TW201242947A - New azaspirodecanone compounds - Google Patents

Abstract

The invention provides novel compounds having the general formula (I) wherein R1 and R2 are as described herein, compositions including the compounds, their pharmaceutically acceptable salts and esters and methods of using the compounds.

Description

201242947 VI. Description of the Invention: [Technical Field] The present invention relates to (four) or preventable organic compounds which are useful in mammals and, in particular, for the treatment of diabetes, metabolic syndrome, ^*lipid abnormalities, arteries Atherosclerosis, obesity, cardiovascular disease, myocardial function. (4) Inhibitory, inflammatory, nonalcoholic fatty liver disease or non-alcoholic lipodystrophy hormone inhibitory lipase (HSL) inhibitor. The present invention provides novel compounds of formula (I) or pharmaceutically acceptable salts thereof:

.R2 (I) wherein R is adentino alkoxyalkyl, pendant oxypyrrolidinylalkyl or pendant oxypiperidinylalkyl; 2R is substituted substituted or substituted pyridyl, wherein The substituted phenyl and substituted pyridyl are substituted with 3 substituents independently selected from the group consisting of a haloalkyl group, a dentylalkyl group, an alkoxy group, and a southern alkoxy group. [Prior Art] The main physiological role of white adipose tissue (WAT) is to provide energy when needed by other tissues. In mammals, white adipose tissue is the main energy reservoir that accumulates fuel reserves in the form of trimethyl glycerol (TAG) during periods of excess energy. Free fatty acid (FFA) is released from TAG via catecholamine 162086.doc 201242947 Stimulated and regulated by hormones (eg insulin, glucagon and adrenaline). According to 彳§ the most important enzyme in the WAT of the hormone-regulated hydrolysis of the noble diglyceride is hormone sensitive lipase (HSL). Abnormal regulation of lipocyte lipolysis leads to an increase in circulating non-esterified fatty acids (NEFA) and is associated with obesity and co-morbidities including the development of type 2 diabetes. Obese or insulin resistant individuals have an increased visceral adipose tissue pool. These pools contain a concentration of HSL protein and exhibit enhanced lipolytic activity when they are resistant to lipolysis inhibition by insulin. This results in increased excitability of free fatty acids (FFA) in blood pooling and further exacerbates insulin resistance due to the accumulation of glycerol in non-WAT tissues such as liver, pancreas and muscle. Therefore, the high plasma concentration caused by high HSL activity promotes and worsens insulin resistance in obese and type 2 diabetic individuals. Reducing excessive blood damage by inhibiting HSL ffa and triglyceride levels will reduce the accumulation of triglyceride in non-WAT tissues (eg liver, muscle and pancreas), thereby reducing hepatic glucose output, increasing muscle fatty acid oxidation and improving Beta-cell function. High F F 有关 is also associated with high cardiovascular risk, including atherosclerosis and myocardial dysfunction. In addition, high lipolytic activity and high FFA lead to decidual resistance and hypertension in hypertensive rats. The FF A accumulates in the liver and results in an increase in the amount of TAG produced, which is encapsulated into secreted very low density lipoprotein (VLDL). Thus, reducing HSL activity will reduce the release of FFA into the blood, thereby limiting the supply of FFA to the liver for synthesis of the tag. Therefore, HSL inhibitors may have beneficial effects as therapeutic agents for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic fatty hepatitis (NASH). The object of the present invention is a compound of the formula (I), and the above salts and esters thereof and their use as therapeutically active substances; a method for producing the compounds; an intermediate; a pharmaceutical composition comprising the same A compound, a pharmaceutically acceptable salt or ester thereof, for use in the treatment or prevention of a disease (especially in the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity) Use of cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or nonalcoholic fatty hepatitis; and the use of such compounds, salts or esters for the treatment or prevention of diabetes, metabolic syndrome, blood lipids Use of drugs for abnormalities, atherosclerosis, obesity, cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or nonalcoholic lipodystrophy. The term "alkoxy" means a group of the formula -0-R., wherein R is an alkyl group, and examples of the alkoxy group include a decyloxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, and a n-butyl group. Oxyl, isobutoxy and tert-butoxy. Specific alkoxy groups include anthracenyloxy, ethoxy, n-propoxy and isopropoxy. Other specific examples are isopropoxy groups. By "alkyl" is meant a monovalent straight or branched chain saturated hydrocarbon radical having from 丨 to 12 carbon atoms, specifically 丄 to 7 carbon atoms, more specifically 丨 to 4 carbon atoms, for example Mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and tert-butyl. Specific alkyl groups include mercapto, ethyl, n-propyl and isopropyl. More specific alkyl sulfhydryl groups. The term "haloalkoxy" means an alkoxy group wherein at least one of the alkoxy groups has been replaced by the same or different hydrazine atoms. Examples of dentate alkoxy groups 162086.doc 201242947 include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, difluoromethylethoxy, difluoro 1 dimethyl Oxyl and pentafluoroethoxy. Particular halogenated alkoxy groups are difluoromethoxy and trifluoroethoxy. More specifically, the oxygen-based system is 1,1,1-trifluoroprop-2-oxy. 5 ""Homo-alkyl group J means an alkyl group in which at least one hydrogen atom in the in-house group has been replaced by the same or different halogen atoms. Examples of the functional group include a methyl group, a monofluoromethyl group, and a difluoroanthyl group. , trifluoroethyl, trifluoromethylethyl and penta-ethyl. The specific letter is a trimethyl group. The terms "fun" and "tooth" are used interchangeably herein and mean fluorine and gas. , bromine or iodine. Specific halogen gas and fluorine. More specific halogen is fluorine. The term "radio-halogenated alkyl" means an alkyl group wherein at least one of the hydrogen atoms in the pendant group has been replaced by a hydroxy group and wherein at least one of the hydrogen atoms in the alkyl group has been halogen-substituted. Examples of the hydroxy-functional alkyl group include a hydroxytrifluoroethyl group, a hydroxytrifluoropropyl group, and a hydroxyhexafluoropropyl group. The specific hydroxy dentate alkyl group is 2,2,2-trifluoro-1_ via ethyl. The term "sideoxy" means a divalent oxygen atom = hydrazine. The term "trioxyl bityl" means a piperidinyl group in which two of the n-position hydrogen groups have been replaced with a pendant oxy group. A specific example is 2-oxopiperidinyl. The term "sideoxy" is more than pyrrolidinyl means a pyrrolidinyl group in which n is substituted with a pendant oxy group of two hydrogen atoms in the thiol group. A specific example is 2-oxooxypyrrolidinyl. The term "oxylpiperidinylalkyl" means an alkyl group wherein at least one hydrogen atom of the alkyl group has been replaced with a pendant oxypiperidinyl group. Specific Examples 2·Side 162086.doc -6 - 201242947 Oxypiperidine-1-ylindenyl The term "sideoxypyrrolidinylalkyl" means wherein at least one hydrogen atom in the alkyl group has been pendant. A pyrrolidinyl substituted alkyl group. A specific example is the 2_ pendant oxy group. Pyrrolidine-1-ylindenyl. The term "pharmaceutically acceptable salt" means that they retain the biological potency and properties of the free base or free acid and are not biologically or otherwise undesirable salts. The salts are derived from inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, acid, and the like, specifically hydrochloric acid) and organic acids (for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid). , maleic acid, malonic acid, spearic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methyl acid, ethyl acid, p-toluene acid, salicylic acid, hydrazine - formed by acetyl cysteine and the like). Further, such salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, bell, lysine, argon, sulphate, and the like. Salts derived from organic tests include, but are not limited to, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and alkali ion exchange resins (eg, isopropylamine, trimethylamine, A salt of diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, hydrazine-ethylpiperidine, piperidine, polyimine resin and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, methanesulfonate and citrate salts. "Pharmaceutically acceptable ester" means that the functional group of the compound of formula (1) can be derivatized to provide a derivative which can be converted in vivo to the parent compound. Examples of such compounds include physiologically acceptable and metabolically unstable ester derivatives such as decyl decyl methacrylate, decyl thiomethyl ester and pentylene decyl oxime ester. Any of the physiologically acceptable equivalents of a compound of formula (I) which can form a parent compound of formula (i) in vivo and which are similar to such metabolically unstable esters are in the present invention. Within the scope. The term "protecting group" (PG), as defined generally in the definition of synthetic chemistry, means selectively blocking the reaction sites in a polyfunctional compound such that the chemical reaction can be selectively carried out at another unprotected reaction site. The group. The protecting group can be removed as appropriate. Exemplary protecting groups are amine protecting groups, buffer protecting groups or hydroxy protecting groups. Specific protecting groups are a third butoxyol group (Boc), > an oxygen group (Cbz), a fluorenylmethoxy group (Fmoc), and a nodal group (Bn). Other specific protecting groups are tert-butoxycarbonyl (B〇c) and fluorenylmethoxy(Fmoc) oxime, a more specific protecting group, benzyl (Bn). The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers (for example, as racemates), optically pure diastereomers. a mixture of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be configured as an "R" or "S". An embodiment of the invention is a compound of formula (I), as described herein, and a pharmaceutically acceptable salt or ester thereof, particularly a compound of formula (I), as described herein, and a pharmaceutically acceptable salt thereof More specifically, it is a compound of formula (1) as described herein. Another embodiment of the invention is a compound of formula (I) as described herein, wherein R1 is a southern alkoxyalkyl group or a pendant oxy-"pyridinylalkyl. A specific embodiment of the invention is a compound of formula (i) as described herein, wherein R1 is haloalkoxyalkyl. Another embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is 2-fluoroethoxyindenyl, 2,2-difluoroethoxyindenyl or 2,2,2-trifluoroethyl Oxymethyl" Another embodiment of the invention is a compound of formula (I) as described herein, wherein R1 is 2-fluoroethoxymethyl or 2,2-difluoroethoxymethyl. Another embodiment of the invention is a compound of formula (I) as described herein, wherein R1 is 2 fluoroethoxy fluorenyl. The invention also relates to compounds of formula (I) as described herein, wherein R1 is 2,2-difluoroethoxymethyl. Another particular embodiment of the invention is a compound of formula (I) as described herein, wherein R1 is 2,2,2·trifluoroethoxymethyl. A more specific embodiment of the invention is a compound of formula (I) as described herein, wherein R1 is pendant oxy. Pyrrolidinyl. A further embodiment of the invention is a compound of formula (I) as described herein, wherein R1 is 2-sided oxypyrrolidin-1ylmethyl. The invention is also directed to compounds of formula (I) as described herein, wherein Ri is a pendant oxyalkylene group. Another embodiment of the invention is a compound of formula (I) as described herein, wherein R1 is 2-sided oxypiperidin-1ylmethyl. Another particular embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is 2-fluoroethoxyindenyl, 2,2-difluoroethoxyindolyl, 2,2,2_ Trifluoroethoxymethyl, 2-sided oxy η is more than bite-l-ylmethyl or 2-sideoxynid 162086.doc 201242947 Bite _ 1 -ylmethyl. A particular embodiment of the invention is a compound of formula (1) as described herein, wherein R1 is 2-fluoroethoxymethyl, 2,2-difluoroethoxymethyl or 2-oxoxypyrrolidin-1 -ylmethyl. Another embodiment of the invention is a compound of formula (I), wherein R2 is substituted phenyl or substituted n is butyl, wherein substituted phenyl and substituted pyridyl are One to three substituents independently selected from the group consisting of an alkoxy group and a halogenated alkoxy group are substituted. The invention also relates to a compound of formula (I) as described herein, wherein R2 is substituted phenyl or substituted n-tackyl, wherein substituted phenyl and substituted pyridyl are one Substituent substitutions selected from the group consisting of trifluoromethyl, 2,2,2-trifluoro-1-hydroxyethyl, isopropoxy and 1,1,1-trifluoroprop-2-yloxy. Another embodiment of the invention is a compound of formula (I), wherein R2 is substituted phenyl, wherein the substituted phenyl is independently selected from the group consisting of dentate alkyl, hydroxy Substituent substitution of haloalkyl, alkoxy and dentate alkoxy groups. Another embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is substituted phenyl, wherein substituted benzene The group is substituted with i substituents selected from the group consisting of haloalkyl, hydroxydentylalkyl, alkoxy and dentate alkoxy. The invention also relates to a compound of formula (1) as described herein, wherein R2 is substituted phenyl, wherein the substituted phenyl is selected from the group consisting of trifluoromethyl, 2,2,2-difluoro-1 - Substituted by a substituent of ethyl, isopropoxy and iota, iotatrifluoroprop-2-yloxy. Another embodiment of the invention is a compound of formula (i) wherein R2 is substituted phenyl, wherein the substituted phenyl is one selected from isopropoxy Substituents substituted with 1,1,1-trifluoroprop-2-yloxy. A further embodiment of the invention is a compound of formula (I) as described herein wherein R is 4-(isopropoxy)phenyl or 4-(1,1,1-trifluoroprop-2-yloxy) Base) Base. Another embodiment of the invention is a compound of formula (I) as described herein wherein R2 is substituted phenyl wherein the substituted strepyl is substituted with a haloalkyl group. A particular embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is 4-(trifluoromethyl)phenyl. Another particular embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is substituted phenyl wherein the substituted phenyl is substituted with a hydroxy dentate group. A further embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is 4(2,2,2-trifluoro-1-hydroxyethyl)phenyl. Another embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is substituted phenyl wherein substituted phenyl is substituted with an alkoxy group. A particular embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is 4-(isopropoxy)phenyl. Another particular embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is substituted phenyl wherein substituted phenyl is substituted with one haloalkoxy. The invention is also directed to a compound of formula (I) as described herein, wherein the rule 2 is 4-162086.doc • 11 201242947 (1,1,1 -tri-l-propyl-2-yloxy)phenyl. Another embodiment of the invention is a compound of formula (I), wherein R2 is substituted pyridyl, wherein substituted pyridyl is 1 to 3 independently selected from haloalkyl, hydroxy Substituents substituted with alkyl, alkoxy and functional alkoxy groups. Another particular embodiment of the invention is a compound of formula (I), wherein R2 is substituted pyridyl, wherein substituted pyridyl is selected from alkoxy and alkoxy The substituent is substituted. The invention also relates to compounds of formula (I) as described herein, wherein R2 is substituted pyridyl, wherein the substituted pyridyl group is selected from the group consisting of isopropoxy and 1,1,1-trifluoro The substituent of the propan-2-yloxy group is substituted. A particular embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is 6-isopropoxypyridine-3-yl. Another embodiment of the invention is a compound of formula (I) as described herein, wherein R2 is 6-(1,1,1-trifluoroprop-2-yloxy)-pyridin-3-yl. Another embodiment of the invention is a compound of formula (I) as described herein, which is in the formula (la):

