CN101351209A - Pharmaceutical use of substituted amides - Google Patents

Pharmaceutical use of substituted amides Download PDF

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Publication number
CN101351209A
CN101351209A CNA2006800502497A CN200680050249A CN101351209A CN 101351209 A CN101351209 A CN 101351209A CN A2006800502497 A CNA2006800502497 A CN A2006800502497A CN 200680050249 A CN200680050249 A CN 200680050249A CN 101351209 A CN101351209 A CN 101351209A
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carbonyl
methyl
benzyl
bicyclo
aza
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Inventor
H·S·安德森
A·S·约恩森
J·P·吉尔伯恩
G·C·T·坎普潘
S·艾伯德鲁普
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vTv Therapeutics LLC
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vTvx Holdings I LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Abstract

The use of substituted amides for modulating the activity of 11ss-hydroxysteroid dehydrogenase type 1 (11ssHSD1) and the use of these compounds as pharmaceutical compositions, are described. Also a novel class of substituted amides, their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds are modulators and more specifically inhibitors of the activity of 11ssHSD1 and may be useful in the treatment of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

Description

The pharmaceutical applications of the amide that replaces
Invention field
[0001] the present invention relates to the application in the active disease of treatment needs adjusting 11 beta-hydroxysteroid dehydrogenases, 1 types (11 β HSD1) of amide that replaces and the pharmaceutical composition that comprises this chemical compound.The present invention also relates to the amide of new replacement, their application in treatment comprise the pharmaceutical composition of this chemical compound, and the application of described chemical compound in the preparation medicine, and comprise the Therapeutic Method of using this chemical compound.This chemical compound is regulated the activity of 11 beta-hydroxysteroid dehydrogenases, 1 type (11 β HSD1), therefore can be used for the favourable disease of wherein this adjusting, for example metabolism syndrome.
Background of invention
[0002] metabolism syndrome is worldwide main health problem.In the U.S., according to estimates, current adult sickness rate is about 25%, and also increases continuing at the U.S. and whole world sickness rate.The feature of metabolism syndrome is insulin resistant, dyslipidemia, obesity and hypertensive combination, causes the M ﹠ M of cardiovascular disease to increase.The danger increase of direct type 2 diabetes mellitus takes place in the people who suffers from metabolism syndrome, and its sickness rate is increasing equally.
[0003] in type 2 diabetes mellitus, fat and dyslipidemia also is very general, and about 70% people who suffers from type 2 diabetes mellitus also suffers from hypertension in addition, and this causes the mortality rate of cardiovascular disease to increase again.
[0004] in clinical setting, knows that for a long time glucocorticoid can be induced all principal characters of metabolism syndrome and type 2 diabetes mellitus.
[0005] at several tissues and organ, mainly comprise in liver and the fatty tissue, the part of 11 beta-hydroxysteroid dehydrogenases, 1 type (11 β HSD1) catalytic activity glucocorticoid produces, but this also can occur in the following tissue, for example some part of skeletal muscle, bone, pancreas, endothelium, eye tissue and central nervous system.Therefore, 11 β HSD1 bring into play effect (people such as Tannin, J.Biol.Chem., 266,16653 (1991) of the active local modulation agent of sugared cortex in its expressed tissue and organ; People such as Bujalska, Endocrinology, 140, 3188 (1999); People such as Whorwood, J.Clin Endocrinol Metab., 86, 2296 (2001); People such as Cooper, Bone, 27, 375 (2000); People such as Davani, J.Biol.Chem., 275, 34841 (2000); People such as Brem, Hypertension, 31, 459 (1998); People such as Rauz, Invest.Ophthalmol.Vis.Sci., 42, 2037 (2001); People such as Moisan, Endocrinology, 127, 1450 (1990)).
[0006] there are a few class evidences to support 11 effects of β HSD1 in metabolism syndrome and type 2 diabetes mellitus.In the people, in the patient of thin healthy volunteer and type 2 diabetes mellitus, improved insulin sensitivity with non-specific 11 beta hsd 1 inhibitors carbenoxolone treatment.Equally, the mice that knocks out 11 β HSD1 is resisted for the insulin resistant of fat and stress-induced.In addition, the mice that knocks out has antiatherogenic lipoid character, reduces the VLDL triglyceride and increases the HDL-cholesterol.On the contrary, the mice of overexpression 11 β HSD1 is developed and insulin resistant, hyperlipemia and internal organs obesity in adipose cell, this be with the similar a kind of sign of people's metabolism syndrome (people such as Andrews, J.Clin.Endocrinol.Metab., 88, 285 (2003); People such as Walker, J.Clin.Endocrinol.Metab., 80, 3155 (1995); People such as Morton, J.Biol.Chem., 276, 41293 (2001); People such as Kotelevtsev, Proc.Natl.Acad.Sci.USA, 94, 14924 (1997); People such as Masuzaki, Science, 294, 2166 (2001)).
[0007] in several rodent models and different cell system, studied aspect level in the cell that 11 β HSD1 regulated and therefore regulated active glucocorticoid more mechanistic.The liver expression of 11 β HSD1 by increasing rate-limiting enzyme (being phosphoenolpyruvate carboxykinase and G-6-Pase) in the glyconeogenesis, promote before adipose cell be divided into adipose cell and therefore quicken fat, directly and indirect stimulation liver VLDL secretion, the contractility that reduces liver LDL picked-up and strengthen blood vessel promote the feature (people such as Kotelevtsev of metabolism syndrome, Proc.Natl.Acad.Sci.USA 94, 14924 (1997); People such as Morton, J.Biol.Chem. 276, 41293 (2001); People such as Bujalska, Endocrinology, 140, 3188 (1999); People such as Souness, Steroids, 67, 195 (2002), Brindley ﹠amp; Salter, Prog.Lipid Res., 30, 349 (1991)).
[0008] WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO 01/90094 have disclosed the various thiazole-sulfa drugss as the inhibitor of people's 11 beta-hydroxysteroid dehydrogenases 1 type enzyme, and have further disclosed described chemical compound and can be used for the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorder, dysimmunity and depression.
[0009] we have had been found that the activity of regulating 11 β HSD1 now, cause the amide of the replacement that the IC of active glucocorticoid changes.More specifically, these chemical compounds suppress the activity of 11 β HSD1, cause the IC of active glucocorticoid to reduce.Therefore, these chemical compounds can be used for the treatment of the disease that needs reduce the level of intracellular reactive glucocorticoid, for example, metabolism syndrome, type 2 diabetes mellitus, glucose tolerance reduce (IGT), fasting glucose infringement (IFG), dyslipidemia, obesity, hypertension, advanced diabetes complication, cardiovascular disease, arteriosclerosis, atherosclerosis, myopathy, amyotrophy, osteoporosis, neural degeneration and the treatment of psychiatric disturbance and use glucocorticoid receptor agonist or the ill effect of therapy.
[0010] an object of the present invention is to provide active compound medicine compositions and this application of compound of regulating 11 β HSD1.
Definition
[0011] in following structural formula and description full text, following term has specified implication.Except as otherwise noted, the example that provides in the application's definition is non-comprising property.They include but not limited to these described examples.
[0012] term " halogen " comprises fluorine, chlorine, bromine and iodine.
[0013] term " trihalomethyl group " comprises trifluoromethyl, trichloromethyl, trisbromomethyl and three iodomethyls.
[0014] term " three halogenated methoxies " comprises trifluoromethoxy, trichlorine methoxyl group, tribromo methoxyl group and triiodo methoxyl group.
[0015] term " alkyl " comprises the C with the carbon atom that specifies number 1-C 8Straight chain saturated and methylene aliphatic group and C 3-C 8Branched saturated hydrocarbon group.For example, this definition comprises methyl (Me), ethyl (Et), propyl group (Pr), butyl (Bu), amyl group, hexyl, isopropyl (i-Pr), isobutyl group (i-Bu), the tert-butyl group (t-Bu), sec-butyl (s-Bu), isopentyl and neopentyl.
[0016] term " thiazolinyl " comprises the C with the carbon atom that specifies number 2-C 6Straight chain unsaturated aliphatic hydrocarbyl moiety and side chain C 3-C 6Unsaturated aliphatic hydrocarbyl moiety.For example, this definition comprises vinyl, acrylic, cyclobutenyl, pentenyl, hexenyl, methylpropenyl and methyl butene base.
[0017] term " alkynyl " comprises the C with the carbon atom that specifies number 2-C 6Straight chain unsaturated aliphatic hydrocarbyl moiety and C 4-C 6The side chain unsaturated aliphatic hydrocarbyl moiety.For example, this definition comprises acetenyl, propinyl, butynyl, pentynyl, hexin base and methyl butynyl.
[0018] term " list of saturated or fractional saturation; two or three-loop system " representative but be not limited to, '-aziridino, the azepan base, azocanyl, pyrrolinyl, pyrrolidinyl, the 2-imidazolinyl, imidazolidinyl, the 2-pyrazolinyl, morpholinyl, piperidyl, the tetrahydro-1,4-thiazine base, piperazinyl, phthalimide, 1,2,3,4-tetrahydrochysene-quinolyl, 1,2,3,4-tetrahydrochysene-isoquinolyl, 1,2,3,4-tetrahydrochysene-quinoxalinyls, indolinyl, 1,6-aza-bicyclo [3.2.1] octane, 2-aza-bicyclo [4.1.1] octane, 2-aza-bicyclo [3.2.1] octyl, 7-aza-bicyclo [4.1.1] octyl, 9-aza-bicyclo [3.3.2] decyl, 4-azepine-three ring [4.3.1.1 3,8] undecyl, 9-azepine-three ring [3.3.2.0 3,7] decyl.
[0019] cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base, cyclonoene base, cyclodecene base, tetrahydrofuran base and THP trtrahydropyranyl represented in term " saturated or fractional saturation ring ".
[0020] cyclopenta, cyclohexyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base, cyclonoene base, cyclodecene base, tetrahydrofuran base, THP trtrahydropyranyl, phenyl, pyridine radicals and pyrimidine radicals represented in the term aromatic ring of fractional saturation " saturated or ".
[0021] term " cycloalkyl " representative have the saturated list of the carbon atom that specifies number-, two-, three-or spiral shell carbocylic radical (for example, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, bicyclo-[3.2.1] octyl group, spiral shell [4.5] decyl, norpinyl, bornyl, norcaryl and adamantyl).
[0022] term " cycloalkyl-alkyl " representative alkyl or the cycloalkyl as defined above (for example, cyclopropyl methyl, cyclobutyl ethyl and adamantyl methyl) that connects of saturated alkyl as defined above by having the carbon atom that specifies number.
[0023] term " cycloalkenyl group " representative have the list of the fractional saturation of the carbon atom that specifies number-, two-, three-or spiral shell carbocylic radical (for example, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base, cyclonoene base and cyclodecene base).
[0024] term " naphthene base carbonyl " representative is by the cycloalkyl as defined above with the carbon atom that specifies number (for example, cyclopropyl carbonyl and cyclohexyl-carbonyl) of carbonyl connection.
[0025] term " cycloalkyl alkyl carbonyl " representative alkyl or the cycloalkyl as defined above (for example, cyclohexyl methyl carbonyl and suberyl ethyl carbonyl) that connects of saturated alkyl as defined above by having the carbon atom that specifies number.
[0026] term " Heterocyclylalkyl " representative has the hetero atom of the atom of given number and 1-4 given number or is selected from nitrogen, oxygen, sulfur and S (O) mThe saturated mono of group (m=0-2)-, two-, three-or spiral shell carbocylic radical (for example, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranose, piperidines and pyridine (pyridzine)).
[0027] Heterocyclylalkyl as defined above (for example, oxolane ylmethyl, THP trtrahydropyranyl ethyl and tetrahydrochysene sulfo-pyranose methyl) that connects by the alkyl with the carbon atom that specifies number represented in term " Heterocyclylalkyl alkyl ".
[0028] term " Heterocyclylalkyl carbonyl " representative is by the Heterocyclylalkyl as defined above with the carbon atom that specifies number (for example, 1-piperidin-4-yl-carbonyl and 1-(1,2,3,4-tetrahydrochysene-isoquinolin-6-yl) carbonyl) of carbonyl connection.
[0029] term " alkoxyl " representative is by the alkyl with the carbon atom that specifies number (for example, methoxyl group, ethyoxyl, propoxyl group, allyloxy and cyclohexyloxy) of oxo bridge connection.
[0030] alkoxyl as defined above (for example, methoxy) that connects by the alkyl with the carbon atom that specifies number represented in term " alkoxyalkyl ".
[0031] term " aryl " comprises monocycle, bicyclo-or polycyclic carbon aromatic ring, for example phenyl, xenyl, naphthyl, anthryl, phenanthryl, fluorenyl, indenyl, pentalene base, azulenyl and biphenylene base.Aryl also comprises the partially hydrogenated derivant of the above-mentioned carbon aromatic ring of enumerating.The example of partially hydrogenated derivant comprises 1,2,3,4-tetralyl and 1,4-dihydro naphthyl.
[0032] term " heteroaryl " comprises pyrrole radicals (2-pyrrole radicals), pyrazolyl (3-pyrazolyl), imidazole radicals (1-imidazole radicals, the 2-imidazole radicals, the 4-imidazole radicals, the 5-imidazole radicals), triazolyl (1,2, the 3-triazol-1-yl, 1,2,3-triazole-2-base, 1,2,3-triazole-4-base, 1,2,4-triazole-3-yl) oxazolyl (2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl) isoxazolyl (3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl), thiazolyl (2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl), thienyl (2-thienyl, the 3-thienyl, the 4-thienyl, the 5-thienyl), furyl (2-furyl, the 3-furyl, the 4-furyl, the 5-furyl), pyridine radicals (2-pyridine radicals, the 3-pyridine radicals, the 4-pyridine radicals, the 5-pyridine radicals), the 5-tetrazole radical, pyrimidine radicals (2-pyrimidine radicals, the 4-pyrimidine radicals, the 5-pyrimidine radicals, the 6-pyrimidine radicals), pyrazinyl, pyridazinyl (3-pyridazinyl, the 4-pyridazinyl, the 5-pyridazinyl), quinolyl (2-quinolyl, the 3-quinolyl, the 4-quinolyl, the 5-quinolyl, the 6-quinolyl, the 7-quinolyl, the 8-quinolyl), isoquinolyl (1-isoquinolyl, the 3-isoquinolyl, the 4-isoquinolyl, the 5-isoquinolyl, the 6-isoquinolyl, the 7-isoquinolyl, the 8-isoquinolyl), benzo [b] furyl (2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b] furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7-benzo [b] furyl), 2, (2-(2 for 3-dihydro-benzo [b] furyl, 3-dihydro-benzo [b] furyl), 3-(2,3-dihydro-benzo [b] furyl), 4-(2,3-dihydro-benzo [b] furyl), 5-(2,3-dihydro-benzo-[b] furyl), 6-(2,3-dihydro-benzo-[b] furyl), 7-(2,3-dihydro-benzo [b] furyl)), 1,4-benzo dioxine (benzodioxin) (2-(1,4-benzo dioxine), 3-(1,4-benzo dioxine), 5-(1,4-benzo dioxine), 6-(1,4-benzo dioxine), 7-(1,4-benzo dioxine), 8-(1,4-benzo dioxine)), benzo [b] thienyl (2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl, 7-benzo [b] thienyl), 2,3-dihydro-benzo [b] thienyl (2-(2,3-dihydro-benzo [b] thienyl), 3-(2,3-dihydro-benzo [b] thienyl), 4-(2,3-dihydrobenzo [b] thienyl), 5-(2,3-dihydro-benzo [b] thienyl), 6-(2,3-dihydro-benzo [b] thienyl), 7-(2,3-dihydro-benzo [b] thienyl)), 4,5,6, (2-(4,5 for 7-tetrahydrochysene-benzo [b] thienyl, 6,7-tetrahydrochysene-benzo [b] thienyl), 3-(4,5,6,7-tetrahydrochysene-benzo [b] thienyl), 4-(4,5,6,7-tetrahydrochysene-benzo [b] thienyl), 5-(4,5,6,7-tetrahydrochysene-benzo [b] thienyl), 6-(4,5,6,7-tetrahydrochysene-benzo [b] thienyl), 7-(4,5,6,7-tetrahydrochysene-benzo [b] thienyl)), thieno [2,3-b] thienyl, 4,5,6,7-tetrahydrochysene-thieno [2,3-c] (4-(4,5,6 for pyridine radicals, 7-tetrahydrochysene-thieno [2,3-c] pyridine radicals), 5-4,5,6,7-tetrahydrochysene-thieno [2,3-c] pyridine radicals), 6-(4,5,6,7-tetrahydrochysene-thieno [2,3-c] pyridine radicals), 7-(4,5,6,7-tetrahydrochysene-thieno [2,3-c] pyridine radicals)), indyl (1-indyl, the 2-indyl, the 3-indyl, the 4-indyl, the 5-indyl, the 6-indyl, the 7-indyl), isoindolyl (1-isoindolyl, the 2-isoindolyl, the 3-isoindolyl, the 4-isoindolyl, the 5-isoindolyl, the 6-isoindolyl, the 7-isoindolyl), 1,3-dihydro-isoindolyl (1-(1,3-dihydro-isoindolyl), 2-(1,3-dihydro-isoindolyl), 3-(1,3-dihydro-isoindolyl), 4-(1,3-dihydro-isoindolyl), 5-(1,3-dihydro-isoindolyl), 6-(1,3-dihydro-isoindolyl), 7-(1,3-dihydro-isoindolyl)), indazole (1-indazolyl, the 3-indazolyl, the 4-indazolyl, the 5-indazolyl, the 6-indazolyl, the 7-indazolyl), benzimidazolyl (1-benzimidazolyl, the 2-benzimidazolyl, the 4-benzimidazolyl, the 5-benzimidazolyl, the 6-benzimidazolyl, the 7-benzimidazolyl, the 8-benzimidazolyl) benzoxazolyl (1-benzoxazolyl, the 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, the 2-[4-morpholinodithio base, the 4-benzothiazolyl, the 5-benzothiazolyl, the 6-benzothiazolyl, the 7-benzothiazolyl), benzo-[1,2,5] oxadiazole base (4-benzos [1,2,5] oxadiazole bases, the 5-benzo [1,2,5] oxadiazole bases), carbazyl (1-carbazyl, the 2-carbazyl, the 3-carbazyl, the 4-carbazyl), piperidyl (2-piperidyl, the 3-piperidyl, the 4-piperidyl) and pyrrolidinyl (1-pyrrolidinyl, the 2-pyrrolidinyl, the 3-pyrrolidinyl).
[0033] aryl as defined above (for example, benzyl, phenylethyl, 3-phenyl propyl, 1-naphthyl methyl and 2-(1-naphthyl) ethyl) that connects by the alkyl with the carbon atom that specifies number represented in term " aralkyl ".
[0034] heteroaryl as defined above (for example, (2-furyl) methyl, (3-furyl) methyl, (2-thienyl) methyl, (3-thienyl) methyl, (2-pyridine radicals) methyl and 1-methyl isophthalic acid-(2-pyrimidine radicals) ethyl) that connects by the alkyl with the carbon atom that specifies number represented in term " heteroarylalkyl ".
[0035] term " aryloxy group heteroaryl " representative is by the aryloxy group as defined above (for example, 2-phenoxy group-pyridine radicals) of heteroaryl connection.
[0036] term " aryloxy group " representative is by the aryl as defined above (for example, phenoxy group and naphthoxy) of oxo bridge connection.
[0037] term " heteroaryloxy " representative is by the heteroaryl as defined above (for example, 2-pyridyloxy) of oxo bridge connection.
[0038] term " alkoxy aryl " representative is by the aralkyl as defined above (for example, benzene ethyoxyl and naphthyl methoxyl group) of oxo bridge connection.
[0039] term " heteroaryl alkoxyl " representative is by the heteroarylalkyl as defined above (for example, 2-pyridine radicals methoxyl group) of oxo bridge connection.
[0040] term " alkoxy carbonyl " representative is by the alkoxyl as defined above (for example, methyl oxygen carbonyl and ethyl oxygen carbonyl) of carbonyl connection.
[0041] term " aryloxycarbonyl " representative is by the aryloxy group as defined above (for example, carbobenzoxy and 2-thiazolyl oxygen carbonyl) of carbonyl connection.
[0042] term " aryl-alkoxy carbonyl " representative is by " alkoxy aryl " as defined above (for example, benzyl oxygen carbonyl and phenylethyl oxygen carbonyl) of carbonyl connection.
[0043] term " alkylthio group " representative is by the alkyl with the carbon atom that specifies number (for example, methyl mercapto and ethylmercapto group) of sulphur bridge connection.
[0044] term " arylthio " representative is by the aryl as defined above (for example, thiophenyl and naphthalene sulfenyl) of sulphur bridge connection.
[0045] term " heteroarylthio " representative is by the heteroaryl as defined above (for example, pyridine-2-sulfenyl and thiazole-2-sulfenyl) of sulphur bridge connection.
[0046] arylthio as defined above (for example, methyl sulfur alkylbenzene and ethyl sulfur Fluhyzon) that connects by the alkyl with the carbon atom that specifies number represented in term " arylthio alkyl ".
[0047] heteroarylthio as defined above (for example, 2-methyl sulfane base-pyridine and 1-ethyl sulfane base-isoquinolin) that connects by the alkyl with the carbon atom that specifies number represented in term " heteroarylthio alkyl ".
[0048] heteroaryloxy as defined above (for example, 1-phenoxy group-isoquinolyl and 2-phenoxypyridines base) of aryl connection is as defined above passed through in term " heteroaryloxy aryl " representative.
[0049] heteroaryloxy as defined above (for example, 1-(2-pyridyloxy-isoquinolin) and 2-(imidazoles-2-oxygen base-pyridine)) of heteroaryl connection is as defined above passed through in term " heteroaryloxy heteroaryl " representative.
[0050] aryloxy group as defined above (for example, phenoxymethyl and naphthoxy ethyl) that connects by the alkyl with the carbon atom that specifies number represented in term " aryloxy alkyl ".
[0051] aryloxy group as defined above (for example, 1-phenoxy group-naphthalene and Phenoxyphenyl) of aryl connection is as defined above passed through in term " aryloxy group aryl " representative.
[0052] alkoxy aryl as defined above (for example, ethoxyl methyl-benzene and 2-methoxy-naphthalene) that connects by the alkyl with the carbon atom that specifies number represented in term " alkoxy aryl alkyl ".
[0053] heteroaryloxy as defined above (for example, 2-pyridyloxy methyl and 2-quinoline oxy ethyl) that connects by the alkyl with the carbon atom that specifies number represented in term " heteroaryloxy alkyl ".
[0054] alkoxyl of heteroaryl as defined above (for example, 4-methoxy-pyrimidine and 2-methoxy methyl yl-quinoline) that connects by the alkyl with the carbon atom that specifies number represented in term " heteroaryl alkoxyalkyl ".
[0055] term " alkyl-carbonyl " representative is by the alkyl with the carbon atom that specifies number (for example, octyl group carbonyl, amyl group carbonyl and 3-hexenyl carbonyl) of carbonyl connection.
[0056] term " aryl carbonyl " representative is by the aryl as defined above (for example, benzoyl) of carbonyl connection.
[0057] term " heteroaryl carbonyl " representative is by the heteroaryl as defined above (for example, 2-thienyl carbonyl, 3-methoxyl group-anthryl Tang Ji are with the oxazolyl carbonyl) of carbonyl connection.
[0058] carbonyl as defined above (for example, acetyl group) that connects by alkyl of term " carbonylic alkyl " with the carbon atom that specifies number.
[0059] alkyl-carbonyl as defined above (for example, third-2-ketone and 4,4-dimethyl-penta-2-ketone) that connects by the alkyl with the carbon atom that specifies number represented in term " alkyl-carbonyl alkyl ".
[0060] aryl carbonyl as defined above (for example, 1-phenyl-third-1-ketone and 1-(3-chloro-phenyl)-2-methyl-Ding-1-ketone) that connects by the alkyl with the carbon atom that specifies number represented in term " aryl alkyl carbonyl ".
[0061] carbonyl of heteroaryl as defined above (for example, 1-pyridine-2-base-third-1-ketone and 1-(1-H-imidazoles-2-yl)-third-1-ketone) that connects by the alkyl with the carbon atom that specifies number represented in term " heteroaryl carbonylic alkyl ".
[0062] term " aromatic alkyl carbonyl " representative is by the aralkyl as defined above with the carbon atom that specifies number (for example, phenylpropyl carbonyl and phenethyl carbonyl) of carbonyl connection.
[0063] heteroarylalkyl as defined above (for example, imidazole radicals amyl group carbonyl) that alkyl wherein connects successively by carbonyl represented in term " heteroarylalkyl carbonyl ".
[0064] " alkyl-carbonyl " as defined above (for example, methyl carbonylamino, cyclopentylcarbonyl-amino methyl and methyl carbonylamino phenyl) that the nitrogen-atoms by amino of carbonyl wherein connects successively represented in term " alkyl-carbonyl-amino ".Nitrogen-atoms itself can be replaced by alkyl or aryl.
[0065] " alkyl-carbonyl-amino " (for example, N-propyl group-acetamide and the N-butyl-propionic acid amide .) that connects by the alkyl with the carbon atom that specifies number represented in term " alkyl-carbonyl-amino alkyl ".
[0066] term " aromatic alkyl carbonyl amino " representative is by amino " aromatic alkyl carbonyl " as defined above (for example, phenyl-acetamides and 3-phenyl-propionic acid amide .) that connects.
[0067] " aromatic alkyl carbonyl amino " (for example, N-ethyl-phenyl-acetamides and the N-butyl-3-phenyl-propionic acid amide .) that connects by the alkyl with the carbon atom that specifies number represented in term " aromatic alkyl carbonyl aminoalkyl ".
[0068] term " aryl-amino-carbonyl " representative is by amino " aryl carbonyl " as defined above (for example, Benzoylamide and naphthalene-1-carboxylic acid amide) that connects.
[0069] " aryl-amino-carbonyl " (for example, N-propyl group-Benzoylamide and the N-butyl-naphthalene-1-carboxylic acid amide) that connects by the alkyl with the carbon atom that specifies number represented in term " aryl-amino-carbonyl alkyl ".
[0070] alkyl-carbonyl as defined above (for example, heptyl carboxyl, cyclopropyl carboxyl and 3-pentenyl carboxyl) that carbonyl wherein connects successively by oxo bridge represented in term " alkyl carboxyl ".
[0071] aryl carbonyl as defined above (for example, benzoic acid) that carbonyl wherein connects successively by oxo bridge represented in term " aryl carboxyl ".
[0072] alkyl carboxyl as defined above (for example, heptyl carboxyl methyl, the propyl group carboxyl tert-butyl group and 3-amyl group carboxy ethyl) that oxygen wherein connects successively by the alkyl bridge represented in term " alkyl carboxyl alkyl ".
[0073] aromatic alkyl carbonyl as defined above (for example, benzylcarboxy and phenyl propyl carboxyl) that carbonyl wherein connects successively by oxo bridge represented in term " aralkyl carboxyl ".
[0074] carboxyl of aralkyl as defined above (for example, benzylcarboxy methyl and phenylpropyl carboxyl propyl group) that carbonyl wherein connects successively by the alkyl with the carbon atom that specifies number represented in term " aralkyl carboxyalkyl ".
[0075] carbonyl of heteroaryl as defined above (for example, pyridine-2-carboxylic acids) that carbonyl wherein connects successively by oxo bridge represented in term " heteroaryl carboxyl ".
[0076] term " heteroarylalkyl carboxyl " carbonyl of heteroarylalkyl as defined above (for example, (1-H-imidazoles-2-yl)-acetic acid and 3-pyrimidine-2-base-propanoic acid) that connects successively by oxo bridge of carbonyl wherein.
[0077] term " alkyl S (O) m" represent alkyl with the carbon atom that specifies number, wherein this alkyl connects by sulphur bridge successively, and wherein sulfur is replaced ((for example, ethylsulfonyl and ethyl sulfinyl) by the individual oxygen atom of m (m=0-2).
