CN101296892A - PPAR active compounds - Google Patents
PPAR active compounds Download PDFInfo
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- CN101296892A CN101296892A CNA200680040053XA CN200680040053A CN101296892A CN 101296892 A CN101296892 A CN 101296892A CN A200680040053X A CNA200680040053X A CN A200680040053XA CN 200680040053 A CN200680040053 A CN 200680040053A CN 101296892 A CN101296892 A CN 101296892A
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Abstract
Compounds are described that are active on at least one of PPAR alpha, PPAR delta, and PPAR gamma, which are useful for therapeutic and/or prophylactic methods involving modulation of at least one of PPAR alpha, PPAR delta, and PPAR gamma.
Description
Related application
[0001] the application requires in the 60/715th of submission on September 7th, 2005, No. 214 U.S. Provisional Applications and on April 5th, 2006 submit to the 60/789th, the rights and interests of No. 387 U.S. Provisional Applications, both all are introduced into this paper as a reference, and are used for all purposes.
Technical field
[0002] the present invention relates to the modulator field, described modulator (modulator) is at the member of the nuclear receptor family that is accredited as peroxisome proliferation-activated receptors (peroxisome proliferator-activated receptor).
Background technology
[0003] providing following description only is in order to help the reader understanding.None reference or the information that provided are admitted to be prior art of the present invention in the reference of being quoted.Each reference cited herein intactly is incorporated in this as a reference, reaches as each reference individually to be shown the same degree that intactly is incorporated in this.
[0004] peroxisome proliferation-activated receptors (peroxisome proliferator-activatedreceptor (PPAR)) forms a sub-family in the nuclear receptor superfamily.So far, identified three isoforms, they are by different genes encodings: PPAR γ, PPAR α and PPAR δ.
[0005] two kinds of the PPAR γ isoforms of expressing, i.e. γ 1 and γ 2 are arranged in the mouse and the mankind on protein level.Their difference only is that the latter has 30 extra amino acid at its N-terminal, this is because the difference promotor in homologous genes is used (differential promoter usage), and selectable RNA processing (alternative RNA processing) subsequently.PPAR γ 2 mainly expresses in fatty tissue, and PPAR γ 1 expresses in a lot of tissues.
[0006] mouse PPAR α is first member of this nuclear receptor hypotype (subclass) that will clone; It is in the past from human cloned.PPAR α expresses in numerous metabolic activity tissues, comprises liver, kidney, heart, skeletal muscle and brown fat.It also is present in monocyte, blood vessel endothelium and the vascular smooth muscle cell.In rodent, the activation-inducing liver peroxisome proliferation of PPAR α, hepatomegaly and liver cancer take place.These toxic effects are not observed in the mankind, activate PPAR α although identical compound is striden species.
[0007] people PPAR δ was cloned in early days in the nineties in 20th century, cloned from rodent subsequently.PPAR δ expresses in a lot of tissues and cell, finds to have in digestive tube, heart, kidney, liver, fat and brain high-caliber expression.
[0008] PPAR is ligand-dependent transcription factor (ligand-dependent transcription factor), and it is by regulating expression of target gene with special combining of peroxisome proliferation response element (peroxisome proliferator response element (PPRE)) in the enhanser site of regulated gene.PPAR has a modular structure of being made up of functional domain, comprises that DNA is in conjunction with territory (DNA binding domain (DBD)) and ligand binding domain (ligand binding domain (LBD)).DBD in the regulation domain of PPAR-responsive genes specifically in conjunction with PPRE.DBD is arranged in C-terminal half part of acceptor, contains ligand-dependent activation domain (ligand-dependent activation domain), AF-2.Each acceptor and its PPRE are combined into the have retinoid X acceptor heterodimer of (retinoid X receptor (RXR)).In case in conjunction with agonist, the configuration of PPAR just is changed and settles out, so just formed in conjunction with crack (bindingcleft), form the part in AF-2 territory, and raise (recruitment) of transcriptional coactivator takes place.Coactivator increases the ability of the initial transcription of nuclear receptor.The results of interaction of PPAR coactivator on PPRE of agonist induction is to have increased genetic transcription.As if the downward modulation of the genetic expression by PPAR take place by indirect mechanism.(Bergen etc., Diabetes Tech.﹠amp; Ther., 2002,4:163-174).
[0009] first time of PPAR (PPAR α), the clone occurred in the process of the molecular target of seeking rodent liver agent for peroxisome proliferator.Thereafter, a lot of lipid acid and their derivative comprise multiple class dodecylic acid and prostaglandin(PG), have demonstrated as the part of PPAR to work.Therefore, these acceptors may play central role in the sensation of trophic level and their metabolic modulation.In addition, PPAR is the main target that has been used for the diabetes and the selection monoid (selected class) of the synthetic compound of the successful treatment of unusual lipidemia (dyslipidemia).Like this, to the characterization of molecules of these acceptors and the understanding of physiological characteristic, the development and application of the medicine that is used for the treatment of metabolism disorder has been become extremely important.
[0010] Kota etc., Pharmacological Research, 2005,51:85-94, the summary of the biomechanism that relates to PPAR is provided, it has comprised the argumentation of the possibility of using PPAR modulator treatment various disease conditions, and described illness comprises chronic inflammation disease for example atherosclerosis, sacroiliitis and inflammatory bowel syndrome (inflammatory bowel syndrome), the retinal diseases relevant with the blood vessel generation, the fertility (increased fertility) and the neurodegenerative disease of increase.
[0011] Yousef etc., Journal of Biomedicine and Biotechnology 2004 (3): 156-166, discussed the anti-inflammatory action of PPAR α, PPAR γ and PPAR delta agonists, shown that the PPAR agonist can have effect aspect treatment neuronal disease such as alzheimer's disease and autoimmune disorder such as inflammatory bowel and the multiple sclerosis.For the PPAR agonist at the latent effect of treatment aspect the alzheimer's disease at Combs etc., Journal of Neuroscience 2000,20 (2): 558 are described, and for the PPAR agonist in treatment this type of effect aspect the Parkinson's disease at Breidert etc., Journal of Neurochemistry, 2002,82:615 discusses.The PPAR agonist is in the function that may be correlated with of treatment aspect the alzheimer's disease--regulating function of APP-processive enzyme BACE--at Sastre etc., Journal of Neuroscience, and 2003,23 (30): 9796 discuss.These researchs show jointly, and the PPAR agonist can have advantage aspect the multiple neurodegenerative disease working by added machinery (complementary mechanisms) to treat.
[0012] discussion of the antiphlogistic effects of PPAR agonist also can obtain in following document: Feinstein, Drug discovery Today:Therapeutic Strategies, 2004,1 (1): 29-34, it relates to multiple sclerosis and alzheimer's disease; Patel etc., The Journal of Immunology, 2003,170:2663-2669, it relates to chronic obstructive pulmonary disease (COPD) and asthma; Lovett-Racke, etc., Journal of Immunology, 2004,172:5790-5798, it relates to autoimmune disorder; Malhotra, etc., Expert Opinions inPharmacotherapy, 2005,6 (9): 1455-1461, it relates to psoriasis; And Storer, etc., Journal ofNeuroimmunology, 2005,161:113-122, it relates to multiple sclerosis.
[0013] a large amount of effects of the PPAR that has been found that show, PPAR α, PPAR γ and PPAR δ can play a role in relating to a large amount of incidents of vascular system, comprise that atherosclerosis plaque forms and stability, thrombosis, vascular tone (vascular tone), blood vessel generation, cancer, pregnancy, tuberculosis, autoimmune disorder and neurological disorder.
[0014] in the PPAR synthetic ligands of identifying, thiazolidinedione (thiazolidinediones (TZDs)) is arranged.These compounds are based in the animal pharmaceuticals research at first, and their insulin sensitizing agent effect is developed.Subsequently, find TZD induced lipolysis cytodifferentiation and increase the adipocyte expression of gene, comprise the conjugated protein aP2 of adipocyte fatty acid.Independently, find that the regulatory element of PPAR γ and aP2 gene interacts, control its adipocyte-specific and express.Based on these innovative researches result, test, determining TZD is PPAR γ part and agonist, and shown they external PPAR gamma activity and their body in a definite dependency is arranged between the insulin sensitizing agent effect.(Bergen etc., the same).
[0015] several TZD, comprise troglitazone (troglitazone), rosiglitazone (rosiglitazone) and Pa Gelie ketone (pioglitazone), in the people who suffers from type ii diabetes and impaired glucose tolerance, have insulin sensitizing agent and anti-diabetic activity.Fa Gelie ketone (Farglitazar) is PPAR-γ-selective agonist of a kind of very virtuous non-TZD, and it demonstrates the effect that has anti-diabetic and change lipid in the mankind recently.Except these virtuous PPAR γ parts and, the subclass of non-steroidal anti-inflammatory drugs (non-steroidalantiinflammatory drug (NSAID)), comprise INDOMETHACIN, fenoprofen (fenoprofen) and Ibuprofen BP/EP, demonstrated weak PPAR γ and PPAR alpha active.(Bergen etc., the same).
[0016] the special class (fibrates) of shellfish has been proved to be useful amphipathic carboxylic acid in the treatment hypertriglyceridemia, is the PPARo part.Before identifying PPAR, the prototype member who has developed this classes of compounds, chlorine Bei Te uses to detect in the rodentine body and estimates fat-reducing effect (lipid-lowering efficacy).(Bergen etc., the same).
[0017] Fu etc., Nature, 2003,425:9093 shows: PPAR α binding compounds, oil base glycollic amide (oleylethanolamide) has produced the increase of sating and having reduced body weight in mouse.
[0018] with respect to PPAR γ, chlorine Bei Te and fenofibrate (fenofibrate) have demonstrated with 10 times of selectively activate PPAR α.Bezafibrate (bezafibrate) plays a role as general agonist (pan-agonist), and it demonstrates similar effectiveness in all three kinds of PPAR isoforms.Wy-14643, the 2-aryl thioacetic acid analogue of chlorine Bei Te is effective mouse PPAR alfa agonists, also is weak PPAR gamma agonist.In the mankind, the special class of all shellfishes must be used with high dosage (200-1200mg/ days), so that obtain effective lipopenicillinase activity.
[0019] also to have been identified be dual PPAR γ/alfa agonists for TZD and non-TZD.Because extra PPAR alfa agonists activity, except the hyperglycemia activity in the animal model of diabetes and lipid disorders, this compounds also has effective lipid and changes effect.KRP-297 be TZD dual PPAR γ/alfa agonists an example (Fajas, J.Biol.Chem., 1997,272:18779-18789); And DRF-2725 and AZ-242 right and wrong TZD dual PPAR γ/alfa agonists.(Lohray etc., J.Med.Chem., 2001,44:2675-2678; Cronet etc., Structure (Camb.), 2001,9:699-706).
[0020] in order to explain the physiology role of PPAR δ, makes efforts, develop the compounds that activates this receptor in a selective manner.Formerly in the alpha-substituted carboxylic acid of Miao Shuing, effectively PPAR 2-delta ligand L-165041 shows: with respect to PPAR γ, have about 30 times agonist selectivity for this receptor; And it to mouse PPAR α be do not have active (Liebowitz etc., 2000, FEBS Lett., 473:333-336).This compound is found in has increased hdl level in the rodent.Also reported GW501516 and be effectively, highly selective PPAR delta agonists, its in rhesus monkey obesity, that have insulin resistance, the useful variation that has produced the serum lipid parameter.(oliver etc., Proc.Natl.Acad.Sci., 2001,98:5306-5311).
