the Drug Delivery Agency in the ventricular system of the heart to bypass the blood-brain barrier. One such implantable delivery system for transferring a medicament to an anatomical region of the body is described in US _ | Μ 0 ^ 1 1 闯 闯 利 利 5 5, 01 1, 472, by way of citation Incorporated herein. The compositions of the present invention may also contain, or contain, other conventionally pharmaceutically acceptable compounding ingredients which are generally referred to as humectants or diluents. Any of the compositions of the present invention may be preserved by the addition of an anti-oxidant such as an acid or a suitable preservative. The S-knowledge program can be used to prepare the appropriate dosage form of the composition 148833.doc • 50- 201102372. "Common medical ingredients that can be used to formulate compositions for the intended route of administration, as needed, include: acidulants such as, but not limited to, acetic acid, citric acid, trans, butadiene: acid, hydrochloric acid, nitric acid; Agents such as, but not limited to, ammonia solution f, ammonium citrate, ethanolamine, monoethanolamine, potassium hydroxide, sodium borate, stone anti-sodium, sodium hydroxide, triethanolamine. 1_trolamine. Pharmaceutical ingredients include, for example, but are not limited to, adsorbents (eg, powdered cellulose and activated carbon); push sprays (eg, carbon oxide, cci2F2, F2cic-CC1F2, and CC1F3); venting agents (eg, nitrogen and argon); Antifungal preservatives (eg, abbreviated, butyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, decyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sodium benzoate) antimicrobial preservatives (eg Ammonium chlorinated ammonium chloride, benzethonium chloride, benzoyl alcohol, gasified hexadecanol, butanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and sulphur water, antioxidants (eg ascorbic acid, palm sulphur) Acid ascorbate, butylated hydroxymethoxy stupid, butyl Alkyl hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium hydrogen sulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (eg block polymers) , natural and synthetic rubbers, polyacrylates, polyurethanes, polyoxo and styrene-butadiene copolymers; buffers (eg potassium metaphosphate, potassium dihydrogen phosphate, sodium acetate, anhydrous citric acid) Sodium and sodium citrate dihydrate); carrier (eg, gum arabic syrup, aromatic syrup, aromatic tincture, cherry syrup), cocoa candy, orange peel syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, Sodium chloride injection and bacteriostatic water for injection); chelating agent (for example, B 148833.doc -51 - 201102372 disodium diamine tetraacetate and edetic acid); coloring agent (for example, FD&C red 3 No., FD&C Red 20, FD&C Yellow 6, FD&C Blue 2, D&C Green 5, D&C Orange 5, D&C Red 8, Caramel and Iron Oxide Red); clarifying agent (eg bentonite); emulsifier (but not limited to Allah) Primary rubber, polytorol (cetornacrog〇i), cetyl alcohol, glycerol monostearate 'lecithin, sorbitan monooleate, polyethylene 5 〇 stearate (polyethylene 50 stearate) Encapsulating agents (such as gelatin and cellulose acetate phthalate); flavoring agents (such as anise oil 'cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanilla extract); humectants (such as glycerin, Propylene glycol and sorbitol); water-grinding agents (such as mineral oil and glycerin); oils (such as peanut oil, mineral oil, eucalyptus oil, peanut oil, sesame oil and vegetable oil); ointment base (such as wool moon, hydrophilic ointment, poly Diol ointment, paraffin, hydrophilic paraffin, white soft, yellow ointment and rose water ointment); penetration enhancer (transdermal delivery) (eg monohydric or polyhydric alcohol, saturated or unsaturated fatty alcohol, saturated Or unsaturated fat-brewed, saturated or unsaturated dicarboxylic acids, essential oils, phospholipids 1 biological brain knows, terpenoids, guanamines, ethers, ketones and glands); plasticizers (eg, neighboring Chu _ _ #本—曱酉文一乙And glycerol); solvent (eg alcohol, corn oil, cottonseed oil, sun 4 ^. (/ towel star / by glycerin, isopropanol, mineral oil, oleic acid, peanut oil, pure water, injection}} Tian I» _ Water 'halogen-free water for injection and sterile rinse water); hardener (eg + Μ 10 /, alcohol, hexadecyl ester wax, microcrystalline wax, paraffin, ten-person alcohol from the soil and steam sacrifice); (d) 丨 1 matrix (for example) Cocoa butter and polyethylene glycol (mixed interface / lingual agent (such as gasified benzoquinone ammonium, nonoxynol ether 1 〇 'Xin - (Xt〇xyno丨9), polysorbate rib, lauryl sulfate Sodium and single 148833.doc -52- 201102372 sorbitan palmitate); suspending agents (eg agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose) , hydroxypropyl tau cellulose, kaolin, methyl cellulose, xanthine and veegum; sweeteners such as aspartame, dextrose, glycerol, mannitol , propylene glycol, sodium saccharin, sorbitol and sucrose); lozenge anti-adhesive (such as magnesium stearate and talc); lozenge adhesive (such as Binder, alginate, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch; tablets and capsules Diluents (eg, calcium hydrogen phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol, and starch); lozenge coating agents (eg, , liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl decyl cellulose, decyl cellulose, ethyl cellulose, cellulose acetate phthalate and shellac); direct compression of tablets Excipients (such as calcium hydrogen phosphate); tablet disintegrants (such as alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose, potassium palladium (p〇lacrillin p〇tassium), sodium alginate, starch Sodium glycolate and starch); lozenge slip agents (eg colloidal cerium oxide, corn starch and talc); lozenge lubricants (eg calcium stearate, magnesium stearate, mineral oil, stearic acid and stearic acid) Zinc acid); lozenge / capsule sunscreen (opaquan t) (eg titanium dioxide); tablet polishes (eg carnauba wax and white wax); thickeners (eg beeswax, cetyl alcohol and rocky soil); tonicity agents (eg dextrose and sodium chloride); Agents (eg alginic acid, expanded soil, carbomer, slow-sodium cellulose sodium, methyl cellulose, povidone, sodium alginate and xanthine); and wetting agent 148833.doc -53- 201102372 (example . For example, heptaethylethoxide, lecithin, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monooleate and polyoxyethylene stearate.化合物 The compounds identified by the methods described herein can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents, wherein the combination does not cause an unacceptable adverse reaction. For example, the compounds of the invention may be combined with known anti-obesity agents or known anti-diabetic agents or other indication agents and their analogous agents, as well as mixtures and combinations thereof. The compounds identified by the methods described herein can also be used in the form of a free base or in the form of a composition, used in research and diagnostics, or as an analytical reference standard and the like. Accordingly, the invention includes compositions comprising an inert carrier and an effective amount of a compound identified by the methods described herein, or a salt or ester thereof. An inert carrier is any material that does not interact with the compound to be carried, and which provides support, transport, accumulating, traceable materials, and the like to the compound to be carried. An effective amount of a compound is an amount that produces a result or exerts an effect on a particular procedure being performed." Formulations suitable for subcutaneous, intravenous, intramuscular, and the like; suitable for pharmaceutical carriers; and techniques for formulating and administering Prepared by any method well known in the art (see, for example, Remington, s pharmaceutieai)