Another embodiment of the invention is a compound of formula (I) as described herein, which is in the formula (lb): 162086.doc • 12· 201242947

Specific examples of the compound of the formula (1) as described herein are selected from the group consisting of: (5Ma)_8·trans-H(2_side oxy-bito-)-mercaptofluoromethyl)phenyl)-2-aza Snail [45] quinone ketone; (5«, 8«)-8-carbyl-8. (2. oxo-oxygen benzyl) 2 (4) phenyl-phenyl)-2-aza-spiro [ 4 5] anthracene; (5Μα)-8-carbyl-2-(4-isopropoxyphenyl)_8_((2_sideoxypyridin-1-yl)methyl)-2-aza Snail [Bus 癸 癸 ketone; (5α, 8α) -8. Light base · 2. (4_Isopropoxy phenyl) _ 8 _ (( 2 _ ethoxy ate) 2-Azaspiro[4^癸^one; (5α,8α)_8_(2,2-difluoro-ethoxyindolyl)-8-carbyl-2-(4-isopropoxyphenyl) -2-Aza-spiro[4.5]癸_ι_ ketone; soil (5α,8α)_8·yl group·2'(6-isopropoxy acyl group) _8·(2• side oxygen^ pyrrolidine _1_ylmethyl)·2-aza-spiro[4.5]dec-1-one; soil (5α,8α)-8-hydroxy-2-(6-isopropoxypyridine·3_*)_8·( (2,2 2 _ ethoxy)methyl)-2-azaspiro [4.5] fluorene-fluorenone; fluoro(5α,8α)-8-hydroxy-8-(2- oxy-.咯 · ^ ^ τ τ τ τ τ τ τ τ τ ; ' · (5α,8α)-8-hydroxy-8-((2-sided oxypyrrolidinyl-i-yl)indolyl) 2 (4 ((R)-l,l,l-trifluoropropene_ 2_yloxy)phenyl)_2_azaspiro[4^癸" ketone; 162086.doc -13· 201242947 (5α,8α)-8-hydroxy-8-((2-hydroxypyrrolidinyl) )methyl)2 (6_((S)-1,1,1-tri-propan-2-yloxy)π-pyridyl_3_yl)_2_gashelix[4 5]nonan-1-one (5α,8α)-8-((2-fluoroethoxy)methyl)_8-hydroxy-trifluoropropan-2-yloxy)pyridin-3-yl)·2-azaspiro[4.5]癸_丨_ketone; (5α'8α)-8-((2-fluoroethoxy)methyl)·8-hydroxy-2(4isopropoxyphenyl)-2-azaspiro[4.5]癸1-ketone; and pharmaceutically acceptable salts thereof. Other specific examples of compounds of formula (I) as described herein are selected from the group consisting of: (5α,8α)-8-carbyl-2-(4-isopropoxyphenyl)-8-((2-oxypyrrolidine) -1-yl)methyl)-2-azaspiro[4,5]癸_1-one; (5α,8α)-8·(2,2-difluoroethoxymethyl)·8_ Hydroxy-2 (4isopropoxy-phenyl)-2_aza-spiro[4.5]癸·ι__ ; (5α,8α)-8-((2-f-ethoxy)methyl)_8 · 2 (6 ((8)·^, Bu III II propen-2-yloxy)" bite _3_yl) _2 azaspiro[4 5] fluorenone; and a pharmaceutically acceptable salt thereof. One object of the invention is a process for the manufacture of a compound of formula (1) as described herein. The preparation of the compound of the formula (I) of the present invention can be carried out in a continuous or astringent synthetic route. The synthesis of the present invention is shown in the following general scheme. The techniques required for carrying out the reaction and purification of the resulting product are known to those skilled in the art. Where a mixture of enantiomers or diastereomers is produced during the reaction, it may be by methods known to those skilled in the art (e.g., such as for palm chromatography or crystallization). ) to isolate these enantiomers 162086.doc 201242947 bulk or diastereomers. The substituents and labels used in the following description of these methods have the established meanings in the text. The relative configuration of the base 2_aza-spiro[45] 癸-1-one backbone is equivalent to [5α,8α] The cis configuration on the cyclohexane ring, and the relative configuration [5α, 8β] corresponds to the trans configuration on the ring of the compound of the above formula (1). As outlined in Scheme 1, at a temperature between RT and reflux temperature, in the presence of a base such as sodium hydride or potassium t-butoxide in a solvent such as DMF, THF or tert-butanol or In the analog), a compound of the formula (1) can be easily obtained by treating a compound of the formula Α8 with a compound of the formula RLH as defined above. Flow chart 1