[0021], described PPAR has been had active some thiazole derivative except compound discussed above.(international open WO 02/062774 intactly introduces herein as a reference for people such as Cadilla, International Application PCT/US01/149320.)
[0022] some three ring-alpha-alkoxy base phenylpropionic acids are at Sauerberg etc., and J.Med.Chem.2002 is described to dual PPAR α/gamma agonist among the 45:789-804.
[0023] at Morgensen etc., Bioorg.﹠amp; Med.Chem.Lett., 2002, among the 13:257-260, described statement PPAR α/gamma/delta has been had active one group of compound of equating.
[0024] people such as oliver has described a kind of selective PPAR delta agonists that promotes reverse cholesterol transport.(oliver etc., the same)
[0025] people's such as Yamamoto United States Patent (USP) 3,489,767 has been described " 1-(phenyl sulfonyl)-indyl aliphatic acid derivative ", and they are described has " anti-inflammatory, pain relieving and antipyretic effect." (the 1st hurdle, 16-19 is capable.)
[0026] people such as Kato; european patent application 94101551.3; publication number 0 610 793 A1; use 3-(5-methoxyl group-1-p-tosyl group indol-3-yl) propionic acid (the 6th page) and 1-(2 have been described; 3,6-triisopropyl phenyl alkylsulfonyl)-the synthetic intermediate that is used as the specific Fourth Ring morpholine derivative of anodyne of indole-3-monoprop (the 9th page) conduct.
Summary of the invention
[0027] the present invention relates to that PPAR is had active compound, it can be used to multiple application, for example comprises, relates to the method that treats and/or prevents of regulating among PPAR α, PPAR δ and the PPAR γ at least one.Comprise the compound that PPAR family (being PPAR α, PPAR δ and PPAR γ) is had general activity (pan-activity), and, has remarkable specific compound (activity of big at least 5 times, 10 times, 20 times, 50 times or 100 times) to single PPAR or to two kinds among three kinds of PPARs.
[0028] on the one hand, the invention provides the compound of formula I, as follows:
Formula I
Its all salt, prodrug, tautomer and isomers,
Wherein:
X is selected from-C (O) OR
16,-C (O) NR
17R
18With the carboxylic acid isostere;
W be selected from covalent linkage ,-NR
51(CR
4R
5)
1-2-,-O-(CR
4R
5)
1-2-,-S-(CR
4R
5)
1-2-,-(CR
4R
5)
1-3-and-CR
6=CR
7-;
R
1And R
2Be independently selected from hydrogen, halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl ,-SR
9With-OR
9, wherein said low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
3Be selected from-[(CR
4R
5)
m-(Y)
p]
r-R
10With-[(CR
4RV (Y)
P]
1-Ar
1-M-Ar
2
L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-,-S (O)
2NR
52-,-NR
52C (Z) NR
52-and-NR
52S (O)
2NR
52-;
Y is selected from-O-,-S-,-NR
53-,-C (Z)-,-S (O)
n-,-C (Z) NR
54-,-NR
54C (Z)-,-NR
54S (O)
2-,-S (O)
2NR
54-,-NR
54C (Z) NR
54-and-NR
54S (O)
2NR
54-;
Ar
1Be selected from optional arylidene that replaces and the optional heteroarylidene that replaces;
M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-,-NR
53-,-C (Z)-and-S (O)
n-;
Ar
2Be selected from optional aryl that replaces and the optional heteroaryl that replaces;
In all cases, R
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
A R
4Or R
5Be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R on the identical or different carbon
4And R
5In any two in conjunction with forming 3-7 unit's monocyclic cycloalkyls or 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
6And R
7Be independently selected from hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In one be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and R
6And R
7In another is hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In conjunction with forming 5-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
9Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
9Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-OR
9O or-SR
9S go up, C
3-6Yet alkynyl--condition is to work as R
9Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-OR
9O or-SR
9S go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace--yet condition is, with-OR
9O or-SR
9S bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein alkyl, C
3-6Alkenyl and C
3-6The cycloalkyl of alkynyl, Heterocyclylalkyl, aryl and heteroaryl substituting group randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
10Be selected from the optional cycloalkyl that replaces, the optional Heterocyclylalkyl that replaces, the optional aryl that replaces and the optional heteroaryl that replaces;
In all cases, R
51And R
52Be independently selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein low-carbon alkyl is randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is, with-NR
51-or-NR
52-N bonded alkyl carbon on any substituting group be fluorine, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
53Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
53Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-NR
53-N go up, C
3-6Yet alkynyl--condition is to work as R
53Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-NR
53-N go up, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-C (Z) NR
11R
12,-S (O)
2NR
11R
12,-S (O)
2R
13,-C (Z) R
13With-C (Z) OR
15, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
53-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
54Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
54Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-NR
54-N go up, C
3-6Yet alkynyl--condition is to work as R
54Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-NR
54-N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
54-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
11And R
12Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
11And/or R
12Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, C
3-6Yet alkynyl--condition is to work as R
11And/or R
12Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
11And R
12Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
In all cases, R
13Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
13Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, C
3-6Yet alkynyl--condition is to work as R
13Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
15Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
15Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to (O) R
15O go up, C
3-6Yet alkynyl--condition is to work as R
15Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to (O) R
15O go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any OR
15O bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-S
R1With-NR
22R
23
R
16Be selected from oxygen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
16When being low-carbon alkyl, with OR
16O bonded alkyl carbon on any substituting group be fluorine;
R
17And R
18Be independently selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
17And/or R
18When being low-carbon alkyl, with NR
17R
18N bonded alkyl carbon on any substituting group be fluorine; Or
R
17And R
18Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
19And R
20Be independently selected from oxygen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein any cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
19And R
20In conjunction with forming 3-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein monocyclic cycloalkyl or monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
21, R
22And R
23Be independently selected from hydrogen or low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group is selected from low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace, yet condition is and OR
21, SR
21, NR
21, NR
22Or NR
23In any one O, S or any substituting group on the low-carbon alkyl carbon that combines of N be fluorine, yet and further condition be and S, S (O), S (O)
2Or C (Z) bonded R
21Not hydrogen; Or
R
22And R
23Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
Z is O or S;
M is 1,2,3 or 4;
N is 1 or 2;
P is 0 or 1, yet, condition be when p is 1, m be 1 and L be-O-,-S-,-NR
52-,-C (Z) NR
52-,-S (O)
2NR
52-,-NR
52C (Z) NR
52-or-NR
52S (O)
2NR
52-time, so Y be not-O-,-S-,-NR
53-,-NR
54C (Z)-,-NR
54S (O)
2-,-NR
54C (Z) NR
54-or-NR
54S (O)
2NR
54-; With
R is 0 or 1.
[0029] in a kind of embodiment of formula I compound, R
1And R
2In at least one is not a hydrogen.In one embodiment, R
1And R
2In one be not hydrogen and R
1And R
2In another is a hydrogen or halogen.In one embodiment, R
1And R
2In one be not hydrogen and R
1And R
2In another is a hydrogen.In one embodiment, R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9In one embodiment, R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, and R
1And R
2In another is a hydrogen or halogen.In one embodiment, R
1And R
2In one be-SR
9Or-OR
9, preferably-OR
9, and R
1And R
2In another is a hydrogen.In one embodiment, R
1And R
2Two all is hydrogen.
[0030] in a kind of embodiment of formula I compound, R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be selected from low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace.In one embodiment, R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-.
[0031] in a kind of embodiment of formula I compound, R
1And R
2In at least one is halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl--randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, preferably R
1And R
2In one be hydrogen, R preferably
1Be hydrogen and R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl.
[0032] in a kind of embodiment of formula I compound, W is-(CR
4R
5)
1-3-or-CR
6=CR
7-.In preferred embodiment, W is-CH
2CH
2-or-CH
2-, more preferably-CH
2-, further wherein X is-COOH.In one embodiment, W is-(CH
2)
1-3-and R
1And R
2In at least one is-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-.In one embodiment, W is-CH
2CH
2-or-CH
2-, more preferably-CH
2-, X is-COOH and R
1And R
2In at least one is-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-.
[0033] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, wherein L preferably-O-or-S (O)
2-, more preferably-S (O)
2-.
[0034] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-O-or-S (O)
2-, more preferably-S (O)
2-, and R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-.
[0035] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-O-or-S (O)
2-, more preferably-S (O)
2-, and W is-(CR
4R
5)
1-3-or-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-.
[0036] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-O-or-S (O)
2-, more preferably-S (O)
2-, and-R
3Be-R
10Or-Ar
1-M-Ar
2
[0037] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-O-or-S (O)
2-, more preferably-S (O)
2-; W is-(CH
2)
1-3-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-, and R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-, further wherein X preferably-C (O) OR
16Or the carboxylic acid isostere, more preferably wherein X is-C (O) OH.
[0038] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-O-or-S (O)
2-, more preferably-S (O)
2-; W is-(CH
2)
1-3-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-, and R
1And R
2In at least one is halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl, randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, preferably R
1And R
2In one be hydrogen, R preferably
1Be hydrogen and R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, further wherein X preferably-C (O) OR
16Or the carboxylic acid isostere, more preferably wherein X is-C (O) OH.
[0039] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-O-or-S (O)
2-, more preferably-S (O)
2-; W is-(CH
2)
1-3-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-,-R
3Be-R
10Or-Ar
1-M-Ar
2, and R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-, further wherein X preferably-C (O) OR
16Or the carboxylic acid isostere, more preferably wherein X is-C (O) OH.
[0040] in a kind of embodiment of formula I compound, L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-O-or-S (O)
2-, more preferably-S (O)
2-; W is-(CH
2)
1-3-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-,-R
3Be-R
10Or-Ar
1-M-Ar
2, and R
1And R
2In at least one is halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl, randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, preferably R
1And R
2In one be hydrogen, R preferably
1Be hydrogen and R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, further wherein X preferably-C (O) OR
16Or the carboxylic acid isostere, more preferably wherein X is-C (O) OH.
[0041] in a kind of embodiment of formula I compound, L is selected from-S (O)
2-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-S (O)
2-; W is-(CH
2)
1-3-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-, and R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-, further wherein X preferably-C (O) OR
16Or the carboxylic acid isostere, more preferably wherein X is-C (O) OH.
[0042] in a kind of embodiment of formula I compound, L is selected from-S (O)
2-,-NR
52S (O)
2-and-S (O)
2NR
52-, preferably-S (O)
2-, W is-(CH
2)
1-3-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-,-R
3Be-R
10Or-Ar
1-M-Ar
2, and R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-, further wherein X preferably-C (O) OR
16Or the carboxylic acid isostere, more preferably wherein X is-C (O) OH.
[0043] in a kind of embodiment of formula I compound, L is-O-and-R
3Be-[(CR
4R
5)
m-(Y)
p]
r-Ar
1-M-Ar
2In a kind of embodiment of formula I compound, L is-O-and-R
3Be R
10, R wherein
10It is the optional phenyl that replaces.In a kind of embodiment of formula I compound, L is-O-and-R
3Be R
10, R wherein
10Be the phenyl that randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl that replaces of low-carbon alkyl, fluorine is (such as CF
3Or CF
2CF
3), the low-carbon alkoxy that replaces of low-carbon alkoxy, fluorine is (such as OCF
3Or OCF
2CF
3), the low-carbon alkyl sulfo-that replaces of low-carbon alkyl sulfo-and fluorine is (such as SCF
3Or SCF
2CF
3).