Sciences, Mack Publishing Co., Easton, Pa., 20th ed., 2000) 以下 The following examples are presented to illustrate the invention described herein, but are not to be construed as limiting the scope of the invention in any way. Capsule Formulation 148833.doc -54- 201102372 The capsule formulation is prepared from the following: Compound of the invention 40 mg Powder 109 mg. Magnesium stearate 1 mg Blend each component 'make it through a suitable mesh and fill it to hard gelatin capsules in. Tablets Formulations Tablets are prepared from the following: 25 mg of the compound of the invention, microcrystalline cellulose, colloidal cerium oxide, stearic acid, various components and pressure coating to improve the palatability of the sterile IV solution 200 mg 10 mg 5.0 mg condensed tablet . Appropriate aqueous and non-aqueous can be applied to improve appearance and stability or delay absorption. A 5 mg/m solution of the compound of the present invention is prepared using sterile injectable water, and the cation value is adjusted as needed. The solution was diluted to 2 mg/ml with sterile 5% dextrose for administration' and administered as an intravenous infusion over 6 minutes. Intramuscular suspension The following intramuscular suspensions were prepared: 50 mg/ml 5 mg/ml 4 mg/ml The compound of the invention sodium carboxymethylcellulose TWEEN 80 148833.doc 55- 201102372 9 mg/ml 9 mg/ml emulsified sodium Benzoyl alcohol is administered intramuscularly with suspension. Hard Shell Capsules A large number of unit capsules were prepared by filling each standard two-stage hard gelatin capsule with 100 mg of powdered active ingredient, 15 mg of lactose, 5 g of cellulose and 6 mg of magnesium stearate. a soft gelatin capsule, a mixture of the active ingredient in a digestible oil such as soybean oil, cotton oil or a withdrawal oil, and injected into the molten gelatin by means of a positive displacement pump to form 3 soft gelatin with 100 mg of active ingredient capsule. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water-miscible medical mixture. Immediate release of tablets/capsules These tablets/capsules are solid oral orally prepared by conventional and novel methods. These singles 70 are used orally without water for immediate dissolution and delivery (4) in MB sugar 1 The active ingredient in the liquid of the ingredients of the sweetener. These liquids are stomatized into solid yam tablets or caplets by freeze drying and solid phase extraction techniques. The drug compound can be compressed with viscoelasticity and thermal bombs, raw sugars and poly-sigma or hair-components to produce a porous matrix that is immediately released without the need for water. F. Methods of treatment (1) Diabetes and related diseases and conditions Compounds of formula I are effective. Bottom TT u σ Ί π type diabetes (including related diabetes dyslipidemia 148833.doc, 56 - 201102372 often and other diabetic complications), and for A variety of other medical uses associated with it, such as hyperglycemia, hyperinsulinemia, abnormal glucose tolerance, impaired fasting blood glucose, dyslipidemia, glycerol triglyceride, syndrome X, and TB. In addition, the compounds of the present invention are also used in the treatment of diseases such as obesity, such as regulating pupa and food, and for treating atherosclerosis, hyperlipidemia, hypercholesterolemia, low hdl content, hypertension Cardiovascular diseases (including atherosclerosis, coronary heart disease, coronary artery disease and hypertension), cerebrovascular diseases and peripheral vascular diseases; and for the treatment of lupus, polycystic ovarian syndrome, carcinogenesis and hyperplasia. The guanidine compound is also suitable for the treatment of physiological conditions associated with, for example, cell differentiation to produce lipid-cumulative cells, such as dysfunctional dysfunction of the adeno-gland, gonadocin-secreting tumors, and/or due to insulin autoantibodies, insulin receptors. Autologous antibodies or autoimmune antibodies to stimulating autologous antibodies to pancreatic beta cells are involved in the regulation of insulin sensitivity and blood glucose levels; macrophage differentiation leads to the formation of atherosclerotic plaques; inflammation Reaction, carcinogenesis, hyperplasia, adipocyte gene expression, adipocyte differentiation, pancreatic 0 cell volume reduction, tensalin secretion, tissue sensitivity to lycopene, liposarcoma cell growth, polycystic nevus disease, chronic absence Typography, male hyperactivity, progesterone production, steroidogenesis, redox potential in cells and oxidative stress, nitric oxide synthase (NOS) production, gamma glutamine transpeptidase, catalase, blood polytrimic acid Glycerin, HDL and LDL cholesterol levels are elevated, and pots are similar. 〃 S } The specific applicable compounds described in the present invention are those having the effects of lowering blood glucose concentration and serum diglyceride content and increasing serum HDL cholesterol content, 148833.doc 57-201102372. Therefore, it is expected that the compounds of the present invention have value as therapeutic agents. Thus, the present invention includes a method of treating a plurality of conditions identified above in a patient, including a mammal, which comprises administering to the patient a composition comprising a compound of formula I in an amount effective to treat the target condition. As indicated above, the compounds of the invention may be administered alone or in combination with one or more additional money reductions. Combination therapies include administration of a single-drug dosage formulation comprising a compound of the invention and/or a plurality of additional hypoglycemic agents, and administration of a separate pharmaceutical dosage formulation of the compound of the invention and each additional hypoglycemic agent itself And the compound of the invention and each additional hypoglycemic agent. For example, the compounds of the present invention and hypoglycemic agents can be co-administered to a patient in the form of a single oral dosage composition such as a lozenge or capsule or each of the agents can be administered as a separate oral dosage formulation. When a separate dosage formulation is used, the compound of the invention and one or more additional hypoglycemic agents can be administered substantially simultaneously (e.g., co-) or at a time (e.g., sequentially) at various staggered times. By way of example, the compounds of the invention may be administered in combination with one or more of the following additional hypoglycemic agents; bismuth; such as metformin or metformin; sulfonamide, such as acesulfame Acetohexamide, chl〇r〇pr〇pamide, tolazamide, t〇ibutamide, glyburide, glyph Glipizide, gizazizide; or any other phytosulinin, such as repaglinide and nateglinide; α-glycosidase inhibitors, such as sugar sulphate , voglibose 148833.doc -58- 201102372 (voglibose) or migliol; or pr adrenergic receptor agonist, such as CL-316,243. As is well known in the art, the compounds of the present invention can also be used in the form of the free base or in the form of compositions, as well as in research and diagnostics or as analytical reference standards and analogs thereof. Thus, the invention includes compositions comprising an inert carrier and an effective amount of a compound of the invention, or a salt or vinegar thereof. An inert carrier is any material that does not interact with the compound to be carried, and which provides support, transport, accumulating, traceable materials, and the like to the compound to be carried. An effective amount of a compound is the amount that produces or affects the results of a particular procedure being performed. In another aspect, the invention provides a method