Formula R-H compounds are commercially available or described in the literature. The synthesis of the formula 8-8 intermediate is summarized in Flowcharts 2 and 3. Thus, as outlined in Scheme 2, the commercially available ketone A1 can be protected, for example, as a ketal (step (a)) according to methods known in the literature to provide compound A2. Subsequent by using a suitable base in a suitable solvent (such as THF, DMF, diethyl ether or the like) (for example, lithium diisopropylamide, hexamethyldiazide or sodium, potassium t-butoxide or the like The treatment is carried out, followed by the addition of a suitable electrophilic agent (for example, 1 - odor-2 - methoxy ethene) to anneal the appropriate position of the condensed a 2 168686.doc 15 201242947 to provide the compound A3 ( Step (b)). If desired, it may be removed from A3, or the ketal group may be removed during the treatment of reaction step (b) (step (c)). Therefore, the crude product VIII is treated at a different temperature of -15 t: to 100 ° C using a strong aqueous mineral acid solution (for example, HCl, H 2 SO 4 , HBr or the like) until the ketal protecting group is completely hydrolyzed (step (c)), To provide compound A4. The reduction of compound A4 (step (d)) can be accomplished in a suitable solvent (e.g., MeOH, EtOH or 2-propanol) by a reducing agent (e.g., NaBH4 or the like) in a suitable solvent (e.g., MeOH, EtOH or 2-propanol) to provide Compound A5, a mixture of cis and trans isomers. According to Scheme 2, it is possible to use a suitable compound of the formula R2_NH2 and a suitable organometallic reagent (for example, (CH^AICI or A1(CH3)3) at a suitable temperature of 〇 to 150 ° C in a suitable solvent (toluene, benzene, Treatment of A5 (as a mixture of cis/trans isomers) in chloroform, dioxane or the like) for subsequent conversion to a compound of formula A6 (a mixture of cis/trans isomers to provide a compound of formula A6) As outlined in Flowchart 2, various oxidizing agents (eg, chlorophyll/DMS〇/amine base, TEMp〇/Na〇ci, TPAP/NMO' Jones (J〇nes) can be used under suitable conditions and temperatures. Reagents or more); see the subsequent oxidation of the compound (step (f)) to provide a compound of the formula A7. Subsequently, using, for example, an azide trimethyloxy chain in the presence of a third butanol And epoxidizing A7 (step (g)) in a DMSO solvent to provide a compound Α8 in a mixture of cis or (10) isomers and trans or (3α'6β) isomers, respectively, which can be easily layered The separation or crystallization method is separated from the mixture. 162086.doc 201242947

COOEt step (8) h〇~〇H A1 flow chart 2

'COOEt

/

Step (ί)

Cis/trans mixture

Another method of synthesizing compound A8 is described in Scheme 3.

R2-X Step 1

162086.doc -17- 201242947 Starting from intermediate A2, in the presence of a suitable base (eg LDA, NaH or the like) in a suitable solvent (eg THF, diethyl ether or the like) with or without the addition of HMPA Alpha-haloacetonitrile is alkylated to provide the compound oxime 9 (step (h)). Subsequently, the intermediate contained in toluene is heated by reducing the nitrile group to a primary amine (for example, catalytic hydrogenation using a Raney-Ni catalyst in a NH^EtOH solvent) and then in the presence of a test such as triethylamine. To effect a ring closure reaction, A9 is further converted to the indoleamine A10 (step (i)). Subsequently, a compound of the formula Al1 can be prepared from A10 and a compound of the formula R2-X (wherein the X-based halogen) by catalytic coupling reaction using Buchwald type copper or palladium (Buchwald et al. JACS, 2002, 124, p. 7421). Conditions suitable for such reactions are, for example, in a solvent such as DMF, Cul and, for example, N,N'-dimercaptoethylenediamine as a ligand and Κ3Ρ04 as a base; or in a solvent such as toluene Among them, palladium (II) acetate is used as a catalyst and, for example, bis(diphenylphosphino)-ferrocene (DPPF) as a ligand, and sodium tributoxide is used as a base. Compound A can then be converted to compound A7 by acidic hydrolysis (e.g., by treatment with an aqueous mineral acid solution such as HCl, HjO4 or the like) (step (k)). Compounds of formula R2-X are commercially available, known in the literature or prepared according to the general synthetic procedures described in this technique. Subsequently, the conversion of A7 to A8 is completed as described in Flowchart 2. A further embodiment of the invention is a process for the preparation of a compound of formula (1) as defined above, which comprises reacting a compound of formula (II) in the presence of a compound of formula (ΠΙ), 3,106.doc • 18_201242947

In particular, in the presence of a base (specifically sodium hydride and a butanol), in a solvent (specifically DMF, THF and tert-butanol), between RT and reflux temperature At the temperature 'where R' and R2 are as defined in the text. A further object of the invention is a compound of formula (I) for use as a therapeutically active substance as described herein. Another object of the invention is a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier. A further object of the invention is the use of a compound of formula (I) as described herein for the treatment or prevention of a disease caused by a hormone-sensitive lipase disorder. The present invention relates to a compound of the above formula (I) for use in the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or non-alcoholic The use of fatty hepatitis. In particular, the invention relates to the use of a compound of formula (I) above for the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity. A specific embodiment of the present invention is the use of the compound of the above formula (1) for the treatment or prevention of diabetes. Another specific embodiment of the present invention is a compound of the above formula (1) for use in therapy or 162086.doc • 19· 201242947 for prevention of type 2 diabetes use. A further embodiment of the invention is the use of a compound of formula (I) above for the treatment or prevention of cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or nonalcoholic lipodystrophy. A particular embodiment of the invention is the use of a compound of formula (I) above for the treatment or prevention of nonalcoholic fatty liver disease or nonalcoholic lipopolysaccharide. The invention also relates to the preparation of the compound of the above formula (I) for the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular disease, myocardial dysfunction, inflammation, non-alcoholic fatty liver disease Or the use of drugs for non-alcoholic fatty hepatitis. The present invention relates to the use of the above compound of the formula (I) for the preparation of a medicament for the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity. A particular embodiment of the invention is the use of a compound of the above formula (Ϊ) for the manufacture of a medicament for the treatment or prevention of diabetes. Another particular embodiment of the invention is the use of a compound of formula (1) above for the manufacture of a medicament for the treatment or prevention of type 2 diabetes. Still another embodiment of the present invention is the use of the compound of the above formula (1) for the preparation of a medicament for the treatment or prevention of cardiovascular disease 'myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or nonalcoholic lipodystrophy. A specific embodiment of the present invention is the use of the compound of the above formula (1) for the preparation of a medicament for the treatment or prevention of nonalcoholic fatty liver disease or nonalcoholic lipophilic hepatitis. In particular, the present invention relates to the use of the above for the treatment or prevention of sugar 162086.doc • 20· 201242947 urinary disease, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular disease, myocardial dysfunction, A compound of formula (I) that is inflammatory, nonalcoholic fatty liver disease or nonalcoholic fatty hepatitis. A specific embodiment of the present invention is a compound of the formula (1) for use in the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity as described above. Another particular embodiment of the invention is a compound of formula (I) for use in the treatment or prevention of diabetes as described above. Another specific embodiment of the invention is a compound of formula (I) for use in the treatment or prevention of π-type diabetes as described above. A further specific embodiment of the invention is a compound of formula (I) as described above for use in the treatment or prevention of cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or nonalcoholic fatty hepatitis. Another specific embodiment of the present invention is a compound of the formula (1) for use in the treatment or prevention of nonalcoholic fatty liver disease or nonalcoholic fatty hepatitis as described above. A further object of the invention is to treat or prevent diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or non-alcoholic fat In a method of hepatitis, the method comprises administering an effective amount of a compound of the above formula (1). Still another specific object of the present invention is a method for treating or preventing diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity, which comprises administering an effective amount of a compound of the above formula (1). A particular embodiment of the invention is a method for treating or preventing diabetes. The method comprises administering an effective amount of a compound of the above formula (1). Another particular embodiment of the invention is a method for the treatment or prevention of π-type diabetes, which comprises administering an effective amount of a compound of formula (1) above. A further embodiment of the present invention is a method for treating or preventing cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or nonalcoholic lipopolyhepatitis, the method comprising administering an effective amount of the above formula (1) Compound. Another embodiment of the present invention is a method for treating or preventing nonalcoholic fatty liver disease or nonalcoholic lipopolyhepatitis, which comprises administering an effective amount of the compound of the above formula (1). Another object of the invention comprises a compound of formula () as described herein, which is prepared according to any of the methods described. Analytical procedure Human full-length hormone-sensitive lipase-His6 production: 1) Colonization: cDNA is produced from commercial human brain poly-a+ RNA and used as a template in overlapping PCR to generate full-length humans containing 3,-His6 markers HSL ORF. This full-length insert was cloned into the pFast_B AC vector and identified for a single pure line of DNA sequences. E. coli strain DH10BAC was transformed with DNA containing the correct full-length pure line of the 3,-His6 tag. The resulting shuttle vector DNA is used to produce a titration baculovirus stock for protein production. The sequence of the encoded HSL is identical to Swissprot entry Q05469 and contains an additional C-terminal His6-tag. 2) Protein purification: Culture: 5.5 L High 25 cells expressing human full-length HSL-His6 containing 25 μM E-64 for 48 hours. Cell count: 162086.doc -22· 201242947 l_78xl01G cells/m Bu 90% of living body. Thaw the cells. On ice, suspend the cells in 4〇c containing ι〇%

