CN1735599A

CN1735599A - 1-propyl alcohol and 1-propylamine derivatives and as the application of glucocorticoid ligands

Info

Publication number: CN1735599A
Application number: CN 200380108207
Authority: CN
Inventors: 约翰·R·普劳德富特; 约翰·R·里甘; 戴维·S·汤姆森; 丹尼尔·库兹米奇; 托马斯·W－H·李; 阿卜杜哈金·哈马奇; 马克·S·拉尔夫; 雷内·津德尔; 尤尼斯·贝卡利; 小托马斯·M·基尔兰特
Original assignee: Boehringer Ingelheim Pharmaceuticals Inc
Current assignee: Boehringer Ingelheim Pharmaceuticals Inc
Priority date: 2003-01-03
Filing date: 2003-12-18
Publication date: 2006-02-15
Also published as: ZA200503959B

Abstract

R in formula (I) compound ¹, R ², R ³, R ⁴, R ⁵, R ⁶Reach X all as the definition in this paper formula (IA) and the formula (IB), or its tautomer, prodrug, solvate or salt; The medical composition that contains this compound, and the method for modulation glucocorticoid receptor function, and in the patient, use these compounds for treating caused or it is characterized by the morbid state of inflammatory, supersensitivity or hyperplasia process or the method for symptom because of glucocorticoid receptor function.

Description

1-propyl alcohol and 1-propylamine derivatives and as the application of glucocorticoid ligands

Technical field that the present invention belongs to

The plan that the invention relates to glucocorticosteroid is like thing or ligand, make the method for this compound, its purposes in medical composition, and in the patient of needs treatments, modulate glucocorticoid receptor function, treatment purposes, and other purposes because of caused morbid state of glucocorticoid receptor function or symptom.

Prior art

Glucocorticosteroid is a kind of reflunomide, and it is the endogenous hormones that immunity system and multiple tract is had far-reaching effect.It is by suppressing inflammatory cytokine, as IL-1, IL-2, IL-6 and TNF, suppress the arachidonic acid metabolism product, comprise prostaglandin(PG) and leukotriene, disappearance T-lymphocyte, and reduce the glutinous expression of molecule on endotheliocyte that connect, to suppress panimmunity and inflammatory function (P.J.Barnes, Clin.Sci., 1998 94, the 557-572 page or leaf; People such as P.J.Barnes, Trends Pharmacol.Sci., 1993, 14, the 436-441 page or leaf).Except these effects, glucocorticosteroid stimulates the generation of glucose in liver, and proteinic catabolism, plays a kind of effect in ionogen and water balance, reduces calcium absorption, and suppresses osteoblastic function.

The anti-inflammatory of endogenous glucocorticosteroid and immunodepression activity have stimulated the development of synthetic glucocorticoid derivative, comprise dexamethasone (dexamethasone), prednisone (prednisone) and prednisolone (prednisolone) (L.Parente, Glucocorticosteroid, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, 2001, the 35-54 pages or leaves).Found that it can be widely used in the treatment inflammatory, immunity and supersensitivity illness, comprise rheumatism, such as rheumatic arthritis, childhood sacroiliitis and rhizomelic spondylitis, tetter, comprise psoriasis and pemphigus, the supersensitivity illness, comprise allergic rhinitis, atopic dermatitis and contact dermatitis, the lung symptom, comprise asthma and chronic obstructive pulmonary disease (COPD), and other immunity and inflammatory diseases, comprise clone disease, ulcerative colitis, systemic lupus erythematosus, the chronic active hepatitis of autoimmunization, osteoarthritis, tendonitis and bursitis (J.Toogood Sugar Cortin, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, 2001, the 161-174 pages or leaves).It also has been used to help the repulsion in the prevention of organ transplant.

Unfortunately, except the desired therapeutic action of glucocorticosteroid, its use is accompanied by multiple adverse side effect, and some of them may be very serious and prestige association life.These comprise development or the deterioration and the osteoporosis of change in fluid and the electrolyte balance, oedema, weight increase, hypertension, muscle weakness, diabetes.Therefore, expect that especially a kind of displaying reduces the side effect distributional pattern, the compound of the antiinflammation of remaining valid simultaneously is especially when treatment of chronic diseases.

The effect of glucocorticosteroid be by glucocorticoid receptor be introduced in the cell level (R.H.Oakley and J.Cidlowski, Glucocorticosteroid, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, 2001, the 55-80 pages or leaves).Glucocorticoid receptor is a member in the intracellular receptor kind of being correlated with on the structure, and it can use the transcription factor (R.M.Evans, Science, 1988,240,889-895 page or leaf) that influences genetic expression as when with the ligand coupling.Other members of steroid receptor family comprise mineralocorticoid, Progesterone, oestrogenic hormon and androgen receptor.About the mentioned effect of glucocorticosteroid, the hormone that this receptor family is had an effect is to stable states such as health, mineral metabolism, pressure is replied and the growth of property feature, all has profound influence except above. Glucocorticosteroid, N.J.Goulding and R.J.Flowers (writing), Boston:Birkhauser, the 2001st, be incorporated herein in full with it in view of the above for reference, so that the current state of this technology to be described more well.

Can cause favourable antiinflammation do not want the molecule mechanism of side effect be suggested (people such as S.Heck for example, EMBO J, 1994, 17, the 4087-4095 page or leaf; People such as H.M.Reichardt, Cell, 1998, 93, the 531-541 page or leaf; People such as F.Tronche, Curr.Opin.in Genetics and Dev., 1998,8,532-538 page or leaf).Think that many metabolism and cardiovascular side effects are a kind of being called to change the result who lives through journey.Live in commentaries on classics, ligand is in conjunction with the nuclear that is displaced to of glucocorticoid receptor, in the promoter region of side effect genes involved, reply element (GRE) back and carry out being bonded to glucocorticosteroid, for example in increasing the situation of glucose production, phosphoenolpyruvic acid ester carboxylic kinases (PEPCK).The increase transcription rate of these genes consequently, this thinks that it finally can cause viewed side effect.Antiinflammation is considered to because due to a kind of process that is called trans-repression.Generally speaking, trans-repression is a kind of irrelevant process that combines with DNA, and it is because the inhibition of NF-kB and AP-1-institute pipeline causes, and causes the downward adjusting of many inflammatories and immune mediator.In addition, think that many side effects of finding may be because the cross reactivity of present adoptable glucocorticosteroid and other steroid receptors causes, particularly mineralocorticoid and progesterone receptor.

Therefore, perhaps can find the ligand to glucocorticoid receptor, it is a high selectivity, and in conjunction with the time, can dissociate effect of change living and trans-repression passage provide to have the therapeutical agent that reduces the side effect distributional pattern.Mensuration is to changeing the detection system of living with trans-repression, the existing description (for example C.M.Bamberger and H.M.Schulte, Eur.J.Clin.Invest., 2000,30 (replenishing 3), 6-9 page or leaf).Selectivity to glucocorticoid receptor can record by comparing for the binding affinity of this acceptor and for the binding affinity that comprises other steroid family acceptors referred to above.

Glucocorticosteroid also stimulates the generation of glucose in liver by a kind of process that is called gluconeogenesis, and thinks that this process causes by changeing the effect of living.The glucose production that increases can worsen type ii diabetes, and therefore, a kind of selectivity suppresses the compound of the caused glucose production of glucocorticosteroid, can in this indication, have treatment usability (people such as J.E.Freidman, J.Biol.Chem., 1997,272, the 31475-31481 pages or leaves).

Novel ligand to glucocorticoid receptor has been described in science and the patent documentation.For example, PCT international publication WO 99/33786 discloses the triphenyl propanamide compounds, and it has potential use in the treatment inflammatory diseases.PCT international publication WO 00/66522 describes the selectivity modulator of non-steroidal compound as glucocorticoid receptor, can be used for treating metabolism and inflammatory diseases potentially.PCT international publication WO 99/41256 describes the Fourth Ring shape modulator of glucocorticoid receptor, and it can be used for treatment immunity, autoimmunization and inflammatory diseases potentially.United States Patent (USP) 5,688,810 describe the modulator of various non-steroidal compounds as glucocorticosteroid and other steroid receptors.PCT international publication WO 99/63976 describes on-steroidal, liver selectivity glucocorticosteroid antagonist, can be used for treating diabetes potentially.PCT international publication WO 00/32584 openly has the non-steroidal compound of dissociated antiphlogistic activity between anti-inflammatory and metabolism.PCT international publication WO 98/54159 describes the replacement of on-steroidal ring-type, has the acyl group anilide of pregnant element of blended and androgenic activity.United States Patent (USP) 4,880,839 descriptions have active acyl group anilid in pregnant early stage, and EP 253503 discloses the acyl group anilid with androgen antagonist character.PCT international publication WO 97/27852 describes, and is the amides of the inhibitor of farnesyl protein transferase.

A kind of finding and the interactional compound of glucocorticoid receptor in conjunction with in detecting, can be agonist or antagonist.The agonist character of this compound can be assessed in effect or trans-repression detection are lived in above-mentioned commentaries on classics.Under the effect and disadvantageous side effect thereof that in inflammatory and Immunological diseases, confirms by adoptable glucocorticoid medicine, still it is novel to need, have the selectivity that surpasses other members of steroid receptor family, and dissociate to change and live and the active glucocorticoid receptor agonist of trans-repression.Perhaps, this compound can be found and have antagonistic activity.As indicated above, glucocorticosteroid can stimulate glucose to produce in liver.By the glucose production of the excessive increase that causes of glucocorticosteroid, existing diabetes are worsened, or trigger the diabetes of hiding.Therefore, a kind of ligand that is used for glucocorticoid receptor and has been found to be antagonist is useful, in particular for treatment or prevent diabetes.

Summary of the invention

The present invention be directed to formula (IA) compound

Wherein:

R ¹Be aryl, heteroaryl or C ₅-C ₁₅Cycloalkyl, each is independent of according to circumstances one to three substituting group replacement, wherein R ¹Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅-alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, aroyl, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₃-C ₅Naphthene amino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, oxo, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is independent of according to circumstances C ₁-C ₅The alkyl or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl or C ₃-C ₅Cycloalkyl substituted; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ¹Each substituting group according to circumstances can be independently replaced by one to four substituting group, substituting group is selected from aryl or heterocyclic radical, wherein heterocycle can independently be replaced by hydroxyl, halogen, methyl or dialkylamino according to circumstances; C ₁-C ₅Carbalkoxy, methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl or C ₁-C ₃Dialkyl group Ammonia or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Amino-sulfonyl or oxime, wherein Sauerstoffatom according to circumstances can be by C ₁-C ₅Alkyl or benzyl replace;

R ²With R ³Each is hydrogen, C independently ₁-C ₅Alkyl or C ₅-C ₁₅Aralkyl, or R ²With R ³With its carbon atom that is connected jointly together, form C ₃-C ₈The spirocyclane basic ring, or

R ¹With R ²When being chromanyl or dihydro benzo furyl together, then C can be replaced according to circumstances by following group ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances;

R ⁴For carbonyl or methylene radical, be selected from C by one or two independently according to circumstances ₁-C ₃The substituting group of alkyl, hydroxyl and halogen replaces;

R ⁵Be tetramethyleneimine, morpholine, thiomorpholine, piperazine, piperidines, 1H-pyridine-4-ketone, the 1H-pyridin-2-ones, the inferior pyridin-4-yl amine of 1H-, the inferior quinolyl-4 amine of 1H-, pyrans, tetrahydropyrans, 1, the 4-Diazesuberane, 2, the 5-diazabicyclo is [2.2.1] heptane also, 2,3,4,5-tetrahydro benzo [b] [1,4] diaza _, dihydroquinoline, tetrahydroquinoline, 5,6,7,8-tetrahydrochysene-1H-quinoline-4-ketone, tetrahydroisoquinoline, Decahydroisoquinolinpreparation, 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indoles, chroman, 1,2,3, the 4-tetrahydroquinoxaline, 1,2-dihydro-indazol-3-ketone, 3,4-dihydro-2H-benzo [1,4] oxazines, 4H-benzo [1,4] thiazine, 3,4-dihydro-2H-benzo [1,4] thiazine, 1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone, 3,4-dihydrobenzo [1,4] oxazine-4-ketone, the 3H-quinazoline-4-one, 3,4-dihydro-1H-quinoxaline-2-ketone, 1H-cinnolines-4-ketone, the 1H-quinazoline-4-one, 1H-[1,5] naphthyridine-4-ketone, 5,6,7,8-tetrahydrochysene-1H-[1,5] naphthyridine-4-ketone, 2,3-dihydro-1H-[1,5] naphthyridine-4-ketone, 1,2-dihydro pyrido [3,2-d] [1,3] oxazine-4-ketone, pyrrolo-[3,4-c] pyridine-1, the 3-diketone, 1, the 2-pyrrolin is [3,4-c] pyridine-3-ketone or tetrahydrochysene [b] [1,4] Diazesuberane ketone groups also, each is independent of according to circumstances one to three substituting group replacement

R wherein ⁵Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ⁵Each substituting group according to circumstances can be independently be selected from following substituting group and replace by one to three: C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Carbalkoxy, acyl group, aryl, benzyl, heteroaryl, heterocyclic radical, halogen, hydroxyl, oxo, cyano group, amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or trifluoromethyl; And

X is hydroxyl or amino, and wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements, or its tautomer, prodrug, solvate or salt.

The present invention comprises formula (IA) compound on the other hand, wherein:

R ¹Be phenyl, dihydro benzo furyl, benzofuryl, indolinyl, indyl, benzo [1,3] dioxole, dihydrobenzo thienyl, benzothienyl, benzoxazole, benzoisoxazole, benzopyrazoles, benzoglyoxaline, thienyl, quinolyl, tetrahydroquinolones, Tetrahydronaphthyridderivates ketone, dihydro chromene, pyridyl, pyrimidyl or pyrazinyl, each is replaced by one to three substituting group according to circumstances independently

R wherein ¹Each substituting group be the independent C that is ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₂-C ₃Alkene oxygen base, C ₁-C ₃Alkyloyl, C ₁-C ₃Carbalkoxy, C ₁-C ₃Alkanoyloxy, halogen, hydroxyl, acyl group, oxo, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ¹Each substituting group according to circumstances can be independently be selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or amino substituting group and be replaced;

R ²With R ²Each is hydrogen, C independently ₁-C ₃Alkyl, benzyl or styroyl, or R ²With R ³With its carbon atom that is connected jointly together, form C ₃-C ₆The spirocyclane basic ring; And

R ⁴Be CH ₂,

Or its tautomer, prodrug, solvate or salt.

Another aspect of the present invention comprises formula (IA) compound, wherein:

R ¹Be phenyl, pyridyl, dihydro benzo furyl or benzofuryl, each is replaced by one to three substituting group according to circumstances independently,

R wherein ¹Each substituting group be methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, acyl group, oxo, C independently ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances, or cyano group;

R ²With R ³Each is methyl independently, or R ²With R ³With its carbon atom that is connected jointly together, form the Spirocyclopropyl ring; And

R ⁴Be CH ₂,

Or its tautomer, prodrug, solvate or salt.

R ¹Be phenyl, dihydro benzo furyl or benzofuryl, each is replaced by one to three substituting group according to circumstances independently,

R wherein ¹Each substituting group be C independently ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₂-C ₃Alkene oxygen base, C ₁-C ₃Alkyloyl, C ₁-C ₃Carbalkoxy, C ₁-C ₃Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances; And

R ²With R ³Each is hydrogen or C independently ₁-C ₃Alkyl,

Or its tautomer, prodrug, solvate or salt.

An aspect of of the present present invention comprises formula (IA) compound, wherein:

R ⁵Be morpholine, thiomorpholine, piperazine, piperidines, 1H-pyridine-4-ketone, pyrans, tetrahydropyrans, dihydroquinoline, tetrahydroquinoline, chroman, 1,2,3, the 4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo [1,4] oxazines, 3,4-dihydro-2H-benzo [1,4] thiazine, 1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone, 3,4-dihydrobenzo [1,4] oxazine-4-ketone, 3,4-dihydro-1H-quinoxaline-2-ketone, 3,4-dihydro-2H-naphthalene-1-ketone, 1H-cinnolines-4-ketone, the 1H-quinazoline-4-one, 1H-[1,5] naphthyridine-4-ketone, 2,3-dihydro-1H-[1,5] naphthyridine-4-ketone, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone, 1,2-dihydro pyrido [3,2-d] [1,3] oxazine-4-ketone, pyrrolo-[3,4-c] pyridine-1, the 3-diketone, tetrahydrochysene [b] [1,4] diaza _ ketone or 1,2-pyrrolin also [3,4-c] pyridine-3-ketone, each is replaced by one to three substituting group according to circumstances independently

R wherein ⁵Each substituting group according to circumstances can be independently replaced by one to three substituting group, substituting group is selected from C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, halogen, hydroxyl, oxo, cyano group, amino or trifluoromethyl,

Or its tautomer, prodrug, solvate or salt.

Following is representative compounds for the formula (IA) according to the present invention:

Or its tautomer, prodrug, solvate or salt.

Preferred formula (IA) compound comprises following:

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,6-lupetazin-1-formaldehyde;

2-(1,1-dioxo-2,3-dihydro-1H-1 λ ⁶-benzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

2-(2,6-thebaine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

2-(2,3-dihydrobenzo [1,4] oxazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,5-lupetidine-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-cinnolines-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-fluoro-4-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(4-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-phenyl-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-[1,5]-naphthyridine-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxyl-2,4-dimethyl amyl group]-3,5-dimethyl-1H-pyridine-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-[1,5] naphthyridine-4-ketone;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydro-1H-1 λ 4-benzo [1,4] thiazine-4-ylmethyl) pentane-2-alcohol;

1-[2-hydroxyl-4-(2-methoxyl group-5-thiophene-2-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(the 6-bromobenzene is [1,3] Dioxol-4-yl also)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[2-hydroxyl-4-(4-Hydroxybiphenyl-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{4-[5-(3,5-dimethyl isoxazole-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-5-thiene-3-yl-phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{4-[5-(3,5-dimethyl isoxazole-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-[1,5] naphthyridine-4-ketone;

1-[2-hydroxy-4-methyl-4-(3-pyridin-3-yl phenyl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-5-morpholine-4-ylmethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-methoxyl group-5-morpholine-4-ylmethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(5-methylol-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

4-methoxyl group-3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl aldehyde;

1-[4-(5-[1,3] dioxane-2-base-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-furans-3-base-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-quinazoline-4-one;

1-[2-hydroxyl-4-(4-methoxyl biphenyl-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-ethanoyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[3,3,3-three fluoro-2-(6-fluoro-4-methyl chroman-4-ylmethyl)-2-hydroxypropyl]-1H-quinoline-4-ketone;

1-[4-{3-[1-(benzyloxy imino-) ethyl] phenyl }-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-cyclopropane carbonyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-ethanoyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(2-hydroxyl-4-{3-[1-(methoxyimino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-bromo-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(2-hydroxyl-4-{3-[1-(oximino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone;

1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3, the 5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3, the 5-3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3] dioxolane-2-yl) phenyl]-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2-methylol-3,5-dimethyl-1H-pyridine-4-ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-[1,5] naphthyridine-4-ketone;

1-[2-hydroxyl-4-(3-hydroxymethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-[1,3] dioxane-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{4-[3-(3,5-dimethyl isoxazole-4-yl) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,5-dimethyl-1H-pyridine-4-ketone;

1-{2-hydroxyl-4-[3-(1-hydroxyethyl) phenyl]-4-Methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,5-dimethyl-1H-pyridine-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2-methylol-3,5-dimethyl-1H-pyridine-4-ketone;

3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl aldehyde;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2-methylol-3,5-dimethyl-1H-pyridine-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methylol-1H-quinoline-4-ketone;

1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-7-hydroxyl-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-6-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methylol-1H-quinoline-4-ketone;

6-chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2-difluoro-methoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(4-biphenyl-3-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone;

6-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxy-5-methyl base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{2-hydroxy-4-methyl-4-[3-(2-oxopropoxy) phenyl]-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(3-isopropyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-phenelyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-methoxyl group-5-aminomethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2, the 5-3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(3-hydroxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(3-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,2-dihydro-indazol-3-ketone;

7-fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,5-dimethyl-1H-pyridine-4-ketone;

7-fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl hexyl)-1H-quinoline-4-ketone;

1-[4-(4-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3, the 4-3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

8-fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

6-fluoro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{4-(5-fluoro-2-(2-oxopropoxy) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

7-chloro-1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-isopropyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2-benzyloxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2-oxyethyl group-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

8-fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

6-fluoro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(5-methanesulfinyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxy-4-methyl-4-(5-methylthio group-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

7-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-fluoro-4-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-nitro-5-Trifluoromethyl-1 H-pyridin-2-ones;

3-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-5-Trifluoromethyl-1 H-pyridin-2-ones;

2-(2,3-indoline-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

1-[2-hydroxy-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and piperazine-1-yl } furans-2-base ketone;

1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

2-[4-(3-chloro-5-5-flumethiazine-2-yl) piperazine-1-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and piperazine-1-yl } furans-2-base ketone;

1-[2-hydroxyl-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-[1,3] dioxane-2-base-4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2, the 4-3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-fluoro-4-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-benzo [1,3] Dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,2-dihydro-indazol-3-ketone;

2-(3,4-dihydro-2H-quinoxaline-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dihydro-2H-quinoxaline-1-ylmethyl) pentane-2-alcohol;

2-(2,3-dihydrobenzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

1-{4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydro-2H-quinoxaline-1-yl } ethyl ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-methoxyl group-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone; And

Carbonic acid 4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] the phenyl ester methyl esters,

Or its tautomer, prodrug, solvate or salt.

Preferred formula (IA) compound comprises following:

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-[1,5] naphthyridine-4-ketone;

1-(4-{3-[1-(benzyloxy imino-) ethyl] phenyl }-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(2-hydroxyl-4-{3-[1-(methoxyimino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone;

1-[4-(5-bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl hexyl)-1H-quinoline-4-ketone;

1-[4-(4-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-cave;

1-(4-benzo [1,3] Dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone; And

1-[2-hydroxyl-4-(2-hydroxyl-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone,

Or its tautomer, prodrug, solvate or salt.

The present invention also provides the method for a kind of manufacturing formula (IV) compound

R wherein ¹, R ², R ³, R ⁵And all definition as mentioned of X, and R ⁴For-CH ₂-, this method comprises:

(a) formula (II) ester and a suitable reductive agent are reacted in appropriate solvent, to form formula (III) glycol

(b) make formula (III) glycol and SULPHURYL CHLORIDE R ' SO ₂The Cl reaction is to form formula (IV) sulphonate

(c) make formula (IV) intermediate and suitable alkali reaction, to form the epoxide of formula V

With

(d) make the epoxide and the desired R of formula V ⁵The H reaction is to form formula (IA) compound

In addition, the present invention also provides the method for a kind of manufacturing formula (IA) compound

R wherein ¹, R ², R ³, R ⁵And all definition as mentioned of X, and R ⁴For-C (O)-, this method comprises:

(a) formula (II) ester is hydrolyzed, with production (X) carboxylic acid

(b) make formula (X) carboxylic acid and R ⁵The H coupling is to provide desired formula (I) compound

The present invention be directed to formula (IB) compound

Wherein:

R ¹Be aryl, heteroaryl or C ₅-C ₁₅Cycloalkyl, each is replaced by one to three substituting group according to circumstances independently, wherein R ¹Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, aroyl, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, oxo, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ¹Each substituting group according to circumstances can be independently be selected from following group and replace by one to three: aryl or heterocyclic radical, (wherein heterocycle is replaced by hydroxyl, halogen, methyl, dialkylamino according to circumstances independently); Methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl or C ₁-C ₃Dialkyl amine or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Amino-sulfonyl, oxime, wherein Sauerstoffatom according to circumstances can be by C ₁-C ₅Alkyl or benzyl replace;

R ²With R ³Each is hydrogen, C independently ₁-C ₅Alkyl or C ₅-C ₁₅Aralkyl, or R ²With R ³The carbon atom that is connected jointly with they forms C together ₃-C ₈Spirocyclane basic ring, or R ¹With R ²When adopting together, be chromanyl or dihydro benzo furyl, replaced C according to circumstances by following group ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances;

R ⁵Be tetramethyleneimine, morpholine, thiomorpholine, piperazine, piperidines, 1H-pyridine-4-ketone, the 1H-pyridin-2-ones, the inferior pyridin-4-yl amine of 1H-, the inferior quinolyl-4 amine of 1H-, pyrans, tetrahydropyrans, 1, the 4-Diazesuberane, 2, the 5-diazabicyclo is [2.2.1] heptane also, 2,3,4,5-tetrahydro benzo [b] [1,4] diaza _, dihydroquinoline, tetrahydroquinoline, 5,6,7,8-tetrahydrochysene-1H-quinoline-4-ketone, tetrahydroisoquinoline, Decahydroisoquinolinpreparation, 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indoles, chroman, 1,2,3, the 4-tetrahydroquinoxaline, 1,2-dihydro-indazol-3-ketone, 3,4-dihydro-2H-benzo [1,4] oxazines, 4H-benzo [1,4] thiazine, 3,4-dihydro-2H-benzo [1,4] thiazine, 1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone, 3,4-dihydrobenzo [1,4] oxazine-4-ketone, the 3H-quinazoline-4-one, 3,4-dihydro-1H-quinoxaline-2-ketone, 1H-cinnolines-4-ketone, the 1H-quinazoline-4-one, 1H-[1,5] naphthyridine-4-ketone, 5,6,7,8-tetrahydrochysene-1H-[1,5] naphthyridine-4-ketone, 2,3-dihydro-1H-[1,5] naphthyridine-4-ketone, 1,2-dihydro pyrido [3,2-d] [1,3] oxazine-4-ketone, pyrrolo-[3,4-c] pyridine-1, the 3-diketone, 1, the 2-pyrrolin is [3,4-c] pyridine-3-ketone or tetrahydrochysene [b] [1,4] diaza _ ketone also, each is replaced by one to three substituting group according to circumstances independently

R wherein ⁵Each substituting group be following group: C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, C ₁-C ₅Alkyl amino sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances.

R wherein ⁵Each substituting group be selected from following substituting group by one to three independently according to circumstances and replace C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Carbalkoxy, acyl group, benzyl, heteroaryl, heterocyclic radical, halogen, hydroxyl, oxo, cyano group, amino, wherein nitrogen-atoms is according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl or trifluoromethyl replace; And

R ⁶Be hydrogen, C ₁-C ₈Alkyl, C ₂-C ₈Thiazolinyl, C ₂-C ₈Alkynyl, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, carbocyclic ring-C ₁-C ₈Alkyl, carboxyl, carbalkoxy, aryl-C ₁-C ₈Alkyl, aryl-C ₁-C ₈Alkylhalide group, heterocyclic radical-C ₁-C ₈Alkyl, heteroaryl-C ₁-C ₈Alkyl, carbocyclic ring-C ₂-C ₈Thiazolinyl, aryl-C ₂-C ₈Thiazolinyl, heterocyclic radical-C ₂-C ₈Thiazolinyl or heteroaryl-C ₂-C ₈Thiazolinyl, each is replaced by one to three substituting group according to circumstances independently,

R wherein ⁶Each substituting group be following group: C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, phenyl, C ₁-C ₅Alkoxyl group, phenoxy group, C ₁-C ₅Alkyloyl, aroyl, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, aminocarboxyl, C ₁-C ₅Alkyl amino-carbonyl, C ₁-C ₅Dialkylamino carbonyl, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ⁶Can not be trifluoromethyl,

Another aspect of the present invention comprises formula (IB) compound, wherein:

R wherein ¹Each substituting group be the independent C that is ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₂-C ₃Alkene oxygen base, C ₁-C ₃Alkyloyl, C ₁-C ₃Carbalkoxy, C ₁-C ₃Alkanoyloxy, halogen, hydroxyl, acyl group, oxo, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom is can be oxidized to sulfoxide or sulfone according to circumstances,

R ²With R ³Each is hydrogen, C independently ₁-C ₃Alkyl, benzyl or styroyl, or R ²With R ³With its carbon atom that is connected jointly together, form C ₃-C ₆The spirocyclane basic ring;

R ⁴Be CH ₂And

R ⁶Be C ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₃-C ₆Cycloalkyl, phenyl, C ₃-C ₆Cycloalkyl-C ₁-C ₃Alkyl, phenyl-C ₁-C ₃Alkyl, phenyl-C ₁-C ₃Alkylhalide group, C ₃-C ₆Cycloalkyl-C ₂-C ₃Thiazolinyl, phenyl-C ₂-C ₃Thiazolinyl, each can independently be replaced by one to three substituting group according to circumstances,

R wherein ⁶Each substituting group be C independently ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, aminocarboxyl, C ₁-C ₃Alkyl amino-carbonyl, C ₁-C ₃Dialkylamino carbonyl, halogen, hydroxyl, oxo, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ⁶Can not be trifluoromethyl,

Or its tautomer, prodrug, solvate or salt.

R ¹Be phenyl, pyridyl, dihydro benzo furyl or benzofuryl, each can be replaced by one to three substituting group according to circumstances independently,

R wherein ¹Each substituting group be methyl, ethyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, acyl group, oxo, C independently ₁-C ₅Alkylthio, wherein sulphur atom is can be oxidized to sulfoxide or sulfone according to circumstances, or cyano group;

R ⁴Be CH ₂,

Or its tautomer, prodrug, solvate or salt.

The present invention comprises formula (IB) compound in addition on the other hand, wherein:

R wherein ¹Each substituting group be C independently ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₂-C ₃Alkene oxygen base, C ₁-C ₃Alkyloyl, C ₁-C ₃Carbalkoxy, C ₁-C ₃Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom is to be oxidized to sulfoxide or sulfone according to circumstances; And

R ²With R ³Independent is hydrogen or C ₁-C ₃Alkyl,

Or its tautomer, prodrug, solvate or salt.

An aspect of of the present present invention comprises formula (IB) compound, wherein:

R ⁵Be morpholine, thiomorpholine, piperazine, piperidines, 1H-pyridine-4-ketone, pyrans, tetrahydropyrans, dihydroquinoline, tetrahydroquinoline, chroman, 1,2,3, the 4-tetrahydroquinoxaline, 3,4-dihydro-2H-benzo [1,4] oxazines, 3,4-dihydro-2H-benzo [1,4] thiazine, 1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone, 3,4-dihydrobenzo [1,4] oxazine-4-ketone, 3,4-dihydro-1H-quinoxaline-2-ketone, 3,4-dihydro-2H-naphthalene-1-ketone, 1H-cinnolines-4-ketone, the 1H-quinazoline-4-one, 1H-[1,5] naphthyridine-4-ketone, 2,3-dihydro-1H-[1,5] naphthyridine-4-ketone, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone, 1,2-dihydro pyrido [3,2-d] [1,3] oxazine-4-ketone, pyrrolo-[3,4-c] pyridine-1, the 3-diketone, tetrahydrochysene [b] [1,4] diaza _ ketone or 1,2-pyrrolin also [3,4-c] pyridine-3-ketone, each can independently be replaced by one to three substituting group according to circumstances

R wherein ⁵Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms is independent of according to circumstances C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or Cx-C ₅Alkylthio, wherein sulphur atom is can independently be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ⁵Each substituting group according to circumstances can be independently one to three substituting group replace, substituting group is selected from C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, halogen, hydroxyl, oxo, cyano group, amino or trifluoromethyl; And

R ⁶Be C ₁-C ₅Alkyl, C ₃-C ₆Cycloalkyl, C ₃-C ₆Methyl cycloalkyl-or benzyl, each is independent of according to circumstances one to three substituting group replacement,

R wherein ⁶Each substituting group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently,

R wherein ⁶Can not be trifluoromethyl,

Or its tautomer, prodrug, solvate or salt.

