CN101175759A

CN101175759A - Nitrogen-containing heterocyclic compounds and methods of use thereof

Info

Publication number: CN101175759A
Application number: CNA2006800169649A
Authority: CN
Inventors: A·帕拉尼; J·苏; D·肖; X·黄; A·U·娆; X·陈; H·唐; J·秦; Y·黄; R·G·阿斯拉尼安; B·麦基特里克
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 2005-05-17
Filing date: 2006-05-11
Publication date: 2008-05-07
Also published as: ZA200709777B

Abstract

A compound having the general structure of Formula (I): Formula (I) or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, wherein: Q is selected from the group consisting of: Formula (a), (b), (c), (d) and (e); and L is selected from the group consisting of: Formula (f), (g), (h), and (i); or a pharmaceutically acceptable salt, solvate, ester, or tautomer thereof, are useful in treating diseases, disorders, or conditions such as metabolic syndrome and dyslipidemia.

Description

Heterogeneous ring compound as the nicotinic acid receptor agonists for the treatment of hyperlipemia

Invention field

The present invention relates to be used for the treatment of metabolic syndrome, hyperlipemia (dyslipidemia), cardiovascular disorder, on every side with the nicotinic acid receptor agonists compound of central nervous system disease, hematologic disease, cancer, inflammation, respiratory disease, gastrointestinal illness, diabetes and non-alcoholic fatty liver disease disease; The pharmaceutical composition that comprises this compounds; The pharmaceutical composition that comprises nicotinic acid receptor agonists compound and other curative; With use described compound and combination treatment illness such as metabolic syndrome, hyperlipemia, cardiovascular disorder, on every side with the method for central nervous system disease, hematologic disease, cancer, inflammation, respiratory disease, gastrointestinal illness, diabetes, fatty degeneration of liver (hepatic steatosis) and non-alcoholic fatty liver disease disease.

Background of invention

Nicotinic acid has been used to treat metabolic syndrome and hyperlipemia.But nicotinic acid has undesirable side effect such as flush and diarrhoea.Therefore being desirable to provide is having the effectiveness of raising aspect treatment metabolic syndrome and the hyperlipemia and is not having the improvement nicotinic acid receptor agonists of undesirable side effect.Compound of the present invention provides this class to improve nicotinic acid receptor agonists.

M.Ridi, Gazzetta Chim.Ital.(1950) 80 volumes 121 pages and M.Ridi, Gazzetta Chim.Ital.(1952) 82 volumes disclose the synthetic of barbituric acid derivatives for 23 pages.FR 2563223 discloses ucleosides and has done thing.T.Paterson etc. J.Chem.Soc., Perkins Trans.I(1972) 8 volume 1041-1050 pages or leaves disclose also [2,3-d] pyrimidine synthetic of 8-substituted pyridines.S.Rao, Indian J.Chem.(1974), 12 (10) 1028-1030 pages or leaves disclose also [2,3-d] pyrimidine synthetic of pyrans.M.Skof, Heterocycles, (1999) 51 (5) 1051-1058 pages or leaves disclose (S)-1-benzoyl-3-[(E)-dimethylamino methylene]-5-methoxycarbonyl-pyrrolidin-2-one changes into quinolizinyl-and step of the alanine derivatives of 2H-2-pyrans ketone group-replacement.R.Toplak J.Heterocyclic Chem.(1999), 36 (1) 225-235 pages or leaves disclose the synthetic of pyran-2-one.But, the compound of above-mentioned document be different from of the present invention those.

WO 2004/110368 has described the combination therapy that is used for hypertension therapeutic, comprises associating antiadipositas drug and antihypertensive drug.But WO 2004/110368 does not describe the associating of nicotinic acid receptor agonists or one or more nicotinic acid receptor agonists and second kind of curative.

WO 2005/000217 has described the combination therapy that is used for the hyperlipemia treatment, comprises antiadipositas drug and anti-lipid unusual medicine Combined Preparation.But WO 2005/000217 does not describe the associating of nicotinic acid receptor agonists or one or more nicotinic acid receptor agonists and second kind of curative.

WO 2004/110375 has described the combination therapy that is used for treating diabetes, comprises antiadipositas drug and antidiabetic drug Combined Preparation.But WO 2004/110375 does not describe the associating of nicotinic acid receptor agonists or one or more nicotinic acid receptor agonists and second kind of curative.

US 2004/0122033 has described the combination therapy that is used for obesity treatment, comprises appetite-inhibiting agent and/or metabolic rate rising agent and/or dietetic alimentation inhibitor Combined Preparation.But US2004/0122033 does not describe the associating of nicotinic acid receptor agonists or one or more nicotinic acid receptor agonists and second kind of curative.US 2004/0229844 has described and has been used for the treatment of atherosclerotic combination therapy, comprises nicotinic acid or another nicotinic acid receptor agonists and DP receptor antagonist Combined Preparation.But nicotinic acid agonist and of the present invention those of US 2004/0229844 have a great difference.

WO2005/077950 has described the xanthine derivative as the agonist of niacin receptor HM74A.But the xanthine derivative of WO2005/077950 and compound of the present invention have a great difference.

Summary of the invention

In one embodiment, the present invention relates to compound or its drug acceptable salt, solvate, ester or the tautomer of formula (I),

Wherein:

Q is selected from:

L is selected from:

R ¹The alkyl that is selected from H, alkyl, thiazolinyl, alkynyl, haloalkyl, is replaced by one or more hydroxyls, cycloalkyl ,-C (O)-alkyl ,-alkylidene group-C (O)-O-alkyl ,-O-R ¹⁰,-alkylidene group-O-alkyl, aryl ,-alkylidene group-aryl, heteroaryl ,-alkylidene group-heteroaryl, halogen ,-(CH ₂) _n-N (R ⁷) ₂,-alkylidene group-cycloalkyl and-alkylidene group-cycloalkenyl group,

R wherein ¹Described cycloalkyl or the cycloalkyl moiety of described-alkylidene group-cycloalkyl does not replace or replaced R by one or more X groups ¹The described aryl or the aryl moiety of described-alkylidene group-aryl do not replace or replaced R by one or more Y groups ¹Described heteroaryl or the heteroaryl moieties of described-alkylidene group-heteroaryl do not replace or replaced by one or more Y groups;

R ²The alkyl that is selected from H, halogen, alkyl, haloalkyl, is replaced by one or more-OH ,-C (O)-alkyl ,-C (O)-O-alkyl ,-C (O)-OH ,-O-R ¹⁰,-alkylidene group-O-alkyl, unsubstituting aromatic yl, the aryl that is replaced by one or more Y groups, not substituted heteroaryl, the heteroaryl and the halogen that are replaced by one or more Y groups; Or

R ¹And R ²The ring carbon atom that connects with them forms 5-or 6-unit's cyclenes basic ring or has 1 or 2 heteroatomic 5-or 6-unit heterocycle;

R ³The alkyl that is selected from H, alkyl, is replaced by one or more hydroxyls ,-alkylidene group-O-alkyl, cycloalkyl ,-alkylidene group-cycloalkyl ,-alkylidene group-C (O)-O-alkyl ,-alkylidene group-O-C (O)-alkyl, thiazolinyl, aryl and heteroaryl, wherein R ³Described cycloalkyl or the cycloalkyl moiety of described-alkylidene group-cycloalkyl does not replace or replaced R by one or more X groups ³Described aryl do not replace or replaced R by one or more Y groups ³Described heteroaryl do not replace or replaced by one or more Y groups;

R ⁴Be selected from H, halogen, alkyl ,-O-R ¹⁰,-C (O)-O-alkyl ,-S (O) _m-R ⁹,-N (R ⁷) ₂,-N (R ⁷)-NH-C (O)-alkyl ,-N (R ⁷)-NH-C (O)-O-alkyl ,-O-N=C (R ¹²) ₂,-N (R ⁷)-N=C (R ¹²) ₂,-C (O)-alkyl, unsubstituted heterocyclic, the heterocyclic radical that is replaced by one or more X groups ,-O-N (R ⁷)-C (O)-O-alkyl ,-C (O)-N (R ⁷) ₂,-CN ,-N ₃With-O-C (O)-alkyl;

R ⁵Be selected from H, alkyl ,-alkylidene group-C (O)-R ⁸,-alkylidene group-C (O)-N (R ¹¹) ₂,-alkylidene group-C (=N-O-alkyl)-aryl, cycloalkyl ,-alkylidene group-cycloalkyl ,-alkylidene group-C (O)-O-alkyl ,-alkylidene group-O-C (O)-alkyl ,-alkylidene group-C (O)-heterocyclic radical and thiazolinyl, wherein R ⁵Described cycloalkyl or the cycloalkyl moiety of described-alkylidene group-cycloalkyl does not replace or replaced R by one or more X groups ⁵The aryl moiety of described-alkylidene group-C (=N-O-alkyl)-aryl do not replace or replaced by one or more Y groups;

R ⁶The alkyl that is selected from H, alkyl, thiazolinyl, is replaced by one or more hydroxyls ,-alkylidene group-O-alkyl ,-O-R ¹⁰, halogen, aryl, heteroaryl and-N (R ⁷) ₂, R wherein ⁶Described aryl do not replace or replaced R by one or more Y groups ⁶Described heteroaryl do not replace or replaced by one or more Z groups;

Each R ⁷Be independently selected from H, alkyl, cycloalkyl, aryl ,-C (O)-alkyl and-C (O)-aryl,

R wherein ⁷Described cycloalkyl do not replace or replaced R by one or more X groups ⁷The aryl moiety or the described aryl of described-C (O)-aryl do not replace or replaced by one or more Y groups;

Two R ⁷The N atom of group and their bondings forms heterocyclic radical together;

R ⁸Be selected from aryl ,-OH and heterocyclic radical, wherein R ⁸Described heterocyclic radical do not replace or replaced R by one or more X groups ⁸Described aryl do not replace or replaced by one or more Y groups;

R ⁹Be selected from alkyl ,-alkylidene group-cycloalkyl, thiazolinyl ,-N (R ¹¹) ₂With-alkylidene group-aryl,

R wherein ⁹The cycloalkyl moiety of described-alkylidene group-cycloalkyl do not replace or replaced R by one or more X groups ⁹The aryl moiety of described-alkylidene group-aryl do not replace or replaced and condition is to work as R by one or more Y groups ⁹For-N (R ¹¹) ₂The time, m is 1 or 2;

R ¹⁰Be selected from H, alkyl ,-alkylidene group-aryl ,-alkenylene-aryl ,-alkylidene group-heteroaryl, thiazolinyl ,-C (O)-alkyl, alkynyl and-alkylidene group-cycloalkyl,

R wherein ¹⁰The cycloalkyl moiety of described-alkylidene group-cycloalkyl do not replace or replaced R by one or more X groups ¹⁰Described-alkylidene group-aryl or-aryl moiety of alkenylene-aryl do not replace or replaced R by one or more Y groups ¹⁰The heteroaryl moieties of described-alkylidene group-heteroaryl do not replace or replaced by one or more Z groups;

R ¹¹Be selected from H, alkyl and aryl, wherein R ¹¹Described aryl do not replace or replaced by one or more Y groups; Or

Two R ¹¹Group forms heterocyclic radical with the N atom that they connect;

Each R ¹²Be independently selected from alkyl, aryl and heteroaryl,

R wherein ¹²Described aryl do not replace or replaced R by one or more Y groups ¹²Described heteroaryl do not replace or replaced by one or more Z groups;

R ^aAnd R ^bBe selected from H, alkyl, aryl and heteroaryl independently of one another,

R wherein ^aAnd R ^bDescribed aryl do not replace or replaced R by one or more Y groups ^aAnd R ^bDescribed heteroaryl do not replace or replaced by one or more Z groups;

R ^cBe selected from H, alkyl, alkylidene group-aryl and-C (O)-alkyl,

R wherein ^cThe aryl moiety of described alkylidene group-aryl do not replace or replaced by one or more Y groups;

R ^dBe selected from H, alkyl and alkylidene group-aryl,

R wherein ^dThe aryl moiety of described alkylidene group-aryl do not replace or replaced by one or more Y groups;

Each X be independently selected from halogen, alkyl, haloalkyl ,-the O-alkyl ,-the O-haloalkyl and-OH;

Each Y be independently selected from halogen, alkyl, haloalkyl ,-the O-alkyl ,-the O-haloalkyl ,-CN ,-NO ₂,-OH ,-S (O ₂)-alkyl ,-S (O ₂)-aryl ,-S (O ₂)-NH ₂,-S (O ₂)-NH-alkyl ,-S (O ₂)-NH-aryl ,-S (O ₂)-N (alkyl) ₂,-S (O ₂)-N (aryl) ₂,-S (O ₂)-N (alkyl) (aryl) and aryl;

Each Z be independently selected from alkyl, haloalkyl, halogen ,-the O-alkyl ,-the O-haloalkyl ,-CN ,-OH, aryl and N-oxide compound;

N is 0,1,2 or 3;

M is 0,1 or 2; With

Condition is to be (f), R as L ², R ³And R ⁵When respectively doing for oneself H, R ₁Be not-CH ₃

In another embodiment, the present invention relates to a kind of pharmaceutical composition, it comprises compound or its drug acceptable salt, solvate, ester or tautomer and at least a drug acceptable carrier of at least a formula (I) for the treatment of significant quantity.

In another embodiment, the present invention relates to treat disease of patient or illness such as metabolic syndrome, hyperlipemia, cardiovascular disorder, on every side with the method for central nervous system disease, hematologic disease, cancer, inflammation, respiratory disease, gastrointestinal illness, diabetes and non-alcoholic fatty liver disease disease.This method comprises compound or its drug acceptable salt, solvate, ester or the tautomer of granting at least a formula (I) of significant quantity to the patient.

In another embodiment, the present invention relates to treat disease of patient or illness such as metabolic syndrome, hyperlipemia, cardiovascular disorder, on every side with the method for central nervous system disease, hematologic disease, cancer, inflammation, respiratory disease, gastrointestinal illness, diabetes, fatty degeneration of liver and non-alcoholic fatty liver disease disease.This method comprises compound or its drug acceptable salt of granting at least a formula (I) of significant quantity to the patient; solvate; ester or tautomer, and at least aly be selected from following additional activity composition: azetidinone (azetidinone) compound that hydroxyl replaces; the 'beta '-lactam compounds that replaces; HMG CoA reductase inhibiter compounds; HMG CoA synthetase inhibitors; the squalene synthetic inhibitor; the squalene epoxidase inhibitor; the sterol biosynthesis inhibitor; nicotinic acid derivates; bile acid chelating agent; inorganic cholesterol sequestrant; AcylCoA: cholesterol O-inhibitors; cholestery ester transfer protein inhibitors; the fish oil that contains omega-3 fatty acid; water-soluble fiber; the fatty acid ester of plant alkanol (plant stanol) and/or plant alkanol (for example Omacor_ of Oslo, Norway Pronova Biocare); the low density lipoprotein receptor activator; antioxidant; the PPAR alfa agonists; PPAR γ-agonist; the FXR receptor modulators; the lxr receptor agonist; the lipoprotein synthetic inhibitor; the renin angiotensin inhibitor; microsome tri-glyceride transporter inhibitors; the bile acide cell reabsorption inhibitor; the PPAR delta agonists; the tri-glyceride synthetic inhibitor; the squalene epoxidase inhibitor; the low density lipoprotein receptor inductor; anticoagulant; 5-LO or FLAP inhibitor; PPAR δ partial agonist; nicotinic acid or nicotinic acid receptor agonists; the 5HT transporter inhibitors; the NE transporter inhibitors; CB ₁Antagonists/inverse agonists, ghrelin antagonist, H ₃Antagonists/inverse agonists; the MCH1R antagonist; the MCH2R agonist/antagonist; the NPY1 antagonist; the NPY5 antagonist; the NPY2 agonist; the NPY4 agonist; the mGluR5 antagonist; leptin (leptins); the leptin agonist/modulator; the leptin derivative; opioid antagonists (opioid antagonists); increase the food factor (orexin) receptor antagonist; the BRS3 agonist; the CCK-A agonist; CNTF; the CNTF derivative; the CNTF agonist/modulator; the 5HT2c agonist; the Mc4r agonist; monoamine reuptake inhibitors; the serotonin reuptake inhibitor; the GLP-1 agonist; PHENTERMINE (phentermine); topiramate; phytopharm compound 57; ghrelin antibody; the Mc3r agonist; the ACC2 inhibitor; β 3 agonists; the DGAT1 inhibitor; the DGAT2 inhibitor; the FAS inhibitor; the PDE inhibitor; the Triiodothyronine beta-agonists; the UCP-1 activator; the UCP-2 activator; the UCP-3 activator; acyl group oestrogenic hormon; glucocorticoid agonists/antagonist; 11 β HSD-1 inhibitor; the SCD-1 inhibitor; lipase inhibitor; the fatty acid transport protein inhibitor; dicarboxylic ester transporter inhibitors (dicarboxylate transporter inhibitor); the glucose transporter inhibitor; phosphoric acid ester transporter inhibitors (phosphate transporterinhibitors); antidiabetic drug; antihypertensive drug; anti-lipid unusual medicine; the DP receptor antagonist; apo-B secretion/microsome tri-glyceride transfer protein (apo-B/MTP) inhibitor; the sympathomimetic nerve agonist; dopamine agonist; the melanotropin receptor analogs; melanochrome concentrating hormone antagonists (melanin concentrating hormone antagonist); lepton (leptons); the galanin receptor antagonist; the bombesin agonist; neuropeptide-γ antagonist; thyromimetic (thyromimetic agent); dehydroepiandrosterone; the dehydroepiandrosterone analogue; the conjugated protein antagonist of urocortin; glucagon-like peptide-1 receptor stimulant; people agouti associated protein (AGRP); neuromedin U receptor stimulant; norepinephrine energy anorexigenic (noradrenergic anorectic agent); appetite-inhibiting agent; the hormone-sensitive lipase antagonist; the MSH-receptor analogs; alpha-glucosidase inhibitor; the contrary cholesterol transport inhibitor (apo A1 milano reverse cholesterol transport inhibitors) of apo A1 milano; fatty acid binding protein inhibitor (FABP) and fatty acid transport protein inhibitor (FATP).

Detailed Description Of The Invention

Other disease that nicotinic acid receptor agonists compound of the present invention is used for the treatment of illness such as metabolic syndrome, hyperlipemia, cardiovascular disorder, lists with central nervous system disease, hematologic disease, cancer, inflammation, respiratory disease, gastrointestinal illness, diabetes, fatty degeneration of liver and non-alcoholic fatty liver disease disease and this paper on every side.One or more compounds of the present invention can be individually dosed or be united one or more other curative administrations described herein.

In first embodiment, the present invention relates to compound or its drug acceptable salt, solvate, ester or the tautomer of formula as described herein (I).

In another embodiment of the compound of formula (I),

R ¹Be selected from-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) thiazolinyl ,-(C ₁-C ₆) alkynyl ,-(C ₁-C ₆) haloalkyl, by hydroxyl replace-(C ₁-C ₆) alkyl ,-(C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) heteroaryl ,-(C ₁-C ₆) alkylidene group-C (O)-O-(C ₁-C ₆) alkyl ,-(CH ₂) _n-N (R ⁷) ₂,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl and-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkenyl group,

Wherein said-(C ₃-C ₇) cycloalkyl or described-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) (the C of cycloalkyl ₃-C ₇) cycloalkyl moiety do not replace or replaced by one or more X groups, and is described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups, and is described-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) (the C of heteroaryl ₂-C ₁₀) heteroaryl do not replace or replaced by one or more Z groups;

R ²The aryl that replaces for H, halogen, unsubstituted aryl, by one or more independent Y groups of selecting, unsubstituted heteroaryl, the heteroaryl that is replaced by one or more independent Y groups of selecting; Or

R ¹And R ²The ring carbon atom that connects with them forms 5-or 6-unit cyclenes basic ring;

R ³Be selected from H, (C ₁-C ₆) alkyl ,-(C ₃-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl, (C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-C (O)-O-alkyl and (C ₁-C ₆) thiazolinyl,

R wherein ³Described (C ₃-C ₇) cycloalkyl or described-(C ₃-C ₆) alkylidene group-(C ₃-C ₇) (the C of cycloalkyl ₃-C ₇) cycloalkyl moiety do not replace or replaced by one or more X groups;

R ⁴Be selected from halogen ,-O-R ¹⁰,-C (O)-O-(C ₁-C ₆) alkyl ,-S (O) _m-R ⁹,-N (R ⁷) ₂,-O-N=C (R ¹²) ₂,-N (R ⁷)-NH-C (O)-O-(C ₁-C ₆) alkyl and-C (O)-(C ₁-C ₆) alkyl;

R ⁵Be selected from H ,-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-C (O)-R ⁸,-(C ₁-C ₆) alkylidene group-C (=N-O-(C ₁-C ₆) alkyl)-(C ₆-C ₁₀) aryl, (C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-C (O)-O-(C ₁-C ₆) alkyl and (C ₂-C ₆) thiazolinyl,

R wherein ⁵Described (C ₃-C ₇) cycloalkyl or described-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) (the C of cycloalkyl ₃-C ₇) cycloalkyl moiety do not replace or replaced R by one or more X groups ⁵Described-(C ₁-C ₆) alkylidene group-C (=N-O-(C ₁-C ₆) alkyl)-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups;

R ⁶Be selected from-O-R ¹⁰, halogen and-N (R ⁷) ₂

Each R ⁷Be independently selected from H, (C ₁-C ₆) alkyl, (C ₃-C ₇) cycloalkyl and (C ₆-C ₁₀) aryl,

R wherein ⁷Described (C ₃-C ₇) cycloalkyl do not replace or replaced R by one or more X groups ⁷Described (C ₆-C ₁₀) aryl do not replace or replaced by one or more Y groups;

R ⁸Be selected from unsubstituted (C ₆-C ₁₀) the aryl, (C that replaced by one or more Y groups ₆-C ₁₀) aryl ,-OH, unsubstituted (C ₂-C ₁₀) heterocyclic radical and the (C that replaced by one or more X groups ₂-C ₁₀) heterocyclic radical;

R ⁹Be selected from (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl, (C ₂-C ₆) thiazolinyl and-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl,

R wherein ⁹Described-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) (the C of cycloalkyl ₃-C ₇) cycloalkyl moiety do not replace or replaced R by one or more X groups ⁹Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups;

R ¹⁰Be selected from H, (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl ,-(C ₂-C ₆) alkenylene-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) heteroaryl, (C ₂-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl and-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl,

R wherein ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) (the C of cycloalkyl ₃-C ₇) cycloalkyl moiety do not replace or replaced R by one or more X groups ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl or-(C ₂-C ₆) alkenylene-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced R by one or more Y groups ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) (the C of heteroaryl ₂-C ₁₀) heteroaryl moieties do not replace or replaced by one or more Z groups;

Each R ¹²Be (C independently ₁-C ₆) alkyl;

R ^aAnd R ^bBe (C independently of one another ₁-C ₆) alkyl;

R ^cBe H;

R ^dBe selected from H, (C ₁-C ₆) alkyl and-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl,

R wherein ^dDescribed-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups;

Each X is independently selected from F, Cl, Br, (C ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl ,-O-(C ₁-C ₆) alkyl ,-O-(C ₁-C ₆) haloalkyl and-OH;

Each Y is independently selected from F, Br, Cl, (C ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl ,-O-(C ₁-C ₆) alkyl ,-O-(C ₁-C ₆) haloalkyl ,-CN ,-NO ₂,-OH ,-S (O ₂)-(C ₁-C ₆) alkyl ,-S (O ₂)-(C ₆-C ₁₀) aryl ,-S (O ₂)-NH ₂,-S (O ₂)-NH-(C ₁-C ₆) alkyl ,-S (O ₂)-NH-(C ₆-C ₁₀) aryl ,-S (O ₂)-N ((C ₁-C ₆) alkyl) ₂,-S (O ₂)-N ((C ₆-C ₁₀) aryl) ₂,-S (O ₂)-N ((C ₁-C ₆) alkyl) ((C ₆-C ₁₀) aryl) and (C ₆-C ₁₀) aryl; With

Each Z is independently selected from (C ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl, F, Br and Cl ,-O-(C ₁-C ₆) alkyl ,-CN ,-OH, (C ₆-C ₁₀) aryl and N-oxide compound.

In another embodiment of formula (I) compound,

R ¹Be selected from-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH (CH ₃) ₂,-CH ₂CH ₂CH ₂CH (CH ₃) ₂,-CH (CH ₃) ₂,-CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH=CHCH ₃,-CH ₂CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂-OH ,-CH (CH ₃)-OH, cyclobutyl ,-CH ₂-C (O)-O-CH ₂CH ₃,-CH ₂CH ₂CH ₂-O-CH ₃,-CH ₂CF ₃,-CHBrCH ₃,-CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂Cl ,-CH ₂-(2-thiophenyl) ,-CH ₂CH ₂CH ₂-(2-thiophenyl) ,-CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂CH ₂CH ₂-cyclobutyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopentyl ,-CH ₂CH ₂CH ₂-cyclopentyl ,-CH ₂CH ₂CH ₂CH ₂-cyclopentyl ,-CH ₂-cyclohexyl ,-CH ₂-(4-methylcyclohexyl) ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-suberyl ,-CH ₂-(the 2-cyclopentenyl ,-CH ₂CH ₂C ≡ CH ,-CH ₂CH ₂CH ₂C ≡ CH ,-CH ₂-phenyl ,-CH ₂-(2-fluorophenyl) ,-CH ₂-(3-fluorophenyl) and-CH ₂-NH (3-p-methoxy-phenyl);

R ²The aryl that is selected from H, F, Cl, Br, unsubstituted aryl, is replaced by one or more Y groups, unsubstituted heteroaryl, the heteroaryl that is replaced by one or more Y groups; Or

R ¹And R ²The ring carbon atom that connects with them forms cyclopentenyl or tetrahydrobenzene basic ring;

R ³Be selected from H ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH=CH ₂With-CH ₂-O-CH ₃

R ⁴Be selected from Cl ,-O-R ¹⁰,-C (O)-O-CH ₃,-S (O) ₂-CH ₃,-S (O)-CH ₃,-S (O)-CH ₂CH ₃,-S (O)-CH (CH ₃) ₂,-S (O)-C (CH ₃) ₃,-S (O)-CH ₂-cyclopropyl ,-S (O)-CH ₂-phenyl ,-S (O)-CH (CH ₃)-phenyl ,-S-CH ₂-CH=CH ₂,-N (R ⁷) ₂,-O-N=C (CH ₃) ₂,-NH-NH-C (O)-O-CH ₃With-C (O)-CH ₃,

R wherein ⁴Described-S (O)-CH ₂-phenyl or-S (O)-CH (CH ₃The phenyl moiety of)-phenyl does not replace or is replaced by one or more Y groups;

R ⁵Be selected from H ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂-C (O)-phenyl ,-CH ₂-C (O)-OH ,-CH ₂-C (=N-O-CH ₃)-phenyl, cyclopropyl, cyclobutyl, cyclopentyl ,-CH ₂-C (O)-piperidyl ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃With-CH ₂-CH=CH ₃,

Wherein said-CH ₂The phenyl moiety of-C (O)-phenyl does not replace or is replaced by one or more Y groups;

R ⁶Be selected from-OR ¹⁰, Cl and-N (R ⁷) ₂

Each R ⁷The phenyl that is independently selected from H, cyclobutyl, unsubstituted phenyl and is replaced by one or more Y groups;

R ¹⁰Be selected from H ,-CH ₃,-CH ₂-cyclopropyl ,-CH ₂-CH=CH ₃,-CH ₂C ≡ C-CH ₃,-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH ₂CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl ,-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl and-CH ₂-pyrimidyl,

R wherein ¹⁰Described-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH ₂CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl or-CH (CH ₂CH=CH ₂The phenyl moiety of)-phenyl does not replace or is replaced R by one or more group Y ¹⁰Described-CH ₂-pyridyl ,-CH ₂-thiazolyl or-CH ₂The pyridyl of-pyrimidyl, thiazolyl or pyrimidyl part do not replace or are replaced by one or more group Z;

R ^aAnd R ^bRespectively do for oneself-CH ₃

R ^cBe H;

R ^dBe selected from H ,-CH ₃With-CH ₂-phenyl,

R wherein ^dDescribed-CH ₂The phenyl moiety of-phenyl does not replace or is replaced by one or more Y groups;

Each Y be independently selected from F, Cl, Br ,-CH ₃,-CF ₃,-O-CH ₃,-O-CF ₃,-CN ,-OH and phenyl; With

Each Z is independently selected from-CH ₃,-CF ₃, F, Br and Cl ,-O-CH ₃,-CN ,-OH, phenyl and N-oxide compound.