Oil, 25 mM Tris-Cn, 300 mM NaCM, 1 mM scented saliva, 1 〇 mM

2-mercaptoethanol, 2 called pepsin inhibitor / (6), 2 眧 leupeptin 叩 2 叩 anti-pain / ml of pH 8.0 in the base buffer, the final volume of 475 (6) and contains 3.75X107 cells / m The sonication was performed in 3 x 30 seconds. Lubr〇1 PX was added to a final concentration of 0.2%, followed by a 15 minute mixing at 4 ° C and a 60 minute centrifugation at 25 kxg for 60 minutes. Soluble protein was mixed with 6 μml of pre-rinsed and equilibrated Ni-NTA agarose (Qiagerl 3〇21〇), then vertically rolled at 4C for 45 minutes, centrifuged at 1 rpm for 5 minutes and The resin was allowed to settle for 5 minutes. The supernatant was removed. The resin was rinsed in a centrifuge container using a volume of 0.2% Lubrol PX base buffer. Centrifuge again and then discard the supernatant. The resin was poured onto a 0. 8 μm film in a disposable filter unit (Nalge 450-0080) and rinsed with 5 volumes of a base buffer containing 0.2% Lubrol PX. It was then rinsed with 30 volumes of base buffer containing 60 mM imidazole and pH 7.5 at 4 °C. 5 volumes of 25 〇 ^ - - C1, 300 mM NaCl, 200 mM imidazole, 10 mM 2-mercaptoethanol (at 4 ° C, pH 7.5), by vertical rolling resin at 4 ° C and buffer The solution was eluted for 30 minutes. The resin was trapped on a 0.2 μηι film disposable filter unit (Millipore SCGP U02 RE) and the eluate was collected in a reservoir. The eluate was concentrated to 20 ml using a 30 k MWCO centrifugal filter (Sartorius Vivascience Vivacell 100, VC 1022). Then at 4 ° C, with 2 L of 10% glycerol, 25 mM Tris-Cl, 300 mM NaC, 0, 2 mM EDTA, 0.2 mM DTT (at 4 ° C, pH 162086.doc -23· 201242947 7.5 Dialysis overnight twice. The protein was filtered using a 〇 22 μιη disposable filter unit (MiUipore SCGP00525). The protein concentration was calculated based on the absorbance at 28 〇 nm using 280 = 0.67 cm·1 mg·1. The total yield is 235 mg. The protein was stored under 8 〇β〇. Human Hormone Sensitive Fatty Plum (HSL) Enzyme Inhibition Assay: By using 2,3-dimercapto-1·propanol tributyrate (Aldrich, St. Louis, MO) as a matrix colorimetric analysis The HSL enzyme activity was determined. Typically, 1.5 mM 2,3-dimercapto-1- contained in 1 μm μ MOPS (pH 7.2 '0.2 mg/ml fatty acid-free BSA) is prepared by ultrasonic vibration at 4C to a uniform suspension. Propyl tributyrate (DMPT). Test compounds (2 mM mother liquor in DMSO) were serially diluted 3 fold in DMSO. The compound solution was diluted 24-fold in 1.5 mM DMPT-containing solution and added to a 384-well microplate (Corning Costar) at 18 μM/well. 12 μl/well human HSL (15 pg/ml) was added and the reaction mixture was incubated at 37 °C for 20 minutes. Add 6 μl of 12 mM disulfo-bis-(2-nitrobenzoic acid) (DTNB) in DMSO (1.2% SDS and 0.6% Triton X-100) and incubate the mixture at room temperature 1 5 minute. Product generation was monitored by reading the absorbance at 405 nm on an Envision reader (PerkinElmer Life and Analytical Sciences, Shelton, CT). Cell Analysis: The following assays were used to determine the inhibition of these compounds in intact cells (adipocytes). The effect of lipolysis. 3T3-L1 precursor adipocytes at 20,000 cells/well (containing 2 μμΐ growth medium (DMEM/10% bovine serum/lx antibiotic-antimycotic)) 162086.doc • 24· 201242947 degrees Add to the 96-well plate until confluent. 48 hours after confluence, the medium was removed and the differentiation medium (DMEM/1 0% FBS/lx antibiotic·antimycotic plus 1 μΜ phosphodiesterase of IBMX (3-isobutyl-1-methylxanthine) was used.抑制剂) Inhibitors, 1 μM dexamethasone, 1 μM Rosiglitazone, 10 pg/ml temsine differentiated these cells into adipocytes. The cells were cultured in the medium for 3 days, and then the medium was changed to the culture medium (DMEM/10% FBS plus 10 pg/mi temsin) and the cells were cultured for another 3 days. The medium was then changed to maintenance medium (DMEM/10% FBS). Maintenance medium was added to the cells every 3 days until use. The lipolysis assay can be performed in a 96-well plate on days 9-14 after the start of differentiation. This lipolysis analysis was carried out as follows. Use 200 μΐ Krebs Ringer

The carbonaceous cells were washed twice with Bicarbonate Hepes buffer (KRBH) / 3 ° / 〇 BSA. The test compound was dissolved in mM DMSO and first diluted to 5 mM in DMSO. It was then serially diluted 5 times (5 mM to 320 pM) in DMSO. Each compound was then diluted 200-fold in KRBH/3% BSA (final 〇.5% DMSO). The resulting solution was finally 25 μΜ to 1_6 ρΜ» 150 μΐ of the diluted compounds were added to each well (triple cover) and the cells were pre-incubated for 30 minutes at 37 °C. Forskolin (50 μΜ final concentration) was added to the wells and the cells were incubated for 120 minutes at 37 °C. 100 μΐ was collected into a new 96-well plate for analysis of glycerol. The glycerol assay kit (Sigma) was used to determine the amount of glycerol produced. 162086.doc •25· 201242947 Example HSL Human IC5〇(μΜ) 1 0.0077 2 0.0681 3 0.0509 4 0.0274 5 0.0163 6 0.264 7 0.0137 8 0.213 9 0.0306 10 0.0418 11 0.01 12 0.037 The compound of formula (i) as described above and A pharmaceutically acceptable salt or ester has an IC5 〇 value between 0.0001 μΜ and 1000 μΜ, a specific compound having an ICsq value between 0.001 μΜ and 500 μΜ, and other specific compounds having a concentration of 0·001 μΜ and 5 μΜ The ICso value between. These results have been obtained by using the aforementioned HSL enzyme inhibition assay (μΜ means micromolar concentration). The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be used as a medicament (e.g., in the form of a pharmaceutical preparation). Such pharmaceutical preparations may be administered internally, for example, orally (for example, in the form of lozenges, coated lozenges, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, nasally) In the form of a spray) or rectal (for example in the form of a suppository), however, the administration may also be carried out parenterally, for example intramuscularly or intravenously (for example, in the form of an injection). The compound of the formula (1) and its pharmaceutically acceptable compound can be treated by a pharmaceutically inert inorganic or organic adjuvant for the manufacture of tablets, coating granules, dragees and hard gelatin 162086.doc •26- 201242947 capsules salt. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such adjuvants for spinners, dragees and hard gelatin capsules. Adjuvants suitable for use in soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid materials and liquid multi-fermented yeasts. Adjuvants suitable for use in the manufacture of solutions and syrups are, for example, water, polyols, cane's invert sugar, glucose, and the like. Adjuvants suitable for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like. Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxy fats, semi-solid or liquid polyols and the like. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for regulating osmotic pressure, buffers, and coverings. Flavor or antioxidant. In addition, they may also contain other therapeutically valuable substances. The dosage can vary over a wide range and will of course meet individual requirements in each particular case. Usually, in the case of oral administration, about 11 mg to 20 mg/kg body weight (preferably about 5 „^ to 4 mg/kg body weight (for example, about 300 people)) should be appropriately applied. The dosage is divided into preferably from 1 to 3 parts by individual doses, for example, of the same amount. However, it should be understood that the indicated upper limit values may be exceeded when indicated. [Embodiment] By way of non-limiting features An example is given to illustrate the invention. 162086.doc -27· 201242947 Where a preparation example is obtained as a mixture of enantiomers, it may be by methods described herein or by methods known to those skilled in the art (eg, Palm chromatography* or crystallization) to separate the pure enantiomers. Example 1 (5«,8α)-8·hydroxy·8_((2_p-oxypyrrolidinyl)-methyl (three Fluoromethyl)phenyl)·2·azaspiro[4.5]癸-1-鲷

Step 1: 1,4-Dioxa-spiro[4.5]ethyl decane-8-carboxylate Ethyl cyclohexa-4-carboxylate (54.8 g) was dissolved in toluene (12 〇mi). Then, ethylene glycol (24.8 ml) and toluene-4·sulfonic acid monohydrate (612 mg) were added to the reaction mixture. The mixture was refluxed overnight and water was removed azeotropically using a Dean-Stark apparatus. The reaction mixture was cooled and poured into ice/water and purified to pH 9 using 2M aqueous NaOH. The combined organic layers were washed with brine, dried over NajEtOAc, filtered and evaporated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut MS (m/e) = 215.3 [MH+]. Step 2: 8-Mercaptomethyl-1,4-dioxa-spiroline 4.5] decane-8-carboxylic acid ethyl ester nBuLi (1.9 Μ hexane solution, 26.09 ml, 51.1 mmol) at -40° Add dropwise to a stirred solution of diisopropylamine (10.09 ml, 69.76 162086.doc -28 - 201242947 mmol) in THF (150 ml), followed by HMPA (3 1 .〇ml, under nitrogen atmosphere. 178.0 mmol), and the reaction mixture was stirred for 30 minutes at 4 ° C. Then further cooled to -78 ° C, and added to one of oxa-spiro[4.5] in THF (20 ml) a solution of -8-deoxyacetate (10 g, 46.5 mmol) and maintaining the temperature below _7 〇eC throughout the addition. After stirring at -78 ° C for 25 minutes, bromoacetonitrile (3.8 ml, slowly added) 55.8 mmol), and then the reaction mixture was warmed to 25 ° C. The mixture was poured into cold water (100 ml) and the aqueous layer was extracted with EtOAc (5×70 ml). The combined organic layers were washed with water (2×50 mL) and brine (1×40 ml), dried (Na2S04), filtered and evaporated in vacuo. Come to pure The obtained crude compound was obtained to give the title compound (6 g) as a pale yellow liquid. MS (m/e): 254.2 [MH+]. Step 3: 1,4-dioxa-10-aza-di. [4.2.4.2] Tetradecan-9-one Addition of Raney-Ni (4.16 g, 70.95 mmol) to a mixture of 8 cyanide in a mixture of NH3_EtOH (200 m b 7: 93) at 25 ° C under nitrogen atmosphere a solution of methyl-1,4-dioxa-spiro[4.5]oxan-8-hyal acid vinegar (12 g, 47.3 mmol), followed by the reaction mixture at 40 ° C Hydrogenation was carried out for 16 hours at 400 psi H2 under pressure. After the reaction was over, the mixture was filtered through a bed of celite and the filtrate was evaporated under reduced pressure. The crude material thus obtained (10 g, 38.9 mmol) was dissolved in anhydrous toluene. (3 ml), Et3N (10 m Bu 71.14 mmol) was added to the stirred solution at 25 ° C under a nitrogen atmosphere. The mixture was then heated under reflux for 24 hours. After the reaction was completed, it was cooled to 25 ° C. The precipitated <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; MS (m/e): 212.2 [MH+]. Step 4: 10-(4-Trifluoromethyl-phenyl)4,4-dioxa-11〇•aza-dioxin 【4·2·4·2】tetradecyl-9-one