[0044] in a kind of embodiment of formula I compound, L is-S (O)
2-and-R
3Be-[(CR
4R
5)
m-(Y)
p]
r-Ar
1-M-Ar
2In a kind of embodiment of formula I compound, L is-S (O)
2-and-R
3Be R
10, R wherein
10It is the optional phenyl that replaces.In a kind of embodiment of formula I compound, L is-S (O)
2-and-R
3Be R
10, R wherein
10Be phenyl, described phenyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl that replaces of low-carbon alkyl, fluorine is (such as CF
3Or CF
2CF
3), the low-carbon alkoxy that replaces of low-carbon alkoxy, fluorine is (such as OCF
3Or OCF
2CF
3), the low-carbon alkyl sulfo-that replaces of low-carbon alkyl sulfo-and fluorine is (such as SCF
3Or SCF
2CF
3).
[0045] in a kind of embodiment of formula I compound, L is-S (O)
2-and-R
3Be R
10, R wherein
10Be the phenyl that randomly replaces, W is-(CH
2)
1-3-, preferably-CH
2CH
2-or-CH
2-, more preferably-CH
2-, and R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-, further wherein X preferably-C (O) OR
16Or the carboxylic acid isostere, more preferably wherein X is-C (O) OH.
[0046] with respect to any in the above-mentioned embodiment, in one embodiment, when L is-S (O)
2NR
52-time, R
52Be hydrogen, and R
2Be hydrogen, R
1Be not-OCH
3With respect to any in the above-mentioned embodiment, in one embodiment, when L is-S (O)
2NR
52-time, R
1Be hydrogen.
[0047] with respect to any in the above-mentioned embodiment, in one embodiment, such compound is left out, wherein L be-O-or-S-, r=1, p=0, m be 1,2,3 or 4 and-R
10Or-Ar
1-be the optional pyrazolyl that replaces, the optional imidazolyl that replaces, the optional De of replacement isoxazolyl, the optional De of replacement oxazolyl, the optional thiazolyl that replaces or the optional isothiazolyl that replaces; Such compound also is left out, and wherein L is-O-, R
3Be-R
10Or-(CR
4R
5)
m-R
10And-R
10Has structure
Wherein
Expression and L or-(CR
4R
5)
m-tie point and R wherein
10Phenyl ring or quinoline ring randomly replaced; Such compound also is left out, and wherein L is-O-, R
3Has structure
Wherein said phenyl ring is randomly replaced, and wherein
The tie point of expression and L; Following compounds also is left out:
[0048] in respect to above-mentioned embodiment in any another kind of embodiment, such compound is left out, wherein LR
3Be any in following, wherein
The tie point of the phenyl ring of expression L and formula I:
[0049] in one embodiment, formula I compound has following inferior formula (formula Ia):
Its all salt, prodrug, tautomer and isomers,
Wherein:
W, X, R
1, R
2, R
4, R
5, Y, M and p define suc as formula I;
Ar
1aBe selected from arylidene and heteroarylidene;
Ar
2aBe selected from aryl and heteroaryl;
In all cases, R
24Be independently selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl ,-NO
2,-CN-OR
26,-SR
26,-OC (O) R
26,-OC (S) R
26,-C (O) R
26,-C (S) R
26,-C (O) OR
26,-C (S) OR
26,-S (O) R
26,-S (O)
2R
26,-C (O) NR
27R
28,-C (S) NR
27R
28,-S (O)
2NR
27R
28,-C (NH) NR
27R
28,-NR
26C (O) R
26,-NR
26C (S) R
26,-NR
26S (O)
2R
26, NR
26C (O) NR
27R
28, NR
26C (S) NR
27R
28,-NR
26S (O)
2NR
27R
28With-NR
27R
28, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
25Be independently selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NO
2,-CN ,-OR
29,-SR
29,-OC (O) R
29,-OC (S) R
29,-C (O) R
29,-C (S) R
29,-C (O) OR
29,-C (S) OR
29,-S (O) R
29,-S (O)
2R
29,-C (O) NR
29R
29,-C (S) NR
29R
29,-S (O)
2NR
29R
29,-C (NH) NR
30R
31,-NR
29C (O) R
29,-NR
29C (S) R
29,-NR
29S (O)
2R
29,-NR
29C (O) NR
29R
29,-NR
29C (S) NR
29R
29,-NR
29S (O)
2NR
29R
29With-NR
29R
29, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
32, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38,-R
35With-R
32, and wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
36,-SR
36,-NR
37R
38,-R
35,-R
33With-R
34
In all cases, R
26, R
27And R
28Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is that tool does not have olefinic carbon to be attached to R
24O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, C
3-6Yet alkynyl--condition is that it does not have alkynes carbon to be attached to R
24O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35Yet further condition is and S, C (O), C (S), S (O) or S (O)
2Bonded R
26Not hydrogen, or
R
27And R
28With the nitrogen that is connected them in conjunction with forming cycloalkyl amino;
In all cases, R
29, R
30And R
31Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is that it does not have olefinic carbon to be attached to R
25O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, C
3-6Yet alkynyl--condition is that it does not have alkynes carbon to be attached to R
25O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, or
R
30And R
31With the nitrogen that is connected them in conjunction with forming 5-7 unit's monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle, wherein low-carbon alkyl is randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
32, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38,-R
35With-R
32, and wherein cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, 5-7 unit's monocyclic heterocycles alkyl and 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OH ,-NH
2,-OR
36,-SR
36,-NHR
36,-NR
37R
38,-R
33,-R
34With-R
35Yet further condition is and S, C (O), C (S), S (O) or S (O)
2Bonded R
29Not hydrogen;
In all cases, R
32Be independently selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
36,-SR
36,-NR
37R
38,-R
33,-R
34With-R
35
In all cases, R
33Be the low carbon chain thiazolinyl independently, described low carbon chain thiazolinyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
34Be the low-carbon (LC) alkynyl independently, described low-carbon (LC) alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
35Be low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38
In all cases, R
36, R
37And R
38Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace or-NR
37R
38Be cycloalkyl amino, yet condition is and OR
36, SR
36, NR
36, NR
37Or NR
38In any one O, S or any substituting group on the low-carbon alkyl carbon that combines of N be fluorine, yet and further condition be and S bonded R
36Not hydrogen;
U is 0,1,2,3 or 4;
V is 0,1,2,3,4 or 5;
S is 0,1,2,3 or 4, yet condition is when s=0, so p=0 and when s be 1,2,3 or 4 and during p=0, Ar so
1aNot pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or isothiazolyl and work as s=0, p=0 and be Ar
2aWhen being phenyl,
Be not
Wherein
Expression and the tie point of O and
Expression and Ar
2aTie point.
[0050] in one embodiment, formula I compound has following inferior formula (formula Ib):
Its all salt, prodrug, tautomer and isomers,
Wherein:
W, X, R
1, R
2, R
4, R
5, Y, M and p define suc as formula I;
Ar
1a, Ar
2a, R
24, R
25, u and v define suc as formula I a; With
T is 0,1,2,3 or 4, yet condition is when t=0, so p=0.
[0051] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In at least one is not a hydrogen.In one embodiment, R
1And R
2In one be not hydrogen and R
1And R
2In another is a hydrogen or halogen.In one embodiment, R
1And R
2In one be not hydrogen and R
1And R
2In another is a hydrogen.In one embodiment, R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9In one embodiment, R
1And R
2In one be-SR
9Or-OR
9, preferably-OR
9, and R
1And R
2In another is a hydrogen or halogen.In one embodiment, R
1And R
2In one be-SR
9Or-OR
9, preferably-OR
9, and R
1And R
2In another is a hydrogen.In one embodiment, R
1Be-SR
9Or-OR
9, preferably-OR
9, and R
2Be hydrogen.In one embodiment, R
2Be-SR
9Or-OR
9, preferably-OR
9, and R
1Be hydrogen.In one embodiment, R
1And R
2Two all is hydrogen.
[0052] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In at least one is halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl--randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, preferably R
1And R
2In one be hydrogen, R preferably
1Be hydrogen and R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl.
[0053] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl are randomly as to the R among the formula I
9Described being substituted.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein cycloalkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that OH, low-carbon alkyl, fluorine replace replace replace, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-and cycloalkyl that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that OH, low-carbon alkoxy, fluorine replace replace, wherein alkyl, C
3-6Alkenyl or C
3-6The naphthenic substituent of alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that OH, low-carbon alkyl, fluorine replace replace replace.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9It is low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-.
[0054] in a kind of embodiment of formula Ia or Ib compound, W is selected from-NR
51(CR
4R
5)
1-2-,-O-(CR
4R
5)
1-2-,-S-(CR
4R
5)
1-2-,-(CR
4R
5)
1-3-and-CR
6=CR
7-, R wherein
51Be hydrogen or low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that fluorine, low-carbon alkoxy, fluorine replace replace, and R wherein
4, R
5, R
6And R
7Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-.In one embodiment, W is-(CR
4R
5)
1-2-.In one embodiment, W is-(CR
4R
5)-.In one embodiment, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, R wherein
4, R
5, R
6And R
7Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is-(CR
4R
5)
1-2-, preferably-(CR
4R
5)-, be R wherein
4And R
5Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is-CH
2CH
2-or-CH
2-, preferably-CH
2-.
[0055] in a kind of embodiment of formula Ia or Ib compound, X is-C (O) OR
16Or the carboxylic acid isostere, preferably X is-COOH.In one embodiment, W is-(CR
4R
5)
1-2-, and X is-C (O) OR
16Or the carboxylic acid isostere, preferably W is-CH
2CH
2-or-CH
2-and X be-COOH.
[0056] in a kind of embodiment of formula Ia or Ib compound, p is 0.In a kind of embodiment of formula Ia compound, Ar
1aBe selected from phenyl, pyridyl, pyrimidyl and thiophenyl.In a kind of embodiment of formula Ib compound, Ar
1aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.In a kind of embodiment of formula Ia or Ib compound, Ar
1aBe selected from phenyl, pyridyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl, preferably phenyl, pyridyl, oxazolyl are with isoxazolyl.
[0057] in a kind of embodiment of formula Ia or Ib compound, R
24Be selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy or low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, R wherein
36, R
37And R
38Suc as formula defining among Ia and the Ib.In one embodiment, R
24Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, R
24Be selected from low-carbon alkyl sulfo-and low-carbon alkyl that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that halogen, low-carbon alkoxy, fluorine replace replace, wherein low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
[0058] in a kind of embodiment of formula Ia or Ib compound, Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.In one embodiment, Ar
2aBe selected from phenyl, pyridyl and thiophenyl, preferably phenyl and thiophenyl.
[0059] in a kind of embodiment of formula Ia or Ib compound, R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, wherein low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.In one embodiment, R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.In one embodiment, R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
[0060] in a kind of embodiment of formula Ia or Ib compound, M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-, preferably M be covalent linkage or-O-.
[0061] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-and p be 0.
[0062] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, p is 0, Ar
1aBe selected from phenyl, pyridyl, oxazolyl and thiazolyl and Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.
[0063] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In one, R preferably
2, be halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl--randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, the preferably low-carbon alkyl, the C that replace of fluorine, chlorine, low-carbon alkyl, fluorine
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl and R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, p is 0, Ar
1aBe selected from phenyl, pyridyl, oxazolyl and thiazolyl and Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.