of treating a disease condition in a patient, wherein the disease is associated with a physiologically harmful amount of phytotoxic, blood, free fatty acid (FFA), cholesterol or triglyceride in the blood. The method comprises administering to the patient a therapeutically effective amount of a compound of formula I. In another embodiment J, the method of treating a disease condition in a patient, wherein the disease is associated with a physiologically harmful amount of insulin, glucose, free fatty acid (tetra) A) or triglyceride in the blood, the method comprises A therapeutically effective amount of a compound of formula 1 is administered to a patient and a therapeutically effective amount of an additional hypoglycemic agent, such as imaginin, a biguanide compound, and the like, is also administered. Kiss fishing is known to be a sulfonate, and his insulin secretagogue can stimulate insulin, but it does not work on 姨 素, and the combination of the present invention: enough to act on insulin resistance, so imagine these drugs The combination can be: the condition of insulin secretion deficiency and insulin resistance are both related. ,. Therefore, the present invention also provides a method for treating a patient's diabetes type I48833.doc • 59· 201102372" comprising administering a compound of the present invention and one or more additional agents such as gg-gland, biguanide, and adrenal gland. Receptor agonist, stimulating (four) inhibitor and mesin. In addition, the compound can be reduced with HMG c〇_A to inhibit d (statin statin), bile acid binding resin or fiber acid derivative, ' Sigma used to improve dyslipidemia and insulin resistant individuals. The compounds of the present invention may also be associated with the regulation of hypertension in individuals with insulin resistance or type 2 diabetes (eg, angiotensin converting enzyme (ace) inhibitors, resistance A combination of a drug, a calcium channel blocker, and a body weight agent. (2) Psoriasis Another aspect of the invention provides a method of preventing or treating psoriasis in an individual. The methods include administering to an individual in need thereof An effective amount of a compound of the invention. In some embodiments, the compound of the invention is administered topically. In another embodiment, the compound of the invention is administered intradermally, subcutaneously, orally, buccally, transdermally, orally. Or administered otic. In some embodiments, a compound of the invention may be administered in combination with one or more therapeutic agents. In one embodiment, the therapeutic agent is selected from the group consisting of: a corticosteroid; a vitamin D analog Amidoxime; cyclosporine; fumarate; Adalimna; aficex; alfazumab; etanercept; infliximab; steroid; retinoid; Antimicrobial compound; anti-oxidant; anti-inflammatory compound; salicylic acid; endothelin antagonist; immunomodulator; angiogenesis inhibitor; inhibitor of FGF, VEGF, HGF or EGF; inhibition of EGF, FGF, VEGF or HGF receptor a tyrosine kinase inhibitor; a protein kinase C inhibitor; and combinations thereof. In another embodiment, the compound of the invention may be combined with one or more selected from phototherapy 148833.doc -60 - 201102372 and/or photochemistry The combination therapy of therapy is administered in combination. (3) Alzheimer's disease according to one aspect of the present invention, provides a method for preventing or treating Alzheimer's disease, and the methods include administering to an individual in need of such treatment An effective amount of a compound of the invention. In some embodiments, the compound is administered intravenously, orally, buccally, transdermally, rectally, nasally or otically. In another embodiment, the compound of the invention may be administered in combination with at least one additional therapeutic agent. ♦ Exemplary additional therapeutic agents include, but are not limited to, antioxidants, anti-inflammatory agents, gamma secretase inhibitors, neurotrophic agents, acetylcholinesterase inhibitors, statin inhibitors, A ρ peptides, and anti-Α peptides The compounds described herein can be administered in combination with one or more other drugs for the treatment or prevention of Alzheimer's disease. Other drugs for the treatment or prevention of Alzheimer's disease include cholinesterase inhibitors. (eg, tacrine, galantamine, rivastigmine or winter niperazole) and NMDA inhibitors (eg, memantine). The compounds described herein can be administered in combination with one or more other drugs for the treatment or prevention of other dementias. Other drugs include non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, ibuprofen, diclofenac, acesulfame, nabumetone, piroxicam, celecoxib and aspirin. Other drugs that may be combined with the compounds described herein include HMG_c〇A reductase inhibitors, such as statin statins (eg, simvastatin (z〇c〇r), atorvastatin (Lipitor), russin a ( Crest〇r), fluvastatin (Lesc〇1)). Depending on the individual drug used in the combination therapy for simultaneous administration, it may be compounded into a combination (where a stable formulation may be prepared and the desired dosage regimen is phase) or the drug may be individually formulated (for The same or optional one of the 148833.doc 201102372 pathways are accompanied or individually administered). In some embodiments, an individual of the invention has one or more risk factors for developing Alzheimer's disease selected from the group consisting of a family history of disease; a genetic predisposition to disease; high serum cholesterol; adult onset diabetes; a high baseline hippocampus Volume; high total tau protein content in cerebrospinal fluid; high phosphorylated tau protein content in cerebrospinal fluid; and low Αβ(1-42) content in cerebrospinal fluid. An HPLC-electrospray was obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, visible wavelength detector, YMC Pro C18 2.0 mm><23 mm column and Finnigan LCQ ion trap mass spectrometer using electrospray ionization. Fog mass spectrometry (HPLC ES-MS). A gradient elution of 90% A to 95% B over 4 minutes was used on HPLC. Buffer A was 98% water, 2% acetonitrile and 0.02% TFA, and Buffer B was 98% acetonitrile, 2% water and 0.018% TFA. The spectra were scanned from 140-1200 amu using variable ion times based on the number of ions in the source. Me4Si (S 0.00) or residual protonation solvent (CHC13 δ 7.26; MeOH δ 3.30; DMSO δ 2.49) was used as a standard for measuring proton & Η NMR on a General Electric GA^-Omega 300 (300 MHz) spectrometer ( NMR) spectra. Carbon (13(:州]\411 spectra were measured using a solvent (CDC13 δ 77.0 ; d3-MeOD ; δ 49.0 ; d6-DMSO δ 3 9.5) as a standard using a General Electric GiV-Omega 300 (75 MHz) spectrometer. Commercially available Chiracel® AD HPLC columns were separated by a solution of isopropanol in hexane (1% to 15%) (addition of 0.1% trifluoroacetic acid) for palm separation. For Example 5, the following analytical instrument was used: 148833.doc -62- 201102372 (1) HPLC: Instrument: Perkin-Elmer Series 200, column: YMC Pro C18, S-3um, 12mm (4.6x150 mm/AS12503-1546WT); Mobile A: 0.1% TFA HPLC H20, mobile B: HPLC CH3CN with 0.1% TFA, temperature = ambient temperature; wavelength = 220 nm gradient: time (min) rate (ml/min) mobile A mobile B 0 1.00 75 25 25 1.00 20 80 27 1.00 10 90 30 1.00 10 90 31 1.00 75 25 36 1.00 75 25 (2) NMR: Bruker 400 MHz (3) Mass Spectrometer: Waters Micromass ZQ Abbreviations and acronyms When used in the following abbreviations, this has the following meaning: Ac2〇乙Anhydride ADDP Γ, Γ-(azodicarbonyl)dipiperidine anhy anhydrous BOC tert-butoxycarbonyl «-BuOH n-butanol i -BuOH tert-butanol i-BuOK potassium butoxide potassium CDI carbonyl diimidazole CD3〇D sterol-a 148833.doc -63 - 201102372