[0078] term " aryl S (O) m" represent aryl as defined above, wherein this aryl connects by sulphur bridge successively, and wherein sulfur is replaced (for example, phenyl sulfinyl and naphthyl-2-sulfonyl) by the individual oxygen atom of m (m=0-2).
[0079] term " heteroaryl S (O) m" represent heteroaryl as defined above, wherein this heteroaryl connects by sulphur bridge successively, and wherein sulfur is replaced (for example, thiazole-2-sulfinyl and pyridine-2-sulfuryl base) by the individual oxygen atom of m (m=0-2).
[0080] term of some above-mentioned definition can occur more than once in structural formula, and in the situation of each appearance, each term should define independently of each other.
[0081] term used herein " optional replace " is meant that the group of being discussed is unsubstituted or is replaced by one or more specific substituent groups.When the group of being discussed was replaced by more than one substituent group, substituent group can be identical or different.
[0082] term " treatment " has defined in order to struggle with disease, disease or obstacle or to alleviate the purpose of these diseases, disease or obstacle and processing and nursing that the patient is carried out, and this term comprises uses reactive compound with prevention or postpone the generation of symptom or complication; Alleviate (temporary transient) symptom or complication with for good and all; And/or eliminate a disease, disease or obstacle.Therefore " treatment " comprise and preventing and/or prevent disease, disease or obstacle.
[0083] term " pharmacy is acceptable " definition is to be fit to be applied to the people and unharmful incident.
[0084] term " prodrug " definition is the chemical modification form of active medicine, and described prodrug is applied to the patient, is converted into active medicine subsequently.The technology of development prodrug is well known in the art.
Detailed Description Of The Invention
[0085] therefore, in one embodiment, the invention provides a kind of amide of new replacement, its prodrug, or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or tautomeric form arbitrarily, wherein this chemical compound is the chemical compound of formula I:
Figure A20068005024900381
[0086] wherein:
[0087] R 1Be selected from H, R 8(C=O)-, R 9S (O) n-, R 10R 11NC (=Y)-and R 10R 11NS (O) n-;
[0088] R 2Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
[0089] alternately, R 1And R 2With the nitrogen that links to each other with them form the saturated or fractional saturation of 3-12 unit by shown in nitrogen, 2-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms monocycle or the bicyclo-formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl-carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace;
[0090] ring A be the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms bicyclo-or three rings formed;
[0091] ring A is selected from C by 0-3 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl or C 1-C 6The group of alkyl-carbonyl replaces, and wherein each alkyl is by 0-3 R 18Replace;
[0092] R 5Be selected from H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, halogen, OH and cyano group;
[0093] R 6And R 7Be independently selected from H, C 1-C 6Alkyl, F, trihalomethyl group and three halogenated methoxies;
[0094] alternately, R 6And R 7With the carbon atom that links to each other with them form the saturated or fractional saturation of 3-8 unit by shown in carbon atom, 2-5 other carbon atom and 0-2 are selected from nitrogen, oxygen and S (O) mThe monocycle formed of other hetero atoms, wherein this ring is by individual halogen, trihalomethyl group, OH, the C of being selected from of 0-3 1-C 6Alkyl, oxo and C 1-C 6The group of alkoxyl replaces;
[0095] R 8Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkyl, heteroaryloxy C 1-C 6Alkyl, aryl C 1-C 6Alkoxy C 1-C 6Alkyl and heteroaryl C 1-C 6Alkoxy C 1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 19Replace;
[0096] R 9Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkyl and aryl C 1-C 6Alkoxy C 1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 20Replace;
[0097] R 10And R 11Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl and heteroaryl C 1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
[0098] alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl-carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
[0099] R 12Be selected from OH, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 8Alkoxyl, aryl, aryl C 1-C 6Alkyl, heteroaryl, heteroaryl C 1-C 6Alkyl, aryloxy group, heteroaryloxy and NR 13R 14
[00100] R 13And R 14Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl and heteroaryl C 1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, aryl and heteroaryl are independently by 0-3 R 22Replace;
[00101] alternately, R 13And R 14With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
[00102] R 15Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
[00103] R 16And R 17Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, halogen, OH, cyano group ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12, C 1-C 8Alkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl are independently by 0-3 R 22Replace;
[00104] R 18Be selected from halogen, hydroxyl, oxo, COOH, cyano group C 1-C 6Alkoxyl, C 3-C 10Cycloalkyloxy, aryloxy group, heteroaryloxy, heteroarylthio and aryl C 1-C 6Alkoxyl;
[00105] R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, methylene dioxo, dihalo-methylene dioxo, C 3-C 6Spiro cycloalkyl group, C 1-C 6Alkoxyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14With-C (=NR 16) NR 17
[00106] R 22Be selected from H, hydroxyl, oxo, halogen, cyano group, nitro, C 1-C 6Alkyl, C 1-C 6Alkoxyl, NR 23R 24, methylene dioxo, dihalo methylene dioxo, trihalomethyl group and three halogenated methoxies;
[00107] R 23And R 24Be independently selected from H, C 1-C 8Alkyl and aryl C 1-C 6Alkyl;
[00108] m is selected from 0,1 and 2;
[00109] n is selected from 1 and 2;
[00110] Y is selected from O and S;
[00111] or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture, or tautomeric arbitrarily form.
[00112] in another embodiment, the invention provides the amide of new replacement, i.e. the chemical compound of formula I, wherein:
[00113] R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
[00114] R 2Be C 1-C 4Alkyl;
[00115] alternately, R 1And R 2With the nitrogen that links to each other with them form 5-6 unit by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O) m, the saturated rings formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (=O) nNR 13R 14,-N (R 13) S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace;
[00116] ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-21 mOther hetero atoms bicyclo-or three rings formed;
[00117] ring A is selected from C by 0-3 1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 4Alkoxyl, C 1-C 4Alkoxy C 1-C 4Alkyl or C 1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkyl is by 0-1 R 18Replace;
[00118] R 5Be H;
[00119] R 6And R 7Be independently selected from H and C 1-C 4Alkyl; With
[00120] n is 2.
[00121] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein:
[00122] R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
[00123] R 2Be C 1-C 4Alkyl;
[00124] alternately, R 1And R 2With the nitrogen that links to each other with them form 5-6 unit by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O) mThe saturated rings formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 1-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (=O) nNR 13R 14,-N (R 13) S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace;
[00125] ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O) mOther hetero atoms bicyclo-or three rings formed;
[00126] ring A is selected from C by 0-3 1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 4Alkoxyl, C 1-C 4Alkoxy C 1-C 4Alkyl or C 1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkyl is by 0-1 R 18Replace;
[00127] R 5Be H;
[00128] R 6And R 7Be independently selected from H and C 1-C 4Alkyl; With
[00129] n is 2.
[00130] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein:
[00131] R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
[00132] R 2Be selected from H, C 1-C 4Alkyl and C 3-C 6Cycloalkyl;
[00133] ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O) mOther hetero atoms bicyclo-or three rings formed;
[00134] ring A is selected from C by 0-3 1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 4Alkoxyl, C 1-C 4Alkoxy C 1-C 4Alkyl or C 1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkyl is by 0-1 R 18Replace;
[00135] R 5Be H;
[00136] R 6And R 7Be independently selected from H and C 1-C 4Alkyl; With
[00137] n is 2.
[00138] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein:
[00139] R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
[00140] R 2Be C 1-C 4Alkyl.
[00141] [3] the invention provides the amide of new replacement in another embodiment, i.e. the application of compound of the chemical compound of formula I and formula I, wherein:
[00142] R 8Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryloxy group C 1-C 4Alkyl and heteroaryloxy C 1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 19Replace;
[00143] R 9Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-6 unit's Heterocyclylalkyl and aryloxy group C 1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 20Replace;
[00144] R 10And R 11Be independently selected from H, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryl and heteroaryl, wherein each cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
[00145] alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-6 unit by shown in nitrogen, 4-5 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-1 mThe monocycle formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl and C 1-C 6The group of alkyl-carbonyl replaces;
[00146] R 12Be selected from OH, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 4Alkoxyl, aryl, aryl C 1-C 4Alkyl, heteroaryl, heteroaryl C 1-C 4Alkyl, aryloxy group and heteroaryloxy;
[00147] R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, dihalo-methylene dioxo, C 1-C 4Alkoxyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl ,-C (=O) R 12,-S (O) nR 12With-S (O) nNR 13R 14With
[00148] n is 2.
[00149] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula Ia:
Figure A20068005024900441
[00150] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula Ib:
Figure A20068005024900442
[00151] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula Ic:
Figure A20068005024900443
[00152] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula Id:
[00153] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula Ie:
Figure A20068005024900452
[00154] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein:
[00155] R 1And R 2With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mThe monocycle formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace.
[00156] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein R 1And R 2With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms monocycle or the bicyclo-formed, wherein this ring is by the individual C that is selected from of 1-3 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y)-NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace.
[00157] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein R 1And R 2With the nitrogen that links to each other with them form by shown in nitrogen, 2-3 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O) m5 yuan of saturated rings forming of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (=O) nNR 13R 14,-N (R 13) S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace.
[00158] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein R 1And R 2With the nitrogen that links to each other with them form by shown in nitrogen, 2-3 carbon atom and 1-2 is selected from nitrogen, oxygen and S (O) m5 yuan of saturated rings forming of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (=O) nNR 13R 14,-N (R 13) S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace.
[00159] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein R 1And R 2With the nitrogen that links to each other with them form by shown in nitrogen, 2-3 carbon atom and 1-2 is selected from nitrogen, oxygen and S (O) m5 yuan of saturated rings forming of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl and C 1-C 6Alkoxy C 1-C 6The group of alkyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace.
[00160] in another embodiment, the invention provides the amide of the new replacement of formula I, wherein R 1And R 2With the nitrogen that links to each other with them be:
Figure A20068005024900471
Wherein this ring is selected from C by 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl and C 1-C 6Alkoxy C 1-C 6The group of alkyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace.
[00161] in another embodiment, the invention provides the amide of the new replacement of formula I, its medium ring A is selected from:
Figure A20068005024900472
[00162] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C (=O) R 12And C 1-C 6Alkoxyl, wherein R 12Be as above to define.
[00163] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is selected from:
Figure A20068005024900481
[00164] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00165] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900482
[00166] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00167] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900483
[00168] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00169] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900484
[00170] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00171] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900491
[00172] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00173] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900492
[00174] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00175] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900493
[00176] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00177] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900494
[00178] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00179] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
Figure A20068005024900501
[00180] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00181] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is
[00182] ring A is by 0-2 R 25Replace; And R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00183] in another embodiment, the invention provides amide or its prodrug of the new replacement of formula I, its medium ring A is an azepan.
[00184] in another embodiment, the invention provides the chemical compound of new formula I, wherein the amide of this replacement or its prodrug are selected from following group:
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-isobutyramide
Cyclopentane carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Cyclohexane-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Piperidines-1-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
1-acetyl group-piperidines-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Cyclopentane carboxylic acid ethyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
2,2-N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-propionic acid amide.
Oxolane-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-4-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
Thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Furan-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3-chloro-4-(propane-2-sulfonyl)-thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
6-chloro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-nicotiamide
5-methyl-isoxazoles-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3,3, N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-butyramide
3-cyano group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-2-phenoxy group-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-the malonamic acid methyl ester
3-methyl-but-2-ene acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-2-phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
1-trifluoromethyl-Cyclobutylcarboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3,5-dimethoxy-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
4-mesyl-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-3-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
2,2-two fluoro-1,3-benzo dioxole-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-6-morpholine-4-base-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-nicotiamide
N-methyl-4-(2,2,2-three fluoro-acetyl group)-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-different phthalamidic acid
2,3-Dihydrobenzofuranes-7-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3-acetyl group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
1,1,3-trimethyl-3-[4-(1,3,3-trimethyl-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-sulfonylurea
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
2,2,2-three fluoro-ethyl sulfonic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-aminomethyl phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-isopropyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-cyclopropyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-ethyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
3-benzoyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-cyclohexyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methyl-phenyl) sulfonyl-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-phenyl-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(2,3-dihydro-1,4-benzo dioxine-2-ylmethyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(tetrahydrochysene-pyrans-4-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the acetic acid methyl ester
1-methyl-3-(5-Trifluoromethyl-1,3,4-thiadiazoles-2-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
2-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-benzoic acid methyl ester
3-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the benzoic acid ethyl ester
1-methyl-3-(3-ethyl sulfur alkyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-ethyl sulfur alkyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
3-(4-benzyloxy-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl sulfur alkyl-phenyls)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-cyano group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(2,2,4,4-tetrafluoro-4H-benzo-[1,3] dioxine-6-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methoxyl group-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-[4-(2,2,2-three fluoro-acetyl group)-cyclohexyl]-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-(4-acetyl group-phenyl)-1,3-dimethyl-3-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-phenyl-3-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-urea
Piperidines-1-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
Piperidines-1-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
1,3-dimethyl-3-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-1-phenyl-urea
1-[4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-amide
Piperidines-1-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-amide
1-[4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
1,3-dimethyl-1-phenyl-3-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-urea
Piperidines-1-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
1-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyridine-2-base-urea groups methyl)-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
Morpholine-4-carboxylic acid [4-(diamantane (obsolete)-2-base carbamoyl)-benzyl]-methyl-amide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-thiazol-2-yl-urea
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-thiazol-2-yl-urea
4-[3-(1-acetyl group-piperidin-4-yl)-1,3-dimethyl-urea groups methyl]-N-diamantane (obsolete)-2-base-Benzoylamide
1-(1-acetyl group-piperidin-4-yl)-3-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-urea
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyrimidine-2-base-urea groups methyl)-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-thiazol-2-yl-urea groups methyl)-Benzoylamide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-phenyl-urea groups methyl)-Benzoylamide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-diamantane (obsolete)-2-base-4-[3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea groups methyl]-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea
1-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-urea
1-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-imidazolidin-2-one
[4-(1,1-dioxo-isothiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-bicyclo-[3.2.1] suffering-6-yl)-ketone
[4-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-bicyclo-[3.2.1] suffering-6-yl)-ketone
(octahydro-quinoline-1-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(4-azepine-three ring [4.3.1.1 3,8]-hendecane-4-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(octahydro-isoquinolin-2-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(3-aza-bicyclo [3.2.2] ninth of the ten Heavenly Stems-3-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(6-aza-bicyclo [3.2.1] suffering-6-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
[4-(5-benzyl-1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
[00185] or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture, or tautomeric arbitrarily form.
[00186] in another embodiment, the invention provides the chemical compound of new formula I, wherein the amide of Qu Daiing or its prodrug are selected from following group:
[4-(1-amino-cyclopropyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Piperidines-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-N-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-butyramide
N-methyl-N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-aza-bicyclo [3.2.2]-nonane-3-carbonyl)-benzyl]-N-methyl-Benzoylamide
3-cyano group-N-methyl-N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-azabicyclic [3.2.2]-nonane-3-carbonyl)-benzyl]-3-cyano group-N-methyl-Benzoylamide
3-fluoro-N-methyl-N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-aza-bicyclo [3.2.2]-nonane-3-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-N-methyl-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-3-cyano group-N-methyl-Benzoylamide
Piperidines-1-carboxylic acid [4-(azepan-1-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(azepan-1-carbonyl)-benzyl]-methyl-amide
N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-azabicyclic [3.2.2]-nonane-3-carbonyl)-benzyl]-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-[(benzoyl-methyl-amino)-methyl]-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-3-cyano group-N-methyl-Benzoylamide
4-[(3-cyano group-benzoyl-methyl-amino)-methyl]-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
4-[(3-fluoro-benzoyl-methyl-amino)-methyl]-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
3-fluoro-N-methyl-N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-Benzoylamide
3-fluoro-N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
N-methyl-N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-Benzoylamide
N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid [4-(azepan-1-carbonyl)-benzyl]-methyl-amide
4-(benzoyl-amido-methyl)-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
3-cyano group-N-methyl-N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-Benzoylamide
3-cyano group-N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
3-fluoro-N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-(3-fluoro-benzoyl-amido-methyl)-N-methyl-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
4-(3-cyano group-benzoyl-amido-methyl)-N-methyl-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-amide
N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-[(benzoyl-methyl-amino)-methyl]-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
3-cyano group-N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-(benzoyl-amido-methyl)-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid [4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-Benzoylamide
4-(3-cyano group-benzoyl-amido-methyl)-N-(diamantane (obsolete)-2-yl)-Benzoylamide
4-(3-fluoro-benzoyl-amido-methyl)-N-(diamantane (obsolete)-2-yl)-Benzoylamide
N-[4-(4-aza-tricycle-[4.3.1.1 *3,8 *] hendecane-4-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-acetamide
4-mesyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-methyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-methyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-acetamide
4-mesyl-N-methyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-[4-(3-aza-bicyclo [3.2.2]-nonane-3-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-methyl-N-[4-(1,8,8-three-methyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-Methanesulfomide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-methyl-N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-first sulphur-amide
N-(3-hydroxyl-diamantane (obsolete)-1-yl)-4-[(mesyl-methyl-amino)-methyl]-Benzoylamide
N-(3-fluoro-diamantane (obsolete)-1-yl)-4-[(mesyl-methyl-amino)-methyl]-Benzoylamide
N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-diamantane (obsolete)-2-base-4-[(mesyl-methyl-amino)-methyl]-Benzoylamide
N-(4-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-the cyclopropyl sulfamoyl]-phenyl)-acetamide
4-chloro-N-{1-[4-(1,3,3-three-methyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-benzene-sulfonamide
1-methyl isophthalic acid H-imidazoles-4-sulfonic acid 1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-amide
N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-ethyl sulfonamide
1-[4-(azepan-1-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(3-hydroxyl-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-hydroxyl-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
4-(1,3-dimethyl-3-phenyl-urea groups methyl)-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
Piperidines-1-carboxylic acid [4-(3-fluoro-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-fluoro-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
4-(1,3-dimethyl-3-phenyl-urea groups methyl)-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyridine-2-base-urea groups methyl)-Benzoylamide
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-pyridine-2-base-urea
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-thiazol-2-yl-urea
1-(1-acetyl group-piperidin-4-yl)-1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-urea
1-(1-acetyl group-piperidin-4-yl)-3-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1]-octane-8-carbonyl)-benzyl]-1,3-dimethyl-urea
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-pyrimidine-2-base-urea
Morpholine-4-carboxylic acid [4-(4-azepine-three ring [4.3.1.1 *3,8 *]-hendecane-4-carbonyl)-benzyl]-methyl-amide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-fluoro-cyclohexyl)-1,3-dimethyl-urea
N-diamantane (obsolete)-2-base-4-[3-(1-cyclopropyl-piperidin-4-yl)-1,3-dimethyl-urea groups methyl]-Benzoylamide
1-[4-(3-methoxyl group-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
N-diamantane (obsolete)-2-base-4-[3-(4-fluoro-phenyl)-2-oxo-imidazolidine-1-ylmethyl]-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-fluoro-phenyl)-imidazolidin-2-one
1-(4-fluoro-phenyl)-3-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-imidazolidin-2-one
N-diamantane (obsolete)-2-base-4-(2-oxo-3-phenyl-imidazolidine-1-ylmethyl)-Benzoylamide
N-diamantane (obsolete)-1-base-4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl) Benzoylamide
N-diamantane (obsolete)-2-base-4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-Benzoylamide
(4-aza-tricycle [4.3.1.1 *3,8 *]-hendecane-4-yl)-[4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-ketone
Azepan-1-base-[4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-ketone
Azepan-1-base-[4-(5-methyl isophthalic acid, 1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-ketone
N-diamantane (obsolete)-1-base-4-(5-methoxy-1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-Benzoylamide
4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
5-[4-(diamantane (obsolete)-1-base-carbamoyl)-benzyl] and-1,1-dioxo-[1,2,5] thiadiazolidine-2-yl }-ra-butyl acetate
Or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture, or tautomeric arbitrarily form.
[00187] [1u] in another embodiment, the invention provides the amide of replacement, the salt of its prodrug or itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or the new application of tautomeric form arbitrarily, wherein the amide of this replacement or its prodrug are the chemical compounds of formula I:
Figure A20068005024900651
[00188] wherein:
[00189] R 1Be selected from H, R 8(C=O)-, R 9S (O) n-, R 10R 11NC (=Y)-and R 10R 11NS (O) n-;
[00190] R 2Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
[00191] alternately, R 1And R 2With the nitrogen that links to each other with them form the saturated or fractional saturation of 3-12 unit by shown in nitrogen, 2-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms monocycle or the bicyclo-formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace;
[00192] ring A be the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms bicyclo-or three rings formed;
[00193] ring A is selected from C by 0-3 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl or C 1-C 6The group of alkyl-carbonyl replaces, and wherein each alkyl is by 0-3 R 18Replace;
[00194] R 5Be selected from H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, halogen, OH and cyano group;
[00195] R 6And R 7Be independently selected from H, C 1-C 6Alkyl, F, trihalomethyl group and three halogenated methoxies;
[00196] alternately, R 6And R 7With the carbon atom that links to each other with them form the saturated or fractional saturation of 3-8 unit by shown in carbon atom, 2-5 other carbon atom and 0-2 are selected from nitrogen, oxygen and S (O) mThe monocycle formed of other hetero atoms, wherein this ring is by individual halogen, trihalomethyl group, OH, the C of being selected from of 0-3 1-C 6Alkyl, oxo and C 1-C 6The group of alkoxyl replaces;
[00197] R 8Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkyl, heteroaryloxy C 1-C 6Alkyl, aryl C 1-C 6Alkoxy C 1-C 6Alkyl and heteroaryl C 1-C 6Alkoxy C 1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 19Replace;
[00198] R 9Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkyl and aryl C 1-C 6Alkoxy C 1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 20Replace;
[00199] R 10And R 11Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl and heteroaryl C 1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
[00200] alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl-carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
[00201] R 12Be selected from OH, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 8Alkoxyl, aryl, aryl C 1-C 6Alkyl, heteroaryl, heteroaryl C 1-C 6Alkyl, aryloxy group, heteroaryloxy and NR 13R 14
[00202] R 13And R 14Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl and heteroaryl C 1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, aryl and heteroaryl are independently by 0-3 R 22Replace;
[00203] alternately, R 13And R 14With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
[00204] R 15Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
[00205] R 16And R 17Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, halogen, OH, cyano group ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12, C 1-C 8Alkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl are independently by 0-3 R 22Replace;
[00206] R 18Be selected from halogen, hydroxyl, oxo, COOH, cyano group C 1-C 6Alkoxyl, C 3-C 10Cycloalkyloxy, aryloxy group, heteroaryloxy, heteroarylthio and aryl C 1-C 6Alkoxyl;
[00207] R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, methylene dioxo, dihalo-methylene dioxo, C 3-C 6Spiro cycloalkyl group, C 1-C 6Alkoxyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, C (=O) R 12, S (O) nR 12, S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14With-C (=NR 16) NR 17
[00208] R 22Be selected from H, hydroxyl, oxo, halogen, cyano group, nitro, C 1-C 6Alkyl, C 1-C 6Alkoxyl, NR 23R 24, methylene dioxo, dihalo methylene dioxo, trihalomethyl group and three halogenated methoxies;
[00209] R 23And R 24Be independently selected from H, C 1-C 8Alkyl and aryl C 1-C 6Alkyl;
[00210] m is selected from 0,1 and 2;
[00211] n is selected from 1 and 2;
[00212] Y is selected from O and S;
[00213] or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or tautomeric arbitrarily form.
[00214] [1] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00215] R 1Be selected from H, R 8(C=O)-, R 9S (O) n-, R 10R 11NC (=Y)-and R 10R 11NS (O) n-;
[00216] R 2Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
[00217] alternately, R 1And R 2With the nitrogen that links to each other with them form the saturated or fractional saturation of 3-12 unit by shown in nitrogen, 2-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms monocycle or the bicyclo-formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each aryl/hetaryl is by 0-3 R 18Replace;
[00218] ring A be the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms bicyclo-or three rings formed;
[00219] ring A is selected from C by 0-3 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkylidene or C 1-C 6The group of alkyl-carbonyl replaces, and wherein each alkyl/alkylidene is by 0-3 R 18Replace;
[00220] R 5Be selected from H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, halogen, OH and cyano group;
[00221] R 6And R 7Be independently selected from H, C 1-C 6Alkyl, F, trihalomethyl group and three halogenated methoxies;
[00222] alternately, R 6And R 7With the carbon atom that links to each other with them form by shown in nitrogen, 2-5 other carbon atom and 0-2 be selected from nitrogen, oxygen and S (O) mThe monocycle of the saturated or fractional saturation of the 3-8 unit that forms of other hetero atoms, wherein this ring is by individual halogen, trihalomethyl group, OH, the C of being selected from of 0-3 1-C 6Alkyl, oxo and C 1-C 6The group of alkoxyl replaces;
[00223] R 8Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkylidene, heteroaryloxy C 1-C 6Alkylidene, aryl C 1-C 6Alkoxy C 1-C 6Alkylidene and heteroaryl C 1-C 6Alkoxy C 1-C 6Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 19Replace;
[00224] R 9Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkylidene and aryl C 1-C 6Alkoxy C 1-C 6Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 20Replace;
[00225] R 10And R 11Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene and heteroaryl C 1-C 6Alkylidene, wherein each alkyl/alkylidene, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
[00226] alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkylidene, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl-carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
[00227] R 12Be selected from OH, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 8Alkoxyl, aryl, aryl C 1-C 6Alkylidene, heteroaryl, heteroaryl C 1-C 6Alkylidene, aryloxy group, heteroaryloxy and NR 13R 14
[00228] R 13And R 14Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene and heteroaryl C 1-C 6Alkylidene, wherein each alkyl/alkylidene, cycloalkyl, aryl and heteroaryl are independently by 0-3 R 22Replace;
[00229] alternately, R 13And R 14With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkylidene, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
[00230] R 15Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
[00231] R 16And R 17Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, halogen, OH, cyano group ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12, C 1-C 8Alkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl are independently by 0-3 R 22Replace;
[00232] R 18Be selected from halogen, OH, oxo and cyano group;
[00233] R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, methylene dioxo, dihalo-methylene dioxo, C 3-C 6Spiro cycloalkyl group, C 1-C 6Alkoxyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14With-C (=NR 16) NR 17
[00234] R 22Be selected from H, hydroxyl, oxo, halogen, cyano group, nitro, C 1-C 6Alkyl, C 1-C 6Alkoxyl, NR 23R 24, methylene dioxo, dihalo methylene dioxo, trihalomethyl group and three halogenated methoxies;
[00235] R 23And R 24Be independently selected from H, C 1-C 8Alkyl and aryl C 1-C 6Alkylidene;
[00236] m is selected from 0,1 and 2;
[00237] n is selected from 1 and 2;
[00238] Y is selected from O and S;
[00239] [2u] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00240] R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
[00241] R 2Be C 1-C 4Alkyl;
[00242] alternately, R 1And R 2With the nitrogen that links to each other with them form by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O) mThe 5-6 unit saturated rings formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (=O) nNR 13R 14,-N (R 13) S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace;
[00243] ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O) mOther hetero atoms bicyclo-or three rings formed;
[00244] ring A is selected from C by 0-3 1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 4Alkoxyl, C 1-C 4Alkoxy C 1-C 4Alkyl or C 1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkyl is by 0-1 R 18Replace;
[00245] R 5Be H;
[00246] R 6And R 7Be independently selected from H and C 1-C 4Alkyl; With
[00247] n is 2.
[00248] [2] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00249] R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
[00250] R 2Be C 1-C 4Alkyl;
[00251] alternately, R 1And R 2With the nitrogen that links to each other with them form by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O) mThe 5-6 unit saturated rings formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene ,-C (=O) R 12,-S (O) nR 12,-S (=O) nNR 13R 14,-N (R 13) S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each aryl/hetaryl is by 0-3 R 18Replace;
[00252] ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O) mOther hetero atom bicyclo-or three rings formed;
[00253] ring A is selected from C by 0-3 1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 4Alkoxyl, C 1-C 4Alkoxy C 1-C 4Alkylidene or C 1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkylidene is by 0-1 R 18Replace;
[00254] R 5Be H;
[00255] R 6And R 7Be independently selected from H and C 1-C 4Alkyl; With
[00256] n is 2.