[0064] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, p is 0, Ar
1aBe selected from phenyl, pyridyl, oxazolyl or thiazolyl, Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl, and M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-.
[0065] in a kind of embodiment of formula Ia or Ib compound, R
1And R
2In one, R preferably
2, be halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl, randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, the preferably low-carbon alkyl, the C that replace of fluorine, chlorine, low-carbon alkyl, fluorine
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, and R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, p=0, Ar
1aBe selected from phenyl, pyridyl, oxazolyl or thiazolyl, Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl, and M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-.
[0066] in a kind of embodiment of formula Ia or Ib compound, R
2Be-OR
9, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, p is 0, t is 0,1,2,3 or 4, s is 0, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, and Ar
2aBe phenyl or thiophenyl.
[0067] in a kind of embodiment of formula Ia or Ib compound, R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, p is 0, t is 0,1,2,3 or 4, s is 0, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, and Ar
2aBe phenyl or thiophenyl.
[0068] in a kind of embodiment of formula Ia or Ib compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl is randomly suc as formula R among the I
9Described being substituted, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, p is 0, t is 0,1,2,3 or 4, s is 0, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, phenyl preferably, R
24Be selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy or low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, R wherein
36, R
37And R
38Suc as formula among Ia and the Ib define Ar
2aBe phenyl or thiophenyl, phenyl preferably, R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, and low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.
[0069] in a kind of embodiment of formula Ia or Ib compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl is optional to be replaced with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-, R
1Be hydrogen, W is-CH
2-, X is-COOH, p is 0, t is 0,1,2,3 or 4, s is 0, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, R
24Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement, Ar
2aBe phenyl or thiophenyl, phenyl preferably, R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, and cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.
[0070] in a kind of embodiment of formula Ia or Ib compound, R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, p is 0, t is 0,1,2,3 or 4, s is 0, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, phenyl preferably, R
24Be selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy or low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, R wherein
36, R
37And R
38Suc as formula among Ia and the Ib define Ar
2aBe phenyl or thiophenyl, preferably phenyl, and R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, and low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.
[0071] in a kind of embodiment of formula Ia or Ib compound, R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH, p is 0, t is 0,1,2,3 or 4, s is 0, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, R
24Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement, Ar
2aBe phenyl or thiophenyl, preferably phenyl, and R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, and cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.
[0072] in one embodiment, formula I compound has following inferior formula (formula Ic):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
Ar
1a, Ar
2a, R
24, R
25, u and v define suc as formula Ia and Ib.
[0073] in one embodiment, formula I compound has following inferior formula (formula Id):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
Ar
1a, Ar
2a, R
24, R
25, u and v define suc as formula Ia and Ib, yet condition is to work as Ar
2aWhen being phenyl,
Be not
Wherein
Expression and the tie point of O and
Expression and Ar
2aTie point.
[0074] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In at least one is not a hydrogen.In one embodiment, R
1And R
2In one be not hydrogen and R
1And R
2In another is a hydrogen or halogen.In one embodiment, R
1And R
2In one be not hydrogen and R
1And R
2In another is a hydrogen.In one embodiment, R
1And R
2In at least one is-SR
9Or-OR
9, preferably-OR
9In one embodiment, R
1And R
2In one be-SR
9Or-OR
9, preferably-OR
9, and R
1And R
2In another is a hydrogen or halogen.In one embodiment, R
1And R
2In one be-SR
9Or-OR
9, preferably-OR
9, and R
1And R
2In another is a hydrogen.In one embodiment, R
1Be-SR
9Or-OR
9, preferably-OR
9, and R
2Be hydrogen.In one embodiment, R
2Be-SR
9Or-OR
9, preferably-OR
9, and R
1Be hydrogen.In one embodiment, R
1And R
2Two all is hydrogen.
[0075] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In at least one is halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl, randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, preferably R
1And R
2In one be hydrogen, R preferably
1Be hydrogen and R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl.
[0076] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl are randomly suc as formula the R among the I
9Described being substituted.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein cycloalkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that OH, low-carbon alkyl, fluorine replace replace replace, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-and cycloalkyl that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that OH, low-carbon alkoxy, fluorine replace replace, wherein alkyl, C
3-6Alkenyl or C
3-6The naphthenic substituent of alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that OH, low-carbon alkyl, fluorine replace replace replace.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9It is low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-.
[0077] in a kind of embodiment of formula Ic or Id compound, W is selected from-NR
51(CR
4R
5)
1-2-,-O-(CR
4R
5)
1-2-,-S-(CR
4R
5)
1-2-,-(CR
4R
5)
1-3-and-CR
6=CR
7-, R wherein
51Be hydrogen or low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that fluorine, low-carbon alkoxy, fluorine replace replace, and R wherein
4, R
5, R
6And R
7Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-.In one embodiment, W is-(CR
4R
5)
1-2-.In one embodiment, W is-(CR
4R
5)-.In one embodiment, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, R wherein
4, R
5, R
6And R
7Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is-(CR
4R
5)
1-2-, preferably-(CR
4R
5)-, be R wherein
4And R
5Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is-CH
2CH
2-or-CH
2-, preferably-CH
2-.
[0078] in a kind of embodiment of formula I c or I d compound, X is-C (O) OR
16Or the carboxylic acid isostere, preferably wherein X is-COOH.In one embodiment, W is-(CR
4R
5)
1-2-, and X is-C (O) OR
16Or the carboxylic acid isostere, preferably W is-CH
2CH
2-or-CH
2-and X be-COOH.
[0079] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.In a kind of embodiment of formula Ic or Id compound, Ar
1aBe selected from phenyl, pyridyl, oxazolyl, thiazolyl, imidazolyl and pyrazolyl, preferably phenyl, pyridyl, oxazolyl and thiazolyl.
[0080] in a kind of embodiment of formula Ic or Id compound, R
24Be selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy or low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, R wherein
36, R
37And R
38Suc as formula defining among Ia and the Ib.In one embodiment, R
24Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, R
24Be selected from low-carbon alkyl sulfo-and low-carbon alkyl that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that halogen, low-carbon alkoxy, fluorine replace replace, wherein low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
[0081] in a kind of embodiment of formula Ic or Id compound, Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.In one embodiment, Ar
2aBe selected from phenyl, pyridyl and thiophenyl, preferably phenyl and thiophenyl.
[0082] in a kind of embodiment of formula Ic or Id compound, R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, and wherein low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.In one embodiment, R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, and cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.In one embodiment, R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, R
25Be perhaloalkyl radical, for example, but without limitation, CF
3Or CF
2CF
3
[0083] in a kind of embodiment of formula Ic or Id compound, M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-, preferably M be covalent linkage or-O-.
[0084] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, and W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-.
[0085] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, Ar
1aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl, preferably phenyl, pyridyl and thiophenyl, and Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.
[0086] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In one, R preferably
2, be halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl, randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, the preferably low-carbon alkyl, the C that replace of fluorine, chlorine, low-carbon alkyl, fluorine
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl and R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, Ar
1aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl, preferably phenyl, pyridyl and thiophenyl, and Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl.
[0087] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, Ar
1aBe selected from phenyl, pyridyl, oxazolyl, thiazolyl, imidazolyl and pyrazolyl, Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl, and M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-.
[0088] in a kind of embodiment of formula Ic or Id compound, R
1And R
2In one, R preferably
2, be halogen, low-carbon alkyl or C
3-6Cycloalkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-and the C that replace
3-6Cycloalkyl, wherein C
3-6Cycloalkyl--as R
1, R
2Or the substituting group of low-carbon alkyl, randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, the preferably low-carbon alkyl, the C that replace of fluorine, chlorine, low-carbon alkyl, fluorine
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl and R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, Ar
1aBe selected from phenyl, pyridyl, oxazolyl, thiazolyl, imidazolyl and pyrazolyl, Ar
2aBe selected from phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl and pyrazolyl, and M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-.
[0089] in a kind of embodiment of formula Ic or Id compound, R
2Be-OR
9, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, and Ar
2aBe phenyl or thiophenyl.
[0090] in a kind of embodiment of formula Ic or Id compound, R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, and Ar
2aBe phenyl or thiophenyl.
[0091] in a kind of embodiment of formula Ic or Id compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl is randomly suc as formula R among the I
9Described being substituted, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, R
24Be selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy or low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, R wherein
36, R
37And R
38Suc as formula among Ia and the Ib define Ar
2aBe phenyl or thiophenyl, phenyl preferably, R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, and low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.
[0092] in a kind of embodiment of formula Ic or Id compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces R with the one or more substituting groups that are selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-
1Be hydrogen, W is-CH
2-, X is-COOH, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, R
24Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy or low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement, Ar
2aBe phenyl or thiophenyl, phenyl preferably, R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, and cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.
[0093] in a kind of embodiment of formula Ic or Id compound, R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, R
24Be selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy or low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula among Ia and the Ib define Ar
2aBe phenyl or thiophenyl, preferably phenyl, and R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, and low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.
[0094] in a kind of embodiment of formula Ic or Id compound, R
2Be low-carbon alkyl, the C of fluorine, chlorine, low-carbon alkyl, fluorine replacement
3-6The C that cycloalkyl or fluorine replace
3-6Cycloalkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH, M be covalent linkage or-O-, Ar
1aBe phenyl, pyridyl, oxazolyl or thiazolyl, R
24Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement, Ar
2aBe phenyl or thiophenyl, preferably phenyl, and R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, and cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.
[0095] in a kind of embodiment of formula Ic or Id compound, Ar
1aIt is phenyl.In other embodiments, Ar
1aBe that phenyl and M are at the S of formula Ic (O)
2Or the contraposition of the O of formula Id and Ar
1aIn conjunction with.In further embodiment, Ar
1aBe phenyl, M is at the S of formula Ic (O)
2Or the contraposition of the O of formula Id and Ar
1aIn conjunction with, and Ar
2aIt is phenyl.
[0096] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe that phenyl and M are at the S of formula Ic (O)
2Or the O of formula Id between the position and Ar
1aIn conjunction with.In further embodiment, Ar
1aBe phenyl, M is at the S of formula Ic (O)
2Or the O of formula Id between the position and Ar
1aIn conjunction with, and Ar
2aIt is phenyl.
[0097] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe phenyl, M be covalent linkage or-O-, and at the S of formula Ic (O)
2Or the contraposition of the O of formula Id and Ar
1aIn conjunction with, u is 0, v is 1, Ar
2aBe phenyl, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces R with the one or more substituting groups that are selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-
1Be hydrogen, W is-CH
2-, X is-COOH, and R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
[0098] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe phenyl, M is-O-and at the S of formula Ic (O)
2Or the contraposition of the O of formula Id and Ar
1aIn conjunction with, u is 0, v is 1, Ar
2aBe phenyl, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH, and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine, wherein R
25Contraposition and Ar at M
2aIn conjunction with.
[0099] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe phenyl, M is-O-and at the S of formula Ic (O)
2Or the contraposition of the O of formula Id and Ar
1aIn conjunction with, u is 0, v is 1, Ar
2aBe phenyl, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH, and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine, wherein R
25Position and Ar between M
2aIn conjunction with.