In another embodiment of formula (I) compound,

Q is:

L is:

R ¹Be selected from-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl, unsubstituted (C ₆-C ₁₀) aryl and the (C that replaced by one or more substituting group Y ₆-C ₁₀) aryl;

R ²Be H or halogen;

R ⁴Be selected from halogen ,-O-R ¹⁰,-C (O)-O-(C ₁-C ₆) alkyl ,-S (O) _m-R ⁹,-N (R ⁷) ₂,-O-N=C (R ¹²) ₂,-N (R ⁷)-NH-C (O)-O-(C ₁-C ₆) alkyl and-C (O)-(C ₁-C ₆) alkyl; R ⁵Be H or (C ₁-C ₆) alkyl;

Each R ⁷Be independently selected from H, (C ₁-C ₆) alkyl, (C ₃-C ₆) cycloalkyl, unsubstituted (C ₆-C ₁₀) aryl and the (C that replaced by one or more Y groups ₆-C ₁₀) aryl;

R ⁹Be selected from (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl, (C ₂-C ₈) thiazolinyl and-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl,

R wherein ⁹Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl do not replace or replaced by one or more Y groups;

R ¹⁰Be selected from H, (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkenylene-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) heteroaryl, (C ₂-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl and-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl,

R wherein ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl or-(C ₁-C ₆) alkenylene-(C ₆-C ₁₀) aryl of aryl do not replace or replaced R by one or more Y groups ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) (the C of heteroaryl ₂-C ₁₀) heteroaryl does not replace or quilt-individual or a plurality of Z groups replace;

Each R ¹²Be independently selected from (C ₁-C ₆) alkyl, (C ₆-C ₁₀) aryl and (C ₂-C ₁₀) heteroaryl,

Wherein said (C ₆-C ₁₀) aryl do not replace or replaced by one or more Y groups, described (C ₂-C ₁₀) heteroaryl do not replace or replaced by one or more Z groups;

Each Y is independently selected from halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl ,-O-(C ₁-C ₆) haloalkyl ,-O-(C ₁-C ₆) alkyl ,-CN ,-NO ₂,-OH ,-S (O ₂)-(C ₁-C ₆) alkyl ,-S (O ₂)-(C ₆-C ₁₀) aryl ,-S (O ₂)-NH ₂,-S (O ₂)-NH-(C ₁-C ₆) alkyl ,-S (O ₂)-NH-(C ₆-C ₁₀) aryl ,-S (O ₂)-N ((C ₁-C ₆) alkyl) ₂,-S (O ₂)-N ((C ₆-C ₁₀) aryl) ₂,-S (O ₂)-N ((C ₁-C ₆) alkyl) ((C ₆-C ₁₀) aryl) and (C ₆-C ₁₀) aryl; With

Each Z is independently selected from (C ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl, halogen ,-the O-alkyl ,-O-(C ₁-C ₆) haloalkyl ,-CN ,-OH, (C ₆-C ₁₀) aryl and N-oxide compound.

In another embodiment of the compound of formula (I),

Q is:

L is:

R ¹For-CH ₂CH ₃, butyl, amyl group ,-CH ₂-CH ₂-CH ₂-cyclopropyl;

R ²The aryl that replaces for H, Br, unsubstituted aryl, by one or more Y groups, unsubstituted heteroaryl, the heteroaryl that is replaced by one or more Y groups;

R ⁴Be selected from Cl ,-O-R ¹⁰,-C (O)-O-CH ₃,-S (O)-CH ₃,-S (O)-CH ₂CH ₃,-S (O)-CH (CH ₃) ₂,-S (O)-C (CH ₃) ₃,-S (O)-CH ₂-cyclopropyl ,-S-CH ₂-CH=CH ₂,-S (O)-CH ₂-phenyl ,-S (O)-CH (CH ₃)-phenyl ,-N (R ⁷) ₂,-O-N=C (CH ₃) ₂,-NH-NH-C (O)-O-CH ₃With-C (O)-CH ₃,

R wherein ⁴Described-S (O)-CH ₂-phenyl or-S (O)-CH (CH ₃The phenyl moiety of)-phenyl does not replace or is replaced by one or more group Y;

R ⁵For H or-CH ₂CH ₃

Each R ⁷Be independently selected from H and cyclobutyl;

R ¹⁰Be selected from H ,-CH ₃,-CH ₂-cyclopropyl ,-CH ₂-CH=CH ₂,-CH ₂C ≡ C-CH ₃,-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH (CH ₂CH ₂CH ₃)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl ,-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl ,-CH ₂-pyrimidyl,

R wherein ¹⁰Described-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl or-CH (CH ₂CH ₂CH ₃The phenyl moiety of)-phenyl does not replace or is replaced R by one or more group Y ¹⁰Described-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl or-CH ₂The pyridyl of-pyrimidyl, thiazolyl or pyrimidyl part do not replace or are replaced by one or more group Z;

Each Y be independently selected from F, Cl, Br ,-CH ₃,-CF ₃,-O-CH ₃,-O-CF ₃And phenyl; With

Each Z is independently selected from-CH ₃, phenyl and N-oxide compound.

In another embodiment of formula (I) compound,

Q is:

L is:

Be selected from-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) thiazolinyl ,-(C ₁-C ₆) alkynyl ,-(C ₁-C ₆) alkylidene group-C (O)-O-(C ₁-C ₆) alkyl ,-(C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) heteroaryl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkenyl group, by one or more hydroxyls replace-(C ₁-C ₆) alkyl ,-(CH ₂) _n-N (R ⁷) ₂With-(C ₁-C ₆) haloalkyl,

Wherein said-(C ₃-C ₇) cycloalkyl or described-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) (the C of cycloalkyl ₃-C ₇) cycloalkyl moiety do not replace or replaced by one or more X groups, and is described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups, and is described-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) (the C of heteroaryl ₂-C ₁₀) heteroaryl moieties do not replace or replaced by one or more Z groups;

R ²Be H;

R ³Be selected from H, (C ₁-C ₆) alkyl, (C ₃-C ₆) cycloalkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl ,-(C ₁-C ₆) alkylidene group-C (O)-O-(C ₁-C ₆) alkyl, (C ₂-C ₆) thiazolinyl and-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl;

R ⁵Be selected from H ,-(C ₁-C ₆) alkyl, (C ₂-C ₆) thiazolinyl ,-(C ₁-C ₆) alkylidene group-C (O)-R ⁸,-(C ₁-C ₆) alkylidene group-C (=N-O-(C ₁-C ₆) alkyl)-(C ₆-C ₁₀) aryl, (C ₃-C ₆) cycloalkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl and-(C ₁-C ₆) alkylidene group-C (O)-O-(C ₁-C ₆) alkyl;

Each R ⁷Be independently selected from H and aryl, wherein R ⁷Described aryl do not replace or replaced by one or more Y groups;

Each X is independently selected from halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) haloalkyl ,-O-(C ₁-C ₆) alkyl ,-O-(C ₁-C ₆) haloalkyl and-OH;

In another embodiment of formula (I) compound,

Q is:

L is:

R ¹Be selected from-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH (CH ₃) ₂,-CH ₂CH ₂CH ₂CH (CH ₃) ₂,-CH (CH ₃) ₂,-CH ₂-C (O)-O-CH ₂CH ₃,-CH ₂CF ₃,-CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH=CHCH ₃,-CH ₂CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂OH ,-CH (CH ₃) OH ,-CH ₂N (R ⁷) ₂, cyclobutyl ,-CH ₂CH ₂CH ₂-O-CH ₃,-CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂Cl ,-CH ₂-(2-thiophenyl) ,-CH ₂CH ₂CH ₂-(2-thiophenyl) ,-CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopentyl ,-CH ₂-cyclohexyl ,-CH ₂-(4-methylcyclohexyl) ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-suberyl ,-CH ₂-(the 2-cyclopentenyl ,-CH ₂CH ₂C ≡ CH ,-CH ₂CH ₂CH ₂C ≡ CH ,-CH ₂-phenyl ,-CH ₂-(2-fluorophenyl) ,-CH ₂-(3-fluorophenyl) and-CHBrCH ₃

R ²Be H; Or

R ³Be selected from H ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃, cyclopropyl, cyclobutyl, cyclopentyl ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH=CH ₂With-CH ₂-O-CH ₃

R ⁵Be selected from H ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃,-CH ₂-C (O)-R ⁸,-CH ₂-C (=N-O-CH ₃)-phenyl, cyclopropyl, cyclobutyl, cyclopentyl ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃With-CH ₂CH=CH ₂

Each R ⁷Be H or phenyl, wherein R independently ⁷Described phenyl do not replace or replaced by one or more Y groups;

R ⁸The phenyl that is selected from unsubstituted phenyl, is replaced by one or more Y groups ,-OH and piperidyl; With

Each Y be independently selected from F ,-CF ₃,-OCH ₃,-CN and-OH.

In another embodiment of formula (I) compound,

Q is:

L is:

R ¹Be selected from-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) thiazolinyl ,-(C ₁-C ₆) alkynyl ,-(C ₁-C ₆) alkylidene group-C (O)-O-(C ₁-C ₆) alkyl ,-(C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) heteroaryl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkenyl group, by one or more hydroxyls replace-(C ₁-C ₆) alkyl ,-(CH ₂) _n-N (R ⁷) ₂With-(C ₁-C ₆) haloalkyl,

R ²Be H; Or

R ⁶Be selected from-O-R ¹⁰, halogen and-N (R ⁷) ₂

R ⁹Be selected from (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl, (C ₂-C ₆) thiazolinyl and-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl,

R wherein ⁹Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups;

R ¹⁰Be selected from H, (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkenylene-(C ₆-C ₁₀) aryl ,-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) heteroaryl, (C ₂-C ₆) thiazolinyl, (C ₂-C ₆) alkynyl and-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl,

R wherein ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl or-(C ₁-C ₆) alkenylene-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced R by one or more Y groups ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) (the C of heteroaryl ₂-C ₁₀) heteroaryl moieties do not replace or replaced by one or more Z groups;

In another embodiment of formula (I) compound,

Q is:

L is:

R ¹Be selected from-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH (CH ₃) ₂,-CH ₂CH ₂CH ₂CH (CH ₃) ₂,-CH (CH ₃) ₂,-CH ₂-C (O)-O-CH ₂CH ₃,-CH ₂-OH ,-CH (CH ₃)-OH ,-CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH=CHCH ₃,-CH ₂CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH ₂CH=CH ₂, cyclobutyl ,-CH ₂CH ₂CH ₂-O-CH ₃,-CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂Cl ,-CH ₂-(2-thiophenyl) ,-CH ₂CH ₂CH ₂-(2-thiophenyl) ,-CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopentyl ,-CH ₂-cyclohexyl ,-CH ₂-(4-methylcyclohexyl) ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-suberyl ,-CH ₂-(the 2-cyclopentenyl ,-CH ₂CH ₂C ≡ CH ,-CH ₂CH ₂CH ₂C ≡ CH ,-CH ₂-phenyl ,-CH ₂-(2-fluorophenyl) ,-CH ₂-(3-fluorophenyl) ,-CHBrCH ₃With-CH ₂CF ₃

R ²Be H; Or

R ⁴Be selected from Cl ,-O-R ¹⁰,-C (O)-O-CH ₃,-S (O) ₂-CH ₃,-S (O)-CH ₃,-S (O)-CH ₂CH ₃,-S (O)-CH (CH ₃) ₂,-S (O)-C (CH ₃) ₃,-S (O)-CH ₂-cyclopropyl ,-S-CH ₂-CH=CH ₂,-S (O)-CH ₂-phenyl ,-S (O)-CH (CH ₃)-phenyl ,-N (R ⁷) ₂,-O-N=C (CH ₃) ₂,-NH-NH-C (O)-O-CH ₃With-C (O)-CH ₃,

R ⁶Be selected from-O-R ¹⁰,-N (R ⁷) ₂And Cl;

Each R ⁷The phenyl and the cyclobutyl that are independently selected from H, unsubstituted phenyl, are replaced by one or more Y groups;

R ¹⁰Be selected from H, CH ₃,-CH ₂-cyclopropyl ,-CH ₂-C ≡ C-CH ₃,-CH ₂-CH=CH ₂,-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH (CH ₂CH ₂CH ₃)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl ,-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl ,-CH ₂-pyrimidyl,

R wherein ¹⁰Described-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl or-CH (CH ₂CH ₂CH ₃The phenyl moiety of)-phenyl does not replace or is replaced R by one or more Y groups ¹⁰Described-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl or-CH ₂The pyridyl of-pyrimidyl, thiazolyl or pyrimidyl part do not replace or are replaced by one or more group Z;

Each Z is independently selected from-CH ₃, F, Br and Cl ,-O-CH ₃,-CN ,-OH, phenyl and N-oxide compound.

In another embodiment of formula (I) compound,

Q is:

L is:

R ¹For-(C ₁-C ₆) alkyl;

R ²Be H;

R ³For H or-(C ₂-C ₆) thiazolinyl; With

R ⁶For-OH or-O-(C ₁-C ₆) alkylidene group-(C ₁-C ₆) cycloalkyl.

In another embodiment of formula (I) compound,

Q is:

L is:

R ¹For-(C ₁-C ₆) alkyl or-(C ₁-C ₆) haloalkyl;

R ²Be H;

R ³Be selected from H ,-(C ₁-C ₆) alkylidene group-(C ₁-C ₆) cycloalkyl ,-(C ₁-C ₆) alkylidene group-C (O)-O-(C ₁-C ₆) alkyl ,-(C ₁-C ₆) cycloalkyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) thiazolinyl and-(C ₁-C ₆) alkylidene group-O-(C ₁-C ₆) alkyl; With

R ⁴For-O-N=C ((C ₁-C ₆) alkyl) ₂

In another embodiment of formula (I) compound,

Q is:

L is selected from:

R ^aAnd R ^bBe selected from H, (C independently of one another ₁-C ₆) alkyl, (C ₆-C ₁₀) aryl and (C ₂-C ₁₀) heteroaryl,

R wherein ^aAnd R ^bDescribed (C ₆-C ₁₀) aryl do not replace or replaced R by one or more Y groups ^aAnd R ^bDescribed (C ₂-C ₁₀) heteroaryl do not replace or replaced by one or more Z groups;

R ^cBe selected from H, (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl and-C (O)-(C ₁-C ₆) alkyl,

R wherein ^cDescribed-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups;

R ¹For-(C ₁-C ₆) alkyl or-(C ₁-C ₆) haloalkyl;

R ²Be H;

R ³Be H;

R ⁴For-O-R ¹⁰

R ⁵For H or-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl;

R ⁶For-O-R ¹⁰

R ¹⁰For H ,-(C ₁-C ₆) alkyl or-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl; With

In another embodiment of formula (I), R ¹For-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₃,-CH (CH ₃) ₂,-CH ₂-C (O)-O-CH ₂CH ₃,-CH ₂CF ₃,-CH ₂-OH ,-CH (CH ₃) OH ,-CH ₂-N (R ⁷) ₂,-CH ₂-NH (3-p-methoxy-phenyl) ,-CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH (CH ₃) ₂,-CH ₂CH ₂CH ₂CH (CH ₃) ₂,-CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH=CHCH ₃,-CH ₂CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH ₂CH=CH ₂, cyclobutyl ,-CH ₂CH ₂CH ₂-O-CH ₃,-CH ₂CF ₃,-CHBrCH ₃,-CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂Cl ,-CH ₂-(2-thiophenyl) ,-CH ₂CH ₂CH ₂-(2-thiophenyl) ,-CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopentyl ,-CH ₂-cyclohexyl ,-CH ₂-(4-methylcyclohexyl) ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-suberyl ,-CH ₂-(the 2-cyclopentenyl ,-CH ₂CH ₂C ≡ CH ,-CH ₂CH ₂CH ₂C ≡ CH ,-CH ₂-phenyl ,-CH ₂-(2-fluorophenyl) ,-CH ₂-(3-fluorophenyl) or-CHBrCH ₃

In another embodiment of formula (I), R ²Be H.

In another embodiment of formula (I), R ²Be Br.

In another embodiment, R ¹And R ²The ring carbon atom that they connect in formula (I) forms cyclopentenyl or tetrahydrobenzene basic ring.

In another embodiment of formula (I), R ³For H ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃, cyclopropyl, cyclobutyl, cyclopentyl ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH=CH ₂Or-CH ₂-O-CH ₃

In another embodiment of formula (I), R ⁴For Cl ,-OH ,-O-CH ₃,-O-CH ₂-cyclopropyl ,-CH ₂-C ≡ C-CH ₃,-O-CH ₂-phenyl ,-O-CH (CH ₃)-phenyl ,-O-CH (CH ₂CH ₃)-phenyl ,-O-CH (CH ₂CH ₂CH ₃)-phenyl ,-O-CH (CH (CH ₃) ₂)-phenyl ,-O-CH (CH ₂CH=CH ₂)-phenyl ,-O-CH ₂-pyridyl ,-O-CH ₂-thiazolyl ,-O-CH (CH ₃)-thiazolyl ,-O-CH ₂-pyrimidyl ,-C (O)-O-CH ₃,-S (O ₂)-CH ₃,-S (O)-CH ₃,-S (O)-CH ₂CH ₃,-S (O)-CH (CH ₃) ₂,-S (O)-C (CH ₃) ₃,-S (O)-CH ₂-cyclopropyl ,-S (O)-CH ₂-phenyl ,-S (O)-CH (CH ₃)-phenyl ,-S (O)-N (R ¹¹) ₂,-S (O ₂)-N (R ¹¹) ₂,-S-CH ₂-CH=CH ₂,-N (H) cyclobutyl ,-N (H) phenyl ,-NH-NH-C (O)-O-CH ₃,-O-CH ₂-CH=CH ₂,-O-N=C (CH ₃) ₂Or-C (O)-CH ₃Wherein any one phenyl moiety all can not replace or is replaced by one or more Y groups that this paper defines in these groups, any one cyclobutyl moiety all can not replace or is replaced by one or more X groups that this paper defines in these groups, and any one pyridyl, thiazolyl or pyrimidyl part all can not replace or replaced by one or more Z groups that this paper defines in these groups.

In another embodiment of the compound of formula (I), R ⁵For H ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂-C (O)-phenyl ,-CH ₂-C (O)-OH ,-CH ₂-C (=N-O-CH ₃)-phenyl, cyclopropyl, cyclobutyl, cyclopentyl ,-CH ₂-C (O)-piperidyl ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃Or-CH ₂-CH=CH ₃, R wherein ⁵Described-CH ₂The phenyl of-C (O)-phenyl does not replace or is replaced R by the Y group that one or more this paper define ⁵Described cyclopropyl, described-CH ₂The cyclopropyl of-cyclopropyl, cyclobutyl, cyclopentyl or described-CH ₂The piperidyl of-C (O)-piperidyl does not replace or is replaced by the X group that one or more this paper define.

In another embodiment of the compound of formula (I), R ⁶For-OH, Cl ,-O-CH ₃,-O-CH ₂-cyclopropyl ,-O-CH ₂-CH=CH ₃,-O-CH ₂-phenyl ,-O-CH (CH ₃)-phenyl ,-O-CH (CH ₂CH ₃)-phenyl ,-O-CH (CH ₂CH ₂CH ₃)-phenyl ,-O-CH (CH (CH ₃) ₂)-phenyl ,-O-CH (CH ₂CH=CH ₂)-phenyl ,-O-CH ₂-pyridyl ,-O-CH ₂-thiazolyl ,-O-CH ₂-pyrimidyl and-N (H) cyclobutyl ,-N (H) phenyl ,-NH-NH-C (O)-O-CH ₃, R wherein ⁶Described-O-CH ₂-phenyl ,-O-CH (CH ₃)-phenyl ,-O-CH (CH ₂CH ₃)-phenyl ,-O-CH (CH ₂CH ₂CH ₃)-phenyl ,-O-CH (CH (CH ₃) ₂)-phenyl or-O-CH (CH ₂CH=CH ₂The phenyl of)-phenyl does not replace or is replaced R by the Y group that one or more this paper define ⁶Described-O-CH ₂-pyridyl ,-O-CH ₂-thiazolyl or-O-CH ₂The pyridyl of-pyrimidyl, thiazolyl or pyrimidyl do not replace or are replaced by the Z group that one or more this paper define.

In another embodiment of the compound of formula (I), each R ⁷Be independently H ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃, unsubstituted phenyl, the phenyl that is replaced by one or more Y groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-C (O)-CH ₃With-C (O)-phenyl.Perhaps, two radicals R ⁷The N atom that connects with them forms azetidine base (azetidinyl), pyrrolidyl, piperidyl, piperazinyl, morpholinyl, pyrrolidone-base (pyrrolidinonyl), triazolyl or pyrroles's basic ring.

In another embodiment of the compound of formula (I), R ⁸For-CH ₃, unsubstituted phenyl, the phenyl that is replaced by one or more Y groups, piperidyl and-OH.

In another embodiment of the compound of formula (I), R ⁹For-CH ₃,-CH ₂CH ₃,-CH (CH ₃) ₂,-C (CH ₃) ₃,-CH ₂-cyclopropyl ,-CH ₂-CH=CH ₂(allyl group) ,-CH ₂-phenyl and-CH (CH ₃)-phenyl.

In another embodiment of the compound of formula (I), R ¹⁰For H ,-CH ₂C ≡ CCH ₃,-CH ₂-cyclopropyl ,-CH ₂CH=CH ₂,-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH ₂-pyridyl ,-CH ₂-thiazolyl ,-CH (CH ₃)-thiazolyl ,-CH ₂-pyrimidyl ,-CH (CH ₂CH=CH ₂)-phenyl ,-CH (CH ₂CH ₂CH ₃)-phenyl, wherein R ¹⁰-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl and-CH (CH ₂CH ₂CH ₃The phenyl moiety of)-phenyl does not replace or replaced by one or more group Y, and is described-CH ₂-pyridyl ,-CH ₂-thiazolyl ,-CH (CH ₃)-thiazolyl ,-CH ₂The pyridyl of-pyrimidyl, thiazolyl and pyrimidyl part do not replace or are replaced by one or more group Z.

In another embodiment of the compound of formula (I), R ¹¹For H ,-CH ₃Or phenyl, wherein said phenyl does not replace or is replaced by one or more group Y.Perhaps, two radicals R ¹¹The N atom that connects with them forms azetidine base (azetidinyl), pyrrolidyl, piperidyl, piperazinyl, morpholinyl, pyrrolidone-base (pyrrolidinonyl), triazolyl or pyrroles's basic ring.

In another embodiment of the compound of formula (I), R ¹²For H ,-CH ₃,-CH ₂CH ₃Or unsubstituting biocides base or the pyridyl that replaced by one or more Z groups.

In another embodiment of the compound of formula (I), R ^aFor H or-CH ₃

In another embodiment of the compound of formula (I), R ^bFor H or-CH ₃

In another embodiment of the compound of formula (I), R ^aAnd R ^bAll be-CH ₃

In another embodiment of the compound of formula (I), R ^cFor H or-CH ₃

In another embodiment of the compound of formula (I), R ^dFor H ,-CH ₃Or-CH ₂-phenyl, wherein R ^dDescribed-CH ₂The phenyl moiety of-phenyl does not replace or is replaced by the Y group that one or more this paper define.

In another embodiment of the compound of formula (I), each X is independently selected from-CH ₃,-CF ₃, F, Br and Cl ,-O-CH ₃,-O-CF ₃,-CN ,-OH, phenyl and N-oxide compound;

In another embodiment of the compound of formula (I), each Y be independently selected from F, Cl, Br ,-CH ₃,-CF ₃,-O-CH ₃,-O-CF ₃,-CN ,-OH and phenyl; With

In another embodiment of the compound of formula (I), each Z is independently selected from-CH ₃,-CF ₃, F, Br and Cl ,-O-CH ₃,-O-CF ₃,-CN ,-OH, phenyl and N-oxide compound.

In yet another embodiment, compound of the present invention is selected from following formula or its drug acceptable salt, solvate, ester or tautomer:

In all embodiments of the present invention, when L is (f), R ², R ³And R ⁵When respectively doing for oneself H, R ¹Be not-CH ₃Those skilled in the art can recognize that the present invention does not comprise following compound or its tautomeric form:

The L part of formula of the present invention (I) can have any chemically stable orientation.That is to say that when L was (f), the compound of formula of the present invention (I) can comprise:

Or its salt, solvate, ester or tautomer.When L was (g), the compound of formula of the present invention (I) can comprise:

Or its salt, solvate, ester or tautomer.When L was (h), the compound of formula of the present invention (I) can comprise:

Or its salt, solvate, ester or tautomer.When L was (i), the compound of formula of the present invention (I) can comprise:

Or its salt, solvate, ester or tautomer.

The compound of formula (I) can be purified to the degree that is suitable as pharmaceutically active substance.That is to say, the compound of formula (I) can have 95wt% or higher purity (does not comprise adjuvant (adjuvant), as drug acceptable carrier, solvent etc., they can be used for the compound of formula (I) is mixed with the conventionally form that is fit to grant in the patient, as pill, capsule, IV solution etc.).Purity can be 97wt% or higher, or 99wt% or higher.The purifying compounds of formula (I) comprises the individual isomer with aforesaid 95wt% or higher, 97wt% or higher or 99wt% or higher purity.

Perhaps, the purifying compounds of formula (I) can comprise mixture of isomers, and every kind of isomer all has the structure of formula (I), and wherein impurity level (promptly not comprising compound or other pollutent of adjuvant as mentioned above) is 5wt% or following, 3wt% or following, or 1wt% or following.For example, the purifying compounds of formula (I) can be the isomeric mixtures of the compound of structure (I), and wherein the amount of two kinds of isomer is than for about 1: 1, and the total amount of two kinds of isomer is 95wt% or higher, 97wt% or higher or 99wt% or higher.

Can there be (for example, being acid amides or imino-ether) with their tautomeric form in compound or its salt, solvate, ester and the prodrug of formula (I).This paper considers that all these tautomeric forms are as a part of the present invention.For example, compound of the present invention comprises tautomeric form as shown below:

It is of equal value that this tautomeric form is considered to.

As mentioned with whole open in employed following term, except as otherwise noted, should be understood that to have following implication:

" Bn " refers to benzyl.

" BnBr " refers to bromotoluene.

" BnOH " refers to benzylalcohol.

" DCM " refers to methylene dichloride (CH ₂Cl ₂).

" DIAD " refers to the diisopropyl azo-2-carboxylic acid.

" DIEA " refers to N, the N-diisopropylethylamine.

" DMF " refers to dimethyl formamide.

" Et " refers to ethyl.

" EtO ₂" refer to diethyl ether.

" EtOAc " refers to vinyl acetic monomer.

" HATU " refers to O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylammonium ammonium hexafluorophosphate.

" HOAc " refers to acetate.

" IBMX " refers to 3-isobutyl-1-methylxanthine.

Between " m-CPBA " refers to-chloroperoxybenzoic acid.

" Me " nail base.

" MeOH " nail alcohol.

" NBS " refers to N-bromine succinimide.

" NEt ₃" refer to triethylamine.

" t-Bu " refers to the tertiary butyl.

" t-BuOK " refers to potassium tert.-butoxide.

" TFA " refers to trifluoroacetic acid.

" THF " refers to tetrahydrofuran (THF).

" TLC " refers to tlc.

" PMBOH " refers to 4-methoxyl group benzylalcohol.

" Prep TLC " refers to preparative thin layer chromatography.

" patient " comprises humans and animals.

" Mammals " refers to people and other Mammals.

" alkyl " refers to can be straight or branched and comprise about 1 aliphatic group to about 20 carbon atoms in chain.Preferred alkyl comprises about 1 to about 12 carbon atoms in chain.Preferred alkyl comprises about 1 to about 6 carbon atoms in chain.Side chain means that one or more low alkyl groups such as methyl, ethyl or propyl group are connected on the linear alkyl chain." low alkyl group " refers to have about 1 group to about 6 carbon atoms in can be the chain of straight or branched." alkyl " can not be substituted or randomly replaced by one or more identical or different substituting groups, each substituting group be independently selected from halogen, alkyl, aryl, cycloalkyl, cyano group, hydroxyl, alkoxyl group, alkylthio, amino ,-NH (alkyl) ,-NH (cycloalkyl) ,-N (alkyl) ₂, carboxyl and-C (O) O-alkyl.The non-limitative example of suitable alkyl comprises methyl, ethyl, n-propyl, sec.-propyl and the tertiary butyl.

" thiazolinyl " refers to comprise at least one carbon-to-carbon double bond and can be straight or branched and comprise about 2 aliphatic groups to about 15 carbon atoms in chain.Preferred thiazolinyl has about 2 to about 12 carbon atoms in chain; More preferably in chain, have about 2 to about 6 carbon atoms.Side chain means that one or more low alkyl groups such as methyl, ethyl or propyl group are connected on the straight-chain alkenyl chain." low-grade alkenyl " refers to have about 2 to about 6 carbon atoms in can be the chain of straight or branched." thiazolinyl " can not be substituted or randomly replaced by one or more identical or different substituting groups, each substituting group be independently selected from halogen, alkyl, aryl, cycloalkyl, cyano group, alkoxyl group and-S (alkyl).The non-limitative example of suitable thiazolinyl comprises vinyl, propenyl, n-butene base, 3-methyl but-2-ene base, positive pentenyl, octenyl and decene base.

" alkylidene group " refers to by removing the double functional group that hydrogen atom obtains from alkyl defined above.The non-limitative example of alkylidene group comprises methylene radical, ethylidene and propylidene.

" alkenylene " refers to by removing the double functional group that hydrogen atom obtains from thiazolinyl defined above.The non-limitative example of alkenylene comprises-CH=CH-,-C (CH ₃)=CH-and-CH=CHCH ₂-.

" alkylidene group-aryl " (or aryl-alkylidene group-) refers to aryl and alkylidene group group as previously described.Pass through alkylidene group with the bonding of parent fraction.Alkylene moiety can be bonded on one or more aryl moieties.Alkylidene group-aryl can comprise low-grade alkylidene.The non-limitative example of suitable alkylidene group-aryl comprises benzyl, 2-styroyl, 2,2-two styrenes and naphthyl methyl.