[00257] [3u] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00258] R 8Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryloxy group C 1-C 4Alkyl and heteroaryloxy C 1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 19Replace;
[00259] R 9Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-6 unit's Heterocyclylalkyl and aryloxy group C 1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 20Replace;
[00260] R 10And R 11Be independently selected from H, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryl and heteroaryl, wherein each cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
[00261] alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-6 unit by shown in nitrogen, 4-5 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-1 mThe monocycle formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl and C 1-C 6The group of alkyl-carbonyl replaces;
[00262] R 12Be selected from OH, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 4Alkoxyl, aryl, aryl C 1-C 4Alkyl, heteroaryl, heteroaryl C 1-C 4Alkyl, aryloxy group and heteroaryloxy;
[00263] R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, dihalo-methylene dioxo, C 1-C 4Alkoxyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl ,-C (=O) R 12,-S (O) nR 12With-S (O) nNR 13R 14With
[00264] n is 2.
[00265] [3] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00266] R 8Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkylidene, heteroaryl C 1-C 4Alkylidene, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryloxy group C 1-C 4Alkylidene and heteroaryloxy C 1-C 4Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 19Replace;
[00267] R 9Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkylidene, heteroaryl C 1-C 4Alkylidene, C 3-C 6Cycloalkyl, 3-6 unit's Heterocyclylalkyl and aryloxy group C 1-C 4Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 20Replace;
[00268] R 10And R 11Be independently selected from H, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryl and heteroaryl, wherein each cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
[00269] alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-6 unit by shown in nitrogen, 4-5 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-1 mThe monocycle formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl and C 1-C 6The group of alkyl-carbonyl replaces;
[00270] R 12Be selected from OH, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 4Alkoxyl, aryl, aryl C 1-C 4Alkylidene, heteroaryl, heteroaryl C 1-C 4Alkylidene, aryloxy group and heteroaryloxy;
[00271] R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, dihalo-methylene dioxo, C 1-C 4Alkoxyl, aryl, heteroaryl, aryl C 1-C 4Alkylidene, heteroaryl C 1-C 4Alkylidene ,-C (=O) R 12,-S (O) nR 12With-S (O) nNR 13R 14With
[00272] n is 2.
[00273] [4u] the invention provides the new application of chemical compound in another embodiment, and wherein the amide of this replacement or its prodrug are the chemical compounds of formula Ia:
Figure A20068005024900741
[00274] [5] the invention provides the new application of chemical compound in another embodiment, and wherein the amide of this replacement or its prodrug are the chemical compounds of formula Ib:
[00275] [6] the invention provides the new application of chemical compound in another embodiment, and wherein the amide of this replacement or its prodrug are the chemical compounds of formula Ic:
Figure A20068005024900752
[00276] [7] the invention provides the new application of chemical compound in another embodiment, and wherein the amide of this replacement or its prodrug are the chemical compounds of formula Id:
Figure A20068005024900753
[00277] [8] the invention provides the new application of chemical compound in another embodiment, and wherein the amide of this replacement or its prodrug are the chemical compounds of formula Ie:
Figure A20068005024900761
[00278] [9u] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00279] R 1And R 2With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms monocycle or the bicyclo-formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace.
[00280] [9] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00281] R 1And R 2With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms monocycle or the bicyclo-formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkylidene, heteroaryl C 1-C 6Alkylidene ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each aryl/hetaryl is by 0-3 R 18Replace.
[00282] [10u] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00283] ring A is selected from:
Figure A20068005024900771
[00284] ring A is by 0-2 R 25Replace; With
[00285] R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C (=O) R 12And C 1-C 6Alkoxyl, wherein R 12Be as above to define.
[00286] [10] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
[00287] ring A is selected from:
[00288] ring A is by 0-2 R 25Replace; With
[00289] R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00290] [11] the invention provides the new application of the chemical compound of formula I in another embodiment, wherein:
Ring A is
Figure A20068005024900781
[00291] ring A is by 0-2 R 25Replace; With
[00292] R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
[00293] in another embodiment, the invention provides the new application of the chemical compound of formula I, wherein the amide of Qu Daiing or its prodrug are selected from following group:
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-isobutyramide
Cyclopentane carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Cyclohexane-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Piperidines-1-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
1-acetyl group-piperidines-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Cyclopentane carboxylic acid ethyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
2,2-N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-propionic acid amide.
Oxolane-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-4-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
Thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Furan-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3-chloro-4-(propane-2-sulfonyl)-thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
6-chloro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-nicotiamide
5-methyl-isoxazoles-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3,3, N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-butyramide
3-cyano group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-2-phenoxy group-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-the malonamic acid methyl ester
3-methyl-but-2-ene acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-2-phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
1-trifluoromethyl-Cyclobutylcarboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3,5-dimethoxy-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
4-mesyl-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-3-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
2,2-two fluoro-1,3-benzo dioxole-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-6-morpholine-4-base-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-nicotiamide
N-methyl-4-(2,2,2-three fluoro-acetyl group)-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-different phthalamidic acid
2,3-Dihydrobenzofuranes-7-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3-acetyl group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
1,1,3-trimethyl-3-[4-(1,3,3-trimethyl-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-sulfonylurea
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
2,2,2-three fluoro-ethyl sulfonic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-aminomethyl phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-isopropyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-cyclopropyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-ethyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
3-benzoyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-cyclohexyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methyl-phenyl) sulfonyl-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-phenyl-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(2,3-dihydro-1,4-benzo dioxine-2-ylmethyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(tetrahydrochysene-pyrans-4-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the acetic acid methyl ester
1-methyl-3-(5-Trifluoromethyl-1,3,4-thiadiazoles-2-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
2-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-benzoic acid methyl ester
3-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the benzoic acid ethyl ester
1-methyl-3-(3-ethyl sulfur alkyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-ethyl sulfur alkyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
3-(4-benzyloxy-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl sulfur alkyl-phenyls)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-cyano group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(2,2,4,4-tetrafluoro-4H-benzo-[1,3] dioxine-6-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methoxyl group-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-[4-(2,2,2-three fluoro-acetyl group)-cyclohexyl]-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-(4-acetyl group-phenyl)-1,3-dimethyl-3-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-phenyl-3-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-urea
Piperidines-1-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
Piperidines-1-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
1,3-dimethyl-3-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-1-phenyl-urea
1-[4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-amide
Piperidines-1-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-amide
1-[4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
1,3-dimethyl-1-phenyl-3-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-urea
Piperidines-1-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
1-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyridine-2-base-urea groups methyl)-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
Morpholine-4-carboxylic acid [4-(diamantane (obsolete)-2-base carbamoyl)-benzyl]-methyl-amide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-thiazol-2-yl-urea
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-thiazol-2-yl-urea
4-[3-(1-acetyl group-piperidin-4-yl)-1,3-dimethyl-urea groups methyl]-N-diamantane (obsolete)-2-base-Benzoylamide
1-(1-acetyl group-piperidin-4-yl)-3-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-urea
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyrimidine-2-base-urea groups methyl)-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-thiazol-2-yl-urea groups methyl)-Benzoylamide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-phenyl-urea groups methyl)-Benzoylamide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-diamantane (obsolete)-2-base-4-[3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea groups methyl]-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea
1-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-urea
1-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-imidazolidin-2-one
[4-(1,1-dioxo-isothiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-bicyclo-[3.2.1] suffering-6-yl)-ketone
[4-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-bicyclo-[3.2.1] suffering-6-yl)-ketone
(octahydro-quinoline-1-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(4-azepine-three ring [4.3.1.1 3,8]-hendecane-4-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(octahydro-isoquinolin-2-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(3-aza-bicyclo [3.2.2] ninth of the ten Heavenly Stems-3-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(6-aza-bicyclo [3.2.1] suffering-6-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
[4-(5-benzyl-1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
[00294] or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture, or tautomeric arbitrarily form.
[00295] in another embodiment, the invention provides the novel formulation of the pharmaceutical composition of active favourable obstacle, disease or the disease for the treatment of adjusting or suppressing 11 β HSD1.
[00296] in another embodiment, the invention provides the novel formulation of pharmaceutical composition, wherein: described obstacle, disease or disease are subjected to the influence of endocellular sugar corticoid level.
[00297] in another embodiment, the invention provides the novel formulation of pharmaceutical composition, wherein: described obstacle, disease or disease be selected from metabolism syndrome, insulin resistant, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, glucose tolerance reduce (IGT), fasting glucose infringement (IFG), IGT to the development of type 2 diabetes mellitus, metabolism syndrome to development, advanced diabetes complication, neural degeneration and the psychiatric disturbance of type 2 diabetes mellitus and the ill effect of glucocorticoid receptor agonist treatment or therapy.
[00298] in another embodiment, the invention provides the novel formulation of pharmaceutical composition, wherein: this pharmaceutical composition is fit to oral, nose, cheek, percutaneous, lung or parenteral and uses.
[00299] in another embodiment, the invention provides the method that active favourable obstacle, disease or the disease of 11 β HSD1 were wherein regulated or suppressed in a kind of treatment, this method comprises that the patient to needs uses the chemical compound of the present invention of effective dose.
[00300] in another embodiment, the invention provides a kind of new method, wherein said obstacle, disease and disease are subjected to the influence of endocellular sugar corticoid level.
[00301] in another embodiment, the invention provides a kind of new method, wherein said obstacle, disease or disease be selected from metabolism syndrome, insulin resistant, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, glucose tolerance reduce (IGT), fasting glucose infringement (IFG), IGT to the development of type 2 diabetes mellitus, metabolism syndrome to development, advanced diabetes complication, neural degeneration and the psychiatric disturbance of type 2 diabetes mellitus and the ill effect of glucocorticoid receptor agonist treatment or therapy.
[00302] in another embodiment, the invention provides a kind of new method, wherein using is by oral, nose, cheek, percutaneous, lung or parenteral approach.
[00303] in another embodiment, the invention provides a kind of new chemical compound, it is to be used for the treatment of the medicament of regulating or suppressing active favourable obstacle, disease or the disease of 11 β HSD1.
[00304] in another embodiment, the invention provides a kind of new method, wherein said obstacle, disease or disease are subjected to the influence of endocellular sugar corticoid level.
[00305] in another embodiment, the invention provides a kind of new method, wherein said obstacle, disease or disease be selected from metabolism syndrome, insulin resistant, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, glucose tolerance reduce (IGT), fasting glucose infringement (IFG), IGT to the development of type 2 diabetes mellitus, metabolism syndrome to development, advanced diabetes complication, neural degeneration and the psychiatric disturbance of type 2 diabetes mellitus and the ill effect of glucocorticoid receptor agonist treatment or therapy.
[00306] in another embodiment, the invention provides a kind of new pharmaceutical composition, comprise chemical compound at least a of the present invention and one or more pharmaceutically acceptable carriers or excipient as active component.
[00307] in another embodiment, the invention provides a kind of new pharmaceutical composition, it is fit to oral, nose, cheek, percutaneous, lung or parenteral and uses.
[00308] chemical compound of the present invention has asymmetric center, can be used as racemic compound, racemic mixture and exists as the form of enantiomer or diastereomer individuality, and all isomeric form and composition thereof all comprise in the present invention.
[00309] the present invention also comprises the acceptable salt of pharmacy of this chemical compound.These salt comprise the acceptable acid-addition salts of pharmacy, the acceptable base addition salts of pharmacy, the acceptable slaine of pharmacy, ammonium salt and alkylating ammonium salt.Acid-addition salts comprises mineral acid and organic acid salt.The representative example of suitable mineral acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulphuric acid and nitric acid.Suitable organic acid representative example comprises formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propanoic acid, benzoic acid, cinnamic acid, citric acid, Fumaric acid, glycolic, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, acetone acid, salicylic acid, succinic acid, methanesulfonic acid, ethyl sulfonic acid, tartaric acid, ascorbic acid, crust is acid not, the dimethylene salicylic acid, ethionic acid, gluconic acid, citraconic acid, Aspartic Acid, stearic acid, Palmic acid, EDTA, glycolic, para-amino benzoic acid, glutamic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, acetate, benzoate, hydroxynaphthoate, glycerophosphate and ketoglutarate.Acceptable other examples inorganic or organic acid addition salt of pharmacy are included in J.Pharm.Sci., 66, the acceptable salt of listing in 2 (1977) of pharmacy, with it by with reference to being incorporated herein.The example of slaine comprises lithium, sodium, potassium, barium, calcium, magnesium, zinc and calcium salt.The example of amine and organic amine comprises ammonium, methylamine, dimethylamine, trimethylamine, ethamine, diethylamine, propylamine, butylamine, tetramethylammonium, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N, N '-dibenzyl ethylidene-diamidogen, N-benzyl-1-phenylethylamine, N-methyl D-glucamine and guanidine.The example of cationic amino acid comprises lysine, arginine and histidine.
[00310] in addition, chemical compounds more of the present invention can form solvate with water or organic solvent commonly used.These solvates comprise within the scope of the invention.
[00311] preparation pharmacy acceptable salt comprises that for example sodium hydroxide, sodium methoxide, sodium hydride, uncle's fourth oxygen potassium, calcium hydroxide and magnesium hydroxide for example react in ether, THF, methanol, tert-butyl alcohol, diox and isopropyl alcohol, the ethanol at solvent with chemical compound of the present invention and 1 to 4 normal alkali.Can use the mixture of solvent.Also can use organic base for example lysine, arginine, diethanolamine, choline, guanidine and their derivant etc.Alternately, can solvent for example ethyl acetate, ether, alcohols, acetone, THF with for example hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, p-methyl benzenesulfonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid, salicylic acid, carbonaphthoic acid, ascorbic acid, Palmic acid, succinic acid, benzoic acid, benzenesulfonic acid and tartaric acid are handled and are prepared spendable acid-addition salts with acid in the diox.Also can use the mixture of solvent.
[00312] preparation forms the stereoisomer of the chemical compound of a part of the present invention, can be included in the possible method by using the reactant of its single enantiomeric form, or react, or split the mixture of stereoisomer by conventional method by reagent or the catalyst that uses single enantiomeric form.Some preferable methods comprise uses microorganism fractionation, enzyme to split, split with operable chiral acid mandelic acid, camphorsulfonic acid, tartaric acid and lactic acid or the chiral base diastereoisomeric salt of strychnine, (R)-or (S)-phenethylamine, cinchona alkaloid and the formation of their derivant for example for example.Method commonly used is edited " Enantiomers, Racemates and Resolution " (Wiley Interscience, 1981) by people such as Jaques.More specifically, chemical compound of the present invention can convert 1: 1 mixture of diastereomer amide to, comprises the amino alcohol processing that produces with Chiral Amine, aminoacid, aminoacid; Conventional reaction condition can be used for acid is changed into amide; Can separate diastereomer by fractional crystallization or chromatography, can come the stereoisomer of preparation I compound by the purified diastereomer amide of hydrolysis.
[00313] the various polymorphics of the chemical compound of a formation part of the present invention can be by preparing described compound crystal under different condition.For example, use different solvents commonly used or their mixture to come recrystallization; Crystallization under different temperatures; During crystallization, use various forms of coolings, from very near very slow cooling.Polymorphic can also by with chemical compound heating or fusion and subsequently gradually or fast cooling obtain can by solid probe NMR spectrographic method, ir spectrographic method, differential scanning sensible heat method, powder x-ray diffraction or similarly other technologies determine polymorphous existence.
[00314] the present invention also comprises the prodrug of these chemical compounds, when using, by metabolic process generation chemical conversion, becomes active medicine then.Usually, these prodrugs are these compound functions derivants, and they change into the desired chemical compound of the present invention in vivo easily.The conventional method of selecting and preparing suitable prodrug derivant is at for example " Design ofProdrugs ", ed.H.Bundgaard, and Elsevier is described in 1985.
[00315] in drug discovery, well-known problem is that chemical compound for example enzyme inhibitor is very effective in selectively in biochemical analysis, but does not but have activity in vivo.The shortage of this so-called bioavailability can for example not absorb in digestive tract or be difficult to and absorb owing to a lot of different factors, first pass metabolism in liver and/or very difficult picked-up in cell.Although also do not understand the factor of determining bioavailability fully, but in scientific literature, there is a lot of examples-as well known to those skilled in the art-can be used for being modified at biochemical analysis effectively and the selective but active in vivo chemical compound that manifests very slow or non-activity, changes it into bioactive medicine
[00316] modifies chemical compound of the present invention (i.e. " former chemical compound ") also within the scope of the invention, modification comprises the chemical group that connects the described chemical compound bioavailability of improvement, and wherein said improvement is by promoting the mode of the picked-up in cell or mammal.
[00317] example of described modification (being not to limit the scope of the invention by any way) comprises and changes one or more carboxyls into ester (for example, methyl ester, ethyl ester, the tert-butyl group, acetic acid methyl, pivaloyl oxygen methyl ester or other acyloxy methyl ester).Modify chemical compound of the present invention by connecting chemical group, promptly former chemical compound and the chemical compound that obtains is called " chemical compound of modification ".
[00318] the present invention also comprises the active metabolite of these chemical compounds.
[00319] changes according to chemical compound of the present invention, more particularly, reduced the level of glucocorticoid in the competent cell, therefore, can be used for the treatment of this change or reduce favourable obstacle, disease or disease.
[00320] therefore, these chemical compounds can be used for the treatment of metabolism syndrome, insulin resistant, dyslipidemia, hypertension, fat, type 2 diabetes mellitus, glucose tolerance reduces (IGT), fasting glucose infringement (IFG), the potential autoimmune type diabetes of adult (LADA), type 1 diabetes, the advanced diabetes complication comprises cardiovascular disease, cardiovascular disorder, lipoidosis, neural degeneration and psychiatric disturbance, the intraocular pressure imbalance comprises glaucoma, immunological diseases, inappropriate immunne response, MSK disease, gastroenteropathy, polycystic ovary syndrome (PCOS), the other diseases that hair growth reduces or influenced by the endocellular sugar corticoid level, the ill effect that the blood levels of active endogenous or exogenous glucocorticoid and combination in any thereof raises, the ill effect that the blood plasma level of the active glucocorticoid of endogenous raises, cushing's disease, Cush, the ill effect of the glucocorticoid receptor agonist treatment of autoimmune disease, the ill effect of the glucocorticoid receptor agonist treatment of inflammation disease, the ill effect of glucocorticoid receptor agonist treatment with disease of inflammatory components, ill effect as the glucocorticoid receptor agonist treatment of a cancer chemotherapeutic part, the ill effect of glucocorticoid receptor agonist treatment in the situation of operation/operation back or other wounds, the ill effect of glucocorticoid receptor agonist treatment or the other diseases of clinical beneficial effect is provided at glucocorticoid receptor agonist in organ or tissue transplants, the ill effect of glucocorticoid receptor agonist treatment in obstacle or the disease.
[00321] more specifically, these chemical compounds can be used for the treatment of metabolism syndrome, type 2 diabetes mellitus, the diabetes that obesity causes, insulin resistant, hyperglycemia, the meals hyperglycemia, hyperinsulinemia, unsuitable insulin secretion reduces, glucose tolerance reduces (IGT), fasting glucose infringement (IFG), hepatic glucose produces to be increased, type 1 diabetes, LADA, child's diabetes, dyslipidemia, the diabetic dyslipidemia, hyperlipemia, hypertriglyceridemia, hyperlipoproteinemia, hypercholesterolemia, the HDL cholesterol reduces, the LDL/HDL ratio is destroyed, lipometabolic other obstacles, fat, the internal organs obesity, the obesity that diabetes cause, food intake increases, hypertension, the advanced diabetes complication, little-/large protein urine, nephropathy, retinopathy, neuropathy, diabetic ulcer, cardiovascular disease, arteriosclerosis, atherosclerosis, coronary artery disease, myocardial hypertrophy, myocardial ischemia, cardiac insufficiency, congestive heart failure, apoplexy, myocardial infarction, arrhythmia, blood flow reduces, erection disturbance (sex), myopathy, the muscular tissue loss, amyotrophy, myolysis, osteoporosis, linear growth reduces, neural degeneration and psychiatric disturbance, Alzheimer, neuronal death, cognitive function is impaired, depressed, anxiety, eating disorders, appetite stimulator, migraine, epilepsy, chemical substance addiction, the intraocular pressure obstacle, glaucoma, polycystic ovary syndrome (PCOS), unsuitable immunne response, unsuitable t helper cell-1/T accessory cell-2 polarization, bacterial infection, mycobacterial infections, fungal infection, viral infection, parasitic infection, the suboptimal of immunity is replied, immune dysfunction, part or alopecia totalis or the other diseases that influenced by the endocellular sugar corticoid level, obstacle or disease and combination in any thereof, the ill effect of the glucocorticoid receptor agonist of treatment inflammation disease, atopy-inflammation disease is the ill effect of the glucocorticoid receptor agonist treatment of asthma and atopic dermatitis for example, respiratory system disease is asthma for example, cystic fibrosis, emphysema, bronchitis, anaphylaxis, pneumonia, the eosinophilic pneumonia, the ill effect of the glucocorticoid receptor agonist treatment of pulmonary fibrosis, for example Ke Laoen is sick and the ill effect of the glucocorticoid receptor agonist treatment of ulcerative colitis for inflammatory bowel; The disease in immune system, connective tissue and joint for example reactive arthritis, rheumatoid arthritis,
Figure A20068005024900921
Syndrome, systemic lupus erythematosus (sle), lupus nephritis,
Figure A20068005024900922
The ill effect of the glucocorticoid receptor agonist treatment of purpura, Wegener ' s granuloma, temporal arteritis, systemic sclerosis, vasculitis, sarcoidosis, dermatomyositis-polymyositis, pemphigus vulgaris; The endocrinology disease is the ill effect of the glucocorticoid receptor agonist treatment of hyperthyroidism, hypoaldosteronism, hypopituitarism for example; Blood disease is the ill effect of the glucocorticoid receptor agonist treatment of hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria for example; Cancer is the ill effect of the inductive nauseating glucocorticoid receptor agonist treatment of neoplasm compressing, the cerebral tumor, acute lymphoblastic leukemia, Hodgkin, the chemotherapy of myelopathy, spinal cord for example, for example myasthenia gravis and hereditary myopathy be (for example for the disease in muscle and neuromuscular joint, the ill effect of glucocorticoid receptor agonist treatment duchenne muscular dystrophy), operation ﹠amp; The transplanting situation for example after wound, the operation stress, operation stress, renal transplantation, liver transplantation, lung transplantation, islet transplantation, blood hepatocyte transplantation, bone marrow transplantation, heart transplantation, adrenal transplantation, graft of trachea, intestinal transplanting, corneal transplantation, skin transplantation, corneal transplantation, crystalline lens transplant and other bad works with glucocorticoid receptor agonist treatment in the favourable additive method of glucocorticoid receptor agonist immunosuppressant; The ill effect of the glucocorticoid receptor agonist treatment of brain abscess, nausea, infection, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, myelopathy, saccular aneurysm perhaps provides the ill effect of glucocorticoid receptor agonist treatment in other diseases, obstacle or the disease of clinical beneficial effect at glucocorticoid receptor agonist.
[00322] therefore, one further aspect, the present invention relates to as pharmaceutical composition according to chemical compound of the present invention.
[00323] the present invention also relates to pharmaceutical composition, comprise at least a as active component according to chemical compound of the present invention and one or more pharmaceutically acceptable carriers or excipient.
[00324] this pharmaceutical composition unit dosage forms preferably comprises about 0.05mg/ day to about 2000mg/ day, and preferably about 0.1mg/ day arrives about 1000mg/ day, more preferably from about arrive 0.5mg/ day about 500mg/ day according to chemical compound of the present invention.
[00325] in another embodiment, use compounds for treating patient according to the present invention at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 2 months, or at least about 4 months.
[00326] in another embodiment, this pharmaceutical composition is used for oral, nose, cheek, percutaneous, lung or parenteral and uses.
[00327] in addition, the present invention relates to chemical compound according to the present invention preparation treatment wherein regulate or the pharmaceutical composition of the active useful obstacle of known 11 β HSD1 and disease in application.
[00328] the present invention also relates to that a kind of treatment is wherein regulated or the active useful obstacle of known 11 β HSD1 and the method for disease, this method comprise the patient to needs use effective dose according to chemical compound of the present invention.
[00329] in embodiment preferred of the present invention, this chemical compound is used to prepare treatment and is subjected to the above-mentioned any disease of endocellular sugar corticoid level and the medicine of disease.
[00330] therefore, in embodiment preferred of the present invention, this chemical compound can be used to prepare disease and disease, for example above-mentioned disease and the medicine of disease that treatment need reduce glucocorticoid level in the competent cell.
[00331] in embodiment preferred of the present invention, this chemical compound can be used for preparation treatment metabolism syndrome, insulin resistant, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, glucose tolerance and reduce (IGT), fasting glucose infringement (IFG), IGT to the development of type 2 diabetes mellitus, the metabolism syndrome medicine to the ill effect of development, advanced diabetes complication, neural degeneration and the psychiatric disturbance of type 2 diabetes mellitus and glucocorticoid receptor agonist treatment or therapy.
[00332] in another embodiment of the invention, route of administration be can effectively send according to chemical compound to effect suitably or the site of expectation is for example oral, nose, cheek, percutaneous, lung or parenteral any approach.
[00333] of the present invention one further aspect, one or more other active compound combined using of this chemical compound and any proper proportion.These other active substance can for example be selected from antiobesity agent, antidiabetic, the lipometabolic medicament of change, hypotensive agent, glucocorticoid receptor agonist, treat and/or prevent that diabetes cause or with the medicament of diabetes complications associated with arterial system and treat and/or prevent that obesity causes or with the medicament of fat complications associated with arterial system.
[00334] therefore, one of the present invention further aspect, this chemical compound can be co-administered with one or more antiobesity agents or appetite stimulator.
[00335] these medicaments can be selected from CART (the cocaine amphetamines is regulated and transcribed) agonist, NPY (neuropeptide tyrosine) antagonist, MC4 (melanocortin 4) agonist, the aricine antagonist, TNF (tumor necrosis factor) agonist, CRF (corticotropin-releasing factor) agonist, CRF BP (corticotropin-releasing factor is conjugated protein) antagonist, agonist, β 3 agonist, MSH (melanocyte-stimulation hormone) agonist, MCH (melanocyte-element concentrates) antagonist, CCK (cholecystokinin) agonist, serotonin reuptake inhibitor, 5-hydroxy tryptamine and NRI, 5-hydroxy tryptamine and norepinephrine energy mixed type chemical compound, 5HT (5-hydroxy tryptamine) agonist, the bombesin agonist, the galanin antagonist, growth hormone, growth hormone releasing compounds, TRH (throtropin releasing hormone) agonist, UCP 2 or 3 (uncoupling protein 2 or 3) regulator, the Leptin agonist, DA agonist (bromocriptine, doprexin), lipase/amylase inhibitor, PPAR (peroxisome Proliferator-activated receptor) regulator, RXR (retinoid X receptor) regulator, the TR beta-agonists, AGRP (with the Agouti proteins associated) inhibitor, the H3 histamine antagonist, opiate antagonist (for example naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
[00336] in one embodiment of the invention, antiobesity agent is a Leptin; Dextroamphetamine or amphetamines; Fenfluramine or Isomeride; Sibutramine; Orlistat; Mazindol or Duromine.
[00337] suitable antidiabetic comprises insulin, insulin analog and derivant for example at EP 792 290 (Novo Nordisk A/S), for example, and N ε B29-four capryl des (B30) insulin humans, EP 214 826 and EP 705 275 (Novo Nordisk A/S), for example, Asp B28Insulin human, US 5,504,188 (Eli Lilly), for example, Lys B28Pro B29Insulin human, EP 368 187 (Aventis), Lantus for example, it all is incorporated herein by reference, GLP-1 (glucagon-like peptide-1) and GLP-1 derivant be those disclosed in the WO98/08871 of Novo Nordisk A/S for example, it is incorporated herein by reference, and the agent of Orally active hypoglycemia.
