CN1976705A - 1,1,1- trifluoro-4-phenyl-4-methyl-2-(1H-pyrrolo not 2,3-C|pyridin-2-ylmethyl)pentan-2-ol derivatives and related compounds as glucocorticoid ligands for the treatment of inflammatory diseases and dia - Google Patents
1,1,1- trifluoro-4-phenyl-4-methyl-2-(1H-pyrrolo not 2,3-C|pyridin-2-ylmethyl)pentan-2-ol derivatives and related compounds as glucocorticoid ligands for the treatment of inflammatory diseases and dia Download PDFInfo
- Publication number
- CN1976705A CN1976705A CNA2004800276942A CN200480027694A CN1976705A CN 1976705 A CN1976705 A CN 1976705A CN A2004800276942 A CNA2004800276942 A CN A2004800276942A CN 200480027694 A CN200480027694 A CN 200480027694A CN 1976705 A CN1976705 A CN 1976705A
- Authority
- CN
- China
- Prior art keywords
- group
- alkyl
- independently
- methyl
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Compounds of formula (IA), IB), IC), and (ID) wherein R<1>, R<2>, R<3>, R<4>, R<5>, and R<6> are as respectively defined herein for formula (IA), (IB), (IC), and (ID), or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.
Description
Technical field
The present invention relates to intend glucocorticoid (glucocorticoid mimetics) or glucocorticoid ligands, and the preparation method of these chemical compounds, their purposes in pharmaceutical composition, and they regulate glucocorticoid receptor function and treatment by the patient of this treatment of needs the purposes in intravital glucocorticoid receptor function disease states mediated or the state of an illness, and other purposes.
Background technology
Glucocorticoid (corticoid) is the endogenous hormone (endogenous hormones) that immune system and many tracts are had profound influence.They are by suppressing inflammatory cytokine (for example IL-1, IL-2, IL-6 and TNF), suppress arachidonic acid metabolite (comprising prostaglandin and leukotriene), exhausting the T-lymphocyte, with reduce adhesion molecule the expression of endotheliocyte suppressed panimmunity and inflammatory function (P.J.Barnes, Clin.Sci., 1998
94, pp.557-572; P.J.Barnes et al., Trends Pharmacol.Sci., 1993,
14, pp.436-441).Except these effects, glucocorticoid also stimulates glucose production and proteinic catabolism in the liver, works in the balance of electrolyte and water, reduces calcium absorption and is suppressed to bone cell function.
The antiinflammatory of endogenous glucocorticoid and immunosuppressive activity have stimulated the development (L.Parente of synthetic glucocorticoid derivant (comprising dexamethasone (dexamethasone), prednisone (prednisone) and dehydrohydro-cortisone (prednisolon))
Glucocorticoids, N.J.Goulding and R.J.Flowers (eds.), Boston:Birkhauser, 2001, pp.35-54).Have been found that these materials are at treatment inflammatory, immunity and allergic disorder (comprising rheumatism, for example rheumatoid arthritis, juvenile arthritis and ankylosing spondylitis); Dermatosis (comprising psoriasis and pemphigus); Allergic disorder (comprising allergic rhinitis, atopic dermatitis and contact dermatitis); Has purposes (J.Toogood widely in pneumonopathy (comprising asthma and chronic obstructive pulmonary disease (COPD)) and other immunity and the inflammatory diseases (comprising Crohn disease (Crohn disease), ulcerative colitis, systemic lupus erythematosus (sle), ACAH, osteoarthritis, tendinitis and bursitis)
Glucocorticoids, N.J.Goulding andR.J.Flowers (eds.), Boston:Birkhauser, 2001, pp.161-174).They also are used for helping to prevent rejection in organ transplantation.
Unfortunately, except required glucocorticoid treatment effect, their purposes is also relevant with multiple disadvantageous side effect, and some side effect may be serious in life-threatening.These side effect comprise change, edema, weight increase, hypertension, the myasthenia of liquid and electrolyte balance, morbidity or the deterioration and the osteoporosis of diabetes.Therefore, show the side effect that alleviates distribute the antiinflammatory action of remaining valid simultaneously chemical compound will and particularly advantageous, particularly when treating chronic disease.
The effect of glucocorticoid on cellular level, mediated by glucocorticoid receptor (GR) (R.H.Oakley and J.Cidlowski,
Glucocorticoids, N.J.Goulding and R.J.Flowers (eds.), Boston:Birkhauser, 2001, pp.55-80).Glucocorticoid receptor (GR) is one of the member of the intracellular receptor class of structure connection, when with ligand coupling, its can play the transcription factor that influences gene expression effect (R.M.Evans, Science, 1988,240, pp.889-895).Other member of steroid receptors family comprises mineralocorticoid, Progesterone, estrogen and androgen receptor.Except the above-mentioned effect of glucocorticoid, the hormone that this receptor family is worked has appreciable impact to the development of health homoiostasis, mineral metabolism, stress and property feature.Will at this
Glucocorticoids, N.J.Goulding and R.J.Flowers (eds.), Boston:Birkhauser, 2001 do as a whole being incorporated herein by reference, to describe prior art better.
Molecule mechanism has been proposed, explain described favourable antiinflammatory action and adverse side effect (for example, S.Heck et al., EMBO J, 1994,
17, pp.4087-4095; H.M.Reichardt et al., Cell, 1998,
93, pp.531-541; F.Tronche et al., Curr.Opin.in Genetics and Dev., 1998,
8, pp.532-538).Multiple metabolism and cardiovascular side effects are considered to the result that so-called commentaries on classics lives through journey.In commentaries on classics is lived, under the situation that glucose production increases, the bonded glucocorticoid receptor (GR) transposition of part to karyon, is bonded to the glucocorticoid responsive element (GRE) in the promoter region of the relevant gene of side effect (for example, phosphoenolpy ruvate carboxy kinase (PEPCK)) then.Consequently these gene transcription speed increase, and think that this has finally caused observed side effect.Antiinflammatory action is considered to suppress (transrepression) process owing to so-called commentaries on classics.Usually, change suppressing is combine irrelevant process with DNA, and this process results from the inhibitory action of NF-kB and AP-1-mediated pathways, thereby causes the decrement adjusting of multiple inflammatory and immune mediator.In addition, think that multiple observed side effect is attributable to the cross reactivity of present obtainable glucocorticoid and other steroid receptors (particularly mineralocorticoid and progesterone receptor).
Therefore, find high selectivity and in conjunction with the time can dissociate to change and live and the glucocorticoid receptor (GR) part of trans inhibition approach is possible, thereby the therapeutic agent that provides the side effect pattern to reduce.Described determine to change live and change the analytical system that suppresses to have influence (for example, C.M.Bamberger and H.M.Schulte, Eur.J.Clin.Invest., 2000,
30(suppl.3), pp.6-9).The selectivity of glucocorticoid receptor (GR) can followingly be determined: the binding affinity and the binding affinity that comprises other steroid receptor of above-mentioned steroid receptor that compare this receptor.
Glucocorticoid also stimulates generation glucose in the liver by so-called gluconeogenesis process, and thinks that this process is by changeing the incident of living mediation.The glucose that increases produces may worsen type ii diabetes, therefore the glucocorticoid compound of the glucose generation of selectivity inhibition mediation can have treatment effectiveness (J.E.Freidman et al., J.Biol.Chem., 1997 in this indication, 272, pp.31475-31481).
Novel glucocorticoid receptor (GR) part has been described in scientific and technical literature and patent documentation.For example, the international open WO 99/33786 of PCT has disclosed the triphenyl propanamide compounds, and this chemical compound has potential purposes in the treatment inflammatory diseases.It is modified as the selectivity of glucocorticoid receptor (GR) that the international open WO 00/66522 of PCT has described the on-steroidal compounds, and this chemical compound is used for the treatment of metabolism and inflammatory diseases potentially.The Fourth Ring class that the international open WO 99/41256 of PCT has described glucocorticoid receptor (GR) is modified, and it is used for the treatment of immunity, autoimmune and inflammatory diseases potentially.United States Patent (USP) 5,688,810 have described various on-steroidal compounds modified as glucocorticoid and other steroid receptors.The international open WO 99/63976 of PCT has described optionally glucocorticoid antagonist of non-steroid, liver, and it is used for the treatment of diabetes potentially.The international open WO 00/32584 of PCT discloses the on-steroidal compounds with isolating anti-inflammatory activity between antiinflammatory and metabolism.The international open WO 98/54159 of PCT has described the anilid that the non-steroid ring-type replaces, and it has gestagen and androgen activity.United States Patent (USP) 4,880,839 described have pregnant before active anilid, EP 253503 has described the anilid with androgen antagonist character.The international open WO 97/27852 of PCT has described the amide as the inhibitor of farnesyl--protein transferase.
Discovery can be agonist or antagonist with the interactional chemical compound of glucocorticoid receptor (GR) in measuring.Can or change the agonist performance that suppresses assessing compound in the mensuration in above-mentioned commentaries on classics work.Consider available glucocorticoid medicine in inflammatory and immune disease effectiveness and their disadvantageous side effect, still need novel glucocorticoid receptor agonist, its other member to steroid receptors family has selectivity and has to be changeed alive and changes active the dissociating property of inhibition.Perhaps, can find that this chemical compound has antagonist activities.As mentioned above, glucocorticoid stimulates the glucose production in the liver.Glucose production by the excessive increase that causes of glucocorticoid can worsen existing diabetes, perhaps triggers potential diabetes.Therefore, find that the glucocorticoid receptor (GR) as antagonist may be useful with part, especially for treatment or prevent diabetes.
At the existing U. S. application 60/367 of this whole introducing, 798 (on March 26th, 2002 submitted to), U.S. Patent application 60/431,817 (December in 2002 submissions on the 12nd), U.S. Patent application 60/442,404 (on January 24th, 2003 submitted to) and U.S. Patent Application Publications 2004/0023999, as a reference.
Summary of the invention
The present invention relates to chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IA)
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements, or urea groups, and wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Perhaps C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo (oxo), cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be hydrogen or C independently of one another
1-C
5Alkyl, or R
2And R
3Form C with their common carbon atoms that connects
3-C
8The spirocyclane basic ring;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is optional separately independently by 1-3 substituent group replacement,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen, amino or oxo; With
R
5Be heteroaryl, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5The alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, heterocyclic radical carbonyl, aroyl, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Perhaps C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, acyl group, C
1-C
3Silicon alkoxyl, C
1-C
5Alkoxy carbonyl group, carboxyl, halogen, hydroxyl, oxo, cyano group, aryl, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces, or trifluoromethyl.
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IA), wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, Er hydrogen benzoxazolyl, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, heterocyclic radical, trifluoromethyl, trifluoromethoxy, nitro, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1The optional substituent group that is selected from independently in methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or the amino of each substituent group replace;
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl, or R
2And R
3Form C with their common carbon atoms that connects
3-C
6The spirocyclane basic ring;
R
4Be CH
2And
R
5Be imidazole radicals, pyridine radicals, indyl, indazolyl, the azaindole base, two azaindole bases, benzofuranyl, the furo pyridine radicals, the furo pyrimidine radicals, the imidazopyrimidine base, the Imidazopyridazine base, the Imidazopyrazines base, benzothienyl, the thienopyridine base, the Thienopyrimidine base, thieno pyridazinyl benzoxazolyl oxazole and pyridine radicals, benzothiazolyl, thiazole and pyridine radicals, benzimidazolyl, imidazopyridyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, hydroxyl, oxo, fluorine, chlorine, bromine, cyano group, trifluoromethyl, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Optional methyl, methoxyl group, fluorine, chlorine, bromine, oxo or trifluoromethyl, hydroxyl, cyano group or amino (the optional C independently of nitrogen-atoms wherein that is selected from independently of each substituent group
1-C
5The alkyl or aryl list replaces or two replacements) replace.
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IA), wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group or C independently
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3Be methyl or ethyl independently of one another, or R
2And R
3Form the spirocyclane basic ring with their common carbon atoms that connects;
R
4Be CH
2And
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino carbonyl, morpholinyl carbonyl, morpholinyl, piperidyl, trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, cyano group independently, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements, or trifluoromethyl.
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IA), wherein:
R
1Be phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone; With
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl.
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IA), wherein:
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement.
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IA), wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, Er hydrogen benzoxazolyl, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, aryl, heteroaryl, halogen, hydroxyl, carboxyl, cyano group, heterocyclic radical, trifluoromethyl, trifluoromethoxy, nitro, amino-sulfonyl, dialkyl amino sulfonyl, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1 or 2 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, morpholinyl or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements;
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl, or R
2And R
3Form C with their common carbon atoms that connects
3-C
6The spirocyclane basic ring;
R
4Be CH
2And
R
5Be imidazole radicals, pyridine radicals, indyl, indazolyl, the azaindole base, two azaindole bases, benzofuranyl, the furo pyridine radicals, the furo pyrimidine radicals, the imidazopyrimidine base, the Imidazopyridazine base, the Imidazopyrazines base, benzothienyl, the thienopyridine base, the Thienopyrimidine base, thieno pyridazinyl benzoxazolyl oxazole and pyridine radicals, benzothiazolyl, thiazole and pyridine radicals, benzimidazolyl, imidazopyridyl, quinolyl or isoquinolyl base, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, heteroaryl, heterocyclic radical, acyl group, dialkyl amino sulfonyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, hydroxyl, oxo, fluorine, chlorine, bromine, cyano group, trifluoromethyl, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Perhaps C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional replaced by 1 or 2 substituent group independently, described substituent group is selected from methyl, methoxyl group, fluorine, chlorine, bromine, oxo, trifluoromethyl, hydroxyl, cyano group, morpholinyl, pyrrolidinyl or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements.
Another aspect of the present invention comprises the chemical compound of general formula (IA), or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, benzodioxole base, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, morpholinyl methyl, dimethylaminomethyl, amino-sulfonyl, dimethylamino sulfonyl, phenyl, pyrimidine radicals, pyridine radicals, thienyl, naphthyl, morpholinyl, piperidyl, cyano group or C independently
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1 or 2 substituent group that is selected from cyano group, chlorine, bromine or the fluorine independently;
R
2And R
3Be methyl or ethyl independently of one another, or R
2And R
3Form the spirocyclane basic ring with their common carbon atoms that connects;
R
4Be CH
2And
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, thieno pyridazinyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be methyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino carbonyl, morpholinyl carbonyl, morpholinyl, piperidyl, phenoxy group, pyrrolidinyl, acetyl group, valeryl, ethyl carbonyl, isopropyl carbonyl, pyridine radicals, pyrimidine radicals, trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, cyano group or amino independently, wherein nitrogen-atoms is optional independently by C
1-C
5Alkyl or trifluoromethyl list replace or two replacements, or aryl,
R wherein
5Each substituent group optional replaced by 1-2 substituent group that is selected from cyano group, halogen, methyl, dimethylamino, morpholinyl, pyrrolidinyl or the piperidyl independently.
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IA), wherein:
R
1Be phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, aryl, heteroaryl, heterocyclic radical or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone; With
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl.
Another aspect of the present invention comprises the chemical compound of general formula (IA), or its tautomer, prodrug, solvate or salt, wherein:
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, thieno pyridazinyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement.
The representational general formula of the present invention (IA) chemical compound such as Table I A are appended, and its intermediate hurdles A is the chemical compound title according to the standard nomenclature principle, and hurdle B is corresponding chemical constitution.
Preferred general formula (IA) chemical compound comprises following:
4-cyclohexyl-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-pyrimidine-5-base-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1h-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(5,7-dimethyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-carbonitriles;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-c] pyridine-4-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [2,3-d] pyridazine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5,7-two chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyls)-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-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-ethyoxyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-(5-benzyloxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-(5-benzyloxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[5-(methylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl] penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-amino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(6-amino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-amino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-methylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
7-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-b] pyridine-7-chloride;
6-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-2-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-6-chloride;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo-[2,3-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-oxygen-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo-[2,3-c] pyridine-1-ylmethyl penta-2-alcohol;
2-benzo [b] thiophene-2-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-thieno [2,3-c] pyridine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-indazole-1-ylmethyl-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-((Z) acrylic)-3-vinyl pyrazoles-1-ylmethyl] penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrazolo [1,5-a] pyridine-2-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
4-(5-fluoro-2-aminomethyl phenyl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-furo [2,3-c] pyridine-2-ylmethyl-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1-furo [2,3-c] pyridine-2-base-2,4-dimethyl-penten-2-alcohol;
4-(5-fluoro-2-aminomethyl phenyl)-1-furo [2,3-c] pyridine-2-base-2,4-dimethyl-penten-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(3-dimethylamino methyl-1H-pyrrolo-[3,2-c] pyridine-2-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-pyrrolo-[3,2-c] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-furo [3,2-c] pyridine-2-ylmethyl-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
4-fluoro-2-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-thieno [3,2-c] pyridine-2-ylmethyl butyl) phenol;
4-fluoro-2-(4,4,4-three fluoro-3-furo [3,2-c] pyridine-2-ylmethyl-3-hydroxyls-1,1-dimethylbutyl) phenol;
4-fluoro-2-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-pyrrolo-[3,2-b] pyridine-1-ylmethyl butyl) phenol;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-Indole-6-carboxylic acid;
2-[4-(5-fluoro-2-first hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-yl } morpholine-4-base ketone;
2-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid amide;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-nitro-1H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
N-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } acetamide;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[4-(3-[1,3] dioxy ring penta-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid-2-trimethyl silyl ethyl ester;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-5-carboxylic acid;
2-[4-(4-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } piperidines-1-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid methyl nitrosourea;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
1-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } piperidin-4-one-;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid (2-ethoxy) amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (4-hydroxy piperidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (3-hydroxyl pyrrolidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid cyano group Methanamide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid (2-dimethylaminoethyl) amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (4-methyl piperazine-1-yl) ketone;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl acetate;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid carbamyl Methanamide;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl butyrate;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) acetic acid;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) butanoic acid;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-Trifluoromethyl-1 H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-5-carboxylic acid;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid dimethylformamide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid Cyanomethyl amides;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-(4-benzo [1,3] dioxole-4-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-4-phenyl-2-quinolyl-4 methyl oneself-2-alcohol;
2-[2-hydroxy-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
7-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl)-2,3-Dihydrobenzofuranes-5-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxy-5-methyl base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-methyl mercapto-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(2-methoxyl group-5-methyl mercapto phenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-mesyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-sulfonic acid dimethylformamide;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-phenyl-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl phenyl]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-hydroxyl-2,4-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1-Methyl-1H-indole-3-formonitrile HCN;
2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl phenyl]-1-Methyl-1H-indole-3-formonitrile HCN;
2-[2-hydroxyl-4-(2-hydroxy-5-methyl sulfonyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-methoxyl group-5-aminomethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
3-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(4-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(4-trifluoromethyl) penta-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(2-difluoro-methoxy-5-fluorophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 6-methyl isophthalic acid, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 4-methyl isophthalic acid, the 4-pyrrolin is [3,2-b] pyridine-5-ketone also;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(6-methoxyl group-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 5-methyl isophthalic acid, the 5-pyrrolin is [3,2-c] pyridine-6-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 3a-pyrrolin is [3,2-c] pyridine-6-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 7-pyrrolin is [3,2-c] pyridine-4 also, the 6-diketone;
6-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 3-methyl isophthalic acid, the 7-pyrrolin is [2,3-d] pyrimidine-2 also, the 4-diketone;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 6-methyl isophthalic acid, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 4-pyrrolin is [3,2-b] pyridine-5-ketone also;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 4-methyl isophthalic acid, the 4-pyrrolin is [3,2-b] pyridine-5-ketone also;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 5-pyrrolin is [3,2-c] pyridine-6-ketone also;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 5-methyl isophthalic acid, the 5-pyrrolin is [3,2-c] pyridine-6-ketone also;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(6-methoxyl group-5,6-dihydro-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 7-pyrrolin is [3,2-c] pyridine-4 also, the 6-diketone;
6-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 3-methyl isophthalic acid, the 7-pyrrolin is [2,3-d] pyrimidine-2 also, the 4-diketone;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(3-morpholine-4-ylmethyl phenyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-morpholine-4-ylmethyl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-morpholine-4-ylmethyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } phenyl ketone;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-yl } phenyl ketone;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } furan-2-base ketone;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-yl } furan-2-base ketone;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-pyridine-2-base penta-2-alcohol;
4-(3-chloro-2-fluoro-5-trifluoromethyl benzyl)-5,5,5-three fluoro-4-hydroxy-2-methyl-2-phenyl pentane nitriles;
1,1,1-three fluoro-4-methyl-4-pyridin-4-yl-2-quinolyl-4 methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[3-(2,6-lutidines-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
1,1,1-three fluoro-4,4-dimethyl-5-phenyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyridin-4-yl methylpent-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-(2-fluorine pyridin-4-yl methyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[3-(2-bromopyridine-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-(6,8-dimethyl quinoline-4-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] pyridine-2-formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] cigarette formonitrile HCN (nicotinonitrile);
4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] quinoline-2-alcohol;
2,6-two chloro-4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2-(2-chloro-8-methylquinoline-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(2,6-dichloroquinoline-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[3-(2-chloro-8-methylquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-[3-(2,6-dichloroquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
4-(2,3-Dihydrobenzofuranes-7-yl)-2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1, between 1-three fluoro-4-methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
4-fluoro-2-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-methylquinoline-4-ylmethyl) butyl] phenol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methylquinoline-4-ylmethyl) penta-2-alcohol;
2-[3-(2,6-lutidines-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 5-fluorophenol;
2-(5,7-dimethyl quinoline-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-Methyl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-methylquinoline-8-yl)-4-methylpent-2-alcohol;
4-(2, the 6-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
2-(3-bromo-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-3-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-methyl-2-[4,4,4-three fluoro-3-hydroxyl-3-(1H-indole-2-ylmethyl)-1,1-dimethylbutyl] phenol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-Dimethoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
2-(2,4-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(2-amino-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(2,4-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-phenyl penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-pyrrolidine-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(5-pyrrolidine-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
2-(5-lignocaine-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-[5-(isopropyl methyl amino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-[5-(isopropyl methyl amino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-4-methyl-4-phenyl penta-2-alcohol;
2-(5-lignocaine-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methyl-4-phenyl penta-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(5-pyrrolidine-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(3-pyrimidine-5-base phenyl) penta-2-alcohol;
2-[5-(2,6-thebaine-4-yl)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-methyl-4-phenyl penta-2-alcohol;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(5-pyrrolidine-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-lignocaine-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-[5-(isopropyl methyl amino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-4-methylpent-2-alcohol;
3 '-3-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl] and-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl }-4 '-methoxyl biphenyl-2-formonitrile HCN;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
3 '-3-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl] and-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl }-4 '-xenol-2-formonitrile HCN;
4 '-hydroxyl-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-morpholine-4-ylmethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino methyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-[5-(4-methyl piperazine-1-ylmethyl)-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl] penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-dimethylamino methyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-ylmethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl) penta-2-alcohol;
4-chloro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-morpholine-4-ylmethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-carbonitriles;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carboxylate methyl ester;
1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl } ethyl ketone;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(6H-pyrrolo-[2,3-g] quinoxaline-7-ylmethyl) penta-2-alcohol;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carboxylic acid amide;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carboxylic acid;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl } morpholine-4-base ketone;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methylol-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-(5-aminomethyl-1,2 H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) butyl] phenol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5H-pyrrolo-[3,2-dd] pyrimidine-6-ylmethyl) butyl] phenol;
2-(6-chloro-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(6-chloro-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl }-2,2-dimethyl propylene-1-ketone;
2-[5-(the 1-tert-butyl group-1-hydroxyl-2,2-dimethyl propyl)-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl]-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl } third-1-ketone;
1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl }-2-methyl-prop-1-ketone;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-methoxyl biphenyl-3-yl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] phenol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] phenol;
3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] biphenyl-4-alcohol;
1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-pyridin-3-yl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(5-phenoxy group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(5-phenoxy group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-[5-(4-fluorophenyl)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-4-methylpent-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[3-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-[3-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 5-fluorophenol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-bromo-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(3-[1,3] dioxane oneself-2-base phenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-methoxyl biphenyl-3-yl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-4-alcohol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-3-formonitrile HCN;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-pyridin-3-yl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-pyridin-3-yl phenyl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-pyrimidine-5-base phenyl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-pyridin-3-yl phenyl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-pyrimidine-5-base phenyl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-pyridine-2-base-1H-indole-2-ylmethyl) penta-2-alcohol;
2-(5-bromo-1H-indole-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-methanesulfinyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
7-[3-(5-bromo-1H-indole-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-2,3-Dihydrobenzofuranes-5-sulfonic acid amides;
7-[3-(5-bromo-1H-indole-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-2,3-Dihydrobenzofuranes-5-sulfonic acid dimethylformamide;
2-(1-benzenesulfonyl-5-pyridin-3-yl-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
3-{2-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } benzonitrile;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyridin-4-yl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyridin-3-yl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyrimidine-5-base-1H-indole-2-ylmethyl) penta-2-alcohol;
2-{2-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } Benzoylamide;
2-[5-(4-dimethylamino phenyl)-1H-indole-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-2-(7-fluoro-1H-indole-2-ylmethyl)-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(4-Methyl-1H-indole-2-ylmethyl) penta-2-alcohol;
4-mesyl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-Trifluoromethyl-1 H-indole-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-2-(7-fluoro-5-Methyl-1H-indole-2-ylmethyl)-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
7-fluoro-2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid methyl ester;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid methyl ester;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-4-carboxylic acid;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid amide;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-formonitrile HCN;
2-(4-ethyl-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[3-(4-ethyl-1H-indole-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(2-isopropyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(2-isopropyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(2-isopropyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyl-3-(2-isopropyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-1,1-dimethylbutyl] phenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] phenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] phenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(2-chloro-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] benzonitrile;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] phenol;
2-(5-ethyoxyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-trifluoromethyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(4-methoxyl biphenyl-3-yl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methylpent-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methyl-4-phenyl penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-methoxyl biphenyl-3-yl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
4-bromo-2-[3-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl] phenol;
2-[3-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-[2-hydroxyl-4-(4-xenol-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-phenol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methyl-4-(5-phenyl-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
2-[2-hydroxyl-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-phenol;
Trifluoromethanesulfonic acid 2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-base ester;
2-[5-(2,6-thebaine-4-yl)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-methyl-4-phenyl penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methyl-4-phenyl penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-lignocaine-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(4-methoxyl group-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 5-pyrrolin is [3,2-c] pyridine-4-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 4-pyrrolin is [3,2-b] pyridine-5-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-5-hydroxyl-1, the 6-pyrrolin is [2,3-c] pyridin-7-one also;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methylpent-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-naphthalene-1-base phenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(2 '-chloro-4-methoxyl biphenyl-3-yl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
4-(2 '-chloro-4-methoxyl biphenyl-3-yl)-1,1,1-three fluoro-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[3-(3-dimethylamino methyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(3-chloro-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl)-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol; With
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol,
Or its tautomer, prodrug, solvate or salt.
Preferred general formula (IA) chemical compound comprises:
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-carbonitriles;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-c] pyridine-4-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [2,3-d] pyridazine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5,7-two chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyls)-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-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo-[2,3-b] pyridine-1-ylmethyl penta-2-alcohol;
2-benzo [b] thiophene-2-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-thieno [2,3-c] pyridine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-((Z) acrylic)-3-vinyl pyrazoles-1-ylmethyl] penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
4-(5-fluoro-2-aminomethyl phenyl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(3-dimethylamino methyl-1H-pyrrolo-[3,2-c] pyridine-2-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-pyrrolo-[3,2-c] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-furo [3,2-c] pyridine-2-ylmethyl-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-yl } morpholine-4-base ketone;
2-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid amide;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-nitro-1H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
N-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } acetamide;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[4-(3-[1,3] dioxane oneself-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid-2-trimethyl silyl ethyl ester;
2-[4-(4-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } piperidines-1-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid methyl nitrosourea;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
1-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } piperidin-4-one-;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid (2-ethoxy) amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (4-hydroxy piperidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (3-hydroxyl pyrrolidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid cyano group Methanamide;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl acetate;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid carbamyl Methanamide;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl butyrate;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) acetic acid;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) butanoic acid;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-Trifluoromethyl-1 H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-5-carboxylic acid;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid diformamide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid Cyanomethyl amides;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-(4-benzo [1,3] dioxole-4-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-4-phenyl-2-quinolyl-4 methyl oneself-2-alcohol;
2-[2-hydroxy-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
7-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl)-2,3-Dihydrobenzofuranes-5-formonitrile HCN;
2-[2-hydroxyl-4-(2-hydroxy-5-methyl base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-methyl mercapto-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-phenyl-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-hydroxyl-2,4-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-methoxyl group-5-aminomethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
3-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(4-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(4-trifluoromethyl) penta-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(2-difluoro-methoxy-5-fluorophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 6-methyl isophthalic acid, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-pyridin-4-yl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyridin-4-yl methylpent-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-(2-fluorine pyridin-4-yl methyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[3-(2-bromopyridine-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-(6,8-dimethyl quinoline-4-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] pyridine-2-formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2-(2,6-dichloroquinoline-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[3-(2-chloro-8-methylquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-[3-(2,6-dichloroquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
4-(2,3-Dihydrobenzofuranes-7-yl)-2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1, between 1-three fluoro-4-methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
4-fluoro-2-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-methylquinoline-4-ylmethyl) butyl] phenol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methylquinoline-4-ylmethyl) penta-2-alcohol;
2-[3-(2,6-lutidines-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 5-fluorophenol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-Methyl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-methylquinoline-8-yl)-4-methylpent-2-alcohol;
4-(2, the 6-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
2-(3-bromo-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-3-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-methyl-2-[4,4,4-three fluoro-3-hydroxyl-3-(1H-indole-2-ylmethyl)-1,1-dimethylbutyl] phenol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-Dimethoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
2-(2,4-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(2-amino-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol; With
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol.
Most preferred general formula (IA) chemical compound comprises following chemical compound or its tautomer, prodrug, solvate or salt:
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-carbonitriles;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-c] pyridine-4-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [2,3-d] pyridazine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5,7-two chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyls)-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-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [2,3-c] pyridine-2-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
4-(5-fluoro-2-aminomethyl phenyl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(3-dimethylamino methyl-1H-pyrrolo-[3,2-c] pyridine-2-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-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-furo [3,2-c] pyridine-2-ylmethyl-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
2-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-nitro-1H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
N-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } acetamide;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[4-(3-[1,3] dioxane oneself-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[4-(4-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } piperidines-1-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid methyl nitrosourea;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid (2-ethoxy) amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (3-hydroxyl pyrrolidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid cyano group Methanamide;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl acetate;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid carbamyl Methanamide;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl butyrate;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-Trifluoromethyl-1 H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl]-1H-indole-5-carboxylic acid diformamide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid Cyanomethyl amides;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-(4-benzo [1,3] dioxole-4-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-4-phenyl-2-quinolyl-4 methyl oneself-2-alcohol;
2-[2-hydroxy-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
7-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl)-2,3-Dihydrobenzofuranes-5-formonitrile HCN;
2-[2-hydroxyl-4-(2-hydroxy-5-methyl base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-methyl mercapto-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-hydroxyl-2,4-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
3-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(4-trifluoromethyl) penta-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(2-difluoro-methoxy-5-fluorophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 6-methyl isophthalic acid, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-(2-fluorine pyridin-4-yl methyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[3-(2-bromopyridine-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-(6,8-dimethyl quinoline-4-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] pyridine-2-formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2-[3-(2,6-dichloroquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
4-(2,3-Dihydrobenzofuranes-7-yl)-2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1, between 1-three fluoro-4-methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
4-fluoro-2-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-methylquinoline-4-ylmethyl) butyl] phenol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methylquinoline-4-ylmethyl) penta-2-alcohol;
2-[3-(2,6-lutidines-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 5-fluorophenol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-Methyl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-methylquinoline-8-yl)-4-methylpent-2-alcohol;
4-(2, the 6-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
2-(3-bromo-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-3-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-methyl-2-[4,4,4-three fluoro-3-hydroxyl-3-(1H-indole-2-ylmethyl)-1,1-dimethylbutyl] phenol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-Dimethoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
2-(2,4-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(2-amino-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol; With
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol,
Or its tautomer, prodrug, solvate or salt.
The present invention also provides the method for preparing general formula (IA) chemical compound
R wherein
1, R
2, R
3, R
4And R
5As defined above, described method comprises:
(a) in suitable solvent, make the ester and the reaction of suitable Reducing agent of general formula (II), generate the glycol of general formula (III)
(b) under suitable oxicracking condition, the glycol of reaction expression (III), the ketone of generation general formula (IV);
(c) in suitable solvent, make the ketone and the suitable organometallic reagent R of general formula (IV)
5R
4M (wherein M is that Li or MgX and X are Cl, Br or I) reaction generates the chemical compound of general formula (IA)
(a ') makes the trifluoroacetamide of general formula (X) and has R in suitable solvent
2And R
3Ethylene bromide base reactive magnesium, obtain the trifluoromethyl ketenes (trifluoromethylenone) of general formula (XI)
(b ') makes the trifluoromethyl ketenes and the reaction of suitable organic copper reagent of general formula (XI) in suitable solvent, generate the ketone of general formula (IV), and described organic copper reagent is by organometallic reagent R
5R
4M (wherein M is Li or MgX) and mantoquita CuX (wherein X is Cl, Br or I) produce
Carry out above-mentioned steps (c).
The invention still further relates to the chemical compound of general formula (IB), or its tautomer, prodrug, solvate or its salt,
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be C independently of one another
1-C
5Alkyl;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is chosen wantonly separately and is replaced by the 1-3 substituent group independently,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen or oxo;
R
5Be the optional heteroaryl that is replaced by the 1-3 substituent group independently,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or trifluoromethyl; With
R
6Be hydrogen, C
1-C
8Alkyl, C
2-C
8Alkenyl, C
2-C
8Alkynes base, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, carbocyclic ring-C
1-C
8Alkyl, carboxyl, alkoxy carbonyl group, aryl-C
1-C
8Alkyl, aryl-C
1-C
8Haloalkyl, heterocyclic radical-C
1-C
8Alkyl, heteroaryl-C
1-C
8Alkyl, carbocyclic ring-C
2-C
8Alkenyl, aryl-C
2-C
8Alkenyl, heterocyclic radical-C
2-C
8Alkenyl or heteroaryl-C
2-C
8Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, phenyl, C
1-C
5Alkoxyl, phenoxy group, C
1-C
5Alkanoyl, aroyl, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
6Not trifluoromethyl,
Another aspect of the present invention comprises the chemical compound of general formula (IB), or its tautomer, prodrug, solvate or salt.Wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional be selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace;
R
2And R
3Be C independently of one another
1-C
3Alkyl;
R
4Be CH
2
R
5Be imidazole radicals, pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, furo pyrimidine radicals, benzothienyl, thienopyridine base, Thienopyrimidine base, benzoxazolyl, oxazole and pyridine radicals, benzothiazolyl, thiazole and pyridine radicals, benzimidazolyl, imidazopyridyl, imidazopyrimidine base, Imidazopyridazine base, Imidazopyrazines base, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, hydroxyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional be selected from methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, oxo, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
Another aspect of the present invention comprises the chemical compound of general formula (IB), or its tautomer, prodrug, solvate or salt.Wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group or C independently
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3Methyl separately;
R
4Be CH
2
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, hydroxyl, fluorine, chlorine, bromine, cyano group or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently,
Another aspect of the present invention comprises the chemical compound of general formula (IB), or its tautomer, prodrug, solvate or salt.Wherein:
R
1Be phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone; With
R
2And R
3Be C independently of one another
1-C
3Alkyl,
Another aspect of the present invention comprises the chemical compound of general formula (IB), or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group or C independently
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, pyridine radicals, hydroxyl, fluorine, chlorine, bromine, cyano group or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently,
In the each side of general formula of the present invention (IB) chemical compound, preferably, R
6Not hydrogen.
The representational general formula of the present invention (IB) chemical compound such as Table I B are appended, and its intermediate hurdles A is the chemical compound title according to the standard nomenclature principle, and hurdle B is corresponding chemical constitution.
Preferred general formula (IB) chemical compound comprises following chemical compound, or its tautomer, prodrug, solvate or salt:
2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
4-(5-fluoro-2-methoxyphenyl)-2,4-dimethyl-1-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopenta-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-(5-fluoro-2-methoxyphenyl)-2,6-dimethyl-4-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) heptan-4-alcohol;
2-(5-fluoro-2-methoxyphenyl)-2,5,5-trimethyl-4-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) heptan-4-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-cyclobutyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-(5-fluoro-2-methoxyphenyl)-2,6,6-trimethyl-4-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) heptan-4-alcohol;
5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-1-alkene-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-1-alkynes-3-alcohol;
1-fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2,2-two fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-fluoro-5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-1-alkene-3-alcohol;
1,1,1-three fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-phenyl-1-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-thieno [2,3-c] pyridine-2-ylmethyl oneself-3-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-(1-fluorine cyclopropyl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-(1-fluorine cyclopropyl)-4-(4-fluorophenyl)-4-methyl isophthalic acid-quinolyl-4 penta-2-alcohol;
2-[4,4-two fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl]-the 4-fluorophenol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1-two fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-bromo-1H-indole-2-ylmethyl)-1,1-two fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol; With
2-[2-difluoromethyl-2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl amyl]-4-Methyl-1H-indole-6-formonitrile HCN,
Preferred general formula (IB) chemical compound comprises following chemical compound or its tautomer, prodrug, solvate or salt:
2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
4-(5-fluoro-2-methoxyphenyl)-2,4-dimethyl-1-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-cyclopenta-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-5-methyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-(5-fluoro-2-methoxyphenyl)-2,6-dimethyl-4-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) heptan-4-alcohol;
2-(5-fluoro-2-methoxyphenyl)-2,5,5-trimethyl-4-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) heptan-4-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-(1-fluorine cyclopropyl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-(1-fluorine cyclopropyl)-4-(4-fluorophenyl)-4-methyl isophthalic acid-quinolyl-4 penta-2-alcohol;
2-[4,4-two fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl]-the 4-fluorophenol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1-two fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-bromo-1H-indole-2-ylmethyl)-1,1-two fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol; With
2-[2-difluoromethyl-2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl amyl]-4-Methyl-1H-indole-6-formonitrile HCN,
Most preferred general formula (IB) chemical compound comprises following chemical compound or its tautomer, prodrug, solvate or salt:
2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-cyclopenta-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-(5-fluoro-2-methoxyphenyl)-2,5,5-trimethyl-4-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) heptan-4-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-(1-fluorine cyclopropyl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-(1-fluorine cyclopropyl)-4-(4-fluorophenyl)-4-methyl isophthalic acid-quinolyl-4 penta-2-alcohol;
2-[4,4-two fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl]-the 4-fluorophenol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-bromo-1H-indole-2-ylmethyl)-1,1-two fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol; With
2-[2-difluoromethyl-2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl amyl]-4-Methyl-1H-indole-6-formonitrile HCN,
The present invention also provides the method for preparing general formula (IB) chemical compound.A kind of method of preparation following general formula (IB) chemical compound is provided,
R wherein
1Be the optional 2-methoxyphenyl that replaces, R
2, R
3, R
4, R
5And R
6As defined above, described method comprises:
(a) in the presence of appropriate base, make the acryloyl chloride reaction of the phenol of optional replacement and the general formula (XIII) of general formula (XXII), the intermedium ester is carried out cyclisation, the lactone of generation general formula (XIV) by handling then with suitable lewis acid
(b) make the lactone and the suitable amine HNR ' R of general formula (XIV) " react, in the presence of appropriate base, handle intermedium phenol then, generate the amide of general formula (XV) with methyl iodide
(c) in suitable solvent, make the amide and the suitable organometallic reagent R of general formula (XV)
6M (wherein M is Li or MgX, and X is Cl, Br or I) reaction, the ketone of generation general formula (XVI)
(d) in suitable solvent, make the ketone and the suitable organometallic reagent R of general formula (XVI)
5R
4M (wherein M is that Li or MgX and X are Cl, Br or I) reaction generates the chemical compound of general formula (IB)
The other method of preparation general formula (IB) chemical compound comprises:
(a ') makes the R that has of the amide of general formula (XVII) and general formula (XVIII) in suitable solvent
2And R
3Ethylene bromide base reactive magnesium, obtain the ketenes of general formula (XIX)
(b ') (b ') makes the ketenes and the reaction of suitable organic copper reagent of general formula (XIX) in suitable solvent, generate the ketone of general formula (XX), and described organic copper reagent is by organometallic reagent R
1M (wherein M is Li or MgX) and mantoquita CuX (wherein X is Cl, Br or I) produce
(c ') makes the ketone and the suitable organometallic reagent R of general formula (XX) in suitable solvent
5R
4M (wherein M is that Li or MgX and X are Cl, Br or I) reaction generates the chemical compound of general formula (IB)
The present invention relates to chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IC):
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be C independently of one another
1-C
5Alkyl;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is chosen wantonly separately and is replaced by the 1-3 substituent group independently,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen or oxo;
R
5For with the carbocyclic fused heteroaryl of saturated or fractional saturation, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, oxo, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or trifluoromethyl; With
R
6Be hydrogen, C
1-C
8Alkyl, C
2-C
8Alkenyl, C
2-C
8Alkynes base, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, carbocyclic ring-C
1-C
8Alkyl, carboxyl, trifluoromethyl, alkoxy carbonyl group, aryl-C
1-C
8Alkyl, aryl-C
1-C
8Haloalkyl, heterocyclic radical-C
1-C
8Alkyl, heteroaryl-C
1-C
8Alkyl, carbocyclic ring-C
2-C
8Alkenyl, aryl-C
2-C
8Alkenyl, heterocyclic radical-C
2-C
8Alkenyl or heteroaryl-C
2-C
8Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, phenyl, C
1-C
5Alkoxyl, phenoxy group, C
1-C
5Alkanoyl, aroyl, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IC), wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional be selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace;
R
2And R
3Be C independently of one another
1-C
3Alkyl;
R
4Be CH
2
R
5Be the heteroaryl that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl, hydroxyl, oxo or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional be selected from methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, trifluoromethyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IC), wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group or C independently
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyrroles, pyrazoles or the imidazoles that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group, hydroxyl, oxo or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, trifluoromethyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently,
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IC), wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, aryl, heteroaryl, heterocyclic radical or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements;
R
2And R
3Be C independently of one another
1-C
3Alkyl;
R
4Be CH
2
R
5Be the heteroaryl that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl, hydroxyl, oxo or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional be selected from methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, trifluoromethyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (IC), wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, pyridine radicals, pyrimidine radicals, pyrazinyl, cyano group or C independently
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R wherein
1The optional substituent group that is selected from cyano group or halogen independently of each substituent group replace;
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyrroles, pyrazoles or the imidazoles that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group, hydroxyl, oxo or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, trifluoromethyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently,
The representational general formula of the present invention (IC) chemical compound such as Table I C are appended, and its intermediate hurdles A is the chemical compound title according to the standard nomenclature principle, and hurdle B is corresponding chemical constitution.
Preferred general formula (IC) chemical compound comprises following:
1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group-1,5,6,7-tetrahydro indole-4-ketone;
1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxy-4-methyl-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-hydroxyl-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-hydroxyl-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone; With
1-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone,
Preferred general formula (IC) chemical compound comprises following chemical compound or its tautomer, prodrug, solvate or salt:
1-[2-hydroxy-4-methyl-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-hydroxyl-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone; With
1-[2-hydroxyl-4-(2-hydroxyl-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone,
Most preferred general formula (IC) chemical compound comprises following chemical compound or its tautomer, prodrug, solvate or salt:
1-[2-hydroxy-4-methyl-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-hydroxyl-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone; With
1-[2-hydroxyl-4-(2-hydroxyl-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone,
The present invention also provides the method for preparing general formula (IC) chemical compound
Synthetic order of preparation general formula (IC) chemical compound is as follows.