Classify according to the present invention the representative compounds of formula (IB) down as:

Preferred formula (IB) compound comprises:

1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone; With

1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone, or its tautomer, prodrug, solvate or salt.

The present invention also provides the method for a kind of manufacturing formula (IB) compound

R wherein ¹, R ², R ³, R ⁵, R ⁶And all definition as mentioned of X, and R ⁴For-CH ₂-, this method comprises:

(a) formula (IA) compound and suitable alkali are reacted in appropriate solvent, to form formula (IIB) ketone

(b) make the reaction of formula (IIB) ketone and organometallic reagent, to form formula (IB) compound

In another aspect of this invention, compound according to the present invention is to be formulated into pharmaceutical composition, and it comprises significant quantity, is preferably the pharmaceutically The compounds of this invention of significant quantity, or its tautomer, prodrug, solvate or salt, and pharmaceutically acceptable vehicle or supporting agent.

The present invention also provides a kind of method of modulating glucocorticoid receptor function to the patient, and this method comprises the The compounds of this invention of the patient being thrown significant quantity, or its tautomer, prodrug, solvate or salt.

The present invention further provides the method for a kind of treatment because of caused morbid state of glucocorticoid receptor function or symptom to the patient of needs treatment, this method comprises gives the pharmaceutically acceptable according to The compounds of this invention of significant quantity to the patient, or its tautomer, prodrug, solvate or salt.

In addition, the present invention also provides a kind of method for the treatment of morbid state or symptom to the patient of needs treatment, this morbid state or symptom are selected from: type ii diabetes, obesity, cardiovascular disorder, hypertension, arteriosclerosis, neurological disease, suprarenal gland and pituitary tumor and glaucoma, this method comprises gives the pharmaceutically acceptable according to The compounds of this invention of significant quantity to patient's throwing, or its tautomer, prodrug, solvate or salt.

The present invention provides a kind of treatment to it is characterized by the method for the disease of inflammatory, supersensitivity or hyperplasia process to the patient of needs treatment, this method comprises gives the pharmaceutically acceptable according to compound of the present invention of significant quantity to this patient's throwing, or its tautomer, prodrug, solvate or salt.In a preferred embodiment of the present invention, the disease that is characterized as inflammatory, supersensitivity or hyperplasia process of disease, it is selected from: (i) tuberculosis; (ii) rheumatism or autoimmune disease or joint disease; (ii) anaphylactic disease; (iv) vasculitis disease; (v) tetter; (vi) ephrosis; (vii) hepatopathy; (viii) gastroenteropathy; (ix) proctology disease; (x) disease of eye; (xi) disease in ear, nose and throat (ENT) district; (xii) neurological disease; (xiii) hematologic disease; (xiv) tumor disease; (xv) endocrinopathy; (xvi) organ and tissue transplantation and graft-right-host's disease; (xvii) Xiu Ke serious state; (xviii) replace treatment; Reach (xix) pain of inflammatory generation.In another preferred embodiment of the present invention, genius morbi is an inflammatory, supersensitivity or hyperplasia process, it is selected from: type i diabetes, osteoarthritis, return-Bai Er Shi (Guillain-Barre) syndromes, because of through the restenosis of skin behind tube chamber coronary vasodilator neoplasty, Ah ear is grown extra large Mo's disease, acute and chronic pain, atherosclerosis, reperfusion injury, bone absorption disease, congestive heart failure exhausts, myocardial infarction, thermal damage, the multiple organ injury of wound supervention, acute purulent meningitis, necrotizing enterocolitis, and and hemodialysis, white corpuscle electrophoresis and the related syndromes of granulocyte infusion.

The present invention further provides the method for treatment morbid state referred to above or symptom to the patient of needs treatment, these methods comprise in succession or the patient are thrown give simultaneously: (a) the pharmaceutically acceptable The compounds of this invention of significant quantity, or its tautomer, prodrug, solvate or salt; With (b) pharmaceutically acceptable glucocorticosteroid.

The present invention further provides a kind of method that detects glucocorticoid receptor function in sample, it comprises: sample is contacted with The compounds of this invention or its tautomer, prodrug, solvate or the salt of selected amount; Amount with the The compounds of this invention or its tautomer, prodrug, solvate or the salt that are bonded to glucocorticoid receptor in (b) test samples.In a preferred embodiment of the invention, according to compound of the present invention or its tautomer, prodrug, solvate or salt is to identify with detectable marker, and this mark is selected from: radio-labeling, fluorescent labelling, chemiluminescence mark, chromophoric group and rotary label.

The present invention also provides a kind of glucocorticoid receptor distribution imaging method that makes among sample or the patient, and this method comprises: (a) make the sample contact or The compounds of this invention or its tautomer, prodrug, solvate or the salt with detectable is given in patient's throwing; (b) in the test samples, have and to detect spatial distribution and the amount that is attached to glucocorticoid receptor, use imaging device to obtain image according to The compounds of this invention or its tautomer, prodrug, solvate or salt; Reach spatial distribution and the amount that is bonded to glucocorticoid receptor in the sample that (c) show according to The compounds of this invention or its tautomer, prodrug, solvate or salt with detectable.In a preferable embodiment of the present invention, imaging device is to be selected from: radioscintigraphy, Magnetic resonance imaging (MRI), x-ray tomography art (CT scan) as calculated or positron emission x-ray tomography art (PET).

The present invention also provides a kind of in vitro fit of diagnostic assay glucocorticoid receptor function that is used in sample, it comprises: (a) diagnosis go up significant quantity according to The compounds of this invention or its tautomer, prodrug, solvate or salt; With (b) working instructions about this diagnosis fit.

Detailed Description Of The Invention

The definition of the term that uses and usage

In the term that defines especially herein, should give by the meaning that in open scope and context, is given of being familiar with this skill.But, unless opposite appointment is arranged, when being used for patent specification and appending claims, following term is to have indicated meaning and following usage.

A. chemical nomenclature, term and usage

In defined hereinafter group, atomic group or the part group, carbonatoms often is specified in before the group, for example, and C ₁-C ₁₀Alkyl is to mean the alkyl with 1 to 10 carbon atom.Being applied to " low-carbon (LC) " speech of any carbon-containing group, is to mean the group that contains 1 to 8 carbon atom, by the suitable mode (meaning is that cyclic group must have at least 3 atoms, to constitute ring) to this group.Generally speaking, for comprising the group that two or more subunits are rolled into a ball, the group of Zhi Chenging is to be the group tie point at last, and for example " alkaryl " is the monoradical that means formula Alk-Ar-, and " aralkyl " is the monoradical (wherein Alk is an alkyl, and Ar is an aryl) that means formula Ar-Alk-.Moreover divalent group is the use of the term of the monoradical of censuring under the suitable situation therein, will be interpreted as censuring indivedual divalent groups, and vice versa.Unless otherwise, otherwise term control and the definition of commonly using of commonly using the stationary atom valency, in all chemical formulas and group, supposed and obtained.

Term " alkyl " or " alkyl group " are to mean side chain or straight chain saturated aliphatic hydrocarbon monoradical.This term is to be example with the following groups, for example (,) methyl, ethyl, just-propyl group, 1-methylethyl (sec.-propyl), just-butyl, just-amyl group, 1,1-dimethyl ethyl (tert-butyl) etc.It can be abbreviated as " alkane (Alk) ".

Term " thiazolinyl " or " alkenyl group " are to mean side chain or linear aliphatic hydrocarbon monoradical, contain at least one carbon-to-carbon double bond.This term is to be example with the following groups, for example (,) vinyl, propenyl, just-butenyl, isobutenyl, 3-methyl but-2-ene base, just-pentenyl, heptenyl, octenyl, decene base etc.

Term " alkynyl " or " alkynyl group " are to mean side chain or linear aliphatic hydrocarbon monoradical, contain at least one carbon-to-carbon triple bond.This term is to be example with the following groups, as ethynyl, proyl, just-and butynyl, 2-butyne base, 3-methyl butynyl, just-pentynyl, heptyne base, octyne base, decynyl etc.

Term " alkylidene group " or " alkylidene group " are to mean side chain or straight chain saturated aliphatic hydrocarbon divalent group, have specified carbonatoms.This term is to be example with the following groups, for example (,) methylene radical, ethylidene, propylidene, just-butylidene etc., and alternately and be equivalent to be expressed as herein-(alkyl)-.

Term " alkenylene " or " alkenylene group " are to mean side chain or linear aliphatic hydrocarbon divalent group, have specified carbonatoms and at least one carbon-to-carbon double bond.This term is to be example with the following groups, for example (,) vinylidene, propenylidene, just-crotonylidene etc., and alternately and be equivalent to be expressed as herein-(thiazolinyl)-.

Term " alkynylene " or " alkynylene group " are to mean side chain or linear aliphatic hydrocarbon divalent group, contain at least one carbon-to-carbon triple bond.This term is to be example with the following groups, as ethynylene, inferior proyl, just-butynelene, 2-butynelene, 3-methyl butynelene, just-Ya pentynyl, inferior heptyne base, inferior octyne base, inferior decynyl etc., and alternately and be equivalent to be expressed as herein-(alkynyl)-.

Term " alkoxyl group " or " alkoxy base " are to mean formula AlkO-monoradical, and wherein Alk is an alkyl.This term is to be example with the following groups, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, the second month in a season-butoxy, uncle-butoxy, pentyloxy etc.

Term " aryloxy " or " aryloxy group " are to mean formula ArO-monoradical, and wherein Ar is an aryl.This term is to be example with the following groups, as phenoxy group, naphthyloxy etc.

" oxo " speech be mean formula (=O) divalence oxygen groups through dual combination, for example, one of alkyl that is replaced by " oxo " example is formula Alk-C (O)-Alk group, wherein each Alk is an alkyl.

Term " alkyl carbonyl ", " alkyl carbonyl group ", " alkyloyl " or " alkyloyl group " are to mean formula AlkC (O)-monoradical, and wherein Alk is alkyl or hydrogen.

Term " aryl carbonyl ", " aryl carbonyl group ", " aroyl " or " aroyl group " are to mean formula ArC (O)-monoradical, and wherein Ar is an aryl.

Term " acyl group " or " carboxyl groups " are to mean formula RC (O)-monoradical, and wherein R is a substituting group, and it is selected from hydrogen or organic substituent.Substituting group for example comprises alkyl, aryl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl etc.Therefore, these terms comprise alkyl carbonyl and aryl carbonyl.

Term " acyl amino " or " acyl amino group " are to mean formula RC (O) N (R)-monoradical, and wherein each R is for being selected from hydrogen or substituent substituting group.

Term " carbalkoxy " or " alkoxycarbonyl group " are to mean formula AlkO-C (O)-monoradical, and wherein Alk is an alkyl.Carbalkoxy for example comprises methoxycarbonyl, ethoxycarbonyl, uncle-butoxy carbonyl etc.

Term " aryloxycarbonyl " or " aryloxycarbonyl group " are to mean formula ArO-C (O)-monoradical, and wherein Ar is an aryl.

Term " alkyl carbonyl oxygen base " or " alkyl carbonyl oxygen base group " or " alkanoyloxy " or " alkanoyloxy group " are to mean formula AlkC (O) O-monoradical, and wherein Alk is an alkyl.

Term " aryl carbonyl oxygen base " or " aryl carbonyl oxygen base group " or " aroyl oxygen base " or " aroyl oxygen base group " are to mean formula ArC (O) O-monoradical, and wherein Ar is an aryl.

Term " alkyl amino-carbonyl oxygen base " or " alkyl amino-carbonyl oxygen base group " are to mean formula R ²NC (O) O-monoradical, wherein each R is independent be hydrogen or low-carbon alkyl.

Term " alkoxycarbonyl amido " or " alkoxycarbonyl amido group " are to mean formula ROC (O) NH-monoradical, and wherein R is a low-carbon alkyl.

Term " alkyl carbonyl amino " or " alkyl carbonyl amino group " or " alkyl amido " or " alkyl amido group " are to mean formula AlkC (O) NH-monoradical, and wherein Alk is an alkyl.Alkyl carbonyl amino for example comprises kharophen (CH ₃C (O) NH-).

Term " alkyl amino-carbonyl oxygen base " or " alkyl amino-carbonyl oxygen base group " are to mean formula AlkNHC (O) O-monoradical, and wherein Alk is an alkyl.

Term " amino " or " amino group " are to mean-NH ₂Group.

Term " alkylamino " or " alkylamino group " are to mean formula (Alk) NH-monoradical, and wherein Alk is an alkyl.Alkylamino for example comprises methylamino-, ethylamino, third amino, butyl amino, tert-butyl amino etc.

Term " dialkylamino " or " dialkylamino group " are to mean (Alk) N-monoradical of formula (Alk), and wherein each Alk is alkyl independently.Dialkylamino for example comprises dimethylamino, methyl ethylamino, diethylin, dipropyl amino, ethyl third amino etc.

Term " amino that is substituted " or " amino group that is substituted " are to mean formula-NR ²Monoradical, wherein each R is independent of being selected from the substituting group (but wherein two R can not be hydrogen) of hydrogen or specified substituent.Substituting group for example comprises alkyl, alkyloyl, aryl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaralkyl etc.

Term " alkoxycarbonyl amido " or " alkoxycarbonyl amido group " are to mean formula AlkOC (O) NH-monoradical, and wherein Alk is an alkyl.

Term " urea groups " or " ureido groups " are to mean formula R ₂NC (O) NH-monoradical, wherein each R is hydrogen or alkyl independently.

Term " halogen " or " halogen group " are to mean fluorine, chlorine, bromine or iodine.

" halo " speech is that the one or more hydrogen atoms that mean this group are replaced by halogen group.

Term " alkylhalide group " or " alkylhalide group group " are to mean side chain or straight chain saturated aliphatic hydrocarbon monoradical, and each is replaced wherein one or more hydrogen atoms by halogen atom independently.This term is to be example with the following groups, as chloromethyl, 1, and 2-two bromotrifluoromethanes, 1,1,1-trifluoro propyl, 2-iodine butyl, 1-chloro-2-bromo-3-fluorine amyl group etc.

Term " sulfenyl ", " sulfenyl group ", " thioether " or " thioether group group " are to mean formula-S-divalent group.

Term " alkylthio " or " alkylthio group " are to mean formula AlkS-monoradical, and wherein Alk is an alkyl.Group for example comprise methylthio group, ethylmercapto group, just-rosickyite base, iprotiazem base, just-butylthio etc.

Term " artyl sulfo " or " artyl sulfo group " are to mean formula ArS-monoradical, and wherein Ar is an aryl.

Term " sulfinyl ", " sulfinyl group ", " sulfinyl " or " sulfinyl group " are to mean formula-SO-divalent group.

Term " alkylsulfonyl " or " alkylsulfonyl group " are to mean formula-SO ₂-divalent group.

Term " sulfuryl amino " or " sulfuryl amino group " are to mean formula-SO ₂The NR-divalent group, wherein R is hydrogen or substituting group.

Term " amino-sulfonyl " or " amino-sulfonyl group " are to mean formula NR ²SO ₂-monoradical, wherein R is hydrogen or substituting group independently respectively.

Term " carbocyclic ring " or " carbocyclic ring family group " are to mean to stablize aliphatic 3-to 15-member monocycle shape or polycyclic unit price or divalent group, only constitute by carbon and hydrogen atom, the ring that it can comprise one or more condensed or bridge joint is preferably 5-to 7-member monocycle shape or 7-to 10-member double-ring ring.Unless otherwise, otherwise carbocyclic ring can connect at any carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.This term comprises cycloalkyl (comprising spiro cycloalkyl group), cycloalkylidene, cycloalkenyl group, inferior cycloalkenyl group, cycloalkynyl radical and inferior cycloalkynyl radical etc.

Term " cycloalkyl " or " naphthene group " are to mean saturated 3-to 15-member monocycle shape or the polycyclic monoradical of stable aliphatic series, it only is made up of carbon and hydrogen atom, the ring that it can comprise one or more condensed or bridge joint is preferably 5-to 7-member's monocycle shape or 7-to 10-member's double-ring ring.Unless otherwise, otherwise cycloalkyl ring can connect at any carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.Cycloalkyl for example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, norborneol alkyl, golden steel alkyl, tetralyl (tetraline), 1-decahydro naphthyl, dicyclo also [2.2.2] octyl, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc.

Term " cycloalkenyl group " or " cycloalkenyl groups " are to mean to stablize aliphatic 3-to 15-member monocycle shape or polycyclic monoradical, it has at least one carbon-to-carbon double bond and only is made up of carbon and hydrogen atom, the ring that it can comprise one or more condensed or bridge joint is preferably 5-to 7-member monocycle shape or 7-to 10-member double-ring ring.Unless otherwise, otherwise the cyclenes basic ring can connect at any carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.Cycloalkenyl group for example comprises cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclonoene base, cyclodecene base, norbornene, 2-methyl cyclopentene base, 2-methyl cyclooctene base etc.

Term " cycloalkynyl radical " or " cycloalkynyl radical group " are to mean to stablize aliphatic 8-to 15-member monocycle shape or polycyclic monoradical, it has at least one carbon-to-carbon triple bond and only is made up of carbon and hydrogen atom, it can comprise one or more condensing or the ring of bridge joint, is preferably 8-to 10-member monocycle shape or 12-to 15-member double-ring ring.Unless otherwise, otherwise the cycloalkyne basic ring can connect at any carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.Cycloalkynyl radical for example comprises, cyclooctyne base, cyclonoyne base, cyclodecyne base, 2-methyl cyclooctyne base etc.

Term " cycloalkylidene " or " cycloalkylidene group " are to mean to stablize radical of saturated aliphatic 3-to 15-member monocycle shape or polycyclic divalent group, it only is made up of carbon and hydrogen atom, the ring that it can comprise one or more condensed or bridge joint is preferably 5-to 7-member monocycle shape or 7-to 10-member double-ring ring.Unless otherwise, otherwise cycloalkyl ring can connect at any carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.Cycloalkylidene for example comprises cyclopentylidene etc.

Term " inferior cycloalkenyl group " or " inferior cycloalkenyl groups " are to mean stable aliphatic 5-to 15-member monocycle shape or polycyclic divalent group, have at least one carbon-to-carbon double bond and only form by carbon and hydrogen atom, the ring that it can comprise one or more condensed or bridge joint is preferably 5-to 7-member monocycle shape or 7-to 10-member double-ring ring.Unless otherwise, otherwise inferior cyclenes basic ring can connect at any carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.Inferior cycloalkenyl group for example comprises cyclopentenylidene, phenylidene, inferior cycloheptenyl, inferior cyclooctene base, inferior cyclonoene base, inferior cyclodecene base, inferior norbornene, 2-methyl cyclopentenylidene, the inferior cyclooctene base of 2-methyl etc.

Term " inferior cycloalkynyl radical " or " inferior cycloalkynyl radical group " are to mean stable aliphatic 8-to 15-member monocycle shape or polycyclic divalent group, have at least one carbon-to-carbon triple bond and only constitute by carbon and hydrogen atom, the ring that it can comprise one or more condensed or bridge joint is preferably 8-to 10-member monocycle shape or 12-to 15-member double-ring ring.Unless otherwise, otherwise inferior cycloalkyne basic ring can connect at any carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.Inferior cycloalkynyl radical for example comprises inferior cyclooctyne base, inferior cyclonoyne base, inferior cyclodecyne base, the inferior cyclooctyne base of 2-methyl etc.

Term " aryl " or " aromatic yl group " are aromatic carbocyclic shape unit price or the divalent groups that means 6 to 14 carbon atoms, have monocycle (for example phenyl or phenylene) or multiple condensed ring (for example naphthyl or anthryl).Unless otherwise, otherwise aryl rings can connect at any suitable carbon atom place that causes rock steady structure, and if be substituted, then can be substituted at any suitable carbon atom place of rock steady structure that causes.Aryl for example comprises phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, xenyl etc.It can be abbreviated as " Ar ".

Term " heteroaryl " or " heteroaryl groups " are to mean to stablize aromatics 5-to 14-member monocycle shape or polycyclic unit price or divalent group, it can comprise the ring of one or more condensed or bridge joint, be preferably 5-to 7-member monocycle shape or 7-to 10-member bicyclic radicals, in ring, has one to four heteroatoms, independently be selected from nitrogen, oxygen and sulphur, wherein any sulfur heteroatom can be oxidized according to circumstances, and any nitrogen heteroatom can be oxidized according to circumstances or quaternized.Unless otherwise, otherwise heteroaryl ring can connect at any suitable heteroatoms that causes rock steady structure or carbon atom place, and if be substituted, then can be substituted at any suitable heteroatoms of rock steady structure or carbon atom place of causing.For example and preferred heteroaryl comprise furyl, thienyl, pyrryl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, the indolizine base, azepine indolizine base, indyl, azaindolyl, the diaza indyl, indolinyl, the dihydro azaindolyl, pseudoindoyl, the azepine pseudoindoyl, benzofuryl, the furo pyridyl, the furo pyrimidyl, the furo pyrazinyl, the furo pyridazinyl, dihydro benzo furyl, dihydrofuran and pyridyl, dihydrofuran and pyrimidyl, benzothienyl, the thienopyridine base, the Thienopyrimidine base, the thieno-pyrazinyl, the thieno-pyridazinyl, the dihydrobenzo thienyl, dihydro-thiophene and pyridyl, the dihydrothieno pyrimidines base, indazolyl, the azaindazole base, the diaza indazolyl, benzimidazolyl-, imidazopyridyl, benzothiazolyl, thiazole and pyridyl, thiazole and pyrimidyl benzoxazolyl oxazole and pyridyl oxazole and pyrimidyl, the benzoisoxazole base, purine radicals, chromanyl, the azepine chromanyl, quinolizinyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, the dihydro-isoquinoline base, tetrahydro isoquinolyl, the cinnolines base, azepine cinnolines base, 2, the 3-phthalazinyl, azepine 2, the 3-phthalazinyl, quinazolyl, azepine azoles quinoline base, quinoxalinyl, the azepine quinoxalinyl, 1, the 5-phthalazinyl, dihydro 1, the 5-phthalazinyl, tetrahydrochysene 1, the 5-phthalazinyl, pteridine radicals, carbazyl, acridyl, phenazinyl, phenothiazinyl phenoxazinyl, benzo [1,3] dioxane, dihydrobenzo imidazolone etc.

Term " heterocycle ", " heterocyclic group ", " heterocyclic radical " or " heterocyclic radical group " are to mean to stablize non-aromatics 5-to 14-member monocycle shape or polycyclic, unit price or divalence ring, it can comprise the ring of one or more condensed or bridge joint, be preferably 5-to 7-member monocycle shape or 7-to 10-member double-ring ring, in ring, has one to three heteroatoms, it is independently selected from nitrogen, oxygen and sulphur, wherein any sulfur heteroatom can be oxidized according to circumstances, and any nitrogen heteroatom can be oxidized according to circumstances or quaternized.Unless otherwise, otherwise heterocyclic ring can connect at any suitable heteroatoms that causes rock steady structure or carbon atom place, and if be substituted, then can be substituted at any suitable heteroatoms of rock steady structure or carbon atom place of causing.For example and preferred heterocycle comprise pyrrolinyl, pyrrolidyl, pyrazolinyl, pyrazolidyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, THP trtrahydropyranyl, tetrahydrochysene sulfo-pyranyl, tetrahydrofuran base, hexahydropyrimidine base, hexahydro-pyridazine base etc.

" The compounds of this invention " speech and suitable expression are to be intended to comprise formula (I) compound as described herein, comprise its tautomer, prodrug, salt, particularly pharmacy acceptable salt with solvate and hydrate, is so to allow in this article.Usually and preferred, The compounds of this invention and the chemical formula of censuring The compounds of this invention should be understood and only comprise its stable compound, and get rid of its unstable compound, are comprised by the compound chemistry formula even unstable compound may be considered to literal going up.Similarly, to the denotion of intermediate, no matter whether itself asks patent right, is to be intended to comprise its salt and solvate, is in this article so to allow.For clarity sake, specific illustration so allows in literary composition, be illustrated in herein sometimes, but these illustrations is illustrative only when so allowing in the literary composition, and does not really want to get rid of other illustrations.

Term " is selected for use " or " according to circumstances " is to mean described subsequently incident or situation can maybe cannot take place, and this description is to comprise the situation that this incident or situation wherein take place, and wherein nonevent situation.For example, " aryl of Qu Daiing according to circumstances " is to mean aryl can maybe cannot replace, and expository writing is to comprise the aryl that is substituted and do not have substituent aryl.

Term " stable compound " or " rock steady structure " are to mean compound sufficient intensity to be arranged with by preserving in the reaction mixture, are separated to useful purity, and can be mixed with effective treatment or diagnostic preparation.For example, have " unsettled valence link " or be not the compound that is included in the present invention for the compound of carboanion.

" be substituted " speech and be any or a plurality of hydrogen that mean on an atom of group or part group, no matter whether specify, be selected from the indicated group replacement of substituting group, its condition is that normal valency and this replacement that can not surpass this atom not cause stable compound.If to a substituent bond is to be shown the bond of crossing two atoms in the shack, then this kind substituting group can be bonded to any atom on the ring.When the substituting group that lists, do not indicate this kind substituting group to be bonded to the atomic time that rest part passed through of compound, then this substituting group can be by any atom combination in this substituting group.For example, when substituting group is piperazinyl, piperidyl or tetrazyl, unless otherwise specified, otherwise this kind piperazinyl, piperidyl or tetrazyl can pass through any atom in this piperazinyl, piperidyl or tetrazyl, and are bonded to the rest part of The compounds of this invention.Generally speaking, when any substituting group or group occurred surpassing one time in any composition or compound, it was irrelevant with its definition under each other situation in the definition under each situation.Therefore, for example, if show that a kind of group is by 0 to 2 R ⁵Group replaces, and then this group is according to circumstances by paramount two R ⁵Group replaces, and R ⁵Be independently to be selected from possibility R under each situation ⁵Definition tabulation.But this combination of substituting group and/or parameter only causes under the stable compound in this kind combination just to allow.

In particular embodiment, the term of " pact " or " approximately " be mean given numerical value or scope 20% in, be preferably in 10%, and be more preferred from 5%.

The productive rate of described herein each reaction is to represent with the per-cent of theoretical yield.

B. salt, prodrug, derivative and solvate term and usage

Term " prodrug " or " prodrug derivatives " are to mean it before showing its pharmacotoxicological effect, stand the parent compound of certain biotransformation at least or active drug substance with covalent manner bonded derivative or supporting agent.Generally speaking, but this kind prodrug has the split-off group of metabolic way, and in vivo changes rapidly, to produce parent compound, for example passes through the hydrolytic action in the blood, and generally comprises the ester class and the amide analogue of parent compound.Prodrug be the prescription (for example hydrogen solubleness of Zeng Jiaing) of organ selectivity, improvement of action period, the improvement of bioavailability, prolongation and/or minimizing with patient's admissibility of chemical stability, the improvement of improvement and adaptability, improvement side effect (for example toxicity) purpose and prepare.Usually, prodrug itself has faint or does not have biologic activity, and under general condition is stable.Prodrug can use method known in the state of the art, easily by parent compound preparation, and as following described, The textbook of medicinal design and development, Krogsgaard-Larsen and H.Bundgaard (writing), Gordon ﹠amp; Breach, 1991, the 5th chapter particularly: " design of prodrug and application "; The design of prodrug, H.Bundgaard (writing), Elsevier, 1985; The precursor medicine Thing: local and eyes drug delivery, K.B.Sloan (writing), Marcel Dekker, 1998; Enzymology method, people such as K.Widder (writing), the 42nd volume, Science Press, 1985,309-396 page or leaf particularly; BurgerShi pharmaceutical chemistry and drug discovery, the 5th edition, M.Wolff (writing), John Wiley ﹠amp; Sons, 1995, particularly the 1st roll up and 172-178 page or leaf and 949-982 page or leaf; As novel transmission system Prodrug, T.Higuchi and V.Stella (writing), Am.Chem.Soc., 1975; In medicinal design Biological reversible supporting agent, E.B.Roche (writing), Elsevier, 1987, its each part all is incorporated herein for reference with it in full.

In " pharmaceutically acceptable prodrug " used herein speech is the prodrug that means The compounds of this invention, it is in the scope that safe and reliable pharmacy is judged, be applicable to human and zootic tissue and contact, and toxicity, pungency, supersensitivity are not replied etc. improperly, be accompanied by rational interests/risk ratio, and effective, and under possible situation zwitterionic form for the purposes that it was intended to.

" salt " speech is the ionic species that means parent compound, or parent compound and suitable acid or the reaction product between alkali, to make the acid-salt or the alkali salt of parent compound.The salt of The compounds of this invention can be synthesized by the parent compound that contains alkalescence or acidic moiety group by commonly using chemical process.Usually, salt be by parent compound and the stoichiometry that makes free state alkali or acid or with excessive inorganic or organic acid or the alkali that forms the salt of wanting, in appropriate solvent or all kinds of SOLVENTS composition, react and make.

" pharmacy acceptable salt " speech, be the salt that means The compounds of this invention, it is in the scope of safe and reliable medical judgment and is applicable to human and zootic tissue and contacts, toxicity, pungency, supersensitivity are replied etc. improperly and do not have, be accompanied by rational interests/risk ratio, be generally the solubility or the dispersibility of water or oil, and effective for its desired purposes.This term comprises pharmaceutically-acceptable acid addition and pharmaceutically acceptable base addition salt.Can free state alkali and salt form when using when The compounds of this invention, in practicality, the use of this salt form is the use that is equivalent to this alkali form.Suitably the catalogue of salt for example can be consulted people such as S.M.Birge, J.Pharm.Sci., and 1977, 66, the 1-19 page or leaf, it is for reference that it lists in this paper at this in full with it.