" alkynyl " refers to comprise at least one carbon-to-carbon triple bond and can be straight or branched and comprise about 2 aliphatic groups to about 15 carbon atoms in chain.Preferred alkynyl has about 2 to about 12 carbon atoms in chain; More preferably in chain, have about 2 to about 4 carbon atoms.Side chain means that one or more low alkyl groups such as methyl, ethyl or propyl group are connected on the straight-chain alkynyl chain." low-grade alkynyl " refers to have about 2 to about 6 carbon atoms in can be the chain of straight or branched.The non-limitative example of suitable alkynyl comprises ethynyl, proyl, 2-butyne base and 3-methyl butynyl." alkynyl " can not be substituted or randomly replaced by one or more identical or different substituting groups, and each substituting group is independently selected from alkyl, aryl and cycloalkyl.

" aryl " refers to comprise about 6 to about 14 carbon atoms, preferred about 6 fragrant monocycle or polycyclic systems to about 10 carbon atoms.Aryl can randomly be replaced by identical or different one or more " member ring systems substituting group " as defined herein.The non-limitative example of suitable aryl comprises phenyl and naphthyl.

" heteroaryl " refers to comprise about 5 to about 14 annular atomses, preferred about 5 fragrant monocycle or polycyclic systems to about 10 annular atomses, and wherein the one or more of annular atoms be carbon element in addition, as nitrogen, oxygen or sulphur, individually or jointly.Preferred heteroaryl comprises about 5 to about 6 annular atomses." heteroaryl " can randomly be replaced by identical or different one or more " member ring systems substituting group " as defined herein.Prefix azepine, oxa-or thia before the heteroaryl root name refer to that at least one nitrogen, oxygen or sulphur atom exist as annular atoms respectively.The nitrogen-atoms of heteroaryl can randomly be oxidized to corresponding N-oxide compound." heteroaryl " also can comprise the above-mentioned heteroaryl that is fused on the above-mentioned aryl.The non-limitative example of suitable heteroaryl comprises pyridyl, pyrazinyl, furyl, thienyl, pyrimidyl, pyridone (comprising the pyridone that N-replaces), different _ the azoles base, isothiazolyl, _ azoles base, thiazolyl, pyrazolyl, the furazan base, pyrryl, pyrazolyl, triazolyl, 1,2, the 4-thiadiazolyl group, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, the oxindole base, imidazo [1,2-a] pyridyl, imidazo [2,1-b] thiazolyl, benzo furazan base, indyl, azaindolyl, benzimidazolyl-, benzothienyl, quinolyl, imidazolyl, the thienopyridine base, quinazolyl, the Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, isoquinolyl, the benzo-aza indyl, 1,2, the 4-triazinyl, benzothiazolyl etc.Term " heteroaryl " also divides saturated heteroaryl moieties in the finger, as tetrahydro isoquinolyl, tetrahydric quinoline group etc.

" aralkyl " or " arylalkyl " refers to wherein aryl and alkyl aryl-alkyl-group as previously described.Preferred aralkyl comprises low alkyl group.The non-limitative example of suitable aralkyl comprises benzyl, 2-styroyl and naphthyl methyl.Pass through alkyl with the bonding of parent fraction.

" alkylaryl " refers to wherein alkyl and aryl alkyl-aryl-group as previously described.Preferred alkylaryl comprises low alkyl group.The non-limitative example of suitable alkylaryl is a tolyl.Pass through aryl with the bonding of parent fraction.

" cycloalkyl " refers to comprise about 3 to about 10 carbon atoms, preferred about 5 to the non-fragrance of about 10 carbon atoms singly or encircle member ring systems more.Preferred cycloalkyl ring comprises about 5 to about 7 annular atomses.Cycloalkyl can randomly be replaced by identical or different one or more " member ring systems substituting group " as defined herein.The non-limitative example of suitable monocyclic cycloalkyl comprises cyclopropyl, cyclopentyl, cyclohexyl, suberyl etc.The non-limitative example of suitable polycyclic naphthene base comprises 1-naphthalane base, norcamphane base (norbornyl), adamantyl etc.

" cycloalkylalkyl " refer to by moieties (top definition) be connected to parent nuclear as top defined cycloalkyl moiety.The non-limitative example of suitable cycloalkylalkyl comprises cyclohexyl methyl, adamantyl methyl etc.

" cycloalkenyl group " refers to comprise about 3 to about 10 carbon atoms, preferred about 5 to about 10 carbon atoms and the non-fragrance that comprises at least one carbon-to-carbon double bond singly or encircle member ring systems more.Preferred cyclenes basic ring comprises about 5 to about 7 annular atomses.Cycloalkenyl group can randomly be replaced by identical or different one or more " member ring systems substituting group " as defined herein.The non-limitative example of suitable monocycle cycloalkenyl group comprises cyclopentenyl, cyclohexenyl, ring heptan-butadienyl etc.The non-limitative example of suitable many ring cycloalkenyl groups is norbornene (norbornylenyl).

" cycloalkenyl alkyl " refer to by moieties (top qualification) be connected to parent nuclear as top defined cycloalkenyl group part.The non-limitative example of suitable cycloalkenyl alkyl comprises cyclopentenyl methyl, cyclohexenyl methyl etc.

" halogen " refers to fluorine, chlorine, bromine or iodine.Be preferably fluorine, chlorine and bromine.

" member ring systems substituting group " refers to be connected on fragrance or the non-aromatic ring system substituting group of available hydrogen (available) on the substituted ring system for example.The member ring systems substituting group can be identical or different, is selected from alkyl independently of one another; thiazolinyl; alkynyl; aryl; heteroaryl; aralkyl; alkylaryl; heteroaralkyl; the heteroaryl thiazolinyl; the heteroaryl alkynyl; miscellaneous alkyl aryl; hydroxyl; hydroxyalkyl; alkoxyl group; aryloxy; aralkoxy; acyl group; aroyl; halogen; nitro; cyano group; carboxyl; alkoxy carbonyl; aryloxycarbonyl; aromatic alkoxy carbonyl; alkyl sulphonyl; aryl sulfonyl; heteroarylsulfonyl; alkylthio; arylthio; heteroarylthio; aromatic alkylthio; assorted aromatic alkylthio; cycloalkyl; heterocyclic radical;-C (=N-CN)-NH ₂,-C (=NH)-NH ₂,-C (=NH)-NH (alkyl), Y ₁Y ₂N-, Y ₁Y ₂The N-alkyl-, Y ₁Y ₂NC (O)-, Y ₁Y ₂NSO ₂-and-SO ₂NY ₁Y ₂, Y wherein ₁And Y ₂Can be identical or different, and independently be selected from hydrogen, alkyl, aryl, cycloalkyl and aralkyl." member ring systems substituting group " also can refer to replace simultaneously on the member ring systems the single part of two available hydrogen (H on each carbon) on two contiguous carbon atoms.The example of this part for for example form methylene-dioxy with the lower section, ethylenedioxy ,-C (CH ₃) ₂-etc.:

With

" heteroarylalkyl " refer to by moieties (top definition) be connected to parent nuclear as heteroaryl moieties defined above.The non-limitative example of suitable heteroaryl comprises 2-pyridylmethyl, quinolyl methyl etc.

" heterocyclic radical " refer to comprise about 3 to about 10 annular atomses, preferred about 5 to the non-fragrant saturated mono ring of about 10 annular atomses or encircle member ring systems more, wherein the one or more atoms in the member ring systems are carbon element in addition, for example nitrogen, oxygen or sulphur, individually or jointly.In member ring systems, there are not adjacent oxygen and/or sulphur atom.Preferred heterocyclic radical comprises about 5 to about 6 annular atomses.Prefix azepine, oxa-or thia before the heterocyclic radical root name refer to that at least one nitrogen, oxygen or sulphur atom exist as annular atoms separately.Any-NH in the heterocyclic ring can protectedly exist, for example conduct-N (Boc) ,-N (CBz) ,-N (Tos) group etc.; This protection also is considered to a part of the present invention.Heterocyclic radical can randomly be replaced by identical or different one or more " member ring systems substituting group " as defined herein.The nitrogen of heterocyclic radical or sulphur atom can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.The non-limitative example of suitable monocyclic heterocycles basic ring comprises piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidyl, 1,4-dioxane base, tetrahydrofuran base, tetrahydro-thienyl, lactan, lactone etc." heterocyclic radical " also can refer to the single part (for example carbonyl) of two available hydrogen on the identical carbon atoms on the while substituted ring system.The example of this part is pyrrolidone (pyrrolidone):

" heterocyclic radical alkyl " refer to by moieties (top definition) be connected to parent nuclear as heterocyclic radical part defined above.The non-limitative example of suitable heterocyclic radical alkyl comprises piperidino methyl, piperazinyl methyl etc.

" heterocycloalkenyl " refer to comprise about 3 to about 10 annular atomses, preferred about 5 to the non-fragrant monocycle of about 10 annular atomses or encircle member ring systems more, wherein the one or more atoms in the member ring systems are the element beyond the carbon, for example nitrogen, oxygen or sulphur atom, individually or jointly, and its comprise at least one carbon-to-carbon double bond or the two keys of carbon-nitrogen.In member ring systems, there are not adjacent oxygen and/or sulphur atom.Preferred heterocycloalkenyl ring comprises about 5 to about 6 annular atomses.Prefix azepine, oxa-or thia before the heterocycloalkenyl root name refer to that at least one nitrogen, oxygen or sulphur atom exist as annular atoms separately.Heterocycloalkenyl can be randomly replaced by one or more member ring systems substituting groups, and wherein " member ring systems substituting group " as hereinbefore defined.The nitrogen of heterocycloalkenyl or sulphur atom can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.The non-limitative example of suitable heterocycloalkenyl comprises 1,2,3,4-tetrahydro pyridyl, 1,2-dihydropyridine base, 1,4-dihydropyridine base, 1,2,3,6-tetrahydro pyridyl, 1,4,5,6-tetrahydro-pyrimidine base, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, glyoxalidine base, dihydro _ azoles base, dihydro _ di azoly, dihydro-thiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuran base, fluorine dihydrofuran base, 7-oxabicyclo [2.2.1] heptenyl, dihydrobenzene sulfenyl, dihydro thiapyran base etc." heterocycloalkenyl " also can refer to the single part (for example carbonyl) of two available hydrogen on the identical carbon atoms on the while substituted ring system.The example of this part is pyrrolidone (pyrrolidinone):

" heterocycloalkenyl alkyl " refer to by moieties (above definition) be connected to parent nuclear as heterocycloalkenyl part defined above.

" cycloalkylidene " refers to by removing the double functional group that hydrogen atom obtains from cycloalkyl defined above.The non-limitative example of cycloalkylidene comprises

With

It should be noted that, contain in the heteroatomic member ring systems that the neighbour on the carbon atom of N, O or S does not have hydroxyl, and the neighbour and not have N or S group on another heteroatomic carbon of the present invention.Therefore, for example, encircling:

In, be not directly connected on the carbon of mark 2 and 5-OH.

Should also be noted that tautomeric form such as part:

With

Be considered to of equal value in some embodiments of the present invention.

" alkynyl alkyl " refers to wherein alkynyl and alkyl alkynyl-alkyl group as previously described.The alkynyl alkyl can comprise low-grade alkynyl and low alkyl group.With the bonding of parent fraction be to pass through alkyl.The non-limitative example of suitable alkynyl alkyl comprises the propargyl methyl.

" heteroaralkyl " refers to wherein heteroaryl and alkyl heteroaryl-alkyl as previously described.Preferred heteroaralkyl comprises low alkyl group.The non-limitative example of suitable aralkyl comprises pyridylmethyl and quinoline-3-ylmethyl.With the bonding of parent fraction be to pass through alkyl.

" hydroxyalkyl " refers to wherein alkyl HO-alkyl as previously described.Preferred hydroxyalkyl comprises low alkyl group.The non-limitative example of suitable hydroxyalkyl comprises hydroxymethyl and 2-hydroxyethyl.

" acyl group " refer to H-C (O)-, alkyl-C (O)-or cycloalkyl-C (O)-, wherein various groups are as previously described.With the bonding of parent fraction be to pass through carbonyl.Preferred acyl group comprises low alkyl group.The non-limitative example of suitable acyl group comprises formyl radical, ethanoyl and propionyl.

" aroyl " refers to aryl-C (O)-group, and wherein aryl as previously described.With the bonding of parent fraction be to pass through carbonyl.The non-limitative example of proper group comprises benzoyl and 1-naphthoyl base.

" alkoxyl group " refers to alkyl-O-group, and wherein alkyl as previously described.The non-limitative example of suitable alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy and n-butoxy.With the bonding of parent fraction be by ether oxygen.

" aryloxy " refers to aryl-O-, and wherein aryl as previously described.The non-limitative example of suitable aryloxy comprises phenoxy group and naphthyloxy.With the bonding of parent fraction be by ether oxygen.

" aralkoxy " refers to aralkyl-O-, and wherein aralkyl as previously described.The non-limitative example of suitable aralkoxy comprises benzyloxy and 1-or 2-naphthalene methoxyl group.With the bonding of parent fraction be by ether oxygen.

" alkylthio " refers to alkyl-S-, and wherein alkyl as previously described.The non-limitative example of suitable alkylthio comprises methylthio group and ethylmercapto group.With the bonding of parent fraction be to pass through sulphur.

" arylthio " refers to aryl-S-, and wherein aryl as previously described.The non-limitative example of suitable arylthio comprises thiophenyl and naphthalene sulfenyl.With the bonding of parent fraction be to pass through sulphur.

" aromatic alkylthio " refers to aralkyl-S-, and wherein aralkyl as previously described.The non-limitative example of suitable aromatic alkylthio is a benzylthio-.With the bonding of parent fraction be to pass through sulphur.

" alkoxy carbonyl " refers to alkyl-O-CO-.The non-limitative example of suitable alkoxy carbonyl comprises methoxycarbonyl and ethoxy carbonyl.With the bonding of parent fraction be to pass through carbonyl.

" aryloxycarbonyl " refer to aryl-O-C (O)-.The non-limitative example of suitable aryloxycarbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.With the bonding of parent fraction be to pass through carbonyl.

" aromatic alkoxy carbonyl " refer to aralkyl-O-C (O)-.The non-limitative example of suitable aromatic alkoxy carbonyl is a benzyloxycarbonyl.With the bonding of parent fraction be to pass through carbonyl.

" alkyl sulphonyl " refers to alkyl-S (O ₂)-.Preferred group is those of low alkyl group for alkyl wherein.With the bonding of parent fraction be to pass through alkylsulfonyl.

" aryl sulfonyl " refers to aryl-S (O ₂)-.With the bonding of parent fraction be to pass through alkylsulfonyl.

The selecteed group that indicates of one or more hydrogen on term " replacement " the expression specified atom replaces, and condition is the normal valence state that is no more than specified atom under environment of living in, and replaces the generation stable compound.Just allow this class combination when having only the combination results stable compound of substituting group and/or variable." stable compound " or " rock steady structure " is meant to be secured to is enough to tolerate the compound that is separated to useful purity and is mixed with effective curative from reaction mixture.

Term " the optional replacement " refers to the optional replacement with concrete group, free radical or part.

The term of compound " purifying ", " purified form " or " separation and purification form " are meant the physical condition of described compound after separating from building-up process (for example from reaction mixture) or natural source or its combination.Therefore, the term of compound " purifying ", " purified form " or " separation and purification form " are meant that described compound is enough to the physical condition that characterizes with standard analytical techniques described herein or well known to those skilled in the art obtaining back and purity from purge process described herein or well known to those skilled in the art (for example chromatographic separation, recrystallization etc.).

Should also be noted that any carbon among text, figure, embodiment and the Biao of this paper and have and suppose that all having enough hydrogen atom numbers satisfies valence state less than the heteroatoms of full price attitude.

When the functional group in the compound is named as " protected ", this means the modified form of getting rid of undesired side reaction when group is in compound and reacts at place, protected position.Suitable blocking group is known to those of ordinary skills, and Protective Groups in organic Synthesis (1991) such as reference standard textbook such as T.W.Greene, and Wiley learns among the New York.

As any variable (for example aryl, heterocycle, R ²Deng) occur surpassing once at any composition or in formula I, the definition when then it occurs at every turn is independent of the definition of its each another one appearance place.

Term used herein " composition " is intended to comprise the product of the appointment composition that comprises specified amount, and any product that is obtained by the combination of the appointment composition of specified amount directly or indirectly.

This paper also considers the prodrug and the solvate of The compounds of this invention.The discussion of prodrug is provided at T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) A.C.S.Symposium Series, 14, with Bioreversible Carriers in Drug Design, (1987) Edward B.Roche, ed., among the American Pharmaceutical Association and PergamonPress.Term " prodrug " refers to change in vivo the compound of production (I) or the compound of its drug acceptable salt, hydrate or solvate (for example prodrug (drugprecursor)).(for example by metabolism or chemical process) can take place by various mechanism in transformation, for example by the hydrolysis in the blood.The discussion that prodrug uses is provided at T.Higuchi and W.Stella, " Pro-drugs as Novel Delivery Systems " A.C.S.SymposiumSeries, the 14th volume, with Bioreversible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press is in 1987.

For example, if drug acceptable salt, hydrate or the solvate of the compound of formula (I) or compound comprise carboxylic acid functional, then prodrug can comprise the ester with the hydrogen atom formation of replacement acidic groups such as following these groups: (C ₁-C ₈) alkyl, (C ₂-C ₁₂) alkanoyloxymethyl, 1-(alkanoyloxy) ethyl with 4-9 carbon atom, 1-methyl isophthalic acid-(alkanoyloxy) ethyl with 5-10 carbon atom, alkoxyl group carbonyl oxy-methyl with 3-6 carbon atom, 1-(alkoxyl group carbonyl oxygen base) ethyl with 4-7 carbon atom, 1-methyl isophthalic acid-(alkoxyl group carbonyl oxygen base) ethyl with 5-8 carbon atom, N-(alkoxy carbonyl) amino methyl with 3-9 carbon atom, 1-(N-(alkoxy carbonyl) amino) ethyl with 4-10 carbon atom, 3-phthalidyl (3-phthalidyl), 4-crotonolactonyl, gamma-butyrolactone-4-base, two-N, N-(C ₁-C ₂) alkylamino (C ₂-C ₃) alkyl (as the beta-dimethyl-amino-ethyl), formamyl-(C ₁-C ₂) alkyl, N, N-two (C ₁-C ₂) alkyl-carbamoyl-(C ₁-C ₂) alkyl and piperidines also-(piperidino-), tetramethyleneimine also-(pyrrolidino-) or morpholine (C also ₂-C ₃) alkyl etc.

Similarly, if the compound of formula (I) comprises alcohol functional group, then prodrug can form by the hydrogen atom that replaces alcohol radicals with for example following these groups of group: (C ₁-C ₆) alkanoyloxymethyl, 1-((C ₁-C ₆) alkanoyloxy) ethyl, 1-methyl isophthalic acid-((C ₁-C ₆) alkanoyloxy) ethyl, (C ₁-C ₆) alkoxyl group carbonyl oxy-methyl, N-(C ₁-C ₆) alkoxycarbonyl amino methyl, succinyl, (C ₁-C ₆) alkyloyl, alpha-amino group (C ₁-C ₄) alkyl, aroyl and alpha-amino group acyl group or alpha-amino group acyl-alpha--aminoacyl, wherein each alpha-amino group acyl group independently is selected from naturally occurring L-amino acid, P (O) (OH) ₂,-P (O) (O (C ₁-C ₆) alkyl) ₂Or glycosyl (removing the group that the hydroxyl of the carbohydrate of hemiacetal form obtains) etc.

If the compound of formula (I) comprises amine functional group, then prodrug can form by come the hydrogen atom in the substituted amido group with group such as following these groups: R-carbonyl, RO-carbonyl, NRR '-carbonyl, wherein R and R ' are (C independently of one another ₁-C ₁₀) alkyl, (C ₃-C ₇) cycloalkyl, benzyl, or the R-carbonyl be natural alpha-amino group acyl group or natural alpha-amino group acyl group ,-C (OH) C (O) OY ¹, Y wherein ¹Be H, (C ₁-C ₆) alkyl or benzyl ,-C (OY ²) Y ³, Y wherein ²Be (C ₁-C ₄) alkyl and Y ³Be (C ₁-C ₆) alkyl, carboxyl (C ₁-C ₆) alkyl, amino (C ₁-C ₄) alkyl or list-N-or two-N, N-(C ₁-C ₆) the alkylamino alkyl ,-C (Y ⁴) Y ⁵, Y wherein ⁴Be H or methyl, Y ⁵Be list-N-or two-N, N-(C ₁-C ₆) alkylamino morpholine subbase, piperidines-1-base or tetramethyleneimine-1-base etc.

One or more compounds of the present invention can and have the medicine acceptable solvent with the non-solvent form, and as the solvation form existence of water, ethanol etc., the present invention is intended to comprise solvation and two kinds of forms of non-solventization." solvate " refers to the physical bond of compound of the present invention and one or more solvent molecules.This physical bond relates to ion and covalent linkage, comprises the various degree of hydrogen bond.In some cases, solvate can separate, for example, and when one or more solvent molecules are attached in the lattice of crystalline solid." solvate " comprises solution phase and separable solvate.The non-limitative example of suitable solvate comprises ethylate, methylate etc." hydrate " is H for solvent molecule wherein ₂The solvate of O.

One or more compounds of the present invention can randomly be transformed into solvate.The preparation of solvate is generally known.Therefore, for example, J.Pharmaceutical Sci such as M.Caira, 93 (3), 601-611 (2004) has described in ethyl acetate and the solvate that is prepared antimycotic fluconazole by water.E.C.van Tonder etc., AAPS PharmSciTech., 5 (1), paper 12 (2004) and A.L Bingham etc., Chem.Commun., 603-604 (2001) have described the similar preparation of solvate, half solvate, hydrate etc.Typical non-limiting process comprises: dissolving compound of the present invention and to be enough to form crystalline speed cooling solution, then by the standard method fractional crystallization in the required solvent (organic solvent or water or its mixture) of the aequum that is higher than envrionment temperature.There is solvent (or water) in analytical technology such as the crystal of I.R. spectrum demonstration as solvate (or hydrate).

" significant quantity " or " treatment significant quantity " is used to describe compound of the present invention or composition can effectively suppress the amount that therefore above-mentioned disease also produces required treatment, improvement, inhibition or preventive effect.

The compound of formula I can form salt, and these salt also within the scope of the invention.This paper is believed to comprise to the mentioning of its salt, except as otherwise noted mentioning of formula I compound.Term used herein " salt " expression and inorganic and/or acid salt that organic acid forms and with subsalt inorganic and/or that organic bases forms.In addition, when the compound of formula I comprise basic moiety as but be not limited to pyridine or imidazoles and acidic moiety as but when being not limited to carboxylic acid, can forming zwitter-ion (" inner salt "), and be included in term used herein " salt " scope.It is preferred that medicine can be accepted (promptly nontoxic, physiology on accept) salt, but other salt also is useful.For example, compound that can be by making formula I and a certain amount of as equivalent acid or alkali in medium such as salt are can be sedimentary the sort of or in water medium, react the salt that freeze-drying then forms formula I compound.

Typical acid salt comprises acetate, ascorbate salt, benzoate, benzene sulfonate, hydrosulfate, borate, butyrates, Citrate trianion, camphorate, camsilate, fumarate, hydrochloride, hydrobromate, hydriodate, lactic acid salt, maleate, mesylate, naphthalenesulfonate, nitrate, oxalate, phosphoric acid salt, propionic salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate (being also referred to as tosylate) etc.In addition, for example, P.Stahl etc., Camille G. (eds.) Handbook of PharmaceuticalSalts.Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S.Berge etc., Journal ofPharmaceutical Sciences (1977) 66 (1) 1-19; P.Gould, International J.of Pharmaceutics (1986) 33 201-217; Anderson etc., ThePractice of Medicinal Chemistry (1996), Academic Press, New York; With at The Orange Book (Food﹠amp; Drug Administration, Washington, D.C. is on their website) in the acid that is considered to usually to be fit to by the useful salt of alkaline drug compound formation medicine has been discussed.This paper introduces these disclosures as a reference.

Typical subsalt comprise ammonium salt, an alkali metal salt such as sodium, lithium and sylvite, alkaline earth salt such as calcium and magnesium salts, with organic bases (for example organic amine) as the salt of dicyclohexyl amine, TERTIARY BUTYL AMINE with the salt of amino acid such as arginine, Methionin etc.Available reagent such as low alkyl group halogen (for example methyl, ethyl and Butyryl Chloride, bromine and iodine), dialkyl sulfate (for example dimethyl, diethyl and dibutyl sulfide hydrochlorate), long-chain halogenide (for example decyl, lauryl and stearyl chloride, bromine and iodine), aralkyl halogen (for example benzyl and phenethyl bromide) and some other next quaternized alkaline nitrogen-containing group.

All these class acid salt and subsalt all are the drug acceptable salt in the scope of the invention, and all acid salt and subsalt all are considered to be equivalent to the free form that is used for respective compound of the present invention.

The medicine acceptable ester of The compounds of this invention comprises following group: the carboxylicesters that (1) obtains by esterified hydroxy groups; wherein the non-carbonyl moiety of the carboxylic moiety of ester grouping (for example is selected from the straight or branched alkyl; ethanoyl, n-propyl, the tertiary butyl or normal-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example benzyl), aryloxy alkyl (for example phenoxymethyl), aryl be (for example randomly by for example halogen, C _1-4Alkyl or C _1-4Alkoxyl group or the amino phenyl that replaces); (2) sulphonate is as alkyl-or aralkyl alkylsulfonyl (for example methylsulfonyl); (3) amino acid ester (for example, L-valyl or L-isoleucyl); (4) phosphonic acid ester and (5) single, two or triguaiacyl phosphate.Available for example C _1-20Alcohol or its reactive derivative or with 2,3-two (C _6-24) the further esterification phosphoric acid ester of acylglycerol.

Can there be (for example, as acid amides or imido ether) with their tautomeric form in the compound of formula I and its salt, solvate, ester and prodrug.Consider that herein all these tautomeric forms are as a part of the present invention.

The compound of formula (I) can comprise asymmetric or chiral centre, therefore, can exist with different stereoisomeric forms in any ratio.All stereoisomeric forms in any ratio of the compound of formula (I) and their mixture comprise that racemic mixture all constitutes a part of the present invention.In addition, the present invention includes all geometry and positional isomerss.For example, if the compound of formula (I) is introduced two keys or condensed ring, then cis and trans two kinds of forms and mixture are included in the scope of the present invention.

Can as physical chemistry difference the diastereo-isomerism mixture separation be become independent diastereomer by method well known to those skilled in the art by chromatography and/or the independent diastereomer of fractional crystallization basis.By the enantiomerism mixture being changed into the diastereo-isomerism mixture, separates diastereomer and diastereomer that will be independent and transform the corresponding pure enantiomer of (for example hydrolysis) one-tenth and separate enantiomer with the reaction of suitable optically-active compound (for example, chiral auxiliary(reagent) such as chiral alcohol or Mosher chloride of acid).In addition, some compounds of formula (I) can be atropisomer (for example biaryl of Qu Daiing) and are considered to a part of the present invention.Also can utilize chirality HPLC post to separate enantiomer.

The compound of formula (I) also can exist with different tautomeric forms, and all this forms all comprise within the scope of the invention.In addition, for example, all keto-enols of compound and imines-enamine form is also included among the present invention.

All steric isomers (for example geometrical isomer, optical isomer etc.) of The compounds of this invention (comprising those salt, solvate, ester and the prodrug of compound and salt, solvate and the ester of prodrug), as existing owing to the asymmetric carbon on the various substituting groups those, comprise that enantiomerism form (itself even exist), rotational isomeric form, atropisomer and diastereo-isomerism form comprise all that within the scope of the invention these are positional isomers (as 4-pyridyl and 3-pyridyl) when not having asymmetric carbon.(for example, if the compound of formula (I) is introduced two keys or condensed ring, then cis-and trans-form and mixture all comprise within the scope of the invention.In addition, for example, all keto-enols of compound and imines-enamine form is also included among the present invention).

The independent steric isomer of compound of the present invention can for example not contain other isomer substantially, or can be used as racemic compound or the steric isomer of other or other selections with all mixes.Chiral centre of the present invention can have the S or the R configuration of IUPAC 1974 Recommendations definition.The use of term " salt ", " solvate ", " ester ", " prodrug " etc. is intended to salt, solvate, ester and the prodrug that equivalence is applicable to enantiomer, steric isomer, rotational isomer, tautomer, positional isomers, racemoid or the prodrug of The compounds of this invention.

The present invention also comprises isotope-labeled The compounds of this invention, and they are identical with those compounds described herein, except one or more atoms are different from atomic mass that nature exists usually by nucleidic mass or total mass number or the atom of total mass number substitutes.The isotopic example that can be attached to compound of the present invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.

Some isotope-labeled compounds of formula (I) (for example, are used ³H and ¹⁴Those of C mark) be used for compound and/or matrix organization's distributional analysis.Contain tritium (promptly ³H) and carbon-14 (promptly ¹⁴C) isotropic substance is especially preferred because they are easy to prepare and detect.In addition, higher isotope such as deuterium are (promptly ²H) replacement may provide some treatment benefit owing to bigger metabolic stability (for example the transformation period increases or the minimizing of dosage demand in the body), and is preferred in some cases therefore.The isotope-labeled compound of formula (I) usually can disclosed those process prepares among synoptic diagram hereinafter and/or the embodiment according to being similar to, and replaces the heterotope labelled reagent with suitable isotope-labeled reagent.

The polycrystalline form of salt, solvate, ester and the prodrug of the compound of formula I and formula I compound is included in the present invention.