[00338] agent of Orally active hypoglycemia preferably comprises sulfonylurea; biguanide; meglitinide; glucosidase inhibitor; glucagon antagonists is for example at Novo Nordisk A/S and Agouron Pharmaceuticals; Inc. those disclosed among the WO 99/01423; the GLP-1 agonist; potassium channel openers is those disclosed in the WO 97/26265 of Novo Nordisk A/S and WO99/03861 for example, with it by with reference to being incorporated herein; DPP-IV (dipeptidyl peptidase-IV) inhibitor; the inhibitor of the liver enzyme relevant with stimulating glyconeogenesis and/or glycogenolysis; the glucose uptake regulator; regulate for example lipidemia agent and antilipemic agent PPAR alpha modulators for example of lipometabolic chemical compound; PPAR δ regulator; cholesterol absorption inhibitor; HSL (hormone-sensitive lipase) inhibitor and HMG CoA inhibitor (Statins); nicotinic acid; the special class of chlorine shellfish; cationite; reduce the chemical compound of food intake; the bile acid resin; rxr agonist and the medicament that acts on the ATP-dependency potassium channel of beta cell.
[00339] in one embodiment, this chemical compound and insulin or insulin analog or derivant N for example ε B29-four decyl des (B30) insulin humans, Asp B28Insulin human, Lys B28Pro B29Insulin human, Lantus
Figure A20068005024900951
Or one or more mix preparation is co-administered to comprise them.
[00340] in a further embodiment, this chemical compound and sulfonylurea for example tolbutamide, glibenclamide, glipizide or gliclazide are co-administered.
[00341] in another embodiment, for example metformin is co-administered for this chemical compound and biguanide.
[00342] in another embodiment, for example repaglinide or senaglinide are co-administered for this chemical compound and meglitinide.
[00343] in another embodiment, this chemical compound can with thiazolidinedione for example troglitazone, ciglitazone, pioglitazone, rosiglitazone or in WO 97/41097 disclosed chemical compound 5-[[4-[3-methyl-4-oxo-3 for example, 4-dihydro-2-quinazolyl] methoxyl group] phenyl-methyl] thiazolidine-2,4-diketone or the acceptable salt of its pharmacy, preferred potassium salt is co-administered.
[00344] in another embodiment, this chemical compound can with (-) 3-[4-[2-phenoxazine-10-yl for example of disclosed insulin sensitizers among the WO 99/19313) ethyoxyl] phenyl]-2-ethoxy-propionic acid or the acceptable salt of its pharmacy, preferred arginine salt is co-administered.
[00345] in another embodiment, for example miglitol or acarbose are co-administered for this chemical compound and alpha-glucosidase inhibitor.
[00346] in another embodiment, for example tolbutamide, glibenclamide, glipizide, gliclazide or repaglinide are co-administered with the medicament of ATP-dependency potassium channel that acts on beta cell for this chemical compound.
[00347] in addition, this chemical compound can be co-administered with Nateglinide.
[00348] in another embodiment, for example cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine are co-administered for this chemical compound and lipidemia agent or antilipemic agent.
[00349] in another embodiment; in this chemical compound and the above-claimed cpd more than one are co-administered, and are for example co-administered with sulfonylurea and metformin, sulfonylurea and acarbose, repaglinide and metformin, insulin and sulfonylurea, insulin and metformin, insulin, insulin and lovastatin or the like.
[00350] in addition, this chemical compound can be co-administered with one or more hypotensive agents.The example of hypotensive agent is a for example alprenolol of beta-Blocking agent, atenolol, timolol, pindolol, Propranolol, metoprolol, bisoprolol, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, the beta 2-receptor blocker for example, the S-atenolol, OPC-1085, ACE (Angiotensin-Converting) inhibitor is quinapril for example, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-MarionRoussel:100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511, calcium channel blocker is nifedipine for example, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine, verapamil, lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, barnidipine, efonidipine, iasidipine, lemildipine, iercanidipine, Manidipine, nilvadipine, pranidipine, furnidipine, α-Zu Zhiji is doxazosin for example, urapidil, prazosin, terazosin, bunazosin and OPC-28326, for example thiazide/the thiamine class (for example for diuretic, bendroflumethiazide, chlortalidone, hydrochlorothiazide and clopamide), loop diuretic (for example, bumetanide, furosemide and torasemide) and potassium-sparing diuretic is (for example, amiloride, spironolactone), Endothelin ET-A antagonist is ABT-546 for example, ambrisetan, atrasentan, SB-234551, C1-1034, S-0139 and YM-598, endothelin antagonist for example, bosentan and J-104133, renin inhibitors such as aliskiren, vassopressin V1 antagonist is OPC-21268 for example, vassopressin V2 antagonist is tolvaptan for example, SR-121463 and OPC-31260, B-type natriuretic peptide agonist is Nesiritide for example, the Angiotensin II antagonist is irbesartan for example, Candesartan Cilexetil, losartan, valsartan, telmisartan, eprosartan, Candesartan, CL-329167, eprosartan, iosartan, Olmesartan, Pratosartan, TA-606 and YM-358, the 5-HT2 agonist is Fenoldopam and ketanserin for example, adenosine A 1 antagonist is naftopidil for example, N-0861 and FK-352, the thromboxane A2 antagonist is KT2-962 for example, endopeptidase inhibitor is ecadotril for example, the nitrous oxide agonist is LP-805 for example, the dopamine D 1 antagonist for example, MYD-37, the dopamine D 2 agonist is nolomirole for example, the n-3 fatty acid is omacor for example, prostacyclin agonists is treprostinil for example, Beraprost, the PGE1 agonist for example, ecraprost, Na+/K+ATP enzyme regulator is PST-2238 for example, potassium channel activator is KR-30450 for example, vaccine is PMD-3117 for example, indopamide, CGRP-unigene, uridylic acid cyclase regulator, hydralazine, methyldopa, docarpamine, moxonidine, CoAprovel, MondoBiotech-811.
[00351] other can reference: Remington:The Science and Practice ofPharmacy, 19 ThEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
[00352] in addition, this chemical compound can be co-administered with one or more glucocorticoid receptor agonists.The example of these glucocorticoid receptor agonists is betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclometasone, butixocort, clobetasol, flunisolide, fluticasone (and analog), mometasone, triamcinolonacetonide, triamcinolone acetonide GW-685698, NXC-1015, NXC-1020, NXC-1021, NS-126, P-4112, P-4114, RU-24858 and T-25 series.
[00353] should be understood that, will be understood that according to chemical compound of the present invention and one or more above-claimed cpds and optional one or more other pharmacological active substance any suitable combination all within the scope of the invention.
Pharmaceutical composition
[00354] chemical compound of the present invention can be used separately or co-administered with pharmaceutically acceptable carrier or excipient with the form of list or multiple dose.Can be according to pharmaceutical composition of the present invention according to routine techniques for example in Remington:The Science and Practice ofPharmacy, 19 ThEdition, Gennaro, Ed., Mack Publishing Co., Easton, PA, those disclosed in 1995 is with pharmaceutically acceptable carrier or diluent and other known adjuvants and excipient preparation arbitrarily.
[00355] pharmaceutical composition can be mixed with especially by any suitable approach, in for example oral, rectum, nose, lung, part (comprising containing and Sublingual), percutaneous, the brain pond, intraperitoneal, vagina and parenteral (comprise in subcutaneous, intramuscular, the sheath, vein and corium) approach uses the preferred oral approach.Should recognize the character and the selected active component of the situation that preferred approach will depend on the patient's that will treat ordinary circumstance and age, will treat.
[00356] oral pharmaceutical composition comprises solid dosage forms for example hard or soft capsule, tablet, buccal tablet, coated tablet, pill, lozenge, powder and granule.In the time of suitably, they can perhaps can prepare them according to method well known in the art with for example enteric coating preparation of coating, for example continue or prolong to discharge with the sustained release that active component is provided.
[00357] oral liquid dosage form comprises solution, Emulsion, suspension, syrup and elixir.
[00358] pharmaceutical composition used of parenteral comprise sterile aqueous and non-aqueous injection solution, dispersion liquid, suspension or Emulsion and use before in aseptic injectable solution or dispersion liquid dissolved again sterilized powder.Should be noted that long acting injection is also included within the scope of the present invention.
[00359] other suitable administration forms comprise suppository, spray, ointment, emulsifiable paste, gel, inhalant, skin patch, implant or the like.
[00360] typical oral dose scope is about 0.001 to about 100mg/kg body weight/day, and preferred about 0.01 to about 50mg/kg body weight/day, more preferably from about 0.05 arrives about 10mg/kg body weight/day, with one or more dosage for example 1 to 3 dosage use.Definite dosage will depend on frequency and mode, the patient's that treats sex, age, body weight and ordinary circumstance, the character that will treat situation and the severity of using, any disease accompanied and other factors that it will be apparent to those skilled in the art that treat.
[00361] said preparation can exist with unit dosage forms by method known to those skilled in the art easily.Can use 1 or repeatedly for example every day, 1 to 3 time oral typical flat dosage form can comprise 0.05 to about 2000mg every day, for example, about 0.1 to about 1000mg, about 0.5mg arrives about 500mg, and about 1mg arrives about 200mg, for example, about 100mg.
[00362] for the parenteral approach, for example in the intravenous, film, intramuscular and similar route of administration, typical dosage be orally use dosage pact half.
[00363] chemical compound of the present invention is generally as dissociant or the acceptable salt of its pharmacy.Example is the base addition salts that has the acid-addition salts of the chemical compound that free alkali uses and have the chemical compound that free acid uses.Term " the acceptable salt of pharmacy " is meant the non-toxic salts of chemical compound used according to the invention, and it generally is to prepare by free alkali and suitable organic or inorganic acid reaction or acid and suitable organic or inorganic alkali reaction.When chemical compound used according to the invention comprises free alkali, prepare these salt in a usual manner, comprise solution or the suspension of handling this chemical compound with the chemical equivalence thing of the acceptable acid of pharmacy.When chemical compound used according to the invention comprises free acid, prepare these salt in a usual manner, comprise solution or the suspension of handling this chemical compound with the chemical equivalence thing of the acceptable alkali of pharmacy.Physiologically acceptable salt with chemical compound of hydroxyl comprises for example combination of sodium or ammonium ion of the anion of described chemical compound and cation arbitrarily.The preparation that acceptable other salt of non-pharmacy also can be used to prepare chemical compound used according to the invention, these have formed another aspect of the present invention.
[00364] uses for parenteral, can use aseptic aqueous solution, aqueous propylene glycol or Oleum sesami or the peanut oil solution of these chemical compounds.If necessary, these aqueous solutions should be suitably buffered, at first make liquid diluent have isotonia with enough saline or glucose.Aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal is used.The sterile aqueous media of using all obtains easily by technology well known by persons skilled in the art.
[00365] suitable pharmaceutical carriers comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.The example of appropriate carriers is a water, saline solution, alcohol, Polyethylene Glycol, poly-hydroxyl-oxethyl Oleum Ricini, Oleum Arachidis hypogaeae semen, olive oil, syrup, phospholipid, gelatin, lactose, Gypsum Fibrosum powder, sucrose, cyclodextrin, amylose, magnesium stearate, Talcum, gelatin, agar, pectin, arabic gum, stearic acid or cellulosic lower alkyl ether, silicic acid, fatty acid, fatty acid amine, fatty acid glycerine one ester and diglyceride, pentaerythritol fatty ester, polyoxyethylene, hydroxy methocel and polyvidon.Similarly, carrier or diluent can comprise any sustained-release material known in the art, and for example glyceryl monostearate or glycerol distearate mix separately or with wax.Said preparation also can comprise wetting agent, emulsifying and suspending agent, antiseptic, sweeting agent or flavoring agent.
[00366] can easily easily use by chemical compound of the present invention is mixed the pharmaceutical composition that forms with pharmaceutically acceptable carrier with the various dosage forms that are fit to described use approach.Said preparation can exist with unit dosage forms by the known method of pharmaceutical field easily.
[00367] be fit to oral preparation of the present invention and can be used as separative element for example capsule or tablet existence, each all comprises the active component of scheduled volume and can comprise appropriate excipients.These preparations can be powder or particulate form, as solution in aqueous or non-aqueous liquid or suspension, or as oil-in-water or water-in-oil type liquid emulsion.
[00368] the oral compositions of expection can prepare according to any known method, these compositionss can comprise one or more and be selected from following reagent, comprise sweeting agent, flavoring agent, coloring agent and antiseptic, so that pharmaceutically suitable and agreeable to the taste preparation to be provided.Tablet can comprise active component and be fit to the mixture of the acceptable excipient of avirulence pharmacy of preparation tablet.These excipient can be for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphates of inert diluent for example; Granulation and disintegrating agent, for example corn starch or alginic acid; Binding agent, for example starch, gelatin or arabic gum; And lubricant, for example magnesium stearate, stearic acid or Talcum.Tablet can be a coating not, and perhaps therefore they can, provide lasting effect in the long period by the known technology coating to postpone disintegrate and the absorption in gastrointestinal tract.For example, can postpone material for example glyceryl monostearate or glycerol distearate service time.Also can pass through U.S.4,356,108; 4,166,452; With 4,265,874 described technology to form the osmotic therapeutic tablets of controlled release, are incorporated herein with these documents they coatings by reference.
[00369] oral preparation can be used as the hard gelatin capsule existence, wherein for example calcium carbonate, calcium phosphate or Kaolin mix active component with inert solid diluent, perhaps can be used as Perle and exist, wherein for example Oleum Arachidis hypogaeae semen, liquid Paraffin or mixed with olive oil of active component and water or oil medium.
[00370] aqueous suspension can comprise the mixture of the excipient of reactive compound and suitable preparation aqueous suspension.These excipient are for example sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, tragakanta and arabic gums of suspending agent; Dispersion or wetting agent can be for example lecithin of naturally occurring phospholipid, or the condensation substance of alkyl oxygen and fatty acid stearic acid polyoxyethylene for example, or the condensation substance of oxygen ethylene and long-chain fatty alcohol heptadecane ethylene oxy hexadecanol for example, or the condensation substance of oxygen ethylene and the partial ester that produces by fatty acid and hexitol polyoxyethylene sorbitol monoleate for example, or the condensation substance of oxygen ethylene and the partial ester that forms by fatty acid and hexitan polyethylene sorbitan monooleate for example.Aqueous suspension also can comprise one or more coloring agent, one or more flavoring agents and one or more sweeting agents, for example sucrose or glucide.
[00371] can for example Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois or mineral oil be for example prepared oil-based suspension in the liquid Paraffin by active component being suspended in vegetable oil.This oil-based suspension can comprise thickening agent for example Cera Flava, hard paraffin or hexadecanol.Can add for example above-mentioned those of sweeting agent and flavoring agent agreeable to the taste oral formulations is provided.By add antioxidant for example ascorbic acid protect these compositionss.
[00372] but be fit to prepare the dispersed powders of aqueous suspension and the mixture that granule provides reactive compound and dispersion or wetting agent, suspending agent and one or more antiseptic by adding entry.Can exemplarily enumerate suitable dispersion or wetting agent and suspending agent by above-mentioned those.The excipient that also can have other, for example sweeting agent, flavoring agent and coloring agent.
[00373] pharmaceutical composition that comprises chemical compound used according to the invention also can be an oil-in-water emulsion.Oil phase can be for example olive oil or an Oleum Arachidis hypogaeae semen of vegetable oil, or mineral oil for example liquid Paraffin or its mixture.Suitable emulsifying agent can be for example arabic gum or tragakanta of naturally occurring glue, naturally occurring phospholipid is soybean phospholipid, lecithin for example, the perhaps ester that produces of fatty acid and hexitan or partial ester sorbitan monooleate for example, with the condensation substance of described ester and oxygen ethylene, for example polyoxyethylene sorbitan monooleate.Emulsion also can comprise sweeting agent and flavoring agent.
[00374] can be with sweeting agent for example glycerol, propylene glycol, Sorbitol or sucrose syrup blend and elixir.These preparations also can comprise wetting agent, antiseptic, flavoring agent and coloring agent.These pharmaceutical compositions can be aseptic injection aqueous or oil-based suspension.Can use above-mentioned suitable dispersion or wetting agent and suspending agent to prepare this suspension according to known method.Aseptic injection preparation also can be aseptic injectable solution or the suspension in avirulence parenteral acceptable diluent or solvent, for example solution in 1,3 butylene glycol.Operable acceptable carrier and solvent be water, Ringer's solution and etc. open sodium chloride solution.In addition, can easily aseptic Combination oil be used as solvent or suspension media.For this purpose, the expressed oi of any gentleness be can use, as synthetic monoglyceride or diester used.In addition, found for example application of oleic acid in the preparation injection of fatty acid.
[00375] said composition can be the form of suppository also, is used for rectal administration chemical compound of the present invention.Can prepare these compositionss by medicine is mixed with suitable non-irritating excipient, wherein said excipient is solid at normal temperatures, but is liquid at the anus relaxing the bowels with purgatives of warm nature, therefore can melt the release medicine in rectum.These materials comprise, for example cocoa butter and Polyethylene Glycol.
[00376] can pay close attention to emulsifiable paste, ointment, gel, solution or suspension of comprising chemical compound of the present invention or the like for the part use.For this application aims, the topical application agent should comprise mouth wass and collutory.
[00377] chemical compound used according to the invention also can be used with the form of liposome delivery system, for example small unilamellar vesicles, large-scale monolayer blister and multilamellar blister.Can for example cholesterol, stearmide or phosphatidylcholine form liposome by various phospholipid.
[00378] in addition, some chemical compounds used according to the invention can form solvate with water or organic solvent commonly used.These solvates are also included within the scope of the present invention.
[00379] therefore, in a further embodiment, a kind of pharmaceutical composition is provided, has comprised chemical compound used according to the invention or the acceptable salt of its pharmacy, solvate or prodrug and one or more pharmaceutically acceptable carriers, excipient or diluent.
[00380] oral if solid carrier is used for, said preparation can be a tablet, is arranged in hard gelatin capsule with powder or ball shape form, and perhaps it can be the form of buccal tablet or lozenge.The amount of solid carrier can be different widely, but generally are that about 25mg is to about 1g.If use liquid-carrier, said preparation can be the forms of syrup, Emulsion, Perle or aseptic parenteral solution style such as aqueous or non-aqueous liquid suspension or solution.
[00381] can comprise by the typical tablet of conventional tabletting technology preparation:
[00382] Nuclear:
[00383] reactive compound (as free cpds or its salt) 5.0mg
[00384] lactose PH.Eur. 67.8mg
[00385] microcrystalline Cellulose (Avicel) 31.4mg
[00386]Amberlite
Figure A20068005024901031
IRP88* 1.0mg
[00387] magnesium stearate PH.Eur. q.s.
[00388] Coating:
[00389] the about 9mg of hydroxypropyl emthylcellulose
[00390] the about 0.9mg of Mywacett 9-40T**
[00391] Polacrillin potassium NF, tablet disintegrant, Rohm and Haas.
[00392] * * is as the acidylate monoglyceride of the plasticizer of film coating.
[00393] chemical compound of the present invention can be applied to the patient, and the patient is a mammal, the people who particularly needs.These mammals also comprise for example domestic pets and non-domestic animal wild animal for example of animal, domestic animal.
[00394] any new feature or combination of features described herein all will be understood that and are equivalent to the present invention.
[00395] the present invention also relates to prepare the following method of chemical compound of the present invention.
[00396] the present invention further illustrates in below the representative embodiment, still, is not to be intended to limit the scope of the invention by any way.
Embodiment, the chemical compound of general formula (I)
[00397] embodiment and conventional method relate to midbody compound and the end product at description and the general formula (I) identified below in synthetic schemes.Use the following example to describe the preparation of the chemical compound of general formula of the present invention (I) in detail.Sometimes, this reaction cannot be as describing the every kind of chemical compound that is included in the scope of the present invention.The chemical compound of this situation is those skilled in the art's identifications easily.In these situations, can successfully carry out this reaction by conventional change the well known by persons skilled in the art, for example, suitably protection is disturbed group, is changed into other conventional reagent, the perhaps conventional reaction condition that changes.Alternately, described herein or other other conventional reactions can be used to prepare respective compound of the present invention.In all preparation methoies, all initial substances all are known or can easily prepare from known initial substance.Can wherein exist and be appointed as the peak that characterizes the title compound proton by the structure of elementary analysis or nuclear magnetic resonance, NMR proof chemical compound in suitable place. 1H NMR moves (δ H) be that millionth unit (ppm) with downfield provides, tetramethylsilane is as the internal reference reference material.M.p.: be fusing point, unit is ℃, and not through overcorrect.With people such as W.C.Still, J.Org.Chem. 43: 2923 (1978) described technology, on Merck silica gel 601Art.9385, carry out column chromatography.Carry out HPLC with 5 μ m C18,4 x 250mm posts and analyze, with the mixture eluting of various water and acetonitrile, flow velocity=1ml/ minute, as described at experimental section.
[00398] microwave oven is synthetic: by microwave radiation in the microwave tube of sealing with PersonalChemistry
Figure A20068005024901041
Monotype Emrys Optimizer EXP heat this reaction.
[00399] preparation property HPLC: post: 1.9 x 15cm Waters XTerra RP-18.Buffer: linear gradient 5-95%, 15 minutes, MeCN, 0.1%TFA, flow velocity 15ml/ minute.Vacuum drying evaporates the part of merging, or vacuum evaporation is until removing MeCN, freezing then and lyophilization.
[00400] abbreviation of using in an embodiment has following meanings:
TLC: thin layer chromatography
CDCl 3: deuterochloroform
CD 3OD: four deuterated methanols
DCM: dichloromethane
DMF:N, the N-dimethylformamide
DMSO-d 6: six deuterated dimethyl sulfoxides
DMSO: dimethyl sulfoxine
DIPEA: diisopropylethylamine
EDAC: hydrochloric acid 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
EtOAc: ethyl acetate
THF: oxolane
HOBT:1-hydroxyl-benzotriazole
MeCN: acetonitrile
The NMP:N-methyl pyrrolidone
TFA: trifluoroacetic acid
Min: minute
Hrs: hour
[00401] conventional method A:
Figure A20068005024901051
Become under the amide condition in standard, use wherein R of coupling agent (III) (for example, the HOBT in anhydrous THF, EDAC and DIPEA) 2, R 5, R 6, R 7With A benzylamine (I) and R wherein as defined above 8Acid (II) coupling as defined above obtains wherein R 2, R 5, R 6, R 7, R 8With A amide (IV) as defined above; Or under alkali condition (for example, triethylamine, K 2CO 3, NaH or the like) R wherein in solvent (for example THF, DCM, DMF, NMP or the like) 2, R 5, R 6, R 7With A as defined above benzylamine (I) be halogen, R with X wherein 8(C=O) O-, C 1-C 6Alkoxyl or aryl C 1-C 6Alkoxyl and R 8Acid derivative (II) reaction as defined above obtains amide (III); R wherein 2, R 5, R 6, R 7, R 8As above define with A.
[00402] conventional method B:
(for example, triethylamine, K under alkali condition 2CO 3, NaH or the like) R wherein in solvent (for example THF, DCM, DMF, NMP or the like) 2, R 5, R 6, R 7With A as defined above benzylamine (I) be halogen and R with X wherein 9Sulfonic acid halide (II) reaction as defined above obtains sulfonamide (III); R wherein 2, R 5, R 6, R 7, R 9As above define with A.
[00403] conventional method C:
Figure A20068005024901061
In solvent (for example THF, DCM, DMF, NMP or the like), incite somebody to action wherein R 2, R 5, R 6, R 7With A benzylamine (I) and R wherein as defined above 10Isocyanates (II) reaction as defined above obtains urea (III); R wherein 2, R 5, R 6, R 7, R 10As above define with A.Can be under alkali condition (for example, triethylamine, K 2CO 3, NaH or the like) in solvent (for example THF, DCM, DMF, NMP or the like) with three-urea (III) that replaces is halogen or OSO with X wherein 2Me and R 11Further reaction of alkyl halide or methanesulfonates (IV) as defined above obtains quaternary urea (V); R wherein 2, R 5, R 6, R 7, R 10, R 11With A as defined above.
[00404] conventional method D:
In solvent (for example THF, DCM, DMF, NMP or the like), incite somebody to action wherein R 2, R 5, R 6, R 7With A benzylamine (I) and R wherein as defined above 10Isocyanates (II) reaction as defined above obtains thiourea (III); R wherein 2, R 5, R 6, R 7, R 10As above define with A.Can be under alkali condition (for example, triethylamine, K 2CO 3, NaH or the like) in solvent (for example THF, DCM, DMF, NMP or the like) with three-thiourea (III) that replaces is halogen or OSO with X wherein 2Me and R 11Further reaction of alkyl halide or methanesulfonates (IV) as defined above obtains quaternary thiourea (V); R wherein 2, R 5, R 6, R 7, R 10, R 11With A as defined above.
[00405] conventional method E:
Figure A20068005024901072
Figure A20068005024901081
(for example, triethylamine, K under alkali condition 2CO 3, NaH or the like) R wherein in solvent (for example THF, DCM, DMF, NMP or the like) 5, R 6, R 7With A as defined above benzylamine (I) be halogen, C with X wherein 1-C 6Alkyl OS (O) 2-, aryl-OS (O) 2-or aryl C 1-C 6Alkyl OS (O) 2-and R 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6Shielded ethamine (II) reaction of alkyl obtains ethylenediamine (III); R wherein 5, R 6, R 7As above define and R with A 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6Alkyl.To wherein R 5, R 6, R 7As above define and R with A 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6The ethylenediamine of alkyl (III) deprotection in the mixture of for example TFA/DCM; Subsequently under alkali condition (for example, triethylamine, DIPEA, DBU or the like) in solvent (for example THF, DCM, toluene or the like) with ethylenediamine (III) and phosgene reaction, obtain 2-oxo-imidazolidine (IV); R wherein 5, R 6, R 7As above define and R with A 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6Alkyl; Or
(for example, triethylamine, K under alkali condition 2CO 3, NaH or the like) R wherein in solvent (for example THF, DCM, DMF, NMP or the like) 5, R 6, R 7, A as defined above and R 27Be C 1-C 6The benzyl sulphonic acid ester (V) of alkyl and aryl and R wherein 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6Shielded ethylenediamine (II) reaction of alkyl obtains ethylenediamine (III); R wherein 5, R 6, R 7As above define and R with A 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6Alkyl.To wherein R 5, R 6, R 7With A as defined above and R 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6The ethylenediamine of alkyl (III) deprotection in the mixture of for example TFA/DCM; Subsequently under alkali condition (for example, triethylamine, DIPEA, DBU or the like) in solvent (for example THF, DCM, toluene or the like) with ethylenediamine (III) and phosgene reaction, obtain 2-oxo-imidazolidine (IV); R wherein 5, R 6, R 7As above define and R with A 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6Alkyl.
R 26Be C 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14And C 1-C 6Alkoxy C 1-C 6Alkyl, wherein R 12, R 13And R 14As above definition, each alkyl, aryl/hetaryl are by the individual R as defined above of 0-3 18Replace.
[00406] conventional method F:
Figure A20068005024901101
(for example, triethylamine, K under alkali condition 2CO 3, NaH or the like) R wherein in solvent (for example THF, DCM, DMF, NMP or the like) 5, R 6, R 7Benzylamine (I) and m wherein are 1,2 or 3 and R as defined above with A 26As the sulfonic acid halide of giving a definition (II) reaction, obtain encircling sulfonamide (III); Wherein m is 1,2 or 3 and R 5, R 6, R 7As above define and R with A 26As give a definition.
R 26Be C 1-C 6Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl; R wherein 12, R 13And R 14As above definition, each alkyl, aryl/hetaryl are by the individual R as defined above of 0-3 18Replace.