" pharmaceutically-acceptable acid addition " speech is to mean the biological effectiveness of maintenance free state alkali and the salt of character, and it biologically or is not on the contrary being expected, form with inorganic acids, such as hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, thionamic acid, nitric acid, phosphoric acid etc., and and organic acid formation, such as acetic acid, Tricholroacetic Acid, trifluoracetic acid, hexanodioic acid, alginic acid, xitix, aspartic acid, Phenylsulfonic acid, phenylformic acid, the 2-acetoxy-benzoic acid, butyric acid, dextrocamphoric acid, the horizontal acid of camphor, styracin, citric acid, glucosulfone acid, ethane sulfonic acid, L-glutamic acid, oxyacetic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, toxilic acid, hydroxymaleic acid, oxysuccinic acid, propanedioic acid, phenylglycollic acid, 1,3,5-trimethylbenzene sulfonic acid, methanesulfonic, naphthene sulfonic acid, nicotinic acid, the 2-naphthene sulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenyl acetic acid, the 3-phenylpropionic acid, picric acid, trimethylacetic acid, propionic acid, pyruvic acid, Whitfield's ointment, stearic acid, succsinic acid, Sulphanilic Acid, tartrate, right-toluenesulphonic acids, undecanoic acid etc.

" pharmaceutically acceptable base addition salt " speech is to mean the biological effectiveness of maintenance free state acid and the salt of character, and it biologically or is not on the contrary being expected, form with inorganic base, oxyhydroxide, carbonate or the hydrocarbonate of for example ammonia, or ammonium or metallic cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminium etc.Special good is ammonium, potassium, sodium, calcium, reaches magnesium salts.By pharmaceutically acceptable organic nontoxic alkali deutero-salt, comprise following salt, primary, the second month in a season and tertiary amines, quaternary ammonium compound, the amine that replaces, comprise the naturally occurring amine that is substituted, cyclic amine and deacidite, such as methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, Isopropylamine, tripropyl amine, Tributylamine, thanomin, diethanolamine, the 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, Methionin, arginine, Histidine, trimethyl-xanthine, Hai Baming, choline, trimethyl-glycine, quadrol, glucosamine, methyl glucoside amine, Theobromine, purine, piperazine, piperidines, N-ethylpiperidine, the tetramethyl-ammonium compound, the tetraethyl ammonium compound, pyridine, N, the N-xylidene(s), the N-methyl piperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N, N-dibenzyl phenylethylamine, the 1-ephenamine, N, N '-dibenzyl-ethylenediamin, versamid 900 etc.Special good organic nontoxic alkali is Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexylamine, choline and caffeine.

" solvate " speech is the physics association that means compound and a kind of or a plurality of solvent molecules, or for example water, ethanol or acetic acid form various stoichiometric mixtures with solvent by solute (for example formula (I) compound).This kind physics association can relate to ionic and covalent linkage knot in various degree, comprises hydrogen bond.In some cases, solvate can separate, for example when one or more solvent molecule is incorporated in the lattice of crystalline solid.Generally speaking, selected solvent can not disturb the biologic activity of solute.Solvate comprises solution and separable solvate.The representative solvents compound comprises hydrate, ethylate, methylate etc.

" hydrate " speech is to mean wherein that solvent molecule is H ₂The solvate of O.

The compounds of this invention as discussed below, comprise its free state alkali or acid, its salt, solvate and prodrug, and in its structure, can comprise sulphur atom or quaternised nitrogen-atoms through oxidation, though not statement or demonstration clearly, particularly pharmaceutically acceptable form.This kind form, particularly pharmaceutically acceptable form is to be intended to be comprised by appending claims.

C. isomer term and usage

" isomer " speech is to mean to have same atoms number and kind, and is the same molecular amount therefore, but about arrangement or the configuration different compound of atom in the space.This term comprises steric isomer and geometrical isomer.

The term of " steric isomer " or " optical isomer " is to mean desmotrope, it has at least one chiral atom or restricted rotation, and cause vertical unsymmetrical plan (for example some biphenyl class, propadiene class and spiro-compounds), and can make the plane polarized light rotation.Because asymmetric center and other chemical structures are present in the compound of the present invention, it can cause steric isomerism, so the present invention will comprise its steric isomer and composition thereof.The compounds of this invention and salt thereof comprise unsymmetrical carbon, and therefore can be with single stereoisomers, racemic modification, and exist with the mixture of enantiomer and diastereomer.Usually, this compound is made racemic mixture.But if need, then this compound can be produced or be separated into pure steric isomer, promptly becomes indivedual enantiomers or diastereomer, or becomes the mixture that is rich in steric isomer.As discussing in more detail hereinafter, indivedual steric isomers of compound are to make in the following manner, by synthetic from containing the optical activity initial substance of wanting the mapping center to some extent, or by preparation enantiomerism mixture of products, then separate or resolve, as change into the mixture of diastereomer, then use mapping parsing agent to separate or recrystallize, chromatographic technique, or on the mapping chromatography column, directly separate enantiomer.Specific stereochemical initial compounds is no matter to be got by commercial, or makes by method hereinafter described, and resolves by technology known in the prior art.

" enantiomer " speech is to mean a pair of steric isomer that can not the eclipsed mirror image of being each other.

The term of " diastereoisomer " or " diastereomer " is the optical isomer that means not to each other mirror image.

The term of " racemic mixture " or " racemoid " is the mixture that means the indivedual enantiomers that contain moiety.

" non-racemic mixture " speech is the mixture that means the indivedual enantiomers that contain unequal part.

" geometrical isomer " speech is to mean desmotrope, it is because around two keys (for example cis-2-butene and trans-2-butene) or in ring texture (cis-1 for example, 3-dichloro tetramethylene and anti-form-1,3-dichloro tetramethylene) in, the result that restricted rotary freedom caused.Because two (alkene) keys of carbon-to-carbon, the two keys of C=N, ring texture etc. can be present in the The compounds of this invention, so the present invention will comprise owing to arrange each different stable geometrical isomer that is caused and composition thereof around these pairs key and the substituting group in these ring texturees.Suitable/anti-usage that substituting group and isomer are to use, or use E or Z system representation, wherein " E " speech is to mean the higher order substituting group of this pair key on opposition side, and " Z " speech is to mean the higher order substituting group of this pair key on the same side.Discussing fully of E and Z isomery is provided in J.March, Advanced Organic Chemistry: reaction, mechanism and structure, the 4th edition, John Wiley ﹠amp; Sons, in 1992, it is for reference that it lists this paper in full with it.Several following embodiment are expression single E isomer, single Z isomer and E/Z mixture of isomers.The mensuration of E and Z isomer can be undertaken by analytical procedure, as the x-radiocrystallgraphy, ¹H NMR reaches ¹³C NMR.

Compounds more of the present invention can exist with more than one tautomeric forms.As indicated above, compound of the present invention comprises all these tautomers.

Known in the prior art, the biology of compound and pharmacological activity are very sensitive to the stereochemistry of compound.Therefore, for example, enantiomer is often showed significantly different biologic activity, comprise the difference on the pharmacokinetic property, comprise metabolism, protein bound etc., with the difference on the pharmacological property, comprise shown active type, activity, toxic degree etc.Therefore, know present technique what will understand is when a kind of enantiomer is rich in respect to another kind of enantiomer, or when with another kind of stage enantiomer separation, can has more activity and maybe can show advantageous effect.In addition, know the knowledge how to know of present technique, separation, enrichment or optionally prepare the enantiomer of The compounds of this invention from this disclosure and prior art.

Therefore, though can use the racemic form of medicine, it is often than throwing the less validity of medicine of giving the equivalent enantiomer-pure; In fact, in some cases, a kind of enantiomer can be inertia on the pharmacology, and only just uses simple and easy thinner as.For example, though Ibuprofen BP/EP (ibuprofen) was before offerd medicine with racemoid, but confirmed that having only the S-isomer of Ibuprofen BP/EP is effectively as antiphlogistic (still, under the Ibuprofen BP/EP situation, though the R-isomer is an inert, but it is to be converted to the S-isomer in vivo, and therefore, the rapid property of the effect of the racemic form of this medicine is lower than pure S-isomer).Moreover the pharmacological activity of enantiomer can have different biologic activity.For example, the S-Trolovol is the therapeutical agent that is used for chronic arthritis, and the R-Trolovol is toxic.In fact, some purified enantiomers have the advantage better than racemoid, as what reported, compare with racemic mixture, and purified individual isomers has faster through the skin transmission rate.Consult United States Patent (USP) 5,114,946 and 4,818,541.

Therefore, if a kind of enantiomer is having more activity, hypotoxicity or have preferred disposal in health more than another kind of enantiomer on the pharmacology, then preferential throw give this enantiomer will be for more favourable in the treatment.Therefore, the patient who receives treatment is the medicine that is exposed to low total dose, and is exposed to the possible poisonous of low dosage or is the enantiomer of the inhibitor of another kind of enantiomer.

Pure enantiomer or the mixture of the enantiomer of wanting excessive (ee) or the preparation of enantiomeric purity, be to finish, know separation or parsing or (b) synthetic or its combination of enantioselectivity of known (a) enantiomer of present technique by one or more of following many methods.These analytic methods generally are to rely in the chirality identification, and comprise synthetic, the dynamic analysis or the effect of spontaneous enantioselectivity crystallization that enzyme is urged urges with non-enzyme of the chromatography that for example uses chiral stationary phase, enantioselectivity host-parasitic are compound, use chiral adjuvant parsing or synthetic, enantioselectivity.This method is to be disclosed in hand prevailingly Property isolation technique: practical approach(the 2nd edition), G.Subramanian (writing), Wiley-VCH, 2000; T.E.Beesley and R.P.W.Scott, The chirality chromatography, John Wiley ﹠amp; Sons, 1999; And SatinderAhuja, Chiral separation by chromatography, Am.Chem.Soc., 2000.Moreover excessive or purity quantitatively has a method of knowing equally for enantiomer, for example GC, HPLC, CE or NMR, and for the appointment of absolute configuration and conformation, for example CD ORD, X-radiocrystallgraphy or NMR.

Generally, all tautomeric forms of chemical structure or compound and isomeric form and mixture, no matter be indivedual geometrical isomers or steric isomer or racemize or non-racemic mixture, all be desired, unless in compound title or structure, indicate specific stereochemistry or isomeric form clearly.

D. administration of medication and diagnosis and treatment term and usage

" patient " speech comprises human and inhuman Mammals.

" significant quantity " speech is the amount that means according to The compounds of this invention, and in its environment that is given or use by throwing, it is to be enough to reach desired effect or result.According to this paper, significant quantity one speech can comprise or go up the significant quantity synonym with significant quantity pharmaceutically or diagnosis.

Term " pharmaceutically significant quantity " or " significant quantity in the treatment " are the amounts that means according to The compounds of this invention, when it is given the patient who needs by throwing, be enough to reach this compound it is had effective treatment of morbid state, symptom or the illness of usability.This kind amount is that the tissue, whole body or the patient's that are enough to cause that researchist or clinician are looked for biology or pharmacy replied.Constitute treatment go up significant quantity according to the The compounds of this invention amount, be to change according to some factors, as the discharge rate of compound and biologic activity thereof, the composition that is used to offer medicine, dispensing time, dosing way, compound, treatment perdurability, the type of treat morbid state or illness and seriousness thereof, with the The compounds of this invention combination or the medicine of use simultaneously, reach patient's age, body weight, general health state, sex and diet.Significant quantity can be made decision with its own knowledge, prior art and this disclosure by generally knowing present technique as a rule in this kind treatment.

" significant quantity in the diagnosis " speech is the amount that means according to The compounds of this invention, when it is used in diagnostic method, device or detects, is to be enough to reach this diagnostic method, device or to detect the necessary diagnosis effect or the biologic activity of wanting wanted.This kind amount is to be enough to draw biology at diagnostic method, device or in detecting or medical science is replied, its can be included in the patient in vitro or the biology in intravital tissue or the system or medical science reply, it is looked for for researchist or clinical expert.Constitute diagnosis and go up the amount according to The compounds of this invention of significant quantity, be to change according to some factors, such as compound and biologic activity thereof, employed diagnostic method, device or detection, the composition that is used to offer medicine, dispensing time, dosing way, compound discharge rate, dispensing perdurability, with The compounds of this invention combination or the medicine and other compounds that use simultaneously, and if the object that the patient offers medicine for diagnosis, then patient's age, body weight, general health state, sex and diet.Significant quantity can determine with its own knowledge, prior art and present disclosure by generally knowing present technique person as a rule in this kind diagnosis.

" modulation " speech is to mean the ability that compound changes glucocorticoid receptor function, for example by being bonded to and stimulating or suppress glucocorticoid receptor function and reply.

In the literary composition of describing The compounds of this invention, " modulator " speech is the compound that means the modulation glucocorticoid receptor function.Therefore, modulator is to include but not limited to agonist, partial agonist, antagonist and partial antagonist.

In the literary composition of describing The compounds of this invention, " agonist " speech is to mean when being bonded to glucocorticoid receptor, can improve or increase the compound of glucocorticoid receptor function.Therefore, agonist comprises partial agonist and full agonist.

In the literary composition of describing The compounds of this invention, " full agonist " speech is to mean the compound that arouse is responded from the maximal stimulation of glucocorticoid receptor, even as the same when the glucocorticoid receptor of unnecessary (unoccupied) exists.

In the literary composition of describing The compounds of this invention, " partial agonist " speech is to mean to arouse the compound of replying from the maximal stimulation of glucocorticoid receptor, even as the same under the saturated concentration of the glucocorticoid receptor that is enough to make existence.

In the literary composition of describing The compounds of this invention, " antagonist " speech is the compound that means direct or indirect inhibition or oppressive glucocorticoid receptor function.Therefore, antagonist comprises partial antagonist and complete antagonist.

In the literary composition of describing The compounds of this invention, " antagonist fully " speech is to mean to arouse the compound of replying from the maximum inhibition of glucocorticoid receptor, even as the same when the glucocorticoid receptor of unnecessary (unoccupied) exists.

In the literary composition of describing The compounds of this invention, " partial antagonist " speech is to mean the maximum that can not arouse from glucocorticoid receptor to suppress the compound of replying, even as the same under the saturated concentration of the glucocorticoid receptor that is enough to make existence.

" treat " or the term of " treatment operation " is the treatment that means morbid state among the patient, and comprise:

(i) the preventing disease state takes place in the patient, particularly, when this patient is that heredity is gone up or other aspects are easy to suffer from this morbid state, but is not diagnosed as yet when having this disease;

(ii) suppress or improve the disease of patient state, promptly contain or its development of slowing down; Or

(iii) alleviate the disease of patient state, promptly cause the degeneration or the healing of this morbid state.

The general synthetic method of manufacturing formula (IA) compound

The present invention also provides the method for manufacturing formula (I) compound.In all are graphic, unless otherwise specified, otherwise the R in the chemical formula hereinafter ¹To R ⁵To have R in the invention described above formula (I) ¹To R ⁵Meaning.No matter the intermediate that uses in the preparation The compounds of this invention is commercial getting, or is easy to preparation by the known method of knowing present technique.

Optimum reaction conditions and reaction times can change according to employed specific reactants.Unless otherwise, otherwise solvent, temperature, pressure and other reaction conditionss can easily select by generally knowing present technique person.Specific program provides in the example of experiment.Usually, if need, the reaction progress can pass through thin layer chromatography (TLC) monitoring, and intermediate and product can pass through chromatography and/or pass through recrystallization and purifying on silica gel.

Formula (IA) compound can be by the method preparation of being summarized among the scheme I.

Formula (IA) compound, wherein R ⁴For-CH ₂-, can be by the method preparation of being summarized among the scheme I.

Scheme I

As shown in scheme I, make the intermediate of R ' wherein, with suitable reductive agent, as lithium aluminium hydride (LiAlH for formula (II) ester of Me or Et ₄), at appropriate solvent such as tetrahydrofuran (THF) (THF) or ether (Et ₂O) reduction in is with 1 of production (III), 2-glycol.Then, make this glycol and reagent, for example R ' SO ₂Cl (R '=methyl or right-tolyl), it will form and break away from basic L, with the primary alconol reaction of formula (III).Suitable disengaging base is for example sulphonate, and (IV, L is-SO as methane sulfonate or tosylate ₂CH ₃Or-SO ₂(right-tolyl)).Intermediate (IV) is separated or react with alkali such as salt of wormwood on the spot, to produce epoxide (V).Epoxide (V) and desired R ⁵The reaction of H provides desired formula (IA) product.Reaction can be passed through R ⁵H and epoxide (V) heat in appropriate solvent such as DME, or pass through R ⁵In solvent, the sodium ethylate in suitable alkali such as EtOH are arranged exists heating down to carry out to H with epoxide (V).

Formula (II) intermediate can be by method preparation known in the prior art.Two kinds of programs are shown among the scheme II.

Scheme II

For carrying out the R of Friedel-Crafts alkylating ¹Group can make to have CF ₃And wherein R ' is the pyruvate (VI) of Me or Et, and has R ²And will become R ³Olefin group (reaction of the bromo methyl alkene (VII) of=CH-R ") is in having manganese and lewis' acid such as zinc chloride to exist down, in appropriate solvent such as THF, with generation 2-hydroxy ester (VIII).R ¹Use this intermediate (VIII) to carry out the Friedel-Crafts alkylating, under the existence of suitable lewis' acid such as aluminum chloride, provide compound (II) (R ³=-CH ₂R ").Perhaps, can carry out to have CF ₃Pyruvate (VI) and have R ¹, R ²And R ³The Grignard reaction of magnesium ethide halogenide (IX), so that desired formula (II) intermediate to be provided.

R wherein ⁴For-C (O)-compound can as shown in scheme III, easily prepare by intermediate (II).

Scheme III

As shown in scheme III, the hydrolytic action of intermediate (II), for example by with aqueous bases such as potassium hydroxide, reflux with suitable cosolvent such as methyl alcohol, so that carboxylic acid (X) to be provided.Formed carboxylic acid (X) can with R ⁵H, coupling under the standard coupling condition of in present technique, knowing (consult, M.Bodanszky for example, Peptide The synthetic practice(Springer-Verlag:1984) its to list in this paper in full with it for reference).For example, can make carboxylic acid (X) and R ⁵H is by with 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (EDC), then handle, in appropriate solvent such as DMF and carry out coupling with I-hydroxybenzotriazole hydrate (HOBT).

Formula (IB) compound can be by the method preparation of being summarized among the scheme IV

(a) formula (IA) compound and suitable alkali are reacted in appropriate solvent, to form the ketone of formula (IIB)

For the more abundant quilt of the present invention is understood, so propose following embodiment.These embodiment are for reaching the purpose of explanation embodiment of the present invention, rather than be interpreted as by any way limiting the scope of the invention, and present technique person understands as knowing, and particular agent or condition can be revised on demand at individual compound.Employed initial substance or for commercial getting, or easily by knowing present technique person's system from the commercial material that gets.

Experimental embodiment

Embodiment 1:2-(2,6-thebaine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol hydrochloride synthetic

In 40 milliliters of THF, in the mixture through being warmed to backflow, add 200 microlitres (2 mmole) 1-bromo-2-methacrylic at 8.5 gram (49.9 mmole) trifluoromethyl Pyruvic Acid Ethyl esters, 6.6 gram (120 mmole) manganese and 0.65 gram (4.8 mmole) zinc chloride.After 30 minutes, during 1 hour in, drip 9.13 milliliters of (90.5 mmole) 1-bromo-2-methacrylics among 30 milliliters of THF.After the interpolation, mixture was refluxed 1 hour, be cooled to 0 ℃ then, and with 150 milliliters of saturated aqueous ammonium chlorides and 100 milliliters of vinyl acetic monomers (EtOAc) dilution.Separate organic phase, and with three parts of 100 milliliters of EtOAc aqueous layer extracted.With the organic layer that merges with two parts of 50 milliliters of saturated aqueous ammonium chlorides, then with two part of 50 mL of saline washing, with sal epsom (MgSO ₄) dehydrate, filter, and concentrate in a vacuum.Make rough residue with the silica gel column chromatography purifying,, and get 5.9 gram (52%) 2-hydroxy-4-methyl-2-trifluoromethyl penta-obtusilic acid ethyl esters with EtOAc-hexane (5: 95) wash-out.

In the above 2-hydroxy-4-methyl-mixture of 2-trifluoromethyl penta-obtusilic acid ethyl ester in 30 milliliters of fluorine-based methyl-phenoxides of 4-of 5.9 grams (26.1 mmole), add 5.2 gram (39.4 mmole) aluminum chloride with several parts.When adding for the first time, mixture becomes heat release, and is transformed into black, and cools off with ice-water bath.Mixture was stirred 3 days, pour into then in 200 milliliters of ice-cold 1N HCl aqueous solution, and with three parts of 150 milliliters of EtOAc extractions.With 50 milliliters of 1N aqueous hydrochloric acids, three part of 50 mL of saline washing dehydrates with sal epsom, filters, and concentrates in a vacuum with the organic layer that merges.Make rough residue with the silica gel chromatography purifying,, and get 6.6 gram (71%) 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl Valeric acid ethylesters with EtOAc-hexane (1: 9,2: 8 then, follow 3: 7,4: 6 then) wash-out.

In the 4-in 100 milliliters of anhydrous THF (5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl Valeric acid ethylester (10.07 gram), under 0-5 ℃, portion-wise addition 1.3 gram lithium aluminium hydride.Make mixture slowly be warmed to room temperature, and stirred two days.Make the reaction cancellation with 1.3 ml waters, 1.3 milliliters of 15%NaOH aqueous solution and 3.9 ml waters.Make mixture through diatomite filtration, with the ether dilution, Yi Shui, salt water washing, and dehydrate with sal epsom.In vacuum, remove volatile matter.With product 4-(5-fluoro-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl pentane-1, the 2-glycol further carries out, and need not to be further purified.

At 4-(5-fluoro-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl pentane-1,2-glycol (8.15 gram) and pyridine (21.2 milliliters) are at 50 milliliters of methylene dichloride (CH ₂Cl ₂) in solution in, under 0 ℃-5 ℃, drip methane sulfonyl chloride (2.63 milliliters).Make mixture be warmed to room temperature, stirring is spent the night, and adds methyl alcohol (80 milliliters) and K ₂CO ₃(36.2 gram).Mixture was stirred 4 hours,,, and dehydrate with sal epsom with water, rare HCl and salt water washing with the ether dilution.Remove volatile matter in vacuum, residue is provided, make it by hurried formula silica gel column chromatography purifying, the 5%EtOAc in the use hexane is as eluent.The wash-out part of product is rich in collection, and removes volatile matter in vacuum, and 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl is provided]-2-trifluoromethyl oxyethane.

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (0.219 gram) and the mixture of 2-6-thebaine (0.26 milliliter) in 2 milliliters of dry DMF, heated 2 hours down in 100 ℃, be cooled to room temperature, dilute with ether, Yi Shui and salt water washing, and dehydrate with sal epsom.Remove volatile matter in a vacuum, a kind of oil is provided, it is dissolved in about 15 milliliters of ether, and add the HCl in the diox.In vacuum, remove volatile matter, and formed solid is developed with ether, and dry in a vacuum, obtain title compound, 133 ℃-135 ℃ of fusing points.

Embodiment 2:2-(2,3-dihydrobenzo [1,4] oxazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol hydrochloride synthetic

Make 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (consulting embodiment 1) (0.139 gram) and 3,4-dihydro-2H-benzo [1, the mixture of 4] oxazines (0.76 gram) is dissolved in about 5 milliliters of methylene dichloride, and adds 0.55 gram hurried formula silica gel (flash silicagel).In vacuum, remove volatile matter, and make residue, and be applied on the hurried formula silicagel column 150 ℃ of following microwave treatment 60 seconds.With EtOAc-hexane (1: 10) wash-out, and in vacuum, concentrate the wash-out part that is rich in product, residue is provided, it is dissolved in the ether.Add the HCl in the diox.In vacuum, remove volatile matter, and with ether development residue.Make formed solid dry in a vacuum, provide title compound, 98 ℃-99 ℃ of fusing points.

Embodiment 3:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

Make 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (consulting embodiment 1) (0.21 gram) and 4-hydroxyquinoline (0.105 gram) and the mixture of sodium ethylate (21 weight % in EtOH) in 4 milliliters of anhydrous EtOH, heated 6 hours down in 85 ℃, be cooled to room temperature, with EtOAc and acetic acid dilution, Yi Shui and salt water washing, and dehydrate with sal epsom.In vacuum, remove volatile matter, a kind of residue is provided, make it, use EtOAc as eluent with hurried formula silica gel purification.In vacuum, concentrate the wash-out part that is rich in product, provide title compound, 170 ℃-172 ℃ of fusing points.

Embodiment 4:2-(3,4-dihydro-2H-quinoxaline-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol synthetic

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (consulting embodiment 1) (54.4 milligrams) and the solution of tetrahydroquinoxaline (124.8 milligrams) in DMF (0.6 milliliter), heated 6 hours down in 100 ℃.Formed mixture is diluted with ether,, dehydrate, filter, and concentrate in a vacuum with sodium sulfate with water and saturated sodium-chloride water solution washing.Make the TLC purifying (with 25% ether-benzene wash-out) of residue, and get title compound, be clean oil (31.2 milligrams) by preparing.

Embodiment 5:1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dihydro-2H-quinoxaline-1-ylmethyl) pentane-2-alcohol synthetic

In 2-(3,4-dihydro-2H-quinoxaline-1-ylmethyl)-1,1, in 1-three fluoro-4-(5-fluoro-2-the methoxyphenyl)-solution of 4-methylpentane-2-alcohol (embodiment 4) (18.6 milligrams) in acetonitrile (3 milliliters), add formaldehyde solution (the 37%w/w aqueous solution, 300 microlitres), then add sodium cyanoborohydride (13.8 milligrams).After following 30 minutes, add acetic acid (50.4 microlitre) in room temperature.Formed mixture was stirred 3 hours, make the reaction cancellation with saturated sodium bicarbonate aqueous solution, and with dichloromethane extraction three times.The organic phase of merging is dehydrated with sodium sulfate, filter, and in vacuum, remove volatile matter.Make the TLC purifying (with 25%EtOAc-hexane wash-out) of residue, and get title compound, be light yellow oil (16.6 milligrams) by preparing.

Embodiment 6:1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thiomorpholine-4-ylmethyl pentane-2-alcohol synthetic

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (consulting embodiment 1) (130 milligrams) and the solution of thiomorpholine (84.6 microlitre) in dimethyl formamide (1 milliliter), heated 15 hours down in 100 ℃.Formed mixture is diluted with ether,, dehydrate filtration with sodium sulfate, and in vacuum, remove volatile matter with water and saturated sodium-chloride water solution washing.Make residue pass through purification by silica gel column chromatography, use the 2%EtOAc-hexane as eluent.In vacuum, concentrate the wash-out part that is rich in product, title compound is provided, be clean oil (161 milligrams).

Embodiment 7:1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(synthesizing of 1-oxo-1 λ 4-thiomorpholine-4-ylmethyl pentane-2-alcohol

In 1,1, in 1-three fluoro-4-(5-fluoro-2-the methoxyphenyl)-4-methyl-2-thiomorpholine-solution of 4-ylmethyl pentane-2-alcohol (embodiment 6) (34 milligrams) in MeOH (1.5 milliliters), add the solution of sodium periodate (20 milligrams) in water (1.5 milliliters)., after following 21 hours another part sodium periodate (7 milligrams) is added in the incomplete reaction in room temperature.Formed mixture was stirred 15 hours, in vacuum, concentrate, with the water dilution, and with twice of extracted with diethyl ether.The organic phase that merges with the salt water washing, is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make residue pass through purification by silica gel column chromatography, with 50% to 70% vinyl acetic monomer-hexane wash-out, and title compound, be white solid (29 milligrams) 135 ℃-136 ℃ of fusing points.

Embodiment 8:2-(1,1-dioxo-λ ⁶-thiomorpholine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol synthetic

In 1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thiomorpholine-4-ylmethyl pentane-2-alcohol (embodiment 6) (65 milligrams) is at CH ₂Cl ₂In the solution in (2 milliliters), add the solution of hydrogen peroxide (the 30%w/w aqueous solution, 46.8 microlitres) in trifluoracetic acid (0.5 milliliter).Formed mixture was stirred 3.5 days, make the reaction cancellation with saturated sodium bicarbonate aqueous solution, and with twice of extracted with diethyl ether.The organic phase that merges is washed with saturated sodium-chloride water solution, dehydrate, filter, and concentrate in a vacuum with sal epsom.Make the TLC purifying (with 50% vinyl acetic monomer-hexane add 0.2% triethylamine wash-out) of residue, and get title compound, be clean oil (13.1 milligrams) by preparing.

Embodiment 9:2-(2,3-dihydrobenzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol synthetic

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (118 milligrams) and 3,4-dihydro-2H-1, the 4-benzothiazine (people such as H.I.El-Subbagh, Arch.Pharm.Med.Chem., 1999, 332, the 19-24 page or leaf) and (122 milligrams) solution in dimethyl formamide (1 milliliter), heated 73 hours down in 140 ℃.Formed mixture is diluted with ether,, dehydrate, filter, and concentrate in a vacuum with sal epsom with saturated sodium bicarbonate aqueous solution, water and salt water washing.Make residue carry out purifying (with 0 to 1% vinyl acetic monomer-hexane wash-out) by the radial chromatography that uses chromatography disk (chromatotron), and title compound, be white solid (53.5 milligrams) 103 ℃-104 ℃ of fusing points.

Embodiment 10:2-(3,5-lupetazin-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol synthetic

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (98.7 milligrams) and 2, the solution of 6-lupetazin (77.2 milligrams) in dimethyl formamide (1 milliliter) heated 5 hours down at 100 ℃.Formed mixture is diluted with ether, and Yi Shui and salt water washing dehydrate with sodium sulfate, filter, and concentrate in a vacuum.Make residue carry out purifying (with 1: 98.5: 0.5 methyl alcohol-methylene dichloride-triethylamine wash-out), and get title compound, be white solid (97.3 milligrams) 61 ℃-62 ℃ of fusing points with the column chromatography of silica gel.

Embodiment 11:1-{4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,6-lupetazin-1-yl } ethyl ketone synthetic

At 2-(3,5-lupetazin-1-ylmethyl)-1,1, in 1-three fluoro-4-(5-fluoro-2-the methoxyphenyl)-solution of 4-methylpentane-2-alcohol (18 milligrams) in methylene dichloride (1 milliliter), add pyridine (55.8 microlitre), then add acetic anhydride (43.4 microlitre).Formed mixture stirred spend the night, make the reaction cancellation with saturated sodium bicarbonate solution, and with twice of dichloromethane extraction.The organic phase of merging is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make residue carry out purifying (with 50% vinyl acetic monomer-hexane wash-out), and get title compound, be clean oil (20 milligrams) by column chromatography with silica gel.

Embodiment 12:4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,6-lupetazin-1-formaldehyde synthetic

In 2-(3,5-lupetazin-1-ylmethyl)-1,1, in 1-three fluoro-4-(5-fluoro-2-the methoxyphenyl)-solution of 4-methylpentane-2-alcohol (20 milligrams) in methylene dichloride (1 milliliter), under 0 ℃, add pyridine (60.7 microlitre), then add formic anhydride (2M, in methylene dichloride, 0.5 milliliter) (formic anhydride is just to have passed through 1 of monovalent, and the 2 equivalent formic acid that 3-di-isopropyl carbodiimide slowly is added in the methylene dichloride are interior and newly formed.Formed suspension was stirred 1 hour, and filter).Formed mixture stirred spend the night, went through 20 hours, filter, pour in the half saturated sodium bicarbonate aqueous solution through the cotton packed column, and with twice of dichloromethane extraction.The organic phase of merging is dehydrated with sal epsom, filter, and concentrate in a vacuum.Make residue pass through column chromatography on silica gel, carry out purifying (with 5% methyl alcohol-methylene dichloride wash-out), and title compound, be clean oil (19.3 milligrams).