The other method of preparation general formula (IC) chemical compound is as follows.
The invention still further relates to chemical compound or its tautomer, prodrug, solvate or the salt of general formula (ID):
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be C independently of one another
1-C
5Alkyl, R
2And R
3In one or two independently by hydroxyl, C
1-C
5Alkoxyl, C
1-C
5(wherein nitrogen-atoms is optional independent of C for alkylthio group (wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone), amino
1-C
5The alkyl or aryl list replaces or two replacements) replace;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is chosen wantonly separately and is replaced by the 1-3 substituent group independently,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen or oxo;
R
5Be the optional heteroaryl that is replaced by the 1-3 substituent group independently,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or trifluoromethyl; With
R
6Be hydrogen, C
1-C
8Alkyl, C
2-C
8Alkenyl, C
2-C
8Alkynes base, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, trifluoromethyl, carbocyclic ring-C
1-C
8Alkyl, carboxyl, alkoxy carbonyl group, aryl-C
1-C
8Alkyl, aryl-C
1-C
8Haloalkyl, heterocyclic radical-C
1-C
8Alkyl, heteroaryl-C
1-C
8Alkyl, carbocyclic ring-C
2-C
8Alkenyl, aryl-C
2-C
8Alkenyl, heterocyclic radical-C
2-C
8Alkenyl or heteroaryl-C
2-C
8Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, phenyl, C
1-C
5Alkoxyl, phenoxy group, C
1-C
5Alkanoyl, aroyl, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (ID), wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional be selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace;
R
2And R
3Be C independently of one another
1-C
3Alkyl, R
2And R
3In one or more independently by hydroxyl, C
1-C
5Alkoxyl replaces;
R
4Be CH
2
R
5Be imidazole radicals, pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, furo pyrimidine radicals, benzothienyl, thienopyridine base, Thienopyrimidine base, benzoxazolyl, oxazole and pyridine radicals, benzothiazolyl, thiazole and pyridine radicals, benzimidazolyl, imidazopyridyl, imidazopyrimidine base, Imidazopyridazine base, Imidazopyrazines base, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional be selected from methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, trifluoromethyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (ID), wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group or C independently
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3Be methyl, R
2And R
3In one or two replaced by hydroxyl or methoxyl group independently;
R
4Be CH
2
R
5Be pyridine radicals, indyl, azaindole base, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, C
3-C
6Methyl cycloalkyl-, trifluoromethyl or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently,
Another aspect of the present invention comprises chemical compound or its tautomer, prodrug, solvate or the salt of general formula (ID), wherein:
R
1Be phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone; With
R
2And R
3Be C independently of one another
1-C
3Alkyl, it is optional separately independently by hydroxyl, C
1-C
3Alkoxyl replaces,
The representational general formula of the present invention (ID) chemical compound such as Table I D are appended, and its intermediate hurdles A is the chemical compound title according to the standard nomenclature principle, and hurdle B is corresponding chemical constitution.
Preferred general formula (ID) chemical compound comprises following chemical compound or its tautomer, prodrug, solvate or salt:
1,1,1-three fluoro-5-methoxyl groups-4-methyl-4-phenyl-2-quinolyl-4 methylpent-2-alcohol; With
5,5,5-three fluoro-2-methyl-2-phenyl-4-quinolyl-4 methylpentane-1, the 4-glycol, the present invention also provides the method for preparing general formula (ID) chemical compound.
One of method for preparing general formula (ID) chemical compound is by intermedium aldehyde, and is as follows.
In others of the present invention, chemical compound of the present invention is formulated into pharmaceutical composition, and it comprises The compounds of this invention or its tautomer, prodrug, solvate or salt and the pharmaceutically acceptable excipient or the carrier of effective dose (preferred medicinal effective dose).
The present invention also provides the method for regulating glucocorticoid receptor function in patient's body, and described method comprises the chemical compound of the present invention of patient's effective dosage or its tautomer, prodrug, solvate or salt.
The present invention also is provided at the method for carrying out described treatment among the patient who needs the treatment glucocorticoid receptor function disease states mediated or the state of an illness, and described method comprises the of the present invention pharmaceutically acceptable chemical compound of patient's effective dosage or its tautomer, prodrug, solvate or salt.
In addition, the present invention also is provided to be needed to treat the method for carrying out described treatment among type ii diabetes, obesity, cardiovascular disease, hypertension, arteriosclerosis, nervous system disease, adrenal gland neoplasms and pituitary tumor and the glaucomatous patient, and described method comprises the of the present invention pharmaceutically acceptable chemical compound of patient's effective dosage or its tautomer, prodrug, solvate or salt.
The invention provides in needs treatments is the method for carrying out described treatment among the patient of disease of feature with inflammation, allergy or breeding, and described method comprises the of the present invention pharmaceutically acceptable chemical compound of patient's effective dosage or its tautomer, prodrug, solvate or salt.In a preferred embodiment of the invention, be that the disease of feature is selected from: (i) pneumonopathy with inflammation, allergy or propagation; (ii) rheumatism or autoimmune disease or joint disease; (iii) allergic disease; (iv) vasculitis; (v) dermatosis; (vi) nephropathy; (vii) hepatopathy; (viii) gastroenteropathy; (ix) rectum disease; (x) oculopathy; (xi) disease in ear, nose and larynx (ENT) zone; (xii) nervous system disease; (xiii) hematopathy; (xiv) tumor disease; (xv) endocrine disease; (xvi) organ and tissue transplantation and graft versus host disease; (xvii) serious shock state; (xviii) alternative medicine; (xix) pain of inflammation formation.In another preferred embodiment of the present invention, be that the disease of feature is selected from inflammation, allergy or propagation: restenosis, Alzheimer, acute pain and chronic pain, arteriosclerosis, reperfusion injury, bone resorption disease, congestive heart failure, myocardial infarction, hot injury, posttraumatic multiple organ injury, acute purulent meningitis, necrotizing enterocolitis and hemodialysis related syndromes, leukocyte separate and the granulocyte infusion behind type i diabetes, osteoarthritis, Guillain-Barre syndrome, the percutaneous transluminal coronary angioplasty.
The present invention also is provided at the method for carrying out described treatment among the patient who needs the above-mentioned morbid state of treatment or the state of an illness, and described method comprises the continuous or administration simultaneously to the patient: (a) the of the present invention pharmaceutically acceptable chemical compound of effective dose or its tautomer, prodrug, solvate or salt; (b) pharmaceutically acceptable glucocorticoid.
The present invention also provides the method for glucocorticoid receptor function in the analytical sample, comprising: this sample is contacted with chemical compound of the present invention or its tautomer, prodrug, solvate or the salt of selected amount; (b) amount of the bonded chemical compound of the present invention of glucocorticoid receptor (GR) or its tautomer, prodrug, solvate or salt in detection and the sample.In a preferred embodiment of the invention, with detectable label labelling chemical compound of the present invention or its tautomer, prodrug, solvate or salt, described detectable label is selected from: radio-labeled, fluorescence labels, chemiluminescence label, chromophore and spin labeling.
The present invention also is provided as the method that glucocorticoid receptor (GR) distributes in picture sample or the patient, and described method comprises: (a) make this sample and the chemical compound of the present invention with detectable or its tautomer, prodrug, solvate or salt contact or to patient's administration chemical compound of the present invention or its tautomer, prodrug, solvate or salt; (b) use imaging method, detect with sample in or bonded, the chemical compound of the present invention of glucocorticoid receptor (GR) or the spatial distribution and the amount of its tautomer, prodrug, solvate or salt in the patient with detectable; (c) with sample in bonded, chemical compound of the present invention or the spatial distribution of its tautomer, prodrug, solvate or salt and the image of amount of glucocorticoid receptor (GR) with detectable.In a preferred embodiment of the invention, imaging method is selected from: radioscintigraphy, NMR (Nuclear Magnetic Resonance)-imaging (MRI), computed tomography (CT scan) or positron emission tomography (PET).
The present invention also provides in-vitro diagnosis to determine the test kit of glucocorticoid receptor function in the sample, comprising: (a) chemical compound of the present invention or its tautomer, prodrug, solvate or the salt of diagnosis effective dose; (b) operation instructions of diagnostic kit.
Preferably, general formula (IA), (IB), (IC) and chemical compound (ID) are got rid of the chemical compound that is disclosed in the U.S. Patent Application Publication 2004/0023999.
The subordinate list summary
Table I A has listed representational general formula (IA) chemical compound;
Table I B has listed representational general formula (IB) chemical compound;
Table I C has listed representational general formula (IC) chemical compound; With
Table I D has listed representational general formula (ID) chemical compound.
The specific embodiment
The used term and the definition of convention
The term that herein is not specifically defined will have the implication that those skilled in the art is provided according to the application's disclosure and context.But as employed in description and the claims, if not opposite explanation, following term has specified meaning, and observes following convention.
A. chemical nomenclature, term and convention
In group (groups), residue (radicals) or the part (moieties) of following definitions, carbon number is often referred to and fixes on before the group, for example, and C
1-C
10Alkyl is meant alkyl group or the residue with 1-20 carbon atom.The term " rudimentary " that is applied to carbon-containing group is meant and is suitable for this group, contains the group (for example, cyclic group must have at least 3 atoms, to constitute ring) of 1-8 carbon atom.Usually, for comprising the group that two or more subbases are rolled into a ball, Ming Ming group is the residue junction point at last, for example, " alkaryl " is meant the monovalence residue of general formula Alk-Ar-, and " aralkyl " is meant the monovalence residue (wherein Alk is that alkyl and Ar are aryl) of general formula Ar-Alk-.In addition, use is specified the monovalence residue and is applicable to that the term of residue of divalent should be construed as denoting corresponding surely residue of divalent, and vice versa.Otherwise indicated, use conventional term definition, and in all general formulas and group hypothesis and realize conventional stable atomicity.
Term " alkyl " or " alkyl " are meant branching or the saturated monovalence aliphatic hydrocarbyl of straight chain.This term is illustrated as following group, for example methyl, ethyl, n-pro-pyl, 1-Methylethyl (isopropyl), normal-butyl, n-pentyl, 1,1-dimethyl ethyl (tert-butyl group) etc.It can be abbreviated as " Alk ".
Term " alkenyl " or " kiki alkenyl group " are meant branching or the straight chain monovalence aliphatic hydrocarbyl that contains at least one carbon-to-carbon double bond.This term is illustrated as following group, for example vinyl, acrylic, n-butene base, isobutenyl, 3-methyl but-2-ene base, positive pentenyl, heptenyl, octenyl, decene base etc.
Term " alkynes base " or " alkynes base group " are meant branching or the straight chain monovalence aliphatic hydrocarbyl that contains at least one carbon-to-carbon triple bond.This term is illustrated as following group, for example acetenyl, propinyl, positive butynyl, 2-butyne base, 3-methyl butynyl, positive pentynyl, heptyne base, octyne base, decynyl etc.
Term " alkylidene " or " alkylidene group " are meant to have branching or the saturated divalent aliphatic alkyl of straight chain that specifies number carbon atom.This term is illustrated as following group, for example methylene, ethylidene, propylidene, inferior normal-butyl etc., and selectively He be expressed as-(alkyl)-with being equal to.
Term " inferior alkylene " or " inferior alkylene group " are meant and contain at least one carbon-to-carbon double bond and have branching or the straight chain divalent aliphatic alkyl that specifies number carbon atom.This term is illustrated as following group, for example ethenylidene, allylidene, inferior n-butene base etc., and selectively He be expressed as-(alkylene)-with being equal to.
Term " inferior alkynes base " or " inferior alkynes base group " are meant the branching or the straight chain divalent aliphatic alkyl that contain at least one carbon-to-carbon triple bond.This term is illustrated as following group, for example ethynylene, inferior propinyl, inferior positive butynyl, 2-butynelene, 3-methyl butynelene, inferior positive pentynyl, inferior heptyne base, inferior octyne base, inferior decynyl etc., and selectively He be expressed as-(alkynes base)-with being equal to.
Term " alkoxyl " or " alkoxy base " are meant that general formula is the monovalence residue of AlkO-, and wherein Alk is an alkyl.This term is illustrated as following group, for example methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, sec-butoxy, tert-butoxy, amoxy etc.
Term " aryloxy group " or " aryloxy group " are meant that general formula is the monovalence residue of ArO-, and wherein Ar is an aryl.This term is illustrated as following group, for example phenoxy group, naphthoxy etc.
Term " oxo " be meant general formula be (=O) two key formula bivalence oxygen residues, for example the example of alkyl that is replaced by " oxo " is that general formula is the group of Alk-C (O)-Alk, wherein Alk is alkyl.
Term " alkyl-carbonyl ", " alkyl-carbonyl group ", " alkanoyl " or " alkanoyl group " be meant general formula be AlkC (O)-the monovalence residue, wherein Alk is alkyl or hydrogen.
Term " aryl carbonyl ", " aryl carbonyl group ", " aroyl " or " aroyl group " be meant general formula be ArC (O)-the monovalence residue, wherein Ar is an aryl.
Term " acyl group " or " carboxyl groups " be meant general formula be RC (O)-the monovalence residue, wherein R is the substituent group that is selected from hydrogen or organic substituent.Exemplary substituent group comprises alkyl, aryl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaryl alkyl etc.Therefore, this term comprises alkyl-carbonyl and aryl carbonyl.
Term " acylamino-" or " acylamino-group " be meant general formula be RC (O) N (R)-the monovalence residue, wherein R respectively does for oneself and is selected from hydrogen or substituent substituent group.
Term " alkoxy carbonyl group " or " alkoxycarbonyl group " be meant general formula be AlkO-C (O)-the monovalence residue, wherein Alk is an alkyl.Exemplary alkoxy carbonyl group comprises methoxycarbonyl group, ethoxy carbonyl, tert-butoxycarbonyl etc.
Term " alkyl amino carbonyl oxy " or " alkyl amino carbonyl oxy group " are meant that general formula is R
2The monovalence residue of NC (O) O-, wherein Alk is hydrogen or low alkyl group independently of one another.
Term " alkoxycarbonyl amido " or " alkoxycarbonyl amido group " are meant that general formula is the monovalence residue of ROC (O) NH-, and wherein R is a low alkyl group.
Term " alkyl-carbonyl-amino ", " alkyl-carbonyl-amino group ", " alkanoylamino " or " alkanoylamino group " are meant that general formula is the monovalence residue of AlkC (O) NH-, and wherein Alk is an alkyl.Exemplary alkyl-carbonyl-amino comprises acetylamino (CH
3C (O) NH-).
Term " alkyl amino carbonyl oxy " or " alkyl amino carbonyl oxy group " are meant that general formula is the monovalence residue of AlkNHC (O) O-, and wherein Alk is an alkyl.
Term " amino " or " amino group " are meant-NH
2Base.
Term " alkylamino " or " alkylamino group " are meant that general formula is the monovalence residue of (Alk) NH-, and wherein Alk is an alkyl.Exemplary alkylamino comprises methylamino, ethylamino, third amino, fourth amino, uncle's fourth amino etc.
Term " dialkylamino " or " dialkylamino group " are meant that general formula is (Alk) (Alk) monovalence residue of NH-, and wherein each Alk is alkyl independently.Exemplary dialkylamino comprises dimethylamino, Methylethyl amino, lignocaine, dipropyl amino, ethyl propyl amino etc.
Term " amino of replacement " or " amino group of replacement " are meant that general formula is-NR
2The monovalence residue, wherein R is hydrogen or specified substituent group (but wherein two R can not be hydrogen simultaneously) independently of one another.Exemplary substituent group comprises alkyl, alkanoyl, aryl, aralkyl, cycloalkyl, heterocyclic radical, heteroaryl, heteroaryl alkyl etc.
Term " alkoxycarbonyl amido " or " alkoxycarbonyl amido group " are meant that general formula is the monovalence residue of AlkOC (O) NH-, and wherein Alk is an alkyl.
Term " urea groups " or " ureido groups " are meant that general formula is R
2The monovalence residue of NC (O) NH-, wherein the Ar hydrogen or alkyl of respectively doing for oneself.
Term " halogen " or " ' halogen group " are meant fluorine, chlorine, bromine or iodine group.
Term " halo " is meant that one or more hydrogen atoms of this group are replaced by halogen group.
Term " haloalkyl " or " halogenated alkyl group " are meant the saturated monovalence aliphatic hydrocarbyl of branching or straight chain, and wherein one or more hydrogen atoms of this group are replaced by halogen atom independently of one another.This term is illustrated as following group, a chloromethyl, 1 for example, 2-two bromoethyls, 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 " are meant that general formula is-residue of divalent of S-.
Term " alkylthio group " or " alkylthio group group " are meant that general formula is the monovalence residue of AlkS-, and wherein Alk is an alkyl.Exemplary group comprises methyl mercapto, ethylmercapto group, positive rosickyite base, iprotiazem base, positive butylthio etc.
Term " sulfonyl " or " sulfonyl group " are meant general formula-SO
2-the residue of divalent that is.
Term " sulfonamido " or " sulfonamido group " are meant that general formula is-SO
2The residue of divalent of NR-, wherein R is hydrogen or substituent group.
Term " amino-sulfonyl " or " amino-sulfonyl group " are meant that general formula is NR
2SO
2-the monovalence residue, respectively do for oneself hydrogen or substituent group of R wherein.
Term " carbocyclic ring " or " carbon ring group " are meant stable aliphatic 3-to 15-unit's monocycle or multi-ring monovalence or residue of divalent, it only is made up of carbon and hydrogen atom, and can comprise one or more condensed or bridged rings, preferred 5-to 7-unit's monocycle or 7-to 10-unit dicyclo.Otherwise indicated, carbocyclic ring can be connected on any carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable carbon atom that produces rock-steady structure.This term comprises the inferior alkynes base of cycloalkyl (comprising spiro cycloalkyl group), cyclic alkylene, cycloalkenyl group, loop chain alkenylene, cycloalkynyl group and ring etc.
Term " cycloalkyl " or " group of naphthene base " are meant stable aliphatic saturated 3-to 15-unit's monocycle or multi-ring monovalence residue, it only is made up of carbon and hydrogen atom, and can comprise one or more condensed or bridged rings, preferred 5-to 7-unit's monocycle or 7-to 10-unit dicyclo.Otherwise indicated, cycloalkyl ring can be connected on any carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable carbon atom that produces rock-steady structure.Exemplary cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, norborneol alkyl, adamantyl, tetralyl (1,2,3,4-tetrahydronaphthalene), 1-decahydronaphthalenes base, dicyclo [2.2.2] octyl, 1-methyl cyclopropyl, 2-methylcyclopentyl, 2-methyl ring octyl group etc.
Term " cycloalkenyl " or " cycloalkenyl group " are meant stable aliphatic 3-to 15-unit's monocycle or the multi-ring monovalence residue with at least one carbon-to-carbon double bond, it only is made up of carbon and hydrogen atom, and can comprise one or more condensed or bridged rings, preferred 5-to 7-unit's monocycle or 7-to 10-unit dicyclo.Otherwise indicated, the cycloalkenyl ring can be connected on any carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable carbon atom that produces rock-steady structure.Exemplary cycloalkenyl comprises cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base, cyclonoene base, cyclodecene base, norbornene, 2-methyl cyclopentene base, 2-methyl cyclo-octene base etc.
Term " cycloalkynyl group " or " cycloalkynyl group group " are meant stable aliphatic 8-to 15-unit's monocycle or the multi-ring monovalence residue with at least one carbon-to-carbon triple bond, it only is made up of carbon and hydrogen atom, and can comprise one or more condensed or bridged rings, preferred 8-to 10-unit's monocycle or 12-to 15-unit dicyclo.Otherwise indicated, the cycloalkyne basic ring can be connected on any carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable carbon atom that produces rock-steady structure.Exemplary cycloalkynyl group comprises cyclooctyne base, cyclonoyne base, cyclodecyne base, 2-methyl cyclooctyne base etc.
Term " cyclic alkylene " or " cyclic alkylene group " are meant stable aliphatic saturated 3-to 15-unit's monocycle or multi-ring residue of divalent, it only is made up of carbon and hydrogen atom, and can comprise one or more condensed or bridged rings, preferred 5-to 7-unit's monocycle or 7-to 10-unit dicyclo.Otherwise indicated, cycloalkyl ring can be connected on any carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable carbon atom that produces rock-steady structure.Exemplary cyclic alkylene comprises ring pentylidene etc.
Term " encircles inferior alkylene " or " encircling inferior alkylene group " is meant stable aliphatic 5-to 15-unit's monocycle or the multi-ring residue of divalent with at least one carbon-to-carbon double bond, it only is made up of carbon and hydrogen atom, and can comprise one or more condensed or bridged rings, preferred 5-to 7-unit's monocycle or 7-to 10-unit dicyclo.Otherwise indicated, encircle inferior alkene basic ring and can be connected on any carbon atom that produces rock-steady structure, and, can on any suitable carbon atom that produces rock-steady structure, be substituted if replace.The inferior alkylene of exemplary ring comprises ring inferior pentenyl, cycloethylene thiazolinyl, encircles inferior heptenyl, encircles inferior octenyl, the inferior nonene base of ring, the inferior decene base of ring, inferior norbornene, 2-methyl ring inferior pentenyl, the inferior octenyl of 2-methyl ring etc.
Term " encircles inferior alkynes base " or " encircling inferior alkynes base group " is meant stable aliphatic 8-to 15-unit's monocycle or the multi-ring residue of divalent with at least one carbon-to-carbon triple bond, it only is made up of carbon and hydrogen atom, and can comprise one or more condensed or bridged rings, preferred 8-to 10-unit's monocycle or 12-to 15-unit dicyclo.Otherwise indicated, encircle inferior alkynes basic ring and can be connected on any carbon atom that produces rock-steady structure, and, can on any suitable carbon atom that produces rock-steady structure, be substituted if replace.The inferior alkynes base of exemplary ring comprises the inferior octyne base of ring, the inferior n-heptylacetylene base of ring, encircles inferior decynyl, the inferior octyne base of 2-methyl ring etc.
Term " aryl " or " aromatic yl group " are meant aromatic carbocyclic monovalence or the residue of divalent with 6-14 carbon atom, and it has monocycle (for example, phenyl or phenylene) or a plurality of condensed ring (for example, naphthyl or anthryl).Otherwise indicated, aromatic ring can be connected on any suitable carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable carbon atom that produces rock-steady structure.Exemplary aryl comprises phenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, xenyl etc.It can be abbreviated as " Ar ".
Term " heteroaryl " or " heteroaryl groups " are meant stable aromatics 5-to 14-unit's monocycle or multi-ring monovalence or residue of divalent, it can comprise one or more condensed or bridged rings, preferred 5-to 7-unit's monocycle or 7-to 10-unit dicyclo, in described ring, have 1-4 hetero atom that independently is selected from nitrogen, oxygen and the sulfur, wherein sulfur heteroatom can be randomly oxidized arbitrarily, and nitrogen heteroatom can be randomly oxidized or quaternized arbitrarily.Otherwise indicated, hetero-aromatic ring can be connected on any suitable hetero atom or carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable hetero atom that produces rock-steady structure or carbon atom.Exemplary and preferred heteroaryl comprises furyl, thienyl, pyrrole radicals oxazolyl, thiazolyl, imidazole radicals, pyrazolyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, tetrazole radical, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, the indolizine base, a word used for translation indolizine base, indyl, the azaindole base, two azaindole bases, indolinyl, dihydro azaindole base (dihydroazaindoyl), isoindolyl (isoindolyl), a word used for translation isoindolyl (azaisoindolyl), benzofuranyl, the furo pyridine radicals, the furo pyrimidine radicals, the furo pyrazinyl, the furo pyridazinyl, dihydro benzo furyl, dihydrofuran and pyridine radicals, dihydrofuran and pyrimidine radicals, benzo dioxy cyclopenta, benzothienyl, the thienopyridine base, the Thienopyrimidine base, the thieno pyrazinyl, the thieno pyridazinyl, the dihydrobenzo thienyl, dihydro-thiophene and pyridine radicals, the dihydrothieno pyrimidines base, indazolyl, the a word used for translation indazolyl, two a word used for translation indazolyls, benzimidazolyl, imidazopyridyl, benzothiazolyl, thiazole and pyridine radicals, thiazole and pyrimidine radicals benzoxazolyl oxazole and pyridine radicals oxazole and pyrimidine radicals, the benzoisoxazole base, purine radicals, Chromanyl, azepine Chromanyl (azachromanyl), quinolizinyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, the dihydro-isoquinoline base, tetrahydro isoquinolyl, once quinoline base, azepine cinnolines base (azacinnolinyl), 2, the 3-phthalazinyl, azepine (2, the 3-phthalazinyl) (azaphthalazinyl), quinazolyl, azepine quinazolyl (azaquinazolinyl), quinoxalinyl, azepine quinoxalinyl (azaquinoxalinyl), 1, the 5-phthalazinyl, 1,5-diaza dihydro naphthyl (dihydronaphthyridinyl), 1,5-diaza tetralyl (etrahydronaphthyridinyl), pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl is with phenoxazine group etc.
Term " heterocycle ", " heterocyclic group ", " heterocyclic radical " or " heterocyclic radical group " are meant stable non-aromatics 5-to 14-unit's monocycle or multi-ring monovalence or residue of divalent, it can comprise one or more condensed or bridged rings, preferred 5-to 7-unit's monocycle or 7-to 10-unit dicyclo, in described ring, have 1-3 hetero atom that independently is selected from nitrogen, oxygen and the sulfur, wherein sulfur heteroatom can be randomly oxidized arbitrarily, and nitrogen heteroatom can be randomly oxidized or quaternized arbitrarily.Otherwise indicated, heterocycle can be connected on any suitable hetero atom or carbon atom that produces rock-steady structure, and if replace, can be substituted on any suitable hetero atom that produces rock-steady structure or carbon atom.Exemplary and preferred heterocycle comprises pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, morpholinyl, thio-morpholinyl (thiomorpholinyl), piperazinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, tetrahydrofuran base, hexahydropyrimidine base, hexahydro-pyridazine base etc.
Allow as context, term " chemical compound of general formula (I) " and the expression intention that is equal to comprise the chemical compound of general formula (IA), the chemical compound of general formula (IB), the chemical compound of general formula (IC) and the chemical compound of general formula (ID), comprise independent chemical compound, perhaps some combinations, perhaps whole chemical compounds.
Allow as context, term " chemical compound of the present invention " and the expression intention that is equal to comprise the chemical compound of general formula described herein (I), comprise its tautomer, prodrug, salt (particularly officinal salt) and solvate and hydrate.Usually and preferably, chemical compound of the present invention and specify the general formula of The compounds of this invention to be interpreted as only comprising the stable compound of The compounds of this invention but get rid of unstable compounds is even unstable compounds is contemplated as falling with in this chemical compound general formula on may be literal.Similarly, allow as context, when mentioning intermedium, no matter itself whether be required protection, the intermedium intention comprises their salt and solvate.For clarity sake, when context allows, go out instantiation sometimes, but these examples only are illustrative, and intention is got rid of other example when context allows at the text middle finger.
Term " optional " or " randomly " are meant that incident or the situation described subsequently can take place or can not take place, and comprise situation that incident or situation take place and situation about not taking place in the description.For example, " the optional aryl that replaces " is meant that aryl can be substituted or not be substituted, and the aryl that comprises the aryl of replacement in the description and do not have to replace.
Term " stable chemical compound " or " stable structure " are meant that chemical compound is enough firm, are able to take to be separated to useful purity from reactant mixture, and are mixed with effective preventive or diagnostic agent.For example, have " unsettled valence link (dangling valency) " chemical compound or for the chemical compound of carbanion be not the chemical compound that the present invention considers.
Term " replacement " be meant the appointed substituent group of any one or a plurality of hydrogen (no matter whether specifically specifying) on the atom of group or part select replace, condition is the normal atom quantivalence that is no more than atom, and described replacement generates stable chemical compound.If be connected to substituent key table reveal with connecting ring on the key of two atoms intersect, so described substituent group can be connected to ring and go up arbitrary atom.When not pointing out when listing substituent group described substituent group by which atom is connected with the remainder of this chemical compound, so described substituent group can be connected by the arbitrary atom on the described substituent group.For example, when substituent group was piperazinyl, piperidyl or tetrazole radical, otherwise indicated, described piperazinyl, piperidyl or tetrazole radical can be connected with the remainder of chemical compound of the present invention by the arbitrary atom on described piperazinyl, piperidyl or the tetrazole radical.Usually, when any substituent group or group occurred more than once in any substituent group or the chemical compound, its definition when at every turn occurring was independent of other each definition that occurs.Therefore, for example, if group is expressed by 0 to 2 R
5Replace, the optional quilt of so described group is two R at the most
5Group replaces, and each R
5Be independently selected from possible R
5Definition enumerate.Yet only when the stable chemical compound of the combination results of this substituent group and/or variable, described combination is only permission.
In specific embodiments, term " about " or " being similar to " be meant set-point or scope 20% in, preferably in 10%, more preferably in 5%.
The rate schedule of each reaction described herein is shown the percentage ratio of theoretical yield.
B. salt, prodrug, derivant and solvate term and convention
Term " prodrug " or " prodrug derivant " are meant the covalency keyed jointing derivant or the carrier of parent compound or active drug, and they experienced at least some biotransformations before showing pharmacological action.Usually, but described prodrug has the group of metabolism fracture, and conversion fast in vivo, produces parent compound, and for example by the hydrolysis in blood, and described prodrug generally includes the ester and the amide analogue of parent compound.In order to improve chemical stability, improve patient's acceptance and compliance, improvement bioavailability, prolongation effect time limit, to improve the organ selectivity, improve preparation (for example increasing water solublity) and/or reduce side effect (for example toxicity), the preparation prodrug.Usually, prodrug itself has weak biological activity under normal operation or does not have biological activity, and is stable.Utilize method well known in the art, can from parent compound, prepare prodrug easily, those that describe in for example following document of described method,
A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard (eds.), Gordon ﹠amp; Breach, 1991, chapter 5 particularly: " Design andApplications of Prodrugs ";
Design of Prodrugs, H.Bundgaard (ed.), Elsevier, 1985;
Prodrugs:Topical and Ocular Drug Delivery, K.B.Sloan (ed.), MarcelDekker, 1998;
Methods in Enzymology, K.Widder et al. (eds.), Vol.42, Academic Press, 1985,309-396 page or leaf particularly;
Burger ' s Medicinal Chemistry and Drug Discovery, 5th Ed., M.Wolff (ed.), John Wiley ﹠amp; Sons, 1995, particularly roll up 1 and 172-178 page or leaf and 949-982 page or leaf;
Pro-Drugs as Novel Delivery Systems, T.Higuchi and V Stella (eds.), Am.Chem.Soc., 1975;
Bioreversible Carriers in Drug Design, E.B.Roche (ed.), Elsevier, 1987, at these whole these documents of introducing, as a reference.
The term of Shi Yonging " pharmaceutically acceptable prodrug " is meant the prodrug of The compounds of this invention herein, in rational medical judgment scope, described prodrug is applicable to human and contacts with the tissue of rudimentary animal, and there are not over-drastic toxicity, stimulation, anaphylaxis etc., suitable with rational interests/relative risk, and be effective for its desired use; As possible, be zwitterionic form.
Term " salt " is meant acid salt or the appropriate acid of basic salt or the product of alkali of ionic species or the parent compound and the preparation parent compound of parent compound.Can pass through the conventional chemical method, synthesize the salt of The compounds of this invention from the parent compound that contains basic moiety or acidic moiety.Usually, be prepared as follows salt: in suitable solvent or in the various combinations of solvent, make required salify free alkali or acid parent compound and chemical dose amount or excessive inorganic or organic acid or alkali reaction.
The term of Shi Yonging " officinal salt " is meant the salt of The compounds of this invention herein, in rational medical judgment scope, described salt is applicable to human and contacts with the tissue of rudimentary animal, and there are not over-drastic toxicity, stimulation, anaphylaxis etc., suitable with rational interests/relative risk, normally water miscible or oil-soluble or dispersible, and be effective for its desired use.This term comprises pharmaceutically acceptable acid addition salts and pharmaceutically acceptable alkali formula addition salts.Because the free alkali and the salt form of chemical compound in fact of the present invention all are useful, so the use of salt form is equivalent to the use of alkali formula.Enumerating of acceptable acid addition salts, as S.M.Birge et al., J.Pharm.Sci., 1977,
66, shown in the pp.1-19, this whole introducing, as a reference.
Term " pharmaceutically acceptable acid addition salts " is meant the biopotency of reservation free alkali and those salt of performance, they are not undesirable biologically, and form with following mineral acid and organic acid, described mineral acid, for example hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, sulfamic acid, nitric acid, phosphoric acid etc.; Described organic acid, for example acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, the 2-acetoxy-benzoic acid, butanoic acid, dextrocamphoric acid., camphorsulfonic acid, cinnamic acid, citric acid, didextrose acid, ethyl sulfonic acid, glutamic acid, glycolic, phosphoglycerol, half sulfinic acid (hemisulfic acid), enanthic acid, caproic acid, formic acid, fumaric acid, 2-ethylenehydrinsulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid (hydroxymaleic acid), malic acid, malonic acid, mandelic acid, sym-toluenesulfonic acid, methanesulfonic acid, LOMAR PWA EINECS 246-676-2, nicotinic acid, the 2-LOMAR PWA EINECS 246-676-2, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, the 3-phenylpropionic acid, picric acid, neopentanoic acid, propanoic acid, acetone acid, acetone acid, salicylic acid, stearic acid, succinic acid, p-anilinesulfonic acid., tartaric acid, p-methyl benzenesulfonic acid, hendecanoic acid etc.
Term " pharmaceutically acceptable alkali formula addition salts " is meant the biopotency of reservation free acid and those salt of performance, they are not undesirable biologically, and form with following inorganic base, described inorganic base, for example hydroxide, carbonate or the bicarbonate of ammonia or ammonium or metal cation (for example sodium, potassium, lithium, calcium, magnesium, ferrum, zinc, copper, manganese, aluminum etc.).Be preferably ammonium salt, potassium salt, sodium salt, calcium salt and magnesium salt especially.The salt that comprises primary amine, secondary amine and tertiary amine derived from pharmaceutically acceptable organic avirulent alkali; Quaternary ammonium compound; The amine that replaces, comprise the amine that natural formation replaces, cyclammonium and deacidite, methylamine for example, dimethylamine, trimethylamine, ethamine, diethylamine, triethylamine, 2-aminopropane., tripropyl amine (TPA), tri-n-butylamine, ethanolamine, diethanolamine, the 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, breathe out amine (hydrabamine), choline, betaine, ethylenediamine, glycosamine, methylglucosamine, theobromine, purine, piperazine, piperidines, N-ethylpiperidine, the tetramethyl-ammonium chemical compound, the tetraethyl ammonium chemical compound, pyridine, N, accelerine, the N-methyl piperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N, N-dibenzyl phenethylamine, 1-ephenamine (ephenamine), N, N '-dibenzyl-ethylenediamin, polyamines resin etc.Particularly preferred organic nontoxic alkali is 2-aminopropane., diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
Term " solvate " is meant that the physics of chemical compound and one or more solvent molecules associates (physical association) or by solute (for example, the chemical compound of general formula (I)) and solvent (for example, water, ethanol or acetic acid) form have a variable stoichiometric complex.This physics association can comprise ionic bond and covalent bond in various degree, comprises hydrogen bond.In some cases, for example when in the lattice that one or more solvent molecules is mixed crystalline solid, solvate can dissociate.Usually, the solvent of selection does not disturb the biological activity of solute.Solvate comprises solution phase and separable solvent.Representational solvate comprises hydrate, alcoholate, methylate etc.
Term " hydrate " is meant that wherein one or more solvent molecules are H
2The solvate of O.
As described below, chemical compound of the present invention comprises its free alkali or free acid, their salt, solvate and prodrug; Although do not set forth or demonstration, in their structure, can comprise the sulphur atom or the quaternized nitrogen-atoms, particularly its pharmaceutically acceptable form of oxidation.This form, particularly pharmaceutically acceptable form intention is included in claims scope.
C. isomer term and convention
Term " isomer " is meant to have the identical atom number and the chemical compound of kind, therefore have identical molecular weight, but atom is in spatial arrangement or configuration difference.This term comprises stereoisomer and geometric isomer.
Term " stereoisomer " or " optical isomer " are meant stable isomer, it has at least one chiral atom or has obstruction rotation (for example, some biphenyl classes, allene class and spiro-compound) and the rotatable linearly polarized light that produces vertical asymmetric faces.May produce stereomeric asymmetric center and other chemical constitution because exist in chemical compound of the present invention, the present invention expects stereoisomer and their mixture.Therefore chemical compound of the present invention and their salt comprise asymmetric carbon atoms, and can exist and exist with the form of enantiomer and diastereomer with independent stereoisomer, racemic modification form.Usually, this chemical compound is prepared to racemic mixture.Yet if desired, this chemical compound can be prepared to or be separated into pure stereoisomers, is independent enantiomer or diastereomer, perhaps is the rich mixture that closes stereoisomer.As described in more detail below, the independent stereoisomer of chemical compound can be from the synthetic preparation of the optical activity parent material that contains required chiral centre; Perhaps prepare the enantiomer mixture of products, separate then or split, for example convert the mixture of diastereomer to, by separation or recrystallization, chromatographic technique, use the chiral separation agent or direct enantiomer separation on chiral chromatographic column then.The initial compounds of specific stereochemical structure can commercially be bought, and perhaps can split by following method preparation with techniques well known.
Term " enantiomer " is meant the stereoisomer of a pair of non-overlapped mirror image each other.
Term " diastereomer " or " diastereomer " are meant the optical isomer of non-mirror image each other.
Term " racemic mixture " or " racemic compound " are meant the mixture that contains the independent enantiomer of equivalent.
Term " non-racemic mixture " is meant the mixture of the independent enantiomer of inequality.
Term " geometric isomer " is meant owing to (for example rotating the free desmotrope that produces round the limited of two keys, suitable-2-butylene and anti--2-butylene) or desmotrope with ring structure is (for example, suitable-1,3-dichloro Tetramethylene. and anti--1,3-dichloro Tetramethylene .).Because the two keys of carbon-to-carbon double bond (alkene key), C=N, ring structure etc. can be present in the chemical compound of the present invention, thus the present invention includes generate by carry out free radical to arrange round these pairs key or have in various stable geometric isomers in these ring structures and composition thereof each.Use the cis/trans agreement or use E or Z system appointment substituent group and isomer, wherein term " E " is meant that the more preferably high substituent group of order is positioned at the opposite side of two keys, and term " Z " is meant that the higher substituent group of order is positioned at the homonymy of two keys.About developing of E and Z stereo-isomerism, see J.March,
Advanced Organic Chemistry:Reactions,
Mechanisms, and Structure, 4th ed., John Wiley ﹠amp; Sons, 1992, at this its integral body is introduced, as a reference.Several following examples have been represented independent E isomer, independent Z isomer, E/Z mixture of isomers.E and Z isomer determine can by X-ray diffraction crystal analysis method for example, 1H-NMR and
13Analytical methods such as C-NMR are finished.
Chemical compounds more of the present invention can exist with more than a kind of tautomeric form.As mentioned above, chemical compound of the present invention comprises all these tautomers.
Well known in the art is that the biology of chemical compound and pharmacologically active are responsive to the spatial chemistry of chemical compound.Therefore, for example enantiomer presents significantly different biological activity usually, comprises the pharmacokinetic performance difference of (comprising metabolism, protein binding etc.); And the difference of pharmacological properties (comprising the active type degree that shows, toxicity etc.).Therefore, those skilled in the art will appreciate that when a kind of enantiomer with respect to other enantiomer be rich in or when separating from other enantiomer, it may be more active, perhaps presents beneficial effect.In addition, according to the knowledge of present disclosure and prior art, those skilled in the art will know how to separate, enrichment or optionally prepare the enantiomer of The compounds of this invention.
Therefore, although can use raceme type medicine, this does not have the pure medicine of administration equivalent mapping build effective usually; In fact, in some cases, a kind of enantiomer may be that pharmacology is inactive, and only plays the effect of simple diluent.For example, although the ibuprofen of administration racemic compound form in the past, but demonstrate, having only the S-isomer of ibuprofen as antiinflammatory is effectively (yet under the situation for ibuprofen, although yet the R-isomer is inactive, but it converts the S-isomer in vivo to, so the speed of action of raceme type medicine is lower than the speed of action of pure S-isomer).In addition, the pharmacologically active of enantiomer can have different biological activitys.For example, the S-penicillamine is the therapeutic agent of chronic arthritis, and the R-penicillamine is deleterious.In fact, the enantiomer of some purification is more favourable than racemic modification, and as having reported, the independent ratios of the isomers racemic mixture of purification has percutaneous penetrance faster.Referring to United States Patent (USP) 5,114,946 and 4,818,541.
Therefore, if a kind of enantiomer is more active on pharmacology than other enantiomer, toxicity is lower, perhaps has preferred distribution (disposition) in vivo, and the administration enantiomer will be more favourable in treatment so according to qualifications.By this way, the patient who receives treatment will be exposed in the lower medicine accumulated dose, and what be exposed to low dosage more may be the inhibitor of deleterious enantiomer or other enantiomer.
Pure enantiomer or the preparation with mixture of required enantiomeric excess (ee) or enantiomeric purity are finished by in the several different methods one or more: (a) separate or split enantiomer; Or (b) enantioselectivity well known by persons skilled in the art is synthetic, or their combination.These method for splitting depend on chiral Recognition usually, comprise, for example use chiral stationary phase chromatography, enantioselectivity host-guest complexation, use chiral auxiliary fractionation or synthetic, enantioselectivity is synthetic, enzyme and non-enzyme kinetics split, or spontaneous enantioselectivity crystallization.Be described in to these method general introduction property
Chiral Separation Techniques: A Practical Approach(2nd Ed.), G.Subramanian (ed.), Wiley-VCH, 2000; T.E.Beesley and R.P.W.Scott,
Chiral Chromatography, John Wiley ﹠amp; Sons, 1999; And Satinder Ahuja,
Chiral Separations by Chromatography, Am.Chem.Soc., 2000.In addition, there is the known method that is equal to of quantitative enantiomeric excess or purity, for example GC, HPLC, CE or NMR, and the distribution of absolute configuration and conformation, for example CD/ORD, x ray crystallography or NMR.
Usually, if in chemical compound title or structure, do not specifically note concrete spatial chemistry or isomerism type, mean all tautomerism types and the isomerism type and the mixture of chemical constitution or chemical compound so, no matter be independent geometric isomer or stereoisomer or raceme or non-racemic mixture.Usually, when resolving racemic mixtures, be preferably a kind of enantiomer.
D. administration and diagnosis and treatment term and convention
Term " patient " comprises the mankind and non-human mammal.
Term " effective dose " is meant in administration or uses in the context of The compounds of this invention that the amount of The compounds of this invention enough obtains required effect or result.Depend on context, the term effective dose can comprise medicinal effective dose or diagnosis effective dose, perhaps with its synonym.
Term " medicinal effective dose " or " treatment effective dose " are meant that when administration needs the patient of The compounds of this invention the amount of The compounds of this invention is enough treated The compounds of this invention it is had morbid state, the state of an illness or the obstacle of effectiveness.This amount is enough to the tissue, system or the patient's that bring out research worker or clinicist and seek biology or medical response.The amount that constitutes the The compounds of this invention of treatment effective dose will change with following factor, for example, described factor be the kind of the discharge rate, treatment time limit of compositions, administration time, route of administration, the chemical compound of chemical compound and biological activity thereof, administrable, state of an illness state to be treated or obstacle and seriousness thereof, with The compounds of this invention coupling or the medicine, patient's age, body weight, general health, sex and the diet that use simultaneously.This treatment effective dose can be determined by convention by the those skilled in the art that possess the open knowledge of its knowledge, prior art and the application.