[00407] conventional method G:
Figure A20068005024901111
At Mitsunobu condition (PPh for example 3And DIAD) in solvent (for example THF or the like), incites somebody to action wherein R under 5, R 6, R 7With A sulfonamide (I) and R wherein as defined above 26As the ethoxy halogen (II) of giving a definition reaction, the sulfonamide that obtains replacing (III); R wherein 5, R 6, R 7With A as defined above and R 26As give a definition.To wherein R 5, R 6, R 7As above define and R with A 26As the sulfonamide of the replacement of giving a definition (III) is at alkali condition (K for example 2CO 3, in DMSO) and cyclisation down, [1,2, the 5] thiadiazolidine 1 that obtains replacing, 1-dioxide (IV); R wherein 5, R 6, R 7As above define and R with A 26As give a definition.Other substituent introducings can followingly realize: incite somebody to action wherein R 5, R 6, R 7As above define and R with A 26As [1,2,5] thiadiazolidine 1 of the replacement of giving a definition, 1-dioxide (IV) deprotection (for example TFA/DCM), [1,2, the 5] thiadiazolidine 1 that obtains replacing, 1-dioxide (V); R wherein 5, R 6, R 7With A as defined above and R 26As give a definition and can use (VI) alkylation, wherein can be down or pass through Mitsunobu condition (PPh for example at alkali condition (for example NaH, in DMSO or DMF) 3[1,2, the 5] thiadiazolidine 1 that and DIAD) in solvent (for example THF or the like), will replace, 1-dioxide (V) and R wherein 27As the alcohol of giving a definition (VII) reaction, [1,2, the 5] thiadiazolidine 1 that obtains replacing, 1-dioxy (VIII); R wherein 5, R 6, R 7With A as defined above and R 26And R 27As give a definition.
R 26Be C 1-C 6Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl and C 1-C 6Alkoxy C 1-C 6Alkyl; Wherein each alkyl, aryl/hetaryl are by the individual R as defined above of 0-3 18Replace.
R 27Be C 1-C 6Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14, C 1-C 6Alkoxy C 1-C 6Alkyl; R wherein 12, R 13And R 14As above definition, each alkyl, aryl/hetaryl are by the individual R as defined above of 0-3 18Replace.
Specific embodiment
Embodiment 1-1 (conventional method (A))
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl Base)-benzyl]-acetamide
Figure A20068005024901121
Steps A:
[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester
Stir at ambient temperature down to 4-(tert-butoxycarbonyl amino-methyl)-benzoic acid (15.0g, 59.69mmol) THF (200mL) solution in add HOBt (8.87g 65.66mmol), add EDAC (12.59g then, 65.66mmol), mixture was being stirred 30 minutes.In resulting mixture, add 1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane, hydrochloride (12.46g, 65.66mmol) and DIPEA (21.84mL, 125.36mmol).At ambient temperature reactant mixture was stirred 16 hours.Evaporating solvent adds entry (100mL) in residue.With EtOAc (3x50mL) extraction mixture, with the organic facies of saturated aqueous ammonium chloride solution (3x50mL) washing merging.Dry organic facies (MgSO 4) and evaporating solvent, obtain rough amide, this amide is dissolved among the EtOAc (50mL), and filters by the silica gel sheet, use EtOAc as eluent.Evaporate the each several part that merges, obtain [4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester of 23g (99%).
1H NMR(400MHz，CDCl 3)δ0.94(d，3H)，1.02(d，3H)，1.12(d，3H)，1.17-1.59(m，14.5H)，1.75(m，1H)，2.23(m，0.5H)，3.23(q，0.5H)，3.26(d，0.5H)，3.58(d，0.5H)，3.96(m，0.5H)，4.33(bs，2H)，4.60(m，0.5H)，5.02(bs，0.5H)，7.29(m，2H)，7.40(t，2H)。
HPLC-MS (method Z1): m/z=387 (M+1); t r=x.xx minute (yy%ELS).
Step B:
Methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester
Stir at ambient temperature down that (560mg, THF 1.45mmol) (30mL) add sodium hydride (151mg, 3.77mmol is 60%, in mineral oil), and mixture is stirred 1h to above-mentioned carbamate.In resulting mixture, add the methyl iodide be dissolved in THF (1mL) (514mg, 3.62mmol).At ambient temperature reactant mixture was stirred 16 hours.Evaporating solvent adds entry (30mL) in residue.With EtOAc (3x25mL) extraction mixture, water (3x25mL), the organic facies that saline (25mL) washing merges, dry (MgSO 4) and evaporating solvent, obtain methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester of the 560mg (97%) of solid shape.
1H NMR(400MHz，DMSO-d 6)δ0.89(d，3H)，0.96(d，3H)，1.05(d，3H)，1.15-1.50(m，13.5H)，1.74(m，1H)，2.04(m，0.5H)，2.78(s，3H)，3.11(m，1H)，3.28(d，0.5H)，3.42(d，0.5H)，3.92(m，0.5H)，4.39(m，2.5H)，7.26(m，2H)，7.38(d，1H)，7.44(d，1H)。
HPLC-MS (method Z1): m/z=401 (M+1); t r=x.xx minute (yy%ELS).
Step C:
(4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Figure A20068005024901141
(560mg adds TFA (3mL) in DCM 1.4mmol) (9mL) solution, mixture was stirred 16 hours to above-mentioned amide under stirring at ambient temperature.Evaporating solvent adds entry (10mL) and regulates pH to 11 in residue.With DCM (3x15mL) extraction mixture, with the organic facies that saline (15mL) washing merges, dry (MgSO 4) and evaporating solvent, obtain (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone of buttery 410mg (97%).
1H NMR(400MHz，MeOD)δ0.95(d，3H)，1.02(d，3H)，1.12(d，3H)，1.2-1.68(m，5H)，1.84(m，1H)，2.16(m，0.5H)，2.72(s，3H)，3.19(m，1H)，3.59(d，0.5H)，4.01(t，0.5H)，4.20(s，2H)，4.52(t，0.5H)，7.50-7.58(m，4H)。
HPLC-MS (method Z1): m/z=301 (M+1); t r=1.44 minutes (100%ELS).
Step D:
(155mg, (107 μ L, (41 μ L 0.568mmol), stir mixture 16 hours 0.774mmol) to add chloroacetic chloride then to add TEA in DCM 0.516mmol) (3mL) solution to above-mentioned benzylamine under stirring at ambient temperature.Water (3x1mL) purging compound, dry (MgSO 4), and evaporating solvent.With preparation property HPLC (method Z4) purification residue: isolating amount=47mg; t r=10.48 minutes, the buttery title compound of (27%).
1H NMR (400MHz, MeOD) δ 0.95 (d, 3H), 1.02 (d, 3H), 1.12 (d, 3H), 1.2-1.67 (m, 5H), 1.82 (m, 1H), 2.17 (m, 3.5H), 2.93+3.02 (2x s, 3H, rotamer), 3.19 (m, 1H), 3.57 (d, 0.5H), 4.03 (m, 0.5H), 4.50 (m, 0.5H), 4.62-4.68 (m, 2H), 7.3-7.52 (m, 4H).
HPLC-MS (method Z1): m/z=343 (M+1); t r=1.78 minutes (100%ELS).
Embodiment 1-2 (conventional method (A))
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl Base)-benzyl]-isobutyramide
Figure A20068005024901151
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and isobutyryl chloride with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=371 (M+1); t r=1.89 minutes (100%ELS).
Embodiment 1-3 (conventional method (A))
The Cyclopentane carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-amide
Figure A20068005024901152
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and Pentamethylene. carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=397 (M+1); t r=2.08 minutes (100%TIC).
Embodiment 1-4 (conventional method (A))
The cyclohexane-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-amide
By preparing title compound, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and cyclohexane extraction carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=411 (M+1); t r=2.16 minutes (100%ELS).
Embodiment 1-5 (conventional method (A))
Piperidines-1-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-amide
Figure A20068005024901161
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and piperidines-1-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=412 (M+1); t r=2.09 minutes.
Embodiment 1-6 (conventional method (A))
1, and 3-dimethyl-3-phenyl-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] Octane-6-carbonyl)-benzyl]-urea
Figure A20068005024901162
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and N-methyl-N-phenyl amino formyl chloride with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=435 (M+1); t r=2.19 minutes.
Embodiment 1-7 (conventional method (A))
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl Base)-benzyl]-Benzoylamide
Figure A20068005024901171
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and Benzenecarbonyl chloride. with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=405 (M+1); t r=1.98 minutes.
Embodiment 1-8 (conventional method (A))
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901172
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 1-acetyl group-piperidines-4-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=454 (M+1); t r=1.61 minutes.
Embodiment 1-9 (conventional method (A))
1-acetyl group-piperidines-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901173
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 1-acetyl group-piperidines-3-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=454 (M+1); t r=1.65 minutes.
Embodiment 1-10 (conventional method (A))
The Cyclopentane carboxylic acid ethyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-amide
Figure A20068005024901181
By preparing title compound, begin from (4-ethylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and Pentamethylene. carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=411 (M+1); t r=2.17 minutes.
Embodiment 1-11 (conventional method (A))
Morpholine-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-amide
Figure A20068005024901182
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and morpholine-4-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=414 (M+1); t r=1.74 minutes.
Embodiment 1-12 (conventional method (A))
2, and 2-N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-propionic acid amide.
Figure A20068005024901191
By preparing title compound with embodiment 1 described similar method, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 2,2-dimethyl-propionyl chloride begins.
HPLC-MS (method Z1): m/z=385 (M+1); t r=2.04 minutes.
Embodiment 1-13 (conventional method (A))
Oxolane-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] Octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901192
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and oxolane-3-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=399 (M+1); t r=1.68 minutes.
Embodiment 1-14 (conventional method (A))
N-methyl-4-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
Figure A20068005024901193
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 4-trifluoromethoxy-Benzenecarbonyl chloride. with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=489 (M+1); t r=2.24 minutes.
Embodiment 1-15 (conventional method (A))
The thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-amide
Figure A20068005024901201
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and thiophene-2-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=411 (M+1); t r=1.97 minutes.
Embodiment 1-16 (conventional method (A))
Furan-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-amide
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and furan-2-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=395 (M+1); t r=1.96 minutes.
Embodiment 1-17 (conventional method (A))
3-chloro-4-(propane-2-sulfonyl)-thiophene-2-carboxylic acid methyl-[4-(1,3, the 3-trimethyl -6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901203
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3-chloro-4-(propane-2-sulfonyl)-thiophene-2-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=551 (M+1); t r=2.0 minutes.
Embodiment 1-18 (conventional method (A))
6-chloro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-nicotiamide
Figure A20068005024901211
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 6-chloro-nicotinoyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=440 (M+1); t r=1.90 minutes.
Embodiment 1-19 (conventional method (A))
5-methyl-isoxazoles-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901212
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 5-methyl-isoxazoles-3-carbonyl chlorine with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=410 (M+1); t r=1.91 minutes.
Embodiment 1-20 (conventional method (A))
3,3, and N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-butyramide
Figure A20068005024901221
By preparing title compound with embodiment 1 described similar method, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3,3-dimethyl-butyl chloride begins.
HPLC-MS (method Z1): m/z=399 (M+1); t r=2.12 minutes.
Embodiment 1-21 (conventional method (A))
3-cyano group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-Benzoylamide
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3-cyano group-Benzenecarbonyl chloride. with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=430 (M+1); t r=1.92 minutes.
Embodiment 1-22 (conventional method (A))
N-methyl-2-phenoxy group-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering Alkane-6-carbonyl)-benzyl]-acetamide
Figure A20068005024901223
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and phenoxy group-chloroacetic chloride with embodiment 1 described similar method.
HPLC-MS (method Z 1): m/z=435 (M+1); t r=2.02 minutes.
Embodiment 1-23 (conventional method (A))
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl Base)-benzyl]-the malonamic acid methyl ester
Figure A20068005024901231
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and chloroformyl-acetic acid methyl ester with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=401 (M+1); t r=1.69 minutes.
Embodiment 1-24 (conventional method (A))
3-methyl-but-2-ene acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] Octane-6-carbonyl)-benzyl]-amide
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3-methyl-Ding-2-acyl chlorides with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=383 (M+1); t r=1.92 minutes.
Embodiment 1-25 (conventional method (A))
N-methyl-2-phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-acetamide
Figure A20068005024901241
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and phenyl-chloroacetic chloride with embodiment 1 described similar method.
HPLC-MS (method Z1): m/z=419 (M+1); t r=2.03 minutes.
Embodiment 1-26 (conventional method (A)) 1-trifluoromethyl-Cyclobutylcarboxylic acid methyl -[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901242
(33.6mg, (27mg, 0.2mmol), (38mg 0.2mmol), stirs mixture 30 minutes to add EDAC then to add HOBt in THF 0.2mmol) (5mL) solution to 1-trifluoromethyl-Cyclobutylcarboxylic acid under stirring at ambient temperature.Adding (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (embodiment 1 for 50mg, 0.17mmoL) and DIPEA in resulting mixture (35 μ L, 0.2mmol).At ambient temperature reactant mixture was stirred 16 hours.Evaporating solvent, use preparation property HPLC purification residue (method Z4): the title compound of isolating amount=40mg (53%) is oily.
1H NMR (400MHz, CDCl 3) δ 0.94 (d, 3H), 1.04 (d, 3H), 1.13 (d, 3H), 1.17-1.60 (m, 4.5H), 1.75-1.90 (m, 2H), 2.10 (m, 1H), 2.24 (m, 0.5H), 2.55 (m, 2H), 2.73 (m, 2H), (2.83+2.86 2 x s, 3H, rotamer), 3.15 (d, 0.5H), 3.26 (t, 1H), 3.60 (d, 0.5H), 3.98 (bs, 0.5H), 4.46 (bs, 0.5H), 4.63 (m, 2H), 7.29 (m, 2H), 7.40 (t, 2H).
HPLC-MS (method Z 1): m/z=451 (M+1); t r=2.18 minutes.
Embodiment 1-27 (conventional method (A))
3, and 5-dimethoxy-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
Figure A20068005024901251
By preparing title compound with embodiment 1 described similar method, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3,5-dimethoxy-Benzenecarbonyl chloride. begins.
HPLC-MS (method Z1): m/z=465 (M+1); t r=2.05 minutes.
Embodiment 1-28 (conventional method (A))
4-mesyl-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] Octane-6-carbonyl)-benzyl]-Benzoylamide
Figure A20068005024901252
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 4-mesyl-benzoic acid with embodiment 23 described similar methods.
HPLC-MS (method Z1): m/z=483 (M+1); t r=1.78 minutes.
Embodiment 1-29 (conventional method (A))
N-methyl-3-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3-trifluoromethoxy-benzoic acid with embodiment 23 described similar methods.
HPLC-MS (method Z1): m/z=489 (M+1); t r=2.23 minutes.
Embodiment 1-30 (conventional method (A))
2,2-two fluoro-1,3-benzo dioxole-4-carboxylic acid methyl-[(1,3,3-three for 4- Methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901261
By preparing title compound with embodiment 23 described similar methods, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 2, [1,3 dioxole-4-carboxylic acid begins 2-two fluoro-benzos.
HPLC-MS (method Z1): m/z=485 (M+1); t r=2.21 minutes.
Embodiment 1-31 (conventional method (A))
N-methyl-6-morpholine-4-base-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] Octane-6-carbonyl)-benzyl]-nicotiamide
Figure A20068005024901262
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 6-morpholine-4-base-nicotinic acid with embodiment 23 described similar methods.
HPLC-MS (method Z1): m/z=491 (M+1); t r=1.52 minutes.
Embodiment 1-32 (conventional method (A))
N-methyl-4-(2,2,2-three fluoro-acetyl group)-N-[4-(1,3,3-trimethyl-6-azepine- Bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
Figure A20068005024901271
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 4-(2,2,2-three fluoro-acetyl group)-benzoic acid with embodiment 23 described similar methods.
HPLC-MS (method Z1): m/z=519 (M+18); t r=1.84 minutes.
Embodiment 1-33 (conventional method (A))
3-acetyl group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering Alkane-6-carbonyl)-benzyl]-Benzoylamide
Figure A20068005024901272
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3-acetyl group-benzoic acid with embodiment 23 described similar methods.
HPLC-MS (method Z1): m/z=447 (M+1); t r=1.90 minutes.
Embodiment 1-34 (conventional method (A))
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl Base)-benzyl]-different phthalamidic acid
Figure A20068005024901273
(72mg, (54mg, 0.4mmol), (77mg 0.4mmol), stirs mixture 30 minutes to add EDAC then to add HOBt in THF 0.4mmol) (10mL) solution to different peptide acid monomethyl ester under stirring at ambient temperature.Adding (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (embodiment 1 for 100mg, 0.33mmoL) and DIPEA in reactant mixture (70 μ L, 0.4mmol).At ambient temperature reactant mixture was stirred 16 hours.Evaporating solvent is used preparation property HPLC purification residue (method Z4): N-methyl-N-[4-of isolating amount=100mg (65%) (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-different phthalamidic acid methyl ester, be oily.
In the EtOH of ester (100mg) (5mL) solution, add entry (2mL) and 1N NaOH (0.5mL).Stirred the mixture the evaporation volatile matter at ambient temperature 6 hours.Residue is dissolved in water (5mL), and uses Et 2O (2x10mL) washing is regulated pH to 1 by 1N HCl.With EtOAc (3x10mL) aqueous phase extracted, dry (MgSO 4) organic facies that merges, and evaporation obtains the title compound of the 73mg (49%) of solid shape.
1H NMR (400MHz, CDCl 3) δ 0.95 (d, 3H), 1.05 (s, 3H), 1.14 (d, 3H), 1.33-1.49 (m, 3.5H), 1.58 (m, 1H), 1.79 (m, 1H), 2.27 (m, 0.5H), 2.88+3.08 (2 x s, 3H, rotamer), 3.28 (m, 1.5H), 3.63 (d, 0.5H), 4.02 (m, 0.5H), 4.53-4.79 (m, 2.5H), 7.21-7.70 (m, 6H), 8.15 (m, 2H).
HPLC-MS (method Z 1): m/z=449 (M+1); t r=1.76 minutes.
Embodiment 1-35 (conventional method (A))
2,3-Dihydrobenzofuranes-7-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-azepine-two Ring [3.2.1] octane-6-carbonyl)-benzyl]-amide
By preparing title compound with embodiment 23 described similar methods, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 2,3-Dihydrobenzofuranes-7-carboxylic acid begins.
HPLC-MS (method Z1): m/z=447 (M+1); t r=2.02 minutes.
Embodiment 1-36 (conventional method (A))
N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl Base]-Benzoylamide
Figure A20068005024901291
Stir at ambient temperature down to [4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester (11g, 28.5mmoL, embodiment 1) DCM (40mL) solution in add TFA (20mL), mixture was stirred 16 hours.Evaporating solvent adds entry (50mL) and regulates pH to 11 in residue.With DCM (3x20mL) extraction mixture, with the organic facies that saline (20mL) washing merges, dry (MgSO 4) and evaporating solvent, obtain (4-amino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone of buttery 7.7g (94%).
1H NMR(400MHz，CDCl 3)δ0.97(d，3H)，1.02(d，3H)，1.12(d，3H)，1.15-1.44(m，4.5H)，1.56(t，1H)，1.75(m，1H)，2.23(m，0.5H)，3.01(b s，2H、NH 2)，3.15(d，0.5H)，3.57(d，0.5H)，3.89(d，2H)，3.97(t，0.5H)，4.58(t，0.5H)，7.38(m，4H)。
HPLC-MS (method Z1): m/z=287 (M+1); t r=1.2 minutes (100%ELS).
((150 μ L, 1.05mmol), (60 μ L 0.52mmol), stir mixture 16 hours to add Benzenecarbonyl chloride. then to add TEA among the 100mg, DCM 0.35mmol) (5mL) to above-mentioned benzylamine under stirring at ambient temperature.Water (3x1mL) purging compound, dry (MgSO 4), and evaporating solvent.With preparation property HPLC purification residue (method Z4): the title compound of isolating amount=95mg (70%) is oily.
1H NMR(400MHz，CDCl 3)δ0.92(d，3H)，0.95(d，3H)，1.01(d，3H)，1.13-1.58(m，4.5H)，1.74(m，1H)，2.21(m，0.5H)，3.12(d，0.5H)，3.22(t，1H)，3.56(d，0.5H)，3.94(t，0.5H)，4.58(m，2.5H)，7.22-7.32(m，4H)，7.40(t，2H)，7.49(m，2H)，7.87(d，2H)。
HPLC-MS (method Z1): m/z=391 (M+1); t r=1.91 minutes (100%ELS).
Embodiment 1-(conventional method (A))
[4-(1-amino-cyclopropyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Under 0 ℃ to NaH (1.95g, 0.049moL, 60%, in mineral oil, with doing THF washing 2 times) dried DMF (50mL) in drip [4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-acetonitrile (7,0g, 0, dried DMF (180ml) solution 024mol).In resulting mixture, drip glycol dibromide (8,14mL, 0, dried DMF (25mL) solution 094mol) at room temperature stirs mixture 16 hours, then by adding the trash ice cooling.With AcOEt (3x250mL) aqueous phase extracted, water (2x100mL), the organic facies that saline (1x100mL) washing merges, dry (MgSO4) filters, and evaporates volatile matter then.Obtain 1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl of buttery rough 5.28g (69%)]-the cyclopropane nitrile.
HPLC-MS (method Z1): m/z=323 (M+1); t r=2.02 minutes (100%ELS).
(5.25g, 16.28mmol) the middle mixture that adds dense HCl (120mL) and AcOH (30mL) stirred 18 hours down at 80 ℃ to above-mentioned nitrile.Regulate pH to 3 with frozen water (300mL) diluted reaction mixture and by adding 4N NaOH.With diethyl ether (3x200mL) extraction oily precipitation, water (2x100mL), the organic facies that saline (1x80mL) washing merges, dry (MgSO 4), filter and the vacuum evaporation volatile matter, obtain 1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl of the 4.7g (85%) of solid shape]-cyclopropane-carboxylic acid.
HPLC-MS (method Z1): m/z=342 (M+1); t r=1.83 minutes (100%ELS).
(3.00g adds H in DCM 8.79mmol) (600mL) solution to above-mentioned carboxylic acid 2SO 4(7.2mL), add NaN then 3(1.38g, 21.23mmol).Mixture was stirred 16 hours down at 45 ℃, be cooled to room temperature, and add frozen water (300mL) cooling.Regulate pH to 11 by adding 4N NaOH, with DCM (2x150mL) extraction mixture.The evaporation volatile matter, and, obtain [4-(1-amino-cyclopropyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone of buttery 2.7g (98%) with being prepared property of residue HPLC purification.
HPLC-MS (method Z1): m/z=313 (M+1); t r=1.30 minutes (100%ELS).
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，0.99-1.03(m，5H)，1.13(m，5H)，1.17-1.5(m，3.5H)，1.58(d，1H)，1.75(m，1H)，2.17(bs，2H、NH 2)，2.24(dd，0.5H)，3.17(d，0.5H)，3.28(t，1H)，3.58(d，0.5H)，3.99(t，0.5H)，4.60(m，0.5H)，7.29-7.33(m，2H)，7.37-7.42(m，2H)。
Stir at ambient temperature down to [4-(1-amino-cyclopropyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (150mg, 0.48mmol) DCM (4mL) solution in add TEA (100 μ L, 0.72mmol), (61 μ L 0.53mmol), stir mixture 16 hours to add Benzenecarbonyl chloride. then.Water (3x1mL) purging compound, dry (MgSO 4), and evaporating solvent.With preparation property HPLC purification residue (method Z4): the title compound of isolating amount=116mg (58%) is oily.
1H NMR(400MHz，CDCl 3)δ0.92(d，3H)，1.00(s，3H)，1.11(s，3H)，1.13-1.44(m，5.5H)，1.57(m，1H)，1.71(m，2H)，2.20(m，0.5H)，3.11(d，0.5H)，3.25(m，1H)，3.55(d，1H)，3.96(m，0.5H)，4.58(m，0.5H)，7.09(t，2H)，7.28(dd，2H)，7.44(t，2H)，7.51(t，1H)，7.63(d，1H)，7.90)d，2H)。
HPLC-MS (method Z1): m/z=417 (M+1); t r=2.0 minutes (100%ELS).
[00408] gets the row chemical compound ready as above-mentioned conventional method A guidance system.
Figure A20068005024901311
Figure A20068005024901321
Figure A20068005024901331
Figure A20068005024901341
Figure A20068005024901351
Figure A20068005024901361
Figure A20068005024901371
Figure A20068005024901381
Embodiment 2-1 (conventional method (B1))
1, and 1-dimethyl-3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] Octane-6-carbonyl)-benzyl]-sulfonamide
Figure A20068005024901391
Stir at ambient temperature down to (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (100mg, 0.33mmoL, embodiment 1) DCM (25mL) solution in add TEA (140 μ L 1mmol), add dimethylamino sulfonic acid chloride (54 μ L then, 0.5mmol), mixture was stirred 1 hour.Evaporating mixture, and with preparation property HPLC purification residue (method Z4): the title compound of isolating amount=28mg (21%) is oily.
1H NMR(400MHz，CDCl 3)δ0.94(d，3H)，1.03(d，3H)，1.13(d，3H)，1.17-1.61(m，4.5H)，1.77(m，1H)，2.24(m，0.5H)，2.70(s，3H)，2.86(s，6H)，3.16(d，0.5H)，3.26(m，1H)，3.60(d，0.5H)，3.97(t，0.5H)，4.34(d，2H)，4.61(m，0.5H)，7.38(m，2H)，7.44(t，2H)。
HPLC-MS (method Z1): m/z=408 (M+1); t r=1.98 minutes (100%ELS).
Embodiment 2-2 (conventional method (B1))
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl Base)-benzyl]-Methanesulfomide
Figure A20068005024901392
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and mesyl chloride with embodiment 33 described similar methods.
HPLC-MS (method Z1): m/z=379 (M+1); t r=1.8 minutes (100%ELS).
Embodiment 2-3 (conventional method (B1))
2,2,2-three fluoro-ethane sulfonic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Figure A20068005024901401
By preparing title compound with embodiment 33 described similar methods, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 2,2,2-three fluoro-ethyl sulfonic chlorides begin.
HPLC-MS (method Z1): m/z=447 (M+1); t r=2.09 minutes.
Embodiment 2-4 (conventional method (B1))
N-aminomethyl phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6- Carbonyl)-benzyl]-Methanesulfomide
Figure A20068005024901402
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and benzyl sulfonic acid chloride with embodiment 33 described similar methods.
HPLC-MS (method Z1): m/z=455 (M+1); t r=2.17 minutes.
Guidance system according to above-mentioned conventional method (B2) is got the row chemical compound ready.
Embodiment 2-(conventional method (B2))
Three fluoro-N-isopropyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-Methanesulfomide
Figure A20068005024901411
Steps A:
4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-benzoic acid
Figure A20068005024901412
At ambient temperature to 4-methylol-benzoic acid methyl ester (6.0g, 36.11mmol) and 3,4-dihydro-2H-pyrans (16.47mL, and adding p-methyl benzenesulfonic acid monohydrate in the refrigerative solution of DCM 180.53mmol) (125mL) frozen water (69mg, 0.36mmol).Mixture was stirred 4 hours.Evaporating solvent obtains buttery rough (～9g) 4-(tetrahydrochysene-pyrans-2-base oxygen ylmethyl)-benzoic acid methyl ester (LC/MS:272[M+23]).
(add 1NNaOH (55mL) in～9g) EtOH (50mL) solution, mixture was stirred 16 hours to ester at ambient temperature.The evaporation volatile matter is used Et 2O (50mL) washs water.By adding the pH to 3 of 1N HCl adjusting water.Use Et 2O (2x50mL) extraction precipitation thing, dry (Na 2SO 4), and evaporate, obtain 4-(tetrahydrochysene-pyrans-2-oxygen ylmethyl)-benzoic acid of the 6g (71%) of solid shape.
1H NMR(400MHz，CDCl 3)δ1.55-1.92(m，6H)，3.55(m，1H)，3.91(t，1H)，4.59(d，1H)，4.74(t，1H)，4.87(d，1H)，7.48(d，2H)，8.09(d，2H)。
HPLC-MS (method Z1): m/z=259 (M+23); t r=1.42 minutes.