Embodiment 13:4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydro-1H-quinoxaline-2-ketone synthetic

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (105 milligrams) and 3,4-dihydro-1H-quinoxaline-2-ketone (people such as R.E.TenBrink, J.Med.Chem., 1994, 37, the 758-768 page or leaf) and (267 milligrams) solution in dimethyl formamide (0.75 milliliter), heated 45 hours down in 140 ℃.Formed mixture is poured in the water, and with twice of extracted with diethyl ether.The organic phase that merges with the salt water washing, is dehydrated with sal epsom, filter, and concentrate in a vacuum.Make residue carry out purifying (with 30% vinyl acetic monomer-hexane wash-out), and get title compound, be faint yellow solid (67.8 milligrams) 69 ℃-71 ℃ of fusing points by column chromatography with silica gel.

Embodiment 14:4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1-methyl-3,4-dihydro-1H-quinoxaline-2-ketone synthetic

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (98.8 milligrams) and 1-methyl-3,4-dihydro-1H-quinoxaline-2-ketone is (according to being similar to about 3,4-dihydro-1H-quinoxaline-described the program of 2-ketone prepares with the small number of regions isomer; People such as R.E.TenBrink, J.Med.Chem., 1994, 37, the 758-768 page or leaf) and (165 milligrams) solution in dimethyl formamide (0.75 milliliter), heated 60 hours down in 140 ℃.Formed mixture is poured in the saturated sodium bicarbonate solution, and with twice of extracted with diethyl ether.The organic phase of merging is dehydrated with sal epsom, filter, and concentrate in a vacuum.Make residue carry out purifying (with 20% vinegar ester ethyl ester-hexane wash-out), and get title compound, be faint yellow solid (16.2 milligrams) 132 ℃-134 ℃ of fusing points by column chromatography with silica gel.

Embodiment 15:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methylol-1H-quinoline-4-ketone synthetic

With the mixture of 4-hydroxyquinoline (5.0 gram), aqueous sodium hydroxide solution (1M, 42 milliliters) and formaldehyde solution (in water 37%, 6 milliliter) in 45 ℃ of heating 18.5 hours down.Reaction mixture is filtered, with 2N HCl (21 milliliters) acidifying, and with ethyl acetate extraction.By the chilling water layer, to obtain the white solid product of 4-hydroxyl-3-hydroxymethyl quinoline (2.0 gram).

In 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (344 milligrams) and the suspension of 4-hydroxyl-3-hydroxymethyl quinoline (412 milligrams) in dehydrated alcohol (2.5 milliliters) in, add sodium ethylate (21 weight % solution in ethanol, 439 microlitres).In 85 ℃ down heating after 17 hours reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, and with twice of ethyl acetate extraction.The organic phase of merging is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make residue carry out purifying (with 80%-100% vinyl acetic monomer-hexane wash-out), and get title compound, be white solid (405 milligrams) 183 ℃-184 ℃ of fusing points by column chromatography with silica gel.

Embodiment 16:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methoxymethyl-1H-quinoline-4-ketone synthetic

In 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methylol-1H-quinoline-4-ketone (51.5 milligrams) and the suspension of silver suboxide (I) (127 milligrams) in acetonitrile (3 milliliters) in, add methyl iodide (68.5 microlitre).After heating 15 hours under 50 ℃, filter reaction mixture, and in vacuum, concentrate.Make residue carry out purifying (with 50%-70% vinyl acetic monomer-hexane wash-out), and get title compound, be white solid (37.5 milligrams) by column chromatography with silica gel.

Embodiment 17:1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-imino--4H-quinoline-1-ylmethyl)-4-methylpentane-2-alcohol synthetic

With the 4-quinolylamine (people such as H.Shinkai, J.Med.Chem., 2000, 43, the 4667-4677 page or leaf) and (251 milligrams), chloro tritane (533 milligrams) and the mixture of triethylamine (266 microlitre) in methylene dichloride (5 milliliters), at room temperature stirred 24 hours.Then, reaction mixture is poured in the saturated sodium bicarbonate solution, and with twice of dichloromethane extraction.The organic phase of merging is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make residue carry out purifying (with 50% vinyl acetic monomer-hexane wash-out), obtain quinolyl-4 trityl amine, be weak yellow foam body (610 milligrams) by column chromatography with silica gel.

In the suspension of quinolyl-4 trityl amine (428 milligrams) in anhydrous dimethyl sulfoxide (3.4 milliliters) and tetrahydrofuran (THF) (0.6 milliliter), once to add sodium hydride (60% dispersion liquid in Dormant oils, 44.3 milligrams).After 30 minutes, add 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (292 milligrams), and with mixture stirring 3 hours.Mixture is poured in the half saturated aqueous ammonium chloride solution, and with twice of ethyl acetate extraction.Organic phase Yi Shui, salt water washing with merging dehydrate with sodium sulfate, filter, and concentrate in a vacuum.Make residue carry out purifying (with 0.2% triethylamine-vinyl acetic monomer wash-out) by column chromatography with silica gel, and quinolyl-4 trityl amine and product 1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(trityl imino-)-4H-quinoline-1-ylmethyl] 2: 1 mixtures of pentane-2-alcohol (480 milligrams), can continue to use and need not to be further purified.

In 1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(trityl imino-)-4H-quinoline-1-ylmethyl] in the solution of pentane-2-alcohol (470 milligrams) in methylene dichloride (50 milliliters), add trifluoracetic acid (2 milliliters).After 2 hours, add the trifluoracetic acid (1 milliliter) of another part, and with mixture restir 4 hours.Make the reaction cancellation by slow interpolation saturated sodium bicarbonate solution, and with twice of ethyl acetate extraction.The organic phase of merging is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make residue carry out purifying (with 8 to 10% methyl alcohol-methylene dichloride wash-out) by column chromatography with silica gel, and title compound (84.2 milligrams), 137 ℃-140 ℃ of fusing points.

Embodiment 18:1-[2-hydroxy-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

In 3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl aldehyde (0.05 gram, 0.12 mmole), ethylene dichloride (3.0 milliliters) and acetic acid are (0.09 milliliter, 1.46 mmole) in the solution in ice bath, add morpholine (0.26 milliliter, 3.00 mmoles).Make solution be warmed to room temperature, and stirred 0.5 hour.Add sodium triacetoxy borohydride (0.06 gram, 0.30 mmole), and make solution be distributed in EtOAc and 3%NH in stirring under the room temperature after 3.0 hours reactant ₄Among the OH (3 milliliters).With the EtOAc aqueous phase extracted.The organic layer that merges with the salt water washing, is dehydrated with sal epsom, filter, and evaporating solvent in a vacuum.Make product by hurried formula chromatography column,, and in vacuum, concentrate, get 1-[2-hydroxy-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-trifluoromethyl amyl group with EtOAc/ hexane wash-out]-1H-quinoline-4-ketone, be colorless solid (0.03 gram, 45%).

Embodiment 19:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinazoline-4-one synthetic

With 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (500 milligrams) and the solution of 2-aminobenzamide (1.17 gram) in dimethyl formamide (2.5 milliliters), heated 19.5 hours down in 140 ℃.Formed mixture is diluted with ether,, dehydrate, filter, and concentrate in a vacuum with sodium sulfate with water and saturated brine washing.Make residue carry out purifying (with 15 to 30% vinyl acetic monomer-hexane wash-out) and obtain 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group amino by column chromatography with silica gel] benzamide, be white foam body (447 milligrams).

In 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group amino] in the solution of benzamide (106 milligrams) in tri-methyl ortho formate (6 milliliters), add trifluoracetic acid (0.1 milliliter).1.5 after hour, concentrated reaction mixture in vacuum.Make residue carry out purifying (with 70% vinyl acetic monomer-hexane wash-out), and get title compound, be white solid (82 milligrams) 118 ℃-121 ℃ of fusing points by column chromatography with silica gel.

Embodiment 20:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-cinnolines-4-ketone synthetic

In 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (216 milligrams) and cinnolines-4-alcohol (people such as V.G.Chapoulaud, Tetrahedron, 2000, 56, the 5499-5507 page or leaf) and in (216 milligrams) suspension in dehydrated alcohol (1.2 milliliters), add sodium ethylate (21 weight % solution in ethanol, 276 microlitres).Reaction mixture is diluted with vinyl acetic monomer after 16 hours in heating under 85 ℃, dehydrate, filter, and concentrate in a vacuum with sodium sulfate.Make the TLC purifying (with 40% vinyl acetic monomer-hexane wash-out) of residue, and get title compound, be faint yellow solid (26 milligrams) 122 ℃-123 ℃ of fusing points by preparing.

Embodiment 21:1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2-methylol-3,5-dimethyl-1H-pyridine-4-ketone synthetic

(4-methoxyl group-3,5-lutidine-2-yl) methyl alcohol (1.0 gram) was heated 43 hours under refluxing with the mixture of Lithium chloride (anhydrous) (0.76 milligram) in dimethyl formamide (10 milliliters).Add sodium hydroxide solution (10%w/v, 30 milliliters) then, and with formed solution with twice of extracted with diethyl ether.With among the 1N HCl (21 milliliters) and water, and under vacuum, remove volatile matter.Making formed solid carry out the wash-out that purifying (with 10% methyl alcohol-methylene dichloride wash-out) will be rich in product by the column chromatography with silica gel partly merges, in vacuum, concentrate, and develop with chloroform-acetonitrile (4: 1), and product 2-methylol-3,5-lutidine-4-alcohol is white solid (0.78 gram).

In 7-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl]-2,3-Dihydrobenzofuranes (30.0 milligrams) and 2-methylol-3, in the suspension of 5-lutidine-4-alcohol (32.2 milligrams) in dehydrated alcohol (0.25 milliliter), add sodium ethylate (21 weight % solution in ethanol, 39.0 microlitres).Reaction mixture is diluted with vinyl acetic monomer after 18 hours in heating under 85 ℃, dehydrate, filter, and concentrate in a vacuum with sodium sulfate.Make residue carry out purifying (with 4% to 7% methyl alcohol-methylene dichloride wash-out) by column chromatography with silica gel, and title compound, be white solid (10.4 milligrams) 160 ℃-162 ℃ of fusing points.

Embodiment 22:1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-3,5-dimethyl-1H-pyridine-4-ketone synthetic

In the suspension of iodate trimethylammonium sulfoxonium (trimethylsulfoxonium iodide) (1.36 gram) in anhydrous dimethyl sulfoxide (7.7 milliliters), add sodium hydride (60% dispersion liquid in Dormant oils, 246 milligrams).Formed solution was stirred under room temperature 30 minutes, drop to 1,1 then, in the solution of 1-three fluoro-4-methyl-4-(5-methylthio group-2,3-Dihydrobenzofuranes-7-yl) pentane-2-ketone (1.63 gram) in anhydrous dimethyl sulfoxide (6.5 milliliters).After 2 hours, add water (100 milliliters), and with formed mixture with three parts of 100 milliliters of extracted with diethyl ether.With the organic phase that merges with twice of water washing, with the salt water washing, dehydrate with sal epsom, filter, and concentrate in a vacuum, and get 7-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl]-5-methylthio group-2, the 3-Dihydrobenzofuranes is clean oil (1.64 gram), can use and need not to be further purified.

In 7-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl]-5-methylthio group-2, in the solution of 3-Dihydrobenzofuranes (535 milligrams) in acetonitrile (30 milliliters) and water (10 milliliters), add sodium periodate (1.03 gram), then add ruthenium chloride (III) (1 milligram).After 2 hours, reaction mixture is diluted with water, and with ethyl acetate extraction.The organic phase of merging is dehydrated with sal epsom, filter, and concentrate; and 7-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl]-5-methane sulfonyl-2, the 3-Dihydrobenzofuranes; be tawny solid (568 milligrams), can use and need not to be further purified.

In 7-[1; 1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl]-5-methane sulfonyl-2; 3-Dihydrobenzofuranes (51.0 milligrams) and 3; 5-lutidine-4-alcohol (people such as B.Boduszek; Synthesis, 1979, the 452-453 pages or leaves) in (34 milligrams) suspension in dehydrated alcohol (0.40 milliliter); add sodium ethylate (21 weight % solution in ethanol, 52.0 microlitres).Reaction mixture is diluted with vinyl acetic monomer after 16 hours in heating under 85 ℃, dehydrate, filter, and concentrate in a vacuum with sodium sulfate.Make residue carry out purifying (with 4% methyl alcohol-methylene dichloride wash-out), and get title compound, be white solid (47 milligrams) 150 ℃-152 ℃ of fusing points by column chromatography with silica gel.

Embodiment 23:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,2-dihydro-indazol-3-ketone synthetic

In 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (0.29 gram) and 1, in the solution of 2-dihydro-indazol-3-ketone (0.17 gram) in anhydrous dimethyl sulfoxide (1 milliliter), add two (TMS) acid amides (1.0M of sodium, in tetrahydrofuran (THF), 1.0 milliliters).After 14 days, reaction mixture is diluted with vinyl acetic monomer, and with twice of water washing.Organic phase is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make the TLC purifying (with 1% ethanol-methylene dichloride wash-out) of residue by preparing, obtain 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,2-dihydro-indazol-3-ketone is white solid (91 milligrams), 141 ℃-144 ℃ of fusing points.

Embodiment 24:1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone synthetic

In 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (2.25 grams, 5.14 mmole) in the solution in DMF (40 milliliters), add salt of wormwood (2.13 grams, 154 mmoles), then in sealed reaction vessel, be heated to 120 ℃, went through 14 hours.Solution is diluted with 300 milliliters of ether, wash with a 200 milliliters of saturated sodium bicarbonates, three part of 100 ml water, a 100 mL of saline, with sodium sulphite anhydrous 99.3 (Na ₂SO ₃) dehydrate, and concentrate in a vacuum.Make crude material by hurried formula column chromatography purification (5%MeOH/CH ₂Cl ₂), and get 1-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo amyl group]-1H-quinoline-4-ketone, be brown foams (1.07 grams, 57%).

Make the round-bottomed flask that Cerium II Chloride (0.27 gram, 1.08 mmoles) is housed through oven drying, in vacuum and 140 ℃ dry 1 hour down, then at room temperature, vacuum dry 14 hours again.Flask is sealed with partition,, and charge into argon gas in the vacuum lower pumping.Add THF (3 milliliters), and made the slurries sonication 1 hour, obtain yellow suspension.In these slurries, interpolation has been dissolved in 1 milliliter of 1-[4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo amyl group among the THF]-1H-quinoline-4-ketone (0.20 gram, 0.54 mmole), and cause forming deep brown solution.It was at room temperature stirred 1 hour, then add cyclopropyl bromination magnesium (2.18 milliliters, 0.5 mol) down in 0 ℃.Reactant was stirred 3 hours under this temperature, then make the reaction cancellation, and cause the formation of white depositions by adding saturated ammonium chloride (10.0 milliliters).Filter biphasic system, and separate water layer.Organic layer is washed with a 25 mL of saline, dehydrates, filter with sodium sulphite anhydrous 99.3, and in vacuum evaporating solvent, yellow oil.On silica gel,, use the EtOAc-hexanes mixtures, obtain pure products 1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group as eluent by hurried formula chromatography]-1H-quinoline-4-ketone (2.0 milligrams, 1%).

Embodiment 25:1-[2-hydroxyl-4-(3-hydroxymethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

In 3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl aldehyde (20.0 milligrams, 0.05 mmole) in the solution among methyl alcohol (0.50 milliliter) and the THF (0.50 milliliter), add NaBH ₄(20.0 milligrams, 0.48 mmole).With the reaction vessel sealing, and stirred 45 minutes.Evaporating solvent in a vacuum, and pale solid is dissolved in EtOAc and the water again, and be transferred to separating funnel.With two parts of 10 milliliters of EtOAc aqueous layer extracted, and the organic layer that merges wash with a 10 mL of saline, dehydrate, filter with sal epsom, and evaporating solvent in a vacuum, and must the white foam body.This material of chromatography (6%MeOH/CH ₂Cl ₂, 0.5%NH ₄OH), and get desired compound 1-[2-hydroxyl-4-(3-hydroxymethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone, be white foam body (6.6 milligrams, 36%).

Embodiment 26:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone synthetic

With aniline (10.7 gram) and the mixture of careless propionic acid diethyl ester (21.7 milliliters) in 75 milliliters of methylene dichloride heated overnight under refluxing, be cooled to room temperature, with 1N HCl, water, salt water washing, and dehydrate with sal epsom.In vacuum, remove volatile matter, and residue (2-methyl-3-(phenylimino) ethyl succinate) is carried out next step operation and need not other purifying.

The mixture of 2-methyl-3-(phenylimino) ethyl succinate (2.42 gram) in silicone oil (7 milliliters) heated 20 minutes down in 240 ℃-245 ℃, and remove ethanol, be cooled to room temperature,, and filter with the hexane dilution by distillation.Make solid (3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester) dry in vacuum.Output: 0.91 gram.

With 3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, ethyl ester (1.42 gram) heated 3 hours down in refluxing with the mixture of the NaOH aqueous solution (18.4 milliliters, 1N solution), was cooled to room temperature, with dense HCl acidifying, filtered, and made solid dry in vacuum.Solid (1.1 gram) is suspended in 10 milliliters of silicone oil, and heated 10 minutes down, be cooled to room temperature,, and filter with the hexane dilution at 260 ℃-265 ℃.Make solid (3-methyl isophthalic acid H-quinoline-4-ketone) dry in vacuum.

With 3-methyl isophthalic acid H-quinoline-4-ketone (0.76 gram), 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-(0.18 milliliter of sodium ethylate in 2-trifluoromethyl oxyethane (0.089 gram) and the ethanol, 21 weight % solution) mixture in 2 milliliters of dehydrated alcohols, heated 12 hours down in 85 ℃, be cooled to room temperature, and in vacuum, remove most of volatile matter.Residue is diluted with ether and methyl alcohol, and Yi Shui and salt water washing, and dehydrate with sal epsom.Make residue by hurried formula silica gel column chromatography purifying, use vinyl acetic monomer as eluent.The wash-out part that is rich in product is concentrated in vacuum, and dry, and get 1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone.Fusing point＞225 ℃.

Embodiment 27:1-[4-(2-oxyethyl group-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

With 1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (0.053 gram), iodic ether (0.011 milliliter) and the mixture of powdered potassium carbonate (0.090 gram) in 1 milliliter of dry DMF be in 80 ℃ of heating 18 hours down, be cooled to room temperature, and with the water dilution, and filter.Make solid with hurried formula silica gel column chromatography purifying, use vinyl acetic monomer effect eluent.In vacuum, concentrate the wash-out part that is rich in product, 1-[4-(2-oxyethyl group-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group be provided]-1H-quinoline-4-ketone.195 ℃-196 ℃ of fusing points.

Embodiment 28:1-[4-(2-difluoro-methoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

With 1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (0.05 gram), 2-chloro-2,2-two methyl fluoracetates (0.014 milliliter) and cesium carbonate (0.195 gram) mixture in 1.5 milliliters of DMF heated 20 hours down in 60 ℃, be cooled to room temperature, with the vinyl acetic monomer dilution, and with aqueous acetic acid, water and salt water washing.Make residue pass through the reversed-phase HPLC purifying, use acetonitrile/water as eluent.In vacuum, concentrate the wash-out part that is rich in product, 1-[4-(2-difluoro-methoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group be provided]-1H-quinoline-4-ketone.150 ℃-155 ℃ of fusing points.

Embodiment 29:1-[2-hydroxyl-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

In 2-methoxyphenyl magnesium bromide solution (131 milliliters, 65.7 mmoles, the 0.5M solution in THF), under 0 ℃, add CuI (12.5 grams, 65.7 mmoles).Make reaction mixture be warmed to room temperature, and stirred 1 hour.Add the 4-methyl isophthalic acid, 1,1-trifluoro penta-3-alkene-2-ketone (10.0 grams, 65.74 mmoles) (making) solution in ether (200 milliliters) by the program in PCT international application case WO 03/082280 example 10, and reaction mixture stirred spend the night.Make the reaction cancellation with saturated aqueous ammonium chloride (50 milliliters), and with three parts of 300 milliliters of ethyl acetate extractions.Organic layer Yi Shui and salt water washing with merging dehydrate with sal epsom, filter, and concentrate in a vacuum.Make residue pass through the silica gel column chromatography purifying, the 0%-5% vinyl acetic monomer in the use hexane is as eluent.In vacuum, concentrate the wash-out part that is rich in product, obtain 14 grams (82%) 1,1,1-three fluoro-4-(2-methoxyphenyl)-4-methylpentane-2-ketone.

Make N-bromo succinimide (6.84 grams, 38.42 mmoles), benzoyl peroxide (catalytic amount) and 1,1,1-three fluoro-4-(2-methoxyphenyl)-4-methylpentane-2-ketone (10.0 grams, 38.42 mmoles) are at tetracol phenixin CCl ₄Mixture in (120 milliliters) refluxed two days.After cooling, solution with water (60 milliliters) and 1.0M NaOH (60 milliliters) washing, is dehydrated (Na with sodium sulfate ₂SO ₄), and concentrate in a vacuum, obtaining 1,1,1-three fluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentane-2-ketone and initial substance are 3: 1 mixtures (13.0 gram).

The preparation of inner salt stock solution:

In the iodate trimethylammonium sulfur oxide in 30 milliliters of anhydrous DMSO (8.0 grams, 36.3 mmoles), NaH (1.46 grams, 36.35 mmoles are added in gradation; 60% dispersion liquid in Dormant oils).Mixture was stirred 30 minutes.

The formation of epoxide:

In 1,1, in the solution of 1-three fluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentane-2-ketone (5 grams, 14.7 mmoles) in 5 milliliters of anhydrous DMSO, at room temperature, in 5 minutes, add 14.6 milliliters of alkylidene compound stock solutions (17.3 mmole).After 2 hours, make the reaction cancellation with water and ether.With the extracted with diethyl ether water layer.Organic layer Yi Shui and salt water washing with merging dehydrate with sal epsom, filter, and concentrate in a vacuum, and get 2-[2-(5-bromo-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane, be dark yellow oil.

With 2-[2-(5-bromo-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane (5.0 grams, 14.2 4-hydroxyquinoline (3.08 grams mmole),, 21.2 mmole) and sodium ethylate (21 weight % solution in ethanol, 5.3 milliliter, 14.2 mmoles) mixture in ethanol (120 milliliters) is in 85 ℃ of down heating 14 hours.Make the reaction cancellation with water, and in vacuum, concentrate, to remove most of ethanol.Residue is diluted with methylene dichloride, and with half saturated sodium bicarbonate (NaHCO ₃) washing, dehydrate with sal epsom, filter, and concentrate in a vacuum.Product obtains 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group by precipitating in ether-hexane]-1H-quinoline-4-ketone (5.2 grams, 73% productive rate).

With 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (0.2 gram, 0.4 mmole), 3 thienylboronic acid (77 milligrams, 0.6 mmole), yellow soda ash (Na ₂CO ₃85 milligrams, 0.8 mmole) DME-MeOH-DMF (1: 1.5: 0.5; 3.0 the mixture milliliter) stirred 10 minutes, and added Pd (PPh ₃) ₄(46.2 milligrams, 0.04 mmole).Make mixture in 120 ℃ of following microwave treatment 15 minutes, be cooled to room temperature, and through Celite ^_Flocculating aids filters.Residue is diluted with EtOAc (20 milliliters), and with the NaOH aqueous solution (1.0M, 10 milliliters), water and salt water washing, and dehydrate with sodium sulfate, and in vacuum, remove volatile matter.Then, make residue pass through silica gel column chromatography and by the reversed-phase HPLC purifying, to produce 60 milligrams of (30%) 1-[2-hydroxyl-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone, be the white foam body.

Embodiment 30:1-[2-hydroxyl-4-(2-hydroxyl-5-thiene-3-yl-phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

In 1-[2-hydroxyl-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-Methyl-2-trifluoromethyl amyl group]-solution of 1H-quinoline-4-ketone (32 milligrams, 0.06 mmole) in methylene dichloride (1 milliliter) in, under 0 ℃ and argon atmosphere, add BBr ₃(0.06 milliliter, 0.6 mmole).Make mixture be warmed to room temperature, stirred 3 hours, be cooled to 0 ℃, stirred 2 days, and make the reaction cancellation with methyl alcohol (5 milliliters).In vacuum, remove volatile matter, and,, and dehydrate with sal epsom with saturated sodium bicarbonate aqueous solution (5 milliliters) and salt solution (5 milliliters) washing with vinyl acetic monomer (10 milliliters) dilution residue.Remove volatile matter in a vacuum, and make residue pass through the reversed-phase HPLC purifying, to get 1-[2-hydroxyl-4-(2-hydroxyl-5-thienyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (20 milligrams, 68%).

Embodiment 31:1-[2-hydroxyl-4-(4-methoxyl biphenyl-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

With 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (200 milligrams, 0.4 mmole), Pd (OAc) ₂(9 milligrams, 0.04 mmole), DCyBPP ((2-dicyclohexyl phosphino-) xenyl, 28 milligrams, 0.08 mmole), KF is (93 milligrams, 1.6 the mixture in toluene/THF (3/2 milliliter) mmole) is handled with phenyl-boron dihydroxide (98 milligrams, 0.8 mmole) under room temperature.Reaction mixture stirred under room temperature spend the night, and through Celite ^_Flocculating aids filters.Residue with EtOAc (20 milliliters) dilution, is washed with the NaOH aqueous solution (1.0M, 10 milliliters), water and salt solution (10 milliliters).Organic phase is dehydrated with sodium sulfate, filter, reach evaporating solvent in a vacuum.Make residue with silica gel column chromatography, by the reversed-phase HPLC purifying, provide 1-[2-hydroxyl-4-(4-methoxyl biphenyl-3-yl)-4-Methyl-2-trifluoromethyl amyl group then]-1H-quinoline-4-ketone, be white solid.

Embodiment 32:1-[4-(5-ethanoyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

Make 1-[4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (200 milligrams, 0.4 mmole), 1-vinyl oxygen base butane (0.26 milliliter, 2.0 mmoles), Pd (OAc) ₂(5 milligrams, 0.02 mmole), 1, two (diphenylphosphino) propane (DPPP) (10.5 milligrams, 0.03 mmole) of 3-, K ₂CO ₃(66.34 milligrams, 0.48 mmole) and the mixture of water (0.1 milliliter) in DMF (1 milliliter) were in 122 ℃ of following microwave treatment 1 hour.After cooling, mixture is poured among 5 milliliters of 5%HCl, stirred 30 minutes, and with three parts of 10 milliliters of ethyl acetate extractions.With the organic layer that merges with 10%K ₂CO ₃Solution washing, and dry.Make residue with silica gel column chromatography, then by the reversed-phase HPLC purifying, to produce 50 milligrams of (27% productive rate) 1-[4-(5-ethanoyl-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone, be white solid.

Embodiment 33:3-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-5-Trifluoromethyl-1 H-pyridin-2-ones synthetic

The mixture of 3-chloro-5-5-flumethiazine-2-alcohol (135 milligrams, 0.68 mmole) in 1 milliliter of EtOH is added in 0.13 milliliter of 1M alcohol sodium solution in the ethanol, and in the little glass bottle of sealing, is heated to 85 ℃, went through 5 minutes.Make mixture be cooled to room temperature, add 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane, and mixture is heated to 85 ℃ spends the night in the little glass bottle of sealing.Remove volatile matter in a vacuum, and residue is diluted with water, and extract with EtOAc.Organic collection liquid is merged, dehydrate, and concentrate in a vacuum with sodium sulfate.Make residue purifying (hexane-EtOAc (8: 2)) on the PLC plate, and get 125 milligrams of 3-chloro-1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-5-Trifluoromethyl-1 H-pyridin-2-ones, be solid.

Embodiment 34:1-{4-[3-(3,5-dimethyl isoxazole-4-yl) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone synthetic

Make 3-bromoacetophenone (9.9 milliliters, 0.075 mole), malonic methyl ester nitrile (9.8 milliliters, 0.112 mmole, 1.5 equivalent), benzylamine is (0.87 milliliter, 0.008 mole, 0.1 equivalent) and the solution of acetic acid (4.3 milliliters) in 110 milliliters of toluene reflux and to spend the night, and azeotropic removes water.Reactant is concentrated in vacuum, and, use hexane/ethyl acetate gradient liquid, with eluted product (Z)-3-(3-bromophenyl)-2-cyano group but-2-ene acid methyl esters via hurried formula chromatography purification.Output: 14.13 grams (67%).

In the CuI of Soxlet abstraction purification (14.28 grams, 0.075 mole, 1.5 equivalents) in 150 milliliters of anhydrous diethyl ethers in the suspension of chilling (0 ℃), add the 1.6M solution of lithium methide (84.4 milliliters, 0.135 mole, 2.7 equivalents) in ether.Mixture was stirred 10 minutes, be cooled to-25 ℃, and dropwise add (Z)-3-(3-bromophenyl)-solution of 2-cyano group but-2-ene acid methyl esters (14.13 grams, 0.05 mole) in 150 milliliters of anhydrous diethyl ethers.Mixture was stirred 30 minutes down in-25 ℃, be warmed to room temperature, and stir and spend the night.Make the reaction cancellation with saturated ammonium chloride solution, and with ethyl acetate extraction.The organic substance that merges with the salt water washing, is dehydrated with sodium sulfate, filters, and concentrate in a vacuum, and brown oil.Make oil by hurried formula chromatography purification, use hexane-vinyl acetic monomer gradient liquid, obtain 3-(3-bromophenyl)-2-cyano group-3 Methylbutanoic acid methyl esters.Output: 8.88 grams (60%).

3-(3-bromophenyl)-2-cyano group-3 Methylbutanoic acid methyl esters (8.88 grams, 28.6 mmoles) is refluxed with the mixture of sodium-chlor (4.69 grams, 80.2 mmoles, 2.8 equivalents) in 74 milliliters of methyl-sulphoxides and 3.5 ml waters to spend the night.Make the reactant cooling, and with the salt solution dilution, and with ethyl acetate extraction.Organic layer Yi Shui and salt water washing with merging dehydrate with sodium sulfate, filter, and concentrate in a vacuum, and oily, make it by hurried formula chromatography purification.Use hexane-vinyl acetic monomer gradient liquid, with eluted product.Compile product elutriant part, and in vacuum, concentrate, and get Vandyke brown oil 3-(3-bromophenyl)-3-methylbutyronitrile.Output: 5.1 grams (75%).