[0100] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe phenyl, M be covalent linkage or-O-and at the S of formula Ic (O)
2Or the O of formula Id between the position and Ar
1aIn conjunction with, u is 0, v is 1, Ar
2aBe phenyl, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces R with the one or more substituting groups that are selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-
1Be hydrogen, W is-CH
2-, X is-COOH, and R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
[0101] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe phenyl, M be covalent linkage or-O-and at the S of formula Ic (O)
2Or the O of formula Id between the position and Ar
1aIn conjunction with, u is 0, v is 1, Ar
2aBe phenyl, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH, and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine, wherein R
25Contraposition and Ar at M
2aIn conjunction with.
[0102] in a kind of embodiment of formula Ic or Id compound, Ar
1aBe phenyl, M be covalent linkage or-O-and at the S of formula Ic (O)
2Or the O of formula Id between the position and Ar
1aIn conjunction with, u is 0, v is 1, Ar
2aBe phenyl, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH, and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine, wherein R
25Position and Ar between M
2aIn conjunction with.
[0103] in the embodiment of formula I, Ia, Ib, Ic or Id compound--Ar wherein
1Or Ar
1aBe phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl or pyrazolyl, should be appreciated that it so is for stable compound is provided that ring orientation and ring replace.For instance, work as Ar
1Or Ar
1aWhen being phenyl, pyridyl, pyrimidyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl or pyrazolyl, Ar
1Or Ar
1aBe selected from following compounds, wherein A represents Ar
1Or Ar
1aWith formula I-[(CR
4R
s)
m-(Y)
p]
r-(perhaps when r=0 and L), formula Ia-O-(CR
4R
5)
s(Y)
p-, formula Ib-S (O)
2-(CR
4R
5)
t(Y)
p-, formula Ic-S (O)
2-and formula Id-tie point of O-, and B represents Ar
1Or Ar
1aWith M among formula I, Ia, Ib, Ic or the Id (perhaps when M is a key and Ar
2Or Ar
2a) tie point:
In addition, these structures are randomly located to be substituted at any one or more available annular atomses (one or more), for example, the any available ring carbon atom of imidazoles or pyrazoles or available ring nitrogen are (promptly, wherein these structures=CH-or-hydrogen of NH-is substituted base and replaces), as described in for formula I, Ia, Ib, Ic or Id.
[0104] in one embodiment, formula I compound has following inferior formula (formula Ie):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0105] in one embodiment, formula I compound has following inferior formula (formula If):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0106] in one embodiment, formula I compound has following inferior formula (formula Ig):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0107] in one embodiment, formula I compound has following inferior formula (formula Ih):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0108] in one embodiment, formula I compound has following inferior formula (formula Ii):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0109] in one embodiment, formula I compound has following inferior formula (formula Ij):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0110] in one embodiment, formula I compound has following inferior formula (formula Ik):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0111] in one embodiment, formula I compound has following inferior formula (formula Im):
Its all salt, prodrug, tautomer and isomers,
Wherein:
X, W, M, R
1And R
2Define suc as formula I; With
R
25Define suc as formula Ia and Ib.
[0112] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl are randomly suc as formula the R among the I
9Described being substituted.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein cycloalkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that OH, low-carbon alkyl, fluorine replace replace replace, and wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-and cycloalkyl that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that OH, low-carbon alkoxy, fluorine replace replace, wherein alkyl, C
3-6Alkenyl or C
3-6The naphthenic substituent of alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that OH, low-carbon alkyl, fluorine replace replace replace.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be selected from low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl, wherein low-carbon alkyl, C
3-6Alkenyl, C
3-6Alkynyl and cycloalkyl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9It is low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-.In one embodiment, R
1And R
2In one, R preferably
2, be-SR
9Or-OR
9, preferably-OR
9, R
1And R
2In another, R preferably
1, be hydrogen, and R
9Be perfluoroalkyl (CF for example
3Or CF
2CF
3) or perfluoro alkoxy (OCF for example
3Or OCF
2CF
3).
[0113] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, W is selected from-NR
51(CR
4R
5)
1-2-,-O-(CR
4R
5)
1-2-,-S-(CR
4R
5)
1-2-,-(CR
4R
5)
1-3-and-CR
6=CR
7-, R wherein
51Be hydrogen or low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that fluorine, low-carbon alkoxy, fluorine replace replace, and R wherein
4, R
5, R
6And R
7Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-.In one embodiment, W is-(CR
4R
5)
1-2-.In one embodiment, W is-(CR
4R
5)-.In one embodiment, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, R wherein
4, R
5, R
6And R
7Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is-(CR
4R
5)
1-2-, preferably-(CR
4R
5)-, be R wherein
4And R
5Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, W is-CH
2CH
2-or-CH
2-, preferably-CH
2-.
[00114] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, X is-C (O) OR
16Or the carboxylic acid isostere, preferably X is-COOH.In one embodiment, W is-(CR
4R
5)
1-2-, and X is-C (O) OR
16Or the carboxylic acid isostere, preferably W is-CH
2CH
2-or-CH
2-and X be-COOH.
[0115] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, and wherein low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.In one embodiment, R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, and cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.In one embodiment, R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.In one embodiment, R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine.In one embodiment, R
25Be perfluoroalkyl (CF for example
3Or CF
2CF
3) or perfluoro alkoxy (OCF for example
3Or OCF
2CF
3).
[0116] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-, preferably M be covalent linkage or-O-.
[0117] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, and W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-.
[0118] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
1And R
2In one, R preferably
2, be-OR
9And R
1And R
2In another, R preferably
1, be hydrogen, W is selected from-(CR
4R
5)
1-3-and-CR
6=CR
7-, preferably-CH
2CH
2-or-CH
2-, and M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-and-NR
53-, preferably M be covalent linkage or-O-.
[0119] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
2Be-OR
9, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, and M be covalent linkage or-O-.
[0120] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl is randomly suc as formula R among the I
9Described being substituted, R
1Be hydrogen, W is-CR
4R
5-, X is-C (O) OR
16Or the carboxylic acid isostere, M be covalent linkage or-O-, R
25Be selected from halogen ,-CN, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, low-carbon alkoxy, low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly suc as formula R among Ia or the Ib
25Described being substituted, and low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-R
32,-OR
36,-SR
36With-NR
37R
38, R wherein
32, R
36, R
37And R
38Suc as formula defining among Ia and the Ib.
[0121] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces R with the one or more substituting groups that are selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-
1Be hydrogen, W is-CH
2-, X is-COOH, M be covalent linkage or-O-, and R
25Be selected from halogen,-CN, low-carbon alkyl, low-carbon alkoxy, the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, low-carbon alkyl wherein, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, described substituting group is selected from fluorine, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace, and cycloalkyl wherein, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, and described substituting group is selected from fluorine,-CN, low-carbon alkyl, the low-carbon alkyl that fluorine replaces, low-carbon alkoxy, the low-carbon alkoxy that fluorine replaces, the low-carbon alkyl sulfo-that low-carbon alkyl sulfo-and fluorine replace.
[0122] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH that M is a covalent linkage, and R
25Be the low-carbon alkyl that replaces of fluorine randomly, for instance but without limitation, perfluoroalkyl (CF for example
3Or CF
2CF
3).
[0123] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH that M is a covalent linkage, and R
25Be the low-carbon alkoxy that replaces of fluorine randomly, for instance but without limitation, perfluoro alkoxy (OCF for example
3Or OCF
2CF
3).
[0124] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH that M is-O-, and R
25Be the low-carbon alkyl that replaces of fluorine randomly, for instance but without limitation, perfluoroalkyl (CF for example
3Or CF
2CF
3).
[0125] in a kind of embodiment of formula Ie, If, Ig, Ih, Ii, Ij, Ik or Im compound, R
2Be-OR
9, R wherein
9Be low-carbon alkyl, R
1Be hydrogen, W is-CH
2-, X is-COOH that M is-O-, and R
25Be the low-carbon alkoxy that replaces of fluorine randomly, for instance but without limitation, perfluoro alkoxy (OCF for example
3Or OCF
2CF
3).
[0126] in some embodiments of above-claimed cpd, such compound is left out, and wherein N (except N is the heteroaryl ring atom), O or S combine with carbon, and described carbon also combines with N (except N is the heteroaryl ring atom), O or S; Perhaps wherein N (except N is the heteroaryl ring atom), O, C (S), C (O) or S (O)
n(n is 0-2) combines with the olefinic carbon of alkenyl or combines with the alkynes carbon of alkynyl; Therefore, in some embodiments, comprise that the compound of for example following key is excluded the present invention :-NR-CH
2-NR-,-O-CH
2-NR-,-S-CH
2-NR-,-NR-CH
2-O-,-O-CH
2-O-,-S-CH
2-O-, NR-CH
2-S-,-O-CH
2-S-,-S-CH
2-S-,-NR-CH=CH-,-CH=CH-NR-,-NR-C ≡ C-,-C ≡ C-NR-,-O-CH=CH-,-CH=CH-O-,-O-C ≡ C-,-C ≡ C-O-,-S (O)
0-2-CH=CH-,-CH=CH-S (O)
0-2-,-S (O)
0-2-C ≡ C-,-C ≡ C-S (O)
0-2-,-C (O)-CH=CH-,-CH=CH-C (O)-,-C ≡ C-C (O)-,-C (O)-C ≡ C-,-C (S)-CH=CH-,-CH=CH-C (S)-,-C ≡ C-C (S)-or-C (S)-C ≡ C-.
[0127] mentioning of this paper formula I compound comprised to specifically the mentioning of the subgroup of formula I compound described herein and subclass (for example, comprising formula Ia-Im and above-mentioned all embodiments), unless indicate reverse situation.When the compound that formula I is described in detail in detail or a plurality of compound,, the detailed description of such compound (one or more) is comprised this compound (one or mores') pharmacy acceptable salt unless clearly indicate reverse situation.
[0128] another aspect of the present invention relates to the new purposes that formula I compound is used for the treatment of the disease relevant with PPARs.
[0129] another aspect of the present invention provides such composition, and described composition comprises treatment upward formula I compound and at least a pharmaceutically acceptable carrier, vehicle and/or the thinner of significant quantity.Said composition can comprise a plurality of different pharmaceutically active compounds, and it comprises the compound of one or more formula I.