Step B:
(4-methylol-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Figure A20068005024901421
(6.0g, (3.8g, 27.93mmol), (5.36g 27.93mmol), stirs mixture 30 minutes to add EDAC then to add HOBt in dried THF (100mL) solution 25.40mmol) to above-mentioned benzoic acid under stirring at ambient temperature.In resulting mixture, add 1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane, hydrochloride (5.3g, 27.93mmol) and DIPEA (9.29mL, 53.33mmol).At ambient temperature reactant mixture was stirred 16 hours.Evaporating solvent adds entry (100mL) in residue.Use Et 2O (3x35mL) extracts mixture, dry (MgSO 4) organic facies that merges, and evaporating solvent, obtain rough amide, it is dissolved in MeOH (100mL).In this mixture, add p-methyl benzenesulfonic acid (1g), at ambient temperature mixture was stirred 2 hours.Evaporating solvent, and with silica gel column chromatography (Flash 40) purification residue, at first use EtOAc-heptane (1: 2) mixture (500mL) uses EtOAc-heptane 2: 1 as eluent then.Collect pure part, be evaporated to 1/10 volume, the filtering precipitation is used Et 2O (20mL) washs, and obtains (4-methylol-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone of the 5.2g (71%) of solid shape after drying.
TLC (EtOAc-heptane) 2:1 Rf:0.2.
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.02(d，3H)，1.12(s，3H)，1.14-1.60(m，5H)，1.75(m，1H)，2.23(m，0.5H)，2.54(bs，1H)，3.19(q，0.5H)，3.26(d，0.5H)，3.59(d，0.5H)，3.96(t，0.5H)，4.60(m，0.5H)，4.69(d，2H)，7.34-7.40(m，4H)。
HPLC-MS (method Z1): m/z=288 (M+1); t r=1.81 minutes.
Step C:
[4-(isopropyl amino-methyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Figure A20068005024901422
(500mg, 1.74mmol), (0.5mL, (203 μ L 2.61mmol), stir mixture 1 hour TEA to add mesyl chloride in DCM 3.48mmol) (40mL) ice-water-cooled solution to above-mentioned benzylalcohol under stirring at ambient temperature.Water (20mL) purging compound, dry (MgSO 4), and evaporating solvent.The residue that will be dissolved in DCM (20mL) joins in the 2-aminopropane. (800mL), mixture is stirred 1 hour at ambient temperature, then evaporating solvent.With silica gel column chromatography (Flash 40) purification residue, use AcOEt as eluent.Collect pure part, and evaporate, obtain [4-(isopropyl amino-methyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone of buttery 300mg (53%).
1H NMR(400MHz，CDCl 3)δ0.92(d，3H)，1.02(d，3H)，1.12(m，9H)，1.18-1.45(m，4H)，1.56(m，1H)，1.75(m，1H)，1.94(bs，1H)，2.24(dd，0.5H)，2.87(m，1H)，3.20(q，0.5H)，3.27(dd，0.5H)，3.57(d，0.5H)，3.82(d，2H)，3.97(d，0.5H)，4.60(m，0.5H)，7.38(m，4H)。
HPLC-MS (method Z1): m/z=329 (M+1); t r=1.28 minutes (100%ELS).
Step D:
Be cooled to-50 ℃ (dry ice/acetone) under-50 ℃, (100mg adds TEA (130 μ L in DCM 0.304mmol) (15mL) solution to above-mentioned 2-aminopropane. under stirring, 0.913mmol), (100 μ L 0.61mmol), stir mixture 30 minutes to add trifluoromethanesulfanhydride anhydride then.In this mixture, add entry (0.2mL), evaporating solvent, use preparation property HPLC purification residue (method Z4): the title compound of isolating amount=65mg (46%) is oily.
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.03(d，3H)，1.13(bs，9H)，1.16-1.61(m，4.5H)，1.77(m，1H)，2.24(dd，0.5H)，3.18(q，1H)，3.28(d，0.5H)，3.60(d，0.5H)，3.94(t，0.5H)，4.25(m，1H)，4.31-4.85(bs，2H)，4.62(m，0.5H)，7.45(m，4H)。
HPLC-MS (method Z1): m/z=461 (M+1); t r=2.50 minutes (100%ELS).
Embodiment 2-6 (conventional method (B2))
N-cyclopropyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-Methanesulfomide
Figure A20068005024901441
By preparing title compound, begin from (4-cyclopropyl amino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and three fluoro-methanesulfonic anhydride with embodiment 46 described similar methods.
HPLC-MS (method Z1): m/z=459 (M+1); t r=2.45 minutes.
Embodiment 2-7 (conventional method (B2))
N-ethyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-Methanesulfomide
Figure A20068005024901442
By preparing title compound, begin from (4-ethylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and three fluoro-methanesulfonic anhydride with embodiment 46 described similar methods.
HPLC-MS (method Z1): m/z=447 (M+1); t r=2.43 minutes (100%ELS).
Embodiment 2-8 (conventional method (B2))
Three fluoro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-Methanesulfomide
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and three fluoro-methanesulfonic anhydride with embodiment 46 described similar methods.
HPLC-MS (method Z1): m/z=433 (M+1); t r=2.35 minutes.
[00409] gets the row chemical compound ready according to the guidance system of above-mentioned conventional method B1 and B2.
Figure A20068005024901451
Figure A20068005024901461
Figure A20068005024901471
Embodiment 3-1 (conventional method (C))
3-benzoyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] Octane-6-carbonyl)-benzyl]-urea
In ambient temperature to (4-methylamino methyl-phenyl)-(1; 3; 3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (70mg; 0.23mmoL; embodiment 1) DCM (20mL) solution in add benzoyl isocyanates (51mg; 0.35mmol), mixture was stirred 16 hours.Evaporating mixture is gone up the purification residue at silica gel column chromatography (Flash 40), and the mixture that at first uses AcOEt-heptane (1: 1) is used purified AcOEt eluting then as eluent.Collect pure part, and evaporate, obtain the title compound of 45mg (43%).
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.03(s，3H)，1.13(s，3H)，1.16-1.60(m，4.5H)，1.76(m，1H)，2.23(m，0.5H)，2.99(b s，3H)，3.16(d，0.5H)，3.26(m，1H)，3.58(d，0.5H)，3.96(m，0.5H)，4.61(m，0.5H)，4.64(s，2H)，7.42(m，6H)，7.55(t，1H)，7.89(m，2H)，8.66(bs，1H)。
HPLC-MS (method Z1): m/z=448 (M+1); t r=1.85 minutes (100%ELS).
Embodiment 3-2 (conventional method (C))
3-cyclohexyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering Alkane-6-carbonyl)-benzyl]-urea
Figure A20068005024901481
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and isocyanates-cyclohexane extraction with embodiment 37 described similar methods.
HPLC-MS (method Z1): m/z=426 (M+1); t r=2.06 minutes.
Embodiment 3-3 (conventional method (C))
3-(4-methyl-benzenesulfonyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-azepine-two Ring [3.2.1] octane-6-carbonyl)-benzyl]-urea
By preparing title compound, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 4-methyl-benzenesulfonyl isocyanates with embodiment 37 described similar methods.
HPLC-MS (method Z1): m/z=499 (M+1); t r=2.02 minutes.
Embodiment 3-4 (conventional method (C))
3-(2,3-dihydro-1,4-benzo dioxine-2-ylmethyl)-1-methyl -1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
Figure A20068005024901483
Steps A:
1-methyl-3-{ methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamoyl }-3H-imidazoles-1-, iodide
Figure A20068005024901491
At ambient temperature to (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (1.1g, 3.66mmoL, embodiment 1) DCM (40mL) solution in add CDI (0.9g 5.49mmol), stir mixture 16 hours.Water (25mL) purging compound, dry (Na 2SO 4) and evaporation.(2.5mL 36.61mmol), stirs resulting mixture 16 hours to add methyl iodide at ambient temperature in the residue that is dissolved in MeCN (40mL).Evaporating solvent obtains 1-methyl-3-{ methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamoyl of 2g (～100%) }-3H-imidazoles-1-, iodide.
Step B:
To 2, (22mg, (16 μ L 0.134mmol) add above-mentioned imidazole salts (60mg, DCM 0.112mmol) (2mL) solution to 3-dihydro-benzo [1,4] dioxine-2-base-methylamine in the solution of mixture for DCM 0.134mmol) (2mL) and TEA.At ambient temperature mixture was stirred 16 hours.Evaporating solvent.With preparation property HPLC purification residue (method Z4): the title compound of isolating amount=50mg (91%) is solid shape.
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.02(s，3H)，1.12(s，3H)，1.16-1.60(m，4.5H)，1.76(m，1H)，2.23(m，0.5H)，2.88(s，3H)，2.97(bs，1H)，3.14(d，0.5H)，3.25(t，1H)，3.53(m，0.5H)，3.59(d，0.5H)，3.68(m，0.5H)，3.97(m，2H)，4.30(d，2H)，4.53(d，2H)，4.60(m，0.5H)，4.96(t，0.5H)，6.85(m，4H)，7.27(m，2H)，7.41(t，2H)。
HPLC-MS (method Z1): m/z=493 (M+1); t r=2.10 minutes (100%ELS).
Embodiment 3-5 (conventional method (C))
3-(3-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
Figure A20068005024901501
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 3-methoxyl group-benzylamine with embodiment 40 described similar methods.
HPLC-MS (method Z1): m/z=465 (M+1); t r=2.02 minutes (100%ELS).
Embodiment 3-6 (conventional method (C))
3-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-)-1-methyl isophthalic acid-[4-(1,3, the 3-trimethyl -6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
Figure A20068005024901502
By preparing title compound with embodiment 40 described similar methods, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 1,1-dioxo-tetrahydrochysene-thiophene-3-amine begins.
HPLC-MS (method Z1): m/z=463 (M+1); t r=1.63 minutes (100%ELS).
Embodiment 3-7 (conventional method (C))
1-methyl-3-(tetrahydrochysene-pyrans-4-yl)-1-[4-(1,3,3-trimethyl-6-azepine-two Ring [3.2.1] octane-6-carbonyl)-benzyl]-urea
Figure A20068005024901503
By preparing title compound, from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and tetrahydrochysene-pyrans-4-base-amine with embodiment 40 described similar methods.
HPLC-MS (method Z1): m/z=429 (M+1); t r=1.69 minutes (100%ELS).
Embodiment 3-8 (conventional method (C))
1, and 3-dimethyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane -6-carbonyl)-benzyl]-urea groups }-the acetic acid methyl ester
Figure A20068005024901511
By preparing title compound 40, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and methylamino-acetic acid methyl ester with the described similar method of embodiment.
HPLC-MS (method Z1): m/z=431 (M+1); t r=1.85 minutes (100%ELS).
Embodiment 3-9 (conventional method (C))
(5-Trifluoromethyl-1,3,4-thiadiazoles-2-yl)-(1,3,3-three for 1-[4-for 1-methyl-3- Methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
Figure A20068005024901512
By preparing title compound, begin from (4-methylamino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone and 5-trifluoromethyl-[1,3,4] thiadiazoles-2-amine with embodiment 40 described similar methods.
HPLC-MS (method Z1): m/z=497 (M+1); t r=2.19 minutes (100%ELS).
[00410] knows the preparation following compounds according to above-mentioned conventional method C.
Figure A20068005024901521
Figure A20068005024901531
Figure A20068005024901551
Figure A20068005024901561
Figure A20068005024901571
Figure A20068005024901581
Figure A20068005024901611
Embodiment 4-1 (conventional method (E))
1-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl Base)-benzyl]-imidazolidin-2-one
Figure A20068005024901612
Steps A:
(2-hydroxyl-ethyl)-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester
Figure A20068005024901613
Stir at ambient temperature down to [4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester (1.7g, 4.4mmoL, embodiment 1) DMF (50mL) solution in add sodium hydride (211mg, 8.8mmoL, 60%, in mineral oil), mixture was stirred 15 minutes.Adding (2-bromo-ethoxyl methyl)-benzene in reactant mixture (1.1mL, 5.28mmol).At ambient temperature reactant mixture was stirred 16 hours.Add saturated aqueous ammonium chloride solution (50mL), add entry (50mL) quencher then.Use Et 2O (2x100mL) extracts mixture, with the organic facies that saturated aqueous ammonium chloride solution (2x100mL) washing merges, and dry (Na 2SO 4), and evaporating solvent.With silica gel column chromatography (Flash 40) purification residue, obtain (2-benzyloxy-ethyl)-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester of buttery 1.4g.
HPLC-MS (method Z1): m/z=521 (M+1); t r=2.67 minutes.
(1.4g 2.69mmol) adds 10%Pd/C (750mg, 50% water), and the resulting mixture of hydrogenation under 1atm is until the H that uses 1eqv. to the above-mentioned benzylic ether that is dissolved in EtOH (50mL) 2Filtering mixt, and evaporating solvent obtain (2-hydroxyl-ethyl)-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-carbamic acid tertiary butyl ester of solid shape 0.9g (47%).
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.03(d，3H)，1.13(d，3H)，1.17-1.79(m，15H)，2.23(m，0.5H)，3.15(m，0.5H)，3.26(m，0.5H)，3.41(bs，3H)，3.59(d，0.5H)，3.71(m，2H)，3.97(t，0.5H)，4.50(m，2H)，4.61(m，0.5H)，7.27(m，2H)，7.42(t，2H)。
HPLC-MS (method Z1): m/z=431 (M+1); t r=1.99 minutes.
Step B:
4-[(2-methylamino-ethylamino)-methyl]-phenyl }-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Figure A20068005024901621
(300mg, 0.696mmol), (0.3mL, (135 μ L 1.72mmol), stir mixture 1 hour TEA to add mesyl chloride in DCM 2.3mmol) (40mL) ice-water cooling solution to above-mentioned tertiary butyl ester under stirring at ambient temperature.The adding methylamine (5mL, 33%, in EtOH), at ambient temperature mixture was stirred 16 hours.Evaporating solvent adds entry (50m) and AcOEt (50mL) in residue.Separate organic facies, and evaporation, in residue, add DCM (20mL), add TFA (10mL) then.At ambient temperature resulting mixture was stirred 4 hours, and evaporating solvent.With preparation property HPLC purification residue (method Z4): isolating amount=175mg (44%) 4-[(2-methylamino-ethylamino)-methyl]-phenyl-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone, be oily.
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.02(d，3H)，1.12(d，3H)，1.15-1.46(m，3H)，1.56(m，1H)，1.75(m，1H)，2.16(d，0.5H)，2.25(m，0.5H)，2.42(s，3H)，2.74(m，4H)，3.15-3.29(m，1.5H)，3.60(d，0.5H)，3.82(d，2H)，3.98(m，0.5H)，4.60(m，0.5H)，7.38(m，4H)。
HPLC-MS (method Z1): m/z=344 (M+1); t r=1.09 minutes.
Step C:
(50mg adds phosgene (0.1mL, 0.29mmoL is 30%, in toluene) in DCM 0.146mmol) (10mL) solution, mixture was stirred 30 minutes to above-mentioned amide at ambient temperature.Evaporating solvent, use preparation property HPLC purification residue (method Z4): the title compound of isolating amount=11mg (21%) is oily.
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.02(d，3H)，1.13(d，3H)，1.15-1.60(m，4.5H)，1.75(m，1.5H)，2.23(m，0.5H)，2.84(s，3H)，3.16(m，2H)，3.28(m，3H)，3.58(d，0.5H)，3.97(t，0.5H)，4.39(d，2H)，4.60(m，0,5H)，7.29(dd，2H)，7.40(t，2H)。
HPLC-MS (method Z1): m/z=370 (M+1); t r=1.71 minutes.
[00411] gets the row chemical compound ready according to the guidance system of above-mentioned conventional method E.
Figure A20068005024901631
Figure A20068005024901641
Embodiment 5-1 (conventional method (F))
[4-(1,1-dioxo-isothiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6- Aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Figure A20068005024901642
At ambient temperature to (4-amino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (100mg, 0.349mmol), TEA (100 μ L, 0.698mmol) and the mixture of DCM (20mL) in add 3-chloro-propane-1-sulfonic acid chloride (51 μ L 0.419mmol), stir mixture 2 hours.Evaporating solvent is dissolved in dried THF (20mL) with residue.The adding sodium hydride (25mg, 1.05mmoL, 60%, in mineral oil), mixture was stirred 90 minutes.Under reflux temperature.Cooling mixture of water (100 μ L) and evaporation.With preparation property HPLC purification residue (method Z4): the title compound of isolating amount=39mg (29%) is oily.
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.03(d，3H)，1.13(d，3H)，1.17-1.60(m，4.5H)，1.71-1.79(m，2H)，2.23(m，0.5H)，2.32(m，2H)，3.09-3.29(m，4.5H)，3.60(d，0.5H)，3.97(t，0.5H)，4.20(d，2H)，4.61(m，0.5H)，7.38-7.45(m，4H)。
HPLC-MS (method Z1): m/z=391 (M+1); t r=1.8 minutes.
Embodiment 6-1 (conventional method (G))
[4-(1,1-dioxo-2H-1,2,5-thiadiazolidine-2-ylmethyl)-benzene Base]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Steps A:
1-tert-butoxycarbonyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-sulfonamide
(360 μ L, (400 μ L 4.19mmol), stir mixture 30 minutes to add the tert-butyl alcohol in DCM 4.19mmol) (20mL) ice-water cooling solution to chloro sulfonyl isocyanate at ambient temperature.(1.2g, 4.19mmol), (1.7mL is in DCM 12.57mmol) (25mL) solution for TEA under 0 ℃ resulting mixture to be joined (4-amino methyl-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone.Mixture was stirred 2 hours, make it reach room temperature, water (25mL) washing then, dry (Na 2SO 4), and evaporate, obtain 1-tert-butoxycarbonyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl of buttery 1.8g (92%)]-sulfonamide.
1H NMR(400MHz，CDCl 3)δ0.93(d，3H)，1.03(s，3H)，1.12(s，3H)，1.15-1.59(m，13.5H)，1.76(m，1H)，2.23(m，0.5H)，3.13-3.28(m，1.5H)，3.58(d，0.5H)，3.96(m，0.5H)，4.11(s，2H)，4.59(m，0.5H)，5.75(bs，1H)，7.39(m，4H)，9.0(bs，1H)。
HPLC-MS (method Z1): m/z=466 (M+1); t r=1.98 minutes.
Step B:
1,1-dioxo-5-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-1,2,5-thiadiazolidine-2-carboxylic acid tertiary butyl ester
Figure A20068005024901661
With 1-tert-butoxycarbonyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-sulfonamide (0.8g, 1.72mmol), 2-chloro-ethanol (130 μ L, 1.89mmol), triphenylphosphine (0.7g, 2.58mmol) THF (50mL) solution of mixture in add DIAD (0.5mL 2.58mmol), stir mixture 1 hour.Evaporating solvent, with silica gel column chromatography (Flash 40) purification residue, with the mixture of AcOEt-heptane (1: 1) as eluent, obtain rough 1-tert-butoxycarbonyl-1-(2-ethoxy)-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-sulfonamide, it can be used for next step and need not to be further purified.
HPLC-MS (method Z1): m/z=528 (M+1).
At ambient temperature to above-mentioned 1-tert-butoxycarbonyl-1-(2-ethoxy)-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-add K in DMSO (15mL) solution of sulfonamide 2CO 3(0.36g 2.58mmol), stirs mixture 2 hours.Add entry (25mL), extract resulting mixture with AcOEt (2x25mL).The organic facies that evaporation merges, with silica gel column chromatography (Flash 40) purification residue, at first use the mixture of AcOEt-heptane (4: 1), the mixture of using AcOEt-heptane (4: 1) then obtains 1 of buttery 250mg (30%), 1-dioxo-5-[4-(1 as eluent, 3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-and benzyl]-1,2,5-thiadiazolidine-2-carboxylic acid tertiary butyl ester.
HPLC-MS (method Z1): m/z=492 (M+1); t r=2.24 minutes (100%ELS).
Step C:
[4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
At ambient temperature to 1,1-dioxo-5-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-and benzyl]-1,2, (0.25g adds TFA (5mL) in DCM 0.51mmol) (10mL) solution to 5-thiadiazolidine-2-carboxylic acid tertiary butyl ester, and mixture was stirred 16 hours.Evaporating mixture, use preparation property HPLC purification residue (method Z4): the title compound of isolating amount=190mg (95%) is oily.
1H NMR(400MHz，CDCl 3)δ0.94(d，3H)，1.04(s，3H)，1.13(s，3H)，1.18-1.60(m，4.5H)，1.77(m，1H)，2.23(m，0.5H)，3.15-3.30(m，3.5H)，3.44(t，2H)，3.60(d，0.5H)，3.97(t，0.5H)，4.18(m，2H)，4.61(m，0.5H)，5.01(bs，1H)，7.43(m，4H)。
HPLC-MS (method Z1): m/z=392 (M+1); t r=1.73 minutes (100%ELS).
Embodiment 6-2 (conventional method (G))
[4-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-benzene Base]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Figure A20068005024901671
To [4-(1,1-dioxo-2H-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone (60mg, 0.15mmol), K 2CO 3(30mg, add in the DMSO of mixture 0.31mmol) (4mL) solution iodomethane (13 μ L, 0.31mmol).At ambient temperature mixture was stirred 1 hour, and evaporation.With preparation property HPLC purification residue (method Z4): the title compound of isolating amount=45mg (73%) is oily.
1H NMR(400MHz，CDCl 3)δ0.94(d，3H)，1.04(s，3H)，1.13(s，3H)，1.18-1.61(m，4.5H)，1.77(m，1H)，2.23(m，0.5H)，2.79(s，3H)，3.15-3.20(m，2H)，3.23-3.30(m，3.5H)，3.61(d，0.5H)，3.98(t，0.5H)，4.24(d，2H)，4.61(m，0.5H)，7.42(m，4H)。
HPLC-MS (method Z 1): m/z=406 (M+1); t r=1.86 minutes (100%ELS).
[00412] gets the row chemical compound ready according to the guidance system of above-mentioned conventional method G.
Figure A20068005024901681
Figure A20068005024901691
Figure A20068005024901701
Pharmacological method
[00413] 11 β HSD1 enzyme is analyzed
[00414] Material
[00415] 3The flicker of H-cortisone and anti--rabbit Ig coating is got close to mensurations (SPA) pearl and is bought from Amersham Pharmacia Biotech, and β-NADPH is from Sigma, and rabbit resists-and hydrocortisone antibody is from Fitzgerald.Use h-11 β HSD1 conversion zymic extract (people such as Hult, FEBS Lett., 441, 25 (1998)) and as the source of enzyme.Test-compound is dissolved in DMSO (10mM).Comprising 50mM TRIS-HCl (SigmaChemical Co), 4mM EDTA (Sigma Chemical Co), 0.1%BSA (SigmaChemical Co), 0.01%Tween-20 (Sigma Chemical Co) and 0.005% bacitracin (Novo Nordisk A/S) carry out all dilutions in the buffer of pH=7.4.Optiplate 96 orifice plates are provided by Packard.At TopCount NXT, the last mensuration of Packard is bonded with the SPA pearl 3The amount of H-hydrocortisone.
[00416] Method
[00417] with h-11 β HSD1,120nM 3The serial dilutions of H-cortisone, 4mM β-NADPH, antibody (1: 200), test-compound and SPA granule (2mg/ hole) join in the hole.Come initiation reaction by mixing different components, vibrate 60 minutes down to react at 30 ℃.Add 10 times of excessive buffer stopped reaction that stop, the described buffer that stops to comprise 500 μ M carbenoxolone and 1 μ M cortisone.With GraphPad Prism software analysis data.
[00418] table 1
[00419] suppresses 11 β HSD1 by chemical compound of the present invention
Embodiment No. h-11βHSD1 IC 50Value (nM)
1-28 19
2-5 10
3-8 500
[00420], those skilled in the art will appreciate that and to make various changes, change and displacement and do not break away from the spirit and scope of the present invention although describe and explained the present invention with reference to some embodiment preferred.In addition, according to rely on selected particular active compounds or do not have pharmaceutical carrier, and employed preparation type and method of application, the concrete pharmacology who observes replys can be different, according to purpose of the present invention and enforcement, pay close attention to the change or the difference of these expectations among the result.Therefore, the present invention is not limited to the restriction of appended claims.
[00421] feature described of above-mentioned description and/or claim can be separately or combination in any, be familiar with material of the present invention with different forms.
[00422] the preferred feature of the present invention is:
1. the acid amides of a replacement, the salt of its prodrug or itself and the acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily comprise racemic mixture or tautomeric form arbitrarily, wherein this compound is the compound of formula I:
Figure A20068005024901721
Wherein:
R 1Be selected from H, R8(C＝O)-、R 9S(O) n-、R 10R 11NC (=Y)-and R10R 11NS(O) n-；
R 2Be selected from H, C1-C 6Alkyl and C3-C 6Cycloalkyl;
Alternately, R1And R2With the nitrogen that links to each other with them form the saturated or fractional saturation of 3-12 unit by shown in nitrogen, 2-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms monocycle or two rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, C3-C 10Cycloalkyl, C3-C 10Heterocyclylalkyl, C3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、-S(O) n NR 13R 14、-N(R 13)S(O) nR 12、-N(R 15)C(＝Y)NR 13R 14、-C(＝NR 16)NR 17, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R18Replace;
Ring A be the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms two rings or three rings that form;
Ring A is selected from C by 0-31-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl or C1-C 6The group of alkyl-carbonyl replaces, and wherein each alkyl is by 0-3 R18Replace;
R 5Be selected from H, C1-C 6Alkyl, C3-C 6Cycloalkyl, halogen, OH and cyano group;
R 6And R7Be independently selected from H, C1-C 6Alkyl, F, trihalomethyl group and three halogenated methoxies;
Alternately, R6And R7With the carbon atom that links to each other with them form the saturated or fractional saturation of 3-8 unit by shown in carbon atom, 2-5 other carbon atom and 0-2 are selected from nitrogen, oxygen and S (O)mThe monocycle that forms of other hetero atoms, wherein this ring is by individual halogen, trihalomethyl group, OH, the C of being selected from of 0-31-C 6Alkyl, oxo and C1-C 6The group of alkoxyl replaces;
R 8Be selected from C1-C 8Alkyl, C2-C 8Thiazolinyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C1-C 6Alkyl, heteroaryloxy C1-C 6Alkyl, aryl C1-C 6Alkoxy C1-C 6Alkyl and heteroaryl C1-C 6Alkoxy C1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R19Replace;
R 9Be selected from C1-C 8Alkyl, C2-C 8Thiazolinyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C1-C 6Alkyl and aryl C1-C 6Alkoxy C1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R20Replace;
R 10And R11Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl, heteroaryl, aryl C1-C 6Alkyl and heteroaryl C1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R21Replace;
Alternately, R10And R11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms single, two or three rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, hydroxyl, oxo, COOH, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C1-C 6Alkyl-carbonyl, heteroaryl C1-C 6Alkyl-carbonyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl-carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces;
R 12Be selected from OH, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C1-C 8Alkoxyl, aryl, aryl C1-C 6Alkyl, heteroaryl, heteroaryl C1-C 6Alkyl, aryloxy group, heteroaryloxy and NR13R 14；
R 13And R14Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, aryl, heteroaryl, aryl C1-C 6Alkyl and heteroaryl C1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, aryl and heteroaryl are independently by 0-3 R22Replace;
Alternately, R13And R14With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms single, two or three rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C1-C 6Alkyl-carbonyl, heteroaryl C1-C 6Alkyl-carbonyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces;
R 15Be selected from H, C1-C 6Alkyl and C3-C 6Cycloalkyl;
R 16And R17Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, halogen, OH, cyano group ,-C (=O) R12、-S(O) nR 12、-S(O) nNR 13R 14、-N(R 13)S(O) nR 12、C 1-C 8Alkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl are independently by 0-3 R22Replace;
R 18Be selected from halogen, hydroxyl, oxo, COOH, cyano group, C1-C 6Alkoxyl, C3-C 10Cycloalkyloxy, aryloxy group, heteroaryloxy, heteroarylthio and aryl C1-C 6Alkoxyl;
R 19，R 20And R21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, methylene dioxo, dihalo-methylene dioxo, C3-C 6Spiro cycloalkyl group, C1-C 6Alkoxyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、 -S(O) nNR 13R 14、-N(R 13)S(O) nR 12、-N(R 15)C(＝Y)NR 13R 14With-C (=NR16)NR 17；
R 22Be selected from H, hydroxyl, oxo, halogen, cyano group, nitro, C1-C 6Alkyl, C1-C 6Alkoxyl, NR23R 24, methylene dioxo, dihalo methylene dioxo, trihalomethyl group and three halogenated methoxies;
R 23And R24Be independently selected from H, C1-C 8Alkyl and aryl C1-C 6Alkyl;
M is selected from 0,1 and 2;
N is selected from 1 and 2;
Y is selected from O and S;
Or the salt of itself and the acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily comprises racemic mixture, or tautomeric form arbitrarily.