Term " pharmaceutical composition " also be used to comprise powder composition (bulk composition) and discrete dosages unit (individual dosage unit) both, they all comprise more than one (for example two kinds) pharmaceutically active agents such as compound of the present invention and are selected from additional medicaments and any pharmaceutical inert vehicle of additional medicaments tabulation described herein.Powder composition and each discrete dosages unit all can comprise above-mentioned " more than one pharmaceutically active agents " of fixed amount.Powder composition is not for also forming the unitary material of discrete dosages.Exemplary dosage device is oral dosage unit such as tablet, pill etc.Similarly, grant above-mentioned powder composition and discrete dosages unit described herein also comprising by the method for granting medicine composite for curing patient of the present invention.

Compound or its drug acceptable salt, solvate or ester according to formula of the present invention (I) have pharmacological property; Especially the compound of formula (I) can be nicotinic acid receptor agonists.

According to the compound of formula of the present invention (I) or its drug acceptable salt, solvate or ester are used for the treatment of disease or illness comprises hyperlipemia and metabolic syndrome.

Can be with any suitable form for example separately or in pharmaceutical composition, unite compound or its drug acceptable salt, solvate or the ester of the formula of granting (I) with drug acceptable carrier, vehicle or thinner according to the standard drug way.Can be oral or parenteral grant compound or its drug acceptable salt, solvate or the ester of formula (I), comprise intravenously, intramuscular, intraperitoneal, subcutaneous, rectum or topical approach, if or select like this, by uniting one or more aforesaid methods.

Comprise that at least a compound of formula (I) or the pharmaceutical composition of its drug acceptable salt, solvate, ester or tautomer can be the form that is fit to oral administration, for example, but tablet, tablet, capsule, lozenge, water-based or oil-based suspension dispersed powders or particle, emulsion, syrup or elixir.Oral compositions can prepare by the pharmaceutical methods of any routine, and also can comprise sweeting agent, perfume compound, tinting material and sanitas.

Can and want sanatory severity to determine to grant patient's the compound of formula (I) or the amount of its drug acceptable salt, solvate, ester or tautomer by the doctor according to patient's age, body weight and reaction.For example, the amount of granting patient's formula I compound or its drug acceptable salt, solvate, ester or tautomer can be about 0.1mg/kg body weight every day to about 60mg/kg/d, and preferably about 0.5mg/kg/d arrives about 40mg/kg/d.

The compound of formula (I) or its drug acceptable salt, solvate or ester also can with other curative Combined Preparation.For example, one or more compounds of formula (I) or its drug acceptable salt; solvate or ester can be with being selected from one or more following additional activity composition administrations: the azetidinone compounds that hydroxyl replaces; the 'beta '-lactam compounds that replaces; HMG CoA reductase inhibiter compounds; HMG CoA synthetase inhibitors; the squalene synthetic inhibitor; the squalene epoxidase inhibitor; the sterol biosynthesis inhibitor; nicotinic acid derivates; bile acid chelating agent; inorganic cholesterol sequestrant; AcylCoA: cholesterol O-inhibitors; cholestery ester transfer protein inhibitors; the fish oil that contains omega-3 fatty acid; water-soluble fiber; the fatty acid ester of plant alkanol and/or plant alkanol; antioxidant; the PPAR alfa agonists; PPAR γ-agonist; the FXR receptor modulators; the lxr receptor agonist; the lipoprotein synthetic inhibitor; the renin angiotensin inhibitor; microsome tri-glyceride transporter inhibitors; the bile acide cell reabsorption inhibitor; the PPAR delta agonists; the tri-glyceride synthetic inhibitor; the squalene epoxidase inhibitor; low density lipoprotein receptor inductor or activator; anticoagulant; 5-LO or FLAP inhibitor; PPAR δ partial agonist; nicotinic acid or nicotinic acid receptor agonists; the 5HT transporter inhibitors; the NE transporter inhibitors; CB ₁Antagonists/inverse agonists, ghrelin antagonist, H ₃Antagonists/inverse agonists; the MCH1R antagonist; the MCH2R agonist/antagonist; the NPY1 antagonist; the NPY5 antagonist; the NPY2 agonist; the NPY4 agonist; the mGluR5 antagonist; leptin; the leptin agonist/modulator; the leptin derivative; opioid antagonists; increase food factor acceptor antagonist; the BRS3 agonist; the CCK-A agonist; CNTF; the CNTF derivative; the CNTF agonist/modulator; the 5HT2c agonist; the Mc4r agonist; monoamine reuptake inhibitors; the serotonin reuptake inhibitor; the GLP-1 agonist; PHENTERMINE; topiramate; phytopharm compound 57; ghrelin antibody; the Mc3r agonist; the ACC inhibitor; β 3 agonists; the DGAT1 inhibitor; the DGAT2 inhibitor; the FAS inhibitor; the PDE inhibitor; the Triiodothyronine beta-agonists; the UCP-1 activator; the UCP-2 activator; the UCP-3 activator; acyl group oestrogenic hormon; glucocorticoid agonists/antagonist; 11 β HSD-1 inhibitor; the SCD-1 inhibitor; lipase inhibitor; the fatty acid transport protein inhibitor; the dicarboxylic ester transporter inhibitors; the glucose transporter inhibitor; the phosphoric acid ester transporter inhibitors; antidiabetic drug; antihypertensive drug; anti-lipid unusual medicine; the DP receptor antagonist; apo-B secretion/microsome tri-glyceride transfer protein (apo-B/MTP) inhibitor; the sympathomimetic nerve agonist; dopamine agonist; the melanotropin receptor analogs; the melanochrome concentrating hormone antagonists; lepton; the galanin receptor antagonist; the bombesin agonist; neuropeptide-γ antagonist; thyromimetic; dehydroepiandrosterone; the dehydroepiandrosterone analogue; the conjugated protein antagonist of urocortin; glucagon-like peptide-1 receptor stimulant; people agouti associated protein (AGRP); neuromedin U receptor stimulant; the norepinephrine energy anorexigenic; appetite-inhibiting agent; the hormone-sensitive lipase antagonist; the MSH-receptor analogs; alpha-glucosidase inhibitor; the contrary cholesterol transport inhibitor of apo A1 milano; fatty acid binding protein inhibitor (FABP) and fatty acid transport protein inhibitor (FATP).

With nicotinic acid receptor agonists of the present invention unite azetidinone compounds (azetidinone) that the hydroxyl that uses replaces and replacement 'beta '-lactam compounds non-limitative example as United States Patent (USP) 5767115,5624920,5668990,5656624 and 5688787,5756470, U.S. Patent application 2002/0137690 and 2002/0137689 and PCT patent application WO2002/066464 in those disclosed, this paper introduces each as a reference in full.Preferred azetidinone compounds is ezetimibe (ezetimibe, for example ZETIA that can obtain from Schering-PloughCorporation ^_).

The non-limitative example of uniting the HMG CoA reductase inhibiter compounds that uses with nicotinic acid receptor agonists of the present invention (for example can be from Merck﹠amp as lovastatin; Co. the MEVACOR that obtains ^_), Simvastatin (for example can be from Merck﹠amp; Co. the ZOCOR that obtains ^_), the Pravastatin (PRAVACHOL that can obtain from Bristol Meyers Squibb for example ^_), atorvastatin, fluvastatin, Cerivastatin, Cl-981, upright his spit of fland (the rivastatin) (7-(4-fluorophenyl)-2 that cuts down, 6-di-isopropyl-5-methoxymethyl pyridin-3-yl) ZD-4522 (CRESTOR of AstraZeneca Pharmaceuticals-3,5-dihydroxyl-6-enanthic acid sodium), ^_), pitavastatin (as the NK-104 of Japanese Negma Kowa).

The non-limitative example of uniting the HMG CoA synthetase inhibitors compound of use with nicotinic acid receptor agonists of the present invention is for example L-659,699 ((E, E)-and 11-[3 ' R-(hydroxyl-methyl)-4 '-oxygen-2 ' R-oxetanyl]-3,5,7R-trimethylammonium-2,4-undecandienoic acid (undecadienoicacid).

The non-limitative example of uniting the squalene synthetic inhibitor of use with nicotinic acid receptor agonists of the present invention is for example squalestatin 1 (squalestatin-1).

The non-limitative example of uniting the squalene epoxidase inhibitor of use with nicotinic acid receptor agonists of the present invention is for example NB-598 ((E)-N-ethyl-N-(6, the 6-dimethyl-2-hepten-4-ynyl)-3-[(3,3 '-two sulphur benzene-5-yl) methoxyl group] benzene-methylamine hydrochloride).

The non-limitative example of uniting the sterol biosynthesis inhibitor of use with nicotinic acid receptor agonists of the present invention is for example DMP-565.

The non-limitative example of uniting the nicotinic acid derivates (for example comprise the compound of pyridine-3-carboxylic acid ester structure or pyrazine-2-carboxylicesters structure, comprise sour form, salt, ester, zwitter-ion and tautomer) of use with nicotinic acid receptor agonists of the present invention is pentaerythritol tetranicotinate, nicofuranose and Olbetam (5-methylpyrazine-2-carboxylic acid 4-oxide compound).

(styrene diethylene benzene copoly mer that comprises quaternary ammonium cation group that can conjugated bile acid is as the QUESTRAN that can obtain from Bristol-Myers Squibb as QUESTRAN for the non-limitative example of uniting the bile acid chelating agent that uses with nicotinic acid receptor agonists of the present invention ^_Or QUESTRAN LIGHT ^_QUESTRAN), (Diethylenetriamine and 1-chloro-2, the multipolymer of 3-propylene oxide is as the COLESTID that can obtain from Pharmacia for colestipol ^_Tablet), the hydrochloric acid colesevelam is (as the WelChol that can obtain from Sankyo ^_Tablet (with epichlorohydrin cross-linked and with 1-bromo-decane and (6-bromine hexyl)-trimethylammonium bromide alkylating poly-(hydrochloric acid allylamine)), soluble derivative be as 3,3-ioene, N-(cycloalkyl) alkylamine and Poliglusam (poliglusam), insoluble quaternized polystyrene, saponins and their mixture.

The non-limitative example of uniting the inorganic cholesterol sequestrant that uses with nicotinic acid receptor agonists of the present invention adds montmorillonitic clay, aluminium hydroxide and lime carbonate antacid as bismuth salicylate.

Unite the acyl-CoA that uses with nicotinic acid receptor agonists of the present invention: the non-limitative example of cholesterol O-acyltransferase (" ACAT ") inhibitor is avasimibe ([[2,4,6-three (1-methylethyl) phenyl] ethanoyl] thionamic acid, 2, two (1-methylethyl) phenylesters of 6-, be called Cl-1011 in the past), HL-004, (N-(2 for lecimibide (DuP-128) and CL-277082, the 4-difluorophenyl)-N-[[4-(2, the 2-dimethyl propyl) phenyl] methyl]-N-heptyl urea), with " Current; New and Future Treatments inDyslipidaemia and Atherosclerosis " such as P.Chang, Drugs 2000 Jul; 60 (1); The compound of describing among the 55-93, this paper are introduced it as a reference.

The non-limitative example of uniting cholesteryl ester transfer protein (" the CETP ") inhibitor that uses with nicotinic acid receptor agonists of the present invention is PCT patent application WO 00/38721, United States Patent (USP) 6,147,090,6,958,346,6,924,313,6,906,082,6,861,561,6,803,388,6,794,396,6,787,570,6,753,346,6,723,752,6,723,753,6,710,089,6,699,898,6,696,472,6,696,435,6,683,113,5,519,001,5,512,548,6,410,022,6,426,365,6,448,295,6,387,929,6,683,099,6,677,382,6,677,380,6,677,379,6,677,375,6,677,353,6,677,341,6,605,624,6,586,433,6,451,830,6,451,823,6,462,092,6,458,849,6,458,803,6,455,519,6,583,183,6,562,976,6,555,113,6,544,974,6,521,607,6,489,366,6,482,862,6,479,552,6,476,075,6,476, those disclosed in 057 and 6,897,317, this paper induces one each as a reference; " Substituted 1,3,5-Triazines As Cholesteral Ester Transfer ProteinInhibitors " such as Yan Xia, Bioorganic﹠amp; Medicinal Chemistry Letters, vol.6, No.7,1996, the compound of describing in the 919-922 page or leaf, this paper is incorporated herein by reference; S.Coval etc. " Wiedendiol-A and-B, Cholesteryl Ester Transfer Protein InhibitorsFrom The Marine Sponge Xestosponga Wiedenmayeri ", Bioorganic﹠amp; Medicinal Chemistry Letter, vol.5, No.6, the 605-610 page or leaf, the natural product of describing in 1995, this paper is incorporated herein by reference; J.A m.Chem.Soc such as Barrett, 188, the compound of describing among the 7863-63 (1996), this paper is incorporated herein by reference; J.Am.Chem.Soc such as Kuo, 117, the compound of describing among the 10629-34 (1995), this paper is incorporated herein by reference; Bioorg.Med.Chem.Lett. such as Pietzonka, 6, the compound of describing among the 1951-54 (1996), this paper is incorporated herein by reference; J.Antibiotics such as Lee, 49, the compound of describing among the 693-96 (1996), this paper is incorporated herein by reference; Lipids such as Busch, 25,216-220, the compound of describing in (1990), this paper is incorporated herein by reference; Morton and Zilversmit J.Lipid Res., 35, the compound of describing among the 836-47 (1982), this paper is incorporated herein by reference; Biochem.Biophys.Res.Comm. such as Connolly, 223, the compound of describing among the 42-47 (1996), this paper is incorporated herein by reference; Lipids such as Bisgaier, 29, the compound of describing among the 811-8 (1994), this paper is incorporated herein by reference; The compound of describing among the EP 818448, this paper is incorporated herein by reference; The compound of describing among the JP 10287662, this paper is incorporated herein by reference; The compound of describing among PCT application WO 98/35937, WO 9914174, WO 9839299 and the WO 9914215, this paper introduces each as a reference; EP application EP 796846, EP801060,818448 and 818197 compound, this paper introduces each as a reference; The probucol or derivatives thereof, as United States Patent (USP) 6,121, disclosed AGI-1067 and other derivative in 319 and 6,147,250, this paper is incorporated herein by reference; Low-density lipoprotein (LDL) receptor activators such as HOE-402, active imidazolidyl-the pyrimidine derivatives of a kind of direct stimulation ldl receptor, be described in " Hypolipidemic activity of HOE-402 is Mediatedby Stimulation of the LDL Receptor Pathway " such as M.Huettinger, Arterioscler.Thromb.1993; Among the 13:1005-12, this paper is incorporated herein by reference; 4-carboxyamino-2-replaces-1,2,3, the 4-tetrahydroquinoline, and for example torcetrapib is described in (this paper introduces each as a reference) among WO 00/017164, WO00/017166, WO 00/140190, WO 00/213797 and the WO 2005/033082.Torcetrapib can unite (WO 00/213797, and WO 2004/056358, WO 2004/056359 and WO2005/011634) with HMG-CoA reductase inhibitor such as atorvastatin.

The non-limitative example of uniting the fish oil that contains omega-3 fatty acid that uses with nicotinic acid receptor agonists of the present invention is 3-PUFA.

The non-limitative example of uniting the water-soluble fiber that uses with nicotinic acid receptor agonists of the present invention is psyllium (psyllium), guar-bean (guar), oat (oat) and pectin.

Unite the non-limitative example of fatty acid ester of the plant alkanol of use and/or plant alkanol at BENECOL with nicotinic acid receptor agonists of the present invention ^_The Sitosterol ester that uses in the oleomargarine.

The non-limitative example of uniting the antioxidant of use with nicotinic acid receptor agonists of the present invention comprises probucol.

The non-limitative example of uniting the PPAR alfa agonists of use with nicotinic acid receptor agonists of the present invention comprises Sgd-24774 (beclofibrate), bezafibrate, Win-35833, clofibrate, etofibrate, fenofibrate and gemfibrozil.

The non-limitative example of uniting the lipoprotein synthetic inhibitor of use with nicotinic acid receptor agonists of the present invention comprises nicotinic acid and nicotinic acid.

The non-limitative example of uniting 5HT (serotonin) transport inhibitors of use with nicotinic acid receptor agonists of the present invention comprises paroxetine, fluoxetine, Phenfluoramine (fenfluramine), fluvoxamine, Sertraline and imipramine.

The non-limitative example of uniting NE (norepinephrine) transport inhibitors of use with nicotinic acid receptor agonists of the present invention comprises GW 320659, despiramine, thiophthalan and nomifensine.

Unite the CB of use with nicotinic acid receptor agonists of the present invention ₁The non-limitative example of antagonists/inverse agonists comprises Rimonabant (rimonabant), SR-147778 (Sanofi Aventis) and US 5,532,237, US 4,973,587, US 5,013,837, US 5,081,122, US5,112,820, US 5,292,736, US 5,624, and 941, US 6,028,084, WO 96/33159, WO 98/33765, WO 98/43636, WO 98/43635, WO 01/09120, WO98/31227, WO 98/41519, WO 98/37061, WO 00/10967, WO 00/10968, WO 97/29079, WO 99/02499, WO 01/58869, the compound of describing among WO 02/076949 and the EP-658546 (this paper introduce in the document of front each as a reference).

The non-limitative example of uniting the ghrelin antagonist of use with nicotinic acid receptor agonists of the present invention comprise those that describe among WO 0,1/8,733 5 and the WO 02/08250 (this paper introduce in the document of front each as a reference).The ghrelin antagonist also is called GHS (secretagogue receptor) antagonist.Therefore drug regimen of the present invention and method comprise uses the GHS antagonist to replace ghrelin antagonist (with nicotinic acid receptor agonists associating of the present invention).

Unite the H of use with nicotinic acid receptor agonists of the present invention ₃The non-limitative example of antagonists/inverse agonists comprises Thioperamide (thioperamide), N-(4-pentenyl) carboxylamine-3-(1H-imidazol-4 yl) propyl ester, clobenpropit, iodophenpropit, imoproxifan and GT2394 (Gliatech), those (this paper introduces for referencial use) of describing among the WO 02/15905; Kiec-Kononowicz, K. etc., O-[3-(1H-imidazol-4 yl) propyl alcohol of describing among the Pharmazie, 55:349-55 (2000)] carbamate (this paper introduces for referencial use); Lazewska D. etc., the histamine H of describing among the Pharmazie, 56:927-32 (2001) that contains piperidines ₃-receptor antagonist (this paper introduces for referencial use); Sasse, benzophenone derivates and the related compound (this paper introduces for referencial use) described among the A. etc., Arch.Pharm. (Weinheim) 334:45-52 (2001); Reidemeister, S. etc., the replacement N-phenylcarbamate of describing among the Pharmazie, 55:83-6 (2000) (this paper introduces for referencial use); Sasse, A. etc., the proxifan derivative of describing among the J.Med.Chem.43:3335-43 (2000) (this paper introduce aforementioned documents each as a reference).

The non-limitative example of uniting MCH1R (melanochrome the assemble hormone 1 acceptor) antagonist of use and MCH2R (melanochrome is assembled hormone 2 acceptors) agonist/antagonist with nicotinic acid receptor agonists of the present invention comprises those that describe among WO 01/82925, WO 01/87834, WO 02/06245, WO02/04433, WO 02/51809 and the JP 13226269 (this paper introduce aforementioned documents each as a reference) and T-226296 (Takeda).

The non-limitative example of uniting the NPY1 antagonist of use with nicotinic acid receptor agonists of the present invention comprises US 6,001,836, those that describe among WO 96/14307, WO 01/23387, WO 99/51600, WO01/85690, WO 01/85098, WO 01/85173 and the WO 01/89528 (this paper introduce aforementioned documents each as a reference); With BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906 and GI-264879A.

The non-limitative example of uniting the NPY5 antagonist of use with nicotinic acid receptor agonists of the present invention comprises US 6,140,354, US 6,191,160, US 6,258,837, US 6,313,298, US6,337,332, US6,329,395, US 6,340,683, US 6,326,375, US 6,335,345, EP-01010691, EP-01044970, WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/85714, WO01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO01/09120, WO 02/22592, WO 0248152, WO 02/49648, WO 01/14376, WO 04/110375, those that describe among the J.Med.Chem.43:4288-4312 (2000) such as WO 05/000217 and Norman (this paper introduce aforementioned documents each as a reference); With 152,804, GW-569180A, GW-594884A, GW-587081X, GW-548118X; FR226928, FR240662, FR252384; 1229U91, Gl-264879A, CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104.

The non-limitative example of uniting the NPY2 agonist of use with nicotinic acid receptor agonists of the present invention comprises Batterham etc.; the PYY3-36 that describes among the Nature.418:650-654 (2003); [Leu (28 for NPY3-36 and other Y2 agonist such as N-ethanoyl; 31)] NPY 24-36 (White-Smith and Potter; Neuropeptides 33:526-33 (1999)); TASP-V (Malis etc.; Br.J.Pharmacol.126:989-96 (1999)), ring-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY (Cabrele and Beck-SickingerJ-Pept-Sci.6:97-122 (2000)) (this paper introduce aforementioned documents each as a reference).

The non-limitative example of uniting the NPY4 agonist of use with nicotinic acid receptor agonists of the present invention comprises pancreas peptide (PP) and other Y4 agonist such as 1229U91 (Raposinho etc., the Neuroendocrinology.71:2-7 (2000) (this paper introduces these two pieces of documents as a reference) that Batterham etc. describes in J.Clin.Endocrinol.Metab.88:3989-3992 (2003).

MGluR5 (the metabotropic glutamate hypotype 5 acceptors) antagonist of uniting use with nicotinic acid receptor agonists of the present invention comprises 2-methyl-6-(phenylacetylene base)-pyridine (MPEP) and (3-[(2-methyl isophthalic acid, 3-thiazole-4-yl) ethynyl] pyridine) (MTEP) and Anderson J. etc. at J, Eur J Pharmacol.Jul.18,2003,473 (1): among the 35-40, Cosford N. etc. are at Bioorg Med Chem Lett.Feb.10,2003,13 (3): among the 351-4 and Anderson J. etc. at J Pharmacol Exp Ther.December 2002:303 (3): those compounds of describing among the 1044-51 (this paper introduce aforementioned documents each as a reference).

Unite leptin, the leptin derivative of use with nicotinic acid receptor agonists of the present invention, the non-limitative example of leptin agonist/modulator comprises rh-Leptin (PEG-OB, Hoffman LaRoche) and reorganization methionyl people's leptin (Amgen).The leptin derivative that uses among the present invention (for example clipped form of leptin (truncated form)) comprises US 5,552,524, US5,552,523, US 5,552, and 522, US 5,521,283, those that describe among WO 96/23513, WO 96/23514, WO 96/23515, WO 96/23516, WO 96/23517, WO 96/23518, WO 96/23519 and the WO 96/23520 (this paper introduce aforementioned documents each as a reference).

The non-limitative example of uniting the opiate antagonist (opioidantagonist) of use with nicotinic acid receptor agonists of the present invention comprises Nalmefene (Revex ^TM), the opiate antagonist described among 3-methoxyl group TREXUPONT, naloxone and TREXUPONT and the WO 00/21509.

The non-limitative example that increases food factor acceptor antagonist of uniting use with nicotinic acid receptor agonists of the present invention comprises SB-334867-A and WO 01/96302, those that describe among WO 01/68609, WO02/51232 and the WO 02/51838 (this paper introduce aforementioned documents each as a reference).

The non-limitative example of uniting the CNTF (special ciliary neurotrophic factor) of use with nicotinic acid receptor agonists of the present invention comprises GI-181771 (Glaxo-SmithKline); SR146131 (Sanofi Aventis); Butabindide; PD170292, PD 149164 (Pfizer).

The non-limitative example of uniting the CNTF derivative of use and CNTF agonist/modulator with nicotinic acid receptor agonists of the present invention comprises those that describe among axokine (Regeneron) and WO 94/09134, WO 98/22128 and the WO 99/43813 (this paper introduce aforementioned documents each as a reference).

The non-limitative example of uniting the 5HT2c agonist of use with nicotinic acid receptor agonists of the present invention comprises BVT933, DPCA37215, WAY161503 and R-1065, and US3,914,250, those that describe among WO 02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO 02/51844, WO 02/40456 and the WO 02/40457 (this paper introduce aforementioned documents each as a reference).

The non-limitative example of uniting the Mc4r agonist of use with nicotinic acid receptor agonists of the present invention comprises CHIR86036 (Chiron); ME-10142 and ME-10145 (Melacure), and those (this paper introduce aforementioned documents each as a reference) of describing among WO 01/991752, WO 01/74844, WO 02/12166, WO 02/11715 and the WO02/12178.

The non-limitative example of uniting the monoamine reuptake inhibitors of use with nicotinic acid receptor agonists of the present invention comprises sibutramine (Meridia ^TM/ Reductil ^TM) and WO 01/27068, WO01/62341, US 4,746,680, US 4,806,570, US 5,436,272 and US 2002/0006964 in those (this paper introduce aforementioned documents each as a reference) of describing.

The non-limitative example of uniting the serotonin reuptake inhibitor of use with nicotinic acid receptor agonists of the present invention comprises Isomeride, fluoxetine and US 6,365,633, those that describe among WO 01/27060 and the WO 01/162341 (this paper introduce aforementioned documents each as a reference).

The non-limitative example of uniting the GLP-1 agonist of use with nicotinic acid receptor agonists of the present invention comprises exendin-3 and exendin-4.

The estrogenic non-limitative example of acyl group of uniting use with nicotinic acid receptor agonists of the present invention comprises oleoyl-estrone.

The non-limitative example of uniting 11 β HSD-1 inhibitor of use with nicotinic acid receptor agonists of the present invention comprises those (this paper introduces the two as a reference) of describing among WO 03/065983 and the WO 03/104207.

The non-limitative example of uniting the lipase inhibitor of use with nicotinic acid receptor agonists of the present invention comprises orlistat.

The antidiabetic drug of uniting use with nicotinic acid receptor agonists of the present invention comprises sulfonylurea, meglitinide (meglitinides), alpha-amylase inhibitor, α-glucoside hydrolase inhibitor, the PPAR-gamma agonist, PPAR α/gamma agonist, biguanides, the PTP-1B inhibitor, the DP-IV inhibitor, insulin secretagogue (insulin secreatagogue), fatty acid oxidation inhibitors, the A2 antagonist, the amino-terminated kinase inhibitor of c-un, Regular Insulin, insulin mimetic, glycogen phosphorylase inhibitors, the VPAC2 receptor stimulant, activators of glucokinase and non-thiazolidinedione PPAR part.The non-limitative example of uniting the sulfonylurea of use with nicotinic acid receptor agonists of the present invention comprises acetohexamide, P-607, P-607, Glyburide, Glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide and tolbutamide.

The non-limitative example of uniting the meglitinide of use with nicotinic acid receptor agonists of the present invention comprises repaglinide and nateglinide.

The non-limitative example of uniting the alpha-amylase inhibitor of use with nicotinic acid receptor agonists of the present invention comprises tendamistat (tendamistat), his fourth (trestatin) and A1-3688 come together.

The non-limitative example of uniting the α-glucoside hydrolase inhibitor of use with nicotinic acid receptor agonists of the present invention comprises acarbose, adipose, Camiglibose, emiglitate (emiglitate), miglitol, voglibose, pradimicin-Q, salbostatin, CDK-711, MDL-25637, MDL-73945 and MOR 14.

The non-limitative example of uniting the PPAR-gamma agonist of use with nicotinic acid receptor agonists of the present invention comprises Ba Gelie ketone (balaglitazone), ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone, rosiglitazone, troglitazone, tesaglitazar, netoglitazone (netoglitazone), GW-409544, GW-501516, CLX-0921,5-BTZD, GW-0207, LG-100641, LY-300512, LY-519818, R483 (Roche) and T131 (Tularik).

The non-limitative example of uniting the PPAR α/gamma agonist of use with nicotinic acid receptor agonists of the present invention comprises CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB 219994.

The non-limitative example of uniting the biguanides of use with nicotinic acid receptor agonists of the present invention comprises buformin, N1,N1-Dimethylbiguanide and phenformin.

The non-limitative example of uniting the PTP-1B inhibitor (Protein Tyrosine Phosphatases-1B inhibitor) of use with nicotinic acid receptor agonists of the present invention comprises A-401674, KR 61639, OC-060062, OC-83839, OC-297962, MC52445 and MC52453.

The non-limitative example of uniting the DP-IV inhibitor (DPP IV i inhibitor) of use with nicotinic acid receptor agonists of the present invention comprises Isoleucine thiazolidine, NVP-DPP728, P32/98, LAF 237, TSL 225, Xie Ansuan tetramethyleneimine (valine pyrrolidide), TMC-2A/2B/2C, CD-26 inhibitor and SDZ 274-444.

The non-limitative example of uniting the insulin secretagogue of use with nicotinic acid receptor agonists of the present invention comprises linogliride and A-4166.

The non-limitative example of uniting the fatty acid oxidation inhibitors of use with nicotinic acid receptor agonists of the present invention comprises clomoxir and etomoxir.

The non-limitative example of uniting the A2 antagonist of use with nicotinic acid receptor agonists of the present invention comprises midaglizole, isaglidole, Deriglidole, Racemic idazoxan, earoxan and fluparoxan.

The non-limitative example of uniting the insulin mimetic of use with nicotinic acid receptor agonists of the present invention comprises that biophase (biota), LP-100, novarapid, insulin detemir, Insulin lispro, Lantus, lente insulin (imitate slowly and surpass slowly and imitate), Lys-Pro Regular Insulin, GLP-1 (73-7) are (insulintropin) and GLP-1 (7-36)-NH2).