Dissolving 1,4·dioxa-10-aza-dispiro[4.2.4.2]tetradecane-9-one (4 g) in DMF (189 ml) t β under RT and argon, followed by addition 1. Soil (trifluoromethyl)benzene (6.39 g), hydrazine, Ν'-dimethylethylenediamine (sym) (3.34, iodide (5.41 g) and K3P〇4 (7_13 g) and The current character was heated for 12 hours at 〇〇 ° C. The reaction mixture was cooled to RT, filtered and added with aq. NH.sub.1 solution. The mixture was then extracted twice with AcOEt and the combined organic layer was washed with brine. Drying, filtration and evaporation of the solvent in EtOAc EtOAc (EtOAc:EtOAc:EtOAc: Compound (4 g) MS (m/e): 356.146 [MH+]. Step 5: 2-(4-trifluoromethyl-phenyl)-2-aza-spiro- </ br> _ two classes

162086.doc •30- 201242947 10-(4-Trifluoromethylphenyl)-indole dioxa·1〇_aza. snail K2.4.2]tetradecane _9-one (6.7 g) Dissolved in tetrahydrofuran (i89 mi), aqueous hydrochloric acid (2 M, 94.3 m) was added and the mixture was stirred at RT for 12 h. The reaction mixture was poured into ice/water and extracted twice with ethyl acetate. The combined organic layers were washed with EtOAc (EtOAc m.) MS (m/e): 311 [M+]. Step 6 : (3«,6«)-8_(4_trifluoromethyl.phenyl)oxyxanthene•gas-disulfide U.2.4.2]12-burning _7-ketone

F

Dissolve 2-(4-trifluoromethyl-phenyl)-2-aza-spiro[4-5]nonane-1,8-dione (4.9 g) and trimethyloxonium iodide (5.37 g) MDMS 〇 (28 8...^. Subsequently, a solution of potassium terp-butoxide (2.74 g) in DMSO (28.8 ml) was added and the mixture was stirred at RT for 2 hours. The reaction mixture was poured into ice. / </ RTI> </ RTI> </ RTI> The residue was purified to give the title compound (3 816 g).

F

Ms(m/e) : 326·2[ΜΗ+]. Step 7. (5α,8α)-8-Hydroxy-8-((2-o-oxypyrrolidin-1-yl)methyl)_2_(4(monofluoromethyl)phenyl)_2-azaspiro[ 4.5]癸_ι_ketone 162086.doc -31 · 201242947 Add 2-° to acridone (52.3 mg) to 氢化C of sodium hydride (69.7 mg) in DMF (5.25 mL) under argon The suspension was stirred and the reaction mixture was stirred for 10 minutes. Addition of (3α,6α)-8-(4-trifluoromethyl-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecane in DMF (2 ml) A solution of -7-ketone (200 mg, product of Step 1 of Example 1) and the reaction mixture was heated at 11 ° C for 12 hours. The reaction mixture was poured into water, extracted with EtOAc EtOAc (EtOAc)EtOAc. The crude residue was purified by EtOAc (EtOAc): MS (m/e): 411.188 (MH+). Example 2 8-Hydroxy-8-(2-oxo-piperidin-1-ylmethyl)_2_(4-trifluoromethylphenyl)-2-aza-spiro[4.5]癸-1-_

From (3α,6α)-8-(4-trifluoromethyl. stupyloxa-8-aza-dispiro[2.2.4.2]dodec-7-one (product of step 6 of Example 1) and The title compound was obtained as a white solid. mp (m/e): 425.204 [MH+]. Example 3 (5α, 8α)-8-hydroxy-2-. (4-isopropoxyphenyl sideoxylpyrrolidine _ 162086.doc -32- 201242947 1-yl)methyl)-2-azaspiro[4.5]nonan-1-one

Step 1: 1,4-Dioxa-spiro [4.5 decane-8-carboxylic acid ethyl ester. Ethyl cyclohexanone-4-carboxylate (54.8 g) was dissolved in a stupid (12 〇 丨 ^ ^ Then 'ethylene glycol (24.8 ml) and methyl 4-sulfonic acid monohydrate (6 丨 2 mg) were added to the reaction mixture. The mixture was refluxed overnight and used in the Dean _ Stark apparatus. The water was removed by boiling. The reaction mixture was cooled, poured into ice/water and basified to pH 9 using 2M aqueous NaOH. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was rinsed with brine over Na2S. The title compound (39,5 g) was obtained as a pale yellow liquid (yield). MS (m/e) = 215.3 [MH+]. Step 2: 1-(2-methoxy-ethyl &lt;RTI ID=0.0&gt; A solution of 1,4-dioxa-spiro[4 5 ]decane-8-carboxylic acid ethyl ester (39 5 g) in thf (200 ml) was added dropwise over THF over 45 min. 300 μM of lithium isopropyl guanamine (2 μ THF solution '184.3 mL) In the mixture, stirring was continued for 25 hours. The reaction mixture was cooled to _5 ° C and 2-bromoethyl decyl ether (34.0 ml) was added dropwise over 3 hrs. stirring was continued for 12 hours at RT. The reaction mixture was cooled to 0&lt;0&gt;&lt;0&gt;&gt; and aqueous <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> • 33- 201242947 Ethyl acetate was extracted twice. The combined organic layers were washed with brine, dried over Nasssssssssssssssssssssssssssss The residue was purified to give the title compound (25.2 g), m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ethyl hexanecarboxylate Ethyl 1-(2.methoxy-ethyl)-4-oxo-cyclohexanecarboxylate (5 〇g) was dissolved in 2-propanol (400 ml). The mixture was cooled to 〇 °c and sodium borohydride (1 〇g) was added over 8 liters over 2 Torr. Stirring was continued for 2 hrs. The reaction mixture was partitioned between brine and The ethyl acetate was saturated with ice/water, the layers were separated and the aqueous layer was further extracted with AcOEt. The combined organic layers were rinsed with water, dried over NadO4, filtered and evaporated. cis and trans. The title compound (41.7 g) was obtained as a white oil. MS (EI) = 230.0 [M+]. Step 4: 8-Phenyl-2-(4-isopropoxy-phenyl)_2-infrared-spiro[4.5]癸·1__

4-Isopropoxy-aniline (11.3 g) was added to ethyl 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylate in toluene (36 丨mi) (丨丨$g) in the solution. The mixture was stirred at RT for 1 minute. Subsequently, vaporized dimercaptoaluminum (0.9 hexane solution, 99 ml) was added dropwise and the reaction mixture was heated to reflux for 4 hours. The mixture was then cooled to 〇 ° C, and water (5 〇 ml) and AcOEt (300 ml) were added dropwise. Further, the mixture was stirred for 30 minutes, and AcOEt was added in an amount of 162086.doc • 34·201242947, and then the layers were separated, and the organic layer was dried over MgS04, filtered and evaporated. The crude product was triturated with diethyl ether / heptane to give the title compound (14 g. g.) as a brown solid as a mixture of cis/trans isomers. MS (m/e): 304.190 [MH+]. Step 5: 2-(4-Isopropoxy-phenyl)-2-aza-spiro[4.5]癸-1,8-dione

A solution of potassium bromide (549 mg) in water (60 ml), sodium hypogasate (52.8 ml) and sodium hydrogencarbonate (5.81 g) were added to the second gas chamber (25 ml). 8-Carboxy-2-(4-isopropoxy-phenyl)-2-azaspiro[4.5]nonan-1-one (7 g) and 2,2,6,6-tetra methyl. The reaction mixture was stirred at RT for 3 hours at the bottom of a solution of 1-oxyl (721 mg). The reaction mixture was poured into ice/water and extracted three times with CH.sub. The combined organic layers were washed with brine, dried over Na.sub.2.sub.4, filtered and evaporated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut MS (m/e): 302·174 [ΜΗ+]. Step 6: (3α,6α)-8-(4-Isopropoxy-phenyl)-1-oxa-8-aza-dispiro[2.2.4.2]dodecane-7-one

162086.doc -35- 201242947 2-(4-Isopropoxy-phenyl)_2_aza-spiro[4.5]decane-1,8-dione (3 g) and trimethyloxetate锍 (3·4 g) was dissolved in DMSO (72 ml) Yin. Then, a solution of potassium terp-butoxide (1.73 g) in DMSO (72 ml) was added and the mixture was stirred at RT for 2 hours. The reaction mixture was poured into ice/water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na-EtOAc and filtered. The solvent was evaporated and the residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut ). MS (m/e): 316.I90 [MH+]. Step 7: (5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)_8-((2_p-oxy-indolyl-1-yl)methyl)·2-nitrogen Heterotropy 4.5]癸_ι_keto from (3α,6α)-8·(4-isopropoxy-phenyl)-1-oxa-8-aza-dispiro[2.2·4.2]12 The title compound was obtained as an off-white solid, m.p. Ms_): 401.242 [MH+]. Example 4 (5α,8α)-8-Pyridyl-2-(4-isoproprane hairpin endooxyphenyl)-8-((2-trioxypiperidinyl)methyl)- 2-azaspiro[4.5]癸

2-piperidone, the title compound was obtained as a white solid, mp. MS (m/e): 415·258_+]. Example 5 Μ8 material (2,2·difluoro-ethoxymethyl) benzyl-2-(4.isopropoxy-phenyl)-2-aza-spiro[4]^癸"·阑: Seven°,, '

[2 2 from: 2:): (4-isopropoxyphenyl) small oxaza aza-dispiro[..] deca-alkane phase (product of step 3 of Example 3) and 2, alcohol, It was made white in a manner similar to that of the m step 7; compound ^8_): 398.212 pottery +]. 'Professional Example 6 (5α,8α)-8-hydroxy·2-(6·iso-vopropoxy-pyridin-3-yl HH2-sideoxy-small-small-small methyl)-2·aza-snail [4.5] 癸小明氧咕 0

Indole ketone isopropoxy group · terminal 3 · group) money miscellaneous - snail [4.5

162086.doc -37- 201242947 Similar to Example 3, Step 4, self-contained in 6-isopropyloxy- in toluene (360 ml). Bispin-3-ylamine (11.4 g), 4-hydroxy-1-(2-decyloxyethyl)-cyclohexanecarboxylic acid ethyl ester (11.5 g) and vaporized dimethyl aluminum (〇· The title compound (7.49 g) was obtained as a pale red solid. MS (m/e): 305.2 [MH+]» Step 2: 2-(6-isopropoxy- acridine·3·yl)-2-aza-spiro-5]癸-i,8-dione