2. 1 compound, wherein:
R 1Be selected from R8(C＝O)-、R 9S(O) 2-、R 10R 11NC (=O)-and R10R 11NS(O) 2-；
R 2C1-C 4Alkyl;
Alternately, R1And R2With the nitrogen that links to each other with them form 5-6 unit by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O)m, the saturated rings that forms of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-21-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、-S(＝O) nNR 13R 14、 -N(R 13)S(O) nR 12, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R18Replace;
Ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O)mOther hetero atoms two rings or three rings that form;
Ring A is selected from C by 0-31-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C1-C 4Alkoxyl, C1-C 4Alkoxy C1-C 4Alkyl or C1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkyl is by 0-1 R18Replace;
R 5H;
R 6And R7Be independently selected from H and C1-C 4Alkyl; With
N is 2.
3. 1 compound, wherein:
R 8Be selected from C1-C 6Alkyl, C2-C 6Thiazolinyl, aryl, heteroaryl, aryl C1-C 4Alkyl, heteroaryl C1-C 4Alkyl, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryloxy group C1-C 4Alkyl and heteroaryloxy C1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R19Replace;
R 9Be selected from C1-C 6Alkyl, C2-C 6Thiazolinyl, aryl, heteroaryl, aryl C1-C 4Alkyl, heteroaryl C1-C 4Alkyl, C3-C 6Cycloalkyl, 3-6 unit's Heterocyclylalkyl and aryloxy group C1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R20Replace;
R 10And R11Be independently selected from H, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryl and heteroaryl, wherein each cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R21Replace;
Alternately, R10And R11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-6 unit by shown in nitrogen, 4-5 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-1m, the monocycle that forms of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-21-C 8Alkyl, aryl, heteroaryl, hydroxyl, oxo, COOH, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl and C1-C 6The group of alkyl-carbonyl replaces;
R 12Be selected from OH, C1-C 4Alkyl, C3-C 6Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C1-C 4Alkoxyl, aryl, aryl C1-C 4Alkyl, heteroaryl, heteroaryl C1-C 4Alkyl, aryloxy group and heteroaryloxy;
R 19，R 20And R21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C1-C 6Alkyl, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, dihalo-methylene dioxo, C1-C 4Alkoxyl, aryl, heteroaryl, aryl C1-C 4Alkyl, heteroaryl C1-C 4Alkyl ,-C (=O) R12、-S(O) nR 12With-S (O)nNR 13R 14 With
N is 2.
4. 1 compound, wherein this compound is the compound of formula Ia:
5. 1 compound, wherein this compound is the compound of formula Ib:
6. 1 compound, wherein this compound is the compound of formula Ic:
Figure A20068005024901771
7. 1 compound, wherein this compound is the compound of formula Id:
Figure A20068005024901772
8. 1 compound, wherein
R 1And R2With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms monocycle or two rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, C3-C 10Cycloalkyl, C3-C 10Heterocyclylalkyl, C3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、-S(O) nNR 13R 14、 -N(R 13)S(O) nR 12、-N(R 15)C(＝Y)NR 13R 14、-C(＝NR 16)NR 17, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R18Replace.
9. 1 compound, wherein:
Ring A is selected from:
Figure A20068005024901781
Ring A is by 0-2 R25Replace; With
R 25Be selected from C1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C (=O) R12And C1-C 6Alkoxyl, wherein R12As above to define.
10. 1 compound, wherein:
Ring A is selected from:
Figure A20068005024901782
Ring A is by 0-2 R25Replace; With,
R 25Be selected from C1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C1-C 6Alkoxyl.
11. the compound of item 1, wherein:
Ring A is
Figure A20068005024901783
Ring A is by 0-2 R25Replace; With
R 25Be selected from C1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C1-C 6Alkoxyl.
12. the compound of item 1, wherein this compound is selected from:
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-isobutyramide
Cyclopentane-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
Cyclohexane-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
Piperidines-1-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-azepine-two ring [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
1-acetyl group-piperidines-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-azepine-two ring [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
Cyclopentane-carboxylic acid ethyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
Morpholine-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
2,2-N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-propionamide
Oxolane-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
N-methyl-4-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
Thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
Furans-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
3-chloro-4-(propane-2-sulfonyl)-thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
6-chloro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-niacinamide
5-methyl-isoxazoles-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-azepine-two ring [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
3,3, N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-butyramide
3-cyano group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
N-methyl-2-phenoxy group-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-malonamic acid (malonamic acid) methyl ester
3-methyl-but-2-ene acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
N-methyl-2-phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
1-trifluoromethyl-cyclobutane-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
3,5-dimethoxy-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
4-mesyl-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
N-methyl-3-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
2,2-, two fluoro-1,3-benzo dioxole-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
N-methyl-6-morpholine-4-base-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-niacinamide
N-methyl-4-(2,2,2-, three fluoro-acetyl group)-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-different phthalamidic acid
2,3-Dihydrobenzofuranes-7-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
3-acetyl group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-benzamide
1,1,3-trimethyl-3-[4-(1,3,3-trimethyl-two ring [3.2.1] octane-6-carbonyl)-benzyl]-sulfonylurea
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
2,2,2-, three fluoro-ethyl sulfonic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acid amides
N-aminomethyl phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-isopropyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-cyclopropyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-ethyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
3-benzoyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-cyclohexyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methyl-phenyl) sulfonyl-1-methyl isophthalic acid-[4-(1,3,3-, three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-phenyl-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(2,3-dihydro-Isosorbide-5-Nitrae-benzo dioxine-2-ylmethyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(tetrahydrochysene-pyrans-4-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the acetic acid methyl ester
1-methyl-3-(5-Trifluoromethyl-1,3,4-thiadiazoles-2-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
2-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-benzoic acid methyl ester
3-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the benzoic acid ethyl ester
1-methyl-3-(3-ethyl sulfanyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-ethyl sulfanyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
3-(4-benzyloxy-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl sulfanyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-, three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-, three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-cyano group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-, three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-, three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(2,2,4,4-tetrafluoro-4H-benzo-[1,3] dioxine-6-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methoxyl group-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-[4-(2,2,2-, three fluoro-acetyl group)-cyclohexyl]-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-(4-acetyl group-phenyl)-1,3-dimethyl-3-[4-(1,3,3-, three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-phenyl-3-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-urea
Piperidines-1-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-acid amides
Piperidines-1-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-acid amides
Morpholine-4-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-acid amides
Morpholine-4-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-acid amides
1,3-dimethyl-3-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-1-phenyl-urea
1-[4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-acid amides
Piperidines-1-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-acid amides
Morpholine-4-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-acid amides
Morpholine-4-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-acid amides
1-[4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
1,3-dimethyl-1-phenyl-3-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-urea
Piperidines-1-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-acid amides
Morpholine-4-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-acid amides
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
1-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-acid amides
Morpholine-4-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-acid amides
N-adamantane-2-base-4-(1,3-dimethyl-3-pyridine-2-base-urea groups methyl)-benzamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
Morpholine-4-carboxylic acid [4-(adamantane-2-base carbamoyl)-benzyl]-methyl-acid amides
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-thiazol-2-yl-urea
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-thiazol-2-yl-urea
4-[3-(1-acetyl group-piperidin-4-yl)-1,3-dimethyl-urea groups methyl]-N-adamantane-2-base-benzamide
1-(1-acetyl group-piperidin-4-yl)-3-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-urea
N-adamantane-2-base-4-(1,3-dimethyl-3-pyrimidine-2-base-urea groups methyl)-benzamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-adamantane-2-base-4-(1,3-dimethyl-3-thiazol-2-yl-urea groups methyl)-benzamide
N-adamantane-2-base-4-(1,3-dimethyl-3-phenyl-urea groups methyl)-benzamide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-adamantane-2-base-4-[3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea groups methyl]-benzamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea
1-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-3-[4-(2-oxa--5-azepine-two ring [2.2.1] heptane-5-carbonyl)-benzyl]-urea
1-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-imidazolidin-2-one
[4-(1,1-dioxo-isothiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-two ring [3.2.1] suffering-6-yl)-ketone
[4-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-two ring [3.2.1] suffering-6-yl)-ketone
(octahydro-quinoline-1-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(4-azepine-three ring [4.3.1.13，8]-hendecane-4-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(octahydro-isoquinolin-2-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(3-aza-bicyclo [3.2.2] ninth of the ten Heavenly Stems-3-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(6-aza-bicyclo [3.2.1] suffering-6-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
[4-(5-benzyl-1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Or the salt of itself and the acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily comprises racemic mixture or tautomeric form arbitrarily.
13. the compound arbitrary according to item 1-12, it is to be used for the treatment of the medicament of wherein regulating or suppressing active favourable obstacle, illness or the disease of 11 β HSD1.
14. according to the compound of item 13, wherein said obstacle, illness and disease are subject to the impact of endocellular sugar corticoid level.
15. according to the compound of item 15, wherein obstacle, illness or disease are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, diabetes B, impaired glucose tolerance (IGT), fasting blood-glucose infringement (IFG), IGT to the development of diabetes B, metabolic syndrome to development, diabetic complications, neurodegeneration and the psychiatric disturbance of diabetes B and the ill-effect of glucocorticoid receptor agonist treatment or therapy.
16. a pharmaceutical composition comprises at least a arbitrary according to item 1-12 compound and one or more pharmaceutically acceptable carriers or the excipient as active component
17. according to the pharmaceutical composition of item 16, it is fit to oral, nose, cheek, uses outside skin, lung or stomach and intestine.
18. the acid amides that replaces, its prodrug, or the salt of itself and the acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or the arbitrarily application of tautomeric form, wherein the acid amides of this replacement or its prodrug are the compounds of formula I:
Figure A20068005024901871
Wherein:
R 1Be selected from H, R8(C＝O)-、R 9S(O) n-、R 10R 11NC (=Y)-and R10R 11NS(O) n-；
R 2Be selected from H, C1-C 6Alkyl and C3-C 6Cycloalkyl;
Alternately, R1And R2With the nitrogen that links to each other with them form the saturated or fractional saturation of 3-12 unit by shown in nitrogen, 2-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms monocycle or two rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, C3-C 10Cycloalkyl, C3-C 10Heterocyclylalkyl, C3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、-S(O) n NR 13R 14、-N(R 13)S(O) nR 12、-N(R 15)C(＝Y)NR 13R 14、-C(＝NR 16)NR 17, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R18Replace;
Ring A be the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms two rings or three rings that form;
Ring A is selected from C by 0-31-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl or C1-C 6The group of alkyl-carbonyl replaces, and wherein each alkyl is by 0-3 R18Replace;
R 5Be selected from H, C1-C 6Alkyl, C3-C 6Cycloalkyl, halogen, OH and cyano group;
R 6And R7Be independently selected from H, C1-C 6Alkyl, F, trihalomethyl group and three halogenated methoxies;
Alternately, R6And R7With the carbon atom that links to each other with them form the saturated or fractional saturation of 3-8 unit by shown in carbon atom, 2-5 other carbon atom and 0-2 are selected from nitrogen, oxygen and S (O)mThe monocycle that forms of other hetero atoms, wherein this ring is by individual halogen, trihalomethyl group, OH, the C of being selected from of 0-31-C 6Alkyl, oxo and C1-C 6The group of alkoxyl replaces;
R 8Be selected from C1-C 8Alkyl, C2-C 8Thiazolinyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C1-C 6Alkyl, heteroaryloxy C1-C 6Alkyl, aryl C1-C 6Alkoxy C1-C 6Alkyl and heteroaryl C1-C 6Alkoxy C1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R19Replace;
R 9Be selected from C1-C 8Alkyl, C2-C 8Thiazolinyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C1-C 6Alkyl and aryl C1-C 6Alkoxy C1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R20Replace;
R 10And R11Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl, heteroaryl, aryl C1-C 6Alkyl and heteroaryl C1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R21Replace;
Alternately, R10And R11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms single, two or three rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, hydroxyl, oxo, COOH, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C1-C 6Alkyl-carbonyl, heteroaryl C1-C 6Alkyl-carbonyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl-carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces;
R 12Be selected from OH, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C1-C 8Alkoxyl, aryl, aryl C1-C 6Alkyl, heteroaryl, heteroaryl C1-C 6Alkyl, aryloxy group, heteroaryloxy and NR13R 14；
R 13And R14Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, aryl, heteroaryl, aryl C1-C 6Alkyl and heteroaryl C1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, aryl and heteroaryl are independently by 0-3 R22Replace;
Alternately, R13And R14With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms single, two or three rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C1-C 6Alkyl-carbonyl, heteroaryl C1-C 6Alkyl-carbonyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces;
R 15Be selected from H, C1-C 6Alkyl and C3-C 6Cycloalkyl;
R 16And R17Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, halogen, OH, cyano group ,-C (=O) R12、-S(O) nR 12、-S(O) nNR 13R 14、-N(R 13)S(O) nR 12、C 1-C 8Alkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl are independently by 0-3 R22Replace;
R 18Be selected from halogen, hydroxyl, oxo, COOH, cyano group C1-C 6Alkoxyl, C3-C 10Cycloalkyloxy, aryloxy group, heteroaryloxy, heteroarylthio and aryl C1-C 6Alkoxyl;
R 19，R 20And R21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, methylene dioxo, dihalo-methylene dioxo, C3-C 6Spiro cycloalkyl group, C1-C 6Alkoxyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、 -S(O) nNR 13R 14、-N(R 13)S(O) nR 12、-N(R 15)C(＝Y)NR 13R 14With-C (=NR16)NR 17；
R 22Be selected from H, hydroxyl, oxo, halogen, cyano group, nitro, C1-C 6Alkyl, C1-C 6Alkoxyl, NR23R 24, methylene dioxo, dihalo methylene dioxo, trihalomethyl group and three halogenated methoxies;
R 23And R24Be independently selected from H, C1-C 8Alkyl and aryl C1-C 6Alkyl;
M is selected from 0,1 and 2;
N is selected from 1 and 2;
Y is selected from O and S;
Or the salt of itself and the acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or, tautomeric form arbitrarily.
19. the application of item 18, wherein:
R 1Be selected from H, R8(C＝O)-、R 9S(O) n-、R 10R 11NC (=Y)-and R10R 11NS(O) n-；
R 2Be selected from H, C1-C 6Alkyl and C3-C 6Cycloalkyl;
Alternately, R1And R2With the nitrogen that links to each other with them form the saturated or fractional saturation of 3-12 unit by shown in nitrogen, 2-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms monocycle or two rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, C3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene ,-C (=O) R12、-S(O) nR 12、-S(O) nNR 13R 14、-N(R 13)S(O) nR 12、 -N(R 15)C(＝Y)NR 13R 14、-C(＝NR 16)NR 17, hydroxyl, oxo, C1-C 6Alkoxyl, aryl-C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each aryl/hetaryl is by 0-3 R18Replace;
Ring A be the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms two rings or three rings that form;
Ring A is selected from C by 0-31-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkylidene or C1-C 6The group of alkyl-carbonyl replaces, and wherein each alkyl/alkylidene is by 0-3 R18Replace;
R 5Be selected from H, C1-C 6Alkyl, C3-C 6Cycloalkyl, halogen, OH and cyano group;
R 6And R7Be independently selected from H, C1-C 6Alkyl, F, trihalomethyl group and three halogenated methoxies;
Alternately, R6And R7With the carbon atom that links to each other with them form the saturated or fractional saturation of 3-8 unit by shown in carbon, 2-5 other carbon atom and 0-2 are selected from nitrogen, oxygen and S (O)mThe monocycle that forms of other hetero atoms, wherein this ring is by individual halogen, trihalomethyl group, OH, the C of being selected from of 0-31-C 6Alkyl, oxo and C1-C 6The group of alkoxyl replaces;
R 8Be selected from C1-C 8Alkyl, C2-C 8Thiazolinyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C1-C 6Alkylidene, heteroaryloxy C1-C 6Alkylidene, aryl C1-C 6Alkoxy C1-C 6Alkylidene and heteroaryl-C1-C 6Alkoxy C1-C 6Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R19Replace;
R 9Be selected from C1-C 8Alkyl, C2-C 8Thiazolinyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C1-C 6Alkylidene and aryl C1-C 6Alkoxy C1-C 6Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R20Replace;
R 10And R11Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl, heteroaryl, aryl C1-C 6Alkylidene and heteroaryl C1-C 6Alkylidene, wherein each alkyl/alkylidene, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R21Replace;
Alternately, R10And R11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms single, two or three rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene, hydroxyl, oxo, COOH, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkylidene, C1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C1-C 6Alkyl-carbonyl, heteroaryl C1-C 6Alkyl-carbonyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl-carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces;
R 12Be selected from OH, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C1-C 8Alkoxyl, aryl, aryl C1-C 6Alkylidene, heteroaryl, heteroaryl C1-C 6Alkylidene, aryloxy group, heteroaryloxy and NR13R 14；
R 13And R14Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, aryl, heteroaryl, aryl C1-C 6Alkylidene and heteroaryl C1-C 6Alkylidene, wherein each alkyl/alkylidene, cycloalkyl, aryl and heteroaryl are independently by 0-3 R22Replace;
Alternately, R13And R14With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms single, two or three rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkylidene, C1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C1-C 6Alkyl-carbonyl, heteroaryl C1-C 6Alkyl-carbonyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces;
R 15Be selected from H, C1-C 6Alkyl and C3-C 6Cycloalkyl;
R 16And R17Be independently selected from H, C1-C 8Alkyl, C3-C 10Cycloalkyl, halogen, OH, cyano group ,-C (=O) R12、-S(O) nR 12、-S(O) nNR 13R 14、-N(R 13)S(O) nR 12、C 1-C 8Alkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl are independently by 0-3 R22Replace;
R 18Be selected from halogen, OH, oxo and cyano group;
R 19，R 20And R21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C1-C 8Alkyl, C3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, methylene dioxo, dihalo-methylene dioxo, C3-C 6Spiro cycloalkyl group, C1-C 6Alkoxyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene ,-C (=O) R12、 -S(O) nR 12、-S(O) nNR 13R 14、-N(R 13)S(O) nR 12、-N(R 15)C(＝Y)NR 13R 14With-C (=NR16)NR 17；
R 22Be selected from H, hydroxyl, oxo, halogen, cyano group, nitro, C1-C 6Alkyl, C1-C 6Alkoxyl, NR23R 24, methylene dioxo, dihalo methylene dioxo, trihalomethyl group and three halogenated methoxies;
R 23And R24Be independently selected from H, C1-C 8Alkyl and aryl C1-C 6Alkylidene;
M is selected from 0,1 and 2;
N is selected from 1 and 2;
Y is selected from O and S;
20. according to the application of item 18, wherein:
R 1Be selected from R8(C＝O)-、R 9S(O) 2-、R 10R 11NC (=O)-and R10R 11NS(O) 2-；
R 2C1-C 4Alkyl;
Alternately, R1And R2With the nitrogen that links to each other with them form 5-6 unit by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O)mThe saturated rings that forms of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-21-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、-S(＝O) nNR 13R 14、-N(R 13)S(O) nR 12, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R18Replace;
Ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-1mOther hetero atoms two rings or three rings that form;
Ring A is substituted 0-3 group C that is selected from1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C1-C 4Alkoxyl, C1-C 4Alkoxy C1-C 4Alkyl or C1-C 4Alkyl-carbonyl, wherein each alkyl/alkyl is substituted 0-1 R18；
R 5H;
R 6And R7Be independently selected from H and C1-C 4Alkyl; With
N is 2.
21. according to the application of item 19, wherein:
R 1Be selected from R8(C＝O)-，R 9S(O) 2-，R 10R 11NC (=O)-and R10R 11NS(O) 2-；
R 2C1-C 4Alkyl;
Alternately, R1And R2With the nitrogen that links to each other with them form 5-6 unit by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O)m, the saturated rings that forms of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-21-C 8Alkyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene ,-C (=O) R12、-S(O) nR 12、-S(＝O) nNR 13R 14、 -N(R 13)S(O) nR 12, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each aryl/hetaryl is by 0-3 R18Replace;
Ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O)mOther hetero atoms two rings or three rings that form;
Ring A is selected from C by 0-31-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C1-C 4Alkoxyl, C1-C 4Alkoxy C1-C 4Alkylidene or C1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkylidene is by 0-1 R18Replace;
R 5H;
R 6And R7Be independently selected from H and C1-C 4Alkyl; With
N is 2.
22. according to the application of item 18, wherein:
R 8Be selected from C1-C 6Alkyl, C2-C 6Thiazolinyl, aryl, heteroaryl, aryl C1-C 4Alkyl, heteroaryl C1-C 4Alkyl, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryloxy group C1-C 4Alkyl and heteroaryloxy C1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R19Replace;
R 9Be selected from C1-C 6Alkyl, C2-C 6Thiazolinyl, aryl, heteroaryl, aryl C1-C 4Alkyl, heteroaryl C1-C 4Alkyl, C3-C 6Cycloalkyl, 3-6 unit's Heterocyclylalkyl and aryloxy group C1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R20Replace;
R 10And R11Be independently selected from H, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryl and heteroaryl, wherein each cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R21Replace;
Alternately, R10And R11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-6 unit by shown in nitrogen, 4-5 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-1mThe monocycle that forms of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-21-C 8Alkyl, aryl, heteroaryl, hydroxyl, oxo, COOH, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl and C1-C 6The group of alkyl-carbonyl replaces;
R 12Be selected from OH, C1-C 4Alkyl, C3-C 6Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C1-C 4Alkoxyl, aryl, aryl C1-C 4Alkyl, heteroaryl, heteroaryl C1-C 4Alkyl, aryloxy group and heteroaryloxy;
R 19，R 20And R21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C1-C 6Alkyl, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, dihalo-methylene dioxo, C1-C 4Alkoxyl, aryl, heteroaryl, aryl C1-C 4Alkyl, heteroaryl C1-C 4Alkyl ,-C (=O) R12、-S(O) nR 12With-S (O)nNR 13R 14 With
N is 2.
23. according to the application of item 19, wherein:
R 8Be selected from C1-C 6Alkyl, C2-C 6Thiazolinyl, aryl, heteroaryl, aryl C1-C 4Alkylidene, heteroaryl C1-C 4Alkylidene, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryloxy group C1-C 4Alkylidene and heteroaryloxy C1-C 4Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R19Replace;
R 9Be selected from C1-C 6Alkyl, C2-C 6Thiazolinyl, aryl, heteroaryl, aryl C1-C 4Alkylidene, heteroaryl C1-C 4Alkylidene, C3-C 6Cycloalkyl, 3-6 unit's Heterocyclylalkyl and aryloxy group C1-C 4Alkylidene, wherein each alkyl/alkylidene, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R20Replace;
R 10And R11Be independently selected from H, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryl and heteroaryl, wherein each cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R21Replace;
Alternately, R10And R11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-6 unit by shown in nitrogen, 4-5 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O)mThe monocycle that forms of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-21-C 8Alkyl, aryl, heteroaryl, hydroxyl, oxo, COOH, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl and C1-C 6The group of alkyl-carbonyl replaces;
R 12Be selected from OH, C1-C 4Alkyl, C3-C 6Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C1-C 4Alkoxyl, aryl, aryl C1-C 4Alkylidene, heteroaryl, heteroaryl C1-C 4Alkylidene, aryloxy group and heteroaryloxy;
R 19，R 20And R21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C1-C 6Alkyl, C3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, dihalo-methylene dioxo, C1-C 4Alkoxyl, aryl, heteroaryl, aryl C1-C 4Alkylidene, heteroaryl C1-C 4Alkylidene ,-C (=O) R12、-S(O) nR 12With-S (O)nNR 13R 14 With
N is 2.
24. according to the application of item 18, the acid amides or its prodrug that wherein replace are the compounds of formula Ia:
Figure A20068005024901961
25. according to the application of item 18, the acid amides or its prodrug that wherein replace are the compounds of formula Ib:
Figure A20068005024901962
26. according to the application of item 18, the acid amides or its prodrug that wherein replace are the compounds of formula Ic:
Figure A20068005024901971
27. according to the application of item 18, the acid amides or its prodrug that wherein replace are the compounds of formula Id:
28. according to the application of item 19, the acid amides or its prodrug that wherein replace are the compounds of formula Ie:
Figure A20068005024901973
29. according to the application of item 18, wherein:
R 1And R2With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms monocycle or two rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, C3-C 10Cycloalkyl, C3-C 10Heterocyclylalkyl, C3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C1-C 6Alkyl, heteroaryl C1-C 6Alkyl ,-C (=O) R12、-S(O) nR 12、-S(O) nNR 13R 14、 -N(R 13)S(O) nR 12、-N(R 15)C(＝Y)NR 13R 14、-C(＝NR 16)NR 17, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R18Replace.
30. according to the application of item 19, wherein:
R 1And R2With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2mOther hetero atoms monocycle or two rings that form, wherein this ring is by the individual C that is selected from of 0-31-C 8Alkyl, C3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C1-C 6Alkylidene, heteroaryl C1-C 6Alkylidene ,-C (=O) R12、-S(O) nR 12、-S(O) nNR 13R 14、-N(R 13)S(O) nR 12、 -N(R 15)C(＝Y)NR 13R 14、-C(＝NR 16)NR 17, hydroxyl, oxo, C1-C 6Alkoxyl, aryl C1-C 6Alkoxyl, heteroaryl C1-C 6Alkoxyl, C1-C 6Alkoxy C1-C 6Alkyl, C1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C1-C 6Alkyl carboxyl and heteroaryl C1-C 6The group of alkyl carboxyl replaces, and wherein each aryl/hetaryl is by 0-3 R18Replace.
31. according to the application of item 18-30, wherein:
Ring A is selected from:
Figure A20068005024901981
Ring A is by 0-2 R25Replace; With
R 25Be selected from C1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C (=O) R12And C1-C 6Alkoxyl, wherein R12As above to define.
32. according to the application of item 18-3O, wherein:
Ring A is selected from:
Figure A20068005024901991
Ring A is by 0-2 R25Replace; With
R 25Be selected from C1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C1-C 6Alkoxyl.
33. according to the application of item 18-30, wherein:
Ring A is selected from:
Figure A20068005024901992
Ring A is by 0-2 R25Replace; With
R 25Be selected from C1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C1-C 6Alkoxyl.
34. according to the application of item 18 or 19, the acid amides that wherein replaces or its prodrug are selected from the group of item 12.
35. an arbitrary application of 18-34 is for the preparation for the treatment of the pharmaceutical composition of wherein regulating or suppress active favourable obstacle, illness or the disease of 11 β HSD1.
36. according to the application of item 35, wherein said obstacle, illness and disease are subject to the impact of endocellular sugar corticoid level.
37. according to the application of item 35, wherein obstacle, illness or disease are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, diabetes B, impaired glucose tolerance (IGT), fasting blood-glucose infringement (IFG), IGT to the development of diabetes B, metabolic syndrome to development, diabetic complications, neurodegeneration and the psychiatric disturbance of 2 type diabetes and the ill-effect of glucocorticoid receptor agonist treatment or therapy.
38. the application arbitrary according to item 18-37, wherein this pharmaceutical composition is fit to oral, nose, cheek, uses outside skin, lung or stomach and intestine.
39. the method for active favourable obstacle, illness or the disease of 11 β HSD1 is wherein regulated or suppressed in a treatment, the method comprises that the patient to needs uses the compound arbitrary according to item 1-12 of effective dose.
40. according to the method for item 39, wherein said obstacle, illness and disease are subject to the impact of endocellular sugar corticoid level.
41. according to the method for item 39, wherein obstacle, illness or disease are selected from metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, diabetes B, impaired glucose tolerance (IGT), fasting blood-glucose infringement (IFG), IGT to the development of diabetes B, metabolic syndrome to development, diabetic complications, neurodegeneration and the psychiatric disturbance of 2 type diabetes and the ill-effect of glucocorticoid receptor agonist treatment or therapy.