The non-limitative example of uniting the glycogen phosphorylase inhibitors of use with nicotinic acid receptor agonists of the present invention comprises CP-368296, CP-316819 and BAYR3401.

The non-limitative example of uniting the non-thiazolidinedione PPAR part of use with nicotinic acid receptor agonists of the present invention comprises JT-501 and Fa Gelie ketone (GW-2570/GI-262579).

The antihypertensive drug of uniting use with nicotinic acid receptor agonists of the present invention comprises diuretic(s), beta-adrenergic blocking agent, alpha antiadrenergic agent, aldosterone inhibitor, α 1 blocker, calcium channel blocker, angiotensin converting enzyme inhibitor, neutral endopeptidase inhibitor, angiotensin II receptor antagonists, endothelin antagonist, vasodilator, α 2a agonist and α/Beta-3 adrenergic blocker.

The non-limitative example of uniting the diuretic(s) of use with nicotinic acid receptor agonists of the present invention comprises chlorthalidone, chlorothiazide, Dichlorophenamide (dichlorophenamide), Hydroflumethiazide, indapamide, hydrochlorothiazide, bumetanide, Ethacrynic Acid, Furosemide, torasemide (torsemide), guanamprazine, triamterene, spironolactone and epirenone.

The non-limitative example of uniting the beta-adrenergic blocking agent of use with nicotinic acid receptor agonists of the present invention comprises acebutolol, atenolol USP 23, betaxolol, bevantolol, bisoprolol, Bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metoprolol, nadolol, nebivolol, penbutolol, pindolol, Propranololum, sotalol, Tertatolol, tilisolol and timolol.

The non-limitative example of uniting α 1 blocker of use with nicotinic acid receptor agonists of the present invention comprises terazosin, urapidil, Prazosin, bunazosin, trimazosin, Doxazosin, naftopidil, Indoramine, WHIP 164 and XEN010.

The non-limitative example of uniting the calcium channel blocker of use with nicotinic acid receptor agonists of the present invention comprises amlodipine, Aranidipine, Azelnidipine, barnidipine, benidipine, Bepridil, cinaldipine, Clevidipine, Odizem, efonidipine, felodipine, methoxyverapamil, Isrodipine, Lacidipine (62, Lemildipine, lercanidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, Manidipine, pranidipine and verapamil.

The non-limitative example of uniting the angiotensin converting enzyme inhibitor of use with nicotinic acid receptor agonists of the present invention comprises alacepril, benazepril, SQ-29852, captopril, Yipingshu, delapril, enalapril, fosinopril, imidapril, losinopril, moveltopril, moexipril, quinapril, quinaprilat, Ramipril, perindopril, peridropril, quanipril, spirapril, temocapril, Trolapril and zofenopril.

The non-limitative example of uniting the neutral endopeptidase inhibitor of use with nicotinic acid receptor agonists of the present invention comprises omapatrilat (omapatrilat), cadoxatril, ecadotril (ecadotril), fosidotril, Sampatrilat, AVE7688 and ER4030.

The non-limitative example of uniting the angiotensin II receptor antagonists of use with nicotinic acid receptor agonists of the present invention comprises Candesartan, Eprosartan, irbesartan, losartan, Pratosartan (pratosartan), Tasosartan, telisartan, valsartan, EXP-3137, FI6828K, RNH6270, losartan one potassium and losartan potassium hydrochlorothiazide.

The non-limitative example of uniting the endothelin antagonist of use with nicotinic acid receptor agonists of the present invention comprises tezosentan, A308165 and YM62899.

The non-limitative example of uniting the vasodilator of use with nicotinic acid receptor agonists of the present invention comprises hydralazine (Aprelazine), clonidine (clonidine), minoxidil (U-10858) and nicotinic alcohol (3-piconol).

The non-limitative example of uniting the α 2a agonist of use with nicotinic acid receptor agonists of the present invention comprises lofexidine, thiamenidine, moxonidine, rilmenidine and guanobenz.

The non-limitative example of uniting the α/Beta-3 adrenergic blocker of use with nicotinic acid receptor agonists of the present invention comprises nipradolol, Arottnolol and amosulalol.

The DP receptor antagonist of uniting use with nicotinic acid receptor agonists of the present invention comprises those (this paper is incorporated herein by reference) of describing among the US2004/0229844.

Can comprise acetylsalicylic acid with the non-limitative example that nicotinic acid receptor agonists of the present invention is united the additional medicaments of use, Niaspan, Norvsac_ (amlodipine), NSAID (non-steroidal anti-inflammatory drug) (celecoxib (Celebrex_) for example, diclofenac (Cataflam_, Voltaren_, Arthrotec_), diflunisal (Dolobid_), R-ETODOLAC (Lodine_), fenoprofen (Nalfon_), Flurbirofen (Ansaid_), Ibuprofen BP/EP (Motrin_, ADVIL_, NUPRIN_, Tab-Profen_, Vicoprofen_, Combunox_), indomethacin (Indocin_, Indo-Lemmon_, Indornethagan_), Ketoprofen (Oruvail_), ketorolac (Toradol_), mefenamic acid (Ponstel_ can obtain from First HorizonPharmaceutical commercial), Flufenamic Acid ([N-(3-trifluoromethyl) anthranilic acid]), meloxicam (Mobic_), Naburnetone (Relafen_), Naproxen Base (Naprosyn_, ALEVE_, Anaprox_, Naprelan_, Naprapac_), Taisho) (Daypro_), piroxicam (Feldene_), sulindac (Clinoril_) and tolmetin (Tolectin_)), antihypertensive drug (Prazosin_, Proprasylyte, nadolol, timolol, metoprolol, pindolol, Trate, guanethidine, serpentine, clonidine, methyldopa, guanabenz, captopril, enalapril, lisinopril, losartan, verapamil, Odizem, nifedipine, hydrochlorothiazide, chlorthalidone (chlorothalidone), Furosemide, triamterene, hydralazine, minoxidil), PGE2 receptor antagonist (for example EP2 and EP4).

Can comprise Homocysteine desulfurase (homocysteinase) with the non-limitative example that nicotinic acid receptor agonists of the present invention is united the additional medicaments of use; orphan GPCR conditioning agent; gene therapy based on HRE; gene therapy; dual PPAR α/gamma agonist; reorganization FGF-1; VRI-1; CRx-150; therapy based on VEGF-114; CT-500; regadenosan; CK-1827452; the JAK2 tyrosine kinase inhibitor; the regenerative cell of adipose-derived (adipose-derivedregenerative cell); STARBURST dendrimer-base MRI contrast medium (starburstdendrimer-based MRI contrast agent); TBC-11299; HEMOxygenation; heparin; GO-EPO; IDN-6734; ISIS-301012; HIF-α gene therapy; α 2b adrenoceptor antagonists; KI-0002; the adenosine conditioning agent; Ki-23095; PR-5 (Melacure); L-364373; histone deacetylase inhibitors; ACI (for example, the HI-30435 of Millennium); MITO-0139 (from MitoKor); NV-04 (from Novogen); M-118 (Momenta); anoxic response element (hypoxia response element); PI-99 (from progen); NEXVAS (from Resverlogix); CS-207 (from ShenzhenChipscreen Biosciences); oestrogenic hormon-regulatory gene therapy; SLV-327 (from SolvaY); TNX-832 (from Sunol Molecular Corp); SLx-2101 (from SurfaceLogix); recombinant human annexin (from SurroMed); rotten enzyme (Chymase) inhibitor (for example from Toa Eiyo); VM-202 (from ViroMed); liver x receptor modulators (for example from Exelixis/Bristol Myers Squibb); Heberkinasa (from Y.M.Biosciences); atorvastatin-amlodipine associating; AGN-195795 (Allergan); angiotensisn (1-7) agonist (for example from Arena); Toprol XL/ hydrochlorothiazide (from AstraZeneca); Teczem (Aventis); the sGC stimulant; calcium channel blocker; CYT-006-AngQb (CytosBiotechnology); renin inhibitor (for example from Roche/Speedel); Coxagen (from geneRx+Inc); MC-4262 (from Medicure); VNP-489 (from Novartis); felodipine (from Pierre Fabre SA); 2-methoxyestradiol (from PR Pharmaceuticals); α 1 adrenoceptor antagonists (for example from Recordati SpA); lercanidipine-enalapril associating (from Recordati SpA) .NO donor 9 is for example from Renopharm); CR-3834 (from Rottapharm Gr); Iloprost (from Schering AG); SPP-1100 (from The Speedel Group); proangiotensin; MC-4232 (from Medicure); ACE inhibitor (from Servier); LCP-Feno/Stat. (from LifeCycle Pharma); APA-01/ Statins associating (from Phosphagenics Ltd); KH-01502 (from Kos); KS-01019 (from Kos); nicotinic acid-lovastatin associating (from Kos/Merck KGaA); MK-0524/ slowly-releasing nicotinic acid/Simvastatin associating (from Merck); MK-0524/ slowly-releasing associating (from Merck); Pro-NAD (from Niadyne Inc); Beraprost; perindopril tert-butylamine salt; barnidipine; irbesartan; valsartan; valsartan-HCTZ associating; meclinertant; TAK-536; SR-121463; the irbesatran+HCTZ associating; darusentan (darusentan); PMD-2850; CR-2991; SLV-306; bisoprolol fumarate+HCTZ associating; NV-04; FG-3019; TRC-4149; AVE-7688; PV-903; Odizem; QC-BT 16; cardiotherpay (from Cytopia); treprostinil sodium; enalapril+Odizem associating; eprosartan mesilate+HCTZ associating; renin inhibitor (from Vitae); the LG-105 inhibitor (from Lexicon (; LG-844 inhibitor (from Lexicon); NO-strengthens the PDE inhibitor; Unidasa; propranolol hydrochloride; BIO-236; RWJ-351647; metoprolol; YM-222546; bLN-5; Olmesartan+Azelnidipine associating (from Sanyo); moxonidine+HCTZ associating; NS-304; BIO-123; aldosterone antagonist; clonidine; BIO-003 and CR-3834.

In addition, nicotinic acid receptor agonists of the present invention also can be united with two or more curatives.The non-limitative example of uniting two or more curatives of use with nicotinic acid receptor agonists of the present invention is compound of the present invention and VYTORIN ^_The associating of (associating of Simvastatin and ezetimibe).

Illustrate invention disclosed herein with following preparation and embodiment, these preparations and embodiment should not be regarded as the limit publicity scope.Alternative mechanism approach and similar structures it will be apparent to those skilled in the art that.

When the NMR data are provided, Varian VXR-200 (200 MHz, ¹H), obtain the 1H spectrum on VarianGemini-300 (300 MHz) or the XL-400 (400 MHz), and be recited as from Me ₄The ppm to low field displacement of Si puts down in writing proton number, multiple degree simultaneously and in the coupling constant of Hz in bracket.When the LC/MS data are provided, use Applied Biosystems API-100 mass spectrograph and Shimadzu SCL-10A LC post: Altech platinum C18,3 microns, 33mm * 7mm ID; Gradient current: 0min-10%CH ₃CN, 5min-95%CH ₃CN, 7min-95%CH ₃CN, 7.5min-10%CH ₃CN, 9min-stops.Provide retention time and observed parent ion.

Following solvent and reagent can be quoted by the abbreviation in bracket:

Tlc: TLC

Methylene dichloride: CH ₂Cl ₂

Ethyl acetate: AcOEt or EtOAc

Methyl alcohol: MeOH

Trifluoro-acetate: TFA

Triethylamine: Et ₃N or TEA

Butoxy carbonyl: n-Boc or Boc

NMR (Nuclear Magnetic Resonance) spectrum: NMR

Liquid chromatography mass: LCMS

High resolution mass spec: HRMS

Milliliter: mL

Mmole: mmol

Microlitre: μ l

Gram: g

Milligram: mg

Room temperature or rt (environment): about 25 ℃

N-bromosuccinimide: NBS

N-chlorosuccinimide: NCS

Embodiment

Experiment

Preparation embodiment 1

Steps A:

Do not having under the solvent propionyl methyl acetate (12.5g, 96.1mmol, 1.23 equivalents) and barbituric acid (10g, 78.1mmol, 1 equivalent) is admixed together, heated mixt to 195 ℃ kept 2 hours in air, and this moment, all liquid was evaporated.With twice of ebullient distilled water wash solid.Obtain 4g embodiment 1 with 2-methyl cellosolve/remaining solid of water recrystallization, be yellow solid (productive rate 20%).

¹H?NMR(CD ₃OD)：δ1.20(t，3H，J＝7.3Hz)，3.00(q，2H，J＝7.3Hz)，5.80(s，1H)

¹³C?NMR(CD ₃OD)：δ12.6，27.4，92.0，104.2，149.5，158.4，161.8，162.1，164.1

C ₉H ₉N ₂O ₄(MH) ⁺Quality: 209.Experimental value: 209.

Preparation embodiment 2

By preparing embodiment 2, replace the propionyl methyl acetate except using the acetonyl methyl acetate with the similar method of preparation embodiment 1 method therefor.

¹H?NMR(CD ₃OD)：δ2.41(s，3H)5.75(s，1H)

C ₈H ₇N ₂O ₄(MH) ⁺Quality: 195.Experimental value: 195.

Preparation embodiment 3

By preparing embodiment 3, replace the propionyl methyl acetate except using the butyryl radicals methyl acetate with the similar method of preparation embodiment 1 method therefor.

¹H?NMR(CD ₃OD)：δ0.96(t，3H，J＝7.6Hz)，1.57(m，2H)，2.86(m，2H)，5.75(s，1H)

C ₁₀H ₁₁N ₂O ₄(MH) ⁺Quality: 223.Experimental value: 223.

Preparation embodiment 4

By preparing embodiment 4 with preparation embodiment 1 method therefor similar method, replace the propionyl methyl acetate except using the isobutyl-ethyl acetate, and by HPLC (in 10 minutes in the water 5% acetonitrile to 95% acetonitrile) purifying embodiment 4.

¹H?NMR(CD ₃OD)：δ1.14(d，6H，J＝6.8Hz)，4.03(m，1H)，5.86(s，1H)

C ₁₀H ₁₁N ₂O ₄(MH) ⁺Quality: 223.Experimental value: 223.

Preparation embodiment 5

Steps A:

Mix embodiment 1 (5g, 24.04mmol, 1 equivalent), POCl ₃(36.86g, 240mmol, 10 equivalents) and pyridine (0.95g, 12mmol, 0.5 equivalent), and be heated to 115 ℃ of maintenances 8 hours.Behind the cool to room temperature, remove and desolvate, use flash chromatography to use the 20%EtOAc/ hexane as the light brown resistates of eluting solvent purifying.Obtain required product (4g), productive rate 68%.

¹H?NMR(CD ₃OD)：δ1.29(t，3H，J＝7.2Hz)，3.12(m，2H)，6.39(s，1H)

C ₉H ₇Cl ₂N ₂O ₂(MH) ⁺Quality: 245.Experimental value: 245.

Preparation embodiment 6

Steps A:

Mixing cpd 1 in the anhydrous THF of 3mL (0.15g, 0.61mmol, 1 equivalent) and aniline (0.06g, 0.64mmol, 1.05 equivalents) also stirred 12 hours.Remove and desolvate, TLC obtains required product with the 25%EtOAc/ hexane as eluting solvent purifying resistates by preparation, is first flow point (7mg, productive rate 4%).

¹H?NMR(CD ₃OD)：δ1.27(t，3H，J＝7.2Hz)，3.05(m，2H)，6.11(s，1H)，7.11(t，1H，J＝7.6Hz)，7.34(m，2H)，7.48(brs，1H)，7.60(d，2H，J＝8.0Hz)

C ₁₅H ₁₃ClN ₃O ₂(MH) ⁺Quality: 302.Experimental value: 302.

Preparation embodiment 7

Steps A:

The method that use is used to prepare embodiment 6 prepares embodiment 7, except obtaining embodiment 7 as second cut (8mg, productive rate 4%) by preparation TLC.

¹H?NMR(CD ₃OD)：δ1.43(t，3H，J＝7.2Hz)，2.96(m，2H)，6.22(s，1H)，7.37-7.48(m，5H)

C ₁₅H ₁₃ClN ₃O ₂(MH) ⁺Quality: 302.Experimental value: 302.

Preparation embodiment 8

Steps A:

By preparing embodiment 8 with the similar method of preparation embodiment 1 method therefor, except using 1,3-Bing Tongersuosuan diethyl ester replaces the propionyl methyl acetate.

¹H?NMR(CD ₃OD)：δ1.20(t，3H，J＝7.3Hz)，3.88(s，2H)，4.10(q，2H，J＝7.3Hz)，5.81(s，1H)

¹³C?NMR(CD ₃OD)：δ13.4，39.6，61.2，92.2，108.1，149.7，153.1，157.8，161.7，162.0，170.3

C ₁₁H ₁₁N ₂O ₆(MH) ⁺The HRMS quality: calculated value 267.0617, experimental value 267.0623.

Preparation embodiment 9

Steps A:

Heating 3,3, the 3-trifluoroacetic acid (16g, 125mmol), thionyl chloride (29.75g, 250mmol) and the mixture to 70 of DMF (0.5mL) ℃ maintenance 4 hours.Under reduced pressure the distillation reaction mixture obtains 3,3,3-trifluoropropyl chloride of acid (11.5g, 72%).

Step B:

To Meldrum acid (2,2-dimethyl-4,6-dioxy-1,3-two _ alkane; 9g, 62mmol) and pyridine (9.8g is 68mmol) at anhydrous CH ₂Cl ₂Being cooled to (10mL) adds 3,3 in 0 ℃ the solution, and 3-trifluoropropyl chloride of acid (10g, 68mmol).At N ₂In stirred down the reaction mixture that obtains 1 hour at 0 ℃, at room temperature stirred then 2 hours.Concentrated reaction mixture under reduced pressure then.The paste that obtains is mixed with MeOH (20mL), and be heated to 80 ℃ of maintenances 5 hours.Remove and desolvate, the mixture that distillation under reduced pressure obtains obtains compound 9a (6.2g, 54%).

With compound 9a (2.2g, 12mmol) and the mixture heating up to 180 of barbituric acid ℃ kept 1 hour, obtain black solid.Behind the cool to room temperature, black solid is dissolved in the hot water (70mL).With the ethyl acetate (mixture that 4 * 50mL) extractions obtain.Dry (Na ₂SO ₄) organic solution and under reduced pressure concentrated.Obtain embodiment 9 (0.17g, 5%) by reversed-phase HPLC with formic acid (0.1%)/acetonitrile wash-out purifying crude product.Electron spray(ES) MS[M+1] ⁺263.

Preparation embodiment 10

Steps A:

165 ℃ of heating 4 down, (20.0g, 138.7mmol) (21.8mL, mixture 173.4mmol) is up to the ester complete reaction with the propionyl methyl acetate for 6-dihydroxyl-2-sulfydryl-pyrimidine.Reaction mixture also is poured in the water (75mL), filters by sinter funnel then.(2 * 20mL) washing solid residues are also dry under vacuum, produce compound 10a (11.6g, 37%) for water.

Step B:

At room temperature to compound 10a (4.0g, 17.86mmol) add in the suspension in DMF (40mL) Mel (2.23mL, 35.72mmol).At room temperature stirred reaction mixture spends the night.Reaction mixture is poured in the water (250mL) and then and filter by sinter funnel.(2 * 50mL) washing solid residues are also dry under vacuum, obtain compound 10b (4.1g, 96%) for water.

Step C:

At room temperature (2.0g is 8.4mmol) at CH to compound 10b ₂Cl ₂Add in the suspension (150mL) m-CPBA (3.1g, 70%, 12.6mmol).From suspension, remove after 3 hours and desolvate, use silica gel flash column chromatography purifying crude product, at first use hexane/EtOAc (v/v=1/1) to use CH then ₂Cl ₂/ MeOH (v/v=2/1) wash-out obtains embodiment 10 (2.0g, 94%).Electron spray(ES) MS[M+1] ⁺255.1.

Preparation embodiment 11

Steps A:

(the 0.35g's embodiment 10 of heating in MeOH (40mL) 1.37mmol) spends the night under refluxing.Behind the cool to room temperature, under reduced pressure remove and desolvate, use silica gel flash column chromatography purifying crude product, use CH ₂Cl ₂/ MeOH (v/v=50/1) wash-out obtains embodiment 11 (0.23g, 76%).Electron spray(ES) MS[M+1] ⁺223.1.

Preparation embodiment 12

Steps A:

At room temperature to embodiment 10 (0.404g, 1.58mmol) and NEt ₃(0.22mL is 1.58mmol) at CH ₃Add in the solution among the CN (12.0mL) BnOH (2.46mL, 23.76mmol).85 ℃ of following reacting by heating mixture overnight.Behind the cool to room temperature, (0.09mL 1.58mmol), under reduced pressure removes and desolvates to add HoAc.Use silica gel flash column chromatography purifying crude product, use CH ₂Cl ₂/ MeOH (v/v=50/1) wash-out obtains embodiment 12 (0.20g, 42%).Electron spray(ES) MS[M+1] ⁺299.1.

Preparation embodiment 13

Steps A:

At room temperature to compound 10a (0.5g, 2.24mmol) add in the suspension in DMF (5.0mL) the cyclopropyl monobromomethane (1.30mL, 13.4mmol).85 ℃ of following stirred reaction mixtures 2 days.Reaction mixture is also poured in the water (75mL), filters by sinter funnel then.(2 * 20mL) washing solid residues are also dry under vacuum, obtain compound 1 3a (0.55g, 88%) for water.

Step B:

At room temperature (0.25g is 0.9mmol) at CH to compound 13a ₂Cl ₂Add in the suspension (30mL) m-CPBA (0.33g, 70%, 1.35mmol).Remove after 3 hours and desolvate, use silica gel flash column chromatography purifying crude product, use EtOAc/CH ₂Cl ₂/ MeOH (v/v=4/1/2) wash-out obtains embodiment 13 (0.15g, 57%).Electron spray(ES) MS[M+1] ⁺295.1.

Preparation embodiment 14

Steps A:

Heating embodiment 10 under refluxing (0.205g, 0.804mmol) and NH ₂NHCO ₂(0.145g, 1.608mmol) mixture in MeCN (4.0mL) is 3 hours for Me.Behind the cool to room temperature, under reduced pressure remove and desolvate, (3 * 25mL) by the filtration washing crude product for water.Drying solid under vacuum obtains embodiment 14 (0.2g, 89%).Electron spray(ES) MS[M+1] ⁺281.1.

Preparation embodiment 15

Steps A:

At room temperature to compound 10a (1.5g, 6.7mmol) add in the suspension in DMF (15.0mL) allyl bromide 98 (1.74mL, 20.1mmol).Spend the night at 45 ℃ of following stirred reaction mixtures.Reaction mixture is also poured in the water (200mL), filters by sinter funnel then.(2 * 40mL) washing solid residues are also dry under vacuum, obtain embodiment 15 (1.55g, 92%) for water.Electron spray(ES) MS[M+1] ⁺265.1.

Preparation embodiment 16

Steps A:

At room temperature (0.050g is 0.196mmol) at CH to embodiment 10 ₃Add in the solution among the CN (0.8mL) cyclopropyl-carbinol (0.79mL, 9.8mmol).85 ℃ of following reacting by heating mixture overnight.Behind the cool to room temperature, under reduced pressure remove and desolvate.Use silica gel flash column chromatography purifying crude product,, obtain embodiment 16 (0.027g, 52%) with hexane/EtOAc (v/v=1/1) wash-out.Electron spray(ES) MS[M+1] ⁺263.1.

Preparation embodiment 17

Steps A:

Heating embodiment 10 under refluxing (0.10g, 0.392mmol) and t-BuSH (0.66mL, 5.88mmol) 1, the mixture in 4-two _ alkane (2.0mL).Behind the cool to room temperature, under reduced pressure remove and desolvate.Use silica gel flash column chromatography purifying crude product,, obtain compound 17a (0.045g, 41%) with hexane/EtOAc (v/v=1/1) wash-out.

Step B:

At room temperature (0.040g is 0.143mmol) at CH to compound 17a ₂Cl ₂Add in the suspension (2.5mL) m-CPBA (0.049g, 70%, 0.20mmol).Remove after 3 hours and desolvate, use silica gel flash column chromatography purifying crude product, at first use hexane/EtOAc (v/v=1/1) to use CH then ₂Cl ₂/ MeOH (v/v=5/1) wash-out obtains embodiment 17 (0.030g, 71%).Electron spray(ES) MS[M+1] ⁺297.1.

Preparation embodiment 18

Steps A:

To compound 10a (1.5g, 6.7mmol) add in the suspension in DMF (20mL) Etl (2.1g, 13.4mmol).After at room temperature stirring is spent the night, reaction mixture is poured in the water (50mL), and filters by Buchner funnel.(2 * 50mL) washing solid residues are also dry under vacuum, obtain compound 18a (1.3g, 76%) for water.

Step B:

At room temperature (0.5g is 2mmol) at CH to compound 18a ₂Cl ₂Add in the suspension (50mL) m-CPBA (74mg, 70%, 3mmol).After at room temperature stirring 3 hours, remove and desolvate, use silica gel flash column chromatography purifying crude product, use AcOH/MeOH/CH ₂Cl ₂(v/v/v=0.1/4.9/95) wash-out obtains embodiment 18 (0.4g, 74%).Electron spray(ES) MS[M+1] ⁺269.

Preparation embodiment 19

Steps A:

To compound 10a (1g, 4.5mmol) add in the suspension in DMF (20mL) bromotoluene (1.54g, 9mmol).After at room temperature stirring is spent the night, reaction mixture is poured in the water (50mL), and filters by Buchner funnel.(2 * 50mL) washing solid residues are also dry under vacuum, obtain compound 19a (1.3g, 92%) for water.

Step B:

At room temperature (0.5g is 2mmol) at CH to compound 19a ₂Cl ₂Add in the suspension (50mL) m-CPBA (72mg, 70%, 3mmol).After at room temperature stirring 3 hours, remove and desolvate, use silica gel flash column chromatography purifying crude product, use AcOH/MeOH/CH ₂Cl ₂(v/v/v=0.1/2.9/97) wash-out obtains embodiment 19 (0.5g, 76%).Electron spray(ES) MS[M+1] ⁺331.

Preparation embodiment 20

Steps A:

At room temperature to compound 10a (1g, 4.5mmol) add in the suspension in DMF (20.0mL) (1-bromotrifluoromethane) benzene (3.4g, 18mmol).70 ℃ of following stirred reaction mixtures 1 day.Reaction mixture also is poured in the water (50mL), filters by Buchner funnel then.(2 * 20mL) washing solid residues are also dry under vacuum, obtain compound 20a (1.3g, 87%) for water.Electron spray(ES) MS[M+1] ⁺329.

Step B:

At room temperature (0.33g is 1mmol) at CH to compound 20a ₂Cl ₂Add in the suspension (30mL) m-CPBA (0.3g, 70%, 1.2mmol).Remove after 3 hours and desolvate, use silica gel flash column chromatography purifying crude product, (v/v=1: the 5%EtOH wash-out 1) obtains embodiment 20 (0.1g, 50%) to be used in the EtOAc/ hexane.Electron spray(ES) MS[M+1] ⁺345.

Preparation embodiment 21

Steps A:

To compound 10a (1g, 4.5mmol) add in the suspension in DMF (20.0mL) 2-iodopropane (1.53g, 9mmol).80 ℃ of following stirred reaction mixtures 1 day.Reaction mixture also is poured in the water (50mL), filters by Buchner funnel then.(2 * 20mL) washing solid residues are also dry under vacuum, obtain compound 21a (1.05g, 88%) for water.

Step B:

At room temperature (0.53g is 2mmol) at CH to compound 21a ₂Cl ₂Add in the suspension (30mL) m-CPBA (0.74g, 70%, 3mmol).Remove after 3 hours and desolvate, use silica gel flash column chromatography purifying crude product, be used in MeOH/CH ₂Cl ₂(v/v=2: the 0.1%AcOH wash-out 98) obtains embodiment 21 (0.45g, 80%).Electron spray(ES) MS[M+1] ⁺283.

Preparation embodiment 22 and 23

Steps A:

At room temperature to embodiment 11 (29.6mg, 0.133mmol) and Etl (0.064mL 0.8mmol) adds K in the mixture in DMF (1.0mL) ₂CO ₃(36.7mg, 0.266mmol).Spending the night by reaction stirred before adding the dilution of EtOAc (50mL) and water (10mL).Water (3 * 15mL), salt solution (15mL) washing organic phase, and at MgSO ₄Last dry.After filtering and concentrating, use preparation TCL purifying crude product, hexane/CH ₂Cl ₂/ EtOAc (v/v/v=7/3/1) obtains embodiment 22 (7.0mg, 21%) and embodiment 23 (20mg, 60%) as eluent.Electron spray(ES) MS[M+1] ⁺251.1.

Preparation embodiment 24

Steps A:

(the 0.216g's embodiment 10 of heating in vinyl carbinol (3.0mL) 0.847mmol) spends the night under refluxing.Behind the cool to room temperature, under reduced pressure remove and desolvate, use silica gel flash column chromatography purifying crude product,, obtain compound 24a (0.1g, 48%) with EtOAc/MeOH (v/v=5/1) wash-out.

Step B:

At room temperature (0.040g is 0.161mmol) at CH to compound 24a ₂Cl ₂Add in the solution (2.0mL) NBS (36mg, 0.202mmol).Removed with 1 hour and to desolvate, use silica gel flash column chromatography purifying crude product,, obtain embodiment 24 (0.025g, 48%) with hexane/EA (v/v=1/1) wash-out.Electron spray(ES) MS[M+1] ⁺327.1.