In the mixture of 3-(3-bromophenyl)-3-methylbutyronitrile (5.1 grams, 21 mmoles) in anhydrous methylene chloride (94 milliliters), under-78 ℃, dropwise add diisobutylaluminium hydride (1M is in methylene dichloride).Reactant was stirred 1 hour, slowly be warmed to room temperature, and make the reaction cancellation with the aqueous solution of saturated RochelleShi salt, and with ethyl acetate extraction.The organic substance that merges with the salt water washing, is dehydrated with sodium sulfate, filters, and concentrate in a vacuum and oily matter.Make this oil by hurried formula chromatography purification, use hexane-vinyl acetic monomer gradient liquid, with wash-out 3-(3-bromophenyl)-3-methyl butyraldehyde.

At 3-(3-bromophenyl)-3-methyl butyraldehyde (3.1 grams, 12.8 mmole) at trimethylammonium (trifluoromethyl) silane in the 0.5M solution among the THF (25.7 milliliters, 12.8 mmoles), in 2 minutes, add tetrabutylammonium (2.6 milliliters, the 1M solution in THF).Mixture was stirred 30 minutes, and add the 1M solution of other 10.3 milliliters of tetrabutylammonium.Mixture is diluted with water, and with ethyl acetate extraction.The organic substance that merges with the salt water washing, is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make residue by hurried formula chromatography with purifying, use hexane-vinyl acetic monomer gradient liquid, with wash-out 4-(3-bromophenyl)-1,1,1-three fluoro-4-methylpentane-2-alcohol.Output: 2.048 grams (51%).

At 4-(3-bromophenyl)-1,1, in the solution of 1-three fluoro-4-methylpentane-2-alcohol (2.05 grams, 6.58 mmoles) in methylene dichloride (33 milliliters), add Dess-Martin and cross iodine alkane (3.9 grams, 9.2 mmoles).Mixture was stirred 48 hours, in vacuum, concentrate then.Residue is diluted with hexane, and filter.Filtrate is concentrated in a vacuum, and by hurried formula chromatography with purifying, use hexane-vinyl acetic monomer gradient liquid, with eluted product 4-(3-bromophenyl)-1,1,1-three fluoro-4-methylpentane-2-ketone.Output: 68 milligrams (34%).

At 4-(3-bromophenyl)-1,1, (68 milligrams of 1-three fluoro-4-methylpentanes-2-ketone, 2.2 mmole) in the solution in 2.9 milliliters of anhydrous DMSO, in 5 minutes, (3.3 milliliters of the interior salts solutions of interpolation iodate trimethylammonium sulfur oxide, 0.8M DMSO solution, 2.66 gram (12.1 mmole) the iodate trimethylammonium sulfur oxides of system in 15 milliliters of anhydrous DMSO, and 483 milligrams of 60%NaH (12.1 mmole) in Dormant oils of portion-wise addition, and aging 30 minutes).Mixture was stirred 2 hours, and make the reaction cancellation with water and vinyl acetic monomer.With organic phase Yi Shui and salt water washing, and dehydrate with sodium sulfate.In vacuum, remove volatile matter, yellow oil 2-[2-(3-bromophenyl)-2-methyl-propyl be provided]-2-trifluoromethyl oxyethane, can use and need not to be further purified.

With 2-[2-(3-bromophenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane, 4-hydroxyquinoline (2 equivalent) and sodium ethylate (21 weight % solution in ethanol, 1 equivalent) mixture in ethanol, heated 14 hours down in 85 ℃, make the reaction cancellation with water, and concentrate in a vacuum, to remove most of ethanol.The aqueous solution and methylene dichloride dilution residue with the semi-saturation sodium bicarbonate.Organic phase is dehydrated with sodium sulfate, filter, and concentrate in a vacuum.Make residue by hurried formula chromatography with purifying, use vinyl acetic monomer-hexane gradient liquid, and concentrate the wash-out part that is rich in product, obtain 1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone.

Make 1-[4-(3-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-(30 milligrams in 1H-quinoline-4-ketone, 0.064 mmole), 3, (9 milligrams of 5-dimethyl isoxazoles-4-boric acid, 0.064 mmole, 1 equivalent), two dichloride base triphenylphosphinyl palladiums (II) (catalytic amount) and cesium carbonate are (21 milligrams, 0.064 mmole) mixture in 1.1 milliliters of ethylene glycol dimethyl ether-water-ethanols (7: 3: 2) outgases, be sealed in the little glass bottle, and under 160 ℃, shine (microwave) twice, went through 300 seconds.Make reactant be cooled to room temperature, and pass through Celite ^_Flocculating aids filters.Filtrate is diluted with water, and with extracted with diethyl ether.The organic layer that merges with the salt water washing, and is dehydrated with sodium sulfate.In vacuum, remove volatile matter, get residue, make it pass through the HPLC purifying, and get 1-{4-[3-(3,5-dimethyl isoxazole-4-yl) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone.

Embodiment 35:1-[4-(3-cyclopropane carbonyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

In the Grignard reagent solution that derives from 2-(3-bromophenyl)-[1,3] dioxane (52.6 milliliters, 0.25M, in THF, 13.1 mmoles), add cupric iodide (I) (25 grams, 13.1 mmoles) down at 0 ℃.After 45 minutes, add 1,1,1-three fluoro-4-methylpent-3-alkene-2-ketone (2 grams, 13.1 mmoles), and make reaction mixture slowly be warmed to room temperature, and stir and spend the night.Make the mixture cancellation with saturated aqueous ammonium chloride, and with ethyl acetate extraction.The organic layer that merges is washed with saturated sodium-chloride water solution, dehydrate, and concentrate in a vacuum with sodium sulfate.Residue is developed with hexane, and filtered.Concentrated filtrate in vacuum, and acquisition 4-(3-[1,3] dioxane-2-base phenyl)-1,1,1-three fluoro-4-methylpentane-2-ketone.

In 4-(3-[1,3] dioxane-2-base phenyl)-1,1, in the solution of 1-three fluoro-4-methylpentane-2-ketone (1 gram, 3 mmoles) in 4.1 milliliters of anhydrous DMSO, in 5 minutes, add the interior sodium salt (3.0 milliliters, the 0.8M solution in DMSO) of iodate trimethylammonium sulfur oxide.Reactant was stirred 2 hours, and make the reaction cancellation with water and vinyl acetic monomer.With organic layer Yi Shui and salt water washing, and dehydrate with sodium sulfate.In vacuum, remove volatile matter, obtain 2-{3-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl] phenyl }-[1,3] dioxane, be yellow oil.

With 2-{3-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl] phenyl }-[1,3] dioxane (0.910 gram, 2.75 mmole), the 4-hydroxyquinoline is (806 milligrams, 5.55 mmole) and sodium ethylate (21 weight % solution in ethanol, 1.03 milliliter, 2.7 mmoles) mixture in ethanol (7.7 milliliters) is added a cover, and in 85 ℃ of heating 14 hours down.Make the mixture cancellation with water, and in vacuum, concentrate, to remove most of ethanol.With semi-saturation sodium hydrogen carbonate solution and methylene dichloride dilution residue.Organic layer is dehydrated with sodium sulfate, and in vacuum, concentrate.Make residue by hurried formula chromatography with purifying, use vinyl acetic monomer-hexane as eluent.Make the wash-out part that is rich in product in vacuum, be condensed into 1-[4-(3-[1,3] dioxane-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone.

With 1-[4-(3-[1,3] dioxane-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone (0.99 gram, 2.09 mmole), ethanol (66 milliliters), water (13.2 milliliters) and pyrrole ingot right-(262 milligrams of toluenesulphonic acidss, 1.04 mixture mmole) is in the heating down 3 hours that refluxes, be cooled to room temperature, and concentrate to remove ethanol in a vacuum.With vinyl acetic monomer and water dilution residue.With the ethyl acetate extraction water layer.The organic layer that merges with saturated sodium bicarbonate aqueous solution and salt water washing, and is dehydrated with sodium sulfate.In vacuum, remove volatile matter, obtain 3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl aldehyde.Output: 77 milligrams (89%).

In 3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl aldehyde (0.10 gram, 0.24 mmole) in anhydrous tetrahydro furan (5 milliliters), and in ice/isopropanol bath, in the refrigerative solution, dropwise add (0.71 milliliter in cyclopropyl bromination magnesium, 0.84M solution in THF, 0.6 mmole).Make mixture slowly be warmed to room temperature, make the reaction cancellation with saturated ammonium chloride solution, and with ethyl acetate extraction.The organic layer that merges with the salt water washing, is dehydrated with sodium sulfate, and concentrates in a vacuum.The mixture stirred for several in THF hour with residue and hydrazine resin, and filter.In vacuum, remove volatile matter, obtain pure 1-{4-[3-(cyclopropyl methylol) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone.

With 1-{4-[3-(cyclopropyl methylol) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone (26 milligrams, 0.057 mmole) and MnO ₂(5 milligrams, 0.57 mmole) mixture in methylene dichloride (2 milliliters) stirred 48 hours under room temperature and argon atmospher, and at CELITE ^_Filter on the flocculating aids.Concentrated filtrate in vacuum, and make residue pass through the reversed-phase HPLC purifying, and get 1-[4-(3-cyclopropane carbonyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone.Output: 9 milligrams (35%).

Embodiment 36a and 36b:1-(2-hydroxyl-4-{3-[1-(oximino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone and 1-(2-hydroxyl-4-{3-[1-(methoxyimino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone synthetic

With 3-bromoacetophenone (10 milliliters, 75.6 mmoles), ethylene glycol (10.1 milliliters, 181 mmoles) and the mixture heating up of right-toluenesulphonic acids hydrate (120 milliliters) in toluene, and azeotropic removes water.After 4 hours, add second part of ethylene glycol, and mixture was heated 48 hours down in refluxing.Make reactant be cooled to room temperature, and with saturated sodium bicarbonate solution and salt water washing, and dehydrate with sodium sulfate.In vacuum, remove volatile matter, residue be provided, make its by hurried formula chromatography purifying.Concentrate the wash-out part that is rich in product, obtain 2-(3-bromophenyl)-2-methyl-[1,3] dioxolane, be transparent oil body.Output: 2.44 grams

In the solution of 2-(3-bromophenyl)-2-methyl-[1,3] dioxolane (1 restrains) in THF (5 milliliters), magnesium metal (0.2 gram) is added in gradation, and reactant was heated 30 minutes down in refluxing.Make mixture be cooled to room temperature, and add CuBr-DMS mixture (846 milligrams, 4.11 mmoles).Mixture was stirred under room temperature 3 minutes, be cooled to 0 ℃, and dropwise add 1,1 among 20 milliliters of THF, 1-three fluoro-4-methylpent-3-alkene-2-ketone (62 milligrams, 4.11 mmoles).Mixture was stirred 30 minutes down in 0 ℃, be warmed to room temperature, stirring is spent the night, and makes the reaction cancellation with aqueous ammonium chloride solution and vinyl acetic monomer.Organic layer with the salt water washing, is dehydrated with sodium sulfate, and concentrates in a vacuum, and residue, make its by hurried formula chromatography purifying.In vacuum, concentrate the wash-out part that is rich in product, obtain 0.56 gram 1,1,1-three fluoro-4-methyl-4-[3-(2-methyl-[1,3] dioxolane-2-yl) phenyl] pentane-2-ketone.

In 1,1,1-three fluoro-4-methyl-4-[3-(2-methyl-[1,3] phenyl two oxa-s, penta ring-2-yl)] pentane-2-ketone (0.56 gram, 1.8 mmole) in the solution in anhydrous DMSO (23 milliliters), in 5 minutes, add the interior sodium salt (2.6 milliliters, the 0.8M solution in DMSO) of iodate trimethylammonium sulfur oxide.Mixture was stirred 2 hours, make the reaction cancellation with water, and with ethyl acetate extraction.With organic layer Yi Shui and the salt water washing that merges, and dehydrate with sodium sulfate.Concentrated solution in vacuum, and get yellow oil body 2-{3-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl] phenyl }-2-methyl-[1,3] dioxolane, it can use and need not to be further purified.

With 2-{3-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl] phenyl }-2-methyl-[1,3] two oxa-s, penta ring (0.514 gram, 1.55 mmoles), 4-hydroxyquinoline (0.433 gram, 2.98 mmoles) and sodium ethylate (21 weight % solution in ethanol, 0.55 milliliter, 1.49 the mixture in ethanol (4.2 milliliters) mmole) heated 14 hours down in 85 ℃, was cooled to room temperature, make the reaction cancellation with water, and concentrate to remove most of ethanol in a vacuum.Residue is diluted with the semi-saturation sodium bicarbonate aqueous solution, and with dichloromethane extraction.Organic layer is merged, dehydrate, and concentrate in a vacuum with sodium sulfate.Make residue by hurried formula chromatography purification, use vinyl acetic monomer-hexane as eluent.In vacuum, concentrate the wash-out part that is rich in product, and get 1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3] dioxolane-2-yl) phenyl]-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone.Output: 0.35 gram

With 1-{2-hydroxy-4-methyl-4-[3-(2-methyl-[1,3] phenyl dioxolane-2-yl)]-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone (0.35 gram, 0.75 mmole), ethanol (24 milliliters), water (4.8 milliliters) and right-toluenesulphonic acids pyridine are (95 milligrams, 0.37 mixture heating up mmole) is to refluxing, went through 3 hours, be cooled to room temperature, and concentrate to remove most of ethanol in a vacuum.With vinyl acetic monomer and water dilution residue.With the ethyl acetate extraction water layer.The organic layer that merges with saturated sodium bicarbonate aqueous solution and salt water washing, and is dehydrated with sodium sulfate.In vacuum, remove volatile matter, obtain 1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone.Output: 0.27 gram (84%).

With 1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-(60 milligrams in 1H-quinoline-4-ketone; 0.14 mmole), salt of wormwood is (79 milligrams; 0.57 mmole) and (39 milligrams of hydroxylamine hydrochlorides; 0.55 mmole) mixture in methyl alcohol (1 milliliter) heated 3 hours down in 65 ℃; be cooled to room temperature, and concentrate in a vacuum.Residue is diluted with water, and with ethyl acetate extraction.The organic layer that merges with the salt water washing, is dehydrated with sodium sulfate, and concentrates in a vacuum.Make residue by hurried formula chromatography purification, and 1-(2-hydroxyl-4-{3-[1-(oximino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone.Output: 38 milligrams.

With 1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-(55 milligrams in 1H-quinoline-4-ketone; 0.12 mmole), salt of wormwood is (72 milligrams; 0.52 mmole) and (42 milligrams of methoxy amine hydrochlorates; 0.51 mmole) mixture in 1 ml methanol heated 3 hours down in 65 ℃; be cooled to room temperature, and concentrate in a vacuum.Residue is diluted with water, and with ethyl acetate extraction.The organic layer that merges with the salt water washing, is dehydrated with sodium sulfate, and concentrates in a vacuum.Make residue by hurried formula chromatography purification, and 1-(2-hydroxyl-4-{3-[1-(methoxyimino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl-amyl group)-1H-quinoline-4-ketone.Output: 48 milligrams.

Embodiment 37:1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone synthetic

In 10 gram (29 mmole) 4-(2,3-Dihydrobenzofuranes-7-the yl)-2-hydroxy-4-methyl-solution of 2-trifluoromethyl Valeric acid ethylester in 20 milliliters of acetic acid (HOAc), dropwise add the solution of 1.55 milliliters of (30 mmole) bromines in 10 milliliters of HOAc.By proton N MR monitoring reaction.Add other 0.5 milliliter of Br ₂Mixture is diluted with saturated sodium bicarbonate aqueous solution, and with extracted with diethyl ether.Organic layer is dehydrated with sal epsom, and in vacuum, concentrate, and get 11.7 gram (95%) 4-(5-bromo-2,3-two-hydrogen cumarone-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl Valeric acid ethylesters.

In 1.25 gram (33 mmole) LiAlH ₄In the suspension in 50 milliliters of THF, under 0 ℃, dropwise add 11.7 gram (27.5 mmole) 4-(5-bromo-2,3-Dihydrobenzofuranes-7-the yl)-2-hydroxy-4-methyl-solution of 2-trifluoromethyl Valeric acid ethylester in 20 milliliters of THF.Make reactant be warmed to room temperature, stirred 2 hours, be cooled to 0 ℃,, then make the reaction cancellation carefully, and extract with EtOAc with 1N HCl with water.Organic layer is merged, dehydrate, and in vacuum, concentrate with sal epsom.With hexane development residue, and by solid collected by filtration, and get 7.6 gram (72%) 4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl pentanes-1, the 2-glycol.

With 7.6 gram (20 mmole) 4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl pentane-1,2-glycol and 0.754 restrains (4 mmole), and the right-mixture of toluenesulphonic acids monohydrate in 200 milliliters of acetone stirred 6 days under room temperature, and removes volatile matter in a vacuum.Residue is dissolved among the EtOAc, with the saturated sodium bicarbonate aqueous solution washing, dehydrates, and concentrate in a vacuum with sal epsom.With the extracted with diethyl ether residue, and in vacuum concentrated filtrate, and 6.3 gram (75%) 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3] dioxolane-4-yl)-1, the 1-dimethyl ethyl] 2, the 3-Dihydrobenzofuranes.

In 1 gram (2.4 mmole) 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3] dioxolane-4-yl)-1, the 1-dimethyl ethyl]-2, in the solution of 3-Dihydrobenzofuranes in 20 milliliters of THF, under-78 ℃, add the 2.5M solution of 1.05 milliliters of (2.6 mmole) n-BuLi in hexane.After 20 minutes, add 0.255 milliliter (2.8 mmole) two sulphur that methylate, and make reactant be warmed to room temperature.Use the TLC monitoring reaction.Make mixture be cooled to-78 ℃, and make the reaction cancellation with saturated ammonium chloride, and with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, and concentrate in vacuum, and get 0.89 gram oil body, make it pass through the silica gel column chromatography purifying, 5% to 40% methylene dichloride in the use hexane is as eluent.In vacuum, concentrate the wash-out part that is rich in product, obtain 0.31 gram (34%) 7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3] dioxolane-4-yl)-1, the 1-dimethyl ethyl]-5-methylthio group-2, the 3-Dihydrobenzofuranes.

With 0.31 gram 7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3] dioxolane-4-yl)-1, the 1-dimethyl ethyl]-5-methylthio group-2,3-Dihydrobenzofuranes and the solution of 0.015 gram right-toluenesulphonic acids (p-TsOH) monohydrate in methyl alcohol (10 milliliters) stirred 7 days under room temperature, were heated to backflow, went through 1 minute, and remove volatile matter in a vacuum.Residue is diluted with saturated sodium bicarbonate aqueous solution, and filter.Solid is with water and hexane wash, and dry, obtain 0.235 gram 4-methyl (5-methylthio group-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl pentane-1, the 2-glycol.

In 0.313 gram (0.8 mmole) 4-methyl-4-(5-methylthio group-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl pentane-1,2-glycol and 0.06 milliliter of methane sulfonyl chloride are at 10 milliliters of MeOH/CH ₂Cl ₂In solution in, under 0 ℃, add 0.015 gram (0.08 mmole) p-TsOH monohydrate.Make mixture be warmed to room temperature, stirring is spent the night, and adds (0.01 gram) p-TsOH monohydrate in addition.Mixture was stirred 3 days, and in vacuum, concentrate.Residue is diluted with saturated sodium bicarbonate aqueous solution, and pass through solid collected by filtration.Solid is with water and hexane wash, and dry, and 0.235 gram (84%) solid, it is dissolved among 10 milliliters of THF, and is cooled to 0 ℃.Add NaH (0.064 gram, 60% oily dispersion liquid), and make mixture be warmed to room temperature, and stir and spend the night.With saturated aqueous ammonium chloride (NH ₄Cl) make the mixture cancellation, and with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, and in vacuum, concentrate.Make residue purifying (hexane-EtOAc (95: 5)) on the PLC plate, obtain 0.145 gram 7-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl]-5-methylthio group-2, the 3-Dihydrobenzofuranes.

According to embodiment 35, make 7-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl]-5-methylthio group-2,3-Dihydrobenzofuranes and 4-hydroxyquinoline and sodium ethylate reaction, and 1-[2-hydroxy-4-methyl-4-(5-methylthio group-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone.

In 0.03 gram (0.06 mmole) 1-[2-hydroxy-4-methyl-4-(5-methylthio group-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone and 0.04 gram (0.18 mmole) NaIO ₄In the solution in 3 milliliters of acetonitriles and 1 ml water, at room temperature, add the RuCl of catalytic amount ₃Mixture was stirred 30 minutes, dilute, and extract with EtOAc with water.Organic layer is merged, dehydrate, and concentrate in a vacuum with sodium sulfate.Make residue purifying on the PLC plate, with methylene chloride-methanol (CH ₂Cl ₂/ MeOH, 95: 5) wash-out, and get 0.008 gram (27%) 1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone.

Embodiment 38:1,1,1-three fluoro-3-(6-fluoro-4-methyl chroman-4-yl) third-2-ketone synthetic

10.0 gram (60 mmole) 6-fluoro chroman-4-ketone, 7.9 milliliters of (90 mmole) malonic methyl ester nitriles, 0.54 milliliter of (5 mmole) benzylamine and the mixture heating up of 3 milliliters of acetic acid in 100 milliliters of toluene are extremely refluxed, and azeotropic removes water.After 18 hours, add other malonic methyl ester nitrile and acetic acid.By the TLC monitoring reaction, reactant is concentrated under nitrogen gas stream.Residue uses EtOAc-hexane (1: 9) by silicagel pad, and 3.4 gram (22%) cyano group-[6-fluoro chroman-(4E/Z)-subunit] ritalin, it is the mixture of geometrical isomer.

In 4.3 the gram (22.6 mmole) cupric iodides (I) in 75 milliliters of ether in the suspension of chilling (0 ℃), add the 1.6M solution of 26 milliliters of (41.6 mmole) lithium methides in ether.After 5 minutes, make mixture be cooled to-20 ℃, and add 3.36 gram (13.6 mmole) cyano group-[6-fluoro chroman-(4E/Z)-subunit] ritalin solution in 20 milliliters of ether.Make mixture slowly be warmed to room temperature, and by proton N MR monitoring.Make-78 ℃ of reactant coolings, and make the reaction cancellation, and be warmed to room temperature with saturated aqueous ammonium chloride.Then, through the diatomite filtration mixture, and separate water layer, with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, and in vacuum, concentrates, and 3.1 gram (86%) cyano group-(6-fluoro-4-methyl chroman-4-yl) ritalins, be the mixture of diastereomer, can use and need not to be further purified.

Make 3.1 gram (11.8 mmole) cyano group-(6-fluoro-4-methyl chroman-4-yl) ritalins and the mixture of 2.47 gram (42.4 mmole) sodium-chlor in 30 milliliters of moisture DMSO be warmed to backflow.Reaction is monitored by TLC.After 4 hours, make the reactant cooling, and with the water dilution, with extracted with diethyl ether.The organic layer that merges with four parts of water, salt water washing, is dehydrated with sal epsom, and concentrates in a vacuum, and 2.1 gram (87%) (6-fluoro-4-methyl chroman-4-yl) acetonitriles, be oily matter.

In 2.1 gram (10.2 mmole) (6-fluoro-4-methyl chroman-4-yl) acetonitriles in 30 milliliters of methylene dichloride in chilling (40 ℃) solution, add the 1M solution of 11.4 milliliters of (11.4 mmole) diisobutylaluminium hydrides in methylene dichloride.Make mixture be warmed to room temperature.After 1 hour, make the mixture cancellation carefully, dehydrate with sal epsom with minimum water, by diatomite filtration, and concentrate in a vacuum, and get 1.7 gram (80%) (6-fluoro-4-methyl chroman-4-yl) acetaldehyde, be oily matter, can use and need not to be further purified.

In 1.7 gram (8.16 mmole) (6-fluoro-4-methyl chroman-4-yl) acetaldehyde and 1.69 milliliters of (11.4 mmole) trimethylammoniums (trifluoromethyl) silane in 15 milliliters of tetrahydrofuran (THF)s, add the 1M solution of 1 milliliter of (1 mmole) tetrabutylammonium in tetrahydrofuran (THF).Mixture was stirred 1 hour, add the 1M solution of other 9 milliliters (9 mmole) tetrabutylammonium in tetrahydrofuran (THF) then.After 18 hours, mixture is concentrated in vacuum, and with the dilution of the 1N HCl aqueous solution, and with three parts of 50 milliliters of extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, and in vacuum, concentrates, and 2.4 grams are rough 1,1,1-three fluoro-3-(6-fluoro-4-methyl chroman-4-yl) propan-2-ol is the mixture of diastereomer.Use raw oil, need not to be further purified.

In 2.4 gram (8.62 mmoles) 1,1, in 1-three fluoro-3-(the 6-fluoro-4-methyl chroman-4-yl) solution of propan-2-ol in 20 milliliters of methylene dichloride, add 11.8 mmole Dess-Martin and cross iodine alkane.After 18 hours, mixture is adsorbed on the silica gel, and,, and gets 1.05 gram (44%) title compounds, be oily matter with EtOAc-hexane (1: 9) washing by silicagel pad.

Following trifluorumethylketones is also made by the method for embodiment 34:

1,1,1-three fluoro-3-(1-methyl indane-1-yl) third-2-ketone;

1,1 ,-three fluoro-3-(6-fluorobenzene and dihydropyrane-4-yl), third-2-ketone (by preamble copper acid methyl esters step, and in standard hydrogenation conditions (Pd/C, H ₂Atmosphere) following two keys of reduction and making;

3-chroman-4-base-1,1,1-trifluoropropyl-2-ketone; And

4-benzo [1,3] Dioxol-4-yl-1,1,1-three fluoro-4-methylpentane-2-ketone.

Synthesizing of embodiment 39:1-benzo [1,3] Dioxol-4-yl ethyl ketone

In 10 gram benzo [1,3] dioxy cyclopentenes-4-formaldehyde in 200 milliliters of THF in chilling (78 ℃) solution, by adding the liquid funnel, add the 1.6M MeLi solution in 43.7 milliliters of ether.Make reactant slowly be warmed to room temperature, and stir and spend the night.Reaction is to monitor by TLC.Then, make mixture be cooled to-78 ℃, and make the reaction cancellation, and concentrate in a vacuum with saturated aqueous ammonium chloride.With the EtOAc extraction leftover.The organic layer of merging is dehydrated with sal epsom, and concentrate in vacuum, obtain 11 gram 1-benzo [1,3] Dioxol-4-yl ethanol, be the brown oil body, it is crystallization when leaving standstill.

In the solution of 11 gram 1-benzo [1,3] Dioxol-4-yl ethanol in 100 milliliters of THF, add 17.26 gram MnO with portion ₂, and with the TLC monitoring reaction.After a few hours, TLC shows new product and initial substance.Add other MnO ₂TLC shows that reaction is still incomplete.Make mixture pass through Celite ^_Flocculating aids filters, and concentrates in vacuum, and gets oil body, and it is a partial crystallizationization.In 9.24 milliliters of chlorination oxalyl in 120 milliliters of methylene dichloride in chilling (60 ℃) solution, add the solution of 15 milliliters of DMSO in 20 milliliters of methylene dichloride.After 10 minutes, add the solution of above-mentioned alcohol/alcohol/ketone mixtures (53 mmole) in 20 milliliters of methylene dichloride.After 15 minutes, add 44.3 milliliters of triethylamines.Make reactant slowly be warmed to ambient temperature overnight, be poured on ice then.The separation organic layer, and with five part of 100 ml water washing, with the salt water washing, dehydrate with sal epsom, filter, and concentrate in a vacuum, and get the tawny solid.With the hexane development, obtain 9.33 gram title compounds.

Make 1-benzo [1,3] Dioxol-4-yl ethyl ketone change into its corresponding trifluorumethylketone according to embodiment 34.

Synthesizing of embodiment 40:2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl ethyl hexanoate

In the solution of 5 gram (38 mmole) 2-phenyl propionitrile in 50 milliliters of DMSO, add the 1M solution of 42 milliliters of NaHMDS in THF.After 15 minutes, make reaction be cooled to 0 ℃, and add 4.6 milliliters of iodoethanes.Reaction is to monitor with TLC.After 30 minutes, mixture is poured in the water, and with extracted with diethyl ether.The organic substance that merges with four parts of water washings, with the salt water washing, is dehydrated with sal epsom, filters, and concentrate in a vacuum, and 6.1 gram 2-methyl-2-phenylbutyronitriles, be oily matter.

In the 6.1 gram 2-methyl-solution of 2-phenylbutyronitrile in 50 milliliters of methylene dichloride, at room temperature, dropwise add the 1M solution of 57 milliliters of DIBAI in methylene dichloride.Reaction is to monitor with TLC.After 30 minutes, reactant is poured in 100 milliliters of 1N HCl aqueous solution carefully, and separated organic layer, and concentrate in a vacuum.Residue is diluted with ether, merge with water layer, and with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, and in vacuum, concentrate.Make residue purifying on silicagel column,, and get 4.2 gram 2-methyl-2-phenyl butyraldehyde, be water white oil with vinyl acetic monomer-hexane (0-2%) wash-out.

In 7.4 gram (diethoxy phosphoryl) oxyethyl group vinyl acetic monomers in 30 milliliters of THF in the solution of chilling (0 ℃), add the 1.8M solution of 16 milliliters of LDA.After 30 minutes,, dropwise add the gram of 4.2 among 30 milliliters of THF 2-methyl-2-phenyl butyraldehyde by syringe.Make mixture be warmed to room temperature, make the reaction cancellation with saturated aqueous ammonium chloride, and with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, and in vacuum, concentrates, and 8.3 gram 2-oxyethyl group-4-methyl-4-phenyl oneself-2-olefin(e) acid ethyl ester, be orange oil, and be the mixture (2: 1) of geometrical isomer.

8.3 gram 2-oxyethyl group-4-methyl-4-phenyl oneself-solution of 2-olefin(e) acid ethyl ester in 25 milliliters of acetic acid in, add 116 milliliters of 1M aqueous sulfuric acid (H ₂SO ₄).With reactant stirred for several hour under room temperature.Reaction is to monitor with TLC.Make reactant warm spending the night under 100 ℃.Add other 2 milliliters of vitriol oils and 20 milliliters of acetic acid.After 1 hour, make reactant be cooled to room temperature, and with extracted with diethyl ether.The organic substance that merges with four parts of water washings, with the salt water washing, is dehydrated with sal epsom, filters, and concentrate in a vacuum, and 2.5 gram orange oil.Proton N MR is shown as 1: 1 mixture of less isomer and aldehyde.With the EtOAc aqueous layer extracted.The vinyl acetic monomer layer of merging is dehydrated with sal epsom, and in vacuum, concentrate, and get brown liquid.NMR shows that the mixture of products of wanting is a ketone acid.Mixture with 200 milliliters of alcohol dilutions, is added 1 milliliter of dense HCl, and the mixture backflow is spent the night.Make reactant be cooled to room temperature, and in vacuum, concentrate.Residue is diluted with water, and with extracted with diethyl ether.The organic substance of merging is dehydrated with sal epsom, filter, and concentrate in a vacuum, and get 4.3 gram 4-methyl-2-oxo-4-phenyl ethyl hexanoates, be orange oil.