Similar to the oxidation of 8-hydroxy-2-(6-isopropoxy-pyridine-3-yl)-2-aza-spiro[4.5]nonan-1-one (4.5 g), similar to Example 5, step 5. The title compound was obtained as a yellow amorphous solid (2.43 g). MS (m/e): 303.169 [MH+]. Step 3 · (3α,6α)·8-(6-Isopropoxy-pyridin-3-yl)·ι·oxa~8_aza_二螺[2.2.4.2]Dodecane_7-_

Similar to the step 6 of Example 3, obtained by epoxidation of 2_(6-isopropoxypyridin-3-yl)2·gas-spiro[4.5] 癸院_丨,8_dione (25 g) The title compound (0 73 g) was obtained as a yellow solid. Ms (m / e): 317 184 [mh +]. Step 4: (5«,8«)-8_Pycleyl-2_(6_isopropoxypyridyl_3·ylindole (2·sideoxy-pyrrolidin-1-ylmethyl)_2• Aza-spiroquinone 4 S] 癸·1 ketone from (3α,6α)-8-(6-isopropoxy-pyridine_3_yl)_丨_oxa~8 aza_2 1620S6.doc • 38· 201242947 snail [2.2.4.2] dodecane-7-one and 2-pyrrolidone, the title compound was obtained as a pale yellow solid. 238 [ΜΗ+] ° Example 7 (5α,8α)-8-hydroxy-2·(6-isopropoxypyridin-3-yl)-8-((2,2,2-trifluoroethoxy) )methyl)-2-azaspiro[4.5]癸-1·one

From (3α,6α)-8-(6-isopropoxy-D to 0-but-3-yl)-1-oxa-8-aza-dispiro[2·2_4·2]dodecane- The title compound was obtained as an off-white solid in EtOAc (m.). MS (m/e): 417·199 [ΜΗ+]. Example 8 (5α,8α)-8-hydroxy-8-(2-o-oxy-indolyl-1-ylmethyl)-2-[4-((R)-2,2,2-trifluoro 1-hydroxy-ethyl)-phenyl]-2-aza-spiro[4.5]nonan-1-one

Step 1: 4-[(R)_l-(4-bromophenyl)-2,2,2-trifluoroethoxymethyl]-phenol

Br

162086.doc -39- 201242947 (R)-l-(4-bromophenyl)_2,2,2-trifluoroethanol (3.5 g, as described in j. 〇rg Chem. 2009 under argon atmosphere) , 74, pp. 1605-1610) Dissolved in THF (50 ml), added NaH (719 mg) at 〇 ° C, followed by sequential addition of tetrabutylammonium bromide (507 mg) and 4-methoxy Base benzyl bromide (3.04 g), and the mixture was stirred at 20 ° C for 3.5 hours. The reaction was quenched by water (15 ml) and then 1 n aqueous EtOAc (15 ml) and EtOAc (30 ml). The layers were separated and the aqueous layer was extracted twice with EtOAc EtOAc EtOAc The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut H-NMR (δ, CDC13): 7.55 (m, 2H), 7.3 (m, 2H), 7.2 (m, 2H), 6.88 (m, 2H), 4.63 (d, 1H, J = 11.5 Hz), 4.58 (q, 1H, J = 4.6 Hz), 4.38 (d, 1H, J = 11.5 Hz), 3.82 (s, 3H). Step 2: 10-{4-[(R)-2,2,2-trifluoro-1-(4-methoxy-benzyloxy)ethyl]-phenyl}-1,4-dioxan -10-aza-dispiro[4.2.4.2]tetradecane-9- Ming 0—

From 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecane-9-one (2.05 g) (described in Step 3 of Example 1) and 4-[(R)-l -(4-bromo-phenyl)-2,2,2-tri-40 _ 162086.doc 201242947 fluoro-ethoxymethyl; I-phenol (4.66 g), similar to the method of Example 4, Step 4. The title compound (4-9 g) was obtained as a white solid. Step 3: 2-{4-丨(R)-2,2,2-trifluoromethoxy-benzyloxy)-ethyl]·phenyl}-2-aza-spiro[4.5]癸烧- 1,8-two

Similar to Example 5, Step 5, by treatment with 2 M HCl (58.3 ml) in THF (68 2 ml), 1 〇_{4_[(R)_2 2 2 trifluoromethane (4 oxime) Oxy)-ethyl]- phenyl hydrazino, 4-dioxaxanthracepin- aza-dispiro[4 2 4 2]tetradecane 9 ketone (4.91 g) 3.5 g). Step 4: (3a,6a)-8_{4_[(R)_2,2,2 trifluoro 1 (4 methoxy ethoxy) ethyl bphenyl} small oxa-8-aza-tertiary [2.2.4.2]12 Hyun-7-嗣

Similar to Example 1 Step 6 oxy-benzyloxy fluorene 1 , less 6' by 2-{4-[(R)-2,2,2-trifluoro-bu(4-decyloxy) _Ethylphenyl}-2-aza-spiro[4.5]decane-1,8-dione 162086.doc • 41 · 201242947 (2.5 g) epoxidation to give the title compound as a yellow solid ). MS (m/e): 476.2 [MH+] 〇 Step 5: (5α,8«)-8-hydroxy-8-(2-o-oxy-rhhhhhhhhhhhhhhhh 2,2-trifluoro-1-(4.methoxy-benzyloxy)-ethylphenylphenyl 2aza-spiro[4.5]癸-1-明

Potassium terp-butoxide (47.2 mg) was added to a mixture of 3,5,6-{4-[(R)-2 in a mixture of third butanol (5 mi) and THF (2 ml). ,2,2-ilq_(4_T-oxyoxy)-ethyl]-phenyl}-l-oxa-8-aza-dispiro[2.2.4.2]dodecane-7-one (250 mg) And a solution of pyrrolidin-2-one (58_2 mg), and the mixture was stirred at 80 ° C for 12 hours. The solvent was removed in vacuo and the residue was taken in EtOAc then rinsed with water and brine The residue was purified by EtOAc EtOAc (EtOAc) MS (m/e) = 561.3 [MH+]. Step 6 ··(5α,8α)-8·hydroxy-8-(2-o-oxy-pyrrolidin-1-ylmethyl)-2-[4 -((R)-2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2-aza-spiro[4.5]nonan-1-one (5ct,8c〇-8- Hydroxy-8-(2-o-oxy-pyrrolidin-1-ylmethyl)-2·{4-162086.doc •42· 201242947 [(R)-2,2,2-trifluoro-1-( 4-decyloxybenzyloxy)-ethyl]-phenyl}-2-aza-spiro[4.5]nonan-1-one (134 mg) dissolved in dioxane In 5 ml), water (0.25 ml) and DDQ (163 mg) were added sequentially and the reaction mixture was stirred at RT for 18 hours. Then the mixture was partitioned between KHC03 aqueous solution and di-methane to separate the layers and sequentially The organic layer was washed with aq. EtOAc (aq.) and brine, dried over EtOAc EtOAc EtOAc. The residue was purified to give the title compound </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Oxyloindole-1-yl)methyl)_2_(4-((R)·trifluoropropan-2-yloxy)phenyl)-2-azaspiro[4.5]nonan-1-one

Step 1: 4-((R)-2,2,2-Trifluoro-1-methyl-ethoxy)-phenylamine Add sodium hydride (55% ' 3.22 g) to DMF (20 mL) The mixture was cooled to 0 °C. Subsequently, trifluoro-2-propanol (8.5 g) [CAS 17628-73-8] was added over 1 hour and stirring was continued for 3 minutes at 〇 °c. A solution of 1·fluoro-4-nitrobenzene [CAs 350-46-9] (10 g) in DMF (15 mL) was added over 1.5 hours while maintaining the internal temperature at 5 to 15 <) (: After the addition, the mixture was allowed to warm to RT and the mixture was further stirred for 12 hours 162086.doc -43·201242947. The reaction mixture was acidified and partitioned between ethyl acetate and water. The layer was dried over Na.sub.2.sub.4 and evaporated to dryness. The residue was dissolved in methanol (150 ml) and Pd/carbon (10% Pd, 1 g) was added. The mixture was then hydrogenated at RT for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to afford crude 4-[(R)-2,2,2-trifluoro-1-indolyl-ethoxy)-aniline as a dark liquid. 14.5 g) MS (m/e): 206.1 (MH+) Step 2: 8-hydroxy-2-[4-((R)-2,2,2-trifluoro-1-methyl-ethoxy )_Phenyl]-2-isomer-spiro[4.5]癸-1-明 (mixture of cis and trans diastereoisomers) 4-((R)-2,2,2-three Fluorin-1-methyl-ethoxy)-phenylamine (7.57 g) was added to 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylate in toluene (150 ml) Ethyl acetate 5.0 g 'obtained from the solution of Example 3, step 3). The mixture was stirred for 10 minutes at RT. Subsequently, gasified dimethyl sulphate (1 μ hexane solution '65 · 1 mL) was added dropwise over 45 minutes. The reaction mixture was heated to reflux for 2 hours and then kept at 95 ° C for 16 hours. The mixture was cooled, poured into ice/water and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over Naj. The title compound (5.79 g) was obtained eluted eluted eluting : 358.3 [MH+]. Step 3: 2-[4-((only)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl) 2 -aza-spiro) 4.5] A solution of potassium bromide (482 mg) in water (16 mL) was added to 8-hydroxy-2 contained in 162086.doc 44· 201242947 CH2C12 (85 ml). -[4-((R)-2,2,2·trifluoro-1-indolyl_ethoxy)-phenyl]-2-aza-spiro[4.5]indole-1-one (5.79 g) And a solution of 2,2,6,6-tetramethyl 0 bottom bite-1-oxyl radical (TEMPO) (506 mg) Subsequently, sodium hypogasate (13%, 42.5 mL) was added dropwise over 10 minutes, followed by the addition of sodium hydrogencarbonate (NaHCO3) (4.08 g). The mixture was stirred at RT for 15 hours. TLC shows the residue of the starting material. Additional TEMPO (125 mg) and sodium hypo-sodium solution (10 mL) were added to the reaction mixture and the mixture was further stirred at rt for 2 hours. The reaction mixture was poured into ice/water and extracted three times with CH.sub.2:. The combined organic layers were washed with brine, dried over Na.sub.2SO. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut . Step 4: (3a,6a)-8-[4-((R)-2,2,2-Trifluoro-1-methyl-ethoxy)-phenyldi 1-oxa-8-aza - bismuth 2.2.4.2] dodecane-7-one is similar to Example 3, step 6 'by 2-[4-((R)-2,2,2-trifluoro-1-indenyl) ethoxylate Epoxidation of phenyl-phenyl- 2-indole-spiro[4.5]decane-1,8-dione (2.5 g) The title compound was obtained. MS (m/e): 370.2 [MH+]. Step S: (5a,8a)-8-hydroxy-8_((2. ethoxylated pyridinium-4-yl)methyl)_2_ (4-((R)-l,i,i_trifluoropropene· 2-(yloxy)phenyl)2 azaspiro[4.5]decanone from (3a,6a)-2-[4-((R)-2,2,2-trifluoro-1-methyl- Ethoxy)-phenyl]-2-aza-spiro[4·5]decane-1,8-di- and 2-pyrrolidinone, obtained in a pale yellow color similar to the method of Example 7 Step 7. The title compound of the solid. MS (m/e): 445.214 [MH+]. Example 10 162086.doc •45· 201242947 (5α,8α)-8-hydroxy-8-((2-o-oxo oxime*-pyridyl-j•yl)methyl b 2_(6 ((s)_ 1, 1,1-trifluoropropan-2-yloxy)pyridine_3_yl)_2·azaspiro