Term " diagnosis effective dose " is meant that when being used for diagnostic method, device and detection the amount of The compounds of this invention enough obtains this diagnostic method, device or detects required diagnosis effect or required biological activity.This amount is to bringing out biology at diagnostic method, device or in detecting or medical response is enough, and described biology or medical response comprise the biology or the medical response of patient that research worker or clinicist seek interior or external or in-vivo tissue or system.The amount that constitutes the The compounds of this invention of diagnosis effective dose will change with following factor, for example, if described factor be compositions, administration time, route of administration, the chemical compound of chemical compound and biological activity, employed diagnostic method, device or detection, administrable discharge rate, treatment time limit, with The compounds of this invention coupling or the medicine and the experimenter that use simultaneously be the patient, then patient's age, body weight, general health, sex and diet.This diagnosis effective dose can be determined by convention by the those skilled in the art that possess the open knowledge of its knowledge, prior art and the application.
Term " adjusting " is meant that chemical compound changes the ability of glucocorticoid receptor function, for example by combination, stimulation or the reaction of inhibition glucocorticoid receptor function.
The term " modified " that uses in the context of describing The compounds of this invention is meant the chemical compound of regulating glucocorticoid receptor function.Therefore, modified agonist, partial agonist, antagonist and the partial antagonist of including, but not limited to.
The term " agonist " that uses in the context of describing The compounds of this invention is meant when combining with glucocorticoid receptor (GR), strengthens or increase the chemical compound of glucocorticoid receptor function.Therefore, agonist comprises partial agonist and full agonist.
The term " full agonist " that uses in describing the context of The compounds of this invention brings out the chemical compound that maximal stimulus reacts when being meant the glucocorticoid receptor (GR) of standby when existing even (not occupying) from glucocorticoid receptor (GR).
The term " partial agonist " that uses in describing the context of The compounds of this invention can not bring out the chemical compound of maximal stimulus reaction even be meant under the saturated enough concentration of the glucocorticoid receptor (GR) that makes existence from glucocorticoid receptor (GR).
The term " antagonist " that uses in the context of describing The compounds of this invention is meant the chemical compound of direct or indirect inhibition glucocorticoid receptor function.Therefore, antagonist comprises partial antagonist and complete antagonist.
The term that uses in describing the context of The compounds of this invention " antagonist fully " brings out the chemical compound of maximum inhibitory reaction even when being meant the glucocorticoid receptor (GR) of standby when existing (not occupying) from glucocorticoid receptor (GR).
The term " partial antagonist " that uses in describing the context of The compounds of this invention can not bring out the chemical compound of maximum inhibitory reaction even be meant under the saturated enough concentration of the glucocorticoid receptor (GR) that makes existence from glucocorticoid receptor (GR).
Term " treatment (treating) " or " handling (treatment) " are meant the morbid state in the treatment patient, and comprise:
(i) prevent to take place in the patient morbid state, particularly work as in this patient's heredity or this morbid state of easy infection, but still be not diagnosed as this disease;
(ii) suppress or alleviate morbid state in the patient, promptly stop or slow down its morbidity; Or
The (iii) morbid state in the reduction of patient is even morbid state disappears or treats morbid state.
The synthetic method general introduction of preparation general formula (IA), general formula (IB), general formula (IC) and general formula (ID) chemical compound
The present invention also provides the method for preparing general formula (IA), general formula (IB), general formula (IC) and general formula (ID) chemical compound.In whole schemes, otherwise indicated, the R in the following general formula
1To R
5Should have the R in the invention described above general formula (I)
1To R
5Meaning; And when suitable, the R in the following general formula
1To R
6Should have the R in the invention described above general formula (IB), general formula (IC) or the general formula (ID)
1To R
6Meaning.The intermedium that preparation is used in the The compounds of this invention can be bought and obtain or easily by method preparation known to those skilled in the art.
The optimum reaction conditions and response time can change with employed concrete reactant.Otherwise indicated, the easy selective solvent of those of ordinary skill in the art, temperature, pressure and other reaction condition.Detailed process partly provides in EXPERIMENTAL EXAMPLE.Usually, when needing, can pass through thin layer chromatography (TLC) monitoring reaction progress, and intermedium and product can come purification by the chromatography on the silica gel and/or by recrystallization.
The method of summarizing among the chemical compound available solutions I of general formula (IA), general formula (IC) and general formula (ID) prepares.
Scheme I
Described in scheme I, in suitable solvent (for example THF or ether),, generate 1 of general formula (III), the 2-glycol with the ester intermedium (wherein R ' is Me or Et) of appropriate reductant (for example lithium aluminium hydride reduction) reduction general formula (II).1, the oxidative cracking reaction of 2-glycol is well known in the art, and can obtain with periodic acid or lead tetra-acetate in suitable solvent (for example, methanol), to generate ketone (IV).In suitable solvent (for example THF or ether), make ketone (IV) and suitable organometallic reagent R
5R
4M (Grignard reagent for example, wherein M is MgBr or MgCl, perhaps lithium metal reagent, wherein M is Li) reaction generates the chemical compound of required general formula (I).This lithium metal reagent or Grignard reagent are well known in the art, and for example Grignard reagent is prepared as follows easily: under anhydrous condition, make corresponding halogenide (R
5R
4X, wherein X is Br or Cl) react in suitable solvent (for example ether or THF) with magnesium metal.Above-mentioned lithium metal reagent is prepared as follows easily: under anhydrous condition, make R
5R
4H (R wherein
5Be heteroaryl) react in suitable solvent (for example ether or THF) with alkyl lithium reagents (for example, diisopropylamino lithium (LDA)).
Alternatively, make ketone (IV) and suitable agent reaction, generate epoxide (V).Reacting epoxy thing (V) and required R
5H or R
5M (M is Na or Li) generates required general formula (I) product.Reaction can followingly be carried out: heating R in suitable solvent (for example DMF)
5H and epoxide (V); In the presence of appropriate base (for example Sodium ethylate in the ethanol), the common R in solvent of heating
5H and epoxide (V); Perhaps in suitable solvent (for example DMF or DMSO), react R
5M and epoxide (V).This organometallic reagent can be by using NaH, LiH or other agent treated R in suitable solvent (for example THF, DMF or DMSO)
5H or the known method of use those of ordinary skill in the art generate.
Scheme II has summarized the other method that can be used for obtaining general formula (IA) chemical compound.
Scheme II
In scheme II, make the pi-allyl Grignard reagent reaction of trifluoroacetone acetoacetic ester and replacement, generate alkene (VI).At suitable lewis acid (AlCl for example
3) there is alkene (VI) and 2 down, 3-Dihydrobenzofuranes reaction (being called " Friedel-Crafts alkylating " in this area) obtains ester (VII).With suitable Reducing agent (for example lithium aluminium hydride reduction (LAH)) ester reduction (VII) in solvent (for example THF), generate 1,2-glycol (VIII).1, the oxidative cracking reaction of 2-glycol (VIII) can be realized with sodium metaperiodate or lead tetra-acetate in suitable solvent (for example, methanol), to generate ketone (IX).Ketone (IX) and suitable halogen (Cl
2, Br
2Or I
2) or halide reagent (for example N-bromosuccinimide (NBS)) reaction, obtain ketone (X).With suitable organometallic reagent R
5R
4M (wherein M is that Li or MgX and X are Cl, Br or I) handles ketone (IX) or (X), generates the chemical compound of required general formula (IA), wherein R
1Be 2 of optional replacement, 3-dihydro benzo furyl and R
1Be methyl.
The method that the chemical compound of general formula (IA) is also summarized among the available solutions III prepares.
Scheme III
In the method, under alkali condition, coupling trifluoroacetic anhydride and N, O-dimethyl hydroxylamine hydrochloride obtains trifluoroacetamide (XI) (Weinreb amide).Make Weinreb amide (XI) and have R
2And R
3Ethylene bromide base magnesium, obtain trifluoromethyl ketenes intermedium (XII).Make the reaction of trifluoromethyl ketenes intermedium (XII) and organic copper reagent, obtain 1,4-addition compound product (IV), described organic copper reagent is handled Grignard reagent or organolithium reagent with mantoquita and is obtained.Make this trifluoro ketone intermedium (IV) and organometallic reagent R
4R
5M (as described in scheme I) reacts, and obtains the chemical compound of required general formula (IA).
The chemical compound of general formula (IA) (R wherein
4-R
5Be the optional benzimidazolyl-2 radicals-ylmethyl that replaces) can prepare by the process of summarizing in the plan V.
Scheme IV
Described in scheme IV, in the presence of highly basic (for example diisopropylamino lithium (LDA)), in suitable solvent (for example THF), make trifluoromethyl ketone (IV) and acetic acid ethyl reaction.Hydrolysis intermedium ester for example by handling with aqueous slkali, generates carboxylic acid intermedium (XIII).Then, under standard coupling condition known in the art, with this carboxylic acid intermedium (XIII) and the optional phenylenediamine coupling that replaces, for example at suitable solvent (N for example, dinethylformamide (DMF)) in, in the presence of I-hydroxybenzotriazole, handle, obtain chemical compound (XIV) with 1-(3-dimethylamino-propyl)-3-ethyl carbodiimides (EDC).The ring effect of being undertaken by approach well known of closing (for example, by handle the acid catalysis ring effect of carrying out of closing with polyphosphoric acid) generates required general formula (IA) chemical compound.
The process that the chemical compound of general formula (IB) is also summarized among the available solutions V prepares.
Plan V
In plan V, in the presence of appropriate base (for example triethylamine), make the phenol (XV) of replacement and have R
2And R
3Acryloyl chloride (XVI) reaction, generate the intermedium ester; In suitable solvent (for example Carbon bisulfide), handle and this intermedium ester of cyclisation with lewis acid (for example aluminum chloride), generate lactone (XVII)." R (for example morpholine) handles lactone (XVII), makes that " R will be used as leaving group to-NR in subsequent reaction in the amide (XVIII) that generates with suitable amine HNR.The intermedium phenol that protection forms for example by in the presence of appropriate base (for example potassium hydroxide), with the methyl iodide reaction, forms the phenol (XVIII) of protection, has methoxyl group this moment.In suitable solvent (for example THF or ether), make amide (XVIII) and organometallic reagent R then
6M (Grignard reagent for example, wherein M is MgBr or MgCl, perhaps organolithium reagent, wherein M is Li) reaction, generate ketone (XIX).Described in scheme I final step, make ketone (XIX) and R
5R
4The M reaction generates required general formula (IB) chemical compound, wherein R
1Be the optional methoxyphenyl that replaces.
In more common program, be suitable for various R
1Be to use the method for describing among the scheme III that is similar to.Described in plan V I, use to have R
6The Weinreb amide, but the method described in the operational version III prepares the required ketone (XX) and the chemical compound of general formula (IB).
Plan V I
Set forth the alternative method of the ketone (XX) of the intermedium (IV) of preparation scheme I, III and IV and plan V among the plan V II.
Plan V II
Described in plan V II, be called in the reaction of Knoevenagel condensation in this area, make to have R
1And R
2Ketone (XXI) and cyan-acetic ester (XXII) condensation (wherein R ' be Me or Et), generation alkene (XXIII).In the presence of mantoquita (for example CuI), make alkene (XXIII) and suitable organometallic reagent (R for example
1M, wherein M is MgBr, MgCl or Li) reaction, obtain ester (XXIV).Ester hydrolysis (XXIV) in suitable solvent mixture (for example DMSO and water), in the presence of suitable agent (for example sodium chloride), is followed decarboxylation to the acid that generates then, generates corresponding nitrile (XXV).Nitrile reducing (XXV) obtains aldehyde (XXVI), for example in suitable solvent (for example dichloromethane) by reducing with suitable Reducing agent (for example diisobutyl aluminium hydride (DIBAL)), form aldehyde (XXVI).In the presence of suitable fluoride source (for example tetrabutylammonium),, generate alcohol (XXVII) with trimethyl (trifluoromethyl) silane treatment aldehyde (XXVI).Oxidation alcohol (XXVII) for example handles oxidation alcohol (XXVII) with Dess-Martin periodinane reagent in suitable solvent (for example dichloromethane) by means commonly known in the art, generates ketone (IV).
Alternatively, in suitable solvent (for example THF or ether), with suitable organometallic reagent R
6M (Grignard reagent for example, wherein M is MgBr or MgCl, perhaps organolithium reagent, wherein M is Li) and handle aldehyde (XXVI), generate alcohol (XXVIII).Use method oxidation alcohol well known in the art (XXVIII) subsequently, generate ketone (XX).
In addition, the ketone (IV) that can describe from plan V III of the ketone (XX) among the plan V II prepares.
Plan V III
In plan V III, in the presence of the appropriate base (for example NaOH) and in suitable solvent mixture (water and alcoholic acid mixture), cracking ketone (IV) generates acid (XXIX).With suitable amine HN R " R ' ' ' (for example morpholine) processing acid (XXIX), make-" R will be used as leaving group to NR in subsequent reaction.In suitable solvent (for example THF or ether), make the amide (XXX) and organometallic reagent R of generation then
6M (Grignard reagent for example, wherein M is MgBr or MgCl, perhaps organolithium reagent, wherein M is Li) reaction, generate ketone (XX).Alternatively, in solvent (for example THF), handle acid (XXIX), generate alcohol (XXXI) with suitable Reducing agent (for example lithium aluminium hydride reduction (LAH)).According to method oxidation alcohol known to a person of ordinary skill in the art (XXXI), for example in suitable solvent (for example dichloromethane), handle oxidation alcohol (XXXI) with Dess-MaRTin periodinane reagent, generate aldehyde (XXVI).
Described in the plan V II, in solvent (for example THF or ether), make aldehyde (XXVI) and suitable organometallic reagent R as described above
6M (M is MgBr, MgCl or Li) reaction generates alcohol (XXVIII); Be oxidized to alcohol (XXVIII) by for example Swern oxidation or with methods such as Dess-Martin periodinane processing, generate ketone (XX).
The chemical compound of general formula (IA) (R wherein
4-R
5Be the optional indole-2-ylmethyl that replaces) can synthesize by the process of summarizing among the scheme IX.
Scheme IX
IX is described as scheme, in suitable solvent (for example DMSO), makes ketone (IV) and sulfur ylide (sulfur ylide) reaction, generates epoxide (V).In suitable solvent (for example DMSO), (for example trimethyl silyl ethinylation lithium (M is Li) is opened epoxide (V), carries out deprotection with suitable fluoride source then in suitable solvent, generates alkynes (XXXI) with suitable acetylide reagent.At suitable catalyst, alkali and solvent (for example, two (triphenylphosphine) palladiums (II) of dichloro, CuI, triethylamine and DMF) existence under, handle alkynes (XXXI) with suitable coupling gametophyte (coupling partner) (for example optional aniline or the Nitrobenzol (X is OTf, I or Br) that replaces), generate alkynes (XXXII).In suitable solvent (for example acetic acid),, generate aniline (XXXIII) with suitable metal Reducing agent (for example ferrum) reduction intermedium (XXXII).With appropriate protection group (for example trifluoroacetyl group) protection aniline (XXXIII) is well known in the art, and can be in suitable solvent (for example dichloromethane) handles with trifluoroacetic anhydride and realize.In suitable solvent (for example methanol), with the intermedium that appropriate base (for example 1,1,3,3-tetramethyl guanidine) cyclisation generates, generate the indole of trifluoroacetyl group protection, this indole experiences the acyl group deprotection in position, generates the chemical compound of general formula (IA).
The chemical compound of general formula (IA) (R wherein
4-R
5Be the optional azaindole-2-ylmethyl that replaces) can prepare by the process of summarizing among the scheme X.
Scheme X
In suitable solvent (for example THF), handle ketone (IV), obtain alkynes (XXXI) with suitable propargyl reagent (for example propargyl sesquialter aluminium bromide).At suitable catalyst, alkali and solvent (for example; two (triphenylphosphine) palladiums (II) of dichloro, CuI, triethylamine and DMF) existence under; make high propargyl alcohol (homopropargylalcohol) (XXXI) with suitable coupling gametophyte (for example; the amino pyridazine of the aminopyrimidine of the aminopyridine of optional that replace and protection, optional that replace and protection or optional that replace and protection) reaction; generate alkynes (XXXIV); one or two atom that wherein is selected among A, W, Y and the Z is a nitrogen; and remaining atom is a carbon; X is I or Br, and PG is H or BOC (tert-butoxycarbonyl).In suitable solvent (for example N-Methyl pyrrolidone (NMP)),, alkynes (XXXIV) (wherein PG is H) is converted to the azaindole or two azaindoles of corresponding optional protected general formula (IA) by handling with appropriate base (for example potassium tert-butoxide).In addition, in suitable solvent mixture (for example water and methanol mixture), contain the alkynes (XXXIV) of N-BOC group, generate required general formula (IA) product with appropriate base (for example, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU)) cyclisation.Alternatively, the N-BOC blocking group of alkynes (XXXIV) can generate corresponding amine salt by removing with appropriate acid (for example HCl) processing in suitable solvent (for example ethyl acetate); In the presence of potassium tert-butoxide, this amine salt of cyclisation in NMP, the chemical compound of generation general formula (IA).
In addition, the chemical compound of general formula (I) (R wherein
1Be the optional aryl that replaces) can be converted into the chemical compound (R wherein of general formula (I) by the order described in the scheme XI
1Further optional functionaliseding).
Scheme XI
Described in scheme XI, can be at suitable temperature with under suitable atmosphere (for example argon), in suitable solvent or solvent mixture (for example mixture of DME, methanol and DMF), in the presence of suitable catalyst (for example tetrakis triphenylphosphine palladium (O)) and appropriate base (for example potassium carbonate), with suitable coupling gametophyte, (for example, boric acid (boronic acid) or borate (boronic ester)) handles the chemical compound (R wherein of general formula (I)
1Be the optional aryl that replaces, wherein one of substituent group is suitable coupling base, for example Cl, Br, I or OTf), the chemical compound of generation general formula (I), wherein R
1Further optional functionaliseding.Alternatively, [1,1 '-two (diphenylphosphino) ferrocene] under the existence of palladium chloride (II), in DME and potassium carbonate, under appropraite condition (for example, 100 ℃ of heating), (for example with suitable coupling gametophyte, two (the pinacol root closes) two boron (bis (pinacolato) diboron) are with the chemical compound of general formula (I) (R wherein
1Be the optional aryl that replaces, and contain proper group, for example Cl, Br, I or OTf) be converted into its corresponding borate (XXXV).Then, by handling, and under suitable, above-mentioned specified coupling condition, handle, the borate of general formula (XXXV) is converted into the chemical compound (R wherein of general formula (I) with suitable aryl halide
1Optional functionaliseding).According to the commercial or synthetic availability of coupling gametophyte, in described two kinds of methods, to select, this depends on those skilled in the art's judgement.
Described in scheme XII, can be with the chemical compound of general formula (IA) (R wherein
4R
5Be the azaindole-2-ylmethyl of cyano group-replacement or the indole-2-ylmethyl of cyano group-replacement) be converted into the chemical compound (R wherein of general formula (IA)
4R
5Optional functionaliseding).
Scheme XII
By handling with suitable organometallic reagent (R ' M for example, wherein M is MgI, MgBr, MgCl or Li, R ' is alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic radical), can be with the chemical compound of general formula (IA) (R wherein
4R
5For the azaindole-2-ylmethyl (X is that nitrogen and Y are carbon, and perhaps X is that carbon and Y are nitrogen) or the indole-2-ylmethyl (X and Y are carbon) of cyano group-replacement of cyano group-replacement is converted to corresponding ketone.In suitable solvent (for example THF),, generate the chemical compound of the general formula (IA) that has 1 ° of amine moiety with suitable Reducing agent (for example borine dimethyl sulfide complex) reduction cyano group.In addition, in the presence of acid catalyst (for example HCl), handle the chemical compound of the general formula (IA) have cyano group, obtain corresponding ester with alcohol (for example methanol).In suitable solvent mixture (for example THF, water and methanol mixture),,, generate the chemical compound of the general formula (IA) that contains carboxylic moiety with the ester that hydrolysis generates by handling with appropriate base (for example Lithium hydrate).Use standard peptide coupling condition known to those skilled in the art, the carboxylic acid of the general formula (IA) that generates can be converted to amide.This conversion can be by at appropriate base (N for example, the N-diisopropyl ethyl amine) under the existence, " R and suitable activating reagent (for example 1,3-dicyclohexyl carbodiimide (DCC)) are handled and are carried out with suitable amine HNR in appropriate solvent (for example DMF or acetonitrile).Alternatively, in suitable solvent (for example THF), reduce general formula (IA) chemical compound that has ester group, obtain corresponding alcohol with suitable Reducing agent (for example lithium aluminium hydride reduction (LAH)).In suitable solvent (for example acetone),, generate the chemical compound of the required general formula that contains aldehyde radical (IA) with the alcohol that suitable oxidizers (for example manganese (IV) oxide) oxidation generates.Can as the reproducibility ammonification, this aldehyde be converted to corresponding amine by means commonly known in the art.In suitable solvent (for example 1,2-dichloroethanes), in the presence of suitable Reducing agent (for example sodium triacetoxy borohydride) and suitable acid catalyst (for example acetic acid), " the mutual conversion of this functional group is carried out in the reaction of R by aldehyde and suitable amine HNR.
The process that the chemical compound of general formula (ID) is also summarized among the available solutions XIII prepares.
Scheme XIII
In scheme XIII, in the presence of appropriate base (for example two (trimethyl silyl) Sodamide. (NaHMDS)), in suitable solvent (for example DMSO), handle nitrile (XXXVIII) with allyl bromide, bromoallylene, generate corresponding nitrile (XXXIX).In appropriate solvent (for example dichloromethane),, obtain aldehyde (XL) with suitable Reducing agent (for example DIBAL) nitrile reducing (XXXIX).With suitable Reducing agent (for example lithium aluminium hydride reduction (LAH)) further reduction aldehyde (XL) in suitable solvent (for example THF), generate alcohol (XLI).In the presence of appropriate base (for example sodium hydride (NaH)), in appropriate solvent (for example DMF), make the reaction of alcohol (XLI) and methyl iodide, generate ether (XLII).By oxicracking method well known in the art, for example use ozonization, ether (XLII) is converted to aldehyde (XLIII).In the presence of fluoride source (for example tetrabutylammonium (TBAF)), make suitable nucleophilic trifluoromethyl reagent (for example trimethyl (trifluoromethyl) silane) and aldehyde (XLIII) reaction, generate alcohol (XLIV).Use suitable oxidant (for example Dess-Martinperiodinane reagent) oxidation alcohol (XLIV) subsequently, generate trifluoromethyl ketone (XLV).In suitable solvent (for example THF), make ketone (XLV) and suitable organometallic reagent R
5R
4M (wherein M is that Li or MgX and X are Cl, Br or I) reaction obtains the chemical compound of general formula (ID).
For a more complete understanding of the present invention, following embodiment has been proposed.Just as the skilled personnel to recognize, the purpose of these embodiment is to set forth embodiment of the present invention, and should not be construed as by any way and limit the scope of the invention, and concrete reagent or condition can change according to the needs of independent chemical compound.Therefore, embodiment has set forth the synthetic of specific compound of the present invention or intermedium (it can be used for synthetic chemical compound of the present invention), as skilled person understands that whole chemical compound disclosed herein can disclosed from here one or more methods prepare.The parent material that uses can be bought and obtain, perhaps the material preparation that can be buied easily by those skilled in the art.
EXPERIMENTAL EXAMPLE
Embodiment 1: synthetic (3-iodo pyridin-4-yl) t-butyl carbamate and (4-iodo pyridin-3-yl) t-butyl carbamate
According to T.A.Kelly et al., J.Org.Chem., 1995,60, the p.1875 middle method of describing prepares title product.
Embodiment 2: synthetic (2-pyridine bromide-3-yl) t-butyl carbamate
(25.0mL, (87.7g in 800mL aqueous solution 555mmol), and refluxes and stirs this mixture 213mmol) to add potassinm permanganate with 2-bromo-3-picoline.After 5 hours, distill out 600mL water, filter remaining suspension.With two parts of 50mL hot wash residues, with the thing that leaches of concentrated hydrochloric acid acidify merging.Filter out white precipitate, and dry in vacuum drying oven, obtain 26.8 gram 2-bromo nicotinic acid (62% productive rate).
With diphenyl phosphoryl azide add 2-bromo nicotinic acid (15.0g, 74.0mmol) and triethylamine (11.4mL is in 140mL anhydrous tertiary butanol solution 81.4mmol).Reflux and stirred this reactant mixture 2 hours, be cooled to room temperature, and vacuum concentration.Residue is dissolved in the 150mL ethyl acetate, and with three parts of 50mL water three parts of 50mL saturated sodium bicarbonate aqueous solutions and with the water washing of two portions of 50mL salt.Organic layer magnesium sulfate (MgSO
4) drying, filter, and vacuum concentration.Residue leaves standstill post crystallization, obtains 15.3 gram title product (76% productive rate).
Embodiment 3: synthetic 4-amino-3-iodo-2-picoline and 4-amino-3-iodo-6-picoline
Slowly (3.80g, 100mL acetic acid solution 24.6mmol) and iron powder (6.89g, 124mmol) (attention: be reflected at become after brown to be strong heat release) of the 2-methyl-4-nitropyridine-N-oxide in the big flask of heating.The slurry that generates was heated 2 hours at 80 ℃.Vacuum is removed excessive acetic acid, and residue dissolving (take up) in 20% sodium hydrate aqueous solution, is added 100mL chloroform (CHCl
3), by CELITE filter aid filtering mixt.With two parts of 200mL chloroform extraction waters.Organic layer with dried over mgso merges filters, and vacuum concentration.Use crude product (2.2g, 83% productive rate), and be not further purified.
With KI (1.96g, 11.9mmol) and I
2(1.87g, 7.36mmol) solution in 10mL water add 2-picoline-4-base amine (1.00g, 9.25mmol) and sodium carbonate (683mg is in the reflux solution of 5mL water 6.44mmol).Mixture heated was refluxed 2 hours, be cooled to room temperature, and handle with 20mL ethyl acetate (EtOAc).Separate each phase, with three parts of 20mL ethyl acetate extraction water layers.With saturated aqueous sodium thiosulfate (Na
2S
2O
3) wash the organic layer that merges, use dried over mgso, and vacuum concentration.The residue that generates is carried out flash chromatography analysis (hexane solution to 100% ethyl acetate of 30% ethyl acetate, gradient), obtain 4-amino-3-iodo-6-picoline (first eluting: 226mg, 11% productive rate) and 4-amino-3-iodo-2-picoline (second eluting: 116mg; 5% productive rate).
Embodiment 4: synthetic 4-amino-3-bromo-2,6-lutidines
Iron powder (21.8g with some aliquots, 390mmol) handle 4-nitro-2,6-di nitryl pyridine-N-oxide (11.0g, 50mL acetic acid solution 65.4mmol), stir the mixture fast simultaneously, be heated to 50 ℃ (note: being reflected at this temperature is strong heat release) gradually.After heat release stops, with mixture 80 ℃ of reheat 1 hour.With the curing mixture of 50mL water treatment generation, and by CELITE filter aid filtering suspension liquid.Handling to leach thing with about 200mL 6N sodium hydroxide solution, be alkaline (＞12) up to the pH value of this solution.Green suspension with three parts of 300mL chloroform extractions generations.Merge extract, use dried over mgso, filter, and vacuum concentration, light yellow crystal (5.70g, 71% productive rate) obtained.
Under the room temperature, in water-bath, last 10 minutes, (0.84mL, 2mL acetic acid solution 16.3mmol) dropwise handles 2,6-lutidines-4-base amine (2.00g, 5mL acetic acid solution 16.4mmol) with bromine.After 1 hour, handle the slurry that generates with 40mL 20% sodium hydroxide solution, with three parts of 100mL dichloromethane (CH
2Cl
2) extraction.The extract that merges is dry on magnesium sulfate, filters, and vacuum concentration.The solid (parent material-required product-dibromo by-product (1: 3: 1)) that generates is dissolved in the hot ethane of 100mL, and heat filtering, remove insoluble parent material.Make to leach thing and be cooled to room temperature, obtain title product, be the fine spicule of white (1.30g, 40% productive rate).
Embodiment 5: synthetic 4-amino-3-bromo-6-cyano group-2-picoline
At nitrogen (N
2) in the atmosphere, under 70 ℃, heating 4-p-picoline-N-oxide (10.0g, 64.9mmol) and dimethyl sulfate (6.39mL, 64.5mmol) 6 hours.Solidified crineous mixture is dissolved in the 20mL water in the time of will being cooled to room temperature, is cooled to-10 ℃, the while vigorous stirring, and (5.04g, 20mL aqueous solution 77.4mmol) is dropwise handled with KCN.This mixture is heated up in ambient temperature overnight.The black multiphase mixture that generates is dissolved in 50mL ethyl acetate and the 50mL water.Separate each phase, water layer is with two parts of 50mL ethyl acetate extraction water layers.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.Flash chromatography is analyzed (hexane solution of 20% to 50% ethyl acetate, gradient), obtains brown solid product (2.80g, 27% productive rate).
With 50mL ethanol and 15mL saturated ammonium chloride (NH
4Cl) (1.9g, 11.6mmol) (7.00g 60.9mmol) is heated to 6 ℃ to the 2-cyano group in the mixture of aqueous solution-6-methyl-4-nitropyridine, and keeps 3 days with the indium powder.Add 20mL water then, filter slurry, use the methanol wash padding by CELITE filter aid.Vacuum concentration leaches thing, removes volatile organic matter, with three parts of 20mL dichloromethane extractions.The extract that merges is dry on magnesium sulfate, filters, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution to 100% ethyl acetate of 30% ethyl acetate, gradient) obtains sepia solid (580mg, 27% productive rate).
According to preparation 4-amino-3-bromo-2, the method for 6-lutidines is converted to title product with 4-amino-6-picoline-2-formonitrile HCN, and productive rate is 57%.
Embodiment 6: synthetic 5-amino-6-bromopyridine-2-formonitrile HCN
(2.38g 20mmol) is dissolved in the 6mL glacial acetic acid with 5-aminopyridine-2-formonitrile HCN.Last 30 minutes, (1mL, 2.5mL glacial acetic acid solution 20mmol) is controlled to be room temperature with water-bath simultaneously dropwise to add bromine.The slurry that at room temperature stir to generate 1 hour is washed with 50mL 20% aqueous sodium hydroxide washes, and with three parts of 160mL dichloromethane extractions.The organic layer that merges sodium sulfate (Na
2SO
4) drying, filter, and vacuum concentration.By from ethyl acetate-hexane crystallization, the purification residue obtains 5-amino-6-bromopyridine-2-formonitrile HCN (1.42g, 35% productive rate).
Embodiment 7: synthetic (6-cyano group-4-iodo pyridin-3-yl) t-butyl carbamate
At room temperature, (3.2g 10mmol) is dissolved in the 100mL dimethoxy-ethane with (4-iodo pyridin-3-yl) t-butyl carbamate.(15mmol), and at room temperature stirring reaction spends the night for 77% weight, 3.36g to add metachloroperbenzoic acid.Vacuum concentrated mixture is dissolved in the 400mL ethyl acetate once more, with two parts of 200mL saturated sodium bicarbonate (NaHCO
3) solution washing.Separate each phase, water layer is with two parts of 100mL ethyl acetate extractions.With the organic layer that the salt water washing merges, dry on magnesium sulfate, filter, and vacuum concentration.From ethyl acetate-hexane crystallization, obtain (4-iodo-pyridine 1-oxide-3-yl) t-butyl carbamate (2.65g, 79% productive rate).
90 ℃ of heating (4-iodo-pyridine 1-oxide-3-yl) t-butyl carbamate (2.65g, 7.6mmol), trimethylsilyl cyanide (4mL, 30mmol), triethylamine (2.6mL, 18.9mmol) and the mixture of 40mL anhydrous acetonitrile 2.5 hours.Vacuum concentrated mixture is with the dilution of 500mL dichloromethane, with saturated sodium carbonate (Na
2CO
3) aqueous solution is handled, and is alkalescence up to water layer.Separate each mutually after, dry on sodium sulfate with salt water washing organic layer, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (2: 98 to 8: 92 ethyl acetate-hexanes, gradient) obtains (6-cyano group-4-iodo pyridin-3-yl) t-butyl carbamate (185mg, 7% productive rate).
Embodiment 8: synthetic (2-cyano group-3-iodo pyridin-4-yl) t-butyl carbamate
At room temperature, (3.2g 10mmol) is dissolved in the 100mL dimethoxy-ethane with (3-iodo pyridin-4-yl) t-butyl carbamate.(15mmol), and at room temperature stirring reaction spends the night for 77% weight, 3.36g to add metachloroperbenzoic acid.After the solvent removed in vacuo, residue is dissolved in the 400mL ethyl acetate, and washs with two parts of 200mL saturated sodium bicarbonate aqueous solutions.Separate each phase, water layer is with two parts of 100mL ethyl acetate extractions.With the organic layer that the salt water washing merges, dry on magnesium sulfate, filter, and vacuum concentration.From ethyl acetate-hexane crystallization, obtain (3-iodo-pyridine 1-oxide-4-yl) t-butyl carbamate (1.95g, 58% productive rate).
At 90 ℃ of heating (3-iodo-pyridine 1-oxide-4-yl) t-butyl carbamate (1.95g, 5.79mmol), trimethylsilyl cyanide (3mL, 23mmol), (2mL, 14.5mmol) mixture in the 30mL anhydrous acetonitrile reaches 2.5 hours to refluxing to triethylamine.Solvent removed in vacuo then.With 500mL dichloromethane dilution residue, with saturated sodium carbonate (Na
2CO
3) aqueous solution is handled, and is alkalescence up to water layer.Separate each phase, dry on sodium sulfate with salt water washing organic layer, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (2: 98 to 8: 92 ethyl acetate-hexanes, gradient) obtains (2-cyano group-3-iodo pyridin-4-yl) t-butyl carbamate (1.22g, 61% productive rate).
Embodiment 9: synthetic 5-amino-6-bromo-2-methoxypyridine
Dropwise handle 2-methoxyl group-5-aminopyridine (10g, 0.081mol, 1.0 equivalents) and sodium acetate (6.6g, 0.081mol, 1.0 equivalents) stirring the mixture in 60mL acetic acid with bromine (12.9g, 0.081mol, 1.0 equivalents).After 20 minutes, reactant mixture is poured onto in 1000mL 10% sodium hydrate aqueous solution, and with three parts of 250mL ethyl acetate extractions.The dry organic layer that merges filters, and is evaporated to dried on magnesium sulfate.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (dichloromethane solution of 20% ethane) obtains 5-amino-6-bromo-2-methoxypyridine (6.5g, 40% productive rate), is the purple solid.
Embodiment 10: synthetic (4-iodo-6-phenylpyridine-3-yl) t-butyl carbamate
To Pd (PPh
3)
4(354mg, 1.58mmol), 2-chloro-5-nitropyridine (5.00g, 31.5mmol) and phenylboric acid (4.61g, 37.8mmol) the mixture degassing, and charge into nitrogen three times.With 40mLDME and 2M potassium carbonate (80.0mmol) aqueous solution treatment mixture, and reflux.After 4 hours, reactant mixture is cooled to room temperature, and dilutes with 100mL ethyl acetate and 50mL water.Separate each phase, water layer is with three parts of 100mL ethyl acetate extractions.With the organic layer that the water washing of 100mL salt merges, dry on magnesium sulfate, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 0% to 50% ethyl acetate, gradient) obtains 4.60 gram 5-nitro-2-phenylpyridines (73% productive rate).
(10%, on carbon, (4.60g is 23.0mmol) with BOC acid anhydride (15.0g, 68.9mmol) solution in 25mL methanol and 25mL ethyl acetate mixture 500mg) to handle 5-nitro-2-phenylpyridine with palladium.At room temperature, in the hydrogen (H of 50psi
2) in, the mixture that vibration generates.After 18 hours, with 20mL dichloromethane diluted mixture thing, by the padding filtration of CELITE filter aid, and vacuum concentration.Pulverize the solid that generates with ethyl acetate, filter, and dry, obtain 5.54 gram (6-phenylpyridine-3-yl) t-butyl carbamates, be white solid (89% productive rate).
Under-78 ℃, with n-BuLi handle (6-phenylpyridine-3-yl) t-butyl carbamate (5.54g, 20.5mmol) and TMEDA (6.49mL, 100mL anhydrous ether solution 43.0mmol).-78 ℃ handle 15 minutes after, mixture is warming up to-10 ℃, and restir 3 hours.Then, reactant mixture is cooled to-78 ℃, dropwise adds in the solution of iodine in the mixture of 10mL THF and 100mL ether.-78 ℃ handle 2 hours after, make mixture be warming up to 0 ℃, and with the quencher of 400mL saturated aqueous ammonium chloride.With five parts of 100mL saturated aqueous sodium thiosulfate washing organic layers.Water layer with three parts of 200mL ethyl acetate extractions merging.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 0% to 70% ethyl acetate, gradient) obtains the 900mg title product, is yellow oil, and it solidifies (11% productive rate) along with the time.
Embodiment 11: synthetic (4 '-iodo-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-5 '-yl) t-butyl carbamate
(10g 63.3mmol) is dissolved among the 150mL THF with 2-chloro-5-nitropyridine.Then, add the 20mL piperidines, and at room temperature stirred the mixture that generates 18 hours.Then, have a large amount of sedimentary reactant mixtures with 200mL water and the dilution of 100mL ether.Fully mix each layer, and separate.Organic layer is dry on sodium sulfate, and vacuum concentration.The bright yellow solid is dissolved in the 35mL dichloromethane once more, and strong agitation, add ethane, begin precipitation up to product.Filter to collect the bright yellow solid, and dry, obtain 12.5 grams 5 '-nitro-3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl.
In Parr agitator bottle, with 5 '-nitro-3,4,5,6-tetrahydrochysene-2H-[1,2 '] (12.5g 60.4mmol) is suspended in the 125mL methanol bipyridyl, and adds 16 gram di-tert-butyl dicarbonic acid esters, adds the 500mg platinum oxide then.Hydrogen (H in 55psi
2) in, the mixture that vibration generates 2 hours stirs under argon gas atmosphere then and spends the night.After 16 hours, by diatomaceous padding filtering mixt, and vacuum concentration.Pulverize thick residue with hexane, and filter.Chromatography on the silica gel (dichloromethane solution of 100% dichloromethane to 30% ethyl acetate, gradient) generate 6.9g's (41.2% productive rate) (3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-5 '-yl) t-butyl carbamate, be white solid.
With with preparation described same way as during (4-iodo-6-phenylpyridine-3-yl) t-butyl carbamate, from (3,4,5,6-tetrahydrochysene-2H-[1,2 '] bipyridyl-5 '-yl) t-butyl carbamate prepares title product.
Embodiment 12: amino synthetic 4-[(tertbutyloxycarbonyl)]-3-iodo-2-methoxypyridine
4-amino-2-chloropyridine (15g, 117mmol, 1.0 equivalents) is dissolved in 100mL THF.The methanol solution (1.0M, 234mL, 234mmol, 2.0 equivalents) that adds Feldalat NM, and the solution that generates refluxed 16 hours.Reactant mixture is poured onto in the quick saturated sodium bicarbonate solution that stirs of 500mL.Add the 500mL ethyl acetate, and separate each layer.Organic layer is dry on sodium sulfate, decantation, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 30% ethyl acetate) generates title compound, is yellow solid (2.1g).
4-amino-2-methoxypyridine (2.1g, 16.9mmol, 1.0 equivalents) is dissolved in the 35mL ethyl acetate.Add BOC acid anhydride (5.4g, 25.4mmol, 1.5 equivalents), and the solution that generates was refluxed 3 hours.Cooling reaction, and vacuum concentration.Pulverize residue with the 100mL hexane, generate linen precipitate, collecting precipitation thing, and vacuum drying obtain title product (1.8g).
Under inert atmosphere, use 2.79mL N, N, N ', N '-tetramethylethylenediamine (18.5mmol, 2.3 equivalents) handle the 4-[(tertbutyloxycarbonyl) amino]-the 100mL anhydrous ether solution of 2-methoxypyridine (1.8g, 8.03mmol, 1.0 equivalents).The solution that generates is cooled to-78 ℃, handles with n-BuLi (2.5M, 7.2mL, 18.0mmol, 2.24 equivalents), and be warming up to-7 ℃.-7 ℃ to 0 ℃ stirring reactions 3 hours, be cooled to-78 ℃, and (3.05g, 30mL anhydrous THF solution 12mmol) is handled with iodine.At room temperature, the mixture of stirring generation is 16 hours.Add 200mL saturated ammonium chloride solution and 100mL ether.Separate each phase, with 100mL sodium thiosulfate (10% aqueous solution) washing organic layer, in dried over sodium sulfate, decantation, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (dichloromethane solution of 100% dichloromethane to 5% methanol, gradient) generates title product (650mg, 23% productive rate), is white wax.
Embodiment 13: amino synthetic 5-[(tertbutyloxycarbonyl)]-4-iodo-2-(isopropoxy) pyridine
(15g 95mmol) and the 100mL anhydrous THF solution of the mixture of 28mL isopropyl alcohol (366mmol), dissolves up to solid to stir 2-chloro-5-nitropyridine.The solution that cooling generates in ice bath, and (1M is in THF, and 115mL 115mmol) dropwise handles with potassium tert-butoxide to last 45 minutes.React with the quencher of 75mL saturated aqueous ammonium chloride, and dilute with the 100mL ethyl acetate.Separate each phase, organic layer is dry on magnesium sulfate, filter, and vacuum concentration.Pulverize this residue with hexane, at room temperature stir and spend the night.Filtering mixt, vacuum concentration leaches thing, obtains the dark orange of 15.7 grams, and this grease is used for next step, without being further purified.
(15.7g 86mmol) is dissolved in the 125mL methanol, and transfers in the Parr bottle with 5-nitro-2-isopropoxy pyridine.Add palladium (10%, on carbon, 1.57g) and the BOC acid anhydride (28.2g, 129mmol).In the hydrogen of 50pis, on the Parr agitator, the mixture overnight that vibration generates.With 5 gram CELITE filter aid treatment mixture, filter by CELITE filter aid padding, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane-ethyl acetate (9: 1)) obtains pink solid (16.1g).This solid is dissolved in the dichloromethane, handles, filter, obtain 13.7 gram title product, be white solid with hexane.
With 13.7 gram 5-[(tertbutyloxycarbonyls) amino]-2-(isopropoxy) pyridine (54.3mmol) and 18.1mL N, N, N ', the 200mL anhydrous ether solution of N '-tetramethylethylenediamine (120mmol) is cooled to-78 ℃, and in inert atmosphere with n-BuLi (2.5M, in hexane, 48mL 120mmol) handles.This mixture is placed-8 ℃ of baths 1 hour, and make it slowly be warming up to room temperature.After 40 minutes, this flask is cooled to-8 ℃, and stirred 4 hours.Then, this mixture is cooled to-78 ℃, (19.0g, 75mmol) 100mL anhydrous THF solution is handled, and stirs the mixture that generates 16 hours, makes simultaneously to bathe to be warming up to 11 ℃ with iodine.Reactant mixture is poured onto in the saturated aqueous ammonium chloride (200mL) of quick stirring, and dilutes with 100mL water and 300mL ether.Separate each phase, water layer 200mL extracted with diethyl ether.With the organic layer that two parts of 200mL sodium thiosulfate (10% aqueous solution) washing merges, dry on sodium sulfate, decantation, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 10% to 50% ethyl acetate, gradient) obtains title product (13g, 63% productive rate), is grease, and when leaving standstill, this grease solidifies.