Celite® Algae Filter,®Celite Corp. CH2C12 Dichloromethane CI-MS Chemical Ionization Mass Spectrometry Cone Concentrated DCC Dicyclohexylcarbodiimide DCM Dichloromethane de Diastereomeric excess DEAD Azodicarboxylic acid Diethyl ester dec decomposes DIA diisopropylamine DIBAL-H diisobutylaluminum hydride DMAP diamine. Bipyridine DME Dimethoxyethane DMF dimethyl decylamine DMSO Diterpenoid EDC1 1-(3-difaminopropyl)-3-ethylcarbodiimide hydrochloride ee enantiomeric Excessive ELSD Evaporative Light Scattering Detector ES-MS Electrospray Mass Spectrometry EtOAc Ethyl Acetate EtOH Ethanol (100%) EtSH Ethyl Mercaptan Et20 Ethyl Ether Et3N Triethylamine 148833.doc -64- 201102372 GC-MS Gas Phase Chromatography-mass spectrometry HPLC high performance liquid chromatography IPA isopropylamine LAH lithium aluminum hydride LC-MS liquid chromatography-mass spectrometry LDA diisopropylamine lithium m/z mass-to-charge ratio MeCN acetonitrile NMM 4-methyl Morpholine Ph3P Triphenylphosphine Pd(dppf)Cl2 [1,Γ-bis(diphenylphosphino)ferrocene]digas palladium(II) Pd(PPh3)4 肆(triphenylphosphine)palladium(0) Pd( OAc)2 Palladium acetate P(〇)Cl3 Oxygenation Rf Retention rate (TLC) RT Retention time (HPLC) rt Room temperature TEA Triethylamine THF Tetrahydrofuran TFA Trifluoroacetic acid TLC Thin layer chromatography TMAD Ν, Ν, Ν ',Ν'-tetradecylethylenediamine TMSC1 trimethylsulfonium alkyl chloride Example 1. 148833.doc -65- 201102372 Preparation of Compound 1 (5·{2-[5-ethyl-2-(4-hydroxyl) -phenyl)-cacao I- 4-ethoxy} - indan-1-yl) - acetic acid