Preparation embodiment 25

Steps A:

At CH ₃Dissolving embodiment 1 among the CN (10mL) (0.5g, 2.4mmol).In suspension, add triethylamine (0.33mL, 2.4mmol), be then the cyclopropyl monobromomethane (0.26mL, 2.64mmol) and NaI (0.36g, 2.4mmol).The reacting by heating mixture spends the night to refluxing.Behind the cool to room temperature, evaporating solvent in a vacuum.By coming the purifying crude product, obtain embodiment 25 (0.25g, 40%) from the crystallization of EtOAc/ hexane.

Preparation embodiment 26

Steps A:

At CH ₃Dissolving embodiment 1 among the CN (3.0mL) (0.1g, 0.48mmol).In suspension, add triethylamine (0.067mL, 0.48mmol), be then methyl bromoacetate (0.046mL, 0.48mmol).At room temperature stirred reaction mixture spends the night.Under reduced pressure remove and desolvate,,, obtain embodiment 26 (0.06g, 45%) with EtOAc/ hexane (2/3:v/v) wash-out by column chromatography purifying crude product.

Preparation embodiment 27

Steps A:

At CH ₃Dissolving embodiment 1 among the CN (3.0mL) (1.0g, 0.48mmol).In suspension, add triethylamine (0.67mL, 0.48mmol), be then the brooethyl methyl ether (0.44mL, 4.8mmol).At room temperature stirred reaction mixture is 10 minutes, concentrates then.By column chromatography purifying crude mixture,, obtain compound 27a (0.6g, 50%) with EtOAc/ hexane (2/3:v/v) wash-out.

Step B:

To 0 ℃ compound 27a (0.335g, 1.33mmol) add in the mixture in 8mL DMF sodium hydride (0.058g, 1.46mmol), be then the cyclopropyl monobromomethane (0.142mL, 1.46mmol).At room temperature stirred suspension spends the night, and uses EtOAc (10mL) dilution then and by adding entry (5mL) quencher.With EtOAc (2 * 5mL) aqueous phase extracted.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, obtain compound 27b (0.175g, 43%) with EtOAc/ hexane (2/3:v/v) wash-out.

Step C:

(0.175g is 0.57mmol) at CH to-78 ℃ compound 27b ₂Cl ₂Add boron tribromide (2.85mL, 2.85mmol, 1.0 M solution in DCM) in the solution (8.0mL).Reaction stirred 2 hours, water (5.0mL) quencher then.With EtOAc (2 * 5mL) extractive reaction mixtures.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, obtain compound 27 (0.1g, 67%) with EtOAc/ hexane (2/3:v/v) wash-out.

Preparation embodiment 28

Steps A:

To 0 ℃ compound 27a (0.100g, 0.396mmol) add in the mixture in 2mL DMF sodium hydride (0.016g, 0.396mmol), be then methyl bromoacetate (0.041mL, 0.44mmol).At room temperature stirred suspension spends the night, and uses EtOAc (5mL) dilution then and by adding entry (5mL) quencher.With EtOAc (2 * 5mL) aqueous phase extracted.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, obtain compound 28a (0.07g, 54%) with EtOAc/ hexane (2/3:v/v) wash-out.

Step B:

(0.07g is 0.22mmol) at CH to-78 ℃ compound 28a ₂Cl ₂Add boron tribromide (1.1mL, 1.1mmol, 1.0 M solution in DCM) in the solution (3.0mL).Reaction stirred 2 hours, water (5.0mL) quencher then.With EtOAc (2 * 5mL) extractive reaction mixtures.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, obtain compound 28 (0.02g, 33%) with EtOAc/ hexane (2/3:v/v) wash-out.

Preparation embodiment 29

Steps A:

To 0 ℃ compound 27a (0.500g, 1.98mmol) add in the mixture in 8mL DMF sodium hydride (0.080g, 1.98mmol), be then the 2-bromoacetophenone (0.434g, 1.98mmol).At room temperature stirred suspension spends the night, and uses EtOAc (5mL) dilution then and by adding entry (5mL) quencher.With EtOAc (2 * 5mL) aqueous phase extracted.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, obtain compound 29a (0.37g, 50%) with EtOAc/ hexane (2/3:v/v) wash-out.

Step B:

(0.350g is 0.95mmol) at CH to-78 ℃ compound 29a ₂Cl ₂Add boron tribromide (4.7mL, 4.7mmol, 1.0 M solution in DCM) in the solution (10.0mL).Reaction stirred 2 hours, water (5.0mL) quencher then.With EtOAc (2 * 15mL) extractive reaction mixtures.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, obtain embodiment 29 (0.175g, 56%) with EtOAc/ hexane (2/3:v/v) wash-out.

Preparation embodiment 30 and 31

Steps A:

CH to cyclopentamine ₂Cl ₂Add trimethylsilyl isocyanate in the solution.Stirred reaction mixture spends the night.In mixture, add 200mL CH ₃OH, and restir mixture 2 hours.Concentrated reaction mixture uses the diethyl ether titration to obtain the pale precipitation thing.Obtain encircling penta carbamide compound 30a by the Buchner funnel filtering precipitate, be white crystalline solid compound (13.0g, 86%).(5.0g, (4.0g 38.7mmol), was diacetyl oxide (18mL) then, 70 ℃ of following reaction stirred 12 hours to add propanedioic acid in 38.7mmol) to this carbamide compound 30a in acetate (11mL).Concentrated reaction mixture cools off in ice bath, and uses 4/1EtO ₂/ EtOAc titration.Be settled out light yellow crystalline solid.Filtering precipitate, and use cold diethyl ether washing 2-3 time, obtain light yellow solid compound 30b (2.5g, 33%).

Step B:

Use in the presence of thionamic acid that (3.82mmol) (0.48mL, 3.82mmol) condensation, and be heated to 140 ℃ and kept 6 hours form the dun solid with the propionyl methyl acetate for 0.75g, 1.0 equivalents with compound 30b.Use the EtOAc diluted reaction mixture, use H ₂Na is used in the O washing ₂SO ₄Drying concentrates and obtains crude mixture.At 95/5 CH ₂Cl ₂/ CH ₃With preparation TLC purifying crude mixture, obtain N among the OH ₁And N ₃Isomer, embodiment 30 LCMS:(M+1) 277.1 and embodiment 31 LCMS:(M+1) 277.1.

Use similar two step process to synthesize embodiment 32-43.

Preparation embodiment 44

To at MeOH: H ₂(0.456g, 2.2mmol) the middle allyl bromide 98 that adds is LiOH to embodiment 1 among the O (1: 1) then, reacting by heating mixture to 82 ℃ maintenance 8 hours.With TLC monitoring reaction process, the existence of TLC indicating section raw material.And then reacting by heating mixture 6 hours.Produce the salmon precipitation thing, use diethyl ether from solution, to filter out throw out.Use preparation TLC95/5 CH ₂Cl ₂/ CH ₃OH purifying filtrate obtains embodiment 44 LCMS:(M+1) 249.0.

Use embodiment 10 and suitable correspondent alcohol, according to preparing the following examples 45-47,51,61-64,66-67,69-79 with the similar process of the used process of the preparation of embodiment 12.

Preparation embodiment 48

Steps A:

At room temperature to compound 10b (0.5g, 2.10mmol), BnOH (0.261mL, 2.52mmol) and PPh ₃(0.661g, 2.52mmol) drip in the solution in THF (6.0mL) DIAD (0.488mL, 2.52mmol).The reaction mixture that stirring obtains 5 hours uses the solid sample stowage further to handle by the silica gel flash column chromatography then, with hexane/EtOAc (v/v=5/1) wash-out, obtains compound 48a (0.25g, 36%).

Step B:

At room temperature (0.17g is 0.518mmol) at CH to compound 48a ₂Cl ₂Add in the solution (5mL) m-CPBA (0.384g, 1.55mmol, 60-70%).Stirred reaction mixture 5 hours adds Me then ₂S (76 μ L, 1.55mmol) quenchers.Then with EtOAc diluted mixture thing and use NaHCO ₃Solution washing.Water, salt water washing organic phase, dry (Na ₂SO ₄).Under reduced pressure remove and desolvate, by silica gel flash column chromatography purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=7/3/2) wash-out obtains compound 48b (0.15g, 80%).

The poly-C of step horse:

At room temperature to compound 48b (85.8mg, 0.238mmol) add in the solution in DMF (1.5mL) NaCN (14.0mg, 0.286mmol).At room temperature stirred reaction mixture is 2 hours, then by further handling with EtOAc and water dilution.Water (2 *), salt water washing organic phase, and dry (MgSO ₄).Under reduced pressure remove and desolvate, by silica gel flash column chromatography purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=5/1/1) wash-out obtains compound 48c (37mg, 50%).

Step D:

(10mg, 0.0326mmol) solution in 4.0M HCl, two _ alkane (0.7mL) and MeOH (0.7mL) is 7 hours for the compound 48c of heating in sealed tube under 70 ℃.Cooling mixture under reduced pressure removes and desolvates to room temperature, obtains crude product.With preparation thin layer silica gel chromatography purification crude product, with hexane/CH ₂Cl ₂/ MeOH (v/v/v=6/4/1) wash-out obtains compound 48 (5mg, 61%).Electron spray(ES) MS[M+1] ⁺251.1.

Preparation embodiment 49

Steps A:

At room temperature in the suspension of NaH (87.4mg, 2.0mmol is in mineral oil 55%) in THF (3.0mL), drip (R)-phenylethyl alcohol (0.24mL, 2.0mmol).Stirred the mixture 2 hours, transparent up to solution.The alkoxide that at room temperature will form like this is added drop-wise to compound 10 (0.27g is 1.0mmol) in the solution in DMF (3.0mL) then.Stirred reaction mixture 2 hours is then by adding HOAc (0.11mL, 2.0mmol) quencher.At EtOAc/CH ₂Cl ₂(8/2) solubilizing reaction mixture in, with rare HCl (0.1M), water and salt water washing, dry then (MgSO ₄).Under reduced pressure remove and desolvate.By silica gel flash column chromatography purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=7/3/2) wash-out obtains compound 49 (0.25g, 80%).Electron spray(ES) MS[M+1] ⁺313.1.

Preparation embodiment 50

Use compound 27a and suitable corresponding bromide, prepare embodiment 50 by being similar to the similar process of preparation embodiment 29 used processes.Electron spray(ES) MS[M+1] ⁺345.1.

Preparation embodiment 52

Use embodiment 10 and (S)-phenylethyl alcohol, prepare embodiment 52 by being similar to the similar process of preparation embodiment 49 used processes.Electron spray(ES) MS[M+1] ⁺313.1.

Preparation embodiment 53

Use compound 27a and suitable corresponding bromide, prepare embodiment 53 by being similar to the similar process of the preparation used process of embodiment 29 steps A.Electron spray(ES) MS[M+1] ⁺439.1.

Preparation embodiment 54

Steps A:

Dissolving embodiment 29 in ethanol (3.0mL) (0.05g, 0.153mmol).In mixture, add methoxy-amine hydrochloride (0.051g, 0.61mmol), be then sodium-acetate (0.038g, 0.46mmol).Spend the night at 60 ℃ of following stirred reaction mixtures.Behind the cool to room temperature, under reduced pressure remove and desolvate, use CH ₂Cl ₂(5mL) and water (5mL) dilution, use CH ₂Cl ₂(2 * 5mL) extraction products are at MgSO ₄Last dry, concentrate.Crude product is dissolved in the CH of minimum ₂Cl ₂In, with the hexane dilution, filter and obtain embodiment 54.Electron spray(ES) MS[M+1] ⁺356.1.

Preparation embodiment 55

Steps A:

At room temperature to compound 10b (2.0g, 8.4mmol), 4-methoxy-benzyl alcohol (1.39g, 10.08mmol) and PPh ₃(2.64g, 10.08mmol) add in the solution in THF (20.0mL) two azo-2-carboxylic acid's di tert butyl carbonates (2.32g, 10.08mmol).The reaction mixture that stirring obtains 4 hours uses the solid sample stowage further to handle by direct silica gel flash column chromatography then, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=9/1/1) wash-out obtains compound 55a (1.6g, 53%).

Step B:

At room temperature (0.287g is 0.80mmol) at CH to compound 55a ₂Cl ₂Add in the solution (8mL) m-CPBA (0.47g, 1.92mmol, 60-70%).Stirred reaction mixture 5 hours is then by adding Me ₂S (124 μ L, 1.92mmol) quenchers.Use EtOAc diluted mixture thing then, use NaHCO ₃Solution washing.Water, salt water washing organic phase, and dry (Na ₂SO ₄).Under reduced pressure remove and desolvate, by silica gel flash column chromatography purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=7/3/2) wash-out obtains embodiment 55 (0.15g, 80%).Electron spray(ES) MS[M+1] ⁺391.1.

Preparation embodiment 56

Steps A:

(0.25g is 1mmol) at CH to embodiment 10 ₃Adding ring butylamine in the suspension among the CN (15mL) (0.14g, 2mmol).At room temperature stirred reaction mixture is 16 hours.Remove and desolvate, use silica gel flash column chromatography purifying crude product, be used in MeOH/CH ₂Cl ₂(v/v=3: the 10%NH 97) ₄The OH wash-out obtains embodiment 56 (0.045g, 17%).Electron spray(ES) MS[M+1] ⁺262.1.

Preparation embodiment 57

Steps A:

Under 40 ℃, be stirred in compound 27a among the DMF (100mL) (2g, 7.9mmol), the monobromo-acetic acid tert-butyl ester (1.7g, 8.7mmol) and diisopropyl ethyl amine (1.1g, mixture 8.7mmol) 4 hours at room temperature stirred 16 hours then.Reaction mixture is mixed with water (200mL), use ethyl acetate (100mL * 3) extraction then.Dry (Na ₂SO ₄) organic solution and concentrated.Use silica gel flash column chromatography purifying crude product, use MeOH/CH ₂Cl ₂(v/v=2: 98) wash-out obtains embodiment 57a (1.8g, 62%).Electron spray(ES) MS[M+1] ⁺367.2.

Step B:

At room temperature (0.95g is 2.26mmol) at CH for agitate compounds 57a ₂Cl ₂(5mL) and trifluoroacetic acid (1.5g, 13mmol) mixture in is 4 hours.Remove and desolvate and excessive trifluoroacetic acid, obtain embodiment 57 (0.8g, 100%).Electron spray(ES) MS[M+1] ⁺311.2.

Preparation embodiment 58

Steps A:

To a cyclobutyl barbituric acid (300mg, 1.6mmol) and 2-methyl-3-oxy pentanoic acid ethyl ester (1.041g, add in mixture 6.59mmol) thionamic acid (77mg, 0.8mmol).140-150 ℃ of following heated mixt 48 hours.With sample on the resistates to the preparation silica-gel plate and use 5%MeOH/CH ₂Cl ₂Wash-out obtains embodiment 58 (42mg, 9%).LCMS：M+1：227.1。

Preparation embodiment 59

Use compound 27a and suitable corresponding bromide, use prepares embodiment 59 with similar two step process of the used process of preparation of embodiment 29.Electron spray(ES) MS[M+1] ⁺252.1.

Preparation embodiment 60

Steps A:

To 0 ℃ compound 27a (0.200g, 0.79mmol) add in the mixture in 3mL DMF sodium hydride (0.035g, 0.869mmol), add then 2-methoxybenzoyl monobromomethane (0.2g, 0.87mmol).At room temperature stirred suspension spends the night, and uses EtOAc (10mL) dilution then, and by adding entry (5mL) quencher.With EtOAc (2 * 5mL) aqueous phase extracted.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, produce compound 60a with EtOAc/ hexane (2/3:v/v) wash-out.

Step B:

(0.105g is 0.262mmol) at CH to compound 60a under-78 ℃ ₂Cl ₂Add boron tribromide (1.3mL, 1.31mmol, the 1.0M solution in DCM) in the solution (5.0mL).Stirred reaction mixture 2 hours, water (5.0mL) quencher then.With EtOAc (2 * 5mL) extractive reaction mixtures.Merge organic layer, at MgSO ₄Last dry, concentrate and obtain crude product.By column chromatography purifying crude mixture,, produce compound 60 with EtOAc/ hexane (2/3:v/v) wash-out.Electron spray(ES) MS[M+1] ⁺343.1.

Preparation embodiment 65

Steps A:

At room temperature (0.068mL 0.705mmol) adds K in the mixture in DMF (2.0mL) to embodiment 12 (70mg, 0.23 5mmol) and cyclopropyl monobromomethane ₂CO ₃(64.7mg, 0.47mmol).Stirred reaction mixture spends the night, then by adding the dilution of EtOAc (50mL) and water (10mL).Water (3 * 15mL), salt solution (15mL) washing organic phase, at MgSO ₄Last dry.After filtering and concentrating, use preparation TLC purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=7/3/1) obtains compound 65a (26mg, 31%) as eluent.

Step B:

(7.8mg, 10wt%) (26mg 0.074mmol), and uses H to the compound 65a of processing in EtOH (5.0mL) at room temperature to use Pd/C ₂Balloon hydrogenation 30 minutes.By short diatomaceous earth filler filter reaction mixture, and with EtOH (15mL) debris.Under reduced pressure remove and desolvate, use preparation TLC purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=3/7/1) obtains compound 65 (6mg, 30%) as eluent.Electron spray(ES) MS[M+1] ⁺263.1.

Preparation embodiment 68

Steps A:

(0.1g is 0.32mmol) at CH at room temperature to stir embodiment 57 ₂Cl ₂(5mL), piperidines (0.027g, 0.32mmol), HATU (0.24g, 0.64mmol) and triethylamine (0.098g, 0.96mmol) mixture in is 2 hours.Reaction mixture is mixed with water (20mL), use CH then ₂Cl ₂(10mL * 2) extraction.Dry (Na ₂SO ₄) organic solution and concentrated.Use silica gel flash column chromatography purifying crude product, (v/v=1: 1) wash-out obtains compound 68a (0.065g, 54%) with the EtOAc/ hexane.Electron spray(ES) MS[M+1] ⁺378.2.

Step B:

(0.056g is added in CH in solution 0.15mmol) to compound 68a under-78 ℃ ₂Cl ₂(0.75mL, 0.75mmol) the 1M BBr in ₃Solution.After 2 hours, add entry (5mL) at-78 ℃ of following stirred reaction mixtures.Dry (Na ₂SO ₄) organic solution and concentrated.Use silica gel flash column chromatography purifying crude product, be used in MeOH/CH ₂Cl ₂(v/v=3: the 10%NH 97) ₄The OH wash-out obtains embodiment 68 (0.01g, 20%).Electron spray(ES) MS[M+1] ⁺334.2.

Preparation embodiment 80

Steps A:

At room temperature at CH ₂Cl ₂Middle dissolved compound 27a (0.1g, 0.33mmol).Add NBS then, reaction stirred 4 hours.After observing reaction and no longer carrying out, add NBS (0.061g, 0.34mmol) mixture in chloroform (4mL).In 70 ℃ of following reacting by heating mixtures 12 hours.TLC (30/70 EtOAc/ hexane) and mass spectrum all show to react to be finished.Reaction mixture is used CH to room temperature ₂Cl ₂Dilution is also used H ₂The O washing.Use Na ₂SO ₄Dry organic phase, removing desolvates obtains crude product.Preparation silica gel chromatography purifying with EtOAc/ hexane (v/v=30/70) produces compound 80a (0.075g, 60%).

Step B:

At CH ₂Cl ₂In dissolved compound 80a (0.070g, 0.18mmol) and cooling mixture to-78 ℃.Add 1M BBr ₃(0.909mL, 0.9mmol).Stirred reaction mixture 4 hours.When reaction finishes, use CH ₂Cl ₂The diluted mixture thing is used H ₂Na is used in the O washing ₂SO ₄Drying obtains crude product except that desolvating then.Use 30/70 EtOAc/ hexane to obtain embodiment 80 by preparation silica gel chromatography purifying crude product.Electron spray(ES) MS[M+1] ⁺341.2.

Preparation embodiment 81

Steps A:

To embodiment 5 (84mg, 0.34mmol) and acetoxime (27.5mg, (0.09ml 0.52mmol), and stirred the mixture 3 days to add DIEA in mixture 0.37mmol).Enriched mixture also carries out silica gel column chromatography and separates, and obtains embodiment 81 (30mg, 31%).LCMS：M+1：282.1。

Preparation embodiment 92

Steps A:

(0.133g 0.341mmol) drips pseudoallyl magnesium bromide (0.95mL, 0.475mmol, 0.5M in THF) in the solution in THF (4.0mL) to embodiment 55 under 0 ℃.Under 0 ℃, stirred the mixture 2 hours, and used HCl (0.2M) quencher then.Dissolving mixt in EtOAc, and water and salt water washing.At MgSO ₄Go up dry organic phase.Under reduced pressure remove and desolvate, by silica gel flash column chromatography purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=4/1/1) wash-out obtains compound 92a (59mg, 49%).

Step B:

At room temperature to compound 92a (46.2mg, 0.131mmol) and OsO ₄(22.2 μ L, 4wt% in water) adds NaIO in the solution of THF (5.0mL) and water (5.0mL) ₄(70.1mg, 0.328mmol).Stirred reaction mixture spends the night, then by adding Me ₂S (20 μ L, 0.328mmol) quenchers.With EtOAc diluted mixture thing, and with HCI (0.5M), water and salt water washing.At MgSO ₄Go up dry organic phase.Under reduced pressure remove and desolvate, by silica gel flash column chromatography purifying crude product, with hexane/CH ₂Cl ₂/ EtOAc (v/v/v=2/1/1) wash-out obtains compound 92b (39mg, 84%).

Step C:

At room temperature to compound 92b (20.8mg, 0.059mmol) add in the solution in MeCN (3.0mL) and water (0.3mL) ceric ammonium nitrate (70.9mg, 0.129mmol).Stirred reaction mixture 2 hours dilutes with EtOAc then.With HCl (0.5M), water and salt water washing organic phase, at MgSO ₄Go up dry organic phase.Under reduced pressure remove and desolvate, by preparation TLC purifying crude product, with hexane/CH ₂Cl ₂/ MeOH (v/v/v=2/8/1) obtains embodiment 92 (8mg, 58%) as eluent.Electron spray(ES) MS[M+1] ⁺235.1.

Use embodiment 10 and suitable correspondent alcohol, by preparing embodiment 82-91 with the similar process of used those processes of the preparation of embodiment 49.

Preparation embodiment 92

1, among 4-two _ alkane (10.5mL) and the THF (1.5mL) with embodiment 2 (0.71g, 3.66mmol, 1 equivalent) and SeO ₂(0.46g, 1.1 equivalents) are admixed together, in air with mixture heating up to 90 ℃ and kept 2 hours.Purifying obtains 5% of crude product on the reversed-phase HPLC post by directly being loaded into, and obtains required product embodiment 92 (7.4mg), is white solid.

¹H?NMR(CD ₃OD)：δ?4.80(s，2H)6.20(s，1H)

C ₈H ₇N ₂O ₅(MH) ⁺Quality: 211, experimental value 211.

Preparation embodiment 93

Steps A:

By preparing compound 93a, further be oxidized to the corresponding aldehyde except making alcohol with the similar process of the pure embodiment 92 used processes of preparation.After using the reversed-phase HPLC purifying several times, obtain compound 93a (90mg).

C ₈H ₅N ₂O ₅(MH) ⁺Quality: 209, experimental value 209.

Step B:

Compound 93b (90mg, 0.43mmol, 1 equivalent) and 3-anisidine (109mg, 2 equivalents) and sodium triacetoxy borohydride (185mg, 2 equivalents) are mixed.After stirring is spent the night, with methyl alcohol quencher reaction mixture.TLC obtains the required product embodiment 93 of 15.3mg by preparation.

¹H?NMR(CD ₃OD)：δ?3.60(s，3H)4.60(s，2H)5.75(s，1H)6.20(m，3H)6.95(m，1H)

C ₁₅H ₁₄N ₃O ₅(MH) ⁺Quality: 316, experimental value 316.

Preparation embodiment 94

By preparing embodiment 94, except oxidation embodiment 1 replaces the embodiment 2 with the similar process of preparation embodiment 92 used processes.

¹H?NMR(CD ₃OD)：δ?1.38(d，2H，J＝6.8Hz)5.50(q，1H，J＝6.8Hz)6.20(s，1H)

C ₉H ₉N ₃O ₅(MH) ⁺Quality: 225, experimental value: 225.

Preparation embodiment 95

Use the 2-butyne-1-alcohol (140mg, 2mmol, 2 equivalents) of 1.6M n-BuLi (1.2mL, 2 equivalents) processing in 4ml THF 5 minutes down at 0 ℃, alkoxide solution is provided.In alkoxide solution, add embodiment 10 (0.25g, 1mmol, 1 equivalent) then.Stir after 1.5 hours, in solution, add 0.12g acetate (2 equivalent).Remove and desolvate, and, obtain white solid with diethyl ether and water extraction.With cold diethyl ether washing solid and dry under vacuum.Obtain the required product embodiment 95 of 80mg.

¹H?NMR(CDCl ₃)：δ?1.20(t，2H，J＝6.8Hz)1.83(s，3H)3.00(q，2H，J＝6.98Hz)5.00(s，2H)6.00(s，1H)

C ₁₃H ₁₃N ₂O ₄(MH) ⁺Quality: 261, experimental value: 261.

Preparation embodiment 96

In excessive propanone, dissolve barbituric acid (1.0g, 7.81mmol).Add triethylamine (2mL), reaction mixture refluxed is spent the night, cool off then and filter.(8: 1: 1/EtOAc: DCM: MeOH) the thick solid of purifying obtained required product embodiment 96 by preparation TLC.

The electron spray(ES) MS[M+1 of embodiment 96] ⁺Be 209.0.

Preparation embodiment 97 and 98

By preparing embodiment 97 and 98, replace the propionyl methyl acetate except using 2-oxygen-hexahydrobenzoic acid methyl esters and 2-oxygen-cyclopentane carboxylic acid methyl respectively with the similar method of preparation embodiment 1 method therefor.

96 and 97 electron spray(ES) MS[M+1] ⁺Be 235.1.

Preparation embodiment 99

With cold Na ₂CO ₃(15%, 450mL) (75g 383mmol) stirs 2 hours to the aqueous solution together with commercially available (Aldrich) compound 99a.With the EtOAc extraction with at Na ₂CO ₃Last dry, obtain compound 99b, be water white oil, immediately should oil under 50 ℃, be used in 200mL and do NH among the EtOH ₄(19.5g 364mmol) handled 60 hours Cl.The cooling crude mixture is also removed and is desolvated.Use cold K ₂CO ₃(30%, 300mL H ₂O) handled the light yellow solid obtain 0.5 hour.With the EtOAc extraction, obtain compound 99c, be light yellow solid (37.92g).Make this solid under 100 ℃ 400mL do among the EtOH with the propionyl methyl acetate (38.0g, 292mmol), 2mL pyridine reaction 24 hours.After cooling and the filtration, wash solid, obtain 18g compound 99d, be white solid, (calculating productive rate 22%) from compound 99a with EtOH.

¹H?NMR(CDCl ₃)：δ?1.20(t，3H，J＝7.3Hz)1.40(t，3H，J＝7.1Hz)2.90(q，2H，J＝7.3Hz)4.30(q，2H，J＝7.1Hz)5.75(s，1H)

C ₁₀H ₁₅N ₂O ₃(MH) ⁺Quality: 211, experimental value: 211.

Under 70 ℃, be used in BnBr (2.44g, 1 equivalent) and K in the 100mL acetone ₂CO ₃(3.94g, 2 equivalents) handle compound 99d (3.0g, 14.28mmol) 17 hours.Remove and desolvate, chromatogram purification (5%EtOAc in hexane) obtains 2.53g pure compound 99e, productive rate 58%.

Under-78 ℃, be used in the Et among the 5mL DCM ₃N (0.22g, 2.2 equivalents), COCl ₂(1.9M in toluene, 0.53mL, 1 equivalent) handles compound 99e (0.3g, 1mmol) 45 minutes.The temperature reaction mixture is to room temperature in 1 hour.Add NH ₃(1, in 4-two _ alkane, 0.5M, 2mL, 1 equivalent), stirred reaction mixture spends the night.Remove then and desolvate, t-BuOK (1M in THF, 1mL, 1 equivalent) is added with the anhydrous THF of 3mL, and stir the mixture and spend the night.Remove and desolvate, add hexane and a small amount of MeOH, collect the white solid that obtains.Further wash solid, obtain 3.8mg embodiment 99, be white solid with anhydrous diethyl ether.

¹H?NMR(CDCl ₃)：δ?1.20(t，3H，J＝7.3Hz)3.10(q，2H，J＝7.3Hz)5.40(s，2H)6.40(s，1H)7.20-7.40(m，4H)8.30(m，2H)

C ₁₆H ₁₆N ₃O ₃(MH) ⁺Quality: 298, experimental value: 298.

Preparation embodiment 100

According to preparing embodiment 100, except using methyl-iodide to replace BnBr and using cyclopropyl-methylamine to replace the ammonia with the similar process of preparation embodiment 99 used those processes.

¹H?NMR(CDCl ₃)：δ?0.40(m，4H)1.18-1.25(m，4H)3.10(q，2H，J＝7.2Hz)(3.82(d，2H，J＝7.4Hz)3.90(s，3H)6.38(s，1H)8.10(br?s，1H)

C ₁₄H ₁₈N ₃O ₃(MH) ⁺Quality: 276, experimental value: 276.