Embodiment 14: synthetic 4-amino-3-bromine pyridazine and 4-amino-5-bromine pyridazine
The 50mL ammonia condensing is equipped with in 3 mouthfuls of flasks of dry-ice condenser at 200mL.Adding crystal Fe (NO
3)
3After, at-78 ℃, add the potassium be small pieces (468mg, 12.0mmol).Remove cooling bath, and make bright navy blue mixture gentle reflux, up to obtaining grayish slurry.After being cooled to-78 ℃, adding 0.35mL (4.80mmol) pyridazine, and stirred the mixture 10 minutes.Add some aliquot solid K MnO
4(2.65g 16.8mmol), removes cooling bath, and stirs the mixture 10 minutes.With the careful quencher reaction of 1.2 gram solid ammonium chlorides.Add 20mL methanol, and in fume hood vaporized ammonia.Filter black mixture by CELITE filter aid, vacuum concentration leaches thing, and at SiO
2(100%CH
2Cl
2CH to 10%MeOH
2Cl
2Solution, gradient) go up the black solid that purification generates, generate pyridazine-4-base amine, be brown solid (380mg; 83% productive rate).
With with preparation 4-amino-3-bromo-2, the same way as of 6-lutidines is carried out bromination to pyrimidine-4-base amine.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution to 100% ethyl acetate of 20% ethyl acetate, gradient, 15% productive rate) and 4-amino-5-bromine pyridazine (second eluting: 5%), be the sepia solid ethyl acetate solution of 2% methanol then), obtain 4-amino-3-bromine pyridazine (first eluting:.
Embodiment 15: synthetic 5-amino-4-bromo pyrimi piperidine
With sodium hydroxide solution (20.0g, 0.50mol is in 60mL water) and palladium (10%, on carbon, 400mg) handle 5-amino-4,6-dichloro pyrimidine (5.0g, 250mL diethyl ether solution 30.5mmol).In 50psi hydrogen, under room temperature, this mixture of vibration is 20 hours on the Parr agitator.Filter this mixture by CELITE filter aid.Separate each phase, water layer is with three parts of 100mL ethyl acetate extractions.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.Crystallization crude product from ethyl acetate obtains pyrimidine-5-base amine, is white crystalline solid (2.8g; 95% productive rate).
With with preparation 4-amino-3-bromo-2, the same way as of 6-lutidines is carried out the bromination of pyrimidine-5-base amine.Think that the crude product (300mg, 35% productive rate) that generates is pure, and use and be not further purified.
Perhaps, according to the synthetic 5-amino of following method-4-bromo pyrimi piperidine: at 0 ℃, with ammonium formate (45g, 714mmol) and palladium (10%, on Linesless charcoal, 1g 0.943mmol) handles 4 continuously, 6-two chloro-5-aminopyrimidines (21g, 250mL MeOH solution 128mmol).At room temperature stir this mixture overnight, and filter by CELITE filter aid.Leach thing and concentrate, obtain yellow solid.Add 100mL water and 250mL ethyl acetate.Separate each organic facies, water layer is with eight parts of 250mL ethyl acetate extractions.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration, obtains canescence crystal (8.1g, 67%).
(3.0g, 150mL dichloromethane 31.5mmol) and the agitating solution of 30mL methanol are cooled to 0 ℃ with the 5-aminopyrimidine.Last 10 minutes, add in batches the tribromide benzyltrimethylammon.um (13.5g, 34.7mmol).Continue to stir 15 minutes at 0 ℃, under the room temperature west, stirred 90 minutes.Using the sodium bicarbonate aqueous solution reaction mixture, is 8 up to the pH value of solution.Separate organic layer, water layer is with three parts of 30mL ethyl acetate extractions.The Organic substance that merges is dry on sodium sulfate, filters, and vacuum concentration.Obtain pale solid (2.8g; 51%), uses this solid and be not further purified.
Embodiment 16: synthetic 4-amino-5-iodine pyrimidine
(0.970g, 20mL acetic acid solution 10.3mmol) obtains a large amount of precipitate, is N-iodo intermedium to handle the 4-aminopyrimidine with iodine monochloride (1.67g, 10.3mmol, 1.01 equivalents).Under argon gas atmosphere, the mixture that reflux to generate 3 hours, and be cooled to about 10 ℃ with water-bath.Collect the precipitate that forms, and dry, obtain title compound, be faint yellow solid (1.4g, 62% productive rate).
Embodiment 17: Synthetic 2,2,2-three fluoro-N-(4-iodo-2-isopropyl pyrimidine-5-yl) acetamide
Lentamente with ethyl nitroacetate (11.7mL, 105mmol) add dimethylformamide dimethyl acetal agitating solution (29.2mL, 220mmol) in.The blush mixture that generates was at room temperature kept 2 hours, and heating is 90 minutes in 100 ℃ oil bath, and is cooled to room temperature.Vacuum concentrated mixture is removed volatile organic matter, and the residue that generates 60 ℃ of heating 1 hour.Obtain reddish orange liquid (18g ,～100% productive rate), it is used for next step, and does not have purification.
To 3-dimethylamino-2-nitro ethyl acrylate (3.8g, in the agitating solution of 50mL dehydrated alcohol 20mmol), add isopropyl amidine hydrochloride (3.1g, 25mmol), add then triethylamine (2.5mL, 25mmol).The mixture that generates 90 ℃ of heating 6 hours.After being cooled to room temperature, vacuum concentrated mixture, and at SiO
2(dichloromethane solution of 3% methanol) goes up the purification crude product, obtains 3.1 gram light brown grease (84% productive rate).
Cooling 2-isopropyl-5-nitro-3H-pyrimidin-4-one in ice bath (1.55g, 8.5mmol) and triethylamine (1.4mL, 10mL dichloromethane suspension 10mmol).Last 5 minutes, slowly add phosphoryl chloride phosphorus oxychloride (1.9mL, 5mL dichloromethane solution 20mmol), and the mixture that stir to generate 90 minutes.With the mixture that dichloromethane dilution generates, dry on sodium sulfate with the ice quencher with saturated sodium bicarbonate solution and water continuous washing, filter, and vacuum concentration, obtain 0.7 gram light brown grease (41% productive rate), directly use and be not further purified.
Handle 4-chloro-2-isopropyl-5-nitro-pyrimidine (0.7g, the 3.5mmol) agitating solution in 10mL dehydrated alcohol and 5mL glacial acetic acid, and with iron powder 90 ℃ of heating blends 20 minutes.After being cooled to room temperature, with 200mL dichloromethane diluted reaction mixture, with saturated sodium bicarbonate solution and water continuous washing, dry on sodium sulfate, filter, and vacuum concentration, obtain 450mg light brown oily thing (75% productive rate), directly use and be not further purified.
(1.97g 13.1mmol) handles 4-chloro-2-isopropyl pyrimidine-5-base amine (450mg, 2.6mmol) stirring the mixture in 10mL HI (40% water solublity) solution with NaI.The mixture that stirring at room temperature generates 2 hours, and be poured onto in the dichloromethane.Separate each phase.With aqueous sodium carbonate, aqueous solution of sodium bisulfite and water washing organic layer, dry on sodium sulfate, filter, and vacuum concentration, obtain the light brown grease of 600mg (87% productive rate), directly use and be not further purified.
At room temperature, (0.43mL, 2mL dichloromethane solution 3mmol) handle 4-iodo-2-isopropyl pyrimidine-5-base amine (600mg, 2.28mmol) agitating solution in the 4mL anhydrous methylene chloride with trifluoroacetic anhydride.After 15 minutes, vacuum concentrated mixture obtains the light brown grease of 0.8 gram, solidifies when this grease leaves standstill, and directly uses this grease, and does not have purification (quantitative yield).
Embodiment 18: synthetic 4-bromo-6-phenyl pyridazine-3-base amine
According to M.Bourotte, N.Pellegrini, M.Schmitt, and J.-J.Bourguignon, Syn.Lett., 2003,
10, the method described in the pp.1482-1484 prepares 4-bromo-6-phenyl pyridazine-3-base amine.
Embodiment 19: synthetic (4-iodo-6-5-flumethiazine-3-yl) t-butyl carbamate
Under nitrogen atmosphere, reflux 6-trifluoromethyl nicotinic acid (1.0g, 5.23mmol), diphenyl phosphoryl azide (1.36mL, 6.3mmol) and triethylamine (1.83mL, 15mL anhydrous tertiary butanol solution 13.1mmol) 5 hours.Reaction is cooled to room temperature, and vacuum concentration.Add 150mL water, with two parts of 150mL ethyl acetate extraction mixture.With the organic layer that 150mL water, the washing of 150mL saturated sodium bicarbonate aqueous solution merge, dry on sodium sulfate, filter, and vacuum concentration.At SiO
2(hexane solution of 10% ethyl acetate) goes up the purification crude mixture, generates title product (0.90g, 66% productive rate).
Under argon gas atmosphere, with (6-5-flumethiazine-3-yl) t-butyl carbamate (0.90g, 3.43mmol) and N, N, N ', (1.29mL, 25mL anhydrous ether solution 8.55mmol) are cooled to-78 ℃ to N '-tetramethylethylenediamine.Last 5 minutes, (2.5M, in hexane, 3.42mL 8.55mmol) dropwise handles the mixture that generates, and makes mixture be warming up to-10 ℃ with n-BuLi.After 30 minutes, mixture is cooled to-78 ℃, and adds I fast
2(1.14g, 5mL anhydrous THF solution 4.5mmol).The mixture that generates is warming up to room temperature, stirred 1 hour, and with the quencher of 50mL water.Organic layer is dry on sodium sulfate, filters, and vacuum concentration.At SiO
2(dichloromethane solution of 10% ethyl acetate) goes up the purification crude mixture, obtains title compound (150mg, 11.3% productive rate).
Embodiment 20: synthetic (4-iodo-2,6-dimethoxy-pyridine-3-yl) t-butyl carbamate
With with the preparation (4-iodo-6-5-flumethiazine-3-yl) t-butyl carbamate same way as, from 2,6-dimethoxy nicotinic acid prepares title product.
Embodiment 21: synthetic (6-chloro-4-iodine pyridine-3-yl) t-butyl carbamate
With with the preparation (4-iodo-6-5-flumethiazine-3-yl) t-butyl carbamate same way as, prepare title product from the 6-chlorine apellagrin.
Embodiment 22: synthetic (2,6-two chloro-4-iodine pyridine-3-yls) t-butyl carbamate
With with the preparation (4-iodo-6-5-flumethiazine-3-yl) t-butyl carbamate same way as, from 2, the 6-dichloro-nicotinic acid prepares title product.
Embodiment 23: synthetic (4-iodo-5-picoline-3-yl) t-butyl carbamate
With with the preparation (4-iodo-6-5-flumethiazine-3-yl) t-butyl carbamate same way as, prepare title product from the 5-methylnicotinic acid.
Embodiment 24: synthetic (2-fluoro-4-iodine pyridine-3-yl) t-butyl carbamate
With with the preparation (4-iodo-6-5-flumethiazine-3-yl) t-butyl carbamate same way as, prepare title product from the 2-fluorine nicotinic acid.
Embodiment 25: synthetic N-(4-bromo-2-iodophenyl) benzsulfamide
With benzene sulfonyl chloride (15mL, 117.5mmol) and triethylamine (25mL 179.6mmol) handles 4-bromo-2-Iodoaniline (8.5g, 200mL dichloromethane solution 28.5mmol) continuously.After 4 days, with 100mL saturated sodium bicarbonate aqueous solution diluted mixture thing, and with three parts of 100mL ethyl acetate extractions.The organic layer that merges is with 50mL saline, three parts of 60mL saturated aqueous ammonium chloride washings, and is dry on magnesium sulfate, filter, and vacuum concentration.Pulverize crude product with ether, obtain 5.74g (35% productive rate) N, two benzenesulfonyl-(the 4-bromo-2-Iodoanilines) of N-.
Use N, two benzenesulfonyl-(the 4-bromo-2-Iodoanilines) of N-(5.78g, 10mmol) divide several parts handle tetrabutylammonium (1M, in THF, 30mL THF solution 11mL).After 18 hours, with 40mL ethyl acetate and 40mL 1N HCl diluted mixture thing.Separate each phase, and with two parts of 40mL ethyl acetate extraction water layers.The organic layer that merges is with two parts of 20mL 1N HCl, two parts of 20mL saturated sodium bicarbonate aqueous solutions, the water washing of 20mL salt, dry on magnesium sulfate, filter, and vacuum concentration, obtain the title compound of 3.95g (90% productive rate), be solid, use this solid and be not further purified.
Embodiment 26: synthetic trifluoromethanesulfonic acid 3-fluoro-2-nitrobenzophenone ester
((1.59g 10mmol) handles 3-two fluoro-2-Nitrobenzol for 1.23g, the anhydrous DMSO solution of 25mL 11mmol) 30 minutes, and with 1 at room temperature to stir potassium tert-butoxide.After 18 hours, use 150mL 1N aqueous sulfuric acid diluted mixture thing, and wash with three parts of 50mL ether.The organic layer that merges washes with water, and is dry on sodium sulfate, filter, and vacuum concentration.Residue is dissolved in the 50mL trifluoroacetic acid.After 30 minutes, at room temperature, vacuum concentrated mixture is handled with 50mL 1N sodium hydrate aqueous solution, and with three parts of 30mL extracted with diethyl ether.With 1N aqueous sulfuric acid acidify water layer, and with two parts of 50mL dichloromethane extractions.The dichloromethane layer that merges washes with water, and is dry on sodium sulfate, filter, and vacuum concentration, obtain 1.3 gram 3-fluoro-2-nitrophenols, be orange (61% productive rate).
Cooling 3-fluoro-2-nitrophenol in ice bath (1.13g, 7.2mmol) and pyridine (0.65mL, 15mL anhydrous methylene chloride solution 8mmol), and with trifluoromethanesulfanhydride anhydride (1.33mL, 3mL anhydrous methylene chloride solution-treated 7.9mmol).After 4 hours, with 100mL dichloromethane diluted reaction mixture, with two parts of 30mL saturated sodium bicarbonate aqueous solutions, two parts of 30mL 1N aqueous sulfuric acids and two parts of 30mL water washings, dry on sodium sulfate, filter, and vacuum concentration, obtain 2 gram title product, be light brown oily thing (96% productive rate).
Embodiment 27: synthetic trifluoromethanesulfonic acid 4-cyano group-2-methyl-6-nitrobenzophenone ester
With chloroacetic chloride (2.8mL, 5mL anhydrous methylene chloride solution-treated 4-bromo-2-methylphenol 26mmol) (5.6g, 30mmol) and pyridine (6.1mL, 75mmol) the ice-cold solution in the 50mL anhydrous methylene chloride.After 2 hours, the vacuum concentration reactant mixture.Handle the residue that generates with trash ice,, wash with water with the dilution of 150mL dichloromethane, dry on sodium sulfate, filter, and vacuum concentration, obtain 6.9 gram 4-bromo-2-aminomethyl phenyl acetass, be light brown oily thing (quantitative yield).
With zinc cyanide (3g, 25.6mmol) and tetrakis triphenylphosphine palladium (O) (4.5g 3.9mmol) handles 4-bromo-2-aminomethyl phenyl acetas (6.9g, 75mL anhydrous dimethyl yl acetamide solution 30mol).The reacting by heating mixture is 2 hours in the time of 100 ℃, is cooled to room temperature, and uses the 300mL cold water treatment.Filter the precipitate that generates, wash with water, and air drying.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (100% dichloromethane) obtains 5.2 gram 4-cyano group-2-aminomethyl phenyl acetass, is colorless oil (99% productive rate) that this grease solidifies when leaving standstill.
At room temperature, (30mmol, 25mL aqueous solution 4.15g) is handled 4-cyano group-2-aminomethyl phenyl acetas (5.2g, 29.7mmol) agitating solution in 75mL methanol with potassium carbonate.After 30 minutes, vacuum concentrated mixture, and use the 1N sulfuric acid treatment.Filter the precipitate that generates, wash with water, drying obtains 3.1 gram 4-hydroxy-3-methyl benzonitriles, is white solid (78% productive rate).
(3.1g, 23.3mmol) agitating solution in the 60mL anhydrous acetonitrile is cooled to-30 ℃, and with nitronium tetrafluoroborate (3.4g, 25.6mmol) batch processing with 4-hydroxy-3-methyl benzonitrile.After 60 minutes, with 100mL water diluted reaction mixture.Filter the light yellow precipitate that generates, wash with water, and dry, obtain 3.9 gram 4-hydroxy-3-methyl-5-nitrobenzonitriles (94% productive rate).
Described method during according to preparation trifluoromethanesulfonic acid 3-fluoro-2-nitrobenzophenone ester is converted to title product with 4-hydroxy-3-methyl-5-nitrobenzonitrile.
Embodiment 28: synthetic 3-fluoro-6-methyl-2-nitrophenol
With the hot solution of 7mL concentrated sulphuric acid in 21mL water add 5-fluoro-2-aminomethyl phenyl amine (5g, 40mmol) in.Cooling mixture is 30 minutes in ice bath, and with sodium nitrite (3.38g, the solution-treated of 10mL water 48mmol) 10 minutes.When 0 ℃ stir 45 minutes after, with 20mL cold water diluting reaction, and with 0.3 gram urea processing.Under 130 ℃, last 10 minutes, the mixture that generates is added the agitating solution of 11mL concentrated sulphuric acid in the 10mL water that contains 15 gram anhydrous sodium sulfates.Stirred 5 minutes at 130 ℃ again, make reaction be cooled to room temperature, and with three parts of 100mL dichloromethane extractions.The organic layer that merges extracts with two parts of 50mL water, and vacuum concentration.Erythroid grease is dissolved in the 250mL ether, and washs with 10% aqueous sodium hydroxide washes of three parts of 50mL.Sodium hydrate aqueous solution extract with two parts of 50mL extracted with diethyl ether merging.With 1N HCl acidified aqueous solution alkaline layer, and with three parts of 100mL dichloromethane extractions.With the dichloromethane layer that two parts of 50mL salt water washings merge, dry on sodium sulfate, filter, and vacuum concentration, obtain shallow erythroid liquid.By at SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 10% ethyl acetate) purification crude product obtains 5 gram 5-fluoro-2-methylphenols, is light brown oily thing (99% productive rate).
(640mg, 5mmol) agitating solution in the 20mL anhydrous acetonitrile is cooled to-30 ℃ to-40 ℃, and (740mg 5.5mmol) handles with nitronium tetrafluoroborate with 5-fluoro-2-methylphenol.After 45 minutes, with 100mL cold water diluted reaction mixture, and with three parts of 50mL dichloromethane extractions.The organic layer that merges is with three parts of 25mL water washings, and is dry on sodium sulfate, and vacuum concentration, obtains blush crystalline solid.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 5% ethyl acetate) obtains 0.58 gram title product, is bright yellow solid (68% productive rate).
Method according to described in the embodiment 26 is converted to corresponding triflate with title compound.
Embodiment 29: synthetic 4-amino-3-fluoro-5-iodine benzonitrile
At 0 ℃, with chloroacetic chloride (3.33mL, 63.1mmol) handle 4-bromo-2-fluorophenyl amine (10.9g, 57.4mmol) and pyridine (9.4mL, 50mL anhydrous methylene chloride solution 115mmol).Handled 10 minutes and in room temperature treatment after 10 minutes at 0 ℃, vacuum concentrated mixture, and with 300mL 1N aqueous sulfuric acid processing residue.The vacuum concentration organic layer obtains 12.9 gram N-(4-bromo-2-fluorophenyl) acetamides, is light gray solid (97% productive rate).
Zinc cyanide (5.53g, 47.1mmol) and tetrakis triphenylphosphine palladium (O) (5.2g is under existence 4.5mmol), at 100 ℃ of heating N-(4-bromo-2-fluorophenyl) acetamides (12.9g, 125mL anhydrous dimethyl yl acetamide solution 55.4mmol) 3 hours.With 300mL cold water diluted mixture thing, filter the solid that generates, wash with water, and dry.Leach thing with 3 parts of 100mL ethyl acetate extractions, the extract of merging is dry on sodium sulfate, filter, and vacuum concentration.Residue that generates and the solid that filters acquisition are merged.Filter the material that merges by silicagel column (100% dichloromethane, 100% ethyl acetate then), obtain 8.5 gram N-(4-cyano group-2-fluorophenyl) acetamides, be light cream-colored solid (86% productive rate).
With potassium iodide (2.3g, 13.9mmol) 15mL aqueous solution handle Dexol (4.2g, 27.3mmol) and sodium tungstate (450mg, 1.4mmol) solution in the mixture of 20mL glacial acetic acid and 15mL acetic anhydride.Handled mixture 15 minutes with the 7.5mL concentrated sulphuric acid.Add N-(4-cyano group-2-fluorophenyl) acetamide (1.79g, the 10mmol) suspension in the 15mL glacial acetic acid, and the mixture that heating generates under 50 ℃.After 1 hour, this mixture is poured onto in the 300mL trash ice, handle with the saturated solution of 100mL sodium thiosulfate, handle with the 100mL sodium sulfite solution then.With three parts of 100mL dichloromethane extraction mixture, the organic layer of merging is with three parts of 50mL sodium bicarbonate solutions, three parts of 50mL water extractions, and is dry on sodium sulfate, and vacuum concentration, obtains the light brown solid.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 50% ethyl acetate) obtains the 400mg title product, is light brown solid (15% productive rate).
Embodiment 30: Synthetic 2-fluoro-6-iodo-4-aminomethyl phenyl amine
At room temperature, with iodine (1.27g, 5mmol) solution-treated 2-fluoro-4-aminomethyl phenyl amine (1.25g, 5mL methanol solution 10mmol) 15 minutes in the mixture of 25mL methanol and 3mL hydrogen peroxide.After 18 hours, with 30mL saturated aqueous sodium thiosulfate quencher reactant mixture, and with three parts of 50mL dichloromethane extractions.The organic layer that merges is with two parts of saturated sodium sulfite solution of 30mL, three parts of 50mL water washings, drying on sodium sulfate, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 10% ethyl acetate) obtains 1.1 gram title product, is light brown oily thing (44% productive rate).
Embodiment 31: Synthetic 2-iodo-4-trifluoromethyl amine
With with the same way as shown in Synthetic 2-fluoro-6-iodo-4-aminomethyl phenyl amine, the preparation title compound.
Embodiment 32: Synthetic 2-iodo-4-nitrobenzophenone amine
With with the same way as shown in Synthetic 2-fluoro-6-iodo-4-aminomethyl phenyl amine, the preparation title compound.
Embodiment 33: synthetic N-(4-amino-3-iodophenyl) acetamide
With with the same way as shown in Synthetic 2-fluoro-6-iodo-4-aminomethyl phenyl amine, the preparation title compound.
Embodiment 34: Synthetic 2-ethyl-6-nitrophenol
Under-30 ℃ to-40 ℃, last 5 minutes, with nitronium tetrafluoroborate (2.93g, 22mmol) batch processing 2-ethyl-phenol (2.44g, 80mL anhydrous acetonitrile 20mmol).After 20 minutes,, use cold water treatment, with three parts of 100mL dichloromethane extractions with this mixture of ice quencher.The organic layer that merges is with two parts of 30mL water washings, and is dry on sodium sulfate, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 20% ethyl acetate) obtains 2.0 gram 2-ethyl-6-nitrophenols, is yellow oil (60% productive rate).
Method according to described in the embodiment 26 is converted to corresponding triflate with title compound.
Embodiment 35: Synthetic 2-methyl-6-nitrophenol
With with the same way as shown in Synthetic 2-ethyl-6-nitrophenol, preparation title compound, and be converted to corresponding triflate according to the method described in the embodiment 26.
Embodiment 36: synthetic 4-iodo-3-(2,2,2-trifluoroacetyl group amino) essence of Niobe
At 0 ℃,, handle 4-iodo-benzoic acid methyl ester (5.24g, sulfuric acid solution 20.0mmol) with the 1.43mL concentrated nitric acid in mode dropwise.After 5 hours, reactant mixture is heated to 40 ℃ in room temperature, and kept 1 hour.The orange solution that generates is added in the 100 gram ice, handle, vibrate 30 minutes, and filter with the 200mL ethyl acetate.Separate each phase, with 200mL ethyl acetate extraction water layer.The organic layer that merges is with saturated sodium bicarbonate solution and salt water washing, and is dry on magnesium sulfate, filter, and vacuum concentration.Make residue pass through silicagel column (100% ethyl acetate), obtain 2.0 gram 4-iodo-3-nitrobenzoic acid methyl ester, be yellow solid (33% productive rate).
(3.6g, (2.0g, the 6.50mmol) solution in 25mL dehydrated alcohol and 15mL glacial acetic acid is at 80 ℃ of these mixture of heating 65.0mmol) to handle 4-iodo-3-nitrobenzoic acid methyl ester with iron powder.After 1 hour,, use washing with alcohol by silicon dioxide padding filter reaction mixture, and vacuum concentration.Dilute residue with solution of potassium carbonate, and use ethyl acetate extraction.The organic layer salt water washing that merges, dry on sodium sulfate, filter, and vacuum concentration, obtain 1.6 gram 3-amino-4-iodo-benzoic acid methyl ester, be white solid (88% productive rate).
Under the room temperature, make 3-amino-4-iodo-benzoic acid methyl ester (1.59g, the solution of 40mL dichloromethane 5.74mmol) and trifluoroacetic anhydride (3mL, 21mmol) reaction.After 30 minutes, the vacuum concentration reactant mixture, and residue is dissolved in the frozen water, filter, and dry, obtain 2.1 gram title product, be pale solid (quantitative yield).
Embodiment 37: Synthetic 2-methyl-5-phenyl-1H-pyrrolo-[2,3-c] pyridine
At-78 ℃, and condensation propine in manometer tube (0.60mL, 11.4mmol).Add (4-iodo-6-phenylpyridine-3-yl) t-butyl carbamate (900mg, 2.27mmol) two (triphenylphosphine) palladium (the II) (80.2mg of 2mL DMF solution, 6mL triethylamine, dichloro, 0.114mmol) and CuI (43.0mg, 0.227mmol), with the seal of tube, at room temperature stir this mixture overnight.Mixture is cooled to-78 ℃, opens sealed tube, add 20mL ethyl acetate and 10mL saturated aqueous ammonium chloride.Separate each phase, with three parts of 10mL ethyl acetate extraction water layers.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.At SiO
2(hexane solution of 0 to 40% ethyl acetate, gradient) goes up the purification crude product, obtains 670mg (6-phenyl-4-third-1-alkynyl pyridin-3-yl) t-butyl carbamate (96% productive rate).
(2.0mL 13.4mmol) handles (6-phenyl-4-third-1-alkynyl pyridin-3-yl) t-butyl carbamate (670mg, 2.17mmol) solution in the mixture of 33mL methanol and 11mL water with DBU.Mixture 60 ℃ of heating generations.After 24 hours, vacuum concentrated mixture adds 50mL water, and mixture is carried out supersound process, filters the solid that generates.Under vacuum, at P
2O
5Last drying solid obtains the 450mg title product, is yellow solid (99% productive rate), directly uses and is not further purified.
Embodiment 38: synthetic 1H-pyrrolo-[3,2-b] pyridine
At room temperature, stirring is present in (2-bromopyridine-3-yl) t-butyl carbamate (1.09mg in the mixture of 12mL triethylamine and 3.0mL dry DMF, 4.00mmol), (TMS) acetylene (2.83mL, 20.0mmol), CuI (75.8mg, 0.400mmol) and dichloro two (triphenylphosphine) palladium (II) (141mg, mixture overnight 0.200mmol).With 50mL ether diluting reaction, and with the quencher of 50mL saturated aqueous ammonium chloride.Organic layer is with the washing of 20mL saturated aqueous ammonium chloride, and the water layer of merging is with three parts of 20mL extracted with diethyl ether.Then, the organic layer of merging is with the water washing of 20mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 20% to 30% ethyl acetate, gradient) obtains 500mg (2-trimethyl silyl ethynyl pyridine-3-yl) t-butyl carbamate (43% productive rate).
At room temperature, (1M 10.3mL) handles (2-trimethyl silyl ethynyl pyridine-3-yl) t-butyl carbamate (500mg, 5mL THF solution 1.72mmol) in THF with TBAF.Mixture heated was refluxed 8 hours, be cooled to room temperature, with the dilution of 100mL ether, and with the quencher of 100mL water.Water layer is with three parts of 50mL extracted with diethyl ether, and the organic layer of merging is with the water washing of 500mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (100%CH
2Cl
2CH to 10%MeOH
2Cl
2Solution, gradient) obtain the 160mg title product, be sepia solid (79% productive rate).
Embodiment 39: Synthetic 2-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine
At-78 ℃, and condensation propine in manometer tube (6.3mL, 124mmol).Add (3-iodine pyridine-4-yl) t-butyl carbamate (7.98g, 24.9mmol) two (triphenylphosphine) palladiums (II) of 15mL DMF solution, 6mL triethylamine, dichloro (877mg, 1.25mmol) and CuI (472mg, 2.49mmol), with the seal of tube, at room temperature stir and spend the night.Add 200mL ethyl acetate and 100mL saturated aqueous ammonium chloride, separate each phase, with three parts of 10mL ethyl acetate extraction water layers.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.At SiO
2(hexane solution of 25% to 40% ethyl acetate, gradient) obtains 5.65 gram (3-third-1-alkynyl pyridin-4-yl) t-butyl carbamates (98% productive rate).
With 30.4mL 4M HCl De dioxane solution handle (3-third-1-alkynyl pyridin-4-yl) t-butyl carbamate (5.65g, 24.3mmol).To the mixture supersound process, dissolve fully up to chemical compound.After 15 hours, vacuum concentrated mixture.The brown solid (4.10g) that generates is dissolved in the 65mL 1-Methyl-2-Pyrrolidone (NMP), and (7.08g 63.2mmol) handles at room temperature to use potassium tert-butoxide.After 18 hours, add 300mL ethyl acetate and 300mL water.Separate each phase, with five parts of 100mL ethyl acetate extraction water layers.The organic layer that merges is with two parts of 20mL water washings, and is dry on magnesium sulfate, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (dichloromethane solution of 10% methanol) generates 2.85 gram title product, is yellow solid (89% productive rate).
Embodiment 40: Synthetic 2,3-dimethyl-1H-pyrrolo-[2,3-c] pyridine
In manometer tube, with 2-butyne (1.5mL, 19.1mmol), Pd (dpPf)
2Cl
2CH
2Cl
2(357mg, 0.438mmol), lithium chloride (367mg, 8.71mmol) and sodium carbonate (1.82g 17.2mmol) handles iodo pyridine (1.80g, 20mL DMF solution 8.18mmol).Seal this pipe, and be heated to 90 ℃.After 24 hours, cool off this pipe and open.Mixture with 20mL ethyl acetate and 20mL saturated aqueous ammonium chloride dilution generation.Separate each phase, and with three parts of 50mL ethyl acetate extraction water layers.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.Flash chromatography is analyzed (CH
2Cl
2CH to 10%MeOH
2Cl
2Solution, gradient) obtain title product, be brown solid (920mg, 77% productive rate).
Embodiment 41: Synthetic 2-methyl-5-methyl mercapto-1H-indole
To 5-bromo-2-Methyl-1H-indole (1.5g, mineral oil (189mg, 7.9mmol) solution of adding 60% sodium hydride in 10mL DMF solution 7.14mmol).After the hydrogen effusion stops, stirring the mixture 10 minutes, use 1mL (7.83mmol) benzene sulfonyl chloride to handle then.By TLC (ethyl acetate-hexane (5: 95)) detection reaction, obtain the main new product of polarity a little less than parent material.After 2 hours, mixture is poured onto in the 50mL saturated aqueous ammonium chloride, and with three parts of 50mL ethyl acetate extractions.With the organic layer that four parts of 25mL salt water washings merge, dry on magnesium sulfate, with active carbon (NORIT A
TM) handle, by diatomite filtration, and vacuum concentration.Residue is adsorbed on the silica gel, and use ethyl acetate-hexane (1: 99,2: 98 then, 3: 97 then) at the enterprising circumstances in which people get things ready for a trip analysis of spectrum of silica gel, obtain 1-benzenesulfonyl-5-bromo-2-Methyl-1H-indole of 1.71g (68.4% productive rate), be transparent grease.
To 1-benzenesulfonyl-5-bromo-2-Methyl-1H-indole (350mg in 4mL THF frozen soln 0.99mmol), adds 440 μ L (1.10mmol) n-BuLi (2.5M solution is in hexane), add then dimethyl disulphide (100 μ L, 1.11mmol).Stir this mixture, it is warming up to room temperature simultaneously, uses the ammonium chloride quencher then, with three parts of 15mL ethyl acetate extractions.The organic layer that merges is with the water washing of three portions of 15mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.Thick material is adsorbed on the silica gel, and uses ethyl acetate-hexane (1: 99,2: 98 then), obtain 1-benzenesulfonyl-2-methyl-5-methyl mercapto-1H-indole of 156mg (44.3% productive rate), be transparent grease at the enterprising circumstances in which people get things ready for a trip analysis of spectrum of silica gel.
(156mg in 10mL alcoholic solution 0.49mmol), adds 10mL 10% sodium hydrate aqueous solution to 1-benzenesulfonyl-2-methyl-5-methyl mercapto-1H-indole.This mixture of heating is 18 hours under refluxing.Then, dilute this mixture, with three parts of 20mL ethyl acetate extractions with 10mL saline.The organic layer that merges is with 10% sodium hydrate aqueous solution of two parts of 10mL, two parts of 20mL saturated aqueous ammonium chlorides and the water washing of two portions of 20mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.Crude product is adsorbed on the silica gel, and use ethyl acetate-hexane (1: 99,2: 98 then, 3: 97 then, 5: 96 then) at the enterprising circumstances in which people get things ready for a trip analysis of spectrum of silica gel, obtain 2-methyl-5-methyl mercapto-1H-indole of 62mg (71.2% productive rate).
Embodiment 42: synthetic 1-benzenesulfonyl-2-methyl-5-phenyl-1H-indole
Will be at the 1-benzenesulfonyl in 20mL toluene, 10mL ethanol and the 5mL 2M sodium carbonate-5-bromo-2-Methyl-1H-indole (810mg; 2.31mmol), phenylboric acid (850mg; 6.97mmol) and tetrakis triphenylphosphine palladium (O) (55mg, mixture reflux 0.029mmol) 4 hours.By TLC (ethyl acetate-hexane (5: 95), 2x expansion; And toluene-hexane (1: 1)) monitoring reaction shows the product that polarization is slightly strong.Cooling mixture is with the dilution of 12% ammonium hydroxide aqueous solution, with three parts of 15mL ethyl acetate extractions.The organic layer that merges is with the water washing of three portions of 15mL salt, and is dry on magnesium sulfate, filters and vacuum concentration.Crude mixture is adsorbed on the silica gel, and use ethyl acetate-hexane (1: 99,2: 98 then, 3: 97 then),, obtain 1-benzenesulfonyl-2-methyl-5-phenyl-1H-indole of 731mg (91% productive rate) at the enterprising circumstances in which people get things ready for a trip analysis of spectrum of silica gel.
As described in embodiment 41, remove phenyl sulfonyl, obtain 2-methyl-5-phenyl-1H-indole.
Embodiment 43: synthetic 1-benzenesulfonyl-2-Methyl-1H-indole-5-sulfonic acid diformamide
(505mg 1.44mmol) in freezing (78 ℃) solution in 5mL ether and 2mLTHF, adds 650 μ L (1.63mmol) n-BuLi (2.5M hexane solution) to 1-benzenesulfonyl-5-bromo-2-Methyl-1H-indole.Stirred the mixture 10 minutes, then with sulfur dioxide (SO
2) gas bubbles by this solution, generates precipitate.Mixture is warming up to room temperature, and filters, obtain 468mg sulfonic acid lithium.With this substance dissolves in 10mL THF, add then N-chloro-succinimide (200mg, 1.49mmol).Stir this mixture 15 minutes, and added the THF solution of the 2M dimethylamine of 4mL (8mmol) then.Then, stirred this mixture 1 hour, with the saturated aqueous ammonium chloride dilution, with three parts of 10mL ethyl acetate washings.The Organic substance that merges is with the water washing of three portions of 10mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration, obtain 365mg 1-benzenesulfonyl-2-Methyl-1H-indole-5-sulfonic acid diformamide.
As described in embodiment 41, remove phenyl sulfonyl, obtain 2-Methyl-1H-indole-5-sulfonic acid diformamide.
Embodiment 44: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpenta-2-ones
With methacrylic chlorination magnesium (0.5M in THF, 1.90L, (124.84g, the solution of 2.0L THF 0.734mol) 4 hours are kept internal temperature simultaneously and are lower than-60 ℃ 0.954mol) to handle the trifluoroacetone acetoacetic ester.Make reactant mixture arrive ambient temperature overnight, vacuum concentration is removed THF, with the quencher of 1L saturated ammonium chloride solution, with three parts of 1L extracted with diethyl ether.The organic facies that merges is with the water washing of 100mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.At the 60mmHg vacuum distilling, obtain 100.1 gram 2-hydroxy-4-methyl-2-trifluoromethyl penta-obtusilic acid ethyl esters, be transparent grease (b.p.97 ℃-103 ℃, 60% productive rate).
Use AlCl
3(87.8g, (100g, 442mmol) and 2, the 3-Dihydrobenzofuranes (keep internal temperature simultaneously and be lower than 10 ℃ by 57.7g, 500mL dichloroethane solution 480mmol) 660mmol) to handle 2-hydroxy-4-methyl-2-trifluoromethyl penta-obtusilic acid ethyl ester.Make reactant mixture arrive ambient temperature overnight, with the cold 1N HCl of 1L quencher.Then, mixture is with three parts of 1L ethyl acetate extractions.The organic layer 1L saturated sodium bicarbonate aqueous solution that merges, the water washing of 1L salt, dry on magnesium sulfate, filter, and vacuum concentration.At SiO
2(hexane solution of 10% ether) purification residue.The solid that recrystallization generates in hot hexane obtains 39.5 gram 4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl ethyl valerates, is white solid (26% productive rate).
At 0 ℃, (27.5g, (4.52g, 119mmol) suspension in 230mL THF is 30 minutes for 40mL THF solution-treated LAH 79.4mmol) with 4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl ethyl valerate.After stirring is spent the night, reaction is cooled to 0 ℃,, handles with 3mL 4M sodium hydroxide solution with the quencher of 3mL water.After 10 minutes,, the mixture that generates is warming up to room temperature, and is incubated 4 hours with another part 18mL water treatment.Filtering mixt is with five parts of 100mL ether washing leaching cakes.Vacuum concentration leaches thing, obtains 24.0 gram 4-(2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyls penta-1, and the 2-glycol is grease (99% productive rate).
At room temperature, stir 4-(2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl penta-1, and the 2-glycol (24.0g, 78.9mmol) and NaIO
4(84.3g, 360mL methanol solution 394mmol) spends the night.Padding by CELITE filter aid filters the mixture that generates, and with three parts of 100mL methanol wash filter cakes.Vacuum concentration leaches thing, is dissolved in the hexane, filters once more, and vacuum concentration, obtains 21.4 gram 4-(2,3-Dihydrobenzofuranes-7-yl)-1,1, and 1-three fluoro-4-methylpenta-2-ones are colorless oil (quantitative yield), directly uses and does not have a purification.
With chlorine (Cl
2) in acetic acid solution (prepare to the acetic acid by chlorine is bubbled ,～1.19M) handle 4-(2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpenta-2-ones (20.8g, the solution of 200mL acetic acid 76.2mmol).By
1The H-NMR detection reaction.Based on the CH in the corresponding ketone
2The integration of signal (parent material: δ=3.32ppm; Product: δ=3.32ppm) determines the ratio of parent material and product.Ratio based on NMR calculates Cl once more
2The concentration of solution, and add another part Cl
2Solution (repeat this process, demonstrate the parent material full consumption) up to NMR.Mixture is with the quencher of 500mL water, and last 1 hour careful add solid sodium bicarbonate (～500g).Mixture is poured on the 500mL ethyl acetate.Separate each phase, water layer is with three parts of 500mL ethyl acetate extractions.The organic layer that merges is with the water washing of two portions of 100mL salt, and is dry on magnesium sulfate, filters, and vacuum concentration, obtains 23.4 and restrains title product (quantitative yield), directly uses and do not have a purification.
Embodiment 45: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methylpenta-2-ones
At 0 ℃, with 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpenta-2-one (1.23g, 4.00mmol) 10mL DMF solution-treated magnesium revolve bits (204mg, 8.40mmol) and trimethylsilyl chloride (2.13mL, 16.8mmol) the 10mL DMF solution of mixture.The mixture overnight that stirring at room generates.Filtering mixt, and vacuum concentration.Residue is suspended among the 20mLTHF, and (1M in THF, 4.0mL) handles at room temperature to use TBAF.After 15 minutes, reaction is with the quencher of 25mL saturated aqueous ammonium chloride, with the dilution of 50mL ether.Separate each phase, water layer is with three parts of 50mL extracted with diethyl ether.The organic layer salt water washing that merges, dry on magnesium sulfate, filter, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 100% hexane to 10% ether, gradient) obtains 550mg title product (48% productive rate).
Embodiment 46: synthetic 5-(5-fluoro-2-aminomethyl phenyl)-2, the 5-dimethyl oneself-3-ketone
At room temperature, (4M in the mixture in the alcoholic solution of 30% water, 40mL) handles 1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpenta-2-one (4.88g, solution 18.6mmol) with sodium hydroxide solution.With mixture heated to 80 ℃, and kept 1 hour.After being cooled to room temperature with 100mL water diluted mixture thing with three parts of 100mL extracted with diethyl ether.Handling water layer with the 150mL ethyl acetate, dropwise handle the mixture of generation with 6M HCl, is 2 up to the pH value of solution.Separate each phase, with three parts of 100mL ethyl acetate extraction water layers.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration, generates 3.92 gram 3-(5-fluoro-2-aminomethyl phenyl)-3 Methylbutanoic acids, is grease, solidifies when this grease leaves standstill, and directly uses and is not further purified (quantitative yield).
At 0 ℃, use SOCl
2(1.98mL 27.1mmol) handles 3-(5-fluoro-2-aminomethyl phenyl)-3 Methylbutanoic acid (3.80g, 18.0mmol) mixture in the 15mL dichloromethane.After 30 minutes, with morpholine (2.36mL, 27.1mmol) and pyridine (4.4mL, 54.2mmol) mixture in the 10mL dichloromethane adds in 0 ℃ the reactant mixture.After carrying out 90 minutes again, add 60mL 2M HCl aqueous solution, separate each phase, water layer is with three parts of 50mL dichloromethane extractions.The organic facies that merges is dry on magnesium sulfate, filters, and vacuum concentration, obtains 5.03 gram 3-(5-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid-morpholine-4-Ji Ding-1-ketone, is grease, directly uses and is not further purified (quantitative yield).
At-78 ℃, (pentane solution of 0.7M 1.28mL) is handled 3-(5-fluoro-2-aminomethyl phenyl)-3-methyl isophthalic acid-morpholine-4-Ji Ding-1-ketone (200mg, 2mL THF solution 0.716mmol) with i-PrLi.-78 ℃ of stirred reaction mixtures 1 hour, make it be warming up to room temperature, with 1mL methanol and the quencher of 5mL saturated aqueous ammonium chloride, with three parts of 50mL ethyl acetate extractions.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 100% hexane to 25% ethyl acetate, gradient) obtains 80.4mg title product (48% productive rate).
Embodiment 47: synthetic 4-(3-[1,3] dioxane oneself-2-base phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones
Under 0 ℃, with Copper diiodide (I) (2.5g, 13.1mmol) handle Grignard reagent solution (described Grignard reagent be in THF by 2-(3-bromophenyl)-[reaction that 1,3] diox and magnesium revolve bits generates, 0.25M, 52.6mL, 13.1mmol).After 45 minutes, add 1,1, (2g 13.1mmol), slowly is warming up to room temperature with reactant mixture to 1-three fluoro-4-methylpent-3-alkene-2-ketone, and stirs and spend the night.Ethyl acetate extraction is used in mixture saturated aqueous ammonium chloride quencher.The organic layer that merges washs with saturated sodium-chloride water solution, uses dried over sodium sulfate, filter, and vacuum concentration.Pulverize residue with hexane, and filter.Vacuum concentration leaches thing, obtains 1.78 gram crude products, directly uses and does not have a purification.