Step 1: S-nitro-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)·acridine in a 4-necked flask 'commercially available 2-gas _ 5-nitroguanidine bite (71.9 g) and (S)_ 1,1,1-trifluoropropan-2-ol (54.3 g) dissolved in DMF (610 ml) at a temperature of 16 to 18 ° C Sodium hydride (2 〇g, 55%) was added (ice-cooled). After the addition, the mixture was stirred for 1 hour. The mixture was poured into ice and allowed to hydrolyze. The suspension was allowed to warm to RT over 12 hours and the solid was filtered and washed with additional water and a small amount (50 mL). The brown solid was dried <RTI ID=0.0></RTI> to <RTI ID=0.0> W-NMR (δ, CDC13): 9.06 (m, 1 Η), 8.43 (dd, 1 Η), 6.93 (d, 1 Η), 5.87 (m, 1H), 1.54 (m, 3H). Step 2: 6-((S)-2,2,2-trifluoromethyl-ethoxy)-pyridine-3-ylamine 5-nitro-2-((S)-2,2,2 -Trifluoro_ι_methyl-ethoxypyridinyl (81 9 g) and palladium on carbon (10% Pd ' 0.0065 mol equivalent) were added to MeOH and the mixture was hydrogenated until argon absorption ceased. The catalyst was removed by filtration and the filtrate was concentrated and dried in vacuo to afford title crystalljjjjjjjjjjjjjjjjjjjjjjjjjj -((S)-2,2,2-trifluoro-1-methyl-ethoxy)·pyridin-3-yl1-2-aza-spiro[4.5]dec-1-one 162086.doc - 46- 201242947 From 6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-ylamine (23.3 g) and 4-hydroxy-1·(2- Ethyl methoxy-ethyl)-cyclohexanecarboxylate (20 g, obtained from Example 3, step 3), m. m/e) : 3 59.3 [MH+] » Step 4: 2-[6-((S)-2,2,2-Trifluoro-1-methyl-ethoxy)-pyridin-3-yl]- 2-Aza-spiro[4.5]decane-1,8-dione was added dropwise to DMSO (16.3 ml) over 5 minutes to 8-hydroxy-2-[6 in dioxane (400 ml). -((S -2,2,2-trifluoro-1-methyl-ethoxy)-pyridin-3-yl]-2-aza-spiro[4·5]nonan-1-one (39·3 g) The solution (which was cooled to -78 ° C in a CO 2 /acetone bath). After 5 minutes, grass chlorobenzene (15.6 ml) was added dropwise over 15 minutes and stirring was continued at -78 ° C for 30 minutes. Triethylamine (42.7 ml) was added dropwise to the reaction mixture over 15 minutes and after 5 minutes, the mixture was allowed to warm to 2 s. (: and stirred at RT for an additional 2 hours. The reaction mixture was poured into ice / The water was acidified to pH 3 with a 2 M aqueous HCl solution. The aqueous phase was extracted twice with two gas and the combined organic layers were rinsed with brine, dried over Na 2 S 〇 4 and filtered. The title compound (23.96 g) was obtained eluted eluted eluted elut elut elut elut elut elut elut elut elut MH+). Step S: (3«,6«)-8-[6-((S)-2,2,2-trifluoroq•methyl_ethoxy)·pyridyl 3-yl]oxa _8_气杂二媒 [2 2 4 2]12炫-7_明自2_[6_((S)-2,2,2-trifluoro-1-methyl-ethoxypyridine_3_ Aza [4.5] decane-dione · 18_ to the method similar to Example 3, Step 6 was prepared as an off-white solid of the title compound. Ms (m / e): 37 丨 3 [mH +]. 162086.doc 201242947 Step name ^ (S«, 8a) -8 marriage _8_ ((2 · side oxime 吼 bite · t base) methyl) · 2 Γ:, 1,1 · trifluoropropane 4 oxygen base). Λ...)·2·Aza-spiral 丨4·5] 劳-1-明自(3〇1,6〇〇-8-[6-((8)-2,2,2-Trifluoro-1_ A farmer; ^铥* base oxygen # 8 ϋ 乙 ethoxy)-pyridine-3_ oxa·8·aza·two snail [2.2.4.2] ruthenium _7· ketone and... biting ketone, similar to Example 标题Step 7 The title compound was obtained as a white solid. MS (m/e): 445.210 [ΜΗ+]. Example 11 fluoroethoxy)methyl)-trifluoropropane . oxy)pyridine-3-yl)-2-azaspiro KS] 癸 small 鲷 from (3α,6α)-8·[6·((8)-2,2,2·trifluoromethylene« Ί , ^ τ 卷-ethoxy)-pyridin-3-yl]·1-oxa-8-aza-dispiro[2 2 4 2]deca-J-alkane-7-one and 2·fluoroethanol , in the same way as the method of step 5 of Example 8! The title compound of the white solid. MS (m/e): 435.189 [MH+] » Example 12 (5α,8α)-8-((2-fluoroethoxy)methyl)·8·, Λ -2-2-(4-isopropoxy Phenyl)·2-gas snail 丨4.5]癸·1-car

162086.doc -48- 201242947 From (3α,6α)-8·(4-isopropoxy-phenyl·oxa~8•氤二二螺[2.2.4.2]dodecane-7-one The title compound was obtained as a brown solid. m.p.: 380.224 [ΜΗ+]

Example A The compound of the formula (I) can be used as an active ingredient in a manner known per se to produce a tablet having the following composition: Active ingredient Microcrystalline cellulose Corn starch Talc

Propylmethylcellulose Example B The compound of the formula (I) can be known per se as a capsule having the following composition: 200 mg 155 mg 25 mg 25 mg 25 mg 425 mg per tablet as an active ingredient' to make an active ingredient Cornstarch lactose talc, magnesium stearate, each capsule 100.0 mg 20.0 mg 95.0 mg 4.5 mg 0.5 mg 220.0 mg 162086.doc • 49·

Claims (1)