42. the method arbitrary according to item 40-41, wherein using is by oral, nose, cheek, through skin, lung or parenteral approach.

Claims (26)

1. the chemical compound of formula I:
Wherein:
R 1Be selected from H, R 8(C=O)-, R 9S (O) n-, R 10R 11NC (=Y)-and R 10R 11NS (O) n-;
R 2Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
Alternately, R 1And R 2Or fractional saturation saturated with the nitrogen that links to each other with them-rise to form 3-12 unit by shown in nitrogen, 2-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms monocycle or the bicyclo-formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, C 3-C 10Cycloalkyl, C 3-C 10Heterocyclylalkyl, C 3-C 6Spiro cycloalkyl group, 3-6 unit spiroheterocyclic alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14,-C (=NR 16) NR 17, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace;
Ring A be the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms bicyclo-or three rings formed;
Ring A is selected from C by 0-3 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl or C 1-C 6The group of alkyl-carbonyl replaces, and wherein each alkyl is by 0-3 R 18Replace;
R 5Be selected from H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, halogen, OH and cyano group;
R 6And R 7Be independently selected from H, C 1-C 6Alkyl, F, trihalomethyl group and three halogenated methoxies;
Alternately, R 6And R 7With the carbon atom that links to each other with them form the saturated or fractional saturation of 3-8 unit by shown in carbon atom, 2-5 other carbon atom and 0-2 are selected from nitrogen, oxygen and S (O) mThe monocycle formed of hetero atom, wherein this ring is by individual halogen, trihalomethyl group, OH, the C of being selected from of 0-3 1-C 6Alkyl, oxo and C 1-C 6The group of alkoxyl replaces;
R 8Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkyl, heteroaryloxy C 1-C 6Alkyl, aryl C 1-C 6Alkoxy C 1-C 6Alkyl and heteroaryl C 1-C 6Alkoxy C 1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 19Replace;
R 9Be selected from C 1-C 8Alkyl, C 2-C 8Thiazolinyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryloxy group C 1-C 6Alkyl and aryl C 1-C 6Alkoxy C 1-C 6Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-3 R 20Replace;
R 10And R 11Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl and heteroaryl C 1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
Alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen-atoms, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl-carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
R 12Be selected from OH, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 8Alkoxyl, aryl, aryl C 1-C 6Alkyl, heteroaryl, heteroaryl C 1-C 6Alkyl, aryloxy group, heteroaryloxy and NR 13R 14
R 13And R 14Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl and heteroaryl C 1-C 6Alkyl, wherein each alkyl/alkyl, cycloalkyl, aryl and heteroaryl are independently by 0-3 R 22Replace;
Alternately, R 13And R 14With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-12 unit by shown in nitrogen, 4-10 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-2 mOther hetero atoms single, two or three rings formed, wherein this ring is by the individual C that is selected from of 0-3 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl-carbonyl, aryl carbonyl, heteroaryl carbonyl, aryl C 1-C 6Alkyl-carbonyl, heteroaryl C 1-C 6Alkyl-carbonyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces;
R 15Be selected from H, C 1-C 6Alkyl and C 3-C 6Cycloalkyl;
R 16And R 17Be independently selected from H, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, halogen, OH, cyano group ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12, C 1-C 8Alkyl, aryl and heteroaryl, wherein alkyl and cycloalkyl are independently by 0-3 R 22Replace;
R 18Be selected from halogen, hydroxyl, oxo, COOH, cyano group C 1-C 6Alkoxyl, C 3-C 10Cycloalkyloxy, aryloxy group, heteroaryloxy, heteroarylthio and aryl C 1-C 6Alkoxyl;
R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 8Alkyl, C 3-C 10Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, methylene dioxo, dihalo-methylene dioxo, C 3-C 6Spiro cycloalkyl group, C 1-C 6Alkoxyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (O) nNR 13R 14,-N (R 13) S (O) nR 12,-N (R 15) C (=Y) NR 13R 14With-C (=NR 16) NR 17
R 22Be selected from H, hydroxyl, oxo, halogen, cyano group, nitro, C 1-C 6Alkyl, C 1-C 6Alkoxyl, NR 23R 24, methylene dioxo, dihalo methylene dioxo, trihalomethyl group and three halogenated methoxies;
R 23And R 24Be independently selected from H, C 1-C 8Alkyl and aryl C 1-C 6Alkyl;
M is selected from 0,1 and 2;
N is selected from 1 and 2;
Y is selected from O and S;
Or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or tautomeric arbitrarily form.
2. according to the chemical compound of claim 1, wherein:
R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
R 2Be C 1-C 4Alkyl;
Alternately, R 1And R 2With the nitrogen that links to each other with them form by shown in nitrogen, 2-4 carbon atom and 0-2 is selected from nitrogen, oxygen and S (O) mThe 5-6 unit saturated rings formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, aryl C 1-C 6Alkyl, heteroaryl C 1-C 6Alkyl ,-C (=O) R 12,-S (O) nR 12,-S (=O) nNR 13R 14,-N (R 13) S (O) nR 12, hydroxyl, oxo, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl, C 1-C 6Alkoxy C 1-C 6Alkyl, C 1-C 6Alkyl carboxyl, aryl carboxyl, heteroaryl carboxyl, aryl C 1-C 6Alkyl carboxyl and heteroaryl C 1-C 6The group of alkyl carboxyl replaces, and wherein each alkyl and aryl/hetaryl are by 0-3 R 18Replace;
Ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O) mOther hetero atoms bicyclo-or three rings formed;
Ring A is selected from C by 0-3 1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 4Alkoxyl, C 1-C 4Alkoxy C 1-C 4Alkyl or C 1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkyl is by 0-1 R 18Replace;
R 5Be H;
R 6And R 7Be independently selected from H and C 1-C 4Alkyl; With,
N is 2.
3. according to the chemical compound of claim 1, wherein:
R 1Be selected from R 8(C=O)-, R 9S (O) 2-, R 10R 11NC (=O)-and R 10R 11NS (O) 2-;
R 2Be selected from H, C 1-C 4Alkyl and C 3-C 6Cycloalkyl;
Ring A be the saturated or fractional saturation of 8-11 unit by shown in nitrogen, 5-10 carbon atom and 0 to 1 are selected from nitrogen, oxygen and S (O) mOther hetero atoms bicyclo-or three rings formed;
Ring A is selected from C by 0-3 1-C 4Alkyl, halogen, hydroxyl, oxo, cyano group, C 1-C 4Alkoxyl, C 1-C 4Alkoxy C 1-C 4Alkyl or C 1-C 4The group of alkyl-carbonyl replaces, and wherein each alkyl/alkyl is by 0-1 R 18Replace;
R 5Be H;
R 6And R 7Be independently selected from H and C 1-C 4Alkyl; With
N is 2.
4. according to the chemical compound of claim 1, wherein:
R 8Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryloxy group C 1-C 4Alkyl and heteroaryloxy C 1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 19Replace;
R 9Be selected from C 1-C 6Alkyl, C 2-C 6Thiazolinyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-6 unit's Heterocyclylalkyl and aryloxy group C 1-C 4Alkyl, wherein each alkyl/alkyl, thiazolinyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl are independently by 0-2 R 20Replace;
R 10And R 11Be independently selected from H, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, aryl and heteroaryl, wherein each cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are independently by 0-3 R 21Replace;
Alternately, R 10And R 11With the nitrogen that links to each other with them form the saturated or fractional saturation of 5-6 unit by shown in nitrogen-atoms, 4-5 carbon atom and individual nitrogen, oxygen and the S (O) of being selected from of 0-1 mThe monocycle formed of other hetero atoms, wherein this ring is by the individual C that is selected from of 0-2 1-C 8Alkyl, aryl, heteroaryl, hydroxyl, oxo, COOH, C 1-C 6Alkoxyl, aryl C 1-C 6Alkoxyl, heteroaryl C 1-C 6Alkoxyl and C 1-C 6The group of alkyl-carbonyl replaces;
R 12Be selected from OH, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, 3-10 unit Heterocyclylalkyl, trihalomethyl group, C 1-C 4Alkoxyl, aryl, aryl C 1-C 4Alkyl, heteroaryl, heteroaryl C 1-C 4Alkyl, aryloxy group and heteroaryloxy;
R 19, R 20And R 21Be independently selected from H, halogen, hydroxyl, oxo, cyano group, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, 3-6 unit Heterocyclylalkyl, trihalomethyl group, three halogenated methoxies, dihalo-methylene dioxo, C 1-C 4Alkoxyl, aryl, heteroaryl, aryl C 1-C 4Alkyl, heteroaryl C 1-C 4Alkyl ,-C (=O) R 12,-S (O) nR 12With-S (O) nNR 13R 14With
N is 2.
5. according to the chemical compound of claim 1, wherein this chemical compound is the chemical compound of formula Ia:
Figure A2006800502490008C1
6. according to the chemical compound of claim 1, wherein this chemical compound is the chemical compound of formula Ib:
7. according to the chemical compound of claim 1, wherein this chemical compound is the chemical compound of formula Ic:
Figure A2006800502490008C3
8. according to the chemical compound of claim 1, wherein this chemical compound is the chemical compound of formula Id:
9. according to the chemical compound of claim 1, wherein this chemical compound is the chemical compound of formula Ie:
10. according to the chemical compound of claim 1, wherein:
Ring A is selected from:
Figure A2006800502490009C3
Ring A is by 0-2 R 25Replace; With
R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group, C (=O) R 12And C 1-C 6Alkoxyl, wherein R 12Be as above to define.
11. according to the chemical compound of claim 1, wherein:
Ring A is
Ring A is by 0-2 R 25Replace; With
R 25Be selected from C 1-C 8Alkyl, halogen, hydroxyl, oxo, cyano group and C 1-C 6Alkoxyl.
12. according to the chemical compound of claim 1, wherein this chemical compound is selected from:
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-isobutyramide
Cyclopentane carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Cyclohexane-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Piperidines-1-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
1-acetyl group-piperidines-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Cyclopentane carboxylic acid ethyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
2,2-N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-propionic acid amide.
Oxolane-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-4-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
Thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
Furan-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3-chloro-4-(propane-2-sulfonyl)-thiophene-2-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
6-chloro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-nicotiamide
5-methyl-isoxazoles-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3,3, N-trimethyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-butyramide
3-cyano group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-2-phenoxy group-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-the malonamic acid methyl ester
3-methyl-but-2-ene acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-2-phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-acetamide
1-trifluoromethyl-Cyclobutylcarboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3,5-dimethoxy-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
4-mesyl-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-3-trifluoromethoxy-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
2,2-two fluoro-1,3-benzo dioxole-4-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-6-morpholine-4-base-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-nicotiamide
N-methyl-4-(2,2,2-three fluoro-acetyl group)-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-different phthalamidic acid
2,3-Dihydrobenzofuranes-7-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
3-acetyl group-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Benzoylamide
1,1,3-trimethyl-3-[4-(1,3,3-trimethyl-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-sulfonylurea
N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
2,2,2-three fluoro-ethyl sulfonic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-aminomethyl phenyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-isopropyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-cyclopropyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
N-ethyl-three fluoro-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
Three fluoro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-Methanesulfomide
3-benzoyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-cyclohexyl-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methyl-phenyl) sulfonyl-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-phenyl-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(2,3-dihydro-1,4-benzo dioxine-2-ylmethyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(tetrahydrochysene-pyrans-4-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1,3-dimethyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the acetic acid methyl ester
1-methyl-3-(5-Trifluoromethyl-1,3,4-thiadiazoles-2-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
2-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-benzoic acid methyl ester
3-{3-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea groups }-the benzoic acid ethyl ester
1-methyl-3-(3-ethyl sulfur alkyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-ethyl sulfur alkyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1]-octane-6-carbonyl)-benzyl]-urea
3-(4-benzyloxy-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl sulfur alkyl-phenyls)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-acetyl group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(3-cyano group-phenyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methyl-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
3-(4-methoxyl group-benzyl)-1-methyl isophthalic acid-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(2,2,4,4-tetrafluoro-4H-benzo-[1,3] dioxine-6-yl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-urea
1-methyl-3-(4-three fluoro-methoxyl group-phenyl)-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-urea
1-methyl-3-[4-(2,2,2-three fluoro-acetyl group)-cyclohexyl]-1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-(4-acetyl group-phenyl)-1,3-dimethyl-3-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-urea
1-phenyl-3-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-urea
Piperidines-1-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
Piperidines-1-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid [4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
1,3-dimethyl-3-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-1-phenyl-urea
1-[4-(3-aza-bicyclo-[3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-amide
Piperidines-1-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-amide
Morpholine-4-carboxylic acid [4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-amide
1-[4-(6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
1,3-dimethyl-1-phenyl-3-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-urea
Piperidines-1-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
1-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-two-methyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-methyl-amide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyridine-2-base-urea groups methyl)-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyridine-2-base-urea
Morpholine-4-carboxylic acid [4-(diamantane (obsolete)-2-base carbamoyl)-benzyl]-methyl-amide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-thiazol-2-yl-urea
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-thiazol-2-yl-urea
4-[3-(1-acetyl group-piperidin-4-yl)-1,3-dimethyl-urea groups methyl]-N-diamantane (obsolete)-2-base-Benzoylamide
1-(1-acetyl group-piperidin-4-yl)-3-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-urea
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyrimidine-2-base-urea groups methyl)-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-thiazol-2-yl-urea groups methyl)-Benzoylamide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-phenyl-urea groups methyl)-Benzoylamide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-pyrimidine-2-base-urea
N-diamantane (obsolete)-2-base-4-[3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea groups methyl]-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea
1-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-urea
1-methyl-3-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-imidazolidin-2-one
[4-(1,1-dioxo-isothiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-bicyclo-[3.2.1] suffering-6-yl)-ketone
[4-(5-methyl isophthalic acid, 1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-bicyclo-[3.2.1] suffering-6-yl)-ketone
(octahydro-quinoline-1-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(4-azepine-three ring [4.3.1.1 3,8]-hendecane-4-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(octahydro-isoquinolin-2-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(3-aza-bicyclo [3.2.2] ninth of the ten Heavenly Stems-3-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
(6-aza-bicyclo [3.2.1] suffering-6-yl)-[4-(1,1-dioxo-1,2,5-thiadiazolidine-2-ylmethyl)-phenyl]-ketone
[4-(5-benzyl-1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or tautomeric arbitrarily form
13. according to the chemical compound of claim 1, wherein this chemical compound is selected from:
[4-(1-amino-cyclopropyl)-phenyl]-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] suffering-6-yl)-ketone
Piperidines-3-carboxylic acid methyl-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-benzyl]-amide
N-methyl-N-[4-(1,3,3-three-methyl-6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-butyramide
N-methyl-N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-aza-bicyclo [3.2.2]-nonane-3-carbonyl)-benzyl]-N-methyl-Benzoylamide
3-cyano group-N-methyl-N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-azabicyclic [3.2.2]-nonane-3-carbonyl)-benzyl]-3-cyano group-N-methyl-Benzoylamide
3-fluoro-N-methyl-N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-aza-bicyclo [3.2.2]-nonane-3-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-N-methyl-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-3-cyano group-N-methyl-Benzoylamide
Piperidines-1-carboxylic acid [4-(azepan-1-carbonyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(azepan-1-carbonyl)-benzyl]-methyl-amide
N-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-azabicyclic [3.2.2]-nonane-3-carbonyl)-benzyl]-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-[(benzoyl-methyl-amino)-methyl]-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-3-cyano group-N-methyl-Benzoylamide
4-[(3-cyano group-benzoyl-methyl-amino)-methyl]-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
4-[(3-fluoro-benzoyl-methyl-amino)-methyl]-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(octahydro-quinoline-1-carbonyl)-benzyl]-amide
N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
3-fluoro-N-methyl-N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-Benzoylamide
3-fluoro-N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
N-methyl-N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-Benzoylamide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-Benzoylamide
N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-Benzoylamide
N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid [4-(azepan-1-carbonyl)-benzyl]-methyl-amide
4-(benzoyl-amido-methyl)-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
3-cyano group-N-methyl-N-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-Benzoylamide
3-cyano group-N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
3-fluoro-N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-(3-fluoro-benzoyl-amido-methyl)-N-methyl-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
4-(3-cyano group-benzoyl-amido-methyl)-N-methyl-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid methyl-[4-(1,8,8-trimethyl-3-aza-bicyclo [3.2.1] octane-3-carbonyl)-benzyl]-amide
N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-[(benzoyl-methyl-amino)-methyl]-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
3-cyano group-N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Benzoylamide
4-(benzoyl-amido-methyl)-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
1-acetyl group-piperidines-4-carboxylic acid [4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-methyl-amide
N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-Benzoylamide
4-(3-cyano group-benzoyl-amido-methyl)-N-(diamantane (obsolete)-2-yl)-Benzoylamide
4-(3-fluoro-benzoyl-amido-methyl)-N-(diamantane (obsolete)-2-yl)-Benzoylamide
N-[4-(4-aza-tricycle-[4.3.1.1 *3,8 *] hendecane-4-carbonyl)-benzyl]-3-fluoro-N-methyl-Benzoylamide
N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-acetamide
4-mesyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-methyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-methyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-acetamide
4-mesyl-N-methyl-N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-Benzoylamide
N-[4-(azepan-1-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-[4-(3-aza-bicyclo [3.2.2]-nonane-3-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-methyl-N-[4-(1,8,8-three-methyl-3-aza-bicyclo [3.2.1]-octane-3-carbonyl)-benzyl]-Methanesulfomide
N-[4-(6-aza-bicyclo [3.2.1]-octane-6-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-methyl-N-[4-(octahydro-1-carbonyl)-benzyl]-Methanesulfomide
N-(3-hydroxyl-diamantane (obsolete)-1-yl)-4-[(mesyl-methyl-amino)-methyl]-Benzoylamide
N-(3-fluoro-diamantane (obsolete)-1-yl)-4-[(mesyl-methyl-amino)-methyl]-Benzoylamide
N-[4-(3-fluoro-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-N-methyl-Methanesulfomide
N-diamantane (obsolete)-2-base-4-[(mesyl-methyl-amino)-methyl]-Benzoylamide
N-(4-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-the cyclopropyl sulfamoyl }-phenyl)-acetamide
4-chloro-N-{1-[4-(1,3,3-three-methyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-benzene-sulfonamide
1-methyl isophthalic acid H-imidazoles-4-sulfonic acid 1-[4-(1,3,3-trimethyl-6-aza-bicyclo-[3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-amide
N-{1-[4-(1,3,3-trimethyl-6-aza-bicyclo [3.2.1] octane-6-carbonyl)-phenyl]-cyclopropyl }-ethyl sulfonamide
1-[4-(azepan-1-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
Piperidines-1-carboxylic acid [4-(3-hydroxyl-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-hydroxyl-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
4-(1,3-dimethyl-3-phenyl-urea groups methyl)-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
Piperidines-1-carboxylic acid [4-(3-fluoro-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
Morpholine-4-carboxylic acid [4-(3-fluoro-diamantane (obsolete)-1-base-carbamoyl)-benzyl]-methyl-amide
4-(1,3-dimethyl-3-phenyl-urea groups methyl)-N-(3-fluoro-diamantane (obsolete)-1-yl)-Benzoylamide
N-diamantane (obsolete)-2-base-4-(1,3-dimethyl-3-pyridine-2-base-urea groups methyl)-Benzoylamide
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-pyridine-2-base-urea
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-thiazol-2-yl-urea
1-(1-acetyl group-piperidin-4-yl)-1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-urea
1-(1-acetyl group-piperidin-4-yl)-3-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1]-octane-8-carbonyl)-benzyl]-1,3-dimethyl-urea
1,3-dimethyl-3-[4-(2-oxa--5-aza-bicyclo [2.2.1] heptane-5-carbonyl)-benzyl]-1-pyrimidine-2-base-urea
Morpholine-4-carboxylic acid [4-(4-azepine-three ring [4.3.1.1 *3,8 *]-hendecane-4-carbonyl)-benzyl]-methyl-amide
1-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-3-(4-hydroxyl-cyclohexyl)-1,3-dimethyl-urea
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-fluoro-cyclohexyl)-1,3-dimethyl-urea
N-diamantane (obsolete)-2-base-4-[3-(1-cyclopropyl-piperidin-4-yl)-1,3-dimethyl-urea groups methyl]-Benzoylamide
1-[4-(3-methoxyl group-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-1,3-dimethyl-3-phenyl-urea
N-diamantane (obsolete)-2-base-4-[3-(4-fluoro-phenyl)-2-oxo-imidazolidine-1-ylmethyl]-Benzoylamide
1-[4-(3-aza-bicyclo [3.2.2] nonane-3-carbonyl)-benzyl]-3-(4-fluoro-phenyl)-imidazolidin-2-one
1-(4-fluoro-phenyl)-3-[4-(3-hydroxyl-8-aza-bicyclo [3.2.1] octane-8-carbonyl)-benzyl]-imidazolidin-2-one
N-diamantane (obsolete)-2-base-4-(2-oxo-3-phenyl-imidazolidine-1-ylmethyl)-Benzoylamide
N-diamantane (obsolete)-1-base-4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl) Benzoylamide
N-diamantane (obsolete)-2-base-4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-Benzoylamide
(4-aza-tricycle [4.3.1.1 *3,8 *]-hendecane-4-yl)-[4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-ketone
Azepan-1-base-[4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-ketone
Azepan-1-base-[4-(5-methyl isophthalic acid, 1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-phenyl]-ketone
N-diamantane (obsolete)-1-base-4-(5-methoxy-1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-Benzoylamide
4-(1,1-dioxo-[1,2,5] thiadiazolidine-2-ylmethyl)-N-(3-hydroxyl-diamantane (obsolete)-1-yl)-Benzoylamide
5-[4-(diamantane (obsolete)-1-base-carbamoyl)-benzyl] and-1,1-dioxo-[1,2,5] thiadiazolidine-2-yl }-ra-butyl acetate
Or the salt of itself and acceptable acid of pharmacy or alkali, or the mixture of optical isomer or optical isomer arbitrarily, comprise racemic mixture or tautomeric arbitrarily form.
14. according to each chemical compound of claim 1-13, it is to be used for the treatment of the medicament that the activity of wherein regulating or suppressing 11 β HSD1 is favourable obstacle, disease or diseases.
15. according to the chemical compound of claim 14, wherein said obstacle, disease and disease are subjected to the influence of endocellular sugar corticoid level.
16. according to the chemical compound of claim 14, wherein obstacle, disease or disease be selected from metabolism syndrome, insulin resistant, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, glucose tolerance reduce (IGT), fasting glucose infringement (IFG), IGT to the development of type 2 diabetes mellitus, metabolism syndrome to development, advanced diabetes complication, neural degeneration and the psychiatric disturbance of type 2 diabetes mellitus and the ill effect of glucocorticoid receptor agonist treatment or therapy.
17. a pharmaceutical composition, comprise as active component at least a according to claim 1-13 each chemical compound and one or more pharmaceutically acceptable carriers or excipient.
18. according to the pharmaceutical composition of claim 17, it is fit to oral, nose, cheek, percutaneous, lung or parenteral and uses.
19. each chemical compound of claim 1-13 is wherein regulated or the activity that suppresses 11 β HSD1 is application in the pharmaceutical composition of favourable obstacle, disease or disease in preparation treatment.
20. the application of claim 19, wherein said obstacle, disease and disease are subjected to the influence of endocellular sugar corticoid level.
21. the application of claim 19, wherein obstacle, disease or disease be selected from metabolism syndrome, insulin resistant, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, glucose tolerance reduce (IGT), fasting glucose infringement (IFG), IGT to the development of type 2 diabetes mellitus, metabolism syndrome to development, advanced diabetes complication, neural degeneration and the psychiatric disturbance of type 2 diabetes mellitus and the ill effect of glucocorticoid receptor agonist treatment or therapy.
22. according to each application of claim 19-21, wherein this pharmaceutical composition is fit to be selected from oral, nose, cheek, percutaneous, lung and parenteral using.
23. a treatment is wherein regulated or the activity that suppresses 11 β HSD1 is the method for favourable obstacle, disease or disease, this method comprises that the patient to needs uses the chemical compound arbitrary according to claim 1-13 of effective dose.
24. the method for claim 23, wherein said obstacle, disease and disease are subjected to the influence of endocellular sugar corticoid level.
25. the method for claim 23, wherein obstacle, disease or disease be selected from metabolism syndrome, insulin resistant, dyslipidemia, hypertension, obesity, type 2 diabetes mellitus, glucose tolerance reduce (IGT), fasting glucose infringement (IFG), IGT to the development of type 2 diabetes mellitus, metabolism syndrome to development, advanced diabetes complication, neural degeneration and the psychiatric disturbance of type 2 diabetes mellitus and the ill effect of glucocorticoid receptor agonist treatment or therapy.
26. the method arbitrary according to claim 23-25, wherein using is, nose oral by being selected from, cheek, percutaneous, lung and parenteral approach.
CNA2006800502497A 2005-11-01 2006-11-01 Pharmaceutical use of substituted amides Pending CN101351209A (en)

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EP05110228.3 2005-11-01
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104024239A (en) * 2011-12-22 2014-09-03 弗·哈夫曼-拉罗切有限公司 BENZYL SULFONAMIDE DERIVATIVES AS RORc MODULATORS
CN104080766A (en) * 2011-03-31 2014-10-01 韩国化学研究院 Sulphamide derivative having an adamantyl group and a pharmaceutically acceptable salt thereof
CN104470917A (en) * 2012-07-11 2015-03-25 弗·哈夫曼-拉罗切有限公司 Aryl sultam derivatives as RORc modulators
CN105085346A (en) * 2015-08-14 2015-11-25 天津小新医药科技有限公司 L-menthol P2Y12 receptor antagonist containing amino groups and application of L-menthol P2Y12 receptor antagonist
CN105085345A (en) * 2015-08-14 2015-11-25 天津小新医药科技有限公司 L-menthol P2Y12 receptor antagonist containing nitro groups and application of L-menthol P2Y12 receptor antagonist
CN108137477A (en) * 2015-08-27 2018-06-08 基因泰克公司 Therapeutic compounds and its application method

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104080766A (en) * 2011-03-31 2014-10-01 韩国化学研究院 Sulphamide derivative having an adamantyl group and a pharmaceutically acceptable salt thereof
CN104080766B (en) * 2011-03-31 2017-02-15 韩国化学研究院 Sulphamide derivative having an adamantyl group and a pharmaceutically acceptable salt thereof
CN104024239A (en) * 2011-12-22 2014-09-03 弗·哈夫曼-拉罗切有限公司 BENZYL SULFONAMIDE DERIVATIVES AS RORc MODULATORS
CN104024239B (en) * 2011-12-22 2016-04-20 弗·哈夫曼-拉罗切有限公司 As the benzyl sulfone amide derivative of RORc conditioning agent
CN104470917A (en) * 2012-07-11 2015-03-25 弗·哈夫曼-拉罗切有限公司 Aryl sultam derivatives as RORc modulators
CN104470917B (en) * 2012-07-11 2017-08-04 弗·哈夫曼-拉罗切有限公司 It is used as the aryl sultam derivative of RORc conditioning agents
CN107235867A (en) * 2012-07-11 2017-10-10 弗·哈夫曼-拉罗切有限公司 It is used as the aryl sultam derivative of RORc conditioning agents
CN105085346A (en) * 2015-08-14 2015-11-25 天津小新医药科技有限公司 L-menthol P2Y12 receptor antagonist containing amino groups and application of L-menthol P2Y12 receptor antagonist
CN105085345A (en) * 2015-08-14 2015-11-25 天津小新医药科技有限公司 L-menthol P2Y12 receptor antagonist containing nitro groups and application of L-menthol P2Y12 receptor antagonist
CN105085346B (en) * 2015-08-14 2017-03-29 天津小新医药科技有限公司 MENTHOL class P2Y12 receptor antagonist of amino-contained and application thereof
CN108137477A (en) * 2015-08-27 2018-06-08 基因泰克公司 Therapeutic compounds and its application method

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