Embodiment 48: synthetic (1-is fluoride-based) dimethylphenylsilaneand
Last 1 hour, under argon gas atmosphere, in that stir and ice-cooled ((internal temperature＜100 ℃)) the anhydrous THF suspension of 200mL of 4.4 gram lithium lines cutting particles in, add the 3,5-dimethylphenyl chlorosilane of every part of 5mL.After about 0.75 hour, peony appears in the silicyl lithium reagent.5 hours (internal temperature remains between 5 ℃ to 10 ℃) again stirs the mixture on ice.Cooling mixture on dry ice/acetone batch; Use three-way valve,, introduce vinylidene fluoride by the air bag that filling and reactant mixture are connected with the reagent cylinder.Air bag is filled with vinylidene fluoride, and is emptied in the reactant mixture 10 times.Make mixture be warming up to room temperature (observing effervescent, may be to be caused by unreacted vinylidene fluoride).Mixture dilutes with the 200mL hexane, and filters by cotton stopper.Leach thing and wash with water, drying is filtered, and vacuum concentration.Under vacuum, carry out four fractional distillation by the Vigreux post, obtain 4.6 gram products.
Embodiment 49: synthetic 1-(1-fluorine cyclopropyl)-3-(4-fluorophenyl)-3-methyl fourth-1-ketone
With the solution of the dichloromethane of the oxalyl chloride of 19mL dichloromethane dilution 12mL 2M, and on dry ice/acetone batch, cool off.In this solution, dropwise add the solution of the 16mL dichloromethane of 3.6mL DMSO.After 10 minutes, and adding 3-(4-fluorophenyl)-3-methyl fourth-1-alcohol (3.6g, 12mL dichloromethane solution 19.8mmol), and stirred this mixture 15 minutes.Add the 14mL triethylamine then, remove cooling bath, make reactant mixture be warming up to room temperature, the water quencher is diluted with hexane.Separate organic layer, wash with water, drying is filtered, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (eluent: hexane is to hexane-dichloromethane (9: 1), gradient) purification residue obtains 1.2 gram 3-(4-fluorophenyl)-3-methyl butyraldehyde, is grease.
Under nitrogen atmosphere, to (1.2g 6.6mmol) He in the mixture of (1-is fluoride-based) methyldiphenyl base silane in 5mL THF adds 1mLTBAF (1M is in THF) at the 3-of cooled on ice (4-fluorophenyl)-3-methyl butyraldehyde.Make this mixture be warming up to room temperature, and keep spending the night.Evaporating solvent is dissolved in residue in the hexane.At the material of the last classification hexane solubility of silica gel (eluent: hexane is to hexane-ethyl acetate (98: 2)), obtain containing the fraction (3.1g) of silylated product and other silane.This fraction is dissolved among the 5mL THF, adds 10mL TBAF solution (the THF solution of 1M).This mixture was placed room temperature 20 minutes, with hexane-ethyl acetate dilution, wash with water, drying is filtered, and vacuum concentration.Silica gel (eluent: hexane-ethyl acetate (99: 1 to 9: 1 gradients)) go up the classification residue, obtain 1.73 gram crude product 2-fluoro-5-(4-fluorophenyl)-5-methyl oneself-1-alkene-3-alcohol, be grease, directly use, and not being further purified.
In nitrogen atmosphere, to above-mentioned stirring and the crude product 2-of cooled on ice fluoro-5-(4-fluorophenyl)-5-methyl oneself-1-alkene-3-alcohol (1.73g, 7.65mmol) in, (1.1M is in toluene, 8.0mL) to add diethyl zinc.After 5 minutes, last 20 minutes, dropwise add the 1.0mL diiodomethane, and stir the mixture, make it reach room temperature, then stirring at room 4 days.Then, add 0.5mL water to reactant mixture, add ethyl acetate then.By the mixture of diatomite filtration generation, solvent removed in vacuo goes up the classification residue at silica gel (hexane-dichloromethane (1: 1) is to dichloromethane gradient), obtains 1-(1-fluorine cyclopropyl)-3-(4-fluorophenyl)-3-methyl fourth-1-alcohol, is grease then.
Solution with the dichloromethane of the oxalyl chloride of 2.5mL dichloromethane dilution 2.2mL 2M cools off on dry ice/acetone batch.In this solution, dropwise add the 2.5mL dichloromethane solution of 0.7mL DMSO.After 10 minutes, (0.72g, 2mL dichloromethane solution 3.0mmol) stirred the mixture 15 minutes to add above-mentioned crude product 1-(1-fluorine cyclopropyl)-3-(4-fluorophenyl)-3-methyl fourth-1-alcohol.Add the 4mL triethylamine, remove cooling bath, make this mixture be warming up to room temperature, water quencher is then diluted with hexane.Separate organic layer, wash with water, drying is filtered, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (eluent: hexane is to hexane-dichloromethane (4: 1) gradient) purification residue obtains 0.37 gram title product, is grease.
Embodiment 50: synthetic 1-(1-fluorine cyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methyl fourth-1-ketone
Last 5 minutes,, in the 40mL DMSO solution of 4-dimethylchroman-2-ketone, add the 5mL aqueous solution (exothermic reaction) of 5.5 gram sodium hydroxide to 6-fluoro-4.After 20 minutes, last 15 minutes, add methyl iodide (20g) in batches, at room temperature stir the mixture and spend the night.Mixture washes with water with the dilution hexane, and drying is filtered, and vacuum concentration, obtains 12.4 gram esters, directly uses, and is not further purified.
In 30 minute time limit, when in argon gas atmosphere, stirring, in the 100mL THF of LAH (1.64g) suspension, dropwise add the solution (vigorous reaction) of above-mentioned 3-(5-fluoro-2-methoxyphenyl)-3 Methylbutanoic acid methyl ester at 10mLTHF.At room temperature stir this mixture overnight.Reaction is diluted with the 200mL ether, and by adding 3mL water (the careful adding) and the quencher of 3mL acetic acid.By the diatomite filtration mixture, wash with ether.Evaporating solvent obtains 10.8 gram 3-(5-fluoro-2-methoxyphenyl)-3-methyl fourth-1-alcohol, directly uses, and is not further purified.
Last 5 minutes, with pyridinium chlorochromate (4.2g, 19.5mmol) batch processing 3-(5-fluoro-2-methoxyphenyl)-3-methyl fourth-1-alcohol (3.30g, 40mL dichloromethane solution 15.5mmol).Stirred this mixture 3 hours, and, used the hexane wash padding by the padding filtration of CELITE filter aid.Vacuum concentration leaches thing.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 30% to 50% dichloromethane, gradient) obtains 2.5 gram 3-(5-fluoro-2-methoxyphenyl)-3-methyl butyraldehyde, is grease (77% productive rate).
To 3-(5-fluoro-2-methoxyphenyl)-3-methyl butyraldehyde (1.1g, 5.2mmol) and above-mentioned (1-is fluoride-based) dimethylphenylsilaneand (2.2g, in 5mL THF solution 12.2mmol), adding 0.6mL tetrabutylammonium (1M, in THF), at room temperature stir this mixture overnight.The TLC display part converts product to.Add cesium fluoride (0.22g), and at room temperature stirred this mixture 3 days.Add 2mL water and 2mL acetic acid, and this mixture is incubated 2 hours down at 60 ℃, to carry out the desilylation reaction of any silylated product.Mixture dilutes with ethyl acetate, washes with water, and drying is filtered, and vacuum concentration.(eluent: hexane-dichloromethane (3: 1 to 1: 3 gradients) is gone up the classification residue at silica gel, obtain 0.798g (59.5% productive rate) 2-fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methyl oneself-1-alkene-3-alcohol, be grease, directly use and be not further purified.
To in nitrogen atmosphere, stir and the 2-of cooled on ice fluoro-5-(5-fluoro-2-methoxyphenyl)-5-methyl oneself-add 8.0mL diethyl zinc (1.1M is in toluene) in 1-alkene-3-alcohol.After 5 minutes, last 20 minutes, dropwise add the 1.0mL diiodomethane, stir this mixture, make it reach room temperature, at room temperature stirred then 2 days.Add 0.5mL water then, then add ethyl acetate, by the diatomite filtration mixture.The vacuum concentration product, (hexane-dichloromethane (1: 1) is to dichloromethane at silica gel, gradient) goes up the classification residue, obtain 0.8 gram 1-(1-fluorine cyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methyl fourth-1-alcohol, be not further purified for grease directly uses.
Solution with the dichloromethane of the oxalyl chloride of 5mL dichloromethane dilution 6mL 2M cools off on dry ice/acetone batch.In this solution, dropwise add the 5mL dichloromethane solution of 1.5mL DMSO.After 10 minutes, and adding crude product 1-(1-fluorine cyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methyl fourth-1-alcohol (0.8g, 4mL dichloromethane solution 3mmol), and stirred this mixture 15 minutes.Add the 4mL triethylamine, remove cooling bath, make reactant mixture be warming up to room temperature, the water quencher is diluted with hexane.Separate organic layer, wash with water, drying is filtered, and vacuum concentration.By the chromatography purification residue on the silica gel (eluent: hexane is to hexane-ethyl acetate (10: 1), gradient), obtain 0.68 gram title product, be grease, directly use and be not further purified.
Embodiment 51: synthesize 1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpenta-2-one
To 1,1, (5.3g 16.7mmol) slowly adds NaIO to 1-three fluoro-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl) penta-2-ketone in the agitating solution in acetonitrile
4(10.7g, 70mL aqueous solution 50mmol).After 10 minutes, add RuCl
3(50mg 0.24mmol), continues at room temperature to stir 30 minutes.Vacuum concentrated mixture, the light gray solid that filter to generate washes with water, and dry, obtains 5.4 gram title product, directly uses and is not further purified (93% productive rate).
Embodiment 52: synthesize 1,1,1-three fluoro-4-(2-methoxyl group-5-methyl mercapto phenyl)-4-methylpenta-2-one
To 4-(2-methoxyl group-5-methyl mercapto phenyl)-4-Methyl-2-trifluoromethyl penta-1, (1.5g in 25mL methanol solution 5.3mmol), adds 2.4 gram lead acetate (IV) (Pb (OAc) to the 2-glycol
4), and stirred reaction mixture, the TLC Indicator Reaction is finished after a few hours.Then, by the bed of diatomaceous earth filter reaction mixture, vacuum concentration leaches thing, obtains 1.12g (83.8% productive rate) 1,1,1-three fluoro-4-(2-methoxyl group-5-methyl mercapto phenyl)-4-methylpenta-2-one.
Embodiment 53: synthetic 4-(2-benzyloxy-5-tert-butyl-phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones
At 0 ℃, (15g 100mmol) and in the frozen soln of 11.12mL 3-methyl but-2-ene acyl chlorides in the 200mL ether, utilize to add funnel and adds the 13.9mL triethylamine to the 4-tert-butyl phenol.Reactant mixture is warming up to room temperature, and stirs, finish up to the TLC Indicator Reaction.Then, by the diatomite filtration reactant mixture, ether layer washes with water twice, use the salt water washing, dry on magnesium sulfate, and vacuum concentration, stay 23 gram 3-methyl but-2-ene acid 4-tert-butyl group phenyl esters, be brown oil, this grease partially crystallizable when leaving standstill.
Last 1 hour, to 3-methyl but-2-ene acid 4-tert-butyl-phenyl ester (23g, 50mL Carbon bisulfide (CS 99mmol)
2) in the solution, add 19.8 gram aluminum chloride (AlCl in batches
3), fierce exothermic reaction takes place.After stirred for several hour, TLC shows that reaction finishes.Concentrated reaction mixture under stream of nitrogen gas, and residue is poured onto on ice, ethyl acetate extraction used.Merge Organic substance, dry on magnesium sulfate, and vacuum concentration.Go up the purification residue at silicon dioxide padding (0% to 5% ethyl acetate-hexane), obtain the 8.1 gram 6-tert-butyl groups-4,4-dimethylchroman-2-ketone is grease.
At 0 ℃, utilize and add funnel, in the frozen suspension liquid of 1.99 gram LAH in 60mL THF, add the 6-tert-butyl group-4,4-dimethylchroman-2-ketone (8.1g, 10mL THF solution 34.9mmol), reactant mixture is warming up to room temperature, stirs, finish up to the TLC Indicator Reaction.After 1 hour, reaction mixture in ice bath, and with the careful quencher of minimum water.Then, dry reaction mixture on magnesium sulfate passes through diatomite filtration.Vacuum concentration leaches thing, and residue is dissolved in the hexane, and the isolated by filtration solid obtains the 5 gram 4-tert-butyl group-2-(3-hydroxyl-1,1-dimethyl propyl) phenol.
(2g 8.5mmol) and in the 10mL DMF solution of 1.1mL benzyl bromide, adds 1.75 gram potassium carbonate (K to the 4-tert-butyl group-2-(3-hydroxyl-1,1-dimethyl propyl) phenol
2CO
3), and stirred reaction mixture at room temperature, finish up to the TLC Indicator Reaction.After stirring is spent the night,, use extracted with diethyl ether with the ice diluted reaction mixture.Merge Organic substance, wash with water four times, use the salt water washing, dry on magnesium sulfate, and vacuum concentration.At COMBIFLASH device (0% to 30% ethyl acetate-hexane) purification residue, obtain 1.7 gram 3-(2-benzyloxy-5-tert-butyl-phenyl)-3-methyl fourth-1-alcohol, be grease.
(1.7g 5.2mmol) in the solution of 20mL dichloromethane, adds 3.27 gram Dess-Martin periodinane, and stirring reaction, finishes up to the TLC Indicator Reaction to 3-(2-benzyloxy-5-tert-butyl-phenyl)-3-methyl fourth-1-alcohol.After 2 hours, make reactant mixture pass through the silicon dioxide padding,, obtain 1.67 gram 3-(2-benzyloxy-5-tert-butyl-phenyl)-3-methyl butyraldehyde, be grease with 5% ethyl acetate-hexane eluting.
Use is similar to the method for embodiment 4 in the U.S. Patent Application Publication 2004/0023999, and 3-(2-benzyloxy-5-tert-butyl-phenyl)-3-methyl butyraldehyde is converted to 4-(2-benzyloxy-5-tert-butyl-phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones.
Embodiment 54: synthetic 4-(2-benzyloxy-5-isopropyl phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones
With with synthetic 4-(2-benzyloxy-5-tert-butyl-phenyl)-1,1, described identical method during 1-three fluoro-4-methylpenta-2-ones prepares 4-(2-benzyloxy-5-isopropyl phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones from the 4-isopropyl-phenol.
Embodiment 55: synthetic 7-(4,4,4-three fluoro-3-hydroxyl-3-methylols-1,1-dimethylbutyl)-2,3-Dihydrobenzofuranes-5-sulfonic acid diformamide
-78 ℃ with n-BuLi (2.5M, in hexane, 4.2mL, 10.5mmol) processing 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3] dioxy ring penta-4-yl)-1, the 1-dimethyl ethyl]-2,3-Dihydrobenzofuranes (4.0g, 8mL THF solution 9.4mmol).After 15 minutes, with excessive SO
2Gas blasts in the mixture, and whether the parent material of monitoring reaction disappears.Then, concentrated reaction mixture under stream of nitrogen gas, with the THF dilution, (1.48g 11.1mmol) handles with N-chloro-succinimide.Stir this mixture 15 minutes, and be divided into three equal parts.(2M, in THF, 10mL 20mmol) handles the 8mL THF liquid storage of sulfonic acid chloride (mixture 1/3) with dimethylamine.After 30 minutes, with 20mL saturated aqueous ammonium chloride diluted mixture thing, with three parts of 10mL ethyl acetate extractions.The organic layer that merges is with three parts of 10mL saturated aqueous ammonium chlorides and the water washing of two portions of 10mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.At the silica gel (hexane solution of 3% to 30% ethyl acetate, gradient) goes up the thick material of purification, obtain the 7-[2-(2 of 1.18g (83% productive rate), 2-dimethyl-4-trifluoromethyl-[1,3] dioxy ring penta-4-yl)-1,1-dimethyl-ethyl]-2,3-Dihydrobenzofuranes-5-sulfonic acid diformamide directly uses and is not further purified.
With 1.18g (2.61mmol) 7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3] dioxy ring penta-4-yl)-1,1-dimethyl-ethyl]-2,3-Dihydrobenzofuranes-5-sulfonic acid diformamide and the mixture reflux of 303mg (1.59mmol) p-methyl benzenesulfonic acid monohydrate in 20mL methanol 3 days.Then, cooling mixture is with the dilution of 15mL saturated sodium bicarbonate aqueous solution, with three parts of 15mL ethyl acetate extractions.The organic layer that merges is with two parts of 15mL saturated sodium bicarbonate aqueous solutions, and the water washing of two portions of 15mL salt is dry on magnesium sulfate, filtration, and vacuum concentration.Pulverize residue with ether, obtain the title compound of 845mg (78% productive rate), be white solid.
According to the method that is disclosed in the U.S. Patent Application Publication 2004/0029932, with 7-(4,4,4-three fluoro-3-hydroxyl-3-hydroxymethyls-1,1-dimethyl-butyl)-2,3-Dihydrobenzofuranes-5-sulfonic acid diformamide is converted to corresponding trifluoromethyl ketone, at this document is introduced, as a reference.
Embodiment 56: synthetic 7-(4,4,4-three fluoro-3-hydroxyl-3-hydroxymethyls-1,1-dimethylbutyl)-2,3-Dihydrobenzofuranes-5-sulfonic acid amides
With with the preparation 7-(4,4,4-three fluoro-3-hydroxyl-3-hydroxymethyls-1, the 1-dimethylbutyl)-2, the same way as of 3-Dihydrobenzofuranes-5-sulfonic acid diformamide is from 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3] dioxy ring penta-4-yl)-1, the 1-dimethyl ethyl]-2, the 3-Dihydrobenzofuranes prepares 7-(4,4,4-three fluoro-3-hydroxyl-3-hydroxymethyls-1, the 1-dimethylbutyl)-2,3-Dihydrobenzofuranes-5-sulfonic acid amides.
Embodiment 57: synthetic 7-(4,4,4-three fluoro-1,1-dimethyl-3-oxo butyl)-2, and 3-Dihydrobenzofuranes-5-sulfonic acid 1-dimethylamino methylene-(E)-the Ji amide
With 7-(4,4,4-three fluoro-1,1-dimethyl-3-oxo butyl)-2,3-Dihydrobenzofuranes-5-sulfonic acid amides (870mg, 2.47mmol) 30mL dichloromethane solution and N, dinethylformamide dimethylacetal (580mg, 4.86mmol) reaction.After 30 minutes, that the mixture vacuum concentration is extremely dry.Pulverize the solid that generates with ether, and collect, obtain 950mg title compound (94% productive rate).
Embodiment 58: synthesize 1,1-two fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpenta-2-one
To 1,1-two fluoro-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl) penta-2-ketone (840mg, 2.8mmol) in the solution in 12mL MeCN and 4mL water, (1.79g 8.4mmol), adds ruthenic chloride (III) hydrate crystal then to add sodium metaperiodate.By the TLC monitoring reaction, no longer obvious up to thioether.After 1 hour, the reaction vacuum concentration, dilute with water is used ethyl acetate extraction.The dry organic layer that merges on magnesium sulfate with handling carbon, filters, and vacuum concentration, obtains the title compound of 910mg (98% productive rate), is white solid.
Embodiment 59: synthetic 4-methoxyl group-3-methyl-3-phenyl butyraldehyde
Last 5 minutes, (4.04g in the solution of 40mL DMSO 30.79mmol), adds the THF solution of two (trimethyl silyl) Sodamide .s (NaHMDS) of 34mL (34mmol) 1M to 2-phenyl propionitrile.After 10 minutes, dropwise add allyl bromide, bromoallylene (6mL, 69.33mmol) (heat release).Use the ice-water bath cooling mixture.Stirred the mixture 20 minutes, and became solid matter.Add 20mL DMSO again.After 10 minutes, with 200mL ammonium chloride diluted mixture thing, with three parts of 100mL ethyl acetate extractions.The organic layer that merges is with the water washing of six portions of 75mL salt, and dry on magnesium sulfate, filtration, and vacuum concentration obtain 5.25g (99.5% productive rate) 2-methyl-2-phenyl penta-4-alkene nitrile, are yellow oil, uses this grease and is not further purified.
Last 15 minutes, (5.25g in 150mL dichloromethane solution 30.65mmol), adds diisobutyl aluminium hydride (DIBAL) (38mL, dichloromethane solution 38mmol) of 1M to 2-methyl-2-phenyl penta-4-alkene nitrile.By the TLC monitoring reaction; After 1 hour, the lower slightly product of TLC (ethyl acetate-hexane (1: 9)) indication polarization.Reactant is poured onto in the ice-cooled 1N HCl aqueous solution, and the separate dichloromethane layer.With two parts of 50mL dichloromethane extraction water layers.The organic layer 50mL saline that merges, two parts of 50mL saturated sodium bicarbonate aqueous solutions, the water washing of 50mL salt, dry on magnesium sulfate, by diatomite filtration, and vacuum concentration, obtain 4.6g (86.1% productive rate) 2-methyl-2-phenyl penta-4-olefine aldehydr, use this product, and be not further purified.
To 2-methyl-2-phenyl penta-4-olefine aldehydr (4.6g, in 100mL THF solution 26.4mmol), add in batches lithium aluminium hydride reduction (LAH) (2.6g, 68.51mmol).Stirred this mixture 3 hours under the room temperature, refluxed then 2 hours.Utilize ethyl acetate-hexane (1: 9), by the TLC monitoring reaction, the stronger new product of indication polarization.Cooling reaction, and the water excessive LAH of quencher dropwise.Then, with 1N HCl aqueous solution diluted mixture thing, with 100mL hexane and two parts of 100mL ethyl acetate extractions.The organic layer that merges 50mL 1N HCl aqueous solution, two parts of 50mL saline, two parts of 50mL saturated sodium bicarbonate aqueous solutions, the water washing of 50mL salt, dry on magnesium sulfate, filter, and vacuum concentration.Use hexane to load sample, on silica gel, thick material is carried out chromatography, use 1% then, obtain 3.2g (68.8) 2-methyl-2-phenyl penta-4-alkene-1-alcohol to 15% ethyl acetate-hexane eluting.
(3.2g in 17mL DMF solution 18.15mmol), adds sodium hydride (1.25g, 31.25mmol is 60%, in mineral oil) to 2-methyl-2-phenyl penta-4-alkene-1-alcohol.Stir this mixture, up to stop the foaming, add then methyl iodide (6mL, 96mmol).After 2 hours, with 50mL saturated aqueous ammonium chloride quencher mixture, with three parts of 50mL ethyl acetate extractions.The organic layer 30mL saturated aqueous ammonium chloride that merges, the water washing of five portions of 25mL salt, dry on magnesium sulfate, filter, and vacuum concentration, obtain 3.4g (98.4% productive rate) (1-methoxy-1-methyl fourth-3-thiazolinyl) benzene, directly use and be not further purified.
(1.67g 8.77mmol) in freezing (78 ℃) solution in methanol-dichloromethane, blasts ozone gas, up to the solution becomes au bleu to (1-methoxy-1-methyl fourth-3-thiazolinyl) benzene.Then, with oxygen purge excessive ozone from mixture, (5mL 68mmol), is warming up to room temperature with mixture, and stirs and spend the night to add dimethyl disulfide then.Then, vacuum concentrated mixture is removed excess dimethyl sulfur, with the dilution of 20mL ammonium chloride, with three parts of 15mL ethyl acetate extractions.The organic layer that merges is with the water washing of three portions of 15mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration, obtaining grease, this grease detects corresponding to dimethylacetal through 1H-NMR.Crude product 40mL acetone diluted, (300mg 1.57mmol), and stirred this mixture 2 hours under the room temperature to add p-TsOH.By the 1H-NMR monitoring reaction, indication exists aldehyde and dimethylacetal.Reaction refluxed 4 hours, and by TLC (ethyl acetate-hexane (1: 9)) monitoring, cooling then is with the saturated sodium bicarbonate aqueous solution dilution, with three parts of 15mL ethyl acetate extractions.The organic layer that merges is with two parts of 10mL saturated sodium bicarbonate aqueous solutions, the water washing of two portions of 10mL salt, and dry on magnesium sulfate, filtration, and vacuum concentration obtain 1.45g (85.9% productive rate) 4-methoxyl group-3-methyl-3-phenyl butyraldehyde.
Described in the embodiment 26 of U.S. Patent Application Publication 2004/0023999 4-methoxyl group-3-methyl-3-phenyl butyraldehyde is converted to 1,1 as above, 1-three fluoro-5-methoxyl groups-4-methyl-4-phenyl penta-2-ketone.
Embodiment 60: synthetic 1-benzo [1,3] Dloxole-4-base ethyl ketone
At-78 ℃, (10g in 200mLTHF solution 66.7mmol), utilizes and adds funnel, adds the diethyl ether solution of the MeLi of 43.7mL 1.6M to benzo [1,3] Dloxole-4-formaldehyde.Sluggish is warming up to room temperature, and stirs and spend the night.The TLC demonstration reaction of aliquot is finished.Then reaction is cooled to-78 ℃, uses the saturated aqueous ammonium chloride quencher, and vacuum concentration.Use the ethyl acetate extraction residue then.It is dry on magnesium sulfate to merge Organic substance, and vacuum concentration, obtains 11g (99.4% productive rate) 1-benzo [1,3] Dloxole-4-base ethanol, is brown oil, and it is crystallization when leaving standstill.
(11g, in 100mL THF solution 66.3mmol), disposable adding 17.26 restrains manganese dioxide (MnO to 1-benzo [1,3] dioxole-4-base ethanol
2), by the TLC monitoring reaction.After a few hours, TLC shows certain product of generation, but stays a large amount of alcohol.Add more manganese dioxide, and agitating solution.Then, TLC shows the most of product of generation, but also has a large amount of alcohol.Then, by the diatomite filtration reactant mixture, and vacuum concentration leaches thing, obtains grease, and it is common crystallization when leaving standstill.At-60 ℃, in the 120mL of 9.24mL oxalyl chloride dichloromethane solution, add the 20mL dichloromethane solution of 15mL DMSO.After 10 minutes, add the 20mL dichloromethane solution of above-mentioned alcohol/alcohol/ketone mixtures (53mmol), after 15 minutes, add the 44.3mL triethylamine.Make sluggish be warming up to ambient temperature overnight.Then, reactant mixture is poured onto on ice, organic layer is with five parts of 100mL water washings, and salt water washing then is dry on magnesium sulfate then.The vacuum concentration Organic substance stays the sepia solid, pulverizes this solid with hexane, and filter and collect, and dry, obtain 9.33g (85.8% productive rate) 1-benzo [1,3] Dloxole-4-base ethyl ketone.
According to the embodiment 26 of U.S. Patent Application Publication 2004/0023999,1-benzo [1,3] Dloxole-4-base ethyl ketone is converted to 4-benzo [1,3] Dloxole-4-base-1,1,1-three fluoro-4-methylpenta-2-ones.
Embodiment 61: Synthetic 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl ethyl hexanoate
(5g in 50mL DMSO solution 38mmol), adds the THF solution of two (trimethyl silyl) Sodamide .s (NaHMDS) of 42mL 1M to 2-phenyl propionitrile.After 15 minutes, reaction is cooled to 0 ℃, adds the 4.6mL ethyl iodide.Then, stirring reaction is 30 minutes.When TLC shows that reaction is finished, reactant mixture is poured onto in the water, use extracted with diethyl ether.Merge Organic substance, wash with water four times, use the salt water washing, dry on magnesium sulfate, and vacuum concentration, obtain 6.1 gram 2-methyl-2-phenylbutyronitriles, be grease.
Under the room temperature, (6.1g in 50mL dichloromethane solution 38.3mmol), adds the dichloromethane solution of 57mL 1M DIBAL to 2-methyl-2-phenylbutyronitrile by syringe.Stirring reaction 30 minutes, this moment, the TLC demonstration reaction of aliquot was finished.Reactant mixture is carefully poured among the 100mL1N HCl, and separate each layer.With the Organic substance vacuum concentration, and be dissolved in the ether, merge, use extracted with diethyl ether with water layer.Merge Organic substance then, dry on magnesium sulfate, and vacuum concentration.Go up the purification residue at silicagel column (hexane solution of 0% to 2% ethyl acetate), obtain 4.2 gram 2-methyl-2-phenyl butyraldehyde, be colorless oil.
At 0 ℃, (7.4g in 30mLTHF solution 27.6mmol), adds heptane/THF/ ethylbenzene solution of 16mL 1.8M LDA to (diethoxy phosphoryl) ethoxy ethyl acetate.Stirred reaction mixture 30 minutes dropwise adds 2-methyl-2-phenyl butyraldehyde (4.2g, 30mL THF solution 25.9mmol) by syringe then.Then, reactant mixture is warming up to room temperature, uses the saturated aqueous ammonium chloride quencher, use extracted with diethyl ether.Merge Organic substance, dry and vacuum concentration on magnesium sulfate, obtain 8.3 gram 2-ethyoxyl-4-methyl-4-phenyl oneself-2: 1 mixture of 2-olefin(e) acid ethyl ester E and Z isomer, be orange.
To 2-ethyoxyl-4-methyl-4-phenyl oneself-(8.3g in 25mLHOAc solution 30mmol), adds the aqueous sulfuric acid of 116.5mL 1M to 2-olefin(e) acid ethyl ester.Stirred reaction mixture a few hours under the room temperature.When the TLC demonstration is not reacted, reactant mixture is placed 100 ℃ of oil baths, and stir and spend the night.When TLC does not have as a result, add 2mL 1M aqueous sulfuric acid and 20mLHOAc more then.After 1 hour, the TLC of aliquot shows that most olefin isomers (speckle that polarity is stronger) are consumed, and minority isomer speckle residue (product can form speckle jointly with the minority isomer).Then reactant mixture is cooled to room temperature, uses extracted with diethyl ether.Merge Organic substance,, use the salt water washing with 4 parts of water washings, dry on magnesium sulfate, and vacuum concentration, obtain 2.5 gram orange.1H-NMR is shown as 1: 1 mixture of minority isomer and aldehyde.The water layer ethyl acetate extraction, the combined ethyl acetate extract, dry on magnesium sulfate, and vacuum concentration, stay brown liquid.1H-NMR shows a large amount of ethyl acetate and HOAc and is the required product of keto acid.This keto acid solution is dissolved in the 200mL ethanol, handles with the 1mL concentrated hydrochloric acid, reflux is spent the night.Then, TLC shows the lower slightly new speckle of polarity.Reactant mixture is cooled to room temperature, and vacuum concentration.The dilute with water residue is used extracted with diethyl ether then.Merge Organic substance, dry on magnesium sulfate, and vacuum concentration, stay 4.3 gram 4-methyl-2-oxo-4-phenyl ethyl hexanoate, be orange.
To 4-methyl-2-oxo-4-phenyl ethyl hexanoate (4.3g, 17.3mmol) and the 50mL THF solution of 3.6mL trifluoromethyl trimethyl silane in, the 1M TBAF solution that adds 1.5mL (0.1 equivalent), and stirring reaction at room temperature, TLC shows that ketone ester is depleted after about 30 minutes.Then, add the TBAF (17.5mL) of remainder, stirred reaction mixture 1 hour.Then, TLC demonstration reaction is finished.The vacuum concentration reactant mixture, residue is used extracted with diethyl ether with 1N HCl dilution.Merge Organic substance, dry on magnesium sulfate, and vacuum concentration, stay brown oil.This oil is dissolved in (muddy outward appearance) in the hexane, add active carbon, by the solution of diatomite filtration generation, and vacuum concentration, stay the non-enantiomer mixture of 3.8g (83% productive rate) 2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl ethyl hexanoate, be light green grease.
According to the embodiment 1 of U.S. Patent Application Publication 2004/0023999, the non-enantiomer mixture of ester is converted to corresponding trifluoromethyl ketone.
Embodiment 62: synthesize 1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpenta-2-one
(20g 183.5mmol) and in the yellow solution of 1.7mL concentrated sulphuric acid, utilizes and adds funnel and add 19.17mL 3-chloro-2-metering system to 4-methylbenzene methyl ether.When reaction heats up, become darkviolet.After 20 minutes, solid begins precipitation.The TLC of aliquot shows that some initial methyl phenyl ethers anisoles are residual, forms the lower slightly new speckle of polarity.Stirred reaction mixture spends the night, and TLC demonstration reaction is finished then.Reactant mixture is poured onto on ice, uses extracted with diethyl ether.Merge Organic substance, dry on magnesium sulfate, and vacuum concentration, stay grease.Residue is dissolved in the hexane, is cooled to-78 ℃, solid collected by filtration obtains 14 gram 2-(2-chloro-1,1-dimethyl ethyl)-1-methoxyl group-4-toluene, is grease during heating.Vacuum concentration leaches thing, obtains 4: 1 mixture of 15.5 gram products and initial methyl phenyl ethers anisole.
In water-bath, in argon gas atmosphere, revolve in the 30mL absolute ether suspension of bits (1.87g) to magnesium, slowly add the 1.62mL Bromofume by syringe, so that internal reaction temperature is no more than 27 ℃.Utilize to add funnel, (4g, 18.9mmol) and the 20mL diethyl ether solution of other Bromofume (1.62mL), adding speed is for making internal temperature keep below 25 ℃ to add 2-(2-chloro-1,1-dimethyl ethyl)-1-methoxyl group-4-toluene.It is green that reactant mixture turns, and forms fine precipitate.After 1 hour, reactant mixture is cooled to-78 ℃; At the bottom of reactant mixture solid block, stop to stir.Utilize and add funnel, in the 4mL diethyl ether solution adding reactant mixture with the 3.98mL trifluoroacetic anhydride, simultaneously with the moving reactant mixture of hand-screw.Then, reactant mixture is warming up to room temperature, on-40 ℃, restarts to stir.The TLC of aliquot shows slightly high new speckle and the parent material of polarity.Then, reactant mixture is poured onto on the cold 1N HCl, uses extracted with diethyl ether.Merge Organic substance, dry on magnesium sulfate, and vacuum concentration.Go up the purification residue at silicagel column (0% to 5% ethyl acetate-hexane), obtain 1,1 of 1.7g (41% productive rate), 1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpenta-2-one are transparent grease.
Embodiment 63: synthesize 1,1,1-three fluoro-4-(2-methoxyl group-3,5-3,5-dimethylphenyl)-4-methylpenta-2-one
According to synthetic 1,1, described same procedure during 1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpenta-2-one, from 1-methoxyl group-2, the 4-dimethyl benzene prepares title product.
Embodiment 64: synthesize 1,1,1-three fluoro-4-(5-methoxyl group-2,4-3,5-dimethylphenyl)-4-methylpenta-2-one
According to synthetic 1,1, described same procedure during 1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpenta-2-one, from 1-methoxyl group-2, the 4-dimethyl benzene prepares title product.
Embodiment 65:4-(2-benzyloxy-5-methyl mercapto phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones
At-78 ℃, (3g in 50mL THF solution 8.6mmol), adds 7.56mL n-BuLi (hexane solution of 2.5M), and stirred reaction mixture 10 minutes to 3-(2-benzyloxy-5-bromophenyl)-3-methyl fourth-1-alcohol.Add the 1.55mL dimethyl disulfide then, and reactant mixture is warming up to room temperature.After 20 minutes, TLC shows the slightly high new speckle (in a large number) of polarity, and other is seldom arranged.Then, extracted with diethyl ether is used in reactant mixture saturated aqueous ammonium chloride quencher.It is dry on magnesium sulfate to merge Organic substance, and vacuum concentration to 2.84 gram 3-(2-benzyloxy-5-methyl mercapto phenyl)-3-methyl fourth-1-alcohol, is grease.
At-60 ℃, in the 15mL of 1.57mL oxalyl chloride dichloromethane solution, add the 5mL dichloromethane solution of 2.55mLDMSO.After 10 minutes, adding 3-(2-benzyloxy-5-methyl mercapto phenyl)-3-methyl fourth-1-alcohol (2.84g, 5mL dichloromethane solution 8.9mmol) (solid rapid precipitation) is after 15 minutes, add the 7.5mL triethylamine, reactant mixture becomes very thick because of having solid.Then, reactant mixture is warming up to room temperature, and monitors by TLC.After 1 hour, the TLC of aliquot demonstration reaction is finished, and therefore water is added in the reactant mixture, and separates the layer that generates.The water layer washed with dichloromethane merges Organic substance, washes with water four times, uses the salt water washing, and is dry on magnesium sulfate, and vacuum concentration, obtains yellow oil.At SiO
2(0% to 10% ethyl acetate-hexane) goes up the purification residue, obtains 3-(2-benzyloxy-5-methyl mercapto the phenyl)-3-methyl butyraldehyde of 2.2g (78.7% productive rate), is colorless oil, and this grease is slow crystallization when leaving standstill.
As the embodiment 26 of U.S. Patent Application Publication 2004/0023999,3-(2-benzyloxy-5-methyl mercapto phenyl)-3-methyl butyraldehyde is converted to 4-(2-benzyloxy-5-methyl mercapto phenyl)-1,1,1-three fluoro-4-methylpent-2-alcohol.
Use above-mentioned Swern condition, with 4-(2-benzyloxy-5-methyl mercapto phenyl)-1,1,1-three fluoro-4-methylpent-2-alcohol are oxidized to 4-(2-benzyloxy-5-methyl mercapto phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones.
Embodiment 66: synthesize 1,1,1-three fluoro-4-methyl-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl) penta-2-ketone
4-in sealed tube (5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpenta-2-one (1.00g, 2.8mmol), (529mg 4.3mmol) and in the mixture of potassium carbonate (787mg), adds 20mL MeOH-DME-DMF (3: 2: 1) to pyrimidine-5-boric acid.In stirring at room after 10 minutes, add tetrakis triphenylphosphine palladium (O) (329mg), and with reactant mixture be heated to 120 ℃ 40 minutes.After being cooled to room temperature,, filter crude mixture by tampon by means of ethyl acetate.Vacuum concentration leaches thing and removes most of methanol, is dissolved in once more in the 160mL ethyl acetate, uses 80mL 1N sodium hydrate aqueous solution, 80mL water and the water washing of 80mL salt respectively.Dry organic facies on anhydrous sodium sulfate is filtered, and vacuum concentration.With 20% to 30% ethyl acetate-hexane,, obtain 620mg (62% productive rate) title compound by the column chromatography analysis purification.
Embodiment 67: synthetic 5-{7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-2,3-Dihydrobenzofuranes-5-yl } pyrimidine
To 1,1,1-three fluoro-4-methyl-4-(5-pyrimidines-5-base-2,3-Dihydrobenzofuranes-7-yl) penta-2-ketone (620mg, 1.8mmol) the anhydrous DMSO-THF of 5mL (1: 1) solution in, last 5 minutes and dropwise add 2.64mL trimethyl sulfoxonium ylide solution (NaH (242mg, 60% dispersion liquid in the mineral oil) and iodate trimethyl sulfoxonium (1.33g 6.0mmol) reacted 30 minutes and the liquid storage of preparation) in the anhydrous DMSO of 7.50mL., after 2 hours reactant mixture is poured onto in the 40mL water in stirring at room, with extracted with diethyl ether (200mL cumulative volume).The organic facies water, the salt water washing that merge, dry on magnesium sulfate, filter, and vacuum concentration, obtain 651mg (99% productive rate) title compound, be light yellow oil, directly use this grease, and be not further purified.
Embodiment 68: synthetic 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-2, the 3-Dihydrobenzofuranes
To iodate trimethyl sulfoxonium (343mg, in the anhydrous DMSO solution of 3mL 1.56mmol), with NaH (60%, in mineral oil, 66.0mg, 1.65mmol) batch processing was stirred this mixture 30 minutes under the room temperature.Last 5 minutes, mixture is transferred to 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1, (400mg in the anhydrous DMSO solution of 1mL 1.30mmol), stirs the mixture overnight that generates to 1-three fluoro-4-methylpenta-2-ones.The quencher of mixture water is with three parts of 20mL ethyl acetate extractions.The organic layer that merges is with two parts of 5mL water washings, and is dry on magnesium sulfate, filter, and vacuum concentration, obtain 380mg (91% productive rate) title product, be yellow oil.Crude product is enough pure, directly uses, and is not further purified.
Embodiment 69: synthetic 7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-5-methyl mercapto-2, the 3-Dihydrobenzofuranes
To iodate trimethyl sulfoxonium (1.36g, 6.1mmol) in the suspension in the anhydrous DMSO of 7.7mL, add sodium hydride (60%, the suspension in mineral oil, 246mg).The solution that generates in stirring at room 30 minutes dropwise is added to 1,1 then, and (1.63g is in the anhydrous DMSO solution of 6.5mL 6.2mmol) for 1-three fluoro-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl) penta-2-ketone.After 2 hours, add 100mL water, the mixture of generation is with three parts of 100mL extracted with diethyl ether.The organic facies water, the saturated sodium-chloride water solution washed twice that merge, dry on magnesium sulfate, filter, and vacuum concentration, obtaining title compound, 1.64g (95% productive rate) directly uses, and is not further purified.
Embodiment 70: synthetic 7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-5-mesyl-2, the 3-Dihydrobenzofuranes
To 7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-5-methyl mercapto-2,3-Dihydrobenzofuranes (535mg, 1.9mmol) the 30mL acetonitrile and the 10mL aqueous solution in, (1.03g 4.8mmol), adds ruthenic chloride (III) (1mg) then to add sodium metaperiodate.After 2 hours, the dilute with water reactant mixture is used ethyl acetate extraction.The organic facies that merges is dry on magnesium sulfate, filters, and vacuum concentration, obtain title compound, be the sepia solid, 568mg (95% productive rate) directly uses, and is not further purified.
Embodiment 71: synthetic 6-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-4-difluoromethyl-6-methyl heptan-1-alkynes-4-alcohol
Aluminium foil among the anhydrous THF of strong agitation 3.5mL (108mg, 4.00mmol) and mercuric chloride (ca.1mg, 0.01mmol) 20 minutes.Slowly add propargyl bromination thing (80%, in toluene, 0.45mL, 4.00mmol) (reaction mixture temperature risings) was in 40 ℃ of mixture that stir generations 1 hour.At 0 ℃, lead propargyl sesquialter aluminium bromide solution is added 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1, (380mg among the anhydrous THF of 10mL 1.32mmol), and makes sluggish be warming up to room temperature to 1-two fluoro-4-methylpenta-2-ones, and stirring is spent the night.Vacuum concentrated mixture is with ice and water quencher and water layer ethyl acetate extraction.The dry organic extract that merges on magnesium sulfate, and vacuum concentration obtain the 420mg title product, are grease (97% productive rate), directly use and are not further purified.
Embodiment 72: synthetic 6-(3-[1,3] dioxane oneself-2-base phenyl)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol
At room temperature, in argon gas atmosphere, by strong agitation be present in aluminium foil among the anhydrous THF of 20mL (1.16g, 14.4mmol) and mercuric chloride (12mg, catalytic amount) 1 hour, preparation aluminum amalgam.In 30-40 ℃ stirred suspension, slowly add propargyl bromination thing (4.80mL, 80wt.% to temperature maintenance, in toluene, 25mL anhydrous THF solution 43.1mmol), and after interpolation, continuation is 40 ℃ of stirrings, up to obtaining lead solution (about 1 hour).At-78 ℃, with propargyl sesquialter aluminium bromide solution add 4-(3-[1,3] dioxane oneself-2-base phenyl)-1,1, (5.6g is in 100mL anhydrous ether solution 14.2mmol) for 1-three fluoro-4-methylpenta-2-ones.This temperature stirred reaction mixture 3 hours, make it be warming up to room temperature then, stirred 12 hours this moment.Then, reactant mixture is poured onto in the 20mL frozen water, and with four parts of 30mL extracted with diethyl ether.The extract that merges is with the water washing of 20mL salt, and is dry on magnesium sulfate, and vacuum concentration.Carry out chromatography at silica gel (hexane solution of 100% hexane to 40% ethyl acetate, gradient), obtain 2.5 gram title compounds, be grease (50% productive rate).