In 4.3 gram 4-methyl-2-oxo-4-phenyl ethyl hexanoates and the solution of 3.6 milliliters of trifluoromethyl trimethyl silanes in 50 milliliters of THF, add 1.5 milliliters of 1M TBAF among (0.1 equivalent) THF.Reaction stirred is till being learnt that by TLC ketone ester has consumed.After 30 minutes, add 17.5 milliliters of TBAF.After 1 hour, enriched mixture in vacuum, and with residue with 1N HCl aqueous solution dilution, and with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, filter, and concentrate in a vacuum, and get brown oil.Residue is diluted with hexane (muddiness), with activated carbon treatment, through Celite ^_Flocculating aids filters, and concentrates in a vacuum, and gets 3.8 gram 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl ethyl hexanoates, is the mixture of diastereomer, is light green oil.

Make the non-enantiomer mixture of ester class change into its corresponding epoxide according to embodiment 1.

Embodiment 41:6-bromo-4-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl] benzo [1,3] dioxole synthetic

At 0.1 gram (0.35 mmole) 4-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl] in the solution of benzo [1,3] dioxole in 5 milliliters of THF, add 0.06 gram (0.35 mmole) N-bromosuccinimide.Reaction is to monitor with TLC.After stirring was spent the night, TLC showed initial substance and new a little more polar spot.Concentration response thing in vacuum, and residue diluted with hexane.Filter formed suspension removing insoluble substance, and make filtrate on silica gel by chromatography purification, with vinyl acetic monomer-hexane (0-10%) wash-out, and oily, learn mixture by proton N MR into initial substance and product (3.5: 1).Residue is dissolved in 3 milliliters of acetonitriles, and adds 0.06 gram (0.35 mmole) N-bromosuccinimide.After 3 hours, TLC demonstration reaction is finished, and by above-mentioned processing, and get 0.07 gram (54%) 6-bromo-4-[1,1-dimethyl-2-(2-trifluoromethyl Oxyranyle) ethyl] benzo [1,3] dioxole, be yellow oil.

Embodiment 42:1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,3-Indolin-2-one synthetic

In the solution of 42 milligrams of (0.31 mmole) oxindoles in 1 milliliter of DMF, add 10 milligrams of 60% sodium hydrides in (0.39 mmole) Dormant oils.After hydrogen release goes out to stop, adding 50 milligrams of (0.17 mmole) 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-trifluoromethyl oxyethane, and make mixture be warmed to 75 ℃.Reaction is to monitor with TLC (vinyl acetic monomer-hexane (15: 85)).After 40 minutes, make the mixture cooling, and with the saturated aqueous ammonium chloride dilution, and with three parts of 5 milliliters of ethyl acetate extractions.The organic layer that merges is washed with three part of 5 mL of saline, dehydrate, and concentrate in a vacuum with sal epsom.Make crude material chromatography (2 * 1 millimeters, vinyl acetic monomer-hexane (15: 85)) on the preparation of silica gel plate.Make material by preparation plate gained from methylene dichloride-hexane-ether recrystallize, and 14 milligrams of title compounds.

Embodiment 43:1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone synthetic

In the fluorine-based phenol of 4-(25.3 gram) and chlorination dimethyl allene acyl (25.9 gram) in Di Iso Propyl Ether (500 milliliters), in ice bath in the refrigerative solution, during 20 minutes, dropwise add triethylamine (35 milliliters), after 1 hour, with reaction mixture Yi Shui and salt water washing, dehydrate with sodium sulfate, and evaporate organic solvent in a vacuum, obtain crude ester.Under vacuum, distill, obtain dimethacrylate 4-fluorobenzene ester (38.20 grams, 87%).

In the suspension through stir of aluminum chloride (18.0 gram) in dithiocarbonic anhydride (30 milliliters), in 0.5 hour, dropwise add dimethacrylate-4-fluorobenzene ester (18.0 grams, 92.7 mmoles).Reaction mixture was stirred under room temperature 14.0 hours.Reactant is poured on ice, and extracts with vinyl acetic monomer-hexane (1: 10,200 milliliters).Organic phase with the washing of saturated carbon ester hydrogen sodium, with the anhydrous sodium sulfate dehydration drying, and is evaporated in a vacuum.With cold hexane development residue, obtain colourless crystallization 6-fluoro-4,4-dimethylbiphenyl dihydropyrane-2-ketone (13.9 grams, 77%).

6-fluoro-4 in being dissolved in DMSO (20.0 milliliters) in 4-dimethylbiphenyl dihydropyrane-2-ketone (5.40 gram) solution, in 5 minutes, adds potassium hydroxide (6.00 gram) solution in water-soluble (10.0 milliliters).After 20 minutes, in 15 minutes, methyl iodide (4.0 milliliters) is added in gradation, and mixture was at room temperature stirred 14.0 hours.Mixture is diluted with hexane,, dehydrate, filter with water washing, and evaporation in a vacuum.Distillation produces 3-methyl-3-(2-methoxyl group-5-fluorophenyl) methyl-butyrate (4.2 grams, 63%).

In the suspension of the lithium aluminium hydride that under nitrogen, stirs (0.75 gram) in THF (20 milliliters), dropwise add 3-methyl-3-(2-methoxyl group-5-fluorophenyl) methyl-butyrate (4.2 gram) solution that is dissolved among the THF (10 milliliters).Mixture was stirred under room temperature 4 hours.Make the reaction cancellation by careful interpolation water (1 milliliter), and dilute with ether (100 milliliters).Through FLORISIL ^_The selective adsorbent filtering mixt, and in vacuum, be evaporated to dry, and 3-methyl-3-(2-methoxyl group-5-fluorophenyl) fourth-1-alcohol, be oily matter (3.30 grams, 89%).

In the solution of the 3-methyl-3-that stirs under the room temperature (2-methoxyl group-5-fluorophenyl) fourth-1-alcohol (3.30 gram) in methylene dichloride (40 milliliters), in 5 minutes, pyridinium chlorochromate (4.2 gram) is added in gradation.Mixture was stirred 3 hours, pass through Celite then ^_Flocculating aids filters.Evaporating solvent in vacuum, and make residue on silica gel with chromatography fractional separation (methylene dichloride-hexane (1: 3 to 1: 1 gradient liquid)), obtain 3-methyl-3-(2-methoxyl group-5-fluorophenyl) butyraldehyde oil (2.5 grams, 76%).

In dry ice/acetone batch, in the solution of refrigerative difluoro methylphosphonic acid diethyl ester (1.35 gram) in THF (5.0 milliliters), in 5.0 minutes, dropwise add LDA (5.0 milliliters, 1.5M is in hexanaphthene).10.0 after minute, dropwise add the solution of 3-methyl-3-(2-methoxyl group-5-fluorophenyl) butyraldehyde (0.94 gram) in THF (5.0 milliliters).After 20.0 minutes, add acetic acid (1 milliliter), and make mixture be warmed to room temperature again.Mixture is diluted with vinyl acetic monomer,, dehydrate, filter with water washing, and evaporation in a vacuum.Make residue fractional separation (eluent: methylene dichloride-vinyl acetic monomer (1: 4)) on silica gel, obtain desired [1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group] diethyl phosphonate (1.15 grams, 40%), be oily matter, it is crystallization when handling with hexane.

Oxalyl chloride solution (2.2 milliliters, 2.0M is in methylene dichloride) is diluted with methylene dichloride (3.0 milliliters), and in dry ice/acetone batch, cool off.In this solution, dropwise add the solution of DMSO (0.7 milliliter) in methylene dichloride (2.5 milliliters).After 10 minutes, add the solution of [1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group] diethyl phosphonate (1.10 gram) in methylene dichloride (3 milliliters), and mixture was stirred 15 minutes.Add triethylamine (4.0 milliliters), remove cooling bath, make reaction mixture be warmed to room temperature, and make the reaction cancellation, and dilute with hexane with water.Separate organic layer,, dehydrate, filter, and concentrate in a vacuum with water washing.Residue passes through chromatography purification (eluent: hexane is to hexane-vinyl acetic monomer (2: 1) gradient liquid) on silica gel, and gets [1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo amyl group] diethyl phosphonate, is oily matter (1.0 grams, 91%).

In the solution of [1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxo amyl group] diethyl phosphonate (1.0 gram) in methyl alcohol (12.0 milliliters), add the solution of sodium hydroxide (0.04 gram) in water (1 milliliter).Mixture was stirred under room temperature 30 minutes.With hexane (50 milliliters) and water (50 milliliters) diluted mixture thing, and separate organic phase, dehydrate, filter, and evaporation in a vacuum, obtain 1,1-two fluoro-4-methyl-4-(2-methoxyl group-5-fluorophenyl) pentane-2-ketone (0.63 gram), oily matter can use and need not other purifying.

Under nitrogen, stir, and in the suspension of iodate trimethylammonium sulfur oxide (0.22 gram) in DMSO (0.5 milliliter) and THF (0.5 milliliter) of cooled on ice, in 5 minutes, dropwise add (1.0 milliliters of hexamethyl two silicon sodiumazide (disilazide), 1.0M, in THF).After 15 minutes, dropwise add the solution of 1,1 ,-two fluoro-4-methyl-4-(2-methoxyl group-5-fluorophenyl) pentane-2-ketone (0.23 gram) in THF (0.6 milliliter), and make mixture in 2 hours, return back to room temperature.Mixture is diluted with hexane,, dehydrate, filter with water washing, and evaporation in a vacuum, and get 2-[2-(5-fluoro-2-methoxyphenyl)-2-methyl-propyl]-2-difluoromethyl oxyethane, be oily matter (0.25 gram).

In 4-hydroxyquinoline and 2-[2-(5-fluoro-2-the methoxyphenyl)-2-methyl-propyl that nitrogen stirs down]-solution of 2-difluoromethyl oxyethane in DMSO (1.0 milliliters) in, dropwise add NaHMDS (1.2 milliliters, 1.0M is in THF).Mixture was stirred under room temperature 15 days.Mixture is diluted with vinyl acetic monomer,, dehydrate, filter with water washing, and evaporation in a vacuum.With ether development residue, obtain product 1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone, be crystalline solid, it is collected by filtering, and dry air (77.7 milligrams, 20%).

Embodiment 44:1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpentane-2-ketone synthetic

In the yellow solution of 20 gram 4-methyl cresyl ethers and 1.7 milliliters of vitriol oils, dropwise add 19.17 milliliters of 3-chloro-2-methacrylics.It is warm that reactant becomes, and be transformed into intense violet color, and formed throw out after 20 minutes.Reaction is with the TLC monitoring, shows new low polarity product.After 18 hours, reactant is poured on ice, and with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, filter, and concentrate in a vacuum, to stay oil.Residue is diluted with hexane, be cooled to-78 ℃, and by solid collected by filtration, and getting 14 gram 2-(2-chloro-1,1-dimethyl ethyl)-1-methoxyl group-4-toluene, it is to dissolve when being warmed to room temperature.Concentrated filtrate in vacuum, and get 15.5 gram product and initial cresyl ethers (4: 1 mixtures).

In the suspension of 1.87 gram Mg Xuan bits in 30 milliliters of anhydrous diethyl ethers, under argon gas, in water-bath, slowly add 1.62 milliliters of ethylene dibromides with syringe, temperature is kept below 27 ℃ simultaneously.By addition funnel, add 4 gram 2-(2-chloro-1,1-dimethyl ethyl)-1-methoxyl group-4-toluene and the other solution of ethylene dibromide (1.62 milliliters) in 20 milliliters of ether, its speed will keep internal temperature to be lower than 25 ℃.Reactant becomes green, and has fine throw out to form.After 1 hour, make reactant be cooled to-78 ℃, have solid to form in the bottom, stop to stir, and add the solution of 3.98 milliliters of trifluoro-acetic anhydrides in 4 milliliters of ether, with hand reactant is spinned simultaneously by addition funnel.Make reactant be warmed to room temperature, and stir to get back to and be higher than-40 ℃.Reaction is with the TLC monitoring, shows a kind of new a little more polar product and initial substance.Reactant is poured on the cold 1N HCl aqueous solution, and with extracted with diethyl ether.The organic layer of merging is dehydrated with sal epsom, and in vacuum, concentrate.Make residue purifying on silicagel column, with vinyl acetic monomer-hexane (0-5%) wash-out, and get 1.7 grams 1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpentane-2-ketone are clean oil.

Embodiment 45:{4-[4-(5-fluoro-2-p-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydro-2H-quinoxaline-yl } furans-2-base ketone

At 2-(3,4-dihydro-2H-quinoxaline-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-p-methoxy-phenyl)-4-methyl-penta-2-alcohol (0.50g, 0.117 mmole) add pyridine (0.24ml in the solution in methylene dichloride (10ml), 0.129 mmole) and 2 furoyl chloride (0.012ml, 0.129 mmole).Be reflected at stirring at room 14 hours.Reaction mixture dilutes with methylene dichloride, and is dry on sodium sulfate with the saturated carbon sodium hydride aqueous solution washing of two parts of 25ml, filters, and boils off solvent in a vacuum.With hurried post chromatograph (5%MeOH/CH ₂CH ₂) purifying, obtain the motif compound (14.5mg) of white solid.

The assessment of biological property

The compounds of this invention is that assessment is to the combination of steroid receptor by the competitive binding assay of fluorescent polarization.Detailed description about employed reorganization glucocorticoid receptor (GR) mixture in the preparation detection be described in the U.S. patent application case communique 2003/00175503, and it is incorporated herein for reference in full.The preparation of surveying thing through the dexamethasone of tetramethylrhodamin (TAMRA) mark be to use the normative document program finish (people such as M.Pons, J.Steroid Biochem., 1985, 22, the 267-273 page or leaf).

A. glucocorticoid receptor is competitive in conjunction with detecting

Step 1. fluorescent is surveyed the characterized of thing

At first, measure fluorescent and survey the maximum excitation of thing and the wavelength of emission.The example of this kind detection thing is the dexamethasone through rhodamine (TAMRA) mark.

Then, in titration experiments, measure and survey the avidity of thing steroid receptor.Surveying the fluorescent polarization value of thing in detecting damping fluid, is on the SLM-8100 fluorometer, uses above-mentioned exciting with emission maximum to measure.Add the sample aliquot of expression vector lysate, and add back measurement fluorescent polarization, till any further change of no longer finding polarization value each time.Use a non-linear young waiter in a wineshop or an inn's square regression analysis, is bonded to the polarization value of surveying thing about lysate, calculate the dissociation constant of surveying thing from what obtain.

Step 2. is surveyed the screening of thing binding inhibitors

This detection is to use fluorescent polarization (FP), competes the ability of system from human glucocorticoid receptor (GR) mixture of insect expression system that be bonded to quantitative testing compound and the dexamethasone through tetramethylrhodamin (TAMRA) mark.The detection buffer reagent is: 10mM TES, 50mM KCl, 20mM Na ₂MoO ₄2H ₂O, 1.5mM EDTA, 0.04%w/v CHAPS, 10%v/v glycerine, 1mM dithiothreitol (DTT), pH7.4.Make testing compound in pure DMSO, be dissolved to 1mM, in being supplemented with the detection damping fluid of 10%v/v DMSO, further be diluted to the 10x detectable level then.In the polypropylene board of 96-hole, with the 10x detectable level, serial dilution is in containing the buffer reagent of 10%DMSO with testing compound.The association reaction mixture is to make in the black Dynex titer plate of 96-hole, its mode is that following detection composition is added in each hole successively: 15 microlitre 10x testing compound solutions, 85 microlitres were diluted in the baculovirus lysate that contains GR that detects in the damping fluid with 1: 170, and 50 microlitre 15nM are through the dexamethasone of TAMRA mark.Positive controls is not for containing the reaction mixture of testing compound; Negative control group (blank test) is for containing the reaction mixture of 0.7 μ M to 2 μ M dexamethasone.The association reaction thing was cultivated under room temperature 1 hour, excited and 580 millimicrons of emissions being set to 550 millimicrons then, be equipped with in the LJL analyzer of rhodamine 561 dichroic mirror and read the fluorescent polarization.IC ₅₀Value is to record by coincideing to the iteration nonlinear curve of the FP message data of 4-parameter logical equatiion.

Discovery is bonded to the compound of glucocorticoid receptor, can assess the combination of progesterone receptor (PR), estrogen receptor (ER) and mineralocorticoid acceptor, with the selectivity of assessment compound to GR.Is identical with above-mentioned GR method about PR with the scheme of MR, but except following: PR insect cell lysate was diluted with 1: 7.1, and the MR lysate was with dilution in 1: 9.4.It is that it is used for the detection that final concn is 5nM through the mifepristone (mifepristone) of TAMRA sign that PR surveys thing, and negative control group (blank test) is for containing the reactant of mifepristone under 0.7 μ M to 2 μ M.

The ER scheme is to be similar to such scheme, but use PanVera external member acceptor, through the detection thing of luciferin sign.Detecting composition is to make under volume same as described above, and being used for ER with generation is 15nM, and ES2 detection thing is the last detectable level of 1nM.In addition, the interpolation of composition is by above-mentioned detection correction in proper order: at first, will survey thing and be added in the plate, and then add acceptor and testing compound.This plate is excited and 530 millimicrons of emissions being set to 485 millimicrons, be equipped with in the LJL analyzer of luciferin 505 dichroic mirror and read.

The detection that compound through finding to be bonded to glucocorticoid receptor is quoted from can be by background of invention (C.M.Bamberger and H.M.Schulte, Eur.J.Clin.Invest., 2000, 30(replenish 3) 6-9), or the detection by hereinafter described, assess trans the dissociating of effect and trans-repression of intensifying.

B. glucocorticoid receptor cell detection

1. aromatase enzyme inducing in inoblast (cell detection of transactivation)

Dexamethasone is a kind of synthetic ligand to glucocorticoid receptor (GR), and it induces the expression of aromatase enzyme in human foreskin inoblast.The activity of aromatase enzyme is in substratum, changes into the middle measurement of carrying out of estradiol by testosterone.Showing the compound that is bonded to GR, is to assess it to induce the ability of aromatase activity in human foreskin inoblast.

5 days before use, human foreskin inoblast (ATCC catalog number CRL-2429, title CCD112SK) with under 50,000 cells in every hole, is layered on 96 orifice plates, at the FBS that is supplemented with 10% activated carbon filtration (Clonetech catalog number SH ₃0068) with the IscoveShi modification Dulbecco substratum (GibcoBRL life technology catalog number 12440-053) of gentamicin (GibcoBRL life technology catalog number 15710-064) in.Testing the same day, with the substratum in the new substratum displacement hole.Cell is handled with testing compound, and making final concn is 10 ^-5M to 10 ^-8M, and the final concn of testosterone is 300 millimicro grams per milliliters.Each hole has the cumulative volume of 100 microlitres.Sample is to make double.Control wells comprises: (a) only accept the hole of testosterone, accept the hole that testosterone adds 2 μ M dexamethasone with (b), so that the maximum inducing action of aromatase enzyme to be provided.Make plate in 37 ℃ of following overnight incubation (15 to 18 hours), and when cultivating end, gather supernatant liquid.Estradiol in the supernatant liquid is the specification sheets according to the producer, uses the ELISA external member (made by ALPCO, derive from U.S. laboratory product catalog number 020-DR-2693) of estradiol to measure.The amount of estradiol be with each hole in the ELISA signal be inversely proportional to.By testing compound inductive aromatase enzyme amount is so that the relative percentage of ground rice pine is represented.The EC of testing compound ₅₀Value is to coincide by nonlinear curve to derive.

2. the IL-6 that is suppressed in the fibrocyte produces (cell detection of trans-repression)

Human foreskin inoblast produces IL-6 when replying the stimulation of pro-inflammatory cytokine IL-1.This inflammatory response when measuring by the generation of IL-6, can be suppressed by dexamethasone effectively, and it is a kind of synthetic ligand to glucocorticoid receptor (GR).Demonstration is to suppress the ability that IL-6 produces through assessing it in human foreskin inoblast to GR bonded compound.

On the same day before use, (ATCC catalog number CRL-2429) is laid on 96 orifice plates with 5,000 cells in every hole with human foreskin inoblast, is being supplemented with the filtering FBS of 10% charcoal (Clonetech catalog number SH ₃0068) with the IscoveShi modification Dulbecco substratum (GibcoBRL life technology catalog number 12440-053) of gentamicin (GibcoBRL life technology catalog number 15710-064) in.In second day, with the substratum in the new substratum displacement hole.With cell with IL-1 (rhIL-1 α, R﹠amp; D system catalog number 200-LA) handle, making final concn is 1 millimicro grams per milliliter, and uses testing compound to handle, and making final concn is 10 ^-5M to 10 ^-8M, the cumulative volume in every hole are 200 microlitres.Sample is made double.The background control wells is not accepted testing compound or IL-1.EL-1 is only accepted in the positive control hole, and the IL-6 of expression maximum (or 100%) amount produces.Make plate in 37 ℃ of following overnight incubation (15 to 18 hours), and when cultivating end, gather supernatant liquid.IL-6 content in the supernatant liquid is according to producer's specification sheets, and the ELISA external member (MedSystems diagnostic reagent GmbH, Vienna, Austria, catalog number BMS213TEN) by IL-6 records.The IL-6 amount that testing compound suppresses is to represent with the per-cent with respect to positive controls.The IC of testing compound ₅₀Value is to coincide by nonlinear curve to derive.

Be bonded to the agonist of compound of glucocorticoid receptor or the assessment of antagonistic activity, can measure by any detection method.

3. the adjusting of tyrosine aminotransferase (TAT) inducing action in the big white mouse liver cancer cell

Test compounds in the big white mouse liver cancer cell, agonist or antagonistic activity in inducing tyrosine aminotransferase (TAT).

Make H ₄-II-E-C ₃Cell in 96 orifice plates (20,000 cell/100 microlitres/wells), in containing 10% heat inactivation FBS and 1% nonessential amino acid whose MEM substratum, overnight incubation.In second day, dexamethasone or the testing compound (be dissolved in DMSO last DMSO concentration 0.2%) of cell with specified concentration stimulated 18 hours.Control cells is handled with 0.2%DMSO.After 18 hours, make cytolysis in the buffer reagent that contains 0.1%Triton X-100, and in spectrophotometer detects, use tyrosine and α-Tong Wuersuan ester as substrate measurement TAT activity.

Be to measure antagonistic activity, before testing compound is applied to cell soon, by adding dexamethasone (concentration range 3 * 10 ^-9M to 3 * 10 ^-8M), stimulate liver cancer cell in advance.Use steroid non-selective GR/PR antagonist mifepristone (mifepristone) in contrast.

4. the adjusting of MMTV-Luc inducing action in the Hela cell

Test compounds in the HeLa cell, agonist or antagonistic activity in stimulating MMTV-(mouse mammary tumor virus) promotor.

Make the HeLa cell containing pHHLuc-plasmid, and express selectivity microbiotic GENETICIN on the structure in luciferase genes (Norden, 1988) the place ahead clone's MMTV-LTR fragment (200 to+100) with respect to transcription initiation site ^_The pcDNA3.1 plasmid (Invitrogen) that resistance arranged is cotransfection stably.Selection has the best inductive clone of MMTV-promotor system, and is used for further experiment.

Make cell overnight incubation in the DMEM substratum, this cultivation salt does not have phenol red, is supplemented with 3%CCS (through the calf serum of charcoal processing), is transferred to then in 96 orifice plates (15,000 cell/100 microlitres/holes).Second day,, stimulate the activation of MMTV-promotor by adding testing compound or the dexamethasone (final concn 0.2%) that has been dissolved among the DMSO.Control cells is only handled with DMSO.After 18 hours, (Promega, catalog number E1531) makes cytolysis with the molten born of the same parents' reagent of cell, adds luciferase detection reagent (Promega, catalog number E1501), and (BMG, Offenburg) the measurement aura is luminous to use luminometer.

Be to measure antagonistic activity, before testing compound is applied to cell soon, by adding dexamethasone (3 * 10 ^-9M to 3 * 10 ^-8M), stimulate the MMTV-promotor in advance.Use the non-selective GR/PR antagonist of steroid mifepristone in contrast.

5. the adjusting that IL-8 produces in the U937 cell

Test compounds in the U-937 cell, agonist or antagonistic activity in inhibition LPS inductive IL-8 that GR causes secretion.

The U-937 cell was cultivated 2 to 4 days in the RPMI1640 substratum that contains 10%CCS (through the calf serum that charcoal is handled).With cell transfer to 96 orifice plate (40,000 cell/100 microlitres/well) in, and (be dissolved among the DMSO at dexamethasone or testing compound, final concn 0.2%) stimulates with 1 mcg/ml LPS (being dissolved among the PBS) under existence or the non-existent situation, control cells is handled with 0.2%DMSO.After 18 hours,, use " the human IL-8 cover of OptEIA group " (Pharmingen, catalog number 2654KI), measure the IL-8 concentration in the cell supernatant liquid by ELISA.

Be to measure antagonistic activity, before testing compound is applied to cell soon, by adding dexamethasone (3 * 10 ^-9M to 3 * 10 ^-8M), suppress the LPS inductive IL-8 of institute secretion.Use the non-selective GR/PR antagonist of steroid mifepristone in contrast.

6. the adjusting that ICAM-Luc expresses in the HeLa cell

Test compounds in the HeLa cell, agonist or antagonistic activity in suppressing TNF-α-caused ICAM-promotor activation.

Make the HeLa cell with expression on the plasmid that contains 1.3kb fragment in luciferase genes the place ahead clone's human ICAM-promotor (1353 to-9, with respect to transcription initiation site, Ledebur and Parks, 1995) and the structure to microbiotic GENETICIN ^_PcDNA3.1 plasmid (Invitrogen) cotransfection stably of resistance.Selection has the clone system of the best inducing action of ICAM-promotor, and is used for further experiment.Make cell transfer to 96 orifice plate (15,000 cell/100 microlitres/wells), in being supplemented with the DMEM substratum of 3%CCS.Second day, by adding 10 millimicro grams per milliliter recombinant chou TNF-α (R﹠amp; D system catalog number 210-TA), induce the activation of ICAM-promotor.Simultaneously, cell is handled with testing compound or dexamethasone (being dissolved among the DMSO final concn 0.2%).Control cells is only handled with DMSO.After 18 hours, (Promega, catalog number E1531) makes cytolysis with the molten born of the same parents' reagent of cell, adds luciferase detection reagent (Promega, catalog number E1501), and (BMG, Offenburg) the measurement aura is luminous to use luminometer.

Be to measure antagonistic activity, before testing compound is applied to cell soon, by adding dexamethasone (3 * 10 ^-9M to 3 * 10 ^-8M), the activation that suppresses the TNF-α of ICAM-promotor-cause.Use the non-selective GR/PR antagonist of steroid mifepristone in contrast.

Representative compounds of the present invention is tested in one or more above-mentioned detections, and has confirmed to have the activity as the glucocorticoid receptor function modulator.For example, following formula of the present invention (IA) has combined at GR with formula (IB) compound and has confirmed to have effective active in the detection:

2-(2,3-dihydrobenzo [1,4] oxazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydro-1H-1 λ 4-benzo [1,4] thiazine-4-ylmethyl) penta-2-alcohol;

1-[2-hydroxyl-4-(2-methoxyl group-5-thiene-3-yl-methyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(4-{3-[1-(benzyloxy imino-) ethyl] phenyl }-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-1H-quinoline-4-ketone;

1-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl hexyl)-1H-quinoline-4-ketone;

6-fluoro-1-[4-(5-fluoro-2-p-methoxy-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

2-(2,3-indoline-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and piperazine-1-yl) furans-2-base ketone;

2-(3,4-dihydro-2H-quinoxaline-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-3,4-dihydro-2H-quinoxaline-1-ylmethyl) penta-2-alcohol;

2-(2,3-dihydrobenzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1-[2-hydroxyl-4-(2-hydroxyl-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

Carbonic acid 4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] the phenyl ester methyl esters;

1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone; And

1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone.

7. suppressing by scleroblast is the osteocalcin that MG-63 produces

One day before use, with human osteosarcoma MG-63 cell (ATCC catalog number CRL-1427) with every hole 20,000 cell is layered on 96 orifice plates, at 200 microlitre 99%D-MEM/F-12 (Gibco-Invitrogen, catalog number 11039-021) in the substratum, it is through replenishing 1% penicillin and Streptomycin sulphate (Gibco-Invitrogen, catalog number 15140-122), 10 mcg/ml vitamins Cs (Sigma catalog number-4544) and 1% charcoal filter fetal bovine serum (HyClone, catalog number SH ₃0068.02).Second day, with new substratum displacement hole.Cell is handled with vitamins D (Sigma, catalog number D1530), and making final concn is 10nM, and is 10 with concentration ^-6M to 10 ^-9The testing compound of M is handled at every hole cumulative volume 200 microlitres.Sample is made double.The background control wells is not accepted vitamins D or compound.The positive control hole is only accepted vitamins D and is not had compound, and the osteocalcin of expression maximum (100%) amount produces.Plate was cultivated 48 hours under 37 ℃ of incubators, and when cultivating end, gathered supernatant liquid.The amount of osteocalcin is according to producer's specification sheets in supernatant liquid, and (Zymed, catalog number 99-0054) records by Glype osteocalcin ELISA external member.Osteocalcin is to represent with the per-cent with respect to positive controls by the inhibition of testing compound.The IC of testing compound ₅₀Value is to derive by the non-rectilinear curves.

Following formula (IA) compound suppresses the production that osteocalcin stimulates through vitamins D:

1-(4-biphenyl-3-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-[1,5] naphthyridine-4-ketone.

The present invention also is provided among the patient method of regulating glucocorticoid receptor function, and it comprises this patient thrown and gives according to compound of the present invention.If regulate the purpose of glucocorticoid receptor function in the patient is treatment morbid state or symptom, and then dispensing comprises preferably that treatment is gone up or the pharmaceutically acceptable The compounds of this invention of significant quantity pharmaceutically.If regulate the purpose of glucocorticoid receptor function among the patient and be for diagnosis or other purposes (for example, for measuring the patient) to the suitability of treatment or to susceptibility according to the various inferior therapeutic doses of The compounds of this invention, the preferred package of then offeing medicine contain significant quantity according to The compounds of this invention, anticipate promptly, by obtaining to be wanted modulating action or the necessary amount of degree.

The method of therepic use

As noted above, The compounds of this invention can be used for regulating glucocorticoid receptor function.When so carrying out, these compounds have therapeutic action in caused morbid state and symptom by glucocorticoid receptor function maybe will have benefited from regulating glucocorticoid receptor function.

Because of The compounds of this invention is regulated glucocorticoid receptor function, it has extremely useful anti-inflammatory and antiallergic property, immunosuppression and anti-proliferative activity, and it can medicine and be used among the patient, particularly is medical composition form as mentioned below, with treatment morbid state and symptom.