[0130] on the other hand, formula I compound can be used for preparing such medicine, described medicine be used for the treatment of the disease of PPAR mediation or illness or wherein the adjusting of PPAR the disease or the illness of result of treatment are provided.Further, this disease or illness are selected from body weight disease (obesity for example, overweight state, Bulimia nerovsa and anorexia nervosa), lipoid dyscrasias (hyperlipidemia for example, the unusual lipidemia (dyslipidemia) that comprises unusual lipidemia of the property followed diabetes and the unusual lipidemia of Combination, slight alpha lipoprotein mass formed by blood stasis (hypoalphalipoproteinemia), hypertriglyceridemia (hypertriglyceridemia), hypercholesterolemia and low HDL (high-density lipoprotein (HDL) (high density lipoprotein))), metabolic trouble (metabolism syndrome for example, type ii diabetes, type i diabetes, hyperinsulinemia (hyperinsulinemia), impaired glucose tolerance, insulin resistance, comprise neuropathy, ephrosis, retinopathy, diabetes type ulcer of foot and cataract are at interior diabetic complication, cardiovascular diseases (hypertension for example, coronary heart disease, in heart failure, congestive heart failure, atherosclerosis, arteriosclerosis, apoplexy, cerebrovascular disease, myocardial infarction, peripheral vascular disease), inflammation (for example, autoimmune disorder is such as vitiligo, uveitis (uveitis), pemphigus foliaceus, inclusion body myositis, polymyositis, dermatomyositis, scleroderma, Exophthalmus goiter (Grave ' s disease), Hashimoto's disease (Hashimoto ' s disease), chronic graft versus host disease (chronic graft versus hostdisease), rheumatoid arthritis, inflammatory bowel trace integration disease, Crohn's disease (Crohn ' s disease), systemic lupus erythematous, sjogren syndrome (Sjogren ' s Syndrome), and multiple sclerosis, disease such as the asthma and the chronic obstructive pulmonary disease that relate to airway inflammation, with other organ inflammation, such as multicystic kidney disease (PKD), polycystic ovarian syndrome, pancreatitis, ephritis and hepatitis), dermatosis (for example epithelium hyperplasia disease such as eczema and psoriasis, dermatitis, it comprises atopic dermatitis, contact dermatitis, allergic dermatitis and chronic dermatitis, with the damage wound healing), neurodegenerative disease (for example, alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Spinal injury and demyelinating disease, it comprises acute disseminated encephalomyelitis (acutedisseminated encephalomyelitis) and guillain-Barre syndrome (Guillain-Barre syndrome)), blood coagulation disease (for example thrombus disease), gastrointestinal illness (for example big or little intestinal obstruction), urogenital disease (renal insufficiency for example, erective dysfunction, the urinary incontinence and neurogenic bladder), ophthalmic diseases is (as eye inflammation, macular degeneration and pathologic neovascularization), infect (HCV for example, HIV and Hp), nervosa or inflammatory pain, sterile and cancer.
[0131] on the other hand, the invention provides test kit, it comprises composition as described herein.In some embodiments, described composition for example is packaged in capsule, bottle, the flask, packaged composition can further be packaged in as in box, big envelope or the bag, described composition is used to give Mammals, for example people by FDA (Food and Drug Adminstration) (U.S.Food and Drug Administration) or similar administration (regulatory agency) approval; Described composition goes through to give Mammals, and for example the people is used for disease or illness that PPAR mediates; This test kit comprise the working instructions write or described composition be suitable for or ratify to give Mammals for example human in the disease of PPAR mediation or other explanation of illness; Described composition is packed with unitary dose or one-pack type, for example, and the pill of single dose, capsule or analogue.
[0132] another aspect, the invention provides a kind of method, be used in animal target treatment or preventing disease or illness, the for example disease or the illness of PPAR mediation, or wherein the adjusting of PPAR provides the disease or the illness of result of treatment, and this is to be undertaken by the prodrug of the formula I compound of giving described object administering therapeutic significant quantity, such compound or such compound or the pharmacy acceptable salt of prodrug.This compound can be individually dosed or as the part administration of pharmaceutical composition.On the one hand, this method relates to the formula I compound of described object administering therapeutic significant quantity and one or more other therapies of this disease or illness.
[0133] another aspect, the invention provides a kind of method, be used for the treatment of or prevent the disease or the illness of PPAR mediation, or wherein the adjusting of PPAR provides the disease or the illness of result of treatment, and wherein said method relates to the composition that comprises formula I compound to described object administering therapeutic significant quantity.
[0134] relate to treat or preventing disease or illness aspect and in the embodiment, this disease or illness are selected from body weight disease (obesity for example, overweight state, Bulimia nerovsa and anorexia nervosa), lipoid dyscrasias (hyperlipidemia for example, the unusual lipidemia (dyslipidemia) that comprises unusual lipidemia of the property followed diabetes and the unusual lipidemia of Combination, slight alpha lipoprotein mass formed by blood stasis (hypoalphalipoproteinemia), hypertriglyceridemia (hypertriglyceridemia), hypercholesterolemia and low HDL (high-density lipoprotein (HDL) (high densitylipoprotein))), metabolic trouble (metabolism syndrome for example, type ii diabetes, type i diabetes, hyperinsulinemia (hyperinsulinemia), impaired glucose tolerance, insulin resistance, comprise neuropathy, ephrosis, retinopathy, diabetes type ulcer of foot and cataract are at interior diabetic complication, cardiovascular diseases (hypertension for example, coronary heart disease, in heart failure, congestive heart failure, atherosclerosis, arteriosclerosis, apoplexy, cerebrovascular disease, myocardial infarction, peripheral vascular disease), inflammation (for example, autoimmune disorder is such as vitiligo, uveitis (uveitis), pemphigus foliaceus, inclusion body myositis, polymyositis, dermatomyositis, scleroderma, Exophthalmus goiter (Grave ' s disease), Hashimoto's disease (Hashimoto ' s disease), chronic graft versus host disease (chronic graft versus host disease), rheumatoid arthritis, inflammatory bowel trace integration disease, Crohn's disease (Crohn ' s disease), systemic lupus erythematous, sjogren syndrome (Sjogren ' s Syndrome), and multiple sclerosis, disease such as the asthma and the chronic obstructive pulmonary disease that relate to airway inflammation, with other organ inflammation, such as multicystic kidney disease (PKD), polycystic ovarian syndrome, pancreatitis, ephritis and hepatitis), dermatosis (for example epithelium hyperplasia disease such as eczema and psoriasis, dermatitis, it comprises atopic dermatitis, contact dermatitis, allergic dermatitis and chronic dermatitis, with impaired wound healing), neurodegenerative disease (for example, alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Spinal injury and demyelinating disease, it comprises acute disseminated encephalomyelitis (acute disseminated encephalomyelitis) and guillain-Barre syndrome (Guillain-Barre syndrome)), blood coagulation disease (for example thrombus disease), gastrointestinal illness (for example big or little intestinal obstruction), urogenital disease (renal insufficiency for example, erective dysfunction, the urinary incontinence and neurogenic bladder), ophthalmic diseases is (as eye inflammation, macular degeneration and pathologic neovascularity generate), infect (HCV for example, HIV and Hp), nervosa or inflammatory pain, sterile and cancer.
[0135] relate to formula I compound aspect some embodiments in, this compound has specificity to any one or any two of PPAR α, PPAR δ and PPAR γ, for example PPAR α is had specificity; PPAR δ had specificity; PPAR γ had specificity; PPAR α and PPAR δ had specificity; PPAR α and PPAR γ had specificity; Or PPAR δ and PPAR γ had specificity.Such specificity is meant that this compound has the activity (preferably greatly at least 10,20,50 or 100 times or more active) of big at least 5 times of other PPAR of comparison (one or more) to this specific PPAR (one or more), wherein said activity is to adopt to be suitable for measuring the active biochemical test mensuration of PPAR, for example those of ordinary skills' any test known or as herein described.In another embodiment, compound all has remarkable activity to PPAR α, PPAR δ and all three of PPAR γ.
[0136] in some embodiments, among PPAR α, PPAR δ and the PPAR γ at least one, the EC of formula I compound
50To be that 100nM is following, 50nM following, 20nM is following, 10nM is following, 5nM is following or below the 1nM, such as in the PPAR activity test of common acceptance mensuration.In one embodiment, among PPAR α, PPAR δ and the PPAR γ any at least two, the EC of formula I compound
50To be below the 100nM, below the 50nM, below the 20nM, below the 10nM, below the 5nM or below the 1nM.In one embodiment, among PPAR α, PPAR δ and the PPAR γ all these three, the EC of formula I compound
50To be below the 100nM, below the 50nM, below the 20nM, below the 10nM, below the 5nM or below the 1nM.In addition in the above-mentioned embodiment any one, compound of the present invention can be any two specific agonist among any one or PPAR α, PPAR δ and the PPAR γ among PPAR α, PPAR δ and the PPAR γ.One specific agonist is such among PPAR α, PPAR δ and the PPAR γ: to one EC among PPAR α, PPAR δ and the PPAR γ
50Will be than other EC of two among PPAR α, PPAR δ and the PPAR γ
50Little about at least 5 times, also have 10 times, also have 20 times, also have 50 times or about at least 100 times.Two specific agonist is such among PPAR α, PPAR δ and the PPAR γ: to two each EC among PPAR α, PPAR δ and the PPAR γ
50Will be than the EC of another one among PPAR α, PPAR δ and the PPAR γ
50Little about at least 5 times, also have 10 times, also have 20 times, also have 50 times or about at least 100 times.
[0137] in some embodiments of the present invention, PPARs is had active formula I compound also have the pharmacological property of expectation.In some embodiments, the pharmacological property of expectation is the general activity of PPAR; PPAR selectivity to any single PPAR (PPAR α, PPAR δ or PPAR γ); Selectivity to any two kinds of PPARs (PPAR α and PPAR δ, PPAR α and PPAR γ or PPAR δ and PPAR γ); Or following any or multiple: serum half-life be longer than 2 hours, in addition be longer than 4 hours, be longer than 8 hours in addition, water-soluble, the oral bioavailability rate is higher than 10%, is higher than 20% in addition.
[0138] other embodiment will become obvious owing to following detailed description and claims.
Embodiment
[0139] as pointed in the above-mentioned summary of the invention, the present invention relates to peroxisome proliferation-activated receptors (peroxisome proliferator-activated receptors (PPARs)), it is identified in human and other Mammals.Identified one group of compound corresponding to formula I, it has activity for PPARs one or more, is in particular one or more people PPARs are had active compound.Such compound can be used as the agonist at PPARs, it comprises among PPAR α, PPAR δ and the PPAR γ at least one agonist and two PPAR agonist and general agonist, for example agonist of the agonist of PPAR α and PPAR δ, PPAR α and PPAR γ, PPAR δ and PPAR γ or PPAR α, PPAR δ and PPAR γ.
[0140] unless otherwise noted, as used herein, use following definition:
[0141] " halogen (Halogen) "--independent or combination is used, and is meant all halogens, just chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).
[0142] " hydroxyl " (hydroxyl) or " hydroxyl " (hydroxy) refer to group-OH.
[0143] " thiol " refers to group-SH.
[0144] " low-carbon alkyl " separately or jointly is meant the group derived from alkane, and it comprises 1 to 6 carbon atom (if being not particularly limited), and it comprises straight chained alkyl or branched-chain alkyl.The straight or branched alkyl group connects to produce stable compound at any and point.In many embodiments, low-carbon alkyl is straight chained alkyl or branched-chain alkyl, comprises 1-6, a 1-4 or 1-2 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl and similar group." low-carbon alkyl of replacement " is meant the low-carbon alkyl that replaces independently with one or more substituting groups as herein described, for example in the description to formula I compound, it is included in any assorted alkyl of substituted cycloalkyl, ring, aryl and heteroaryl of the connection of atom place of reaching to produce the description of stable compound.Preferably, the replacement of low-carbon alkyl is with 1,2,3,4 or 5 substituting group, also can be 1,2 or 3 substituting group.For instance, " fluorine replace low-carbon alkyl " is meant the low-carbon alkyl that is replaced by one or more fluorine atoms, as perfluoroalkyl, wherein preferably, low-carbon alkyl with 1,2,3,4 or 5 fluorine atom, also can be with 1,2 or 3 fluorine atom replacement.