Embodiment 73: synthetic 6-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol
With the anhydrous THF of 40mL add aluminium foil (1.25g, 4.6mmol) and mercuric chloride (100mg is in mixture 0.37mmol).The mixture that strong agitation generates 1 hour cools off in ice bath, and (toluene solution of 80 weight %, 62.9mmol 7mL) handle with propargyl bromination thing.0 ℃ of stirred reaction mixture 1 hour, and stirred 30 minutes under the room temperature.
At-78 ℃, with organo-aluminium agent treated 1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpenta-2-one (5.4g, 15.4mmol) solution in 10mL absolute ether and the anhydrous THF mixture of 10mL.Handled 1 hour and in room temperature treatment after 1 hour reactant mixture saturated ammonium chloride solution quencher, dilute with water at-78 ℃.Water layer is with three parts of 100mL ethyl acetate extractions.The organic layer salt water washing that merges, dry on sodium sulfate, filter, and vacuum concentration, obtain 6.3 and restrain title product, be solid, use this solid, and be not further purified (quantitative yield).
Embodiment 74: synthetic 4-[6-(3-[1,3] dioxane oneself-2-base phenyl)-4-hydroxyl-6-methyl-4-trifluoromethyl heptan-1-alkynyl] pyridin-3-yl t-butyl carbamate
Under the room temperature, in 4mL anhydrous triethylamine and 1mL dry DMF, stir 6-(3-[1,3] dioxane oneself-2-base phenyl)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol (300mg, 0.84mmol), (4-iodine pyridine-3-yl) t-butyl carbamate (270mg, 0.84mmol), two (triphenylphosphine) Palladous chloride. (II) catalyst (29.6mg, 0.04mmol) and Copper diiodide (I) (16mg, mixture 0.08mmol) 12 hours.Use 30mL ether diluted reaction mixture then, with 20mL saturated aqueous ammonium chloride and the water washing of 20mL salt.Dry organic layer on magnesium sulfate, and vacuum concentration.With hexane-ethyl acetate (5: 1 to 1: 1), on silica gel, carry out column chromatography analysis, obtain the 250mg title compound, be foam (54% productive rate).
Embodiment 75: synthetic N-{4-[6-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-4-hydroxyl-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-2-isopropyl pyrimidine-5-yl }-2,2, the 2-trifluoroacetamide
At room temperature, in 0.8mL anhydrous acetonitrile and 0.25mL anhydrous triethylamine, stir chloro Dihydrobenzofuranes alkynes (185mg, 0.533mmol), iodo-pyrimidine (144mg, 0.4mmol), Copper diiodide (I) (9.5mg, 0.05mmol) and dichloro two (triphenylphosphine) palladium (II) (17.5mg, mixture 0.025mmol).After 1 hour, LC-MS indication does not have raw material alkynes, but shows main peak (corresponding to required chemical compound) and show the secondary peak of dimer at M+H=691 at M+H=578.Use the hexane solution eluting of gradient, analyze the purification crude product mixture, obtain title compound, be light brown grease (120mg, 52% productive rate), M+H=577 by silica gel column chromatography as the 0%-25% ethyl acetate.
Embodiment 76: synthetic 6-(5-fluoro-2-aminomethyl phenyl)-1-(3-fluoro-2-nitrobenzophenone)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol
At room temperature, stir trifluoromethanesulfonic acid 3-fluoro-2-nitrobenzophenone ester (149mg, 0.52mmol), two (triphenylphosphine) palladium (the II) (20mg of dichloro, 0.028mmol), Copper diiodide (I) (14mg, 0.074mmol), tetrabutylammonium iodide (200mg, 0.54mmol), the mixture of 0.25mL anhydrous triethylamine, 0.5mL anhydrous acetonitrile and 0.5mL anhydrous tetrahydro furan 30 minutes.With 6-(5-fluoro-2-aminomethyl phenyl)-6-methyl-4-trifluoromethyl heptan-(145mg 0.48mmol) handles the mixture that generates, and at room temperature stirred 18 hours 1-alkynes-4-alcohol.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (dichloromethane solution of 50% hexane), the purification crude product obtains the 96mg title product, is light yellow oil (45% productive rate).
Embodiment 77: synthetic 4-[4-hydroxyl-6-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-3-methyl-5-nitro benzonitrile
At 60 ℃; trifluoromethanesulfonic acid 4-cyano group-2-methyl-6-nitrobenzophenone ester (217mg in the microwave oven in heating 0.8mL dry toluene and the 0.3mL anhydrous triethylamine mixture; 0.7mmol), two (triphenylphosphine) palladium (the II) (24.6mg of dichloro; 0.035mmol), Copper diiodide (I) (13.3mg; 0.7mmol) and 6-(5-mesyl-2; 3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol (273mg, mixture 0.7mmol) 10 minutes.Reactant mixture is applied to SiO
2On the post (hexane solution of 50% ethyl acetate), obtain the 165mg title product, be light yellow oil (43% productive rate).
Embodiment 78: Synthetic 2-(1-benzenesulfonyl-5-bromo-1H-indole-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol
Under 70 ℃, 6-(5-chloro-2 in heating 1mL DMF and the 0.7mL triethylamine, 3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol (170mg, 0.49mmol), N-(4-bromo-2-iodophenyl) benzsulfamide (220mg, 0.50mmol), two (triphenylphosphine) palladium (the II) (20mg of dichloro, 0.03mmol) and Copper diiodide (I) (10mg, mixture 0.05mmol).After 45 minutes, cooling mixture is with the dilution of 7mL saturated aqueous ammonium chloride with three parts of 7mL ethyl acetate extractions.The organic layer that merges is with two parts of 7mL saturated aqueous ammonium chlorides, and the water washing of four portions of 7mL salt is dry on magnesium sulfate, filtration, and vacuum concentration.Use ethyl acetate-hexane (0-30% gradient) eluting,, obtain 126mg (39% productive rate) title compound at the thick residue of silica gel purification.
Embodiment 79: synthetic 4-(3-[1,3] dioxane oneself-2-base phenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol
To { 4-[6-(3-[1,3] dioxane oneself-2-base phenyl)-4-hydroxyl-6-methyl-4-trifluoromethyl heptan-1-alkynyl] pyridin-3-yl t-butyl carbamate (250mg, 0.46mmol) 5mL methanol-water (4: 1) solution in, add DBU (0.7mL, 4.6mmol), and reactant mixture is heated to 65 ℃, kept 2 hours.Vacuum concentrated solution is settled out product from water.Filtering precipitate, and dry, obtain the 176mg title compound, be white solid (86% productive rate).
Embodiment 80: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(2-isopropyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol
To N-{4-[6-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-4-hydroxyl-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-2-isopropyl pyrimidine-5-yl }-2,2,2-trifluoroacetamide (58mg, 0.1mmol) the no Shui dioxane solution of 1mL in, add tetramethyl guanidine (0.05mL, 0.4mmol), and stirred reaction mixture and heating 1 hour in remaining on 100 ℃ oil bath.Use the dichloromethane solution eluting of 5% methanol, by preliminary TLC, purification on silica gel obtains title compound, is light lacteous solid, (25mg, 52% productive rate) M+H=482.
Embodiment 81: Synthetic 2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN
With 4mL glacial acetic acid and iron powder (335mg; 6mmol) handle 4-[4-hydroxyl-6-(5-mesyl-2; 3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-3-methyl-5-nitro benzonitrile (165mg, 6mL absolute ethyl alcohol and stirring solution 0.3mmol).The mixture that generates 90 ℃ of heating 30 minutes is cooled to room temperature, with the dilution of 200mL dichloromethane, and filters by the padding of CELITE filter aid.Leach thing with three parts of 50mL saturated aqueous sodium carbonates and the water washing of two portions of 25mL salt; dry on sodium sulfate; filter; and vacuum concentration; obtain 140mg 3-amino-4-[4-hydroxyl-6-(5-mesyl-2; 3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-5-methyl benzonitrile, be light brown oily thing (90% productive rate).
Cooling 3-amino-4-[4-hydroxyl-6-(5-mesyl-2 in ice bath; 3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-5-methyl benzonitrile (140mg; 0.27mmol) 5mL anhydrous methylene chloride agitating solution; and with trifluoroacetic anhydride (0.075mL 0.54mmol) handles.After 5 minutes, vacuum concentrated mixture.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (100% dichloromethane) obtains 155mgN-{5-cyano group-2-[4-hydroxyl-6-(5-mesyl-2; 3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-the 3-aminomethyl phenyl }-2; 2; the 2-trifluoroacetamide is light brown oily thing (93% productive rate).
1; 1; 3, (0.094mL is under existence 0.75mmol) for the 3-tetramethyl guanidine; in microwave oven; at 140 ℃ of heating N-{5-cyano group-2-[4-hydroxyl-6-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-6-methyl-4-trifluoromethyl heptan-1-alkynyl]-the 3-aminomethyl phenyl }-2,2; 2-trifluoroacetamide (154mg, the anhydrous DMSO solution of 0.6mL 0.25mmol) 10 minutes.Mixture quencher reaction with 1N sulphuric acid and 10mL trash ice.Filter the precipitate that generates, wash with water, and dry.Preliminary TLC chromatography (hexane solution of 50% ethyl acetate, the dichloromethane solution of 15% ethyl acetate then) obtains the 23mg title product, is pale solid (18% productive rate).
Embodiment 82: synthesize 1,1,1-three fluoro-2-(7-fluoro-1H-indole-2-ylmethyl)-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol
(800mg 14.3mmol) handles 6-(5-fluoro-2-aminomethyl phenyl)-1-(3-fluoro-2-nitrobenzophenone)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol (1.05g, 6mL dehydrated alcohol 2.4mmol) and 2mL glacial acetic acid agitating solution with iron powder.The mixture that generates 80 ℃ of heating 2 hours is cooled to room temperature, and with the ether dilution, the padding by CELITE filter aid filters, and vacuum concentration.Residue is dissolved in the ether, handle with Anhydrous potassium carbonate, filter, and vacuum concentration, obtain 900mg 1-(2-amino-3-fluorophenyl)-6-(5-fluoro-2-aminomethyl phenyl)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol, for light brown oily thing (92% productive rate), use this grease, and do not have purification.
With two (triphenylphosphine) palladium (the II) (250mg of dichloro, 0.36mmol) handle 1-(2-amino-3-fluorophenyl)-6-(5-fluoro-2-aminomethyl phenyl)-6-methyl-4-trifluoromethyl heptan-1-alkynes-4-alcohol (900mg, 2.2mmol) the no Shui dioxane solution of 10mL, and at 100 ℃ of heating this mixture 60 hours.At SiO
2(hexane solution of 20% dichloromethane) goes up the purification crude product mixture, obtains the 700mg title product, is yellow oil (78% productive rate).
Embodiment 83: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-pyridine-2-base-1H-indole-2-ylmethyl) penta-2-alcohol
Reflux 2-(1-benzenesulfonyl-5-bromo-1H-indole-2-ylmethyl)-4-(5-chloro-2; 3-Dihydrobenzofuranes-7-yl)-1; 1; 1-three fluoro-4-methylpent-2-alcohol (30mg; 0.046mmol), 2-tributyl tin alkyl pyridine (72mg, 0.196mmol) and two (triphenylphosphine) palladium (II) mixture (10mg) of dichloro 2 hours.Cool off this mixture then, with the ether dilution, add several DBU, the dilute with water mixture is used ethyl acetate extraction.Use ethyl acetate-hexane (35: 65) eluting,,, obtain the partial purification product of stanniferous by-product at the thick material of silica gel top purification by preparation TLC.
The above-mentioned 2-of reflux (1-benzenesulfonyl-5-pyridine-2-base-1H-indole-2-ylmethyl)-4-(5-chloro-2; 3-Dihydrobenzofuranes-7-yl)-1; 1; 1-three fluoro-4-methylpent-2-alcohol (30.1mg; 0.046mmol, the above-mentioned theory maximum) with the mixture of 5mL methanol and 5mL 10% sodium hydrate aqueous solution.After 4 hours, with 7mL saline diluted mixture thing, with three parts of 5mL ethyl acetate extractions.The organic layer that merges is with three parts of 5mL saturated sodium bicarbonate aqueous solutions, 5mL saline, and two parts of 5mL saturated aqueous ammonium chlorides, the water washing of 5mL salt, dry on magnesium sulfate, filtration, and vacuum concentration.Use ethyl acetate-hexane (1: 1), by preliminary TLC, the thick material of purification on silica gel.When from ether-hexane vacuum concentration from material that preliminary TLC plate obtains, obtain 10mg (42% productive rate) title compound.
Embodiment 84: synthesize 1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyridin-3-yl-1H-indole-2-ylmethyl) penta-2-alcohol
The 2-(1-benzenesulfonyl-5-bromo-1H-indole-2-ylmethyl)-1 of reflux in 6mL toluene, 3mL ethanol and 1.5mL 2M aqueous sodium carbonate; 1; 1-three fluoro-4-(5-fluoro-2; 3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol (100mg; 0.156mmol), pyridine-3-boric acid (80mg; 0.65mmol) and tetrakis triphenylphosphine palladium (O) (25mg, 0.022mmol) mixture.By TLC monitoring reaction (ethyl acetate-hexane (6: 4)).Use saturated aqueous ammonium chloride diluted mixture thing then, with three parts of 10mL ethyl acetate extractions.The organic layer that merges is with the water washing of three portions of 10mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.Use ethyl acetate-hexane (gradient 10-60%), the thick material of purification on silica gel obtains 88mg (88% productive rate) material.Recrystallization from ether-hexane obtains 76mg (76% productive rate) 2-(1-benzenesulfonyl-5-pyridin-3-yl-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol.
To above-mentioned 2-(1-benzenesulfonyl-5-pyridin-3-yl-1H-indole-2-ylmethyl)-1; 1; 1-three fluoro-4-(5-fluoro-2; 3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol (71mg; 0.11mmol) 5mL THF solution in; adding 1M tetrabutylammonium (0.5mL, THF solution 0.5mmol), and at 80 ℃ of heating blends.After 18 hours, vacuum concentrated mixture is with the dilution of 1N sodium hydrate aqueous solution with three parts of 5mL ethyl acetate extractions.The organic layer that merges is with two parts of 5mL 1N sodium hydrate aqueous solutions, 5mL saline, and three parts of 5mL saturated aqueous ammonium chlorides washings, dry on magnesium sulfate, filtration, and vacuum concentration.Use methanol-dichloromethane (0: 100,0.5: 99.5 then, 1: 99 then) eluting, purification residue on silica gel obtains 46mg (83% productive rate) title compound.
Embodiment 85: synthesize 1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol
At 120 ℃, 4-among the microwave heating 3.0mL DME-MeOH-DMF (1: 1.5: 0.5) (5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-es [2,3-c] pyridine-2-ylmethyl) penta-2-alcohol (188mg, 0.4mmol), pyridine 3-boric acid 1, the ammediol cyclic ester (89mg, 0.6mmol), potassium carbonate (K
2CO
3166mg, 1.2mmol) and Pd (PPh
3)
4(46.2mg, mixture 0.04mmol) 20 minutes is cooled to room temperature, with the dilution of 20mL ethyl acetate, and passes through diatomite filtration.Leach thing with 5mL1.0M sodium hydrate aqueous solution, water and salt water washing, dry on magnesium sulfate, and vacuum concentration.By the silica gel chromatography analysis, the purification residue obtains 90mg (48% productive rate) title compound, is white foam.
Embodiment 86: synthesize 1,1,1-three fluoro-4-(4-methoxyl biphenyl-3-yl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol
At room temperature, with phenylboric acid (74mg 0.6mmol) handles 4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol (188mg, 0.4mmol), Pd (OAc)
2(9mg, 0.04mmol), DCyBPP ((2-dicyclohexyl phosphino-) biphenyl, 28mg, 0.08mmol) and KF (93mg, 1.6mmol) mixture in 3mL THF.At 120 ℃, microwave heating reactant mixture 20 minutes is cooled to room temperature, with the dilution of 20mL ethyl acetate, and passes through diatomite filtration.Leach thing with 5mL 1.0M sodium hydrate aqueous solution, water and the water washing of 5mL salt.Dry organic facies on magnesium sulfate is filtered, and vacuum evaporating solvent.By the silica gel chromatography analysis, the purification residue obtains 75mg (40% productive rate) title compound, is white solid.
Embodiment 87: Synthetic 2-(3-chloro-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol
At room temperature, with 1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol (33.0mg, 0.5mL DMF solution-treated trichloro-acetic chloride 0.081mmol) (0.045mL, 0.5mL DMF solution 0.403mmol).After 2 days, with 2mL frozen water and the cold 1N sodium hydroxide solution of 2mL quencher reaction.Mixture with three parts of 5mL ethyl acetate extractions generations.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (dichloromethane solution of 100% dichloromethane to 10% methanol, gradient) obtains 20.0mg title product (56% productive rate).
Embodiment 88: Synthetic 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carboxylate methyl ester
During room temperature, with 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-(300mg 0.65mmol) is dissolved in the 10mL methanol 1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles.Introduced HCl gas 2 minutes.The reflux mixture overnight.Solvent removed in vacuo.Residue is with the dilution of 50mL ethyl acetate, with the neutralization of 30mL saturated sodium carbonate solution.Separate organic layer.Water layer is with three parts of 50mL ethyl acetate extractions.Merge organic layer, use the salt water washing, dry on sodium sulfate, and solvent removed in vacuo.By the flash chromatography analysis (with 2% triethylamine inactivation SiO
2, use CH
2Cl
2To CH
2Cl
2-MeOH (95: 5) eluting) purification residue obtains title compound (263mg, 82% productive rate).
Embodiment 89: Synthetic 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carboxylic acid
With 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-(100mg 0.2mmol) is dissolved in the 2mLTHF-MeOH-water (3: 1: 1) 1H-pyrrolo-[3,2-b] pyridine-5-carboxylate methyl ester.Adding Lithium hydrate monohydrate (25mg, 0.6mmol).Stirring reaction is 4 hours under the room temperature.With 5mL water diluted mixture thing, use 6N HCl solution that pH value is adjusted to about 2.With three parts of 50mL ethyl acetate extraction Organic substances, use the salt water washing, dry on anhydrous sodium sulfate.Solvent removed in vacuo obtains title compound (13.5mg, 14% productive rate).
Embodiment 90: synthetic 1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl } ethyl ketone
With 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-(100mg 0.22mmol) is dissolved among the 6mL THF 1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles.This solution is cooled to-78 ℃.Adding iodate methyl magnesium (3M, in ether, 1.2mL, 3.6mmol).Stirring reaction spends the night, and makes temperature arrive room temperature.With 10mL saturated aqueous ammonium chloride quencher reaction, with three parts of 50mL ethyl acetate extractions.Merge organic layer, dry on magnesium sulfate.Solvent removed in vacuo.(use CH by the flash chromatography analysis
2Cl
2To 95: 5CH
2Cl
2-MeOH eluting) purification residue obtains title compound (36mg, 35% productive rate).
Embodiment 91: synthetic 1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl }-2-methyl-prop-1-ketone
With 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-(50mg 0.11mmol) is dissolved among the 3mL THF 1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles.Add isopropylmagnesium chloride (2M, in THF, 0.15mL, 0.3mmol), add then CuBr (7mg, 0.05mmol).Backflow (75 ℃) stirring reaction 30 minutes.To be cooled to the mixed at room temperature thing.Use 1mL water, then 3 concentrated hydrochloric acid quencher reactions.Stirred this mixture 10 minutes, and, be 8 up to pH value with the saturated sodium carbonate solution neutralization.Use the ethyl acetate extraction reactant mixture, use the salt water washing.Solvent removed in vacuo.By preliminary HPLC (middle polarity condition) purification residue, obtain title compound (39mg, 70% productive rate).
Embodiment 92: Synthetic 2-(5-aminomethyl-1,2 H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol
With 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles (100mg, 0.22mmol) be dissolved among the 3mL THF, and adding borine-dimethyl sulfide (10M, 0.065mL, 0.648mmol).Reflux reaction 1 hour is cooled to room temperature then.Add 1mL 6N HCl solution then.The reflux reaction is spent the night.Reaction being cooled to room temperature, with the dilution of 50mL ethyl acetate, using the saturated sodium carbonate solution quencher then, is 12 up to pH value.Separate organic layer, with three parts of 50mL ethyl acetate extraction water layers.The dry organic fraction that merges on sodium sulfate, solvent removed in vacuo.By preliminary HPLC (polarity condition) purification residue, obtain title compound (49mg, 49% productive rate).
Embodiment 93: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-hydroxymethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol
At 0 ℃, to initial ester (0.995g, in 35.0mL THF solution 2.00mmol), dropwise add lithium aluminium hydride reduction (2.40mL, 2.40mmol).Make to be reacted to room temperature, stirred then 2 hours.TLC analyzes (5%MeOH-CH
2Cl
2, 0.5%NH
4OH) showing a product speckle and all parent materials exhausts.With 50mL THF dilute solution, water-THF solution (3.0mL water and 50mL THF) quencher.In it, add magnesium sulfate, and stirred the slurry that generates 30 minutes.By the diatomite filtration suspension, evaporation THF obtains title compound, is yellow foam (0.882g, 94.0% productive rate).
Embodiment 94: Synthetic 2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-formaldehyde
To the alcohol of embodiment 93 (0.882g, in 25mL acetone soln 1.88mmol), add manganese oxide (IV) (3.99g, 9.41mmol).Stirred black suspension 1 hour under the room temperature.By diatomite filtration solution, vacuum evaporation acetone obtains title compound (0.625g, 74.0% productive rate), is yellow foam.
Embodiment 95: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-ylmethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl) penta-2-alcohol
At 0 ℃, to the aldehyde of embodiment 94 (0.050g, 0.107mmol) and in the solution of 0.078mL acetic acid in the 3.0mL dichloroethanes, add morpholine (0.233mL, 2.68mmol).At room temperature stirring reaction is 30 minutes.In this yellow solution, (0.057mg 0.268mmol), continues under the room temperature to stir 14 hours then to add sodium triacetoxy borohydride.Use the 10mL ethyl acetate, the dilution of 2mL 3% Ammonia.Separate this binary system, use the ethyl acetate extraction water.The organic layer that merges is with three parts of 20mL water, and the salt water washing is dry on sodium sulfate, filtration, and vacuum evaporating solvent obtains yellow oil.Should be applied on the flash distillation post by thick material, and use 5%MeOH-CH
2Cl
2, 0.5%NH
4The OH eluting obtains title compound (0.018g, 32.0% productive rate), is white foam.
Embodiment 96: synthetic 3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] benzaldehyde
Stir 4-(3-[1 under the room temperature, 3] dioxane oneself-2-base phenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-es [2,3-c] pyridine-2-ylmethyl) penta-2-alcohol (160mg, 0.36mmol), (200mg, 0.8mmol) 14 hours, vacuum concentration was removed ethanol then for 2mL ethanol, 1mL water and p-methyl benzenesulfonic acid pyridine.With ethyl acetate and water dilution residue.The water layer ethyl acetate extraction.The organic layer that merges saturated sodium bicarbonate aqueous solution and salt water washing, and dry on sodium sulfate.Solvent removed in vacuo obtains 134mg (95% productive rate) title compound.
Embodiment 97: synthesize 1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol
3-[4 in ice bath, 4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] and benzaldehyde (50mg, 0.13mmol), 3mL dichloroethanes and acetic acid (0.1mL, 1.6mmol) in the solution, and disposable adding morpholine (0.28mL, 3.20mmol).This solution is warming up to room temperature, and stirred 0.5 hour.(68g 0.32mmol), and stirs this reaction 3.0 hours to disposable adding sodium triacetoxy borohydride under the room temperature.Dilute this solution with ethyl acetate, and add 3mL 3% Ammonia.This binary system is transferred in the separatory funnel, removes water layer, strip with ethyl acetate.The organic layer salt water washing that merges, dry on magnesium sulfate, filter, and vacuum evaporating solvent.Use methylene chloride-methanol, from flash chromatography post eluted product, and vacuum evaporating solvent, generate title compound (27mg, 45% productive rate).
Embodiment 98: synthetic 7-[3-(5-bromo-1H-indole-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-2,3-Dihydrobenzofuranes-5-sulfonic acid amides
Reflux 7-[3-(1-benzenesulfonyl-5-bromo-1H-indole-2-ylmethyl)-4; 4; 4-three fluoro-3-hydroxyls-1; the 1-dimethylbutyl]-2; 3-Dihydrobenzofuranes-5-sulfonic acid 1-dimethylamino methylene (E)-Ji amide (167mg, 0.22mmol) mixture in 10mL methanol and 3mL 10% sodium hydrate aqueous solution.Use 10mL saline diluted mixture thing after 24 hours, with three parts of 10mL ethyl acetate extractions.The organic layer that merges is with two parts of 5mL saturated sodium bicarbonate aqueous solutions, 5mL saline, and three parts of 5mL saturated aqueous ammonium chlorides, the water washing of 5mL salt, dry on magnesium sulfate, filtration, and vacuum concentration.Use ethyl acetate-hexane (0-50% gradient), on silica gel, thick material is carried out chromatography, pulverize with ether-hexane then, obtain 79mg (64% productive rate) title compound.
Embodiment 99: Synthetic 2-(5-bromo-1H-indole-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol
Reflux 2-(1-benzenesulfonyl-5-bromo-1H-indole-2-ylmethyl)-4-(5-chloro-2; 3-Dihydrobenzofuranes-7-yl)-1; 1,1-three fluoro-4-methylpent-2-alcohol (30mg, 0.046mmol) mixture in 5mL methanol and 5mL 10% sodium hydrate aqueous solution.After 18 hours, with saline diluted mixture thing, with three parts of 7mL ethyl acetate extractions.The organic layer that merges is with three parts of 5mL saline, three parts of 5mL saturated aqueous ammonium chlorides, and the water washing of 5mL salt, dry on magnesium sulfate, filtration, and vacuum concentration.By preliminary TLC (1mm, silica gel, ethyl acetate-hexane (3: 7)) the thick material of purification, obtain 15mg (63% productive rate) title compound.
Embodiment 100: synthesize 1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-methanesulfinyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol
To 1,1, and 1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-methyl mercapto-1H-indole-2-ylmethyl) penta-2-alcohol (25mg, in 10mL methanol solution 0.053mmol), the adding sodium metaperiodate (150mg, 0.70mmol).After 1 hour, with saline diluted mixture thing, with three parts of 10mL ethyl acetate extractions.The organic layer that merges is with the water washing of three portions of 7mL salt, and is dry on magnesium sulfate, filter, and vacuum concentration.Use eluent ethyl acetate,, obtain 19.8mg (77% productive rate) title compound by preliminary TLC purification crude product on silica gel.
Embodiment 101: Synthetic 2-(1-fluorine cyclopropyl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol
(80.0mg in 2mL THF solution 0.605mmol), adds 0.70mL n-BuLi (1.6M is in hexane) to 2-methyl isophthalic acid H-pyrrolo-[2, the 3-c] pyridine that is cooled to-78 ℃.After 5 minutes, (1M in THF, 0.75mL), is warming up to room temperature with mixture, and keeps 1 hour to add potassium tert-butoxide.This mixture is cooled to-78 ℃, add above-mentioned 1-(1-fluorine cyclopropyl)-3-(5-fluoro-2-methoxyphenyl)-3-methyl fourth-1-ketone (150mg, 0.600mmol), as the solution among the 0.5mL THF.Stir this mixture 30 minutes at-78 ℃, and be warming up to room temperature.Add the 5mL ethyl acetate, wash organic facies with water, drying is filtered, evaporation.Preliminary layer chromatography analysis (developing agent: dichloromethane-ethanol (95: 5)), obtain the 100mg title compound, be grease, solidify when this grease leaves standstill (45% productive rate).
Embodiment 102: Synthetic 2-(1-fluorine cyclopropyl)-4-(4-fluorophenyl)-4-methyl isophthalic acid-quinolyl-4 penta-2-alcohol
In that (69mg in THF solution 0.482mmol), adds 0.4mL diisopropylamino lithium (1.5M is in hexane) to the refrigerative 4-methylquinoline of dry ice/acetone.This mixture is placed-20 ℃ to-30 ℃ cooling bath 15 minutes, be cooled to-78 ℃ then.Dropwise add 1-(1-fluorine cyclopropyl)-3-(4-fluorophenyl)-3-methyl fourth-1-ketone (49mg, 0.206mmol), as the solution among the 0.5mL THF.Remove cooling bath then, stirred this mixture 1 hour.Add 0.5mL water quencher reaction, dilute with ethyl acetate.Separate organic facies, wash with water, drying is filtered vacuum evaporating solvent.By preliminary layer chromatography analysis (developing agent: classification residue ethyl acetate-hexane (2: 1)), obtain title compound (0.019g, 24% productive rate) (polarity is a little less than lepidin), be grease, crystallization when this grease rests in the hexane, m.p.152 ℃-155 ℃.
Embodiment 103: synthesize 1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-furo [3,2-c] pyridine-2-ylmethyl-4-methylpent-2-alcohol
At-78 ℃, with diisopropylamino lithium (LDA; 1.5M cyclohexane solution, 195 μ L) dropwise handle the 2-methylfuran also [3,2-c] pyridine (according to T.Kitamura, K.Tsuda, and Y.Fujiwara, Tetrahedron Lett.1998,
39, the preparation of pp.5375-5376 method) and (26.0mg, 2mL THF solution 0.195mmol).Stirred this mixture 30 minutes (color becomes orange red from yellow), and with 1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpenta-2-one (81.5mg, handle slowly by 1mL THF solution 0.293mmol).-78 ℃ of stirring reactions 4.5 hours, with the quencher of 5mL saturated ammonium chloride solution, with the dilution of 20mL ethyl acetate.Separate each mutually and water layer with three parts of 10mL ethyl acetate extractions.The organic layer salt water washing that merges, dry on magnesium sulfate, and vacuum concentration.Flash chromatography is analyzed (ethyl acetate-hexane, 5% to 50% gradient), obtains 36.0mg (45% productive rate) title product, is transparent grease.
Embodiment 104: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol
At-78 ℃, with 450 μ L n-BuLi (2.5M is in hexane) dropwise handle thieno [3,2-c] pyridine (according to J.H.Wikel, M.L.Denney, and R.T.J.Vasileff, Heterocyclic Chem.1993,
30, the preparation of pp.289-290 method) and (152mg, 2mL THF solution 1.12mmol).The dark reactant mixture that stirring generates 30 minutes is with 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-2,3-Dihydrobenzofuranes (180mg, 0.5mL THF solution-treated 0.561mmol).Make reactant mixture arrive ambient temperature overnight, with the mixture quencher of 5mL saturated ammonium chloride solution and 10mL ethyl acetate.Separate each mutually and water layer with three parts of 10mL ethyl acetate extractions.The organic layer salt water washing that merges, dry on magnesium sulfate, and vacuum concentration.Flash chromatography is analyzed (ethyl acetate-hexane, 20%-30% gradient) and is obtained 33.5mg (13% productive rate) title product, is yellow foam.
Embodiment 105: synthetic 5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol
Handle 2-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine (69mg, 4mL THF solution 0.52mmol) at-78 ℃ with 610 μ L n-BuLi (2.5M is in hexane).After 5 minutes, (1M in THF, 1.0mL), and is warming up to room temperature with mixture, keeps 1.5 hours to add potassium tert-butoxide.This orange reaction mixture is cooled to-78 ℃, dropwise adds 5-(5-fluoro-2-methoxyphenyl)-2, the 5-dimethyl oneself-3-ketone (110mg, 2mL THF solution 0.436mmol).Stirred the mixture 30 minutes at-78 ℃, be warming up to room temperature, with the quencher of 10mL saturated ammonium chloride solution, with the dilution of 20mL ethyl acetate.Separate each mutually and water layer with two parts of 10mL ethyl acetate extractions.The dry organic layer that merges on magnesium sulfate, and vacuum concentration.At SiO
2The enterprising circumstances in which people get things ready for a trip analysis of spectrum (CH of MeOH
2Cl
2Solution, gradient, 0% to 10%) obtain 71.4mg (43% productive rate) product, be white solid.
Embodiment 106: synthetic 4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol
At room temperature, (60%, in mineral oil, 16.8mg 0.419mmol) handles 1H-pyrrolo-[3,2-b] pyridine (33.0mg, 4mL DMF solution 0.279mmol) with NaH.After 30 minutes, add 5-chloro-7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-2, (188mg 0.558mmol), stirs the mixture overnight that generates to the 3-Dihydrobenzofuranes.Then, with 5mL ethyl acetate diluting reaction, with the quencher of 5mL saturated ammonium chloride solution.Water layer 5mL ethyl acetate extraction.The dry organic layer that merges filters on magnesium sulfate, and vacuum concentration.Pulverize residue with ether, obtain 55.0mg (45% productive rate) title product, be white solid.
Embodiment 107: synthetic 1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl]-1,5,6,7-tetrahydro indole-4-ketone
To 7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-2,3-Dihydrobenzofuranes (59.2mg, 0.21mmol) and 1,5,6,7-tetrahydro indole-4-ketone (56.0mg, 0.41mmol) 0.4mL dehydrated alcohol suspension in, add 0.077mL alcohol sodium solution (alcoholic solution of 21wt%).Then, heated these reactant mixtures 16 hours at 85 ℃.The mixture that generates is poured onto in the semi-saturation sodium bicarbonate, and uses ethyl acetate extraction.The dry organic facies that merges is filtered on sodium sulfate, and vacuum concentration.By silica gel chromatography analysis (using 35% ethyl acetate-hexane eluting) purification residue, obtain 58.4mg (66% productive rate) title compound, be white solid, m.p.145 ℃-146 ℃.
Embodiment 108: synthetic 1-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone
To 7-[1; 1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-5-mesyl-2; 3-Dihydrobenzofuranes (101mg; 0.33mmol) and 1,5,6; 7-tetrahydro indole-4-ketone (74.9mg; 0.56mmol) 0.75mL dehydrated alcohol suspension in, add Sodium ethylate (alcoholic solution of 21wt.%, 103 μ L).After 16 hours, use the ethyl acetate diluted reaction mixture 85 ℃ of heating, dry on sodium sulfate, filter, and vacuum concentration.Use silica gel (using 50%),, obtain 80.0mg (58% productive rate) title compound, be white solid, m.p.207 ℃-208 ℃ by column chromatography analysis purification residue to 60% ethyl acetate-hexane eluting.
Embodiment 109: synthetic 1-[2-hydroxy-4-methyl-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone
To 5-{7-[1,1-dimethyl-2-(2-trifluoromethyl epoxy ethyl) ethyl]-2,3-Dihydrobenzofuranes-5-yl } pyrimidine (56.0mg, 0.15mmol) and 1,5,6,7-tetrahydro indole-4-ketone (41.6mg, 0.31mmol) 1.0mL dehydrated alcohol suspension in, add alcohol sodium solution (0.057mL, the alcoholic solution of 21wt.%).In 85 ℃ of reacting by heating mixture 15 hours.After being cooled to room temperature, (be used for do load) concentrated reaction mixture on silica gel by silica gel chromatography analysis (using 40% to 70% ethyl acetate-hexane eluting) purification, obtains 42.0mg (55% productive rate) title compound, be white solid, m.p.213 ℃-214 ℃.
Embodiment 110:2-[2-hydroxyl-4-(5-mesyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile
With with the similarity method of the embodiment 4 of U.S. Patent Application Publication 2004/0023999, with 1,1,1-three fluoro-4-(2-methoxyl group-5-methyl mercapto phenyl)-4-methylpenta-2-one is converted to 2-[2-hydroxyl-4-(2-methoxyl group-5-methyl mercapto phenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile.
With with the similarity method of the embodiment 4 of U.S. Patent Application Publication 2004/0023999, with 2-[2-hydroxyl-4-(2-methoxyl group-5-methyl mercapto phenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile is oxidized to 2-[2-hydroxyl-4-(5-mesyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile.
Embodiment 111: Synthetic 2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-3-formonitrile
Use embodiment 4 similar approach of U.S. Patent Application Publication 2004/0023999, with 4-(2-benzyloxy-5-tert-butyl-phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones are converted to 2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile.
Embodiment 112: Synthetic 2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-3-formonitrile
Described similar approach when using Synthetic 2-[4-(the 5-tert-butyl group-2-hydroxy phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-3-formonitrile, with 4-(2-benzyloxy-5-isopropyl phenyl)-1,1,1-three fluoro-4-methylpenta-2-ones are converted to 2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile.
Embodiment 113: Synthetic 2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group l-1H-indole-3-formonitrile and 2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1-Methyl-1H-indole-3-formonitrile HCN
With with embodiment 53 in described similar approach during alkylation 3-(2-benzyloxy-5-tert-butyl-phenyl)-3-methyl fourth-1-alcohol, to 2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile carries out alkylation, obtains 2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-3-formonitrile and 2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1-Methyl-1H-indole-3-formonitrile HCN.
Embodiment 114: Synthetic 2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-3-formonitrile and 2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1-Methyl-1H-indole-3-formonitrile HCN
With with embodiment 53 in described similar approach during alkylation 3-(2-benzyloxy-5-tert-butyl-phenyl)-3-methyl fourth-1-alcohol, to 2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile carries out alkylation, obtains 2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-3-formonitrile and 2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-1-Methyl-1H-indole-3-formonitrile HCN.
Embodiment 115: Synthetic 2-[2-hydroxyl-4-(2-methoxyl group-5-methyl amyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN
As disclosing 2004/0023999 embodiment 8 in the United States Patent (USP), with 1,1,1-three fluoro-4-(2-methoxyl group-5-methyl amyl)-4-methylpenta-2-one is converted to 2-[2-hydroxyl-4-(2-methoxyl group-5-methyl amyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN.
Embodiment 116: Synthetic 2-[2-hydroxyl-4-(2-hydroxy-5-methyl base amyl group)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN
As the embodiment 8 of U.S. Patent Application Publication 2004/0023999, with 2-[2-hydroxyl-4-(2-methoxyl group-5-methyl amyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN is converted to 2-[2-hydroxyl-4-(2-hydroxy-5-methyl base amyl group)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN.
Embodiment 117: Synthetic 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid
With potassium hydroxide (85mg, 1.5mmol) 3mL aqueous solution is handled 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid ethyl ester (220mg, 10mL methanol solution 0.470mmol).The mixture that stirring generates under the room temperature 4 hours refluxed 6 hours, was cooled to room temperature, and vacuum concentration.With cold 1N sulfuric acid treatment residue, with three parts of 30mL dichloromethane extractions.The organic layer that merges washes with water, and is dry on sodium sulfate, filter, and vacuum concentration, obtain the 190mg title product, be light lacteous oily solid (89% productive rate).
Embodiment 118: Synthetic 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid amide
With 105mL triethylamine and TBTU (133mg 0.413mmol) handles 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid (170mg, 2mL acetonitrile solution 0.375mmol).After 15 minutes, add the 53.6mL Ammonia.The reactant mixture that dilute with water generates is used dichloromethane extraction.Dry organic layer on sodium sulfate filters, and vacuum concentration.At SiO
2Enterprising circumstances in which people get things ready for a trip analysis of spectrum (hexane solution of 50% ethyl acetate) obtains the 170mg title product, is pale solid (quantitative yield).
Embodiment 119: Synthetic 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-formonitrile HCN
Make 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-carboxylic acid amide (95mg, 1mL DMF solution 0.21mmol) and cyanuric chloride (46mg, 0.25mmol) reaction.After 3 hours, use the sodium bicarbonate treatment mixture, use dichloromethane extraction.Dry organic layer on sodium sulfate filters, and vacuum concentration, obtains the 33mg title product, is pale solid (36% productive rate).
Use 15% to 25% isopropyl alcohol-hexane eluting, at CHIRALCEL
TMOn the OD post, realize (+)-and the fractionation of (-)-enantiomer by chirality HPLC.
Biological property is estimated
By fluorescence polarization competition binding analysis, estimate The compounds of this invention and the bonded performance of steroid receptors.The detailed description of the preparation of reorganization glucocorticoid receptor (GR) (GR) complex that uses in the evaluation is described in the U.S. Patent Application Publication text 2003/0017503, at this its integral body is incorporated herein by reference.Use the normative document method, finish the dexamethasone probe of tetramethylrhodamin (TAMRA) labelling preparation (M.Pons et al., J.Steroid Biochem., 1985,
22, pp.267-273).
A. glucocorticoid receptor (GR) is competed binding analysis
Not not characterizing of step 1. fluorescent probe
At first, should measure the maximum excitation and the emission wavelength of fluorescent probe.The example of this probe is the dexamethasone of rhodamine (TAMRA)-labelling.
Then, in titration experiments, determine the affinity of probe to steroid receptors.Use above-mentioned exciting and emission maximum, on the SLM-8100 fluorophotometer, the fluorescence polarization value of measurement for Evaluation buffer middle probe.Add the expression vector lysate of five equilibrium, measure fluorescence polarization after each the interpolation, up to the further variation of not observing polarization value.Use the non-linear least square regression analysis, by to calculating the dissociation constant of probe with the bonded polarization value that obtains for lysate of probe.
The screening of the bonded inhibitor of step 2. probe
This detects and uses fluorescence polarization (FP), quantification test compounds and the ability that is used for competing with the dexamethasone of the bonded tetramethylrhodamin of human glucocorticoid receptor (GR) complex (TAMRA)-labelling, described human glucocorticoid receptor (GR) complex is prepared by insect expression system.The detection buffer is: 10mM TES, 50mM KCl, 20mM Na
2MoO
42H
2O, 1.5mM EDTA, 0.04%w/v CHAPS, 10%v/v glycerol, the 1mM dithiothreitol, DTT, pH 7.4.Test compounds is dissolved into the pure DMSO solution of 1mM, in being supplemented with the detection buffer of 10%v/v DMSO, further is diluted to 10 times of detectable concentrations then.In 96 hole polypropylene boards, contain in the buffer of DMSO with 10 times of detectable concentration serial dilution test compounds 10%.Add following detected components by order in each hole of 96 hole black Dynex microwell plates, preparation association reaction mixture in 96 hole black Dynex microwell plates, described detected components is: the test compounds solution that 15 μ L 10 times, 85 μ L are diluted to the dexamethasone of the TAMRA labelling of 1: 170 baculovirus lysate that contains GR and 50 μ L 15nM in detecting buffer.Positive reference is the reactant mixture that does not contain test compounds; Negative reference (blank) is the reactant mixture that contains 0.7 μ M to 2 μ M dexamethasone.Incubated at room temperature association reaction 1 hour, on LJL Analyst, read fluorescence polarization then, the excitation wavelength of described LJLAnalyst is set to 550nm, and emission wavelength is set to 580nm, and rhodamine 561 dichroic mirrors are installed.With FP signal data iteration non-linear curve fitting to 4-parameter logical equation, thereby determine IC
50Value.
Estimate and find and the bonded chemical compound of glucocorticoid receptor (GR) (GR) and progesterone receptor (PR), estrogen receptor (ER) and the bonded performance of mineralcorticoid receptor (MR), thereby estimate the selectivity of this chemical compound glucocorticoid receptor (GR) (GR).The experimental design of PR and MR is identical with above-mentioned GR method, and difference is: PR insect cell lysate is diluted to 1: 7.1, and the MR lysate is diluted to 1: 9.4.The PR probe is the mifepristone of TAMRA-labelling, uses ultimate density 5nM in detection, and negative reference (blank) is for containing the reaction of 0.7 μ M to 2 μ M mifepristone.