201242947 VII. Scope of application: 1 · A compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, Wherein 1^ is alkoxyalkyl, pendant oxy-β-pyridylalkyl or oxypiperidinyl; R is substituted phenyl or substituted pyridyl, wherein substituted The phenyl group and the substituted pyridyl group are substituted with 1 to 3 substituents independently selected from the group consisting of a functional alkyl group, a hydroxyalkyl group, an alkoxy group and a halogenated alkoxy group. 2. A compound as claimed in the '' wherein Ri is a haloalkoxyalkyl group or a pendant oxo-pyridylalkyl group. 3. The compound of claim 1 wherein Ri is a haloalkoxyalkyl group. 4. A compound according to item 1 or 2 wherein R1 is 2-fluoroethoxyindenyl, 2,2.difluoroethoxymethyl or 2,2,2-trifluoroethoxyindenyl. 5. A compound according to claim 1 or 2 wherein R1 is 2-fluoroethoxyindenyl or 2&apos;2-difluoroethoxymethyl. 6. The compound of claim 1 or 2, wherein Ri is 2-fluoroethoxymethyl. 7. The compound of claim 1 or 2, wherein R1 is 2,2-difluoroethoxymethyl. 8. The compound of claim 1 or 2 wherein H1 is 2,2,2·trifluoroethoxyindolyl. 162086.doc 201242947 9. The compound of claim 1 or 2, wherein the TR is a pendant oxypyrrolidinyl group. 1〇·如4求! Or a compound of 2, wherein the Han] is a 2-sided oxygen port which is bitter than the mouth. U. The compound of claim 1 wherein R1 is a pendant oxanthene group. 12. A compound of the formula 丨 or 2, wherein the oxime piperidinyl-1 yl fluorenyl group. 13. The compound of claim 1, wherein the rule 1 is 2-fluoroethoxymethyl, 22-difluoroethoxymethyl, 2,2,2-trifluoroethoxyindolyl, 2-side oxygen base. Bilpyridin-1-ylmethyl or 2-oxopiperidinylmethyl. 14. The compound of claim 2, wherein R%2_glyoxymethyl, 2,2-difluoroethoxymethyl or 2-oxoxy. Pyrrolidinylmethyl. The compound according to any one of claims 1, 2, 11 or 13, wherein R 2 is a substituted phenyl or substituted pyridyl group, wherein the substituted phenyl group and the substituted pyridyl group are 1 to Three substituents independently selected from the group consisting of an alkoxy group and a dentate alkoxy group are substituted. 16. A compound according to any one of claims 1 , 2, 11 or 13 wherein R 2 is substituted phenyl or substituted pyridyl, wherein substituted phenyl and substituted. The pyridyl group is substituted with one substituent selected from the group consisting of trifluoromethyl, 2,2,2-trifluorohydroxyethyl, isopropoxy and 1,1,1·trifluoroprop-2-yloxy 17. The compound of any one of claims 1, 2, 11 or 13, wherein R 2 is substituted phenyl wherein the substituted phenyl is independently selected from 1 to 3 haloalkyl, hydroxy Substitution of alkyl, alkoxy and dentate alkoxy groups 1620S6.doc 201242947 base substitution. The compound according to any one of claims 1, 2, 11 or 13, wherein r2 is a substituted phenyl group wherein the substituted phenyl group is selected from a haloalkyl group, a aryl group Substituted by a substituent of an alkoxy group and a functional alkoxy group. 19. The compound of any one of claims 1, 2, 11 or 13, wherein R2 is a substituted phenyl group wherein the substituted phenyl group is selected from the group consisting of trifluoromethyl, 2, 2, 2 Substituent substitution of trifluoro-1-hydroxyethyl, isopropoxy and trifluoroprop-2-yloxy. 20. The compound of any one of claims 1, 2, 11 or 13, wherein R2 is substituted phenyl, wherein the substituted phenyl is one selected from the group consisting of isopropoxy and M'l-three Substituted by a fluoroprop-2-yloxy group. 21. The compound of any one of clauses i, 2, u or 13 wherein R 2 is 4 —(isopropoxy)phenyl or 4·(1,ΐ,ι_trifluoropropan-2-yloxy ) phenyl. The compound of any one of claims 1, 2, 11 or 13, wherein r2 is a substituted styryl group wherein the substituted phenyl group is substituted with a haloalkyl group. The compound of any one of claims 1, 2, 11 or 3, wherein R2 is 4-(diIImethyl)phenyl. The compound according to any one of claims 1, 2, 11 or 13, wherein R2 is a substituted stupid group wherein the substituted stupid group is substituted with a hydroxydentoalkyl group. A compound according to any one of the items 1, 2, 11 or 13, wherein r2 is a core (2,2,2-trifluoro-indolylhydroxy)phenyl group. The compound of any one of the preceding claims 2, wherein the r2 is a substituted phenyl group, wherein the substituted phenyl group is substituted with a -(tetra)oxy group. 27. The compound of claim 2, wherein the compound is 4-(isopropoxy)phenyl. 28. The compound of any one of claims 1, 2, U413, wherein R2 is substituted phenyl' wherein the substituted phenyl is substituted with a self-substituted alkoxy group. The compound of any one of claims 1, 2, 11 or 13, wherein R2 is 4 (1,1,1-trifluoroprop-2-yloxy)phenyl. The compound according to any one of claims 1, 2, 11 or 13, wherein R 2 is a substituted pyridyl group, wherein the substituted pyridyl group is oxime to 3 independently selected from the group consisting of a methacrylic group and a hydroxy group. Substituting substituents for alkyl, alkoxy and alkoxy groups. The compound of any one of claims 1, 2, 11 or 13, wherein R2 is substituted pyridyl' wherein the substituted pyridyl group is selected from the group consisting of an alkoxy group and a southern alkoxy group. Substituent substitution. The compound of any one of claims 1, 2, 11 or 13, wherein r2 is a substituted pyridyl group wherein the substituted pyridyl group is one selected from the group consisting of isopropoxy and 1,1,1 Substituted by a substituent of difluoroprop-2-yloxy. 33. The compound of any one of claims 1, 2, 11 or 13, wherein R2 is isopropoxyl. 34. The compound of any one of claims 1, 2, 11 or 13, wherein R2 is 6·U,1,1-trifluoroprop-2-yloxy)indan-3-yl. 35. The compound of any of claims 1, 2, 11 or 13 having the formula 162086.doc -4- 201242947 (la): 36. The compound of claim 1, wherein the compound of any one of 2, 11 or 13 has the formula A compound according to any one of the items 1, 2, 11 or 13 of the present invention, which is selected from the group consisting of: (5α'8α)-8·hydroxy-8·((2. oxetyrrolidinyl)methyl) Fluoromethyl)phenyl)-2-azaspiro[4.5]indole_ι-ketone; (5α,8α)_8_hydroxy-8·(2_sideoxy-piperidine-bupyridinyltrifluoromethyl) (phenyl-phenyl)-2-aza-spiro[4.5]indole-ketone; (5α'8α)-8-hydroxy-2-(4-isopropoxyphenyl-oxyl b-pyrrolidine _ 1-yl)methyl)-2-azaspiro[4.5]fluorenone; (5〇1'8〇〇-8_yl 2_2(4-isopropoxyphenyloxypiperidine small group) )methyl)-2-azaspiro[4."癸"·ketone; (5α'8α)_8·(2,2-difluoro'ethoxycarbonyl)-8-yl-2-(4) -isopropoxy-phenyl)-2-aza-spiro[4.5]indole-indole-ketone; (5α,8α)-8-carbamic-2-(6-isopropoxyacridine_3_ Base)_8(2_sideoxy-pyrrolidin-1-ylmethyl)-2_aza moiety 5]indole _ ; (5α'8α)-8-hydroxy-2-(6-isopropoxy Blowing pyridine _3_yl)_8_((2,2,2trifluoroethoxy)indolyl)-2-azaspiro[indolyl]; (5α,8α)-8'yl-side oxy" Called bite" 曱基基162086.doc 201242947 2,2,2-trifluoro-1-yl-ethyl)-phenyl]-2 -aza-spiro[4.5]癸; (5α,8α)-8-hydroxy-8-((2-o-oxypyrrolidinyl)methyl]&gt;2·(4 ((R)-l , 1,1_trifluoroprop-2-yloxy)phenyl)_2-azaspiro[4.5]indole·(5α,8α)-8-hydroxy-8-((2-sideoxy) "Byrrolidin-1-yl)methyl)_2_(6((S)-l,l,l-trifluoroprop-2-yloxypyridin-3-yl)-2-azaspiro[4.5癸. 1-ketone; (5a,8c〇-8-((2-fluoroethoxy)methyl)·8-hydroxytrifluoropropan-2-yloxy)t&gt; than -3-yl) -2 -azaspiro[4·5]nonan-1-one; (5α,8α)·8-((2-fluoroethoxy)methyl)-8-yl-2-(4-isopropyl Oxyphenyl)-2-azaspiro[4.5]indol-1-one; and a pharmaceutically acceptable salt thereof. 38. A compound according to any one of claims 1, 2, 11 or 13 Selected from · (5α,8α)-8-hydroxy-2-(4-isopropoxyphenyl)_8_((2_p-oxypyrrolidin-1-yl)methyl)-2-azaspiro[ 4·5] indole-1-one; (5(1'8€〇-8-(2,2-difluoro-ethoxymethyl)_8-hydroxy_2_(4_isopropoxy-phenyl) )-2-Aza-spiro[4.5]癸-1-French | ; (5α,8α)-8-((2-Fluoroethoxy)indenyl)_8_经基_2 Example (叫丄! • Trifluoropropane-2·yloxy)pyridine·3—yl)_2_azaspiro[4 5]indole·one; and a pharmaceutically acceptable salt thereof. 39. A process for the preparation of a compound according to any one of claims 1 to 38 which comprises reacting a compound of formula (II) in the presence of a compound of formula (111); 162086.doc • 6 · 201242947 Where R1 and R2 are as defined in the request (I) If. The compound of any one of claims 1, 2, 11 or 13, which is used as a therapeutically active substance. 41. A pharmaceutical composition comprising a compound of any one of the claims and a therapeutically inert carrier. 42. The pharmaceutical composition of claim 41 for use in the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, vascular disease, muscle dysfunction, inflammation, nonalcoholic fatty liver disease Or non-alcoholic fatty hepatitis. 43. The pharmaceutical composition of claim 42, which is for use in the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity. 44. The pharmaceutical composition of claim 42 or 43, which is for the treatment or prevention of diabetes. 45. The pharmaceutical composition of claim 42 or 43, for use in the treatment or prevention of type η diabetes. 46. The pharmaceutical composition of claim 42, which is for use in the treatment or prevention of cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or nonalcoholic lipodystrophy. 47. The pharmaceutical composition of claim 42 or 46 for use in the treatment or prevention of nonalcoholic fatty liver disease or nonalcoholic lipodystrophy. The use of a compound according to any one of claims 1 to 38, which is a medicament for the treatment or prevention of a disease caused by an abnormality associated with a hormone-sensitive lipase enzyme. 49. Use of a compound according to any one of claims 1 to 38 for the treatment or prevention of diabetes 'metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular disease, myocardial dysfunction, Inflammatory, nonalcoholic fatty liver disease or non-alcoholic lipodystrophy. 50. The use of claim 49, which is a medicament for the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis or obesity. 51. The use of claim 49 or 50 for the preparation of a medicament for the treatment or prevention of diabetes. The use of any one of claims 49 to 50 for the preparation of a medicament for the treatment or prevention of type 2 diabetes. 53. The use of claim 49 for the manufacture of a medicament for the treatment or prevention of cardiovascular disease, myocardial dysfunction, inflammation, nonalcoholic fatty liver disease or non-alcoholic lipodystrophy. 54. The use of claim 49 or 53, which is a medicament for the treatment or prevention of non-alcoholic fatty liver disease or nonalcoholic lipodystrophy. 55. A compound according to any one of claims 1, 2, 11 or 13 for use in the treatment or prevention of diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, obesity, cardiovascular disease, myocardial dysfunction Inflammatory, nonalcoholic fatty liver disease or nonalcoholic fatty hepatitis ❶ 56. The compound of claim 55, for use in the treatment or prevention of diabetes, on behalf of 162086.doc 201242947 Xie syndrome, heart s &amp; 57. 58. 59 60. 61. ^ Abnormal blood, atherosclerosis or obesity. The compound of claim 55, which is for use in the treatment or prevention of diabetes. A compound of j55, which is a compound for the treatment or prevention of n-type urinary tract, such as the compound of claim 55, for the treatment or prevention of cardiovascular diseases, myocardial dysfunction, inflammation, non-alcoholic fat Liver disease or non-alcoholic fatty hepatitis. The compound of claim 55, which is for use in the treatment or prevention of nonalcoholic fatty liver disease or nonalcoholic lipodystrophy. A compound according to any one of items 1, 2, 11 or 13, which is produced according to the method of claim 39. 162086.doc 201242947 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 162086.doc