Preparation embodiment 101

Use with the similar process of preparation embodiment 99 used those processes to prepare midbody compound 101a, replace the ammonia except using the ring butylamine.

¹H?NMR(CDCl ₃)：δ?1.20(t，2H，J＝7.3Hz)1.60-1.80(m，2H)2.10(m，2H)3.00(m，2H)3.10(q，2H，J＝7.3Hz)5.30(m，1H)5.40(s，2H)6.40(s，1H)7.204.40(m，5H)8.20(br?s，1H)

C ₂₀H ₂₂N ₃O ₃(MH) ⁺Quality: 352, experimental value: 352.

Handling compound 101a (70mg) with 3%Pd/C (50mg), 10mL MeOH down at hydrogen atmosphere (hydrogen balloon) spends the night.After the filtration,, obtain 1.2mg embodiment 101 by preparation HPLC purifying.

¹H?NMR(CDCl ₃)：δ?1.20(t，2H，J＝7.3Hz)1.60-1.80(m，2H)2.10(m，2H)2.95(m，2H)3.20(q，2H，J＝7.3Hz)5.30(m，1H)6.40(s，1H)8.00(br?s，1H).

C ₁₄H ₁₇N ₃O ₃(MH) ⁺Quality: 276, experimental value: 276.

Preparation embodiment 102

In the 25mL round-bottomed flask that is equipped with magnetic stirring bar and nitrogen balloon, put into 1.0g barbituric acid (7.8mmol) and 1.52mL 3-oxygen Methylheptanoate (9.6mmol, 1.23 equivalents).In reaction mixture, add 8mL acetate, and refluxed 16 hours, cool off reactant then to room temperature.Concentrate excessive acetic acid and dry in a vacuum, obtain crude product embodiment 102 and unreacted starting raw material.Week 20mL boiling water stirring crude product several minutes also filters.(2 * 10mL) washing precipitates are also dry, obtain 0.65g (productive rate 35%) embodiment 102 with boiling water.

¹H?NMR(DMSO)：δ0.9(t，3H，J＝7.5Hz)1.32-1.40(m，2H)1.45-1.51(m，2H)2.84-2.87(t，2H，J＝7.5Hz)5.82(s，1H)11.34(s，1H)12.72(br?s，1H)

C ₁₁H ₁₂N ₂O ₄(MH) ⁺Quality: 236.22, experimental value: 237.1.

Embodiment 103-135

Use with the similar process of preparation embodiment 102 used those processes to prepare embodiment 103-135, except the ketone ester that uses suitable replacement replaces 3-oxygen Methylheptanoate.

By preparing embodiment 200,210,241,242,245,246,252-260,274-278,280,281,282,284,285,291 with the similar process of the used process of the preparation of embodiment 30 and 31.

Use barbituric acid and corresponding ketone ester, by preparing embodiment 201,202,204-209,211-218,224-240,243,244,247-251,261-273,279,283,286-290,293,294-297 with the similar process of the used process of the preparation of embodiment 102.

Show the preparation of suitable ketone ester starting raw material below.

Being prepared as follows of the ketone ester starting raw material of embodiment 247.

Preparation embodiment 247a

Dissolving 4-methylhexanoic acid in 40mL THF (3.0g, 23.08mmol).Add 1, (4.49g, 27.69mmol), at room temperature reaction stirred is 1 hour, adds MgCl then for 1 '-carbonyl dimidazoles ₂(2.2g, 23.08mmol) and the potassium malonic ester (5.89g, 34.62mmol).Reaction is at room temperature spent the night.Filter crude product mixture and, produce compound 247a by short silica filler with EtOAc/ hexane (1: 3) wash-out.

Preparation embodiment 223a

The starting raw material of preparation embodiment 23 is as follows.

Step 1: handle 0 ℃ phosphonic acids triethyl (44.8g, 200mmol) solution in THF (30ml) with the 1M solution (200ml) of two (trimethyl silyl amino) sodium in THF.The mixture that stirring at room temperature obtains 0.5 hour is cooled to 0 ℃ then.Drip 1,4-cyclohexanedione one ethylidene ketal (15.6g, the 200mmol) solution in THF (50ml), the solution that stirring at room temperature obtains 18 hours.Reaction mixture to 0 ℃ is handled with cold aqueous citric acid solution then, extracts mixture with EtOAc.Use saturated NaHCO ₃The aqueous solution, salt water washing extract are at Na ₂SO ₄Last dry, filter concentrated filtrate.The chromatographic separation resistates is used CH on silica gel ₂Cl ₂/ EtOAc gradient elution obtains 223b (21g, 91%).

Step 2: compound 223b (20g) is dissolved among the EtOH (150mL), and under latm hydrogen, handled 3 days with 10%Pd/C.Filtering mixt, evaporated filtrate obtain 223c (20.3g, 100%).

Step 3: compound 223c (7g) is dissolved in the formic acid (50ml), and heated 1 hour down at 70 ℃.Concentrated solution, the dissolving resistates is also used saturated NaHCO in EtOAc ₃The aqueous solution, salt water washing are at Na ₂SO ₄Last dry and concentrated.The chromatographic separation resistates obtains 223d (5g) on silica gel.

Step 4: compound 223d (4.6g) is dissolved in CH ₂Cl ₂(10ml), and (DAST 5ml) handled 3 hours at room temperature to fluoridize diethylamino sulphur with three.Reaction mixture is poured in ice/water (30ml), and uses CH ₂Cl ₂Extraction.Use saturated NaHCO ₃The aqueous solution, salt water washing extract are at Na ₂SO ₄Last dry and concentrated, obtain 223e, be brown oil (3.2g, 62%).

Step 5: (3.2g 15.5mmol) is dissolved among the MeOH (5ml), and (559mg, 23.3mmol) processing is spent the night with LiOH with compound 223e.To pH4, and use CH with 3N HCl acidified reaction mixture ₂Cl ₂Extraction.At Na ₂SO ₄Last dry extract also concentrates and obtains 223f, is brown oil (3g, 100%).

Step 6: with compound 223f (900mg 5.0mmol) is dissolved among the THF (15ml), add CDI (972mg, 6.0mmol) and stirred 45 minutes.In above-mentioned solution, add then propanedioic acid methyl esters sylvite (1.02g, 6.0mmol) and MgCl ₂(570mg, 6.0mmol).The mixture overnight that stirring obtains, and by short silica filler filtration, wash with EtOAc.Concentrated filtrate and on silica gel chromatographic separation obtain 223a, be water white oil (400mg, 34%).

By preparing the starting raw material of structure 262,263 with the similar mode of 218a.

Preparation embodiment 262a

By with embodiment 218a in identical mode prepare.

Preparation embodiment 263a

By with embodiment 218a in identical mode prepare.

Preparation embodiment 266a

In the round-bottomed flask that is equipped with stirring rod and nitrogen balloon in THF (20ml) dissolving sodium hydride (1.42g, 35.56mmol).It is cooled to 0 ℃, and drip the methyl acetoacetate be dissolved among the 10mL THF (3.84mL, 35.56mmol).0 ℃ of following stirred reaction mixture 30 minutes, drip then n-BuLi (the 2.5M solution in hexane, 14.2ml, 35.56mmol).Make to be reflected at and carried out under 0 ℃ 30 minutes, be cooled to-25 ℃ then.Dropping is dissolved in bromomethyl tetramethylene among the 20mL THF, and (4.82g 32.32mmol) ,-25 ℃ of following reaction stirred 4 hours, at room temperature spends the night then.By adding saturated NH ₄The Cl quencher, (2 * 30mL) extractions are at MgSO with EtOAc ₄Last dry, concentrate in a vacuum.By biotage (5%EtOAc/ hexane) purifying crude product, obtain compound 266a.

Preparation embodiment 267a

By with embodiment 218a in identical mode prepare.

Preparation embodiment 268a

Will the trifluoroacetic acid among the 50mL DCM (7.84mL, 105.48mmol) and methylene iodide (8.5mL 105.48mmol) is cooled to 0 ℃.The dropping zinc ethyl (the 1.0M solution in hexane, 105.5mL, 105.48mmol).0 ℃ of following reaction stirred 20 minutes, drip then 5-methyl-5-hexenoic acid methyl esters in 20mL DCM (5.0g, 35.16mmol).At room temperature reaction stirred is spent the night.By adding saturated NH4Cl quencher reaction, (2 * 30mL) extractions are at MgSO with DCM ₄Last dry, concentrated in a vacuum obtaining, compound 268b need not be further purified and just use it for next step.

Dissolving ester 268b in MeOH (50mL) (5.0g, 32mmol), and to wherein add NaOH (3.2g, 80mmol).At room temperature reaction stirred is spent the night.Water (50mL) diluting reaction thing, and with dense HCl acidifying.Use Et ₂(2 * 30mL) extractions are used the salt water washing, at MgSO to O ₄Last dry, and concentrate in a vacuum.Need not anyly be further purified with regard to original state and use crude product 268c.

Prepare according to the mode identical with embodiment 262a.

Preparation embodiment 269a

Prepare according to the mode identical with embodiment 266a.

Preparation embodiment 279a

In MeOH (50mL) dissolving 5,5-dimethyl-dihydro-furan 2-ketone (5.0g, 43.8mmol), trimethyl orthoformate (11.5mL, 105.12mmol) and sulfuric acid (0.43g, 4.38mmol).Reaction mixture is heated to 50 ℃ to spend the night.After the cooling, remove in a vacuum and desolvate, use saturated NaHCO ₃Quencher, and with EtOAc (2 * 30mL) extraction.With salt water washing organic layer, at MgSO ₄Last dry, and concentrate in a vacuum, obtaining compound 279b, it need not just anyly be further purified and can use.

Prepare by the mode identical with embodiment 268c.

Prepare by the mode identical with embodiment 262a.

Preparation embodiment 288a

(the 2M solution in THF/ heptane/ethylbenzene, 43.4mL 86.82mmol), and are cooled to-78 ℃ to the dissolving lithium diisopropylamine in THF (30mL).(6g 86.82mmol) and-78 ℃ of following reaction stirred 1 hour, stirred 2 hours down at 0 ℃ the isopropyl cyanide of dropping in THF (10mL).(21.1g 86.62mmol), makes reaction mixture be warmed up to ambient temperature overnight to the benzyl 4-brombutyl ether of dropping in THF (10mL).By adding saturated NH ₄Cl quencher reaction, and use Et ₂The O extraction.With salt water washing organic layer, at MgSO ₄Last dry, and concentrate in a vacuum.Crude compound by biotage (5%EtOAc/ hexane) purifying obtains produces compound 288b.

In the 100mL round-bottomed flask that is equipped with stirring rod and nitrogen balloon at CH ₂Cl ₂Dissolved compound 288b (25mL), and be cooled to-78 ℃.(the 1.0M solution in hexane, 43.2mL 43.2mmol), and make reactant be warmed up to 0 ℃ gradually to drip boron trichloride.After 1 hour, by adding saturated NaHCO ₃The quencher reactant, and use CH ₂Cl ₂Extraction.With salt water washing organic layer, at MgSO ₄Last dry, and concentrate in a vacuum, produce crude compound, filter the purifying crude compound by short silica filler, with 50%EtOAc/ hexane wash-out, produce compound 288c.

Dissolved compound 288c in acetone (20mL) (3.0g, 21.2mmol) and be cooled to 0 ℃.It is constant green to drip Jones reagent color when adding reagent.By adding i-PrOH quenching excess reagent, water (20mL) is used Et ₂The O extraction.With salt water washing organic layer, at MgSO ₄Last dry, and concentrate in a vacuum, produce compound 288d, just be not further purified and use.

Prepare by the mode identical with embodiment 262a.

Preparation embodiment 293a

In the 500mL round-bottomed flask that is equipped with stirring rod and nitrogen balloon in 100mL THF two (trimethyl silyl) Lithamides of dissolving (the 1.0M solution in THF, 108.9mL, 108.9mmol).Cooling solution to 0 ℃, and add in batches that the chlorination of (methoxymethyl) triphenyl _ (37.3g 108.9mmol), stirred dark red solution 45 minutes at 0 ℃.(10g 90.78mmol), 0 ℃ of following reaction stirred 3 hours, is poured into reaction mixture in the hexane the two cyclopropyl ketone of dropping in THF (10mL) then.By the filtered through silica gel mixture, use the hexane wash-out.Removing desolvates obtains thick enol ether.The thick enol ether of dissolving in THF (100mL), and add 10%HCl (100mL).Reactant is refluxed to spend the night.During cooling, dilute with water, and use Et ₂(2 * 50mL) extractions are used the salt water washing, at MgSO to O ₄Last dry, and concentrate in a vacuum.Be not further purified direct use crude mixture 293b.

In the 250mL round-bottomed flask that is equipped with magnetic stirring bar and nitrogen balloon in THF (30mL) dissolving sodium hydride (6.44g, 161mmol).Cooling mixture to 0 ℃.(the 36.1g's triethyl phosphonium mesitoyl acetate of dropping in 20ml THF 161mmol), and at room temperature stirred the mixture 1 hour, cooling is got back to 0 ℃ then, the compound 293b of dropping in 20mL THF (10g, 80.5mmol), and reaction stirred 2 hours at room temperature.React by adding the entry quencher, and use Et ₂The O extraction.With salt water washing organic layer, at MgSO ₄Last dry, and concentrate in a vacuum.With biotage (2%EtOAc/ hexane) purifying crude product, produce compound 293c.

In the 200mL round-bottomed flask in 100mL EtOH dissolved compound 293c.(10wt%, 7.0g 5.7mmol), use hydrogen balloon hydrogenated mixture 12 hours at ambient temperature to add Pd/C in solution.By the diatomite filtration mixture, and use the EtOH wash-out, obtain crude compound 293d when desolvating when removing.

Prepare by the mode identical with embodiment 268c.

Prepare by the mode identical with embodiment 262a.

Preparation embodiment 294a

Prepare by the mode identical with embodiment 288a.

Preparation embodiment 295a

Prepare by the mode identical with embodiment 262a.

Preparation embodiment 292a

The starting raw material that is used to prepare embodiment 292 is as follows:

To phenyl-iodide (10.2g, 50mmol) anhydrous DMSO (150mL) and 3-oxygen Methylheptanoate (15.8g, 100mmol) add in the solution in cupric iodide (I) (1.9g, 10mmol), the L-proline(Pro) (2.3g, 20mmol) and cesium carbonate (65.2g, 200mmol).At N ₂In 40 ℃ down stir 18 hours after, reaction mixture is dissolved in the ethyl acetate (250mL) water (4 * 150ml) washings.Use dried over sodium sulfate organic solution, and under reduced pressure concentrate.The crude product that uses silica gel flash column chromatography purifying to obtain with ethyl acetate/hexane (v/v=5/95) wash-out, obtains compound 292a (4.5g, 38%).

Preparation embodiment 297a

The starting raw material that is used to prepare embodiment 297 is as follows:

To be cooled to 0 ℃ 2-cyclopentyl ethanol (11.4g, 100mmol), anhydrous CH ₂Cl ₂(80mL) and triethylamine (12g, in solution 120mmol) by syringe add MsCl (13.7g, 120mmol).At N ₂In 0 ℃ down stir 1 hour after, at room temperature stirred again 18 hours, (2 * 100mL) washing reaction mixtures use dried over sodium sulfate to water, and the under reduced pressure concentrated clean oil (19g, 100%) that obtains.Oil is dissolved into anhydrous CH ₂Cl ₂(250mL), and with NaI (20g 200mmol) mixes.After at room temperature stirring 18 hours, from the solid filtering reaction mixture.Under reduced pressure concentrate the filtrate that obtains and obtain the brown paste.Paste is dissolved in the diethyl ether (300mL), and (dried over sodium sulfate is used in 2 * 150mL) washings to water, under reduced pressure concentrates and obtains compound 297b (20g, 89%).

To be cooled to 0 ℃ methyl acetoacetate (5.8g, 50mmol) and add in the solution of anhydrous THF (100mL) NaH (60%, 2.4g, 60mmol).At N ₂In 0 ℃ down stir 0.5 hour after, by syringe add n-BuLi (2.5M in hexane, 20mL).After stirring 0.5 hour under 0 ℃, reaction mixture is cooled to-25 ℃, add compound 297b by syringe., at room temperature stirred then 18 hours after 0.5 hour at 0 ℃ of following stirred reaction mixture.With saturated ammonium chloride (200mL) quenching reaction mixture, and with ethyl acetate (2 * 200mL) extraction, water (2 * 100mL) washing.Use dried over sodium sulfate organic solution, and the under reduced pressure concentrated brown oil that obtains, use silica gel flash column chromatography purifying, with ethyl acetate/hexane (v/v=7/93) wash-out, obtain compound 297a (3.2g, 32%).

Preparation embodiment 214

In being equipped with the round-bottomed flask of magnetic stirring bar in DMF (50mL) dissolved compound 214a (10g, 48.04mmol).Add N-iodosuccinimide (22g, 97.79mmol), and reacting by heating mixture to 50 ℃ spends the night in batches.After being cooled to envrionment temperature, add H ₂O (100mL).Filtration product, water, ether washing obtain white pulverulent mixture (＞95% productive rate) successively.Product 214b can be directly used in following step and need not anyly be further purified.

In the 10mL round-bottomed flask at C ₆H ₆Dissolved compound 214b (1mL) (0.1g, 0.3mmol).Add Pd (OAc) ₂(0.004g, 0.018mmol), PPh ₃(0.014g, 0.054mmol) and Na ₂CO ₃(0.5mL, 2M solution), at room temperature stirred reaction mixture is 30 minutes.(0.042g 0.33mmol), and spends the night reaction mixture refluxed (80 ℃) to be added in anti-form-1-hexene-1-ylboronic acid among the EtOH (0.5mL).After the cooling, use H ₂O (2mL) diluted mixture thing is with EtOAc (2 * 10mL) extractions.At MgSO ₄Last dry, concentrate and drying, produce crude compound 214.By preparation TLC (10%MeOH/DCM) purifying, produce compound 214.

Preparation embodiment 219

In the 10mL round-bottomed flask in DMF (3.0mL) dissolved compound 214b (0.1g, 0.3mmol).Add PdCl ₂(PPh ₃) ₂(0.011g, 0.015mmol), phenylacetylene (0.061g, 0.6mmol), CuI (0.006g, 0.03mmol) and triethylamine (0.091g, 0.9mmol), at room temperature stirred reaction mixture spends the night.With ETOAc (5mL) diluted reaction mixture, with 1N HCl neutralization, (2 * 10mL) extractions are at MgSO with EtOAc ₄Last dry, concentrate and drying, produce crude product 219.Dissolving crude product and filtration produce pure compound 219 in ether.

Preparation embodiment 220

(1.0g, 7.81mmol) (1.45g, 9.4mmol), and the reacting by heating mixture spends the night to refluxing dissolving barbituric acid 220a in Glacial acetic acid (8mL) with ketone ester 220b.Behind the cool to room temperature, remove acetic acid in a vacuum, add hot water to remove excessive barbituric acid.Repeat this process several times, up to no longer leaving starting raw material.Wash with ether then.Desciccate 220c and do not need to be further purified.

In the 10mL round-bottomed flask in DMF (1mL) dissolved compound 220c (0.1g, 0.431mmol).Add phenyl-iodide (0.053g, 0.258mmol), PdCl ₂(PPh ₃) ₂(0.003g, 0.0043mmol), CuI (0.002g, 0.0086mmol) and Et ₂(0.157g, 2.15mmol), at room temperature stirred reaction mixture spends the night NH.With ETOAc (2mL) diluting reaction thing, with 1N HCl neutralization, with EtOAc (2 * 10mL) extractions.At MgSO ₄Last dry, concentrate in a vacuum.By preparation TLC (20%MeOH/DCM) purifying crude product, produce compound 220.

Preparation embodiment 216

Dissolving barbituric acid 220a in Glacial acetic acid (8mL) (1.0g, 7.81mmol) and β-ketoadipic acid diethyl ester 216a (2.03g, 9.4mmol), and the reacting by heating mixture spends the night to backflow.Behind the cool to room temperature, remove acetic acid in a vacuum, add hot water to remove excessive barbituric acid.Repeat this process several times, up to no longer leaving raw material.Wash with ether then.Desciccate 216 and do not need to be further purified.

The raw material that is used to prepare embodiment 203 is as follows.

Preparation embodiment 203

Step 1:

To the ethylphenyl acetic ester under-78 ℃ (8.2g, 0.05mol) add in the solution in THF LHMDS (in THF, 1M, 100ml, 0.10mol) and stirred 20 minutes.Quick adding propionic anhydride (6.5ml, 0.05mol).Make mixture be warmed up to 0 ℃, and stirred 30 minutes.Use NH ₄Cl (aqueous solution) quencher, and extract with EtOAc.Carry out conventional processing, obtain roughage, chromatographic separation obtains product on silica gel.

Step 2:

Utilize the cyclobutyl barbituric acid to obtain compound 203 by conventional condensation course.

Preparation embodiment 209

Steps A:

(9.9g 75mmol) is dissolved in THF (100mL) and the water (25mL) with raw material 209a.(3.4g 80.9mmol), at room temperature stirs the mixture overnight that obtains to LiOH.Add 1N HCl (100mL), and extract with EtOAc.Merge organic extract, use the salt water washing, dry (MgS0 ₄), obtain compound 209b (8.8g, 93%).

Step B:

(1.9g 16.1mmol) is dissolved among the THF (50mL) with compound 209c.Add CDI (12.3mmol).The mixture that stirring at room temperature obtains 1 hour.Add MgCl ₂(1.5g, 16.1mmol) and KOCOCH ₂CO ₂(3.8g 24.2mmol), at room temperature stirs the mixture overnight that obtains to Me.Add EtOAc (100mL), water (50mL).Separate water layer and extract with EtOAc.Use the EtOAc aqueous layer extracted.Merge organic extract, use the salt water washing, dry (MgSO ₄), filter and concentrate.Separate resistates by silica gel chromatography, utilize Biotage 40S+ post, use EtOAc: 1: 10 wash-out of hexane, obtain 2.1g (74%) yellow liquid, be compound 209d.

Step B:

In sealed tube, make compound 209c (1.13g, 6.49mmol) and barbituric acid (0.5g 3.90mmol) mixes with HOAc (2mL), and in 125 ℃ oil bath heated overnight.Cooling mixture is removed HOAc, and dissolve resistates in MeOH to room temperature, filters.The volume that reduces mother liquor begins to separate out up to solid, collects beige solid and obtains compound 209 (153mg, 10%).Electron spray(ES) MS[M+1]: 253.1.

By commercial available compound 208a according to preparing compound 208 with compound 209 similar modes.

Preparation embodiment 270

Steps A:

Make the raw material lactone (10g, 116mmol) with allyl bromide 98 (30mL, 346mmol), toluene (75mL) and KOH (19.5g, 348mmol) mixing.Spend the night at 110 ℃ of following heated mixt.Cooling mixture adds entry (100mL) to room temperature.Use the EtOAc aqueous layer extracted.Merge organic extract, use the salt water washing, dry (MgSO ₄), filter and concentrate, obtain yellow liquid, be required compound 270a (11.8g, 55.2%).

Step B:

(3.0g 16.3mmol) is dissolved among the EtOH (20mL), adds 10%Pd/C (300mg) with compound 270a.At H ₂Under stir slurries and spend the night.By the diatomite filtration mixture, concentrated filtrate obtains yellow liquid, is required compound 270b (2.5g, 81%).

Step C:

(3.0g 16.3mmol) is dissolved in THF (20mL)-H with compound 270b ₂Among the O (7mL), and adding LiOH (1.66g, 39.5mmol).At room temperature stir the mixture overnight that obtains.Add 1N HCl (75mL), and use Et ₂The O extraction.Merge organic extract, dry (MgSO ₄), filter and concentrate.Resistates is dissolved among the THF (50mL), adds CDI (12.3mmol).The mixture that stirring at room temperature obtains 1 hour.Add MgCl ₂(1.3g, 13.6mmol) and KOCOCH ₂CO ₂(2.9g 18.5mmol), at room temperature stirs the mixture overnight that obtains to Me.Add EtOAc (100mL), water (50mL).Separate water layer and extract with EtOAc.Use the EtOAc aqueous layer extracted.Merge organic extract, use the salt water washing, dry (MgSO ₄), filter and concentrate.Separate resistates by silica gel chromatography, utilize Biotage 40S+ post, use EtOAc: hexane, 1: 10 wash-out obtains 1.5g (46%) yellow liquid, is compound 270d.

Step D:

In sealed tube, make compound 270d (448mg, 2.22mmol) and barbituric acid (340mg 2.65mmol) mixes with HOAc (2mL), and in 125 ℃ oil bath heated overnight.Cooling mixture is removed HOAc, and dissolve resistates in MeOH to room temperature, filters.Concentrated mother liquor, TLC separates by preparation, with 1: 10: 10 HOAc: DCM: the EtOAc wash-out, obtain required compound 270 (72mg, 11.4%), be white solid.Electron spray(ES) MS[M+1]: 281.2.

Preparation embodiment 271

Steps A:

With raw alcohol (5.2g 28.0mmol) is dissolved among the DCM (100mL), add triethylamine (6mL, 42.7mmol) and MsCl (2.6mL, 32.6mmol).The solution that stirring at room temperature obtains 1 hour.With EtOAc diluted mixture thing, and wash with 1N HCl (50mL * 2).Combining water layer extracts with EtOAc.Merge organic layer, use the salt water washing, dry (MgSO ₄), filter, concentrate and obtain compound 271a (7.26g, 100%).

Step B:

(3.8mL 42mmol) is dissolved among the THF (50mL) with cyclopentanol in nitrogen.Adding NaH (0.85g, 95% oil dispersion, 33.7mmol).The slurries that stirring at room temperature obtains 1 hour.Add mesylate 271a (7.26g, 28mmol) solution in DMF (30mL) by syringe.Heat the mixture overnight that obtains down at 85 ℃.Cooling mixture arrives room temperature, and extracts with EtOAc, water (50mL * 3) washing.Combining water layer, and extract with EtOAc.Merge organic extract, use the salt water washing, dry (MgSO ₄), filter, under vacuum, concentrate.Purifying resistates on silicagel column with EtOAc-hexane (1: 10) wash-out, obtains 4.95g (71%) compound 271b, is amber color liquid.

Step B:

(4.95g 20mmol) is dissolved among the EtOH (100mL), adds 10%Pd/C (0.55g), and stirs under the latm nitrogen atmosphere and spend the night with compound 271b.By diatomite filtration, concentrated filtrate in a vacuum.Purifying resistates on silicagel column with ETOAc-hexane (1: 3) wash-out, obtains 3.1g (98%) compound 271c, is colourless liquid.

Step C:

Make CrO ₃With the dense H of 4.7mL ₂SO ₄Mix.The dilute with water mixture is to 36mL.Compound 271c is dissolved in the acetone (30mL), and adds Jones reagent.At room temperature stirred the mixture 1 hour, dilute with water, and extract with DCM.Merge organic extract, use the salt water washing, dry (MgSO ₄), filter, concentrate and obtain 1.99g (71%).

Step D:

With compound 217d (2.40g 14.0mmol) is dissolved among the THF (50mL), add CDI (2.48g, 15.3mmol).The mixture that stirring at room temperature obtains 1 hour.Add MgCl ₂(1.5g, 15.3mmol) and KOCOCH ₂CO ₂(3.3g 20.9mmol), at room temperature stirs the mixture overnight that obtains to Me.Add EtOAc (100mL), water (50mL).Separate water layer and extract with EtOAc.Use the EtOAc aqueous layer extracted.Merge organic extract, use the salt water washing, dry (MgSO ₄), filter and concentrate.By the silica filler filtration residue, with 1: 3 EtOAc: the hexane wash-out, obtain 2.2g (69%) yellow liquid, be compound 270e.

Step D:

In sealed tube, make compound 271e (448mg, 2.22mmol) and barbituric acid (340mg 2.65mmol) mixes with HOAc (2mL), and in 125 ℃ oil bath heated overnight.Cooling mixture is removed HOAc, and dissolve resistates in MeOH to room temperature, filters.Concentrated mother liquor, TLC separates by preparation, with 1: 10: 10 HOAc: DCM: the EtOAc wash-out, obtain required compound 271 (55mg, 4%), be white solid.Electron spray(ES) MS[M+1]: 307.2.

By corresponding alcohol by preparing compound 273, compound 287 and compound 290 with compound 271 similar modes.

Preparation embodiment 205

(50mg 0.14mmol) is dissolved in DMF (2mL) and H with compound 205a ₂Among the O (2mL), add Pd (dppf) ₂Cl ₂And K ₂CO ₃The mixture that heating obtains under 85 ℃ in nitrogen 5 hours.Cooling mixture arrives room temperature, and passes through diatomite filtration.Concentrated filtrate.Resistates is dissolved among the MeOH, adds DCM, continue up to precipitation.Collecting solid is required compound 205 (21mg, 40%).Electron spray(ES) MS[M+1]: 481.5.

Use corresponding boric acid, by preparing compound 207 with compound 205 similar modes.

Some compounds of the present invention have been shown in the following table and in the table that provides later in this specification sheets.When containing the LCMS data, also show the LCMS data.When measuring and the EC50 data are arranged, also shown active (EC50) data, and be appointed as A, B or C, A=0.001nM-100nM wherein, B＞100 and＜1000nM, C＞1000nM.

NA?EC50

Compound # molecular structure electron spray(ES)

camp?nM

LCMS

[M+1]+

200

B 331.2

201

C 289.2

Use embodiment 10 and suitable correspondent alcohol, by preparing compound 500-690 with the similar process of the used process of the preparation of embodiment 49.