The ER experimental design is similar to above-mentioned experimental design, the different probes that is to use PanVera test kit receptor, fluorescein sodium labelling.Make detected components have identical volume with above-mentioned, so that the final detectable concentration of ER is 15nM, the final detectable concentration of ES2 probe is 1nM.In addition, change the component interpolation order of above-mentioned detection: at first, probe is added to plate, add receptor and test compounds then.In LJLAnalyst plate is carried out reading, the excitation wavelength of described LJLAnalyst is set to 485nm, and emission wavelength is set to 530nm, and fluorescein sodium 505 dichroic mirrors are installed.
For the detection of partly quoting by background technology (C.M.Bamberger and H.M.Schulte, Eur.J.Clin.Invest., 2000,
30Pp.6-9) or following detection (suppl.3), dissociate to change and live and change and suppress, estimate the bonded chemical compound of finding with glucocorticoid receptor (GR).
B. glucocorticoid receptor (GR) cell detection
1. the inducing of aromatase (changeing the cell detection of living) in the fibroblast
Dexamethasone, the synthetic ligands of glucocorticoid receptor (GR) (GR) is induced the expression of aromatase in human foreskin fibroblast.By in culture medium, testosterone being converted to estradiol, measure the activity of aromatase.Evaluation shows bonded chemical compound is induced aromatase activity in human foreskin fibroblast ability to GR.
At preceding 5 days that use, with human foreskin fibroblast (ATCC Cat.No.CRL-2429, designation CCD112SK) is placed on 96 orifice plates among the Iscove ' s Modified Dulbecco ' s Media (GibcoBRL Life Technologies Cat No.12440-053) (being supplemented with the FBS (Clonetech Cat No.SH30068) and the gentamycin (GibcoBRL Life TechnologiesCat.No.15710-064) of 10% charcoal filtering), 50,000 cells in every hole.On the same day that experimentizes, with the culture medium in the fresh culture medium displacement hole.Handle cell with test compounds, to ultimate density be 10
-5M to 10
-8M, the ultimate density of testosterone is 300ng/mL.The cumulative volume that has 100 μ L in every hole.Replica.Control wells comprises: (a) only receive the hole of testosterone and (b) receive testosterone and 2 μ M dexamethasone, thereby provide maximum aromatase inductive hole.Spend the night at 37 ℃ of culture plates (15 to 18 hours), when cultivating end, collect supernatant.According to the description of manufacturer, the ELISA test kit (ALPCO makes, available from American Laboratory Products Cat.No.020-DR-2693) that uses estradiol to use is measured the estradiol in the supernatant.In every hole, the amount of estradiol and ELISA signal are inversely proportional to.Test compounds is shown percentage ratio with respect to dexamethasone to the inductive table of degree of aromatase.The EC of test compounds
50Value is available from non-linear curve fitting.
2. the inhibition (cell detection of trans inhibition) that IL-6 produces in the fibroblast
Human foreskin fibroblast is replied the stimulation of proinflammatory cytokine IL-1 and is produced IL-6.As suppressing by dexamethasone (synthetic ligands of glucocorticoid receptor (GR) (GR)) effectively by the measured inflammatory response of the production of IL-6.Evaluation shows bonded chemical compound to GR and suppress the ability that IL-6 produces in human foreskin fibroblast.
The previous day of using, human foreskin fibroblast (ATCC Cat.No.CRL-2429) is placed on 96 orifice plates among the Iscove ' s Modified Dulbecco ' s Media (GibcoBRL Life Technologies Cat No.12440-053) (being supplemented with the FBS (Clonetech Cat No.SH30068) and the gentamycin (GibcoBRL Life Technologies Cat.No.15710-064) of 10% charcoal filtering), 5,000 cells in every hole.Second day, with the culture medium in the fresh culture medium displacement hole.With IL-1 (rhIL-1 α, R﹠amp; D Systems Cat.No.200-LA) handle cell, to ultimate density be 1ng/mL, and handle with test compounds, to ultimate density be 10
-5M to 10
-8M, the cumulative volume in every hole are 200 μ L.Replica.The background control wells does not have acceptance test chemical compound or IL-1.Positive reference hole only receives IL-1, and the maximum (or 100%) of expression IL-6 production.Spend the night at 37 ℃ of culture plates (15 to 18 hours), when cultivating end, collect supernatant.According to the description of manufacturer, (Austria Cat.No.BMS213TEN), measures the level of IL-6 in the supernatant to the ELISA test kit of using by IL-6 for MedSystems Diagnostics GmbH, Vienna.Test compounds is shown percentage ratio with respect to positive reference to the inhibition table of degree of I1-6.The IC of test compounds
50Value is available from non-linear curve fitting.
Can determine agonist or antagonist activities with the bonded chemical compound of glucocorticoid receptor (GR) by any detection.
3. regulate inducing of tyrosine aminotransferase (TAT) in the rat hepatocytes oncocyte
Test compounds is agonist or the antagonist activities when inducing tyrosine aminotransferase (TAT) in the rat hepatocytes oncocyte
In the MEM culture medium that contains 10% heat inactivation FBS and 1% non essential amino acid, go up cultivation H4-II-E-C at 96 orifice plates (20,000 cells/100 μ L/ holes)
3Cell.Second day, with the indication dexamethasone of concentration or test compounds (be dissolved among the DMSO, final DMSO concentration is 0.2%) irritation cell 18 hours.Handle control cells with 0.2%DMSO.After 18 hours, in the buffer that contains 0.1%Triton X-100, use tyrosine and α-Tong Wuersuan (salt) cytolysis as substrate, in detecting, light quantity measures the TAT activity.
Be to measure antagonist activities, before test compounds is applied to cell soon, by adding dexamethasone (concentration range 3 * 10
-9M to 3 * 10
-8M), pre-cell cultured supernatant oncocyte.Use the non-selective GR/PR antagonist of steroid mifepristone in contrast.
4. regulate inducing of MMTV-Luc in the HeLa cell
Test compounds is agonist or the antagonist activities when stimulating MMTV-(mice mammal tumor virus) to start the factor in the HeLa cell.
With containing MMTV-LTR (200 to+100, with respect to transcribing the beginning site) the pHHLuc-plastid cotransfection HeLa cell stably of fragment, described fragment is set up clone in the luciferase genes (Norden, 1988) of the resistance of constructive expression's selectivity antibiotic GENETICIN and the front of pcDNA3.1 plastid (Invitrogen).Selection has best MMTV-and starts the inductive clone of the factor, and is used for further experiment.
With the DMEM culture medium culturing cell that does not contain phenol red, replenish 3%CCS (calf serum of charcoal treatment), be transferred to then on 96 orifice plates (15,000 cells/100 μ L/ holes).Second day, be dissolved in test compounds or dexamethasone (ultimate density is 0.2%) among the DMSO by interpolation, stimulate MMTV-to start the activation of the factor.Only handle control cells with DMSO.After 18 hours, with cytolysis cytolysis reagent (Promega, Cat.No.E1531) in, add luciferase detectable (Promega, and use photometer (BMG Offenburg) measures aura luminosity (glow luminescence) Cat.No.E1501).
Be to measure antagonist activities, before test compounds is applied to cell soon, by adding dexamethasone (concentration range 3 * 10
-9M to 3 * 10
-8M), sting MMTV-in advance and start the factor.Use the non-selective GR/PR antagonist of steroid mifepristone in contrast.
5. regulate the growth of IL-8 in the U937 cell
Test compounds is agonist or the antagonist activities aspect the excretory GR-mediation of the inductive IL-8 of LPS-inhibition in the U-937 cell.
In the RPMI1640 culture medium that contains 10%CCS (calf serum of charcoal treatment), cultivated the U-937 cell 2 to 4 days.In cell transfer to 96 orifice plate (40,000 cells/100 μ L/ holes), and, stimulate with 1 μ g/mL LPS (being dissolved among the PBS) existing or not existing under the situation of dexamethasone or test compounds (be dissolved among the DMSO, ultimate density is 0.2%).Handle control cells with 0.2%DMSO.After 18 hours, (Pharmingen Cat.No.2654KI), measures the concentration of the IL-8 in the cell conditioned medium liquid by ELISA to use " OptEIA human IL-8set ".
Be to measure antagonist activities, before test compounds is applied to cell soon, by adding dexamethasone (3 * 10
-9M to 3 * 10
-8M), suppress the inductive IL-8 secretion of LPS.Use the non-selective GR/PR antagonist of steroid mifepristone in contrast.
6. regulate the expression of ICAM-Luc in the HeLa cell
Test compounds is suppressing agonist or the antagonist activities of the TNF-α that ICAM starts the factor-when inducing activation in the HeLa cell.
Start the factor (1353 to-9 with containing 1.3kb people ICAM-, with respect to transcribing the beginning site, Ledebur and Parks, 1995) plastid of fragment cotransfection HeLa cell stably, described fragment is set up clone in the luciferase genes of the resistance of constructive expression's selectivity antibiotic GENETICIN and the front of pcDNA3.1 plastid (Invitrogen).Selection has best ICAM-and starts the inductive clone of the factor, and is used for further experiment.With cell transfer to 96 orifice plates (15,000 cells/100uL/ hole) of the DMEM culture medium that is supplemented with 3%CCS.Second day, by adding 10ng/mL reorganization TNF-α (R﹠amp; D System Cat.No.210-TA), induces ICAM-to start the activation of the factor.Simultaneously, handle cell with test compounds or dexamethasone (be dissolved among the DMSO, ultimate density is 0.2%).Only handle control cells with DMSO.After 18 hours, with cytolysis cytolysis reagent (Promega, Cat.No.E1531) in, (Promega, Cat.No.E1501), and (BM G Offenburg) measures aura luminosity to use photometer to add the luciferase detectable.
Be to measure antagonist activities, before test compounds is applied to cell soon, by adding dexamethasone (3 * 10
-9M to 3 * 10
-8M), the TNF-α that suppresses the ICAM startup factor induces activation.Use the non-selective GR/PR antagonist of steroid mifepristone in contrast.
Usually, the scope of preferably tiring in the above-mentioned detection (potency range) is 0.1nM to 10 μ M, and the preferred scope of tiring is 0.1nM to 1 μ M, and the most preferred scope of tiring is 0.1nM to 100nM.
After tested the representational chemical compound of the present invention, and in one or more above-mentioned detections, these chemical compounds show the modified activity as glucocorticoid receptor function.For example, the chemical compound of following general formula of the present invention (IA) or its tautomer, prodrug, solvate or salt show effective activity at GR in measuring.
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-carbonitriles;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-c] pyridine-4-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [2,3-d] pyridazine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5,7-two chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyls)-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-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo-[2,3-b] pyridine-1-ylmethyl penta-2-alcohol;
2-benzo [b] thiophene-2-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-thieno [2,3-c] pyridine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-[4-((Z) acrylic)-3-vinyl pyrazoles-1-ylmethyl] penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
4-(5-fluoro-2-aminomethyl phenyl)-2,4--dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(3-dimethylamino methyl-1H-pyrrolo-[3,2-c] pyridine-2-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-pyrrolo-[3,2-c] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-furo [3,2-c] pyridine-2-ylmethyl-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
2-[4-(5-fluoro-2-hydroxy phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid diformamide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-yl } morpholine-4-base ketone;
2-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxy phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-Indole-6-carboxylic acid amide;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-nitro-1H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
N-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } acetamide;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[4-(3-[1,3] dioxy ring penta-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid-2-trimethyl silyl ethyl ester;
2-[4-(4-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } piperidines-1-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid methyl nitrosourea;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
1-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } piperidin-4-one-;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid (2-ethoxy) amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (4-hydroxy piperidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (3-hydroxyl pyrrolidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid cyano group Methanamide;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl acetate;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid carbamyl Methanamide;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl butyrate;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) acetic acid;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) butanoic acid;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-Trifluoromethyl-1 H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-5-carboxylic acid;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid diformamide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid Cyanomethyl amides;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-(4-benzo [1,3] Dloxole-4-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-4-phenyl-2-quinolyl-4 methyl oneself-2-alcohol;
2-[2-hydroxy-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
7-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl)-2,3-Dihydrobenzofuranes-5-formonitrile HCN;
2-[2-hydroxyl-4-(2-hydroxy-5-methyl base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-methyl mercapto-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-phenyl-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-hydroxyl-2,4-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-methoxyl group-5-aminomethyl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
3-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(4-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(4-trifluoromethyl) penta-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(2-difluoro-methoxy-5-fluorophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 6-methyl isophthalic acid, the 6-pyrrolin is [2,3-c] pyridine-5-ketone also;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-pyridin-4-yl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-pyridin-4-yl methylpent-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-(2-fluorine pyridin-4-yl methyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[3-(2-bromopyridine-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-(6,8-dimethyl quinoline-4-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] pyridine-2-formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2-(2,6-dichloroquinoline-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[3-(2-chloro-8-methylquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-[3-(2,6-dichloroquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
4-(2,3-Dihydrobenzofuranes-7-yl)-2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1, between 1-three fluoro-4-methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
4-fluoro-2-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-methylquinoline-4-ylmethyl) butyl] phenol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methylquinoline-4-ylmethyl) penta-2-alcohol;
2-[3-(2,6-lutidines-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 5-fluorophenol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-Methyl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-methylquinoline-8-yl)-4-methylpent-2-alcohol;
4-(2, the 6-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
2-(3-bromo-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-3-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-methyl-2-[4,4,4-three fluoro-3-hydroxyl-3-(1H-indole-2-ylmethyl)-1,1-dimethylbutyl] phenol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-Dimethoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
2-(2,4-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(2-amino-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol; With
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol.
In addition, after tested chemical compound or its tautomer, prodrug, solvate or the salt of following general formula of the present invention (IA), and in one or more above-mentioned detections, these chemical compounds show the activity as effective agonist of glucocorticoid receptor function.
4-pyrimidine-5-base-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-carbonitriles;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-c] pyridine-4-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [2,3-d] pyridazine-2-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5,7-two chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyls)-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-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(7-fluoro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-Trifluoromethyl-1 H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-thieno [2,3-c] pyridine-2-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
4-(5-fluoro-2-aminomethyl phenyl)-2,4-dimethyl-1-thieno [2,3-c] pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl-2,3-Dihydrobenzofuranes-7-yl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(3-dimethylamino methyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-thieno [3,2-c] pyridine-2-ylmethyl penta-2-alcohol;
2-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-nitro-1H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
N-{2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } acetamide;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[4-(3-[1,3] dioxy ring penta-2-base phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[4-(4-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid methyl nitrosourea;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } (3-hydroxyl pyrrolidine-1-yl) ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid cyano group Methanamide;
(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl acetate;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid carbamyl Methanamide;
4-(2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carbonyl } amino) methyl butyrate;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-Trifluoromethyl-1 H-indole-2-ylmethyl) butyl] phenol;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid diformamide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid Cyanomethyl amides;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } morpholine-4-base ketone;
2-(4-benzo [1,3] Dloxole-4-base-2-hydroxy-4-methyl-2-trifluoromethyl amyl group)-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-methyl-4-phenyl-2-quinolyl-4 methyl oneself-2-alcohol;
2-[2-hydroxy-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
7-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl)-2,3-Dihydrobenzofuranes-5-formonitrile HCN;
2-[2-hydroxyl-4-(2-hydroxy-5-methyl base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-methyl mercapto-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-5-isopropyl phenyl)-4-Methyl-2-trifluoromethyl-amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(2-hydroxyl-3,5-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-hydroxyl-2,4-3,5-dimethylphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[4-(the 5-tert-butyl group-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
2-[2-hydroxyl-4-(5-isopropyl-2-methoxyphenyl)-4-Methyl-2-trifluoromethyl amyl group]-the 1H-indole-3-formonitrile;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
3-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-(4-trifluoromethyl) penta-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-biphenyl-3-base-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(2-difluoro-methoxy-5-fluorophenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
4-(4-dimethylamino phenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(3-dimethylamino methyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-pyridine-2-base penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-quinolyl-4 methyl-4-neighbour-tolyl penta-2-alcohol;
1,1, between 1-three fluoro-4-methyl-2-quinolyl-4 methyl-4--tolyl penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-(2-fluorine pyridin-4-yl methyl)-3-hydroxyl-1,1-dimethylbutyl] phenol;
2-[3-(2-bromopyridine-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-(6,8-dimethyl quinoline-4-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] pyridine-2-formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2,6-two chloro-4-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group] the cigarette formonitrile HCN;
2-[3-(2,6-dichloroquinoline-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
4-(2,3-Dihydrobenzofuranes-7-yl)-2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluorophenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-(2,6-lutidines-4-ylmethyl)-1,1, between 1-three fluoro-4-methyl-4--tolyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
4-fluoro-2-(4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-quinolyl-4 methyl butyl) phenol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-methylquinoline-4-ylmethyl) butyl] phenol;
2-(2,6-lutidines-4-ylmethyl)-1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7-methylquinoline-4-ylmethyl) penta-2-alcohol;
2-[3-(2,6-lutidines-4-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 5-fluorophenol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(2-methylquinoline-4-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-Methyl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(7-fluoro-4-methylquinoline-8-yl)-4-methylpent-2-alcohol;
4-(2, the 6-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
2-(3-bromo-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(3-fluorophenyl)-4-methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-3-aminomethyl phenyl)-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluoro-4-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(3, the 4-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-methyl-2-[4,4,4-three fluoro-3-hydroxyl-3-(1H-indole-2-ylmethyl)-1,1-dimethylbutyl] phenol;
4-(2, the 5-3,5-dimethylphenyl)-1,1,1-three fluoro-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-quinolyl-4 methylpent-2-alcohol;
4-(2, the 5-Dimethoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(1H-indole-2-ylmethyl)-4-methyl-4-(2-trifluoromethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(4-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
2-(2,4-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(2-amino-4-chloro-7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-methylpent-2-alcohol;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-phenyl penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-pyrrolidine-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
2-(5-lignocaine-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-[5-(isopropyl methyl amino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-4-methylpent-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-fluorophenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(3-pyrimidine-5-base phenyl) penta-2-alcohol;
3 '-3-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl] and-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl }-4 '-xenol-2-formonitrile HCN;
4 '-hydroxyl-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-morpholine-4-ylmethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-ylmethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl) penta-2-alcohol;
4-chloro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-morpholine-4-ylmethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carbonitriles;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-carbonitriles;
1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl } ethyl ketone;
2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-carboxylic acid amide;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-hydroxymethyl-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-(5-aminomethyl-1,2 H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5H-pyrrolo-[3,2-c] pyridazine-6-ylmethyl) butyl] phenol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl } third-1-ketone;
1-{2-[4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[3,2-b] pyridine-5-yl }-2-methyl-prop-1-ketone;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-methoxyl biphenyl-3-yl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] phenol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] phenol;
3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] biphenyl-4-alcohol;
1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-pyridin-3-yl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(5-phenoxy group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(3-phenyl-7H-pyrrolo-[2,3-c] pyridazine-6-ylmethyl) penta-2-alcohol;
4-pyridin-3-yl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-phenoxy group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
4-pyridin-3-yl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] phenol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-[5-(4-fluorophenyl)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-4-methylpent-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-fluoro-2-methoxyphenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[3-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-[3-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 5-fluorophenol;
5-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-bromo-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(3-[1,3] dioxane oneself-2-base phenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-methoxyl biphenyl-3-yl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
3-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-4-alcohol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4-thiene-3-yl--2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] phenol;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-3-formonitrile HCN;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-pyridin-3-yl-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl] phenol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-pyridin-3-yl phenyl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-pyrimidine-5-base phenyl)-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-pyridine-2-base-1H-indole-2-ylmethyl) penta-2-alcohol;
2-(5-bromo-1H-indole-2-ylmethyl)-4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-methanesulfinyl-1H-indole-2-ylmethyl)-4-methylpent-2-alcohol;
3-{2-[4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } benzonitrile;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyridin-4-yl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyridin-3-yl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyrimidine-5-base-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[5-(4-dimethylamino phenyl)-1H-indole-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(7-fluoro-4-Methyl-1H-indole-2-ylmethyl)-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methylpent-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-5-formonitrile HCN;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-indole-6-formonitrile HCN;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(4-Methyl-1H-indole-2-ylmethyl) penta-2-alcohol;
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-formonitrile HCN;
2-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-4-formonitrile HCN;
2-(4-ethyl-1H-indole-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(2-isopropyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-2-(2-isopropyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] phenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
4-fluoro-2-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) butyl] phenol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(2-chloro-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(2-phenyl-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-aminomethyl phenyl)-4-methyl-2-(2-pyrrolidine-1-base-5H-pyrrolo-[3,2-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
2-(5-ethyoxyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-trifluoromethyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(4-methoxyl biphenyl-3-yl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methylpent-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methyl-4-phenyl penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(4-methoxyl biphenyl-3-yl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
4-bromo-2-[3-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl] phenol;
2-[3-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
2-[2-hydroxyl-4-(4-xenol-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methyl-4-(5-phenyl-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
2-[2-hydroxyl-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-alcohol;
Trifluoromethanesulfonic acid 2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-base ester;
1,1,1-three fluoro-4-(3-fluorophenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-phenyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(3-fluorophenyl)-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-2-(5-isopropoxy-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methyl-4-phenyl penta-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(3-morpholine-4-ylmethyl phenyl)-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-2-(4-methoxyl group-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
2-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1, the 4-pyrrolin is [3,2-b] pyridine-5-ketone also;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(2-methoxyl group-5-thiene-3-yl-phenyl)-4-methylpent-2-alcohol;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
4-(5-bromo-2-methoxyphenyl)-2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(7H-pyrrolo-[2,3-d] pyrimidine-6-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-naphthalene-1-base phenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(2 '-chloro-4-methoxyl biphenyl-3-yl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methylpent-2-alcohol;
4 '-methoxyl group-3 '-[4,4,4-three fluoro-3-hydroxyls-1,1-dimethyl-3-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) butyl] biphenyl-2-formonitrile HCN;
4-(2 '-chloro-4-methoxyl biphenyl-3-yl)-1,1,1-three fluoro-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[3-(3-dimethylamino methyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-(3-chloro-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-methyl-4-(5-methyl mercapto-2,3-Dihydrobenzofuranes-7-yl)-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol; With
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol.
After tested chemical compound or its tautomer, prodrug, solvate or the salt of following general formula of the present invention (IB), and in one or more above-mentioned detections, these chemical compounds show the activity as the agonist of glucocorticoid receptor function.
2-cyclopropyl-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-cyclopropyl-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-cyclopropyl-4-methyl isophthalic acid-(1H-pyrrolo-[3,2-c] pyridine-2-yl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-(5-fluoro-2-methoxyphenyl)-2,5,5-trimethyl-4-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) heptan-4-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
1,1-two fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-methoxyphenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
2-(1-fluorine cyclopropyl)-4-(5-fluoro-2-methoxyphenyl)-4-methyl isophthalic acid-(1H-pyrrolo-[2,3-c] pyridine-2-yl) penta-2-alcohol;
2-[4,4-two fluoro-3-hydroxyls-1,1-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) butyl]-the 4-fluorophenol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-pyrrolo-[3,2-b] pyridine-1-ylmethyl penta-2-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,2,5-trimethyl-3-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2,5-dimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,2,5-trimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
5-(5-fluoro-2-aminomethyl phenyl)-2,5-dimethyl-3-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) oneself-3-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1-two fluoro-4-methyl-2-(6-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol; With
2-[2-difluoromethyl-2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl amyl]-4-Methyl-1H-indole-6-formonitrile HCN,
After tested chemical compound or its tautomer, prodrug, solvate or the salt of following general formula of the present invention (IC), and in one or more above-mentioned detections, these chemical compounds show the activity as the agonist of glucocorticoid receptor function.
1-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group-1,5,6,7-tetrahydro indole-4-ketone;
1-[4-(2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[4-(5-fluoro-2-aminomethyl phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxy-4-methyl-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl)-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-hydroxyl-5-pyrimidine-5-base phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone;
1-[2-hydroxyl-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone; With
1-[2-hydroxyl-4-(2-hydroxyl-5-pyridin-3-yl phenyl)-4-Methyl-2-trifluoromethyl amyl group]-1,5,6,7-tetrahydro indole-4-ketone,
After tested chemical compound or its tautomer, prodrug, solvate or the salt of following general formula of the present invention (ID), and in one or more above-mentioned detections, these chemical compounds show the activity as the agonist of glucocorticoid receptor function.
5,5,5-three fluoro-2-methyl-2-phenyl-4-quinolyl-4 methylpentane-1,4-glycol.
The present invention also provides the method for regulating glucocorticoid receptor function in the patient, comprises patient's administration The compounds of this invention.If regulating the purpose of glucocorticoid receptor function in the patient is the treatment morbid state or the state of an illness, administration preferably includes the of the present invention pharmaceutically acceptable chemical compound to patient's drug treatment or medicinal effective dose so.If (for example regulate the purpose of glucocorticoid receptor function in the patient and be diagnosis or other purpose, determine that the patient is to the suitability of treatment or to the susceptiveness of the various inferior therapeutic doses of The compounds of this invention), administration comprises the chemical compound of the present invention of effective dose so, that is, obtain to regulate expected effect or the required amount of degree.
7. suppressing from osteoblast is to generate osteoblast the MG-63
The previous day of using, human osteosarcoma MG-63 cell (ATCC Cat.No.CRL-1427) is placed on the 99%D-MEM/F-12 (Gibco-Invitrogen of 200 μ L, Cat.No.11039-021) (be supplemented with 1% penicillin and streptomycin (Gibco-Invitrogen, Cat.No.15140-122), 10 μ g/mL Vitamin C (Sigma, Cat.No.A-4544) and the hyclone (HyClone of 1% charcoal filtering, Cat.No.SH30068.02)) on 96 orifice plates in the culture medium, 20,000 cells in every hole.Second day, replace the hole with fresh culture.With vitamin D (Sigma Cat.No.D1530) handles cell, to ultimate density be 1nM, and be 10 with concentration
-6M to 10
-9The compound treatment of M, the cumulative volume in every hole are 200 μ L.Replica.The background control wells does not receive vitamin D or chemical compound.Vitamin D is only accepted in positive reference hole, does not receive described chemical compound, and is expressed as the maximum (or 100%) that osteocyte produces.37 ℃ of culture plates 48 hours, collect supernatant when finishing cultivating.According to the description of manufacturer, (Zymed Cat.No.99-0054), determines osteoblastic amount in the supernatant to use Glype osteoblast ELISA test kit.Test compounds is expressed as percentage ratio with respect to positive reference to osteoblastic inhibition.The IC of test compounds
50Value is available from non-linear curve fitting.
The chemical compound of following general formula (IA) or its tautomer, prodrug, solvate or salt suppress osteoblastic vitamin D stimulates generation:
2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-6-formonitrile HCN;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(1H-pyrrolo-[2,3-d] pyridazine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-(4,6-dimethyl-1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl)-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-2-(5-methoxyl group-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-Methyl-2-trifluoromethyl amyl group]-4-Methyl-1H-indole-6-formonitrile HCN;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid amide;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-carboxylic acid Cyanomethyl amides;
2-[4-(5-bromo-2,3-Dihydrobenzofuranes-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl amyl group]-1H-indole-5-yl } pyrrolidine-1-base ketone;
1,1,1-three fluoro-4,4-dimethyl-5-phenyl-2-quinolyl-4 methylpent-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-mesyl-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methylpent-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-2-[5-(ethylmethylamino)-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl]-1,1,1-three fluoro-4-methylpent-2-alcohol;
4-(3-bromophenyl)-1,1,1-three fluoro-4-methyl-2-(5-morpholine-4-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(4-methyl isophthalic acid H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-methyl-2-(3-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4-(5-pyrimidine-5-base-2,3-Dihydrobenzofuranes-7-yl) penta-2-alcohol;
2-[3-(5-dimethylamino-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl)-4,4,4-three fluoro-3-hydroxyls-1,1-dimethylbutyl]-the 4-fluorophenol;
4-(3-chlorphenyl)-1,1,1-three fluoro-4-methyl-2-(1H-pyrrolo-[3,2-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2,3-Dihydrobenzofuranes-7-yl)-4-methyl-2-(5-pyridin-3-yl-1H-indole-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyrimidine-5-base phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
1,1,1-three fluoro-4-(2-methoxyl group-5-pyridin-3-yl phenyl)-4-methyl-2-(5-piperidines-1-base-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol;
2-[2-hydroxyl-4-(4-xenol-3-yl)-4-Methyl-2-trifluoromethyl amyl group]-1H-pyrrolo-[2,3-c] pyridine-5-alcohol;
4-(5-chloro-2,3-Dihydrobenzofuranes-7-yl)-1,1,1-three fluoro-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol; With
1,1,1-three fluoro-4-(5-fluoro-2-aminomethyl phenyl)-4-methyl-2-(5-phenyl-1H-pyrrolo-[2,3-c] pyridine-2-ylmethyl) penta-2-alcohol.
The treatment using method
As already pointed out, chemical compound of the present invention is useful to regulating glucocorticoid receptor function.When regulating like this, these chemical compounds are in the mediation of treatment glucocorticoid receptor function or benefit from the morbid state of regulating glucocorticoid receptor function and the state of an illness and have therapeutic use.
Because chemical compound of the present invention can be regulated glucocorticoid receptor function, so they are used for antiinflammatory, anti-allergy, immunosuppressant and antiproliferative activity, and they can be used as the pharmaceutical compositions of medicine, particularly the following stated in the patient, to be used for the treatment of the morbid state and the state of an illness.
Agonist compound of the present invention is used in and is used as the following morbid state of inflammation, allergy or breeding or the medicine of indication followed of treatment among the patient, described process:
(i) pneumonopathy: the chronic obstructive pulmonary disease of any root is specially bronchial asthma and chronic obstructive pulmonary disease (COPD); Adult's RD syndrome (ARDS); Bronchiectasis; The bronchitis of any root; Various forms of restrictive lung diseases are specially allergic pulmonary alveolitis; Various forms of pulmonary edema are specially the toxicity pulmonary edema; The interstitial lung disease of various forms of any roots, for example radiation pneumonia; With sarcoidosis and granulomatosis (granulomatose), be specially Schaumann benign lymphogranuloma.
(ii) rheumatism or autoimmune disease or joint disease: various forms of rheumatism are specially rheumatoid arthritis, acute rheumatic fever and polymyalgia rheumatica; Reactive arthritis; Rheumatic soft tissue diseases; The inflammatory soft tissue diseases of other root; Arthritic symptom in the degeneration joint disease (arthroses); Traumatic arthritis; The collagenosis of any root, for example systemic lupus erythematosus (sle), scleroderma, polymyositis, dermatomyositis, Sjogren syndrome (Sj gren syndrome), Still disease (Still disease) and Felty syndrome (Felty syndrome);
(iii) allergic disease: various forms of atopic reactions, for example vasodilation; Hay Fever; Insect bite; Atopic reaction to medicine, blood derivatives, contrast medium etc.; Anaphylactic shock (anaphylaxis); Urticaria; Vasodilation and contact dermatitis;
(iv) vasculitis: PAN, polyarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis and erythema nodosum;
(v) dermatosis: atopic dermatitis, particularly child's atopic dermatitis; Psoriasis; Pityriasis rubra pilaris; By various noxas, the erythema disease that triggers such as ray, chemical substance and burn for example; The bulla disease; Lichen sample complex disease; Pruritus (for example, allergia generates); Seborrheic dermatitis; Acne erythematosa; Pemphigus vulgaris; Hebra's disease; Balanitis; Vulvitis; Alopecia, for example appearance of alopecia areata; And cutaneous T cell lymphoma;
(vi) nephropathy: nephrotic syndrome; With various nephritis, for example glomerulonephritis;
(vii) hepatopathy: acute hepatocyte disintegrate; The acute hepatitis of various origins, for example virus, toxicity, drug-induced; With chronic aggressivity hepatitis and/or Chronic Intermittent hepatitis;
(viii) gastroenteropathy: inflammatory bowel, for example segmental enteritis (Crohn disease), ulcerative colitis; Gastritis; Reflux esophagitis (reflux oesophagitis); With the gastroenteritis of other root, for example nontropical sprue;
(ix) rectum disease: anal eczema; Testudinis is split; Hemorrhoid; With spy's property sent out proctitis;
(x) oculopathy: allergia keratitis, uveitis or iritis; Conjunctivitis; Blepharitis; Neuritis's optic nerve (neuritis nervi optici); Choroiditis; And sympathetic ophthalmia;
(xi) disease in ear, nose and larynx (ENT) zone: allergic rhinitis or Hay Fever; External otitis is for example caused by contact eczema, infection etc.; Otitis media;
(xii) nervous system disease: the cerebral edema that cerebral edema, particularly tumor are relevant; Multiple sclerosis; Acute encephalomyelitis; Meningitis; Acute spinal cord injury; Apoplexy; With various forms of epilepsy, for example salaam convulsion;
(xiii) hematopathy: acquired hemolytic anemia; And idiopathic thrombocytopenia;
(xiv) tumor disease: acute lymphoblastic leukemia; Malignant lymphoma; Lymphogranulomatosis; Lymphosarcoma; General transferring enzyme among general transferring enzyme (the extensive metastase), particularly breast carcinoma, bronchogenic carcinoma and carcinoma of prostate;
(xv) endocrine disease: endocrine ophthalmopathy; Endocrine orbitopathia; Thyroid crisis; Thyroiditis de Quervain; Chronic lymphocytic thyroiditis; Morbus Basedow; Subacute thyroiditis; Struma lymphomatosa and grave disease (Grave disease);
(xvi) organ and tissue transplantation and graft versus host disease;
(xvii) Xiu Ke serious state, for example septic shock, anaphylactic shock and systemic inflammatory response syndrome (SIRS);
(xviii) alternative medicine in the following situation: congenital primary adrenal insufficiency, for example adrenogenital syndrome; The day after tomorrow primary adrenal insufficiency, for example addison disease (Addison disease), autoimmune adrenalitis, infect back (post-infection), tumor, transferring enzyme etc.; Congenital Secondary cases adrenal insufficiency, for example congenital hypopituitarism; With the Secondary cases adrenal insufficiency day after tomorrow, for example infect back, tumor, transferring enzyme etc.;
(xix) pain of inflammation formation, for example lumbago; With
(xx) various other morbid states or the state of an illness comprise type i diabetes (insulin-dependent diabetes), osteoarthritis, Guillain-Barre syndrome, restenosis behind the percutaneous transluminal coronary angioplasty, Alzheimer, acute pain and chronic pain, arteriosclerosis, reperfusion injury, bone resorption disease, congestive heart failure, myocardial infarction, the hot injury, posttraumatic multiple organ injury, acute purulent meningitis, necrotizing enterocolitis and hemodialysis related syndromes, leukocyte separates and the granulocyte infusion.
In addition, chemical compound of the present invention do not mention more than can be used for treating with, with maybe will with any other morbid state of synthetic glucocorticoid treatment or the state of an illness (for example, referring to H.J.Hatz,
Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien[Glucocorticoids:Immunological Fundamentals, Pharmacology, and Therapeutic Guidelines], Stuttgart:Verlagsgesellschaft mbH, 1998, at this it all is incorporated herein by reference).Most or whole indications in above-mentioned (i) to (xx) are described in detail in H.J.Hatz,
Glucocorticoide:Immunologische Grundlagen, Pharmakologie und TherapierichtlinienIn.In addition, chemical compound of the present invention also can be used for treating except that above-mentioned and enumerates or mention or disease (comprise in the background technology of the present invention those) of discussing herein.
Agonist compounds of the present invention no matter be complete antagonist or partial antagonist, is used in the medicine that is used as following morbid state of treatment or indication among the patient, and without limits: type ii diabetes (noninsulindependent diabetes); Obesity; Cardiovascular disease; Hypertension; Arteriosclerosis; Nervous system disease, for example psychosis and depression; Adrenal gland and pituitary tumor; Glaucoma; With Cushing syndrome (Cushing syndrome) based on ACTH secreting tumor (as pituitary adenoma).Particularly, chemical compound of the present invention be used for the treatment of obesity with not relevant all morbid states and the indication of fatty acid metabolism of modulated, for example hypertension, arteriosclerosis and other cardiovascular disease.Use should antagonism carbohydrate metabolism and fatty acid metabolism as the The compounds of this invention of GR antagonist.Therefore, agonist compounds of the present invention is used for the treatment of metabolic all morbid states of the carbohydrate, protein and the lipid that relate to increase and the state of an illness, and comprises and cause decomposing the metabolic morbid state and the state of an illness as muscle fragility (as the example of protein metabolism) etc.
The diagnosis using method
Chemical compound of the present invention also can be used for diagnostic application and is used for commercial and other purpose as competition in conjunction with the reference material that detects.In these purposes, chemical compound of the present invention can use with they forms own, perhaps they can be by connecting modifications such as radiosiotope, luminous and fluorescent labeling, thereby obtain radiosiotope, luminous or fluorescent probe, just as known for those skilled in the art, these are summarized in
Handbook of Fluorescent Probes and Research Chemicals, 6thEdition, R.P.Haugland (ed.), Eugene:Molecular Probes, 1996;
Fluorescence and Luminescence Probes for Biological Activity, W.T.Mason (ed.), San Diego:Academic Press, 1993;
Receptor-Ligand Interaction, A Practical Approach, E.C.Hulme (ed.), Oxford:IRL Press in 1992, all introduces these documents at this, as a reference.
Common administration and pharmaceutical composition
When the medicine, chemical compound of the present invention is normally with the form administration of pharmaceutical composition.This compositions can prepare by the drug world known method, and this compositions comprises at least a chemical compound of the present invention.Chemical compound of the present invention also can be individually dosed or with the auxiliary agent administration of the stability that strengthens The compounds of this invention, promotion in certain embodiments contains the administration of their pharmaceutical composition, improved dissolving or dispersion are provided, improve and suppress active, auxiliary treatment etc. is provided.Chemical compound of the present invention also can use independently, perhaps uses with other active substance according to the present invention, also randomly unites use with other pharmacological active substance.Usually, the The compounds of this invention of drug treatment or medicinal effective dose, but be diagnosis or other purpose, but the less amount of administration.
Especially, chemical compound of the present invention is used in combination with glucocorticoid or 17-hydroxy-11-dehydrocorticosterone.As already pointed out, the standard treatments of various immunity and inflammatory disorder comprises the administration 17-hydroxy-11-dehydrocorticosterone, 17-hydroxy-11-dehydrocorticosterone have the ability that suppresses immunne response and inflammatory response (A.P.Truhan et al., Annals ofAllergy, 1989,
62, pp.375-391; J.D.Baxter, Hospital Practice, 1992,
27, pp.111-134; R.P.Kimberly, Curr.Opin.Rheumatol., 1992,
4, pp.325-331; M.H.Weisman, Curr.Opin.Rheumatol., 1995,
7, pp.183-190; W.Sterry, Arch.Dermatol.Res., 1992,
284(Suppl.), pp.S27-S29).Although effectively, the use of 17-hydroxy-11-dehydrocorticosterone is relevant with multiple side effect in the treatment, from the extremely fatal side effect of possibility of side effect of gentleness, particularly under the situation that the steroid class of prolongation and/or high dose is used.Therefore, can use the method and composition (being called " the steroid class is saved effect ") of the 17-hydroxy-11-dehydrocorticosterone of low effective dose extremely to need to avoiding unwanted side effect.Chemical compound of the present invention allows to use lower dosage and less frequency administration glucocorticoid or 17-hydroxy-11-dehydrocorticosterone simultaneously by obtaining required curative effect, thereby provides this steroid class to save effect.
Can use the mode of any acceptable administration medicine compositions, the chemical compound of the present invention or the suitable pharmaceutical compositions of the pure form of administration.Therefore, administration can be, for example oral administration, buccally administration are (for example, sublingual administration), nose administration, parenteral, topical, percutaneous dosing, through the form of sheath administration (vaginally) or rectally solid, semisolid, freeze-dried powder or liquid dosage form, for example tablet, suppository, pill, soft elasticity or hard gelatine capsule, powder, solution, suspending agent or gaseous solvents etc. are preferably the unit dosage forms that is applicable to the accurate dosage of simple administration.Pharmaceutical composition generally includes conventional pharmaceutical carrier or excipient and as the chemical compound of the present invention of active agents, comprises other medicament, medicine, carrier, auxiliary agent, diluent, vehicle or their combination in addition.The method that this pharmaceutically acceptable excipient, carrier or additive and preparation are used for various patterns or administration is known to those skilled in the art.This state of the art by this area confirms, for example
Remington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams ﹠amp; Wilkins, 2000;
Handbook of Pharmaceutical Additives, Michael ﹠amp; Irene Ash (eds.), Gower, 1995;
Handbook of Pharmaceutical Excipients, A.H.Kibbe (ed.), American Pharmaceutical Ass ' n, 2000; H.C.Anseland N.G.Popovish,
Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger, 1990; At this every piece of document integral body is introduced, to describe the state of the art of this area better.
Desired as those skilled in the art, will select to be used for the form (for example, salt) of the The compounds of this invention of concrete pharmaceutical preparation, these forms have the required appropriate physical characteristics of effective preparation (for example, water solublity).
The pharmaceutical composition that is applicable to buccally administration (sublingual administration) comprises lozenge and pastille, lozenge comprises the The compounds of this invention that is arranged in seasoning matrix (being generally sucrose and arabic gum or tragakanta), pastille comprises the The compounds of this invention that is positioned in the inertial base (for example, gelatin and glycerol or sucrose and arabic gum).
The pharmaceutical composition that is applicable to parenteral comprises the sterilized water preparation of The compounds of this invention.These preparations are intravenously administrable preferably, but administration also can be carried out by means of subcutaneous injection, intramuscular injection or intradermal injection.Injectable pharmaceutical preparation is usually based on saline, oily suspensions or other injectable carrier known in the art of injectable Sterile Saline, phosphate-buffered, and makes aseptic and wait to blood usually.Therefore, injectable pharmaceutical preparation can be provided as the solution of the sterile injectable in nontoxic injection acceptable diluent or solvent or the form of suspension, described diluent or solvent comprise 1,3-butanediol, water, Ringer's solution, etc. open sodium chloride solution, fixed oil such as synthetic monoglyceride or diglyceride for example, fatty acid such as oleic acid etc. for example.According to known technology, use suitable dispersion or sedimentation agent and suspending agent, prepare this injectable pharmaceutical preparation.Injectable compositions contains 0.1 to 5%w/w The compounds of this invention usually.
The solid dosage forms that is used for this chemical compound of oral administration comprises capsule, tablet, nine doses, powder or granule.For this oral administration, can form the pharmaceutically acceptable compositions of the The compounds of this invention that contains one or more by mixing any excipient commonly used, described excipient is the mannitol, lactose, starch, pregelatinized starch, magnesium stearate, saccharin sodium, Talcum, cellulose ether derivative, glucose, gelatin, sucrose, citrate (salt), propyl gallate etc. of pharmaceutical grade for example.This solid pharmaceutical preparation can comprise preparation well known in the art, medicine is prolonged or be delivered to intestines and stomach constantly with the mechanism by any number, these mechanism comprise, but be not limited to from responsive release of pH of the dosage form that changes based on the small intestinal pH value, tablet or capsular slow erosion, based on the reservation under one's belt of preparation physical property, dosage form is to the bioadhesion of the mucosal surface (mucosal lining) of intestinal, and perhaps the enzyme of active drug from dosage form discharges.
The liquid dosage form that is used for this chemical compound of oral administration comprises emulsion, microemulsion, solution, suspension, syrup and elixir, randomly contains pharmaceutical auxiliary agent in carrier, for example, water, saline, moisture dextrose, glycerol, ethanol etc.These compositionss also can contain other auxiliary agent, for example wetting agent, emulsifying agent, suspending agent, sweeting agent, flavoring agent and aromatic.