Compound 1 obtains a compound by reacting a compound la with a compound by using an organic or inorganic test in a suitable solvent under suitable reaction conditions (for example, CsfO3-containing acetonitrile (Acn) at a high temperature of about 70 ° C) Ic to start the reaction scheme 1 ° under appropriate reaction conditions (eg Na〇I1/EtOH, at about 65T:) with a suitable base to treat the compound 丨c, the ester is partially hydrolyzed, and then followed by deuteration (eg HC1) Compound 1 d is produced. Subsequently, the compound Id is treated with tri-boron boron (BBr3) in dioxane (Dcm) to obtain compound 1 ^ or compound 1 can be obtained by treating compound 1 d with aluminum chloride / dodecyl mercaptan in an appropriate solvent. . Compounds 1 & and 148833.doc -66-201102372 Reaction Scheme 1 ^C〇2Et can be prepared according to the methods described in the literature (for example, U.S. Patent No. 6,828,335), as is known to those skilled in the art.

(1) NaOH/EtOH, 65°C (2) HQ

BBr3 / CH2CI2 or: A1C13/dodecylmercaptan

Example 2 Synthesis of Compound 2 (5-{2-[2-(4-Benzyloxy-phenyl)-5-ethyl-oxazol-4-yl]-ethoxy}-dihydroindole-1- Base)-acetic acid

The reaction scheme 2 is started by coupling the compound la with the compound 2b under suitable reaction conditions (for example, acetonitrile (ACN) containing Cs2C03 at a temperature of 7 ° C) to obtain the compound 2c [I48833.doc •67·201102372. Next, compound 2c is treated with a suitable base under suitable reaction conditions (e.g., NaOH/Et〇H at about 65 ° C) to partially hydrolyze the ester. Compound 2 is then obtained by acidification (using, for example, HCl). Compound 2b can be prepared according to methods described in the literature (e.g., U.S. Patent No. 6,828,335), which is incorporated herein by reference. Reaction Scheme 2 ^C〇2Et

(l) NaOH/EtOH, 65 ° C

COOH Example 3 Alternative Synthesis of Compound 1 According to Reaction Scheme 3, Compound 1 can also be produced by hydrogenolysis of Compound 2c to give Compound 3b. Next, compound 3b can be treated with a suitable base under suitable reaction conditions (e.g., NaOH/EtOH at about 65 ° C) to partially hydrolyze the ester. Subsequent acidification (using, for example, HCl) produces Compound 2. Alternatively, Compound 1 can be produced by hydrogenating Compound 2 to obtain Compound 1. 148833.doc -68- 201102372 Reaction Process 3

Example 4 Preparation of a salt of Compound 1-3 An exemplary procedure for preparing a salt of Compound 1-3 is shown in Reaction Scheme 4. Compound 1-3 can be converted to a salt by appropriate treatment in a suitable solvent (e.g., ethanol containing NaOEt) followed by precipitation with a suitable anti-solvent (e.g., diethyl ether) to afford a salt of compound. 148833.doc 69- 201102372 Reaction Process 4

Compound 1: R4 is OH Compound 2: R4 is -OBn Compound 3: R4 is -CD

--COOH (1) NaOEt/EtOH (2) Antisolvent (eg diethyl ether)

COONa Compound 1: R4 is OH Compound 2: R4 is -OBn Compound 3: R4 is -OCD3 Example 5. Preparation of Compound 4 (5-{2-[5-ethyl-2-(D3-4-methoxy-) Phenyl)-11 oxind-4-yl]-ethoxy}- dioxin Bp _ 1_yl)-acetic acid