The sulfoxide that uses suitable oxygen amino-carbamic acid ester and use embodiment 10 to prepare is by preparing compound 691 and 698 with the similar process of the used process of the preparation of embodiment 49.

NA

Electron spray(ES)

EC50

Compound # molecular structure LCMS

Camp

[M+1]+

nM

500

B 363.1

501

A 363.1

502

B 343

503

B 368

504

B 327

505

B 327

506

C 335

507 A 363

508

C 381.1

509

B 400

510

C 393

511

C 358.2

512

A 275

513

B 304

514

C 435

515

B 363

516

C 381

517

C 375.2

518

B 393.2

519

C 295.1

520

C 376.2

521

B 401.2

522

B 323

523

A 300.2

524

B 267.1

525 B 329.2

526 B 380

527

B 350

528

B 350

529

B 317

530

B 317

531

B 380

532

B 383

533

C 370

534

B 384

535

B 380

536

B 379

537

C 363

538

B 355

539

B 327

540

B 366

541

B 386

542

C 379

543

B 354

544 B 330.2

545

B 368.2

546

B 369.99

547 B 447

548 B 405

549 B 419

550

C 389

551

B 432

552

B 446

553

C 458

554

C 409

555

B 247

556

C 314.2

557 A 289

558

C 427

559

B 393

560

C 426

561

B 405

562

B 406

563

B 376

564

B 409

565

B 435

566 C 393

567

B 400

568

B 368.2

569

A 407.2

570

B 365.1

571

B 366.1

572

B 423.1

573

B 461.1

574 B 394.1

575 B 395.1

576

C 343.2

577 B 343.2

578

C 320.2

579

C 306.2

580

C 281.2

581

C 279.2

582

B 266.1

583 B 379.2

584

B 418

585

B 418

586

A 383.1

587

C 379.1

588

C 315.1

589

A 287

590 B 275

591

A 411.1

592

B 320.2

593

C 307.2

594

C 320.2

595

B 295.2

596

B 343.2

597

C 398.1

598

B 343.1

599

B 343.1

600

C 409.1

601

C 293.1

602

B 398.1

603

B 327.2

604

B 387.2

605

C 309.2

606

C 321

607

B 281.2

608

B 384.2

609

C 376.1

610

C 335

611

C 324.2

612

C 364.2

613 B 412.1

614

B 347.1

615

B 337.1

616 B 379.2

617

B 397.2

618

B 343.2

619B 342.2

620

C 322.2

621

B 322.2

622

B 389.2

623

A 357.2

624

B 365.2

625

B 318.2

626

A 358

627

C 361.2

628

C 366.2

629

B 334.2

630 C 324.2

631

B 277

632

B 281.2

633

B 329.2

634

B 405

635

C 395

636

B 291

637

B 309.2

638

B 329

639

B 283

640

B 400.1

641 A 304

642

B 297.2

643

B 253.1

644

A 291

645

A 305

646

C 373.2

649

B 368

650

B 329.2

651

B 520

652 A 280.1

653

C 399.2

654

A M+Na?391.2

655 B 346.2

656

C 332

657

C 290

658

B 291

659

C 399.2

661

B 371.2

662

A 399.2

663

C 439.2

664 B 305

665

C 304

666

A 332

667

B 346

668

C 304

669

B 319

670

A 319.2

671

A 305

672

B 305

673

B 359

674

A 303

675 B 346

676 B 360

677

A 315

678

B 331

679

A 333

680

A 319

681

C 344.2

682

C 328.2

683

C 360.2

684

A 371.2

685 B 412.2

686

B 279.2

687 B 305.2.

688

B 374.2

689

B 400.2

690

C 241.1

691 A 350.2

The experiment of compound 699-710 is described below:

Preparation embodiment 699

In being equipped with the round-bottomed flask of magnetic stirring bar in DMF (10mL) dissolved compound 699a (0.925g, 3.53mmol).Add N-iodosuccinimide (1.59g, 7.05mmol), reacting by heating mixture to 50 ℃ spends the night in batches.After being cooled to envrionment temperature, add H ₂O (25mL).Filtration product, water are the ether washing then, obtain white pulverulent mixture (productive rate＞95%).Product 699b is directly used in following step, need not anyly be further purified.

In the 10mL round-bottomed flask at 5mL DME/H ₂Dissolved compound 699b among the O (4: 1) (0.1g, 0.258mmol).Add PdCl ₂(PPh ₃) ₂(0.018g, 0.0258mmol), Na ₂CO ₃(0.082g, 0.774mmol) and phenyl-boron dihydroxide (0.057g 0.464mmol), makes reaction mixture refluxed (80 ℃) 6 hours.After the cooling, enriched mixture, and by flash chromatography (CH ₂Cl ₂To 5%MeOH/CH ₂Cl ₂) purifying, obtain compound 699.

Prepare compound 700 by the mode identical with embodiment 699.

Prepare compound 701 by the mode identical with embodiment 699.

Prepare compound 702 by the mode identical with embodiment 699.

Prepare compound 703 by the mode identical with embodiment 699.

Prepare compound 704 by the mode identical with embodiment 699.

Prepare compound 705b by the mode identical with embodiment 699b.

Prepare compound 705 by the mode identical with embodiment 699.

Prepare compound 706 by the mode identical with compound 699.

Prepare compound 707 by the mode identical with compound 699.

Prepare compound 708 by the mode identical with compound 699.

Prepare compound 709 by the mode identical with compound 699.

Prepare compound 710 by the mode identical with compound 699.

Analyze:

Use MesoScale Discovery cAMP detection kit,, assemble the nicotinic acid receptor agonists activity that suppresses to determine The compounds of this invention by following the trail of the cAMP that forskolin stimulates in the cell according to manufacturer's rules.In brief, enzymatic results Chinese hamster ovary (CHO) cell expressing recombinant human niacin receptor (NAR), washing 1X in phosphate buffered saline (PBS) (PBS), and with 3 * 10 ⁶Individual cell/mL is resuspended among the PBS that comprises 0.5mM IBMX.In each hole of the 384-hole culture dish that comprises 10 μ L test compounds, add 10 μ L cell suspending liquids.With the PBS dilution test compound that comprises 6 μ M forskolin.After adding cell, at room temperature hatched culture dish 30 minutes.According to manufacturer's rules, add the dissolving damping fluid (10 μ L/ hole) that comprises cAMP-Tag to each hole.Hatch then culture dish from 45 minutes to a night.Before the reading, add 10 μ L reading damping fluids to each hole, and on Sector 6000 culture dish imagers to the culture dish reading.Use the typical curve on each culture dish that conversion of signals is become cAMP concentration.Determine compd E C by the concentration gradient of test compound ₅₀Value.

The compound of formula of the present invention (I) and its salt, solvate or ester have the cAMP EC less than about 10000nM ₅₀Value, preferably about 1000nM or following, 500nM or following more preferably from about, further preferred about 100nM or following.

Embodiment 1,5,10,29,39,71,101-116 and 118-135 have 100nM or following cAMP EC ₅₀Value.

Below table in shown the activity of the non-limiting tabulation of the exemplary The compounds of this invention by above-mentioned assay determination:

Active table

Compound number molecule knot NA EC50 camp

nM

The activity of several other compounds of the present invention is shown as A, B or C previously in this manual.Those skilled in the art can recognize that The compounds of this invention described herein shows excellent nicotinic acid receptor agonists activity.Although described the present invention in conjunction with above-mentioned specific embodiments, many selections, improvement and other variation are conspicuous to those skilled in the art.All this selections, improvement and variation all drop in the spirit and scope of the present invention.

Claims

1. the compound of formula (I) or its drug acceptable salt, solvate, ester or tautomer,

Wherein:

Q is selected from:

L is selected from:

R ⁵Be selected from H, alkyl ,-alkylidene group-C (O)-R ⁸,-alkylidene group-C (O)-N (R ¹¹) ₂,-alkylidene group-C (=N-O-alkyl)-aryl, cycloalkyl ,-alkylidene group-cycloalkyl ,-alkylidene group-C (O)-O-alkyl ,-alkylidene group-O-C (O)-alkyl ,-alkylidene group-C (O)-heterocyclic radical and thiazolinyl, wherein R ⁵Described cycloalkyl or the cycloalkyl moiety of described-alkylidene group-cycloalkyl does not replace or replaced R by one or more X groups ³The aryl moiety of described-alkylidene group-C (=N-O-alkyl)-aryl do not replace or replaced by one or more Y groups;

R wherein ⁷Described cycloalkyl do not replace or replaced R by one or more X groups ⁷The aryl moiety or the described aryl of described-C (O)-aryl do not replace or replaced by one or more Y groups; Perhaps

R wherein ⁹The cycloalkyl moiety of described-alkylidene group-cycloalkyl do not replace or replaced R by one or more X groups ⁹The aryl moiety of described-alkylidene group-aryl do not replace or replaced by one or more Y groups and

Condition is to work as R ⁹For-N (R ¹¹) ₂The time, m is 1 or 2;

Each R ¹¹Be independently selected from H, alkyl and aryl,

R wherein ¹¹Described aryl do not replace or replaced by one or more Y groups; Or two R ¹¹Group forms heterocyclic radical with the N atom that they connect;

Each R ¹²Be independently selected from alkyl, aryl and heteroaryl,

R ^cBe selected from H, alkyl, alkylidene group-aryl and-C (O)-alkyl,

R ^dBe selected from H, alkyl and alkylidene group-aryl,

N is 0,1,2 or 3;

M is 0,1 or 2; With

2. the compound of claim 1 or its drug acceptable salt, solvate, ester or tautomer, wherein:

R ²Aryl, unsubstituted heteroaryl that replaces for H, halogen, unsubstituted aryl, by one or more Y groups or the heteroaryl that is replaced by one or more Y groups;

R ¹And R ²Form 5-or 6-unit cyclenes basic ring with the ring carbon atom that they connected;

R ⁶Be selected from-OR ¹⁰, halogen and-N (R ⁷) ₂

R ⁹Be selected from (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) cycloalkyl, (C ₂-C ₆) thiazolinyl and-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl, wherein R ⁹Described-(C ₁-C ₆) alkylidene group-(C ₃-C ₇) (the C of cycloalkyl ₃-C ₇) cycloalkyl moiety do not replace or replaced R by one or more X groups ⁹Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups,

Each R ¹²Be (C independently ₁-C ₆) alkyl;

R ^aAnd R ^bBe (C independently of one another ₁-C ₆) alkyl;

R ^cBe H;

3. the compound of claim 2 or its drug acceptable salt, solvate, ester or tautomer, wherein:

R ¹Be selected from-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₃,-CH ₂CH ₂CH (CH ₃) ₂,-CH ₂CH ₂CH ₂CH (CH ₃) ₂,-CH (CH ₃) ₂,-CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH=CHCH ₃,-CH ₂CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂CH ₂CH ₂CH=CH ₂,-CH ₂-OH ,-CH (CH ₃)-OH, cyclobutyl ,-CH ₂-C (O)-O-CH ₂CH ₃,-CH ₂CH ₂CH ₂-O-CH ₃,-CH ₂CF ₃,-CHBrCH ₃,-CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂CH ₂CF ₃,-CH ₂CH ₂CH ₂Cl ,-CH ₂-(2-thiophenyl) ,-CH ₂CH ₂CH ₂-(2-thiophenyl) ,-CH ₂-cyclopropyl ,-CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂-cyclopropyl ,-CH ₂CH ₂CH ₂CH ₂-cyclopropyl) ,-CH ₂-cyclobutyl ,-CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂CH ₂-cyclobutyl ,-CH ₂CH ₂CH ₂CH ₂-cyclobutyl ,-CH ₂-cyclopentyl ,-CH ₂CH ₂-cyclopentyl) ,-CH ₂CH ₂CH ₂-cyclopentyl ,-CH ₂CH ₂CH ₂CH ₂-cyclopentyl ,-CH ₂-cyclohexyl ,-CH ₂-(4-methylcyclohexyl) ,-CH ₂CH ₂-cyclohexyl ,-CH ₂-suberyl ,-CH ₂-(the 2-cyclopentenyl ,-CH ₂CH ₂C ≡ CH ,-CH ₂CH ₂CH ₂C ≡ CH ,-CH ₂-phenyl ,-CH ₂-(2-fluorophenyl) ,-CH ₂-(3-fluorophenyl) and-CH ₂-NH (3-p-methoxy-phenyl);

R ⁶Be selected from-O-R ¹⁰, Cl and-N (R ⁷) ₂

R ^aAnd R ^bRespectively do for oneself-CH ₃

R ^cBe H;

R ^dBe selected from H ,-CH ₃With-CH ₂-phenyl, wherein R ^dDescribed-CH ₂The phenyl moiety of-phenyl does not replace or is replaced by one or more Y groups;

4. the compound of claim 1 or its drug acceptable salt, solvate, ester or tautomer, wherein:

Q is:

L is:

R ²Be H or halogen;

R ⁵Be H or (C ₁-C ₆) alkyl;

Each R ⁷Be independently selected from H, (C ₁-C ₆) alkyl, (C ₃-C ₆) cycloalkyl, unsubstituted (C ₆-C ₁₀) aryl and the (C that replaced by one or more substituting group Y ₆-C ₁₀) aryl;

R ⁹Be selected from (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl, (C ₂-C ₆) thiazolinyl and-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl, wherein R ⁹Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl do not replace or replaced by one or more Y groups;

R wherein ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl or-(C ₁-C ₆) alkenylene-(C ₆-C ₁₀) aryl of aryl do not replace or replaced R by one or more Y groups ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) (the C of heteroaryl ₂-C ₁₀) heteroaryl moieties do not replace or replaced by one or more Z groups;

5. the compound of claim 4 or its drug acceptable salt, solvate, ester or tautomer, wherein:

R ¹For-CH ₂CH ₃, butyl, amyl group or-CH ₂CH ₂CH ₂-cyclopropyl;

R ²Aryl, unsubstituted heteroaryl that replaces for H, Br, unsubstituted aryl, by one or more Y groups or the heteroaryl that is replaced by one or more Y groups;

R ⁵For H or-CH ₂CH ₃

Each R ⁷Be independently selected from H and cyclobutyl;

R ¹⁰Be selected from H ,-CH ₃,-CH ₂-cyclopropyl ,-CH ₂-CH=CH ₂,-CH ₂C ≡ C-CH ₃,-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH (CH ₂CH ₂CH ₃)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl ,-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl and-CH ₂-pyrimidyl,

Each Z is independently selected from-CH ₃, phenyl and N-oxide compound.

6. the compound of claim 1 or its drug acceptable salt, solvate, ester or tautomer, wherein:

Q is:

L is:

R ²Be H;

R ⁸Be selected from unsubstituted (C ₆-C ₁₀) the aryl, (C that replaced by one or more Y groups ₆-C ₁₀) aryl ,-OH, unsubstituted (C ₂-C ₁₀₎Heterocyclic radical and the (C that is replaced by one or more X groups ₂-C ₁₀) heterocyclic radical;

7. the compound of claim 6 or its drug acceptable salt, solvate, ester or tautomer, wherein:

R ²Be H; Or

R ³Be selected from H ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃,-cyclopropyl, cyclobutyl, cyclopentyl ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃,-CH ₂CH=CH ₂With-CH ₂-O-CH ₃

R ⁵Be selected from H ,-CH ₂-cyclopropyl ,-CH ₂-C (O)-O-CH ₃,-CH ₂-C (O)-R ⁸,-CH ₂-C (=N-O-CH ₃)-phenyl, cyclopropyl, cyclobutyl, cyclopentyl ,-CH ₃,-CH ₂CH ₃,-CH ₂CH ₂CH ₃With-CH ₂-CH=CH ₂

Each R ⁷Be H or phenyl independently,

R wherein ⁷Described phenyl do not replace or replaced by one or more Y groups;

Each Y be independently selected from F ,-CF ₃,-OCH ₃,-CN and-OH.

8. the compound of claim 1 or its drug acceptable salt, solvate, ester or tautomer, wherein:

Q is:

L is:

R ²Be H; Or

R ⁶Be selected from-O-R ¹⁰, halogen and-N (R ⁷) ₂

R ⁹Be selected from (C ₁-C ₆) alkyl ,-(C ₁-C ₆) alkylidene group-(C ₃-C ₆) cycloalkyl, (C ₂-C ₆) thiazolinyl and-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl, wherein R ⁹Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) (the C of aryl ₆-C ₁₀) aryl moiety do not replace or replaced by one or more Y groups;

R wherein ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl or-(C ₁-C ₆) alkenylene-(C ₆-C ₁₀) aryl moiety of aryl do not replace or replaced R by one or more Y groups ¹⁰Described-(C ₁-C ₆) alkylidene group-(C ₂-C ₁₀) (the C of heteroaryl ₂-C ₁₀) heteroaryl moieties do not replace or replaced by one or more Z groups;

Each R ¹²Be (C independently ₁-C ₆) alkyl;

9. the compound of claim 8 or its drug acceptable salt, solvate, ester or tautomer, wherein:

R ²Be H; Or

R ⁶Be selected from-O-R ¹⁰,-N (R ⁷) ₂And Cl;

R ¹⁰Be selected from H, CH ₃,-CH ₂-cyclopropyl ,-CH ₂-C ≡ C-CH ₃,-CH ₂-CH=CH ₂,-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH (CH ₃) ₂)-phenyl ,-CH (CH ₂CH ₂CH ₃)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl ,-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl and-CH ₂-pyrimidyl, wherein R ¹⁰Described-CH ₂-phenyl ,-CH (CH ₃)-phenyl ,-CH (CH ₂CH ₃)-phenyl ,-CH (CH ₂CH=CH ₂)-phenyl or-CH (CH ₂CH ₂CH ₃The phenyl moiety of)-phenyl does not replace or is replaced R by one or more group Y ¹⁰Described-CH ₂-pyridyl ,-CH (CH ₃)-thiazolyl or-CH ₂The pyridyl of-pyrimidyl, thiazolyl or pyrimidyl part do not replace or are replaced by one or more group Z;

10. the compound of claim 1 or its drug acceptable salt, solvate, ester or tautomer, wherein:

Q is:

L is:

R ¹For-(C ₁-C ₆) alkyl;

R ²Be H;

R ³For H or-(C ₂-C ₆) thiazolinyl; With

R ⁶For-OH or-O-(C ₁-C ₆) alkylidene group-(C ₁-C ₆) cycloalkyl.

11. the compound of claim 1 or its drug acceptable salt, solvate, ester or tautomer, wherein:

Q is:

L is:

R ¹For-(C ₁-C ₆) alkyl or-(C ₁-C ₆) haloalkyl;

R ²Be H;

R ⁴For-O-N=C ((C ₁-C ₆) alkyl) ₂

12. the compound of claim 1 or its drug acceptable salt, solvate, ester or tautomer, wherein:

Q is:

L is selected from:

R ¹Be (C ₁-C ₆) alkyl or-(C ₁-C ₆) haloalkyl;

R ²Be H;

R ³Be H;

R ⁴For-O-R ¹⁰

R ⁵For H or-(C ₁-C ₆) alkylidene group-cycloalkyl;

R ⁶For-O-R ¹⁰

R ¹⁰Be H, (C ₁-C ₆) alkyl or-(C ₁-C ₆) alkylidene group-(C ₆-C ₁₀) aryl; With

13. a compound or its drug acceptable salt, solvate, ester or tautomer, it is selected from:

14. a compound or its drug acceptable salt, solvate, ester or tautomer, it is selected from:

15. a compound or its drug acceptable salt, solvate, ester or tautomer, it is selected from:

16. the compound of the claim 1 of purifying or its drug acceptable salt, solvate, ester or tautomer.

17. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

18. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

19. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

20. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

21. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

22. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

23. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

24. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

25. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

26. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

27. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

28. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

29. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

30. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

31. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

32. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

33. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

34. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

35. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

36. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

37. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

38. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

39. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

40. have compound or its drug acceptable salt, solvate, ester or the tautomer of following structural formula:

41. a composition comprises:

The compound of at least a claim 1 or its drug acceptable salt, solvate, ester or tautomer; With

At least a drug acceptable carrier.

42. a composition comprises:

The compound of at least a claim 13 or its drug acceptable salt, solvate, ester or tautomer; With

At least a drug acceptable carrier.

43. the composition of claim 41, it also comprises at least a following additional treatment medicine that is selected from: azetidinone compounds, the 'beta '-lactam compounds of replacement, HMGCoA reductase inhibiter compounds, HMG CoA synthetase inhibitors, squalene synthetic inhibitor, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, nicotinic acid derivates, bile acid chelating agent, acetylsalicylic acid, NSAID (non-steroidal anti-inflammatory drug), Vytorin that hydroxyl replaces ^_Ezetimibe; inorganic cholesterol sequestrant; AcylCoA: cholesterol O-inhibitors; cholestery ester transfer protein inhibitors; the fish oil that contains omega-3 fatty acid; water-soluble fiber; the fatty acid ester of plant alkanol and/or plant alkanol; antioxidant; the PPAR alfa agonists; PPAR γ-agonist; the FXR receptor modulators; the lxr receptor agonist; the lipoprotein synthetic inhibitor; the renin angiotensin inhibitor; microsome tri-glyceride transporter inhibitors; the bile acide cell reabsorption inhibitor; the PPAR delta agonists; the tri-glyceride synthetic inhibitor; the squalene epoxidase inhibitor; low density lipoprotein receptor inductor or activator; anticoagulant; 5-LO or FLAP inhibitor; PPAR δ partial agonist; nicotinic acid or nicotinic acid receptor agonists; the 5HT transporter inhibitors; the NE transporter inhibitors; CB ₁Antagonists/inverse agonists, ghrelin antagonist, H ₃Antagonists/inverse agonists; the MCH1R antagonist; the MCH2R agonist/antagonist; the NPY1 antagonist; the NPY5 antagonist; the NPY2 agonist; the NPY4 agonist; the mGluR5 antagonist; leptin; the leptin agonist/modulator; the leptin derivative; opioid antagonists; increase food factor acceptor antagonist; the BRS3 agonist; the CCK-A agonist; CNTF; the CNTF derivative; the CNTF agonist/modulator; the 5HT2c agonist; the Mc4r agonist; monoamine reuptake inhibitors; the serotonin reuptake inhibitor; the GLP-1 agonist; PHENTERMINE; topiramate; phytopharm compound 57; ghrelin antibody; the Mc3r agonist; the ACC inhibitor; β 3 agonists; the DGAT1 inhibitor; the DGAT2 inhibitor; the FAS inhibitor; the PDE inhibitor; the Triiodothyronine beta-agonists; the UCP-1 activator; the UCP-2 activator; the UCP-3 activator; acyl group oestrogenic hormon; glucocorticoid agonists/antagonist; 11 β HSD-1 inhibitor; the SCD-1 inhibitor; lipase inhibitor; the fatty acid transport protein inhibitor; the dicarboxylic ester transporter inhibitors; the glucose transporter inhibitor; the phosphoric acid ester transporter inhibitors; antidiabetic drug; antihypertensive drug; anti-lipid unusual medicine; the DP receptor antagonist; apo-B secretion/microsome tri-glyceride transfer protein (apo-B/MTP) inhibitor; the sympathomimetic nerve agonist; dopamine agonist; the melanotropin receptor analogs; the melanochrome concentrating hormone antagonists; lepton; the galanin receptor antagonist; the bombesin agonist; neuropeptide-γ antagonist; thyromimetic; dehydroepiandrosterone; the dehydroepiandrosterone analogue; the conjugated protein antagonist of urocortin; glucagon-like peptide-1 receptor stimulant; people agouti associated protein (AGRP); neuromedin U receptor stimulant; the norepinephrine energy anorexigenic; appetite-inhibiting agent; the hormone-sensitive lipase antagonist; the MSH-receptor analogs; alpha-glucosidase inhibitor; the contrary cholesterol transport inhibitor of apo A1 milano; fatty acid binding protein inhibitor (FABP) and fatty acid transport protein inhibitor (FATP).

44. the composition of claim 43, wherein said at least a additional treatment medicine are the HMG CoA synthetase inhibitors that is selected from lovastatin, Simvastatin, Pravastatin, atorvastatin, fluvastatin, Cerivastatin, rivastatin, ZD-4522 and pitavastatin.

45. the composition of claim 44, wherein said HMG CoA synthetase inhibitors is a Simvastatin.

46. the composition of claim 43, wherein said at least a additional treatment medicine is a cholestery ester transfer protein inhibitors.

47. the composition of claim 46, wherein said cholestery ester transfer protein inhibitors are torcetrapib.

48. the composition of claim 43, wherein said at least a additional treatment medicine is Vytorin ^_, ezetimibe, acetylsalicylic acid, Ibuprofen BP/EP or paracetamol or its combination.

49. its drug acceptable salt of compound, solvate, ester or the tautomer of at least a claim 1 of treatment significant quantity is used for the treatment of the purposes of disease of patient, illness or symptom that needs treat, wherein said disease, illness or symptom be selected from metabolic syndrome, hyperlipemia, cardiovascular diseases, on every side with central nervous system disease, hemopathy, cancer, inflammation, respiratory disease, gastrointestinal illness, diabetes and non-alcoholic fatty liver disease.

50. the purposes of claim 49, wherein said disease, illness or symptom are hyperlipemia.

51. the purposes of claim 49, it also comprises granting and is selected from following at least a additional treatment medicine: azetidinone compounds, the 'beta '-lactam compounds of replacement, HMGCoA reductase inhibiter compounds, HMG CoA synthetase inhibitors, squalene synthetic inhibitor, squalene epoxidase inhibitor, sterol biosynthesis inhibitor, nicotinic acid derivates, bile acid chelating agent, inorganic cholesterol sequestrant, acetylsalicylic acid, NSAID (non-steroidal anti-inflammatory drug), ezetimibe, Vytorin that hydroxyl replaces ^_, AcylCoA: fatty acid ester, the Omacor of cholesterol O-inhibitors, cholestery ester transfer protein inhibitors, the fish oil that contains omega-3 fatty acid, water-soluble fiber, plant alkanol and/or plant alkanol ^_Antioxidant, the PPAR alfa agonists, PPAR γ-agonist, the FXR receptor modulators, the lxr receptor agonist, the lipoprotein synthetic inhibitor, the renin angiotensin inhibitor, microsome tri-glyceride transporter inhibitors, the bile acide cell reabsorption inhibitor, the PPAR delta agonists, the tri-glyceride synthetic inhibitor, the squalene epoxidase inhibitor, low density lipoprotein receptor inductor or activator, anticoagulant, 5-LO or FLAP inhibitor, PPAR δ partial agonist, nicotinic acid or nicotinic acid receptor agonists, the 5HT transporter inhibitors, the NE transporter inhibitors, CB ₁Antagonists/inverse agonists; the ghrelin antagonist; the H3 antagonists/inverse agonists; the MCH1R antagonist; the MCH2R agonist/antagonist; the NPY1 antagonist; the NPY5 antagonist; the NPY2 agonist; the NPY4 agonist; the mGluR5 antagonist; leptin; the leptin agonist/modulator; the leptin derivative; opioid antagonists; increase food factor acceptor antagonist; the BRS3 agonist; the CCK-A agonist; CNTF; the CNTF derivative; the CNTF agonist/modulator; the 5HT2c agonist; the Mc4r agonist; monoamine reuptake inhibitors; the serotonin reuptake inhibitor; the GLP-1 agonist; PHENTERMINE; topiramate; phytopharm compound 57; ghrelin antibody; the Mc3r agonist; the ACC inhibitor; β 3 agonists; the DGAT1 inhibitor; the DGAT2 inhibitor; the FAS inhibitor; the PDE inhibitor; the Triiodothyronine beta-agonists; the UCP-1 activator; the UCP-2 activator; the UCP-3 activator; acyl group oestrogenic hormon; glucocorticoid agonists/antagonist; 11 β HSD-1 inhibitor; the SCD-1 inhibitor; lipase inhibitor; the fatty acid transport protein inhibitor; the dicarboxylic ester transporter inhibitors; the glucose transporter inhibitor; the phosphoric acid ester transporter inhibitors; antidiabetic drug; antihypertensive drug; anti-lipid unusual medicine; the DP receptor antagonist; apo-B secretion/microsome tri-glyceride transfer protein (apo-B/MTP) inhibitor; the sympathomimetic nerve agonist; dopamine agonist; the melanotropin receptor analogs; the melanochrome concentrating hormone antagonists; lepton; the galanin receptor antagonist; the bombesin agonist; neuropeptide-γ antagonist; thyromimetic; dehydroepiandrosterone; the dehydroepiandrosterone analogue; the conjugated protein antagonist of urocortin; glucagon-like peptide-1 receptor stimulant; people agouti associated protein (AGRP); neuromedin U receptor stimulant; the norepinephrine energy anorexigenic; appetite-inhibiting agent; the hormone-sensitive lipase antagonist; the MSH-receptor analogs; alpha-glucosidase inhibitor; the contrary cholesterol transport inhibitor of apo A1 milano; fatty acid binding protein inhibitor (FABP) and fatty acid transport protein inhibitor (FATP).

52. the purposes of claim 51, wherein said at least a additional treatment medicine are the HMG CoA synthetase inhibitors that is selected from lovastatin, Simvastatin, Pravastatin, atorvastatin, fluvastatin, Cerivastatin, rivastatin, ZD-4522 and pitavastatin.

53. the purposes of claim 52, wherein said HMG CoA synthetase inhibitors is a Simvastatin.

54. the purposes of claim 49 or 51, wherein said granting is oral, intravenously, subcutaneous or their combination.