Can be used for the patient by medicine according to agonist compound of the present invention, to treat following morbid state or the indication that is accompanied by inflammatory, supersensitivity and/or hyperplasia process:

(i) tuberculosis: chronic, the obstructive pulmonary disease, particularly bronchial asthma of any origin and chronic obstructive pulmonary disease (COPD); Adult's Respiratory distress syndrome (ARDS); Bronchiectasis; The bronchitis of various origins; All symptoms of restrictive lung disease, particularly supersensitivity utricle inflammation; The form of ownership of pulmonary edema, particularly toxicity pulmonary edema; The form of ownership of the tissue space lung disease of any origin for example radiates pneumonia; And sarcoidosis and granulomatosis, particularly Boeck disease.

(ii) rheumatism or autoimmune disease or joint disease: the form of ownership of rheumatism, especially rheumatic arthritis, acute rheumatic fever and polymyalgia rheumatosis; Reactive arthritis; The rheumatic soft tissue diseases; The inflammatory soft tissue diseases of other origins; Syndromes in the sex change joint disease (joint disease); Traumatic arthritis; The collagenosis of any origin, for example systemic lupus erythematosus, scleroderma, polymyositis, dermatitis, Sjogren syndromes, StillShi disease and Felty syndromes;

(iii) anaphylactic disease: the form of ownership of anaphylaxis, for example vasodilation, hay fever, lnsect bite, to the anaphylaxis of medicine, blood derivatives, contrast medium etc., anaphylactic shock (anaphylaxis), urticaria, vasodilation and contact dermatitis;

(iv) vasculitis disease: joint knot property panarteritis, joint knot property polyarteritis, temporalis arteritis, Wegner granuloma, giant cells sacroiliitis and erythema nodosum;

(v) tetter: atopic dermatitis, particularly in children; Psoriasis; The red fervent rash of hair; By the erythema disease that the various cause of disease triggered, for example ray, chemical, burn etc.; Big blister tetter; The disease of lichen sample complex; The disease of scratching where it itches (for example supersensitivity origin); Seborrheal dermatitis; Rosacea; Pemphigus vulgaris; The polymorphism exudative erythema; Balanitis; Cysthitis; Hair drops, and for example takes place with bunch shape baldness; And cutaneous T cell lymphoma;

(vi) ephrosis: nephrotic syndrome; And all types of ephritis, for example glomerulosclerosis;

(vii) hepatopathy: acute liver cell is decomposed; The acute hepatitis of various origins, for example virus, toxicity, medicine are caused; And chronic aggressiveness and/or Chronic Intermittent hepatitis;

(viii) gastrointestinal illness: inflammatory bowel disease, for example regional enteritis (clone disease), ulcerative colitis; Gastritis; Reflux esophagitis (reflux oesophagitis); And the gastro-enteritis of other origins, for example non tropie sprue;

(ix) proctology disease: anal eczema; Be full of cracks; Hemorrhoid; And spontaneous rectitis;

(x) disease of eye: anaphylactic keratitis, uveitis or iritis; Conjunctivitis; Blepharitis; The optic nerve neuritis; Choroiditis; And sympatheticophthalmia;

(xi) disease in ear, nose and throat (ENT) district: allergic rhinitis or hay fever; External otitis for example causes because of institutes such as contact eczema, infection; And otitis media;

(xii) neurological disease: the cerebral edema that cerebral edema, particularly tumour are relevant; Multiple sclerosis; Acute encephalomyelitis; Meningitis; Acute spinal cord injury; Apoplexy; And the various forms of bursting, for example nodding spasm;

(xiii) hematologic disease: acquired hemolytic anemia; And spontaneous thrombocytopenia;

(xiv) tumor disease: acute lymphoblastic leukemia; Malignant lymphoma; Lymphogranulomatosis; Lymphosarcoma; Epitaxy shifts, particularly in breast, segmental bronchus and tumor of prostate;

(xv) endocrinopathy: endocrine ophthalmocace; The internal secretion orbital disease; Tiroidina toxicity crisis; De QuervainShi thyroiditis; Struma lymphomatosa; The BasedowShi disease; The granuloma thyroiditis; Struma lymphomatosa; And GraveShi disease;

(xvi) organ-tissue is transplanted and graft-right-host disease;

(xvii) Xiu Ke serious state, for example septic shock, anaphylactic shock and general are inflammatory response syndromes (SIRS);

(xviii) following replacement is treated: congenital primary adrenal insufficiency, for example suprarenogenic syndromes; The day after tomorrow primary adrenal insufficiency, for example AddisonShi disease, autoimmunization paranephritis, infect back, tumour, transfer etc.; Congenital supervention adrenal insufficiency, for example congenital hypopituitarism; Reach the supervention adrenal insufficiency day after tomorrow, for example infect back, tumour, transfer etc.;

(xix) pain of inflammatory origin, for example pain in the back; And

(xx) various other diseases states or symptom, comprise that type i diabetes (insulin-dependent diabetes), osteoarthritis, Guillain-Barre syndromes, restenosis, Ah ear behind the coronary vasodilator neoplasty in Pi Jing chamber grow extra large Mo's disease, acute and chronic pain, atherosclerosis, reperfusion injury, bone absorption disease, congestive heart failure exhaust, myocardial infarction, thermal damage, the multiple organ injury of wound supervention, acute purulent meningitis, necrotizing enterocolitis, and with hemodialysis, white cell electrophoresis and the granulocyte relevant syndromes of transfusing blood.

In addition, compound according to the present invention can be used for treatment above also NM any other morbid state or symptom, its use, just using maybe will use the synthetic glucocorticoid treatment (consult, H.J.Hatz for example, Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien[glucocorticosteroid: immunology principle, pharmacology and treatment are guided], Stuttgart:Verlagsgesellschaft mbH, 1998, it is for reference that it lists in this paper in full).Major part referred to above or all indications (i) to (xx) are described in detail in H.J.Hatz, Glucocorticoide: Immunologische Grundlagen, Pharmakologie und TherapierichtlinienIn.Moreover The compounds of this invention also can be used for treating above listed or mentioned herein or illness in addition is discussed, and is included in the background of invention.

The present invention includes the purposes of using the The compounds of this invention pharmaceutical compositions.The present invention comprises that also use is according to The compounds of this invention and the pharmaceutically acceptable glucocorticosteroid purposes with pharmaceutical compositions.The present invention comprise in addition use according to The compounds of this invention in conjunction with as acceptable vehicle and composition on the other drug that this paper proposed with the purposes of pharmaceutical compositions.The present invention also comprises use compound according to the present invention to prepare the purposes of pharmaceutical composition as described herein, and this pharmaceutical composition is to be used for the treatment of by caused morbid state of glucocorticoid receptor function or symptom; Type ii diabetes, obesity, cardiovascular disorder, hypertension, arteriosclerosis, neurological disease, suprarenal gland and pituitary tumor and glaucoma; Be characterized as the disease of inflammatory, supersensitivity or hyperplasia process, (i) tuberculosis; (ii) rheumatism/autoimmune disease/joint disease; (iii) anaphylactic disease; (iv) vasculitis disease; (v) tetter; (vi) ephrosis; (vii) hepatopathy; (viii) gastrointestinal illness; (ix) proctology disease; (x) disease of eye; (xi) disease in ear, nose and larynx (ENT) zone; (xii) nervous system disease; (xiii) hematologic disease; (xiv) tumor disease; (xv) endocrinopathy; (xvi) organ and tissue transplantation and graft-right-host disease; (xvii) Xiu Ke serious state; (xviii) replace treatment; Reach (xix) pain of inflammatory origin.

According to agonist compounds of the present invention, no matter be complete antagonist or partial antagonist, can be with drug use in the patient, treating following morbid state or illness, but be not limited to: type ii diabetes (non-insulin-dependent diabetes mellitus (NIDDM)); Fat; Cardiovascular disorder; Hypertension; Arteriosclerosis; Neurological disease is such as psychosis and depression; Suprarenal gland and pituitary tumor; Glaucoma; And based on the ACTH secreting tumor Cushing syndromes of pituitary adenoma for example.Particularly, The compounds of this invention can be used for treating fat all morbid states and the indication that reaches relevant for the fatty acid metabolism of imbalance, such as hypertension, atherosclerosis and other cardiovascular disordeies.Use the The compounds of this invention as the GR antagonist, should be can antagonism carbohydrate metabolism and fatty acid metabolism.Therefore, agonist compounds of the present invention can be used for treating all morbid states and the symptom of the carbohydrate, protein and the lipid metabolism effect that relate to increase, and comprise causing catabolic morbid state and symptom, for example muscle weakness (as the example of protein metabolism effect).

The method of diagnostic uses

The compounds of this invention also can be used for diagnostic use, and uses for commercial and other purposes, the standard substance in detecting as competitive combination.In this purposes, The compounds of this invention can compound itself form use, or it modifies by connecting radio isotope, luminous, fluorescent mark or its analogue, with obtain radio isotope, luminous or fluorescent is surveyed thing, as know the known of present technique, and be summarized in Fluorescent is surveyed thing and research chemical handbook, the 6th edition, R.P.Haugland (writing), Eugene: molecular detection thing, 1996; Fluorescent and detection of luminescence thing to biologic activity, W.T.Mason (writing), San Diego: university press, 1993; Acceptor-ligand interaction, a kind of practical approach, E.C.Huhne (writing), Oxford:IRL press, 1992, wherein each all to list in this paper in full with it for reference.

General dispensing and medical composition

When using as medicine, The compounds of this invention is offerd medicine with the medical composition form usually.This composition can use the technical known program of medicine to make, and comprises at least a The compounds of this invention.The compounds of this invention also can be offerd medicine separately, or offers medicine with the adjuvant combination, and adjuvant is the stability that improves The compounds of this invention, help to contain the dispensing of their pharmaceutical composition in certain embodiments, the dissolving or the dispersion of increase are provided, and the inhibition activity of increase provides additional treatment etc.Can use alone according to compound of the present invention, or in conjunction with according to other active substances of the present invention, also capable of being combined according to circumstances other have the material of pharmacological activity.Usually, The compounds of this invention be with treat or medicine on significant quantity and offeing medicine, but for diagnosis or other purposes, can be with low amount dispensing.

Particularly, the combination of The compounds of this invention and glucocorticosteroid or reflunomide is useful.Just as noted above, the standard treatment that is used for panimmunity and inflammatory conditions comprises corticosteroids, its have the ability that suppresses immunity and inflammatory response (people such as A.P.Truhan, the anaphylaxis yearbook, 1989, 62, the 375-391 page or leaf; J.D.Baxter, hospital's practice, 1992, 27, the 111-134 page or leaf; R.P.Kimberly, Curr.Opin.Rheumatol., 1992,4,325-331 page or leaf; M.H.Weisman, Curr.Opin.Rheumatol.1995, 7, the 183-190 page or leaf; W.Sterry, Arch.Dermatol.Res., 1992, 284(replenishing), the S27-S29 page or leaf).Though in treatment is favourable, the utilization of reflunomide is to be accompanied by many side effects, comprises from gentleness to may life-threatening scope, especially is accompanied by long-term and/or the high dosage steroid uses.Therefore, make it possible to use the method and composition (being called as " effect of steroid restraining property ") that hangs down the reflunomide of effective dose, by high expectations, to avoid undesired side effect.The compounds of this invention is by reaching desired result of treatment, allowing simultaneously to use offeing medicine than low dosage and less number of times of glucocorticosteroid or reflunomide, and the effect of this steroid restraining property is provided.

The compounds of this invention is offerd medicine with pure form or with suitable pharmaceutical composition, can use any acceptable drug composition dispensing pattern to carry out.Therefore, dispensing can be for example oral, cheek mode (for example hypogloeeis mode), intranasal mode, non-through intestines mode, local mode, through skin mode, vagina mode or rectal, be solid, semisolid, lyophilized powder or liquid dosages form, for example tablet, suppository, pill, soft elasticity and hard gelatin capsule, powder, solution, suspension or aerosol or its analogue preferably are and are suitable for the unit dosage form that exact dosage desired is given in simple and easy throwing.Pharmaceutical composition will generally comprise the pharmaceutical carriers commonly used or vehicle and as the The compounds of this invention of promoting agent, and in addition, can comprise other therapeutic, medicament, supporting agent, adjuvant, thinner, mediator or its composition.Pharmaceutically acceptable vehicle, supporting agent or the additive of various patterns of this confession or dispensing usefulness, and the method for making pharmaceutical composition, personnel know to present technique.The state of this technology is by for example Remington: pharmacy science and practice, the 20th edition, A.Gennaro (writing), Lippincott Williams ﹠amp; Wilkins, 2000; The medicated premix hand Volume, Michael ﹠amp; Irene Ash (writing), Gower, 1995; Handbook of pharmaceutical excipients, A.H.Kibbe (writing), American Medical Association, 2000; H.C.Ansel and N.G.Popovish, Medicine dosage form and medicine Transmission system, the 5th edition, Lea and Febiger, 1990 confirm; It is for reference that its each part is all listed in this paper in full with it, with the state of better this technology of explanation.

Desired as knowing prior art, employed The compounds of this invention form is that it has the needed suitable physical feature of effective prescription (for example water solubility) through selection (for example salt) in specific medicine prescription.

The pharmaceutical composition that is suitable for cheek (hypogloeeis) dispensing comprises tablet, it is included in the The compounds of this invention in the flavoring base-material, and base-material often is sucrose and gum arabic or tragakanta, and the film agent, comprise this compound in the inertia base-material, base-material such as gelatin and glycerine or sucrose and gum arabic.

Be fit to the sterile aqueous preparations that non-pharmaceutical composition through the intestines dispensing comprises The compounds of this invention.These preparations are preferably offerd medicine in the intravenously mode, and dispensing also can be by subcutaneous, intramuscular or intradermal injection enforcement.Injectable formula of medicine is usually based on salt solution, oleagenous suspension or other injectable supporting agents well known in the prior art of injectable Sterile Saline, phosphate buffered, and generally is to make it aseptic and ooze with blood etc.Therefore, the injectable drug preparation can with non-on intestines sterilization Injectable solution or the form of suspension in acceptable nontoxicity thinner or the solvent provide, solvent comprises 1,3-butyleneglycol, water, Ringer's solution, isotonic sodium chlorrde solution, fixed oil, for example synthetic glycerine monoesters or diester, fatty acid is as oleic acid etc.This kind injectable drug preparation is according to known technology, uses the allotment of suitable dispersion agent or setting agent and suspension agent.This injectable composition generally contains 0.1 to 5%w/w The compounds of this invention.

Supply the solid dosage form of the oral administration medicine supplying of compound, comprise capsule, tablet, pill, powder and particle, for this oral administration medicine supplying, the pharmaceutically acceptable composition that contains The compounds of this invention, it forms by the vehicle that mixes any common employing, for example the starch of the N.F,USP MANNITOL of pharmaceutical grade, lactose, starch, pre-gelledization, Magnesium Stearate, soluble saccharin, talcum powder, cellulose ether derivative, glucose, gelatin, sucrose, Citrate trianion, propyl gallate etc.This solid pharmaceutical preparation can comprise as known prescription in the prior art, the long-term of medicine is provided or continues to transfer to gi tract with mechanism by any number, this mechanism includes but not limited to be discharged by the pH susceptibility of the dosage form that changes based on small intestine pH value, tablet or capsular slow erosion, delay under one's belt, these are based on the physical properties of prescription, and dosage form is to the bio-adhesiveness of intestinal mucosa liner, or are discharged by the enzyme of the active medicine of dosage form.

Liquid dosage form for the compound oral administration medicine supplying comprises emulsion, microemulsion, solution, suspension, syrup and elixir, contains the medicine adjuvant according to circumstances in supporting agent, for example water, salt solution, the dextrose aqueous solution, glycerine, ethanol etc.These compositions also can contain other adjuvants, such as wetting agent, emulsifying agent, suspension agent, sweetener, correctives and perfume compound.

The local dose form of compound, comprise that ointment, paste, emulsifiable paste, lotion, gel, powder, solution, sprays, inhalation, ophthalmic ointment, eye or ear are with dropping liquid, through dipping dressing and aerosol, and in ointment and emulsifiable paste, can contain suitably habitual additive, such as sanitas, the solvent and the tenderizer that help medicine to penetrate.Partially coated can be considered and once a day or once according to general curative.Moreover preferred compound of the present invention can be with form in the nose, uses in the suitable nose supporting agent to offer medicine by the part.Preparation also can contain the compatible supporting agent of commonly using, as emulsifiable paste or ointment base, and the ethanol or the oleyl alcohol that supply lotion to use.This supporting agent can by prescription about 1% to existing up to about 98%, more generally it can be formed up to about 80% of preparation.

Through the skin dispensing also is feasible.Be fit to the pharmaceutical composition through the skin dispensing, the discontinuous subsides medicine that can be suitable for keeping for a long time contacting closely with recipient's epidermal area presents.For offeing medicine through skin transmission system mode, the dispensing of dosage yes in whole dosage instructions about how to take medicine successive, but not intermittent.This subsides medicine suitably contains compound of the present invention, in the buffered of selecting for use according to circumstances, the aqueous solution, through dissolving and/or be scattered in the auxiliary agent, or is dispersed in the polymer.The proper concn of active compound is about 1% to 35%, is preferably about 3% to 15%.

For for inhalation dosing, The compounds of this invention can be easily with the aerosol spray form, transmit from pumping sprays device, and do not need propelling gas, or utilizing suitable propelling agent from pressurized package or spraying gun transmission, propelling agent is Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, Tetrafluoroethane, heptafluoro-propane, carbonic acid gas or other suitable gas for example.In in any case, aerosol spray dosage unit can measure to transmit the amount through measuring by valve is provided, and is with reproducibility and controlled way to cause formed dose inhaler (MDI) through metering, and the dispensing The compounds of this invention.This kind sucker, atomizer or atomizer arrangement are known in the prior art, and for example (its Fig. 6 particularly, it is based on commercially available RESPIMAT at PCT international publication WO97/12687 ^_Spraying gun); WO 94/07607; WO 97/12683; And WO 97/20590, its each part is all listed in this paper for your guidance in full with it.

Rectal administration can utilize unitary dose suppository to carry out, wherein with compound and low melting point is water-soluble or insoluble solid mixes mutually, such as fats, cacao butter, glycerine gelatin, hydrogenated vegetable oil, the mixture of various molecular weight polyethylene glycol or fatty acid ester or its analogue of polyoxyethylene glycol.Active compound is generally less composition, often be about 0.05 to 10 weight %, and rest part is the base-material composition.

In all aforementioned pharmaceutical compositions, The compounds of this invention is allocated with acceptable supporting agent or vehicle.Employed supporting agent or vehicle must be acceptable certainly, and its meaning is can be compatible with other compositions of composition, and must be harmless to the patient.Supporting agent or vehicle can be solid or liquid or both, and preferably allocate with The compounds of this invention and make units dosage composition, tablet for example, and it can contain the active compound of 0.05% to 95% weight.This supporting agent or vehicle comprise inert filler or thinner, tackiness agent, lubricant, disintegrating agent, dissolving retarding agent, absorb accelerator, absorption agent and tinting material.Suitably binding agent comprises starch, gelatin, natural carbohydrate, such as glucose or beta lactose, the corn sweetener, and natural and synthetical glue, as gum arabic, tragacanth gum or sodiun alginate, carboxymethyl cellulose, polyoxyethylene glycol, paraffin etc.Lubricant comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium-acetate, sodium-chlor etc.Disintegrating agent comprises starch, methylcellulose gum, agar, wilkinite, xanthan gum etc.

Generally speaking, effective daily dosage is about 0.001 milligram of The compounds of this invention to about 15 milligrams/kg body weight every day in the treatment; Be preferably every day about 0.1 milligram to about 10 milligrams/kg body weight; And the best be every day about 0.1 milligram to about 1.5 milligrams/kg body weight.For example, for 70 kilograms of individuals' dispensing, dosage range be every day about 0.07 milligram to about 1050 milligrams The compounds of this invention, be preferably about 7.0 milligrams to about 700 milligrams of every day, and the best is about 7.0 milligrams to about 105 milligrams of every day.May need to make routine dose optimizing to a certain degree, with decision optimum take medicine content and pattern.

Pharmaceutically acceptable supporting agent and vehicle comprise all aforementioned additive and analogue thereof.

The example of formula of medicine

A. tablet
A. tablet		Composition	Every dosage (milligram)
Active substance	100	Composition	Every dosage (milligram)
Active substance	100	Lactose	140
W-Gum	240	Lactose	140
W-Gum	240	Polyvinylpyrolidone (PVP)	15
Magnesium Stearate	5	Polyvinylpyrolidone (PVP)	15
Magnesium Stearate	5	Amount to	500

Active substance, lactose and some W-Gums of fine grinding are mixed together.Mixture is sieved, then with solution wetted, kneading, wet type granulation and the drying of Polyvinylpyrolidone (PVP) in water.This particle, remaining W-Gum and Magnesium Stearate are sieved, and be mixed together.With the mixture compression, to make suitable shape and big or small tablet.

B. tablet
B. tablet		Composition	Every dosage (milligram)
Active substance	80	Composition	Every dosage (milligram)
Active substance	80	Lactose	55
W-Gum	190	Lactose	55
W-Gum	190	Polyvinylpyrolidone (PVP)	15
Magnesium Stearate	2	Polyvinylpyrolidone (PVP)	15
Magnesium Stearate	2	The crystallite Mierocrystalline cellulose	35
Sodium starch glycolate	23	The crystallite Mierocrystalline cellulose	35
Sodium starch glycolate	23	Amount to	400

Active substance, some W-Gums, lactose, crystallite Mierocrystalline cellulose and the Polyvinylpyrolidone (PVP) of fine grinding are mixed together, mixture are sieved, and handle,, make its drying and sieve to form particle with all the other W-Gums and water.Add sodium starch glycolate and Magnesium Stearate, and be mixed together, with the mixture compression, to form the tablet of suitable size.

C. sugar coated tablet
C. sugar coated tablet		Composition	Every dosage (milligram)
Active substance	5	Composition	Every dosage (milligram)
Active substance	5	Lactose	30
W-Gum	41.5	Lactose	30
W-Gum	41.5	Polyvinylpyrolidone (PVP)	3
Magnesium Stearate	0.5	Polyvinylpyrolidone (PVP)	3
Magnesium Stearate	0.5	Amount to	90

With active substance, W-Gum, lactose and polyvinyl tetrahydro pyrrolidine ketone thorough mixing, and moistening with water.Moist agglomerate is pushed through having the screen cloth of 1 millimeter mesh size, dry under about 45 ℃, make particle pass through same screens then.After Magnesium Stearate is mixed together, in pelleter, be compressed into protruding tablet core core with 6 millimeters of diameters.In a known way, use to comprise sugar and steatitic coverture basically, apply tablet core core through so making.With the sugar coated tablet finished at last with wax polishing.

D. capsule
D. capsule		Composition	Every capsular amount (milligram)
Active substance	50	Composition	Every capsular amount (milligram)
Active substance	50	W-Gum	268.5
Magnesium Stearate	1.5	W-Gum	268.5
Magnesium Stearate	1.5	Amount to	320

Material is mixed with W-Gum, and moistening with water.Moist agglomerate is sieved, and dry.Dried particles is sieved, and mix with Magnesium Stearate.The mixture of finishing at last is filled in No. 1 hard gelatin capsule.

E. ampoule solution
E. ampoule solution		Composition	The amount of per ampoule bottle
Active substance	50 milligrams	Composition	The amount of per ampoule bottle
Active substance	50 milligrams	Sodium-chlor	50 milligrams
Water for injection	5 milliliters	Sodium-chlor	50 milligrams

Make active substance soluble in water, under its own pH, or according to circumstances at pH5.5 to 6.5 time, and add sodium-chlor, make it become isotonicity.The solution that is obtained is removed by filter pyrogen, and filtrate is transferred in the ampoule under aseptic condition, then with its sterilization, and by melting sealed.Ampoule contains 5 milligrams, 25 milligrams and 50 milligrams of active substances.

F. suppository
F. suppository		Composition	The amount of each suppository (milligram)
Active substance	50	Composition	The amount of each suppository (milligram)
Active substance	50	Solid fat	1650
Amount to	1700	Solid fat	1650

Make the hard butter fusion.Under 40 ℃, the active substance through grinding is dispersed in wherein.Make mixture be cooled to 38 ℃, and pour in refrigerative suppository mould a little.

G. dosing aerosols
G. dosing aerosols		Composition	Amount
Active substance	0.005	Composition	Amount
Active substance	0.005	Three oleic acid sorbic esters	0.1
Single fluoro trichloromethane and methyl chlorofluoride (2: 3)	To 100	Three oleic acid sorbic esters	0.1

This suspension is transferred to has the commonly using in the aerosol container of metering valve.50 microlitre suspension are preferably transmitted in each spraying.If need, then active substance also can higher dosage metering (for example 0.02 weight %).

H. suck and use powder
H. suck and use powder		Composition	Amount
Active substance	1.0 milligram	Composition	Amount
Active substance	1.0 milligram	Lactose monohydrate	To 25 milligrams

I. suck and use powder
I. suck and use powder		Composition	Amount
Active substance	2.0 milligram	Composition	Amount
Active substance	2.0 milligram	Lactose monohydrate	To 25 milligrams

J. suck and use powder
J. suck and use powder		Composition	Amount
Active substance	1.0 milligram	Composition	Amount
Active substance	1.0 milligram	Lactose monohydrate	To 5 milligrams

K. suck and use powder
K. suck and use powder		Composition	Amount
Active substance	2.0 milligram	Composition	Amount
Active substance	2.0 milligram	Lactose monohydrate	To 5 milligrams

In embodiment H, I, J and K, be with usual way for inhalant powder, by being mixed together, make indivedual compositions.

Claims

1. a formula (IA) compound

Wherein:

R ¹Be aryl, heteroaryl or C ₅-C ₁₅Cycloalkyl, each is replaced by one to three substituting group according to circumstances independently, wherein R ¹Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅-alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, aroyl, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl amino, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₃-C ₅Naphthene amino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, oxo, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is according to circumstances can be independently by C ₁-C ₅The alkyl or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl or C ₃-C ₅Cycloalkyl substituted; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ¹Each substituting group replaced by one to four substituting group independently according to circumstances, substituting group is selected from aryl or heterocyclic radical, wherein heterocycle can be replaced by hydroxyl, halogen, methyl or dialkylamino according to circumstances independently; C ₁-C ₅Carbalkoxy, methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl or C ₁-C ₃Dialkyl group Ammonia or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Amino-sulfonyl or oxime, wherein Sauerstoffatom according to circumstances can be by C ₁-C ₅Alkyl or benzyl replace;

R ²With R ³Each is hydrogen, C independently ₁-C ₅Alkyl or C ₅-C ₁₅Aralkyl, or R ²With R ³With with its carbon atom that is connected jointly, form C ₃-C ₈The spirocyclane basic ring, or

R ¹With R ²When adopting together, be chromanyl or dihydro benzo furyl, can be replaced C by following group according to circumstances ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances;

R ⁵Be tetramethyleneimine, morpholine, thiomorpholine, piperazine, piperidines, 1H-pyridine-4-ketone, the 1H-pyridin-2-ones, the inferior pyridin-4-yl amine of 1H-, the inferior quinolyl-4 amine of 1H-, pyrans, tetrahydropyrans, 1, the 4-Diazesuberane, 2, the 5-diazabicyclo is [2.2.1] heptane also, 2,3,4,5-tetrahydro benzo [b] [1,4] diaza _, dihydroquinoline, tetrahydroquinoline, 5,6,7,8-tetrahydrochysene-1H-quinoline-4-ketone, tetrahydroisoquinoline, Decahydroisoquinolinpreparation, 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indoles, chroman, 1,2,3,4-Si Qing quinoxaline, 1,2-dihydro-indazol-3-ketone, 3,4-dihydro-2H-benzo [1,4] oxazines, 4H-benzo [1,4] thiazine, 3,4-dihydro-2H-benzo [1,4] thiazine, 1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone, 3,4-dihydrobenzo [1,4] oxazine-4-ketone, the 3H-quinazoline-4-one, 3,4-dihydro-1H-quinoxaline-2-ketone, 1H-cinnolines-4-ketone, the 1H-quinazoline-4-one, 1H-[1,5] naphthyridine-4-ketone, 5,6,7,8-tetrahydrochysene-1H-[1,5] naphthyridine-4-ketone, 2,3-dihydro-1H-[1,5] naphthyridine-4-ketone, 1,2-dihydro pyrido [3,2-d] [1,3] oxazine-4-ketone, pyrrolo-[3,4-c] pyridine-1, the 3-diketone, 1, the 2-pyrrolin is [3,4-c] pyridine-3-ketone or tetrahydrochysene [b] [1,4] diaza _ ketone also, each can be replaced by one to three substituting group according to circumstances independently

R wherein ⁵Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can independently can be by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ⁵Each substituting group according to circumstances can be independently replaced by one to three substituting group, substituting group is selected from C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Carbalkoxy, acyl group, aryl, benzyl, heteroaryl, heterocyclic radical, halogen, hydroxyl, oxo, cyano group, amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms according to circumstances can be independently by C ₁-C ₅Alkyl replaces; Or trifluoromethyl; And

2. according to formula (IA) compound of claim 1, wherein:

R ¹Be phenyl, dihydro benzo furyl, benzofuryl, indolinyl, indyl, benzo [1,3] dioxole, dihydrobenzo thienyl, benzothienyl, benzoxazole, benzoisoxazole, benzopyrazoles, benzoglyoxaline, thienyl, quinolyl, tetrahydroquinolones, tetrahydrochysene-1,5-phthalazone, dihydro chromene, pyridyl, pyrimidyl or pyrazinyl, each is replaced by one to three substituting group according to circumstances independently

R wherein ¹Each substituting group be C independently ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₂-C ₃Alkene oxygen base, C ₁-C ₃Alkyloyl, C ₁-C ₃Carbalkoxy, C ₁-C ₃Alkanoyloxy, halogen, hydroxyl, acyl group, oxo, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ¹Each substituting group can be substituted base according to circumstances independently and replace, substituting group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or amino;

R ²With R ³Each is hydrogen, C independently ₁-C ₃Alkyl, benzyl or styroyl, or R ²With R ³With its carbon atom that is connected jointly together, form C ₃-C ₆The spirocyclane basic ring; And

R ⁴Be CH ₂,

Or its tautomer, prodrug, solvate or salt.

3. according to formula (IA) compound of claim 1, wherein:

R ⁴Be CH ₂,

Or its tautomer, prodrug, solvate or salt.

4. according to formula (IA) compound of claim 1, wherein:

R ²With R ³Each is hydrogen or C independently ₁-C ₃Alkyl,

Or its tautomer, prodrug, solvate or salt.