(5-{2-[5-ethyl-2*(D3^4-methoxy-phenyl)-oxazolidine]-ethenyl}-dihydroindol-1-yl)·acetic acid can be similar Compounds 4 are prepared starting from compounds Id and 2 by the appropriate deuteration of the starting material or the t-substance as shown in Reaction Scheme 5. MS: m/z: 425.3 (M+H); NMR (CDC13) δ 7.906 (d, 2H), 7.07 (d, H), 6.93 (d, 2H), 6.72 (d, 1H), 6.70 (dd , 1H), 4.19(t, 2H), 3.51(q, 1H), 2.86(t, 2H), 2.75(m, 5H), 2.48(m, 2H), 1.75(t,1H), 1.29(t, 3H). 148833.doc -70- 201102372 Reaction Process 5 ^C〇2Et

It will be apparent to those skilled in the art that the present invention may be modified and modified without departing from the spirit and scope of the invention. 148833.doc -71 -

Claims (1)

201102372 VII. Patent application scope: 1. A compound of formula I, Wherein R is 11 or (^-(:6 alkyl; R1 is oxime, COOH, -Cd-OR1, (:3-(:8-cycloalkyl, Ci_C6^, CVC6-alkenyl or CVC6 alkoxy) It is considered that c _c6 is a base group, and the alkyl group, cycloalkyl group, alkenyl group or alkoxy group may be optionally substituted with one or more groups selected from the group consisting of fluorine, methylenedioxyphenyl group and The present group 'wherein the S-methoxy-1-phenylene group or the phenyl group may be optionally substituted by R6; R2 is an anthracene, a functional group or a CrC6 alkyl group, wherein the alkyl group may optionally consist of one or more selected from the group consisting of Substituting groups of groups: (^-(:6 alkoxy, pendant oxo and fluoro, or R2 is C5-14 aryl, C3-14 heterocyclic or c5_14 heteroaryl, wherein the aryl group a heterocyclic or heteroaryl group optionally substituted by one or more R 6 ; R 3 is fluorene, (^-0: 6 alkyl or phenyl, wherein the alkyl or phenyl group may be optionally substituted with one or more R 6 ; X is 0 or S; R4 is C5-14 aryl, Cn4 heterocyclic or c5_14 heteroaryl 'wherein the aryl, heterocyclic or heteroaryl is substituted by one or more R7, 148833.doc 201102372 R5 is Η, Halogen or C "C6 alkyl" wherein the alkyl group Substituted by a pendant oxy group; R6 is a halo group; CF3; CrC6 alkyl group, wherein the alkyl group may be optionally substituted with a pendant oxy group or a hydroxy group; or optionally an oxy group substituted by fluorine; R7 is selected from the group consisting of Group (a) hydroxy, (b) CVC6 alkoxy, wherein one or more H of the alkoxy group is 2h(d), and (8)-O-CHrPh, wherein the phenyl group is substituted; W _0_c (=0 Wherein R_CiC group or C5" aryl group, wherein the form or aryl group is optionally substituted with one or more groups selected from the group consisting of: _, _ A, u I , -SH, decylamine, carboxylic acid, alkyl, sulfoalkyl, aryl and "hetero-aromatics, and declination of cRd, and independently of gas or sulphur-burning; as oxygen or (Vc6 alkane) Enantiomers: salts, vinegars, prodrugs, stereoisomers, non-2&dimers, enantiomers or racemates. Compounds of claim 1 wherein the compound of formula 1 has the following structure: 148833.doc 201102372 3. The compound of claim 1 or 2, wherein R is Η; R1 is Η; R2 is Η; ... is 匕-仏alkyl; X is Ο; R4 is substituted by one or more R7 a phenyl group, wherein R7 is selected from the group consisting of (a) a meridine, (b) a Ci-Q alkoxy group, and one or more of the alkoxy groups are 2H (D), and (c) - 0-CH2-Ph, wherein the phenyl group is optionally substituted by <^-(:6 alkoxy; and R5 is hydrazine; or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1, wherein This compound has the following structure: Or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, wherein the compound has the structure: Or a pharmaceutically acceptable salt thereof. 148833.doc 201102372 6. The compound of claim 1, wherein the compound has the structure: PhH2CO Or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1, 2, 4, 5 and 6, which is a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of alkali metals a salt, an alkaline earth metal salt, an ammonium salt with an organic base, and a basic nitrogen-containing group in a conjugated base which is quaternized by a reagent selected from the group consisting of an alkyl group and an aralkyl group. 8. The compound of any one of claims 1, 2, 4, 5 and 6, wherein the compound is a glucosamine salt, a potassium salt or a sodium salt. 9. The compound of claim 1, wherein R2 is selected from the group consisting of: phenyl, decyl, thiophene, ° ratio σ, 恶 ° sit, stagnation, ° 〇 Sitting on the base. ratio. Sitting base, different ° ° ° sitting on the base, different ° plug. Sitting base, three-degree sitting base, ° 恶二0 sitting 148833.doc 201102372 base, thiadiazolyl, tetrazolyl, pyridyl, pyrrolidinyl, piperidinyl, tetrahydronaphthyl, tetrahydrothiolan The base, the pyrazinyl group and the acetonyl group can be substituted by one or more R6, as appropriate. 10. The compound of claim 1, wherein r4 is selected from the group consisting of phenyl, naphthyl, furyl, thienyl, pyrrolyltetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, tetrahydrothiophene Base, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl. Evil two ° sitting base,. Saijiji, four. Shengji, ° ratio, biting group, tetrahydrogeninyl, tetrahydrothiopyranyl, pyrimidinyl, D-pyridinyl, pyridazinyl, piperidinyl, morpholinyl, benzofuranyl , Dihydrobenzofuranyl, benzothienyl, dihydrobenzoxanthene, W α, and 丨. Dulphonyl, sulfhydryl, stupid and oxazolyl, stupid thiazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzodioxolyl quin琳基, isoindolyl 'quinazolinyl, quinoxaxazinyl, dihydrobenzopyranyl, dihydrothiothiazepine and M_benzodioxane A group, each of which may be substituted with one or more R7 groups. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 丨 to (7) and a pharmaceutically acceptable carrier. 12. A pharmaceutical composition as claimed, further comprising - or a plurality of hypoglycemic agents. 13. The pharmaceutical composition of claim 12, wherein the hypoglycemic agent is selected from the group consisting of insulin, biguanide, (iv) urea, insulin secretagogue (d) enzyme inhibitor, and beta 3 adrenergic receptor agonist. 14. The pharmaceutical composition according to any one of the preceding claims, further comprising 148833.doc 201102372 one or more agents selected from the group consisting of HMG c〇A reductase inhibitors, bile acid binders, fibric acid derivatives, An agent for regulating hypertension and a medicament for regulating body weight. The pharmaceutical composition according to any one of claims 11 to 13, further comprising one or more agents selected from the group consisting of corticosteroids; vitamin D analogues; meth〇trexate Cyclosporin (cyclin sp〇rin): fumarate; adalimunag; effeet; afaxumab; etanercept ); infUximab; steroids; retinoids; antimicrobial compounds; antioxidants; anti-inflammatory compounds; salicylic acid; endothelin antagonists; immunomodulators; angiogenesis inhibitors; FGF, VEGF, HGF Or an inhibitor of EGF; an inhibitor of EGF, FGF, VEGF or HGF receptor; a tyrosine kinase inhibitor; a protein kinase c inhibitor; and combinations thereof. The pharmaceutical composition according to any one of claims 11 to 13, further comprising one or more agents selected from the group consisting of antioxidants, anti-inflammatory agents, gamma secretase inhibitors, neurotrophic agents, acetamidine Cholinesterase inhibitors, statins, Αβ peptides and anti-Α peptides. 17. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment or prevention of diabetes. 18. The use of a compound according to any one of items 1 to 1 which is for the manufacture of a medicament for the treatment or prevention of syndrome X. 19. Use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment or prevention of a diabetes-related disorder. 148833.doc -6 · 201102372 20. The use of claim 19, wherein the diabetes-related disorder is selected from the group consisting of: hyperglycemia, hyperinsulinemia, glucose tolerance, and fasting blood glucose Abnormalities, dyslipidemia, hypertriglyceridemia, and insulin resistance. 21. Use of a compound according to any one of claims 1 to 1 for the manufacture of a medicament for the treatment or prevention of obesity. 22. Use of a compound according to any one of claims 1 to 2 for the manufacture of a medicament for the treatment or prevention of cardiovascular disease. The use of XX, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, dyslipidemia, hypercholesterolemia, low HDL content, high blood consumption, coronary heart disease, and coronary artery disease. . 24. The use of a compound according to any one of claims 1 to 7 for the manufacture of a medicament for the treatment or prevention of cerebrovascular diseases. 25. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment or prevention of peripheral vascular disease. 26. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment or prevention of lupus. 27. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment or prevention of polycystic ovarian disease. 28. Use of a compound according to any one of claims 1 to 1 for the manufacture of a medicament for the treatment or prevention of carcinogenesis and proliferation. 29. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment or prevention of diabetes, Syndrome X and/or diabetes related disorders in combination with one or more hypoglycemic agents. 148833.doc 201102372 3〇. The material of claim 29, wherein the diabetes-related disorder is selected from the group consisting of hyperglycemia, hyperphosphazeneemia, abnormal glucose tolerance, abnormal fasting glucose, and dyslipidemia High triglyceride and insulin resistance. 31. 32. 33. The use of claim 29 wherein the drug and the one or more hypoglycemic agents are formulated as a single drug dosage formulation. The use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for treating diabetes, a syndrome and/or a diabetes-related disorder in combination with - or a plurality of agents selected from the group consisting of: HMG CM reductase inhibitors, bile acid binders, fibric acid derivatives, agents for regulating hypertension, and agents for regulating body weight. In the case of claim 32, the condition of the diarrhea is selected from the group consisting of high glucose, hyperinsulinemia, abnormal glucose tolerance, abnormal fasting blood glucose, dyslipidemia, and hypertriglyceridemia. And insulin resistance. 34. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment or prevention of psoriasis. 35. The use of claim 34, wherein the drug is administered topically. 36. The use of claim 34, wherein the medicament is administered intradermally, subcutaneously, orally, buccally, transdermally, rectally or otically. 37. For use in claim 34, where the drug is administered with - or multiple additional therapeutic agents. 38. The use of claim 37, wherein the additional therapeutic agent is selected from the group consisting of: corticosteroids; vitamin D analogues; methotrexate; embracing 148833.doc 201102372 primed 'anti-butyls m-adali姆那;阿非赛特; Alfazumab 依依西普; Infliximab; Steroids; Retinoids; Antimicrobial compounds; Antioxidants; Anti-inflammatory compounds; Salicylic acid; Endothelin antagonists Immunomodulator; angiogenesis inhibitor; inhibitor of fgf, vegf, HGF or EGF; inhibitor of tyrosine kinase inhibitor of gamma, FGF, VEGF or HGF receptor; protein kinase c inhibitor; . The use of any of claims 34 to 38t, wherein the drug is administered with one or more synergistic therapies selected from phototherapy or photochemotherapy. 