[0145] " low carbon chain thiazolinyl " separately or jointly is meant and contains 2-6 carbon atom (if being not particularly limited) and at least 1, preferred 1-3, more preferably 1-2, the straight or branched hydrocarbon of 1 carbon-carbon double bond most preferably.Carbon-carbon double bond can be included in the straight or branched part.The low-carbon (LC) non-limiting examples of alkenyls comprises vinyl, propenyl, pseudoallyl, butenyl and similar group." the low carbon chain thiazolinyl of replacement " is meant the low carbon chain thiazolinyl that replaces independently with one or more substituting groups as herein described, for example in the description to formula I compound, it is included in any assorted alkyl of substituted cycloalkyl, ring, aryl and heteroaryl of the connection of atom place of reaching to produce the description of stable compound.Preferably, the replacement of low carbon chain thiazolinyl is with 1,2,3,4 or 5 substituting group, also can be 1,2 or 3 substituting group.For instance, " the low carbon chain thiazolinyl that fluorine replaces " is meant the low carbon chain thiazolinyl that is replaced by one or more fluorine atoms, and wherein preferably, the low carbon chain thiazolinyl also can be that 1,2 or 3 fluorine atom replaces with 1,2,3,4 or 5 fluorine atom.Should be appreciated that substituting group connects to produce stable compound at any atom place that reaches, the replacement of alkenyl is such: halogen, C (O), C (S), C (NH), S (O), S (O)
2, O, S or N (except N is the heteroaryl ring atom) combine with its olefinic carbon atom.In addition, alkenyl be the substituting group of another part or part such as-OR ,-NHR ,-situation of the R group of C (O) R etc. under, the replacement of this part is such: its any C (O), C (S), S (O), S (O)
2, O, S or N (except N is the heteroaryl ring atom) combine with the olefinic carbon of alkenyl substitutents or R group.In addition, alkenyl be the substituting group of another part or part such as-OR ,-NHR ,-situation of the R group of C (O) NHR etc. under, the replacement of alkenyl R base is such: with any O, the S of this part or the replacement of N (except N is the heteroaryl ring atom) bonded alkenyl carbon such replacement is foreclosed--described replacement will cause substituent any O, S or N (except N is the heteroaryl ring atom) to be attached on any O, the S or N bonded alkenyl carbon with this part." alkenyl carbon " is meant any carbon in the alkenyl, no matter be part saturated or carbon-carbon double bond." olefinic carbon " is meant the carbon in the alkenyl, and it is the part of carbon-carbon double bond.
[0146] " low-carbon (LC) alkynyl " separately or jointly is meant the straight or branched hydrocarbon that contains 2-6 carbon atom (if being not particularly limited), and it contains at least 1, preferred 1 carbon carbon triple bond.The example of alkynyl comprises ethynyl, proyl, butynyl and similar group." the low-carbon (LC) alkynyl of replacement " is meant the low-carbon (LC) alkynyl that replaces independently with one or more substituting groups as herein described, for example in the description to formula I compound, it is included in any assorted alkyl of substituted cycloalkyl, ring, aryl and heteroaryl of the connection of atom place of reaching to produce the description of stable compound.Preferably, the replacement of low-carbon (LC) alkynyl is with 1,2,3,4 or 5 substituting group, also can be 1,2 or 3 substituting group.For instance, " fluorine replace low-carbon (LC) alkynyl " is meant the low-carbon (LC) alkynyl that is replaced by one or more fluorine atoms, wherein preferably, the low-carbon (LC) alkynyl with 1,2,3,4 or 5 fluorine atom, also can be 1,2 or 3 fluorine atom replacement.Should be appreciated that substituting group connects to produce stable compound at any atom place that reaches, the replacement of alkynyl is such: halogen, C (O), C (S), C (NH), S (O), S (O)
2, O, S or N (except N is the heteroaryl ring atom) combine with its alkynes carbon atom.In addition, alkynyl be the substituting group of another part or part such as-OR ,-NHR ,-situation of the R group of C (O) R etc. under, the replacement of this part is such: its any C (O), C (S), S (O), S (O)
2, O, S or N (except N is the heteroaryl ring atom) combine with the alkynes carbon of alkynyl substituted base or R group.In addition, alkynyl be the substituting group of another part or part such as-OR ,-NHR ,-situation of the R group of C (O) NHR etc. under, the replacement of alkynyl R base is such: with any O, the S of this part or the replacement of N (except N is the heteroaryl ring atom) bonded alkynyl carbon such replacement is foreclosed--described replacement will cause substituent any O, S or N (except N is the heteroaryl ring atom) to be attached on any O, the S or N bonded alkynyl carbon with this part." alkynyl carbon " is meant any carbon in the alkynyl, no matter be saturated or carbon carbon triple-linked part." alkynes carbon " is meant the carbon in the alkynyl, and it is a carbon carbon triple-linked part.
[0147] " low-carbon alkoxy " is meant group-OR
a, R wherein
aIt is low-carbon alkyl." low-carbon alkoxy of replacement " is meant such low-carbon alkoxy, wherein R
aBe the low-carbon alkyl that replaces with one or more substituting groups as herein described, for example in the description to formula I compound, it is included in any assorted alkyl of substituted cycloalkyl, ring, aryl and heteroaryl of the connection of atom place of reaching to produce the description of stable compound.Preferably, the replacement of low-carbon alkoxy is with 1,2,3,4 or 5 substituting group, also can be 1,2 or 3 substituting group.For instance, " low-carbon alkoxy that fluorine replaces " is meant that wherein low-carbon alkyl is by the low-carbon alkoxy of one or more fluorine atoms replacements, and wherein preferably, low-carbon alkoxy also can be that 1,2 or 3 fluorine atom replaces with 1,2,3,4 or 5 fluorine atom.Should be appreciated that the substituting group on the alkoxyl group connects to produce stable compound at any atom place that reaches, the replacement of alkoxyl group is such: O, S or N (except N is the heteroaryl ring atom) do not combine with the alkyl carbon that is attached to alkoxyl group O.In addition, be described at alkoxyl group under the substituent situation of another part, alkoxyl group oxygen does not combine with the O that is attached to another part, S or the olefinic carbon of N (except N is the heteroaryl ring atom) or another part or the carbon atom on the alkynes carbon.
[0148] " low-carbon alkyl sulfo-" is meant group-SR
b, R wherein
bIt is low-carbon alkyl." the low-carbon alkyl sulfo-of replacement " is meant such low-carbon alkyl sulfo-, wherein R
bBe the low-carbon alkyl that replaces with one or more substituting groups as herein described, for example in the description to formula I compound, it is included in any substituted cycloalkyl, ring heteroaryl, aryl and heteroaryl of the connection of atom place of reaching to produce the description of stable compound.Preferably, the replacement of low-carbon alkyl sulfo-is with 1,2,3,4 or 5 substituting group, also can be 1,2 or 3 substituting group.For instance, " the low-carbon alkyl sulfo-that fluorine replaces " is meant that wherein low-carbon alkyl is by the low-carbon alkyl sulfo-of one or more fluorine atoms replacements, wherein preferably, the low-carbon alkyl sulfo-also can be that 1,2 or 3 fluorine atom replaces with 1,2,3,4 or 5 fluorine atom.Should be appreciated that the substituting group on the alkylthio connects to produce stable compound at any atom place that reaches, the replacement of alkylthio is such: O, S or N (except N is the heteroaryl ring atom) not be attached to alkylthio S on alkyl carbon combine.In addition, be described at alkylthio under the substituent situation of another part, alkylthio sulphur does not combine with the O that is attached to another part, S or the olefinic carbon of N (except N is the heteroaryl ring atom) or another part or the carbon atom on the alkynes carbon.
[0149] " amino (amino) " or " amine (amine) " are meant group-NH
2" alkyl monosubstituted amino " is meant group-NHR
c, R wherein
cIt is low-carbon alkyl." dialkyl amido " is meant group-NR
cR
d, R wherein
cAnd R
dBe low-carbon alkyl independently." cycloalkyl amino " is meant group-NR
eR
f, R wherein
eAnd R
fCombine with nitrogen and to form 5-7 unit Heterocyclylalkyl, wherein this Heterocyclylalkyl can be included in the other heteroatoms of this intra-annular, for example O, N or S, and also can further be replaced by low-carbon alkyl.The example of 5-7 unit Heterocyclylalkyl includes but not limited to piperidines, piperazine, 4-methylpiperazine, morpholine and thiomorpholine.Be to be understood that, when alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino is the substituting group of other parts, be connected when producing stable compound at any atom place that reaches, do not combine with the O that is attached to another part, S or the olefinic carbon of N (except N is the heteroaryl ring atom) or another part or the carbon atom on the alkynes carbon as the nitrogen of substituent alkyl monosubstituted amino, dialkyl amido or cycloalkyl amino.
[0150] " carboxylic acid isostere (carboxylic acid isostere) " is meant such part, and described part is selected from thiazolidinedione (promptly
), hydroxamic acid (promptly-C (O) NHOH), acyl group-cyanamide (promptly-C (O) NHCN), tetrazolium (promptly
), 3-or 5-hydoxyisoxazole (promptly
Or
), 3-or 5-hydroxyl isothiazole (promptly
Or
), sulphonate (promptly-S (O)
2OH) and sulphonamide (promptly-S (O)
2NH
2).In functional term, the carboxylic acid isostere relies on similar physical properties simulation carboxylic acid, and described physical properties includes but not limited to molecular size, charge distribution or shape of molecule.3-or 5-hydoxyisoxazole or 3-or 5-hydroxyl isothiazole can be randomly with low-carbon alkyls or randomly with 1,2 or 3 low-carbon alkyl replacements that substituting group replaces, described substituting group is selected from fluorine, aryl and heteroaryl, wherein aryl or heteroaryl can be further randomly replaced by 1,2 or 3 substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that halogen, low-carbon alkyl, fluorine replace replace replace.The nitrogen of sulphonamide can be randomly replaces with following substituting group, described substituting group be selected from low-carbon alkyl that low-carbon alkyl, fluorine replace, ethanoyl (promptly-C (O) CH
3), aryl and heteroaryl, wherein aryl or heteroaryl can be further randomly replaced with 1,2 or 3 substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-that low-carbon alkoxy, low-carbon alkyl sulfo-and fluorine that low-carbon alkyl, low-carbon alkoxy, fluorine that halogen, low-carbon alkyl, fluorine replace replace replace.
[0151] " aryl " separately or jointly is meant the member ring systems of monocycle or dicyclo, and described system contains aromatic hydrocarbon such as phenyl or naphthyl, its can be randomly with preferred 5-7 unit, more preferably the cycloalkyl or the Heterocyclylalkyl of 5-6 unit ring condense." arylidene " refers to divalent aryl.
[0152] " heteroaryl " separately or jointly, refer to have the monocyclic aromatic rings structure of 5 or 6 annular atomses, or have two cyclophane perfume base groups of 8 to 10 atoms, it has one or more, preferably has 1-4,1-3 more preferably, even 1-2 heteroatoms more preferably, described heteroatoms is independently selected from O, S and N.Heteroaryl also intends comprising the S or the N of oxidation, and as sulfinyl, alkylsulfonyl and uncle encircle the N-oxide compound of nitrogen.Carbon or nitrogen-atoms are the tie points of heteroaryl ring structure, so that produce stable compound.The example of heteroaryl includes but not limited to pyridyl, pyridazinyl, pyrazinyl, quinoxalinyl, indolizine base, benzo [b] thienyl, quinazolyl, purine radicals, indyl, quinolyl, pyrimidyl, pyrryl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, Evil thiadiazolyl group (oxathiadiazolyl), isothiazolyl, tetrazyl, imidazolyl, triazolyl, furyl, benzofuryl and indyl." nitrogenous heteroaryl " is meant that wherein any heteroatom is the heteroaryl of N." heteroarylidene " refers to the divalence heteroaryl.