5. compound, it is selected from:

1-{4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,6-lupetazin-1-yl } ethyl ketone;

1-{5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2, the 5-diazabicyclo also [2.2.1] heptan-the 2-yl ethyl ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydro-2H-quinoxaline-1-formaldehyde;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydro-1H-quinoxaline-2-ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-piperazine-2, the 6-diketone;

2-(2,6-dimethyl thiomorpholine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

2-(1,1-dioxo-1H-1 λ ⁶-benzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

2-(1,1-dioxo-2,3-dihydro-1H-1 λ ⁶-benzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1-{5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3,4,5-tetrahydro benzo [b] [1,4] diaza _-the 1-yl } ethyl ketone;

5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,3,4,5-tetrahydro benzo [b] [1,4] diaza _-2-ketone;

2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] isoindole-1, the 3-diketone;

2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] pyrrolo-[3,4-c] pyridine-1, the 3-diketone;

2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-formonitrile HCN;

2-(2,3-dihydrobenzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;

4-(2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(4-methyl-3,4-dihydro-2H-quinoxaline-1-ylmethyl) pentane-2-alcohol;

1-{4-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydro-2H-quinoxaline-1-yl } ethyl ketone;

4-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydro-1H-quinoxaline-2-ketone;

1-{4-[4-(3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,6-lupetazin-1-yl } ethyl ketone;

4-(2,3-Dihydrobenzofuranes-7-yl)-2-(2,3-dihydrobenzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;

2-(3,4-dihydro-2H-quinoxaline-1-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;

2-(2,6-dimethyl thiomorpholine-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;

2-(1,1-dioxo-2,3-dihydro-1H-1 λ ⁶-benzo [1,4] thiazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;

5-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2, the 5-diazabicyclo also [2.2.1] heptan-3-ketone;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-morpholine-4-ylmethyl penta-2-alcohol;

2-(2,6-thebaine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

2-(2,3-dihydrobenzo [1,4] oxazine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperazine-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methoxyl group-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-quinazoline-4-one;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-sec.-propyl-1H-quinoline-4-ketone;

1-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidin-4-one-;

1-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-cyano-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-formamido-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2, the 6-3,5-dimethylphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-cyclohexyl-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(thiophene-2-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(pyridine-2-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(pyridin-3-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(pyridin-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,5-lupetidine-4-ketone;

1-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-quinazoline-4-one;

1-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-cinnolines-4-ketone;

1-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(4-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-sec.-propyl-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(5-cyano group-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-methoxyl group-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,5-lupetidine-4-ketone;

1-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-quinazoline-4-one;

1-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-cinnolines-4-ketone;

1-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(5-cyanogen-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(4-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3-dihydro-1H-quinoline-4-ketone;

1-[2,2,2-three fluoro-1-hydroxyl-1-(4-methyl chroman-4-ylmethyl) ethyl]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydrobenzo [1,4] oxazine-2-ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,4-dihydrobenzo [1,4] oxazine-2-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3-dihydro-1H-[1,5] naphthyridine-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2,3-dihydro-1H-[1,5] naphthyridine-4-ketone;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-piperazine-1-ylmethyl pentane-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methylpiperazine-1-ylmethyl) penta-2-alcohol;

1-{4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-piperazine-1-yl } ethyl ketone;

2-(3,5-lupetazin-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3,4,5-tri methyl piperazine-1-ylmethyl) penta-2-alcohol;

2-[1,4] Diazesuberane-1-ylmethyl-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl-[1,4] Diazesuberane-1-ylmethyl) penta-2-alcohol;

1-{4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-[1,4] Diazesuberane-1-yl } ethyl ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-[1,4] Diazesuberane-1-formaldehyde;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thiomorpholine-4-ylmethyl penta-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-1 λ ⁵-thiomorpholine-4-ylmethyl) penta-2-alcohol;

2-(1,1-dioxo-1 λ ⁶-thiomorpholine-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydro-1H-1 λ ⁴-benzo [1,4] thiazine-4-ylmethyl) penta-2-alcohol;

1-[2-hydroxyl-4-(4-hydroxyl xenyl-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{4-[5-(3,5-dimethyl isoxazole-4-yl)-2-hydroxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{4-[5-(3,5-dimethyl isoxazole-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-3,5-dimethyl-1H-pyridine-4-ketone;

1-(2-hydroxyl-4-{3-[1-(oximino) ethyl] phenyl }-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{2-hydroxyl-4-[3-(1-hydroxyethyl) phenyl]-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-imino--4H-quinoline-1-ylmethyl)-4-methylpentane-2-alcohol;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-hydroxy-2-methyl-1H-pyridine-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methoxyl group-2-methyl]-1H-pyridine-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-6-hydroxyl-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methoxymethyl-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-7-methoxyl group-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-6-methoxyl group-1H-quinoline-4-ketone;

1-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl hexyl)-1H-quinoline-4-ketone;

2-(3,4-dihydro-2H-quinoline-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidin-4-one-;

1-{4-[5-fluoro-2-(2-hydroxyl propoxy-) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-{4-[5-fluoro-2-(2-oxopropoxy) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidines-4-carboxylic acid amide;

1-[4-(2, the 3-dihydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

3-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 3H-quinazoline-4-one;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1-methyl-3,4-dihydro-1H-quinoxaline-2-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-pyridin-2-ones;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-nitrile;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-quinoline-2-one-;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-nitro-1H-pyridin-2-ones;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-5-nitro-1H-pyridin-2-ones;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyridin-2-ones;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl-3-nitro-1H-pyridin-2-ones;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl-5-nitro-1H-pyridin-2-ones;

2-(3,4-dihydro-1-isoquinoline 99.9-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

2-(1,3-xylylenimine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentane-2-alcohol;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 3-Indolin-2-one;

1-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-diethylin aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-{[2-dimethylaminoethyl) methylamino-] methyl } phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{2-hydroxyl-4-[3-(3-hydroxyl pyrrolidine-1-ylmethyl) phenyl]-4-Methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[4-(3-ethylamino aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxy-4-methyl-4-(3-tetramethyleneimine-1-ylmethyl phenyl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxy-4-methyl-4-(3-piperidines-1-ylmethyl phenyl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{2-hydroxy-4-methyl-4-[3-(4-methylpiperazine-1-ylmethyl) phenyl]-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-{4-[3-(3-dimethylamino tetramethyleneimine-1-ylmethyl) phenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[2-hydroxy-4-methyl-4-(3-methylamino-aminomethyl phenyl)-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(5-chloro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

7-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinoline-1-ylmethyl) butyl]-2,3-Dihydrobenzofuranes-5-sulphonamide;

1-[2-hydroxyl-4-(2-methoxyl group-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(3-ethanoyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-ethanoyl-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(3-bromo-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-Hydroxybiphenyl-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(4-chroman-8-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(4-chroman-8-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

1-[4-(2-ethanoyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methane sulfonyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] benzsulfamide;

4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] benzamide;

4-fluoro-N, N-dimethyl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] benzamide;

1-[4-(5-fluoro-2-oxazole-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-oxazole-5-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-3-oxazole-2-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-3-oxazole-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl } furans-2-base ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl } thiophene-2-base ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl } phenyl ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl }-(4-fluorophenyl) ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl }-(2-fluorophenyl) ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl }-(3-fluorophenyl) ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl } furans-2-base ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl } thiophene-2-base ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl } phenyl ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl }-(4-fluorophenyl) ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl }-(2-fluorophenyl) ketone;

4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and-3,4-dihydro-2H-quinoxaline-1-yl }-(3-fluorophenyl) ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-5,6,7,8-tetrahydrochysene-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-5,6,7,8-tetrahydrochysene-1H-quinoline-4-ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-5-methyl-5,6,7,8-tetrahydrochysene-1H-[1,5] naphthyridine-4-ketone;

1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-5,6,7,8-tetrahydrochysene-1H-[1,5] naphthyridine-4-ketone;

1-[4-(4-fluoro-3-morpholine-4-ylmethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(3-fluoro-4-morpholine-4-ylmethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2-{[ethyl-(2-methoxy ethyl) amino] methyl } phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

2-[4-(3-chloro-5-5-flumethiazine-2-yl) piperazine-1-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1-(4-{4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group) piperazine-1-yl } phenyl) ethyl ketone;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(4-fluorophenyl) piperazine-1-ylmethyl]-4-methylpentane-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-phenylpiperazine-1-ylmethyl) pentane-2-alcohol;

2-[4-(2,4 difluorobenzene base)-piperazine-1-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperazine-1-carboxylic acid, ethyl ester;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperazine-1-yl }-(tetrahydrofuran (THF)-2-yl) ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperazine-1-carboxylic acid benzyl ester;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyrimidine-2-base piperazine-1-ylmethyl) penta-2-alcohol;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-piperidines-3-carboxylic acid amide;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-[1,4] Diazesuberane-1-carboxylic acid benzyl ester;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-(5-pyrazine-2-base-[1,3,4] oxadiazole-2-yl) piperidines-1-ylmethyl) penta-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-pyridine-2-base piperazine-1-ylmethyl) penta-2-alcohol;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-piperidines-4-carboxylate methyl ester;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperazine-2-ketone;

1-{1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidin-4-yl }-1,3-dihydrobenzo imidazoles-2-ketone;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(octahydro isoquinoline 99.9-2-ylmethyl) pentane-2-alcohol;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and piperazine-1-yl } vinyl acetic monomer;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(5-methane sulfonyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(2-ethanoyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-methoxyl group-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[2-hydroxyl-4-(2-hydroxyl-5-thiene-3-yl-phenyl)-4-Methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

1-[4-(3-phenelyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3,3-dimethyl-2,3-dihydro-1H-quinoline-4-ketone;

7-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinoline-1-ylmethyl) butyl]-2,3-Dihydrobenzofuranes-5-sulfonic acid dimethylformamide;

1-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-quinoline-4-ketone;

4-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinoline-1-ylmethyl) butyl]-cyanobenzene;

7-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl]-2,3-Dihydrobenzofuranes-5-sulfonic acid dimethylformamide;

1-[4-(4-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

4-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl]-cyanobenzene;

3-methyl isophthalic acid-[3,3,3-three fluoro-2-(6-fluoro-4-methyl chroman-4-ylmethyl)-2-hydroxypropyl]-1H-quinoline-4-ketone;

3-methyl isophthalic acid-[3,3,3-three fluoro-2-(6-fluoro-4-methyl chroman-4-ylmethyl)-2-hydroxypropyl]-1H-[1,5]-naphthyridine-4-ketone;

1-[3,3,3-three fluoro-2-(6-fluoro-4-methyl chroman-4-ylmethyl)-2-hydroxypropyl]-1H-[1,5] naphthyridine-4-ketone;

2-(4-benzyl diethylenediamine-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

2-(4-benzo [1,3] dioxole-5-ylmethyl piperazine-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(pipecoline-1-ylmethyl) penta-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-trifluoromethyl piperidines-1-ylmethyl) penta-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(4-fluorophenyl) piperidines-1-ylmethyl]-4-methylpent-2-alcohol;

2-[4-(4-bromophenyl) piperidines-1-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl piperidine-1-ylmethyl) penta-2-alcohol;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-[1,4] Diazesuberane-1-carboxylic acid uncle-butyl ester;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-piperazine-1-carboxylic acid uncle-butyl ester;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(2-methoxyphenyl) piperazine-1-ylmethyl]-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-tetramethyleneimine-1-phenylpiperidines-1-ylmethyl) penta-2-alcohol;

2-[1,4 '] connection piperidyl-1 '-ylmethyl-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

2-[4-(2-ethoxyethyl group) piperazine-1-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(2-methoxy ethyl) piperazine-1-ylmethyl]-4-methylpent-2-alcohol;

2-(4-benzyl piepridine-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidines-3-carboxylic acid diethylamide;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidines-3-carboxylic acid, ethyl ester;

1-{1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidin-4-yl }-1, the 3-Indolin-2-one;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-Phenylpiperidine-1-ylmethyl) penta-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-[4-(1H-indoles-2-yl) piperidines-1-ylmethyl]-4-methylpent-2-alcohol;

5-chloro-1-{1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperidin-4-yl }-1,3-dihydrobenzo imidazoles-2-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] and piperidin-4-yl } vinyl acetic monomer;

2-[4-(2, the 4-3,5-dimethylphenyl) piperazine-1-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

2-[4-benzyl-[1,4] Diazesuberane-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-piperazine-1-formaldehyde;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methoxycarbonyl methylpiperazine-1-carboxylic acid uncle-butyl ester;

2-(4-tert-butyl piperazine-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

2-(3-dimethylamino tetramethyleneimine-1-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-tetramethyleneimine-1-ylmethyl penta-2-alcohol;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-piperidines-1-ylmethyl penta-2-alcohol;

Ethyl-carbonate 4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Ethyl aminomethyl acid 4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Ethyl aminomethyl acid 4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Ethyl aminomethyl acid 2-[3-(3,3-dimethyl-4-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-4-fluorobenzene ester;

Methyl aminomethyl acid 2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Carbonic acid 2-[3-(3,5-dimethyl-4-oxo-4H-pyridine-1-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-4-fluorobenzene ester methyl ester;

Methyl aminomethyl acid 2-[3-(3,5-dimethyl-4-oxo-4H-pyridine-1-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-4-fluorobenzene ester;

Cyclopropyl aminomethyl acid 2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

1-cyclopropyl-3-{2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl } urea;

1-cyclopropyl-3-{2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl } urea;

1-methyl-3-{2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl } urea;

1-{2-[3-(3,3-dimethyl-4-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl] phenyl }-the 3-methylurea;

1-(2,2,3,3-tetramethyl-ring propyl group)-3-{2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl } urea;

(2,2,3,3-tetramethyl-ring propyl group) aminomethyl acid 2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Dimethylaminomethyl acid 2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Dimethylaminomethyl acid 2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl-4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Tetramethyleneimine-1-carboxylic acid 2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-oxo-4H-quinoline-1-ylmethyl) butyl] phenyl ester;

Tetramethyleneimine-1-carboxylic acid 2-[3-(3,3-dimethyl-4-oxo-3,4-dihydro-2H-quinoline-1-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl] phenyl ester;

1-[4-(4-[1,3] dioxane-2-base-3-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-3-methyl isophthalic acid H-[1,5] naphthyridine-4-ketone; And

1-(4-benzo [1,3] Dioxol-4-yl-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-3-methyl isophthalic acid H-[1,5] naphthyridine-4-ketone;

Or its tautomer, prodrug, solvate or salt.

6. according to the compound of claim 5, this compound is to be selected from following preferred formula (IA) compound:

1-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-[1,5] naphthyridine-4-ketone;

1-[2-hydroxyl-4-(3-hydroxymethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-pyridine-4-ketone;

1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,2-difluoro indazole-3-ketone;

1-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl hexyl)-1H-quinoline-4-ketone;

4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] piperazine-1-yl }-furans-2-base ketone;

Or its tautomer, prodrug, solvate or salt.

7. according to the compound of claim 6, this compound is selected from:

1-[4-(6-bromo benzo [1,3] Dioxol-4-yl) 2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-{4-[5-(3,5-dimethyl isoxazole-4-yl)-2-methoxyphenyl]-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H quinoline-4-ketone;

1-(4-{3-[1-(benzyloxy imino-) ethyl] phenyl }-2-hydroxy-4-methyl-2-trifluoromethyl amyl group }-1H-quinoline-4-ketone;

1-[4-(5-bromo-2-hydroxyphenyl) 2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-quinoline-4-ketone;

1-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl hexyl)-1H-quinoline-4-ketone;

1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1-oxo-2,3-dihydro-1H-1 λ ⁴-benzo [1,4] thiazine-4-ylmethyl) pentane-2-alcohol;

Or its tautomer, prodrug, solvate or salt.

8. pharmaceutical composition, its comprise significant quantity according to the compound one of in the claim 1 to 7, or its tautomer, prodrug, solvate or salt, and pharmaceutically acceptable vehicle or supporting agent.

9. method of regulating patient's glucocorticoid receptor function, its comprise to the patient give significant quantity pharmaceutically acceptable according to the compound one of in the claim 1 to 7, or its tautomer, prodrug, solvate or salt.

10. the patient that needs are treated is with the method for treatment because of caused morbid state of glucocorticoid receptor function or symptom, its comprise to the patient give significant quantity pharmaceutically acceptable according to the compound one of in the claim 1 to 7, or its tautomer, prodrug, solvate or salt.

11. the patient to the needs treatment is selected from the following diseased state or the method for symptom with treatment: type ii diabetes, obesity, cardiovascular disorder, hypertension, arteriosclerosis, neurological disease, suprarenal gland and pituitary tumor and glaucoma, it comprises gives give significant quantity pharmaceutically acceptable according to the compound one of in the claim 1 to 7 to the patient, or its tautomer, prodrug, solvate or salt.

12. the patient to the needs treatment is characterized as the method for the disease of inflammatory, supersensitivity or hyperplasia process with treatment, it comprises gives give significant quantity pharmaceutically acceptable according to the compound one of in the claim 1 to 7 to the patient, or its tautomer, prodrug, solvate or salt.

13. method according to claim 12, wherein disease is selected from: type i diabetes (insulin-dependent diabetes), osteoarthritis, the Guillain-Barre syndromes, through the restenosis of skin behind tube chamber coronary vasodilator neoplasty, Ah ear is grown extra large Mo's disease, acute and chronic pain, atherosclerosis, reperfusion injury, the bone absorption disease, congestive heart failure exhausts, myocardial infarction, thermal damage, the multiple organ injury of wound supervention, acute purulence meningitis, necrotizing enterocolitis, and and hemodialysis, white corpuscle electrophoresis and the relevant syndromes of granulocyte infusion.

14. according to the method for claim 12, wherein disease is selected from: (i) tuberculosis; (ii) rheumatism/autoimmune disease/joint disease; (iii) anaphylactic disease; (iv) vasculitis disease; (v) tetter; (vi) ephrosis; (vii) hepatopathy; (viii) gastrointestinal illness; (ix) proctology disease; (x) disease of eye; (xi) disease in ear, nose and larynx (ENT) district; (xii) neurological disease; (xiii) hematologic disease; (xiv) tumor disease; (xv) endocrinopathy; (xvi) organ and tissue transplantation and graft-right-host's disease; (xvii) Xiu Ke serious state; (xviii) replace treatment; Reach (xix) pain of inflammatory origin.

15. the patient that needs are treated is to treat because of caused morbid state of glucocorticoid receptor function or symptom, its comprise to the patient one after the other or simultaneously give (a) a kind of significant quantity pharmaceutically acceptable according to the compound one of in the claim 1 to 7, or its tautomer, prodrug, solvate or salt, with (b) a kind of pharmaceutically acceptable glucocorticosteroid.

16. the compound of a formula (IB)

Wherein:

R ¹Be aryl, heteroaryl or C ₅-C ₁₅Cycloalkyl, each is replaced by one to three substituting group according to circumstances independently, wherein R ¹Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, C ₁-C ₅Alkyloyl, aroyl, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, oxo, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is according to circumstances independently by C ₁-C ₅The alkyl or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms is according to circumstances independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom is oxidized to sulfoxide or sulfone according to circumstances,

R wherein ¹Each substituting group replaced by one to three substituting group independently according to circumstances, substituting group is selected from aryl or heterocyclic radical, wherein heterocycle is replaced by hydroxyl, halogen, methyl, dialkylamino according to circumstances independently; Methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or amino, wherein nitrogen-atoms is according to circumstances independently by C ₁-C ₅Alkyl or C ₁-C ₃Dialkyl amine or aryl list-or two replacements; Or urea groups, wherein any nitrogen-atoms is independent of according to circumstances C ₁-C ₅Alkyl replaces; Amino-sulfonyl, oxime, wherein Sauerstoffatom is according to circumstances by C ₁-C ₅Alkyl or benzyl replace;

R ¹With R ²When adopting together, be for chromanyl or dihydrobenzene half furyl, replaced C according to circumstances by following group ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C ₁-C ₅Alkoxyl group, C ₂-C ₅Alkene oxygen base, C ₂-C ₅Alkynyloxy group, aryloxy, acyl group, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl, alkyl amino-carbonyl, dialkylamino carbonyl, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, amino-sulfonyl, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, oxo, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethyl sulfenyl, nitro or amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms is according to circumstances independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom is oxidized to sulfoxide or sulfone according to circumstances;

R ⁵Be tetramethyleneimine, morpholine, thiomorpholine, piperazine, piperidines, 1H-pyridine-4-ketone, the 1H-pyridin-2-ones, the inferior pyridin-4-yl amine of 1H-, the inferior quinolyl-4 amine of 1H-, pyrans, tetrahydropyrans, 1, the 4-Diazesuberane, 2, the 5-diaza-bicyclo is [2.2.1] heptane also, 2,3,4,5-tetrahydro benzo [b] [1,4] diaza _, dihydroquinoline, tetrahydroquinoline, 5,6,7,8-tetrahydrochysene-1H-quinoline-4-ketone, tetrahydroisoquinoline, Decahydroisoquinolinpreparation, 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indoles, chroman, 1,2,3, the 4-tetrahydroquinoxaline, 1,2-dihydro-indazol-3-ketone, 3,4-dihydro-2H-benzo [1,4] oxazines, 4H-benzo [1,4] thiazine, 3,4-dihydro-2H-benzo [1,4] thiazine, 1,2-dihydrobenzo [d] [1,3] oxazine-4-ketone, 3,4-dihydrobenzo [1,4] oxazine-4-ketone, the 3H-quinazoline-4-one, 3,4-dihydro-1H-quinoxaline-2-ketone, 1H-cinnolines-4-ketone, the 1H-quinazoline-4-one, 1H-[1,5] naphthyridine-4-ketone, 5,6,7,8-tetrahydrochysene-1H-[1,5] naphthyridine-4-ketone, 2,3-dihydro-1H-[1,5] naphthyridine-4-ketone, 1,2-dihydro pyrido [3,2-d] [1,3] oxazine-4-ketone, pyrrolo-[3,4-c] pyridine-1, the 3-diketone, 1, the 2-pyrrolin is [3,4-c] pyridine-3-ketone or tetrahydrochysene [b] [1,4] diaza _ ketone also, each is replaced by one to three substituting group according to circumstances independently

R wherein ⁵Each substituting group replaced by one to three substituting group independently according to circumstances, substituting group is selected from C ₁-C ₃Alkyl, C ₁-C ₃Alkoxyl group, C ₁-C ₃Carbalkoxy, acyl group, benzyl, heteroaryl, heterocyclic radical, halogen, hydroxyl, oxo, cyano group, amino, wherein nitrogen-atoms is according to circumstances independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms is according to circumstances independently by C ₁-C ₅Alkyl or trifluoromethyl replace; And

R wherein ⁶Each substituting group be C independently ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₂-C ₅Alkynyl, C ₃-C ₈Cycloalkyl, phenyl, C ₁-C ₅Alkoxyl group, phenoxy group, C ₁-C ₅Alkyloyl, aroyl, C ₁-C ₅Carbalkoxy, C ₁-C ₅Alkanoyloxy, aminocarboxyl oxygen base, C ₁-C ₅Alkyl amino-carbonyl oxygen base, C ₁-C ₅Dialkylamino ketonic oxygen base, aminocarboxyl, C ₁-C ₅Alkyl amino-carbonyl, C ₁-C ₅Dialkylamino carbonyl, C ₁-C ₅Alkyl amido, C ₁-C ₅Alkoxycarbonyl amido, C ₁-C ₅Alkyl sulfonyl-amino, C ₁-C ₅Alkylamino alkylsulfonyl, C ₁-C ₅Dialkylamino alkylsulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms according to circumstances can be independently by C ₁-C ₅The alkyl list-or two replacements; Or urea groups, wherein any nitrogen-atoms is according to circumstances independently by C ₁-C ₅Alkyl replaces; Or C ₁-C ₅Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances,

R wherein ⁶Can not be trifluoromethyl, and

17. the compound formula IB according to claim 16), wherein:

R ¹Be phenyl, dihydro benzo furyl, benzofuryl, indolinyl, indyl, benzo [1,3] dioxole, dihydrobenzo thienyl, benzothienyl, benzoxazole, benzoisoxazole, benzopyrazoles, benzoglyoxaline, thienyl, quinolyl, tetrahydroquinolones, tetrahydrochysene phthalazone, dihydrobenzo dihydropyrane alkene, pyridyl, pyrimidyl or pyrazinyl, each is replaced by one to three substituting group according to circumstances independently

R ⁴Be CH ₂And

R ⁶Be C ₁-C ₅Alkyl, C ₂-C ₅Thiazolinyl, C ₃-C ₆Cycloalkyl, phenyl, C ₃-C ₆Cycloalkyl-C ₁-C ₃Alkyl, phenyl-C ₁-C ₃Alkyl, phenyl-C ₁-C ₃Alkylhalide group, C ₃-C ₆Cycloalkyl-C ₂-C ₃Thiazolinyl, phenyl-C ₂-C ₃Thiazolinyl, each can be replaced by one to three substituting group according to circumstances independently,

R wherein ⁶Can not be trifluoromethyl,

Or its tautomer, prodrug, solvate or salt.

18. according to formula (IB) compound of claim 16, wherein:

R ²With R ³Each independently is a methyl, or R ²With R ³With its carbon atom that is connected jointly together, form the Spirocyclopropyl ring; And

R ⁴Be CH ₂,

Or its tautomer, prodrug, solvate or salt.

19. according to formula (IB) compound of claim 16, wherein:

R ¹Be phenyl, dihydro benzo furyl or benzofuryl, each can independently be replaced by one to three substituting group according to circumstances,

R wherein ¹Each substituting group independently be C ₁-C ₃Alkyl, C ₂-C ₃Thiazolinyl, C ₂-C ₃Alkynyl, C ₁-C ₃Alkoxyl group, C ₂-C ₃Alkene oxygen base, C ₁-C ₃Alkyloyl, C ₁-C ₃Carbalkoxy, C ₁-C ₃Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C ₁-C ₃Alkylthio, wherein sulphur atom can be oxidized to sulfoxide or sulfone according to circumstances; And

R ²With R ³Each independently is hydrogen or C ₁-C ₃Alkyl,

Or its tautomer, prodrug, solvate or salt.

20. a compound, it is selected from:

1-[2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone;

1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxyl-2-sec.-propyl-4-methyl amyl]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-methyl fluoride-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone;

1-[2-cyclobutyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone;

1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxyl-2,4-dimethyl amyl group]-1H-quinoline-4-ketone; And

1-[2-ethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl amyl group]-1H-quinoline-4-ketone,

Or its tautomer, prodrug, solvate or salt.

21. a pharmaceutical composition, its comprise significant quantity according to the compound one of in the claim 16 to 20, or its tautomer, prodrug, solvate or salt, and pharmaceutically acceptable vehicle or supporting agent.

22. the method that the patient is regulated glucocorticoid receptor function, its comprise to the patient give significant quantity pharmaceutically acceptable according to the compound one of in the claim 16 to 20, or its tautomer, prodrug, solvate or salt.

23. the patient that needs are treated is to treat because of caused morbid state of glucocorticoid receptor function or symptom, its comprise to the patient give a kind of significant quantity pharmaceutically acceptable according to the compound one of in the claim 16 to 20, or its tautomer, prodrug, solvate or salt.

24. the patient that needs are treated is to treat the method for morbid state or symptom, this illness is selected from: type ii diabetes, obesity, cardiovascular disorder, hypertension, arteriosclerosis, neurological disease, suprarenal gland and vertical tumour and glaucoma, its comprise to the patient give significant quantity pharmaceutically acceptable according to the compound one of in the claim 16 to 20, or its tautomer, prodrug, solvate or salt.

25. the patient to the needs treatment is characterized as the method for the disease of inflammatory, supersensitivity or hyperplasia process with treatment, its comprise to the patient give significant quantity pharmaceutically acceptable according to the compound one of in the claim 16 to 20, or its tautomer, prodrug, solvate or salt.

26. method according to claim 25, wherein disease is to be selected from: type i diabetes (insulin-dependent diabetes), osteoarthritis, the Guillain-Barre syndromes, through the restenosis of skin behind tube chamber coronary vasodilator neoplasty, Ah ear is grown extra large Mo's disease, acute and chronic pain, atherosclerosis, reperfusion injury, the bone absorption disease, congestive heart failure exhausts, myocardial infarction, thermal damage, the multiple organ injury of wound supervention, acute purulence meningitis, necrotizing enterocolitis, and and hemodialysis, white corpuscle electrophoresis and the relevant syndromes of granulocyte infusion.

27. according to the method for claim 25, wherein disease is to be selected from: (i) tuberculosis; (ii) rheumatism/autoimmune disease/joint disease; (iii) anaphylactic disease; (iv) vasculitis disease; (v) tetter; (vi) ephrosis; (vii) hepatopathy; (viii) gastrointestinal illness; (ix) proctology disease; (x) disease of eye; (xi) disease in ear, nose and larynx (ENT) zone; (xii) neurological disease; (xiii) hematologic disease; (xiv) tumor disease; (xv) endocrinopathy; (xvi) organ and tissue transplantation and graft-right-host's disease; (xvii) Xiu Ke serious state; (xviii) replace treatment; And (xix) pain that causes of inflammatory.

28. the patient that needs are treated is with the method for treatment because of caused morbid state of glucocorticoid receptor function or symptom, it comprises the patient pharmaceutically acceptable according to the compound one of in the claim 16 to 20 with what give (a) significant quantity in succession or simultaneously, or its tautomer, prodrug, solvate or salt, with (b) pharmaceutically acceptable glucocorticosteroid.

29. the purposes according to the compound of claim 1 or 16, it is used for pharmaceutical compositions.

30. the purposes according to the compound of claim 1 or 16, it is used on the bound drug acceptable glucocorticosteroid with the purposes of pharmaceutical compositions.

31. according to the purposes of claim 27 and 28, it is used to prepare the medical composition for the treatment of disease, this disease is because of caused following morbid state of glucocorticoid receptor function or symptom; Type ii diabetes, obesity, cardiovascular disorder, hypertension, arteriosclerosis, neurological disease, suprarenal gland and pituitary tumor and glaucoma; Be characterized as the disease of inflammatory, supersensitivity or hyperplasia process, (i) tuberculosis; (ii) rheumatism/autoimmune disease/joint disease; (iii) anaphylactic disease; (iv) vasculitis disease; (v) tetter; (vi) ephrosis; (vii) hepatopathy; (viii) gastrointestinal illness; (ix) proctology disease; (x) disease of eye; (xi) disease in ear, nose and larynx (ENT) zone; (xii) neurological disease; (xiii) hematologic disease; (xiv) tumor disease; (xv) endocrinopathy; (xvi) organ and tissue transplantation and graft-right-host's disease; (xvii) Xiu Ke serious state; (xviii) replace treatment; Reach (xix) pain of inflammatory origin.

32. purposes according to claim 27 and 28, it is used for preparation and is used for the treatment of following disease medical composition: type i diabetes (insulin-dependent diabetes), osteoarthritis, the Guillain-Barre syndromes, through the restenosis of skin behind tube chamber coronary vasodilator neoplasty, Ah ear is grown extra large Mo's disease, acute and chronic pain, atherosclerosis, reperfusion injury, sclerotin consume disease, congestive heart failure exhausts, myocardial infarction, thermal damage, the multiple organ injury of wound supervention, acute purulence meningitis, necrotizing enterocolitis, and and hemodialysis, white cell electrophoresis and the relevant syndromes of graininess blood cell infusion.