40. Use of a compound of any of the claims lil〇 for the manufacture of a medicament for treating or preventing Alzheimer's disease in need of an individual. 4 1 • The use of claim 40 wherein the drug is administered intravenously, orally, buccally, transdermally, rectally, nasally or otically. 42. The use of claim 41, wherein the drug is administered with or with a plurality of additional therapeutic agents. 43. The use of claim 42, wherein the one or more additional therapeutic agents are for treating or preventing Alzheimer's disease. 44. The use of claim 42, wherein the one or more additional therapeutic agents are a cholesterol esterase inhibitor or an NMDA inhibitor. 45. The use of claim 42, wherein the additional therapeutic agent is selected from the group consisting of tacrine, galantamine, dvastigamine, and winternipazole (d〇nepezil) and memantine 〇 I48833.doc 201102372 46. The use of claim 42, wherein the one or more additional therapeutic agents are selected from the group consisting of antioxidants, anti-inflammatory agents, gamma secretase inhibition Agent, neurotrophic agent, acetylcholinesterase inhibitor, HMG-CoA reductase inhibitor (or statin statin), Αβ peptide and anti-Αβ peptide. 47. The use of claim 42, wherein the one or more additional therapeutic agents are selected from the group consisting of naproxen, ibuprofen, diclofenac, indomethacin , nabumetone, piroxicam, ceieC0xib, aspirin, simvastatin, z〇c〇r, atovava Statins (atovastatin, Lipitor), russin, rosuvastatin 'Crestron' and vavastatin (Lescol). The use of any one of claims 40 to 47, wherein the individual has one or more risk factors for developing Alzheimer's disease selected from the group consisting of a family history of disease; a genetic predisposition of the disease; high serum cholesterol; Adult onset diabetes; high hippocampal baseline volume; high total protein 1 in cerebrospinal fluid; high content of phosphorylated tau protein in cerebrospinal fluid; and low content of a β (ΐ-42) in cerebrospinal fluid. 49. A process for the preparation of a compound of formula la, which comprises dealkylating a compound of formula β to obtain a compound of formula la 148833.doc -10- 201102372 R is an alkyl group; R1 is Η, C〇〇H, _C(=0)-〇R,, 03-(:8-cycloalkyl, Cl_cw-based, CVC6-alkenyl or C丨-C6 alkoxy, wherein r a Ci_c6 alkyl group, and the ?-alkyl, cycloalkyl, alkenyl or alkoxy group may be optionally substituted with one or more groups selected from the group consisting of fluorine, anthracene dioxyphenyl and benzene. Wherein the fluorene dioxyphenyl or phenyl group may be optionally substituted by R6; R is hydrazine, halo or Ci-C6 alkyl, wherein the alkyl group may optionally be selected from the group consisting of Substituted for: Ci_C6 alkoxy, pendant oxy and fluoro, or R2 is C5_M aryl, C3_M heterocycle or c: 5"4 heteroaryl, wherein the aryl, heterocycle and heteroaryl are as appropriate And independently substituted by one or more R6; R3 is H, c^c: 6 alkyl or phenyl, wherein the alkyl or phenyl group may be optionally substituted with one or more R6; X is hydrazine or s; ^ is 匕-decyloxy; R5 is Η 'halo or C〗-C6 alkyl, wherein the alkyl group is optionally substituted with a pendant oxy group; and 148833.doc • 11 · 201102372 R6 is a dentate group, CF3, Substituting a side oxy or hydroxy group for 2Ci_ c< or a fluoro group substituted by fluorine. 50. 51. 52. 53. 54. 55. A method of producing compound B, which comprises dealkylating compound a to rco〇Rc Λ ^ ▲ / H3CO obtains compound B In the COORc solvent, the method of 'BBr3, wherein the Rc is hydrogen or Cl_C6 alkyl, as in the claim 50, is the treatment of the compound A, and the dealkylation is carried out as in the method of claim 51, wherein The solvent is a gas-fired gas. The de-alkylation is carried out by treating the compound A with a chlorinated decyl mercaptan in the same manner as in the method of 5G. For example, in the method of claim 50, wherein R, cvc^, hydrolyzed compound B, the following compound is obtained: H. Knowledge; C. Structure: The method of claim 50, wherein compound A has the following 148833.doc -12- 201102372 And compound B has the following structure: 56. A method of making compound D comprising cleavage of a bond of 〇-CH2Ph of compound C ^cvc6 yard base. 57. The method of claim 56, wherein the cleavage step is carried out by hydrogenolysis into the method of claim 57, wherein the hydrogenolysis is carried out by using a catalyst and hydrogen (H2) gas: effect. A method of claim 7, wherein the catalyst is selected from the group consisting of Pb/carbon, platinum oxide, and Haney nickel. The method of claim 56, wherein the cleavage step is carried out with boron tribromide or boron trioxide hydride C. 148833.doc 201102372 61. The method of claim 56, wherein the compound C is treated with a trimethyl sulfonium alkyl iodide, and the cleavage step is carried out. 62. The method of claim 56, wherein 11 <; is (: 1-(: 6 alkyl, further comprising hydrolyzing compound D, obtaining a compound of the structure: 63. The method of claim 56, wherein compound C has the structure: /COOH And compound D has the following structure 148833.doc -14- 201102372 IV. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 148833.doc -2 -