The topical formulations of chemical compound comprises ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant, eye ointment, eye drop or [, dipping dressing (impregnated dressing) and gaseous solvents, and can comprise suitable conventional additives, for example antiseptic, the solvent of ancillary drug infiltration and the emollient in ointment and the cream.Consider that based on conventional therapy local application can be once a day or repeatedly.In addition, the preferred chemical compound of the present invention can be by the suitable intranasal vehicle intranasal administration of local use.Preparation also can contain compatible conventional carrier, for example cream or ointment base, and use ethanol or oleyl alcohol for lotion.The amount that this carrier exists be preparation about 1% up to about 98%, more commonly, they constitute about 80% of preparation at the most.
Percutaneous dosing also is fine.The pharmaceutical composition that is applicable to percutaneous dosing shows as discrete fragment (discrete patches), changes these sheets, and its maintenance is closely contacted with the epidermis of receptor for a long time.For with dermal delivery system form administration, the dosed administration by dosage regimen certainly should be for continuously, rather than off and on.This fragment suitably contains chemical compound of the present invention, and this chemical compound dissolves and/or is dispersed in the adhesive randomly in buffered aqueous solution, or is dispersed in the polymer.The suitable concn of reactive compound is about 1% to 35%, is preferably about 3% to 15%.
For inhalation, expediently with spray form, never need the pump formula sprayer unit of propelling gas or from use suitable compression wrap (pressurizedpack) of pushing agent (for example dichlorodifluoromethane, isceon, dichlorotetra-fluoroethane, tetrafluoroethane, pentafluoropropane, carbon dioxide or other suitable gas) or aerosol apparatus, send The compounds of this invention.In any case, can quantitatively send, thereby determine the spray dosage unit, make that (metered doseinhaler MDI) is used for can reproduce and controllable mode administration chemical compound of the present invention the metered dose inhaler that generates by valve is provided.This inhaler, aerosol apparatus or atomizer arrangement are known in the prior art, for example in PCT International Application No. WO 97/12687 (particularly Fig. 6 of this application, this is the basis of commercial RESPIMAT aerosol apparatus); WO 94/07607; WO 97/12683; With WO 97/20590, each patent integral body is incorporated herein by reference at this.
Rectally can utilize the suppository of unit dose to carry out, in suppository, this chemical compound mixes with low-melting water solublity or water insoluble solid (for example fatty acid ester of the mixture of fat, cupu oil, glycerin gelatine, hydrogenated vegetable oil, various molecular weight polyethylene glycol or Polyethylene Glycol etc.).Reactive compound is generally microcomponent, is generally about 0.05 to 10% weight, and remaining is basic components.
In all aforementioned pharmaceutical compositions, chemical compound of the present invention is prepared with acceptable carrier or excipient.On the meaning compatible with other composition of compositions, the carrier of use or excipient must be acceptable certainly, and must be harmless to the patient.Carrier or excipient can be solid or liquid, perhaps both, and preferred and chemical compound of the present invention is mixed with the compositions of unit dose, for example can contain the tablet of 0.05% to 95% weight active compound.This carrier or excipient comprise inert filler or diluent, binding agent, lubricant, disintegrating agent, dissolving blocker (solution retardant), absorb accelerator, absorbent and coloring agent.Suitable bonding comprises starch, gelatin, natural sugar, for example glucose or beta lactose; The corn sweetener; Natural and rubber polymer, for example arabic gum, tragakanta or sodium alginate, carboxymethyl cellulose, Polyethylene Glycol, wax etc.Lubricant comprises enuatrol, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc.Disintegrating agent comprises starch, methylcellulose, agar, bentonite, xanthan gum etc.
Usually, treat effective every day dosage and be about 0.001mg The compounds of this invention in about 15mg/ kg body weight/sky extremely; Be preferably about 0.1mg to about 10mg/ kg body weight/sky; Most preferably be about 0.1mg to about 1.5mg/ kg body weight/sky.For example, for people's administration of 70 kilograms, dosage range is the The compounds of this invention of about 0.07mg to about 1050mg/ days, is preferably about 7.0mg to about 700mg/ days, most preferably is about 7.0mg to about 105mg/ days.For determining best dosage level and mode, can require routine dose optimization to a certain degree.
Pharmaceutically suitable carrier and excipient comprise all aforementioned additive etc.
Pharmaceutical preparation embodiment
| A. tablet | |
| Component | Every content (mg) |
| Active substance | 100 |
| Lactose | 140 |
| Corn starch | 240 |
| Polyvinylpyrrolidone | 15 |
| Magnesium stearate | 5 |
| Amount to | 500 |
Pulverizing active substance, lactose and a part of corn starch are mixed.The screening mixture is used the aqueous solution moistening of polyvinylpyrrolidone then, mediates, and wet granulation is also dry.Screen corn starch and the magnesium stearate of this granule, remnants, and be blended together.Pressing mixt generates suitable shape and big or small tablet.
| B. tablet | |
| Component | Every content (mg) |
| Active substance | 80 |
| Lactose | 55 |
| Corn starch | 190 |
| Polyvinylpyrrolidone | 15 |
| Magnesium stearate | 2 |
| Microcrystalline Cellulose | 35 |
| Carboxymethyl starch sodium | 23 |
| Amount to | 400 |
Pulverizing active substance, some corn starchs, lactose, microcrystalline Cellulose and polyvinylpyrrolidone are mixed, the screening mixture, and with remaining corn starch and water processing, form granule, dry then and screening.Add carboxymethyl starch sodium and magnesium stearate, and mix, mixture is pressed into the tablet of suitable size.
| C. coated tablet | |
| Component | Every content (mg) |
| Active substance | 5 |
| Lactose | 30 |
| Corn starch | 41.5 |
| Polyvinylpyrrolidone | 3 |
| Magnesium stearate | 0.5 |
| Amount to | 90 |
Fully mixed active material, corn starch, lactose and polyvinylpyrrolidone are used water-wet.Push the sieve of wet material,, make granule pass through identical sieve then in about 45 ℃ of dryings by the 1mm mesh size.After sneaking into magnesium stearate, the compacting diameter is the convex tablet core of 6mm in the tablet maker.In known manner, make the tablet core of generation like this be coated with the coating of forming by sugar and Talcum basically.The coated tablet of finishing wax glazing.
| D. capsule | |
| Component | Every capsular content (mg) |
| Active substance | 50 |
| Corn starch | 268.5 |
| Magnesium stearate | 1.5 |
| Amount to | 320 |
Mix this material and corn starch, and use water-wet.The wet material of screening, and dry.Screen dried granules, and mix with magnesium stearate.The mixture of finishing is filled in the gelatine capsule of 1 grade of hardness.
| E. injection solution | |
| Component | The content of every injection |
| Active substance | 50mg |
| Sodium chloride | 50mg |
| Water for injection | 5mL |
It is in 5.5 to 6.5 the water for the water of self pH value or optional pH that active substance is dissolved in pH value, adds sodium chloride, and its grade is opened.Filter the solution that obtains, make it not have pyrogen (pyrogens), under aseptic condition, will leach thing and be transferred in the injection (ampoules), then sterilization and melting sealed.Injection contains 5mg, 25mg and 50mg active substance.
| F. suppository | |
| Component | The content of every suppository (mg) |
| Active substance | 50 |
| Hard fat | 1650 |
| Amount to | 1700 |
Melt stearic fat.At 40 ℃, within it with the active substance homodisperse pulverized.This mixture is cooled to 38 ℃, and is poured onto in the refrigerated slightly suppository mould.
| G. measure gaseous solvents | |
| Component | Content |
| Active substance | 0.005 |
| Sorbitan trioleate | 0.1 |
| Fluoro trichloromethane and dichlorodifluoromethane (2: 3) | To 100 |
Suspension is transferred in the conventional gaseous solvents solvent with metering valve.Preferably, 50 μ L float are sent in every spray.If desired, the also active substance of measurable higher metering (for example 0.02% weight).
| H. suck and use powder | |
| Component | Content |
| Active substance | 1.0mg |
| The lactose monohydrate | To 25mg |
| I. suck and use powder | |
| Component | Content |
| Active substance | 2.0mg |
| The lactose monohydrate | To 25mg |
| J. suck and use powder | |
| Component | Content |
| Active substance | 1.0mg |
| The lactose monohydrate | To 5mg |
| K. suck and use powder | |
| Component | Content |
| Active substance | 2.0mg |
| The lactose monohydrate | To 5mg |
In embodiment H, I, J and K,, prepare the suction powder in common mode by independent composition is mixed.
Claims (46)
1. the chemical compound of general formula (IA) or its tautomer, prodrug, solvate or salt
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro, or amino, and wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements, or urea groups, and wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Perhaps C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be hydrogen or C independently of one another
1-C
5Alkyl, or R
2And R
3Form C with their common carbon atoms that connects
3-C
8The spirocyclane basic ring;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is optional separately independently by 1-3 substituent group replacement,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen, amino or oxo; With
R
5Be the optional heteroaryl that is replaced by 1-3 substituent group independently,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5The alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, heterocyclic radical carbonyl, aroyl, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino, and wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Perhaps C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, acyl group, C
1-C
3Silicon alkoxyl, C
1-C
5Alkoxy carbonyl group, carboxyl, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical, or amino, and wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces, or trifluoromethyl.
2. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, Er hydrogen benzoxazolyl, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Optional methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group or the amino substituent group of being selected from independently of each substituent group replace;
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl, or R
2And R
3Form C with their common carbon atoms that connects
3-C
6The spirocyclane basic ring;
R
4Be CH
2And
R
5Be imidazole radicals, pyridine radicals, indyl, the azaindole base, two azaindole bases, benzofuranyl, the furo pyridine radicals, the furo pyrimidine radicals, the imidazopyrimidine base, the Imidazopyridazine base, the Imidazopyrazines base, benzothienyl, the thienopyridine base, the Thienopyrimidine base, thieno pyridazinyl benzoxazolyl oxazole and pyridine radicals, benzothiazolyl, thiazole and pyridine radicals, benzimidazolyl, imidazopyridyl, the imidazopyrimidine base, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, hydroxyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, oxo, cyano group, trifluoromethyl or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, cyano group, or amino, the wherein optional C independently of nitrogen-atoms
1-C
5The alkyl or aryl list replaces or two replacements.
3. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano group independently, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3Be methyl independently of one another, or R
2And R
3Form the spirocyclane basic ring with their common carbon atoms that connects;
R
4Be CH
2And
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group independently, or trifluoromethyl, hydroxyl, cyano group, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements.
4. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein R
2And R
3Form C with their common carbon atoms that connects
3-C
8The spirocyclane basic ring.
5. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein R
2And R
3Be hydrogen or C independently of one another
1-C
5Alkyl.
6. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone; With
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl.
7. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement.
8. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, Er hydrogen benzoxazolyl, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, aryl, heteroaryl, halogen, hydroxyl, carboxyl, cyano group, heterocyclic radical, trifluoromethyl, trifluoromethoxy, nitro, amino-sulfonyl, dialkyl amino sulfonyl, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1 or 2 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, morpholinyl or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements;
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl, or R
2And R
3Form C with their common carbon atoms that connects
3-C
6The spirocyclane basic ring;
R
4Be CH
2And
R
5Be imidazole radicals, pyridine radicals, indyl, indazolyl, the azaindole base, two azaindole bases, benzofuranyl, the furo pyridine radicals, the furo pyrimidine radicals, the imidazopyrimidine base, the Imidazopyridazine base, the Imidazopyrazines base, benzothienyl, the thienopyridine base, the Thienopyrimidine base, thieno pyridazinyl benzoxazolyl oxazole and pyridine radicals, benzothiazolyl, thiazole and pyridine radicals, benzimidazolyl, imidazopyridyl, quinolyl or isoquinolyl base, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, heteroaryl, heterocyclic radical, acyl group, dialkyl amino sulfonyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, hydroxyl, oxo, fluorine, chlorine, bromine, cyano group, trifluoromethyl, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Perhaps urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional replaced by 1 or 2 substituent group independently, described substituent group is selected from methyl, methoxyl group, fluorine, chlorine, bromine, oxo, trifluoromethyl, hydroxyl, cyano group, morpholinyl, pyrrolidinyl or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements.
9. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, benzo dioxy cyclopenta, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy, morpholinyl methyl, dimethylaminomethyl, amino-sulfonyl, dimethylamino sulfonyl, phenyl, pyrimidine radicals, pyridine radicals, thienyl, naphthyl, morpholinyl, piperidyl, cyano group or C independently
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R wherein
1Each substituent group substituent group of being selected from cyano group, chlorine, bromine or fluorine independently replace,
R
2And R
3Be methyl or ethyl independently of one another, or R
2And R
3Form the spirocyclane basic ring with their common carbon atoms that connects;
R
4Be CH
2And
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, thieno pyridazinyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be methyl, phenyl, methoxyl group, ethyoxyl, isopropoxy, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino carbonyl, morpholinyl carbonyl, morpholinyl, piperidyl, phenoxy group, pyrrolidinyl, acetyl group, valeryl, ethyl carbonyl, isopropyl carbonyl, pyridine radicals, pyrimidine radicals, trifluoromethyl, fluorine, chlorine, bromine, hydroxyl, cyano group independently; or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements, or trifluoromethyl,
R wherein
5Optional 1 or 2 substituent group that is selected from cyano group, halogen, methyl, dimethylamino, morpholinyl, pyrrolidinyl or piperidyl independently of each substituent group replace.
10. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, aryl, heteroaryl, heterocyclic radical, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R
2And R
3Be hydrogen or C independently of one another
1-C
3Alkyl.
11. the general formula of claim 1 (IA) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, thieno pyridazinyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement.
12. a pharmaceutical composition comprises among the claim 1-11 of effective dose each chemical compound or its tautomer, prodrug, solvate or salt and pharmaceutically acceptable excipient or carrier.
13. the chemical compound of general formula (IB) or its tautomer, prodrug, solvate or salt,
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be C independently of one another
1-C
5Alkyl;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is chosen wantonly separately and is replaced by the 1-3 substituent group independently,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen, amino or oxo;
R
5Be the optional heteroaryl that is replaced by 1-3 substituent group independently,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical, or amino, and wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or trifluoromethyl; With
R
6Be hydrogen, C
1-C
8Alkyl, C
2-C
8Alkenyl, C
2-C
8Alkynes base, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, carbocyclic ring-C
1-C
8Alkyl, aryl-C
1-C
8Alkyl, aryl-C
1-C
8Haloalkyl, heterocyclic radical-C
1-C
8Alkyl, carboxyl, alkoxy carbonyl group, heteroaryl-C
1-C
8Alkyl, carbocyclic ring-C
2-C
8Alkenyl, aryl-C
2-C
8Alkenyl, heterocyclic radical-C
2-C
8Alkenyl or heteroaryl-C
2-C
8Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, phenyl, C
1-C
5Alkoxyl, phenoxy group, C
1-C
5Alkanoyl, aroyl, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
6It or not trifluoromethyl.
14. the general formula of claim 13 (IB) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, dihydro benzo furyl, benzofuranyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional be selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino independently (wherein nitrogen-atoms be optional independently by C
1-C
5The alkyl or aryl list replaces or two replaces) in substituent group replace;
R
2And R
3Be C independently of one another
1-C
3Alkyl;
R
4Be CH
2
R
5Be pyridine radicals, indyl, azaindole base, benzofuranyl, furo pyridine radicals, imidazopyridyl, imidazopyrimidine base, Imidazopyridazine base, Imidazopyrazines base, benzothienyl, thienopyridine base, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, hydroxyl, oxo, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone.
15. the general formula of claim 13 (IB) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, pyridine radicals, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group independently, or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino carbonyl, morpholinyl carbonyl, hydroxyl, oxo, fluorine, chlorine, cyano group independently, or trifluoromethyl; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently.
16. the general formula of claim 13 (IB) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone; With
R
2And R
3Be C independently of one another
1-C
3Alkyl.
17. the general formula of claim 13 (IB) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group independently, or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, pyridine radicals, hydroxyl, fluorine, chlorine, bromine, cyano group or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently.
18. a pharmaceutical composition comprises among the claim 13-17 of effective dose each chemical compound or its tautomer, prodrug, solvate or salt and pharmaceutically acceptable excipient or carrier.
19. the chemical compound of general formula (IC) or its tautomer, prodrug, solvate or salt
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be C independently of one another
1-C
5Alkyl;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is chosen wantonly separately and is replaced by the 1-3 substituent group independently,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen or oxo;
R
5For with the carbocyclic fused heteroaryl of saturated or fractional saturation, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or trifluoromethyl; With
R
6Be hydrogen, C
1-C
8Alkyl, C
2-C
8Alkenyl, C
2-C
8Alkynes base, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, carbocyclic ring-C
1-C
8Alkyl, carboxyl, trifluoromethyl, alkoxy carbonyl group, aryl-C
1-C
8Alkyl, aryl-C
1-C
8Haloalkyl, heterocyclic radical-C
1-C
8Alkyl, heteroaryl-C
1-C
8Alkyl, carbocyclic ring-C
2-C
8Alkenyl, aryl-C
2-C
8Alkenyl, heterocyclic radical-C
2-C
8Alkenyl, or heteroaryl-C
2-C
8Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, phenyl, C
1-C
5Alkoxyl, phenoxy group, C
1-C
5Alkanoyl, aroyl, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone.
20. the general formula of claim 19 (IC) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1The optional substituent group that is selected from independently in the following group of each substituent group replace: methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements;
R
2And R
3Be C independently of one another
1-C
3Alkyl;
R
4Be CH
2
R
5Be the heteroaryl that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, trifluoromethyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone.
21. the general formula of claim 19 (IC) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group independently, or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyrroles, pyrazoles or the imidazoles that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group, hydroxyl, oxo or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, trifluoromethyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently.
22. the general formula of claim 19 (IC) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, aryl, heteroaryl, heterocyclic radical, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements;
R
2And R
3Be C independently of one another
1-C
3Alkyl;
R
4Be CH
2
R
5Be the heteroaryl that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl, hydroxyl, oxo, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, trifluoromethyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone.
23. the general formula of claim 19 (IC) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, pyridine radicals, pyrimidine radicals, pyrazinyl, cyano group or C independently
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R wherein
1The optional substituent group that is selected from cyano group or halogen independently of each substituent group replace;
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyrroles, pyrazoles or the imidazoles that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group, hydroxyl, oxo or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, trifluoromethyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently.
24. the general formula of claim 19 (IC) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, furyl, thienyl, pyrrole radicals, pyrrolidinyl, oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridine radicals, piperidyl, morpholinyl, thio-morpholinyl, pyridazinyl, pyrimidine radicals, pyrazinyl, piperazinyl, indyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, cyano group independently, or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1The optional substituent group that is selected from following group independently of each substituent group replace: C
1-C
5Alkyl, C
1-C
5Alkoxyl, C
1-C
5Alkoxy carbonyl group, acyl group, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, C
1-C
5Alkanoylamino, hydroxyl, cyano group, halogen, or amino, and wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements,
R
2And R
3The methyl of respectively doing for oneself;
R
4Be CH
2
R
5Be pyrroles, pyrazoles or the imidazoles that is connected with the condensed N-of 5-7 unit's saturated carbon ring, it is optional independently by 1-3 substituent group replacement,
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group, hydroxyl, oxo or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, trifluoromethyl, C
3-C
6Methyl cycloalkyl-or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently.
25. a pharmaceutical composition comprises among the claim 19-24 of effective dose each chemical compound or its tautomer, prodrug, solvate or salt and pharmaceutically acceptable excipient or carrier.
26. the chemical compound of general formula (ID) or its tautomer, prodrug, solvate or salt,
Wherein:
R
1Be aryl or heteroaryl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, C
1-C
5Alkanoyl, aroyl, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, amino-sulfonyl, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
1Each substituent group optional replaced by 1-3 substituent group independently, described substituent group is selected from methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is chosen wantonly independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces;
R
2And R
3Be C independently of one another
1-C
5Alkyl, R
2And R
3In one or two independent replaced by following group: hydroxyl; C
1-C
5Alkoxyl; C
1-C
5Alkylthio group, wherein optional sulfoxide or the sulfone of being oxidized to of sulphur atom; Amino, wherein nitrogen-atoms is optional independent of C
1-C
5The alkyl or aryl list replaces or two replacements;
R
4Be C
1-C
5Alkyl, C
2-C
5Alkenyl or C
2-C
5The alkynes base, it is chosen wantonly separately and is replaced by the 1-3 substituent group independently,
R wherein
4Each substituent group be C independently
1-C
3Alkyl, hydroxyl, halogen or oxo;
R
5Be the optional heteroaryl that is replaced by the 1-3 substituent group independently,
R wherein
5Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, heterocyclic radical, aryl, heteroaryl, C
1-C
5Alkoxyl, C
2-C
5Alkenyloxy, C
2-C
5Alkynyloxy group, aryloxy group, acyl group, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl, alkyl amino-carbonyl, dialkyl amino carbonyl, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom is chosen wantonly and is oxidized to sulfoxide or sulfone,
R wherein
5Each substituent group optional independently by 1-3 substituent group replacement, described substituent group is selected from C
1-C
3Alkyl, C
1-C
3Alkoxyl, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or trifluoromethyl; With
R
6Be hydrogen, C
1-C
8Alkyl, C
2-C
8Alkenyl, C
2-C
8Alkynes base, carbocyclic ring, heterocyclic radical, aryl, heteroaryl, trifluoromethyl, carbocyclic ring-C
1-C
8Alkyl, carboxyl, alkoxy carbonyl group, aryl-C
1-C
8Alkyl, aryl-C
1-C
8Haloalkyl, heterocyclic radical-C
1-C
8Alkyl, heteroaryl-C
1-C
8Alkyl, carbocyclic ring-C
2-C
8Alkenyl, aryl-C
2-C
8Alkenyl, heterocyclic radical-C
2-C
8Alkenyl or heteroaryl-C
2-C
8Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
5Alkyl, C
2-C
5Alkenyl, C
2-C
5Alkynes base, C
3-C
8Cycloalkyl, phenyl, C
1-C
5Alkoxyl, phenoxy group, C
1-C
5Alkanoyl, aroyl, C
1-C
5Alkoxy carbonyl group, C
1-C
5Alkanoyloxy, amino carbonyl oxygen base, C
1-C
5Alkyl amino carbonyl oxy, C
1-C
5Dialkyl amino carbonyl oxy, amino carbonyl, C
1-C
5Alkyl amino-carbonyl, C
1-C
5Dialkyl amino carbonyl, C
1-C
5Alkanoylamino, C
1-C
5Alkoxycarbonyl amido, C
1-C
5Alkyl sulfonyl-amino, C
1-C
5Alkyl amino sulfonyl, C
1-C
5Dialkyl amino sulfonyl, halogen, hydroxyl, carboxyl, cyano group, oxo, trifluoromethyl, nitro, amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl list replaces or two replacements; Or urea groups, wherein any one nitrogen-atoms is optional independently by C
1-C
5Alkyl replaces; Or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone.
27. the general formula of claim 26 (ID) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, dihydro benzo furyl, benzofuranyl, Chromanyl, indolinyl, indyl, dihydrobenzo thienyl, benzothienyl, benzo dioxy cyclopenta, benzoxazolyl, benzoisoxazole base, benzopyrazoles base, benzimidazolyl, thienyl, quinolyl, pyridine radicals, pyrimidine radicals or pyrazinyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
1The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, halogen, hydroxyl, oxo, cyano group, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements;
R
2And R
3Be C independently of one another
1-C
3Alkyl, R
2And R
3In one or two independently by hydroxyl, C
1-C
5Alkoxyl replaces;
R
4Be CH
2
R
5Be imidazole radicals, pyridine radicals, indyl, azaindole base, two azaindole bases, benzofuranyl, furo pyridine radicals, furo pyrimidine radicals, benzothienyl, thienopyridine base, Thienopyrimidine base, benzoxazolyl, oxazole and pyridine radicals, benzothiazolyl, thiazole and pyridine radicals, benzimidazolyl, imidazopyridyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, phenyl, C
1-C
3Alkoxyl, methoxycarbonyl group, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, heterocyclic radical carbonyl, fluorine, chlorine, bromine, cyano group, trifluoromethyl or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone,
R wherein
5The optional substituent group that is selected from following group independently of each substituent group replace: methyl, methoxyl group, fluorine, chlorine, bromine, trifluoromethyl, heteroaryl, heterocyclic radical, or amino, wherein nitrogen-atoms is optional independently by C
1-C
5The alkyl or aryl list replaces or two replacements; With
R
6Be C
1-C
5Alkyl, C
2-C
5Alkenyl, C
3-C
6Cycloalkyl, trifluoromethyl, phenyl, C
3-C
6Cycloalkyl-C
1-C
3Alkyl, phenyl-C
1-C
3Alkyl, phenyl-C
1-C
3Haloalkyl, C
3-C
6Cycloalkyl-C
2-C
3Alkenyl, phenyl-C
2-C
3Alkenyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, amino carbonyl, C
1-C
3Alkyl amino-carbonyl, C
1-C
3Dialkyl amino carbonyl, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone.
28. the general formula of claim 26 (ID) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be thienyl, phenyl, naphthyl, pyridine radicals, Chromanyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1 or 2 substituent group replacement,
R wherein
1Each substituent group be methyl, ethyl, methoxyl group, ethyoxyl, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, cyano group independently, or C
1-C
5Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone;
R
2And R
3Be methyl, R
2And R
3In one or two replaced by hydroxyl or methoxyl group independently;
R
4Be CH
2
R
5Be pyridine radicals, indyl, azaindole base, benzofuranyl, furo pyridine radicals, thienopyridine base, benzoxazolyl, benzimidazolyl, quinolyl or isoquinolyl, it is optional separately independently by 1-3 substituent group replacement
R wherein
5Each substituent group be methyl, phenyl, methoxycarbonyl group, amino carbonyl, methylamino carbonyl, dimethylamino amino carbonyl, morpholinyl carbonyl, fluorine, chlorine, bromine, cyano group or trifluoromethyl independently; With
R
6Be C
1-C
5Alkyl, C
3-C
6Cycloalkyl, C
3-C
6Methyl cycloalkyl-, trifluoromethyl or benzyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
6Each substituent group be methyl, methoxyl group, fluorine, chlorine, bromine, cyano group, trifluoromethyl or hydroxyl independently.
29. the general formula of claim 26 (ID) chemical compound or its tautomer, prodrug, solvate or salt, wherein:
R
1Be phenyl, dihydro benzo furyl or benzofuranyl, it is optional separately independently by 1-3 substituent group replacement,
R wherein
1Each substituent group be C independently
1-C
3Alkyl, C
2-C
3Alkenyl, C
2-C
3Alkynes base, C
1-C
3Alkoxyl, C
2-C
3Alkenyloxy, C
1-C
3Alkanoyl, C
1-C
3Alkoxy carbonyl group, C
1-C
3Alkanoyloxy, halogen, hydroxyl, carboxyl, cyano group, trifluoromethyl, nitro, or C
1-C
3Alkylthio group, wherein sulphur atom randomly is oxidized to sulfoxide or sulfone; With
R
2And R
3Be C independently of one another
1-C
3Alkyl, it is optional separately independently by hydroxyl, C
1-C
3Alkoxyl replaces.
30. a pharmaceutical composition comprises among the claim 26-29 of effective dose each chemical compound or its tautomer, prodrug, solvate or salt and pharmaceutically acceptable excipient or carrier.
31. regulate the method for glucocorticoid receptor function in the patient, described method comprises each pharmaceutically acceptable chemical compound or its tautomer, prodrug, solvate or salt among the claim 1-11 of patient's effective dosage, 13-17,19-24 or the 26-29.
32. the method for carrying out described treatment in the patient of the needs treatments glucocorticoid receptor function disease states mediated or the state of an illness, described method comprise each pharmaceutically acceptable chemical compound or its tautomer, prodrug, solvate or salt among the claim 1-11 of patient's effective dosage, 13-17,19-24 or the 26-29.
33. be selected from the method for carrying out described treatment among the patient of type ii diabetes, obesity, cardiovascular disease, hypertension, arteriosclerosis, nervous system disease, adrenal gland neoplasms and pituitary tumor and the glaucomatous morbid state or the state of an illness in needs treatments, described method comprises each pharmaceutically acceptable chemical compound or its tautomer, prodrug, solvate or salt among the claim 1-11 of patient's effective dosage, 13-17,19-24 or the 26-29.
34. in needs treatments is the method for carrying out described treatment among the patient of disease of feature with inflammation, allergy or breeding, described method comprises each pharmaceutically acceptable chemical compound or its tautomer, prodrug, solvate or salt among the claim 1-11 of patient's effective dosage, 13-17,19-24 or the 26-29.
35. the method for claim 34, wherein said disease is selected from: (i) pneumonopathy; (ii) rheumatism/autoimmune disease/joint disease; (iii) allergic disease; (iv) vasculitis; (v) dermatosis; (vi) nephropathy; (vii) hepatopathy; (viii) gastroenteropathy; (ix) rectum disease; (x) oculopathy; (xi) disease in ear, nose and larynx (ENT) zone; (xii) nervous system disease; (xiii) hematopathy; (xiv) tumor disease; (xv) endocrine disease; (xvi) organ and tissue transplantation and graft versus host disease; (xvii) serious shock state; (xix) pain of inflammation formation.
36. the method for claim 35, described disease is selected from: restenosis, Alzheimer, acute pain and chronic pain, arteriosclerosis, reperfusion injury, bone resorption disease, congestive heart failure, myocardial infarction, hot injury, posttraumatic multiple organ injury, acute purulent meningitis, necrotizing enterocolitis and hemodialysis related syndromes, leukocyte separate and the granulocyte infusion behind type i diabetes, osteoarthritis, Guillain-Barre syndrome, the percutaneous transluminal coronary angioplasty.
37. the method for carrying out described treatment in the patient of the needs treatment glucocorticoid receptor function disease states mediated or the state of an illness, described method comprises the administration to the patient: (a) each pharmaceutically acceptable chemical compound or its tautomer, prodrug, solvate or salt among the claim 1-11 of effective dose, 13-17,19-24 or the 26-29; (b) pharmaceutically acceptable glucocorticoid.
38. in-vitro diagnosis is determined the test kit of glucocorticoid receptor function in the sample, comprising:
(a) each chemical compound or its tautomer, prodrug, solvate or salt in the claim 1,13,19 or 26 of diagnosis effective dose;
(b) operation instructions of diagnostic kit.
39. prepare the method for general formula (IA) chemical compound
R wherein
1, R
2, R
3, R
4And R
5Such as claim 1 definition, described method comprises:
(a) in suitable solvent, make the ester and the reaction of suitable Reducing agent of general formula (II), generate the glycol of general formula (III)
(b) under suitable oxicracking condition, the glycol of reaction expression (III), the ketone of generation general formula (IV);
(c) in suitable solvent, make the ketone and the suitable organometallic reagent R of general formula (IV)
5R
4The M reaction, the chemical compound of generation general formula (IA) is at R
5R
4M is that Li or MgX and X are Cl, Br or I among the M
(a ') makes the trifluoroacetamide of general formula (X) and has R in suitable solvent
2And R
3Ethylene bromide base magnesium compound reaction, obtain the trifluoromethyl ketenes of general formula (XI)
(b ') makes the trifluoromethyl ketenes and the reaction of suitable organic copper reagent of general formula (XI) in suitable solvent, generate the ketone of general formula (IV), and described organic copper reagent is by organometallic reagent R
1M and mantoquita CuX produce, at R
1M is Li or MgX among the M, and X is Cl, Br or I in CuX
Carry out above-mentioned steps (c).
40. prepare the method for general formula (IA) chemical compound
R wherein
1, R
2, R
3, R
4And R
5Such as claim 1 definition, described method comprises:
(a ") makes the ester and the reaction of suitable Reducing agent of general formula (II) in suitable solvent, generate the glycol of general formula (III)
(b ") under suitable oxicracking condition, the glycol of reaction expression (III) generates the ketone of general formula (IV);
(c ") makes for example suitable sulfur ylide reaction of ketone (IV) and suitable epoxidation reagent in suitable solvent, generate the epoxide of logical formula V
(d1 ") makes the epoxide and the suitable metal acetylide reagent reacting of logical formula V in suitable solvent, wherein M is suitable metal; PG is suitable blocking group; thus generate protected alkynes intermedium, remove blocking group then, form the alkynes of general formula (XXXI)
(d2 ") makes the ketone and the suitable propargyl reagent reacting of general formula (IV) in suitable solvent, form the alkynes of general formula (XXXI)
(e ") is in the presence of suitable catalyst, alkali and solvent; make the alkyne reaction of suitable coupling gametophyte and general formula (XXXI); generate the alkynes of general formula (XXXIV), and described coupling gametophyte for example is optional that replace and protected aniline or aminopyridine, and wherein R ' be the R that defines in the claim 1
5Substituent group, A is C or N, and X is I or Br, and PG is H or appropriate protection group
(alkynes of f1 ") cyclisation general formula (XXXIV) in the presence of appropriate base and in suitable solvent, the chemical compound of formation general formula (IA)
(f2 ") by in suitable solvent with appropriate acid reaction, the chemical compound of mutual-through type (XXXIV) carries out the N-deprotection, forms amine salt, the described ammonium salt of cyclisation in the presence of appropriate base and in suitable solvent then forms the chemical compound of general formula (IA)
41. method for preparing general formula (IB) chemical compound
R wherein
1, R
2, R
3, R
4, R
5And R
6Such as claim 13 definition, described method comprises:
(a) in the presence of appropriate base, make the acryloyl chloride reaction of the phenol of optional replacement and the general formula (XVI) of general formula (XV), the intermedium ester is carried out cyclisation, the lactone of generation general formula (XVII) by handling then with suitable lewis acid
(b) make the lactone and the suitable amine HNR ' R of general formula (XVII) " react, in the presence of appropriate base, handle intermedium phenol then, generate the amide of general formula (XVIII) with methyl iodide
(c) in suitable solvent, make the amide and the suitable organometallic reagent R of general formula (XVIII)
6The M reaction, the ketone of generation general formula (XIX) is at R
6M is Li or MgX among the M, and X is Cl, Br or I
(d) in suitable solvent, make the ketone and the suitable organometallic reagent R of general formula (XIX)
5R
4The M reaction, the chemical compound of generation general formula (IB) is at R
5R
4M is that Li or MgX and X are Cl, Br or I among the M
42. method for preparing general formula (IB) chemical compound
R wherein
1, R
2, R
3, R
4, R
5And R
6Such as claim 13 definition, described method comprises:
(a ') makes the amide of general formula (XXXVI) and has R in suitable solvent
2And R
3Ethylene bromide base reactive magnesium, obtain the ketenes of general formula (XXXVII)
(b ') makes the ketenes and the reaction of suitable organic copper reagent of general formula (XXXVII) in suitable solvent, generate the ketone of general formula (XX), and described organic copper reagent is by organometallic reagent R
1M and mantoquita CuX produce, at R
1M is Li or MgX among the M, and X is Cl, Br or I in CuX
(c ') makes the ketone and the suitable organometallic reagent R of general formula (XX) in suitable solvent
5R
4The M reaction, the chemical compound of generation general formula (IB) is at R
5R
4M is that Li or MgX and X are Cl, Br or I among the M
43. method for preparing general formula (IB) chemical compound
R wherein
1, R
2, R
3, R
4, R
5And R
6Such as claim 13 definition, described method comprises:
(a ") makes the ketone and the appropriate base reaction of general formula (IV) in the suitable solvent mixture, form the acid of general formula (XXIX)
(b ") makes the acid and the suitable amine HNR of general formula (XXIX) under suitable coupling condition " R reaction, the amide of formation general formula (XXX) ,-NR ", and R will be used as leaving group in subsequent reaction,
(c ") makes the amide and the reaction of suitable organometallic reagent of general formula (XXX) in suitable solvent, generate ketone (XX), and described organometallic reagent for example is a Grignard reagent, and wherein M is MgBr or MgCl, or lithium metal reagent, and wherein M is Li
(d ") makes the ketone and the suitable organometallic reagent R of general formula (XX) in suitable solvent
5R
4The M reaction, the chemical compound of generation general formula (IB) is at R
5R
4M is Li or MgX among the M, and X is Cl, Br or I
44. prepare the method for general formula (IC) chemical compound
R wherein
1, R
2, R
3, R
4, R
5And R
6Such as claim 19 definition, described method comprises:
(a) in suitable solvent, make the ester and the reaction of suitable Reducing agent of general formula (II), generate the glycol of general formula (III)
(b) make glycol and the suitable alkyl sulfonyl chloride or the aryl sulfonyl chloride reagent reacting of general formula (III), make R ' SO
2O is used as leaving group in next step, make the intermedium and the appropriate base reaction of generation then, generates the epoxide of logical formula V
(c) in the presence of appropriate base, make the epoxide and suitable nucleopilic reagent R of logical formula V
5The H reaction, the chemical compound of generation general formula (IC)
45. method for preparing general formula (IC) chemical compound
R wherein
1, R
2, R
3, R
4, R
5And R
6Such as claim 19 definition, described method comprises:
(a ') makes the ester and the reaction of suitable Reducing agent of general formula (II) in suitable solvent, generate the glycol of general formula (III)
(b ') under suitable oxicracking condition, the glycol of reaction expression (III) generates the ketone of general formula (IV);
(c ') makes the ketone and for example suitable sulfur ylide reaction of suitable epoxidation reagent of general formula (IV) in suitable solvent, generate the epoxide of logical formula V
(d ') makes the epoxide and suitable nucleopilic reagent R of logical formula V in the presence of appropriate base
5The H reaction, the chemical compound of generation general formula (IC)
46. prepare the method for general formula (ID) chemical compound
R wherein
1, R
2, R
3, R
4, R
5And R
6Such as claim 26 definition, described method comprises:
(a) in the presence of appropriate base, make the cyano compound and the suitable olefine reaction of general formula (XXXVIII), generate the alkene of general formula (XXXIX)
(b) alkene of general formula (XXXIX) and suitable Reducing agent are reacted, generate the aldehyde of general formula (XXXX)
(c) aldehyde of general formula (XXX) and suitable Reducing agent are reacted, generate the alcohol of general formula (XXXXI)
(d) appropriate base in the presence of, make the alcohol and the suitable alkylation reactions of general formula (XXXXI), generate the ether of general formula (XXXXII)
(e) under suitable oxicracking condition, the ether of reaction expression (XXXXII), the aldehyde of generation general formula (XXXXIII);
(f) aldehyde of general formula (XXXXIII) and suitable nucleophilic trifluoromethyl reagent are reacted, generate the trifluoromethyl alcohol of general formula (XXXXIV)
(g) the trifluoromethyl alcohol of general formula (XXXXIV) is reacted with suitable oxidizers, generate the trifluoromethyl ketone of general formula (XXXXV)
(h) in suitable solvent, make the ketone and the suitable organometallic reagent R of general formula (XXXXV)
5R
4The M reaction, the chemical compound of generation general formula (ID) is at R
5R
4M is that Li or MgX and X are Cl, Br or I among the M
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50545603P | 2003-09-24 | 2003-09-24 | |
| US60/505,456 | 2003-09-24 | ||
| US50707903P | 2003-09-29 | 2003-09-29 | |
| US60/507,079 | 2003-09-29 | ||
| PCT/US2004/031009 WO2005030213A1 (en) | 2003-09-24 | 2004-09-22 | 1,1,1-trifluoro-4-phenyl-4-methyl-2-(1h-pyrrolo |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102426640A Division CN101948425A (en) | 2003-09-24 | 2004-09-22 | As the compound of glucocorticoid ligands, the pharmaceutical composition that comprises them, test kit and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1976705A true CN1976705A (en) | 2007-06-06 |
| CN1976705B CN1976705B (en) | 2010-09-22 |
Family
ID=38126280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2004800276942A Expired - Fee Related CN1976705B (en) | 2003-09-24 | 2004-09-22 | 1,1,1- trifluoro-4-phenyl-4-methyl-2-(1H-pyrrolo not 2,3-C|pyridin-2-ylmethyl)pentan-2-ol derivatives and related compounds as glucocorticoid ligands for the treatment of inflammatory diseases and dia |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1976705B (en) |
| UA (1) | UA91330C2 (en) |
| ZA (1) | ZA200600316B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102348682A (en) * | 2009-03-26 | 2012-02-08 | 霍夫曼-拉罗奇有限公司 | 1,1,1-trifluoro-2-hydroxypropyl compounds |
-
2004
- 2004-09-22 CN CN2004800276942A patent/CN1976705B/en not_active Expired - Fee Related
- 2004-09-22 UA UAA200604365A patent/UA91330C2/en unknown
-
2006
- 2006-01-12 ZA ZA200600316A patent/ZA200600316B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102348682A (en) * | 2009-03-26 | 2012-02-08 | 霍夫曼-拉罗奇有限公司 | 1,1,1-trifluoro-2-hydroxypropyl compounds |
| CN102348682B (en) * | 2009-03-26 | 2014-07-30 | 霍夫曼-拉罗奇有限公司 | 1,1,1-trifluoro-2-hydroxypropyl compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| UA91330C2 (en) | 2010-07-26 |
| CN1976705B (en) | 2010-09-22 |
| ZA200600316B (en) | 2007-09-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1633296A (en) | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof | |
| CN1262540C (en) | Bicycle androgen and progesterone receptor modulator compounds and methods | |
| CN1308310C (en) | Nitrogenous aromatic ring compounds | |
| CN1678306A (en) | -3 (sulfonamidoethyl) -indole derivaties for use as glucocorticoid mimetics in the treatment of inflammatory, allergic and proliferative diseases | |
| CN1203066C (en) | (Methylsulfonyl) phenyl-2-(5H)-furanones as cox-2 inhibitors | |
| CN1239485C (en) | Benzophenones as inhibitors of IL-1 beta and TNF-alpha | |
| CN101948425A (en) | As the compound of glucocorticoid ligands, the pharmaceutical composition that comprises them, test kit and preparation method thereof | |
| CN1915231A (en) | Use of nonsteroidal in preparing drug of antiinflammatory agents | |
| CN1688549A (en) | Compound having TGF-beta inhibitory activity and medicinal composition containing the same | |
| CN1284948A (en) | Indezole bioisostere replacement of catechol in therafeutically active compounds | |
| CN1498212A (en) | New spirotricyclic derivatives and their use as phosphodiesterase-7-inhibitors | |
| CN1433417A (en) | Pyridopyrimidinone derivatives for treatment of neurodegenerative disease | |
| CN1656073A (en) | Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases | |
| CN1656079A (en) | Pyrazole compounds and pharmaceutical compositions comprising the compound | |
| CN1742007A (en) | Indole-derivative modulators of steroid hormone nuclear receptors | |
| CN1268942A (en) | Sulfonamide compounds and medicinal use thereof | |
| CN1839133A (en) | Substituted naphthyridine derivatives as inhibitors of macrophage migration inhibitory factor and their use in the treatment of human diseases | |
| CN1942428A (en) | CETP inhibitors | |
| CN1267281A (en) | Glucagon antagonists/inverse agonists | |
| CN1278794A (en) | Substituted di-hydroxyl-indol derivatives as protein tyrosine kinase and as protein serine/threenine kinase inhibitors | |
| CN1630632A (en) | Aromatic amino acid derivates and medicinal compositions | |
| CN1784396A (en) | P38 inhibitors and methods of use thereof | |
| CN1993359A (en) | Heterocycle -substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors | |
| CN1882591A (en) | 5,7-diaminopyrazolo '4,3-d!pyrimidines with pde-5 inhibiting activity | |
| CN1761671A (en) | 4-aminothieno [2,3-d] pyrimidine-6-carbonitrile derivatives as PDE7 inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1106446 Country of ref document: HK |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100922 Termination date: 20120922 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1106446 Country of ref document: HK |