[0153] " cycloalkyl " refers to 3-10 ring members of every ring, also can be 3-8 ring members, the monocyclic, bicyclic or tricyclic carbocyclic ring system of the saturated or unsaturated non-fragrance of 3-6 ring members more preferably, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and similar group.
[0154] " Heterocyclylalkyl " refers to have the saturated or unsaturated non-aromatic ring alkyl of 5 to 10 atoms, and wherein 1 to 3 carbon atom in the ring replaces with heteroatoms O, S or N, and heteroaryl-condensed with benzene or 5-6 unit ring randomly.Heterocyclylalkyl also intends comprising the S or the N of oxidation, encircles the N-oxide compound of nitrogen as sulfinyl, alkylsulfonyl and uncle.Heterocyclylalkyl also intends comprising such compound, and one that wherein encircles in the carbon can be that oxygen replaces, that is, this ring carbon is carbonyl, as lactone and lactan.The tie point of heterocycloalkyl ring is at carbon atom or nitrogen-atoms place, makes to keep stable ring.The example of Heterocyclylalkyl includes but not limited to, morpholinyl, tetrahydrofuran base, dihydropyridine base, piperidyl, pyrrolidyl, pyrrolidone-base, piperazinyl, dihydro benzo furyl and indolinyl.
[0155] except as otherwise noted, " the optional aryl that replaces ", " the optional arylidene that replaces ", " the optional heteroaryl that replaces ", " the optional heteroarylidene that replaces ", " the optional cycloalkyl that replaces " and " the optional Heterocyclylalkyl that replaces " refers to respectively by one or more, preferred 1,2,3,4 or 5, also can be 1,2 or 3 aryl that substituting group randomly replaces independently, arylidene, heteroaryl, heteroarylidene, cycloalkyl and Heterocyclylalkyl, described substituting group is connected to any atom that reaches to produce stable compound, and wherein said substituting group is selected from: halogen,-OH,-NH
2,-NO
2,-CN ,-C (O) OH ,-C (S) OH ,-C (O) NH
2,-C (S) NH
2,-S (O)
2NH
2,-NHC (O) NH
2,-NHC (S) NH
2,-NHS (O)
2NH
2,-C (NH) NH
2,-OR
g,-SR
g,-OC (O) R
g,-OC (S) R
g,-C (O) R
g,-C (S) R
g,-C (O) OR
g,-C (S) OR
g,-S (O) R
g,-S (O)
2R
g,-C (O) NHR
g,-C (S) NHR
g,-C (O) NR
gR
g,-C (S) NR
gR
g,-S (O)
2NHR
5,-S (O)
2NR
gR
g,-C (NH) NHR
g,-C (NH) NR
hR
i,-NHC (O) R
g,-NHC (S) R
g,-NR
gC (O) R
g,-NR
gC (S) R
g,-NHS (O)
2R
2,-NR
gS (O)
2R
g,-NHC (O) NHR
g,-NHC (S) NHR
g,-NR
gC (O) NH
2,-NR
gC (S) NH
2,-NR
gC (O) NHR
g,-NR
gC (S) NHR
g,-NHC (O) NR
gR
g,-NHC (S) NR
gR
g,-NR
gC (O) NR
gR
g,-NR
gC (S) NR
gR
g,-NHS (O)
2NHR
g,-NR
6S (O)
2NH
2,-NR
gS (O)
2NHR
g,-NHS (O)
2NR
gR
g,-NR
gS (O)
2NR
gR
g,-NHR
g,-NR
gR
g, R
j,-R
kWith-R
m
Wherein under each situation ,-R
g,-R
hWith-R
iBe independently selected from-R
n,-R
oWith-R
p, or
-R
hWith-R
iWith the nitrogen that is connected them in conjunction with forming 5-7 unit's Heterocyclylalkyl or 5 or 7 membered nitrogen-containing heteroaryl bases, wherein 5-7 unit's Heterocyclylalkyl or 5 or 7 membered nitrogen-containing heteroaryl bases are randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from halogen, cycloalkyl amino ,-NO
2,-CN ,-OH ,-NH
2,-OR
t,-SR
t,-NHR
t,-NR
tR
t,-R
qWith-R
u
Wherein each-R
jBe low-carbon alkyl independently, described low-carbon alkyl is randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from fluorine, cycloalkyl amino ,-OH ,-NH
2,-OR
t,-OR
u,-SR
t,-SR
u,-NHR
t,-NHR
u,-NR
tR
u,-NR
tR
t,-NR
uR
u,-R
jWith-R
m
Wherein each-R
kBe low carbon chain thiazolinyl and low-carbon (LC) alkynyl independently, wherein low carbon chain thiazolinyl or low-carbon (LC) alkynyl randomly use one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from fluorine, cycloalkyl amino ,-OH ,-NH
2,-OR
t,-OR
u,-SR
t,-SR
u,-NHR
t,-NHR
u,-NR
tR
u,-NR
tR
t,-NR
uR
u,-R
jWith-R
m
Wherein each-R
mBe independently selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from halogen, cycloalkyl amino ,-NO
2,-CN ,-OH ,-NH
2,-OR
t,-OR
u,-SR
t,-SR
u,-NHR
t,-NHR
u,-NR
tR
u,-NR
tR
t,-NR
uR
u,-R
qWith-R
u
Wherein each-R
nBe low-carbon alkyl independently, described low-carbon alkyl is randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from fluorine, cycloalkyl amino ,-OH ,-NH
2,-OR
t,-OR
u,-SR
t,-SR
u,-NHR
t,-NHR
u,-NR
tR
u,-NR
tR
t,-NR
uR
uWith-R
mYet condition is and any OR
g, SR
gOr NR
gAny O, S or any substituting group on the N bonded alkyl carbon be selected from fluorine and-R
m
Wherein each-R
oBe independently selected from C
3-6Alkenyl and C
3-6Alkynyl, wherein C
3-6Alkenyl and C
3-6Alkynyl is randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from fluorine, cycloalkyl amino ,-OH ,-NH
2,-OR
t,-OR
u,-SR
t,-SR
u,-NHR
t,-NHR
u,-NR
tR
u,-NR
tR
t,-NR
uR
u,-R
jWith-R
mYet condition is and any OR
g, SR
gOr NR
gAny O, S or any substituting group on N bonded alkenyl or the alkynyl carbon be selected from fluorine ,-R
jWith-R
m
Wherein each-R
pBe independently selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from halogen, cycloalkyl amino ,-NO
2,-CN ,-OH ,-NH
2,-OR
t,-OR
u,-SR
t,-SR
u,-NHR
t,-NHR
u,-NR
tR
u,-NR
tR
t,-NR
uR
u,-R
qWith-R
u
Wherein each-R
qBe independently selected from low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein low-carbon alkyl randomly use one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group is selected from-R
u, fluorine, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that replace, and wherein low carbon chain thiazolinyl or low-carbon (LC) alkynyl are randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group is selected from-R
u, fluorine, low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that replace;
Wherein each-R
tBe independently selected from low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl, wherein low-carbon alkyl randomly use one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group is selected from-R
u, fluorine, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that replace, yet condition is and-OR
tO ,-SR
tS or-NHR
t,-NR
tR
tOr-NR
tR
uN bonded low-carbon alkyl carbon on any substituting group be fluorine or-R
u, and C wherein
3-6Alkenyl or C
3-6Alkynyl is randomly used one or more, and preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group is selected from-R
u, fluorine, low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that replace, yet condition is and-OR
tO ,-S R
tS or-NHR
t,-NR
tR
tOr-NR
tR
uN bonded C
3-6Alkenyl or C
3-6Any replacement on the alkynyl carbon be the low-carbon alkyl that replaces of fluorine, low-carbon alkyl, fluorine or-R
u
Wherein each-R
uBe independently selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly used one or more, preferably 1,2,3,4 or 5, also have 1,2 or 3 substituting group to replace, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace.
[0156] as used herein, relevant with PPAR modulation compound, binding compounds or part, term " has specificity (specific for PPAR) to PPAR " be meant that with relevant similar terms specific compound is with than being attached on the PPAR on other biomolecules statistics higher degree, for example at least 2,3,4,5,10,20,50,100 or 1000 times of ground combinations greatly, described other biomolecules may be present in the specific organism or separate in specific organism at first.Equally, be pointed out that under biological activity rather than the bonded situation, term " PPAR is had specificity (specific for PPAR) " and is meant specific compound than other biomolecules have bigger be attached to PPAR and go up relevant biological activity (for example, with the level shown in the binding specificity).Similarly, this specificity can be at the specific ppar with respect to other PPARs, and described other PPARs may be present in the specific organism or separate in specific organism at first.
[0157] same in the context of the compound that is attached to bio-molecular target, term " higher specificity " is meant compound than being attached to a greater degree on the particular target in conjunction with another biomolecules that can exist under the condition or a plurality of biomolecules relevant, wherein with such other biomolecules in conjunction with producing than being attached to biological activitys different on the described particular target.In some cases, specificity is that for example under the situation of PPARs, this reference can be other acceptor in some cases with reference to one group of limited other biomolecules, and perhaps for specific ppar, it can be other PPARs.In some embodiments, higher specificity is big at least 2,3,4,5,8,10,50,100,200,400,500 or 1000 times a specificity.With the context of the interactional part of PPARs in, term " right ... activity (activity on) ", " right ... activity (activitytoward) " and similar terms be meant at least one PPAR the EC of such part
50Be that 10 μ M are following, 1 μ M following, 100nM is following, 50nM is following, 20nM is following, 10nM is following, 5nM is following or below the 1nM, such as in the PPAR activity test of generally acknowledging usually mensuration.
[0158] term " composition " or " pharmaceutical composition " are meant and are fit to expect that animal target is used for the treatment of the preparation of purpose.Said preparation comprises treatment upward at least a active compound and at least a pharmaceutically acceptable carrier or the vehicle of significant quantity (a therapeutically significant quantity) (i.e. significant quantity (a therapeutically effective amount) is gone up in treatment), and it is to be fit to the form preparation to the object administration.Therefore, said preparation is " pharmaceutically acceptable ", and this shows that it does not possess makes quite careful doctor practitioner avoid the characteristic that this material is used to patient, and this has considered disease or illness and the corresponding route of administration that will treat.In many cases, such pharmaceutical composition is a sterile preparation, for example is used for injection.
[0159] term " the PPAR mediation " disease or illness and similar terms are meant such disease or illness, wherein the biological function of PPAR has influenced the development and/or the process of this disease or illness, and/or wherein the adjusting of PPAR has changed development, process and/or the symptom of this disease or illness.Similarly, phrase " PPAR regulates provides result of treatment (atherapeutic benefit) " is meant that the activity level of PPAR shows that such adjusting has reduced this severity of disease and/or time length in the controlled plant, reduce the possibility of this disease or illness or delayed the outbreak of this disease or illness, and/or made one or more symptoms of this disease or illness improve.In some cases, this disease or illness can be by any one or a plurality of mediation the, for example PPAR γ of PPAR isoform; PPAR α; PPAR δ; PAR γ and PPAR α; PPAR γ and PPAR δ; PPAR α and PPAR δ; Or PPAR γ, PPAR α and PPAR δ.
[0160] term " effective in the treatment " or " significant quantity " are meant that these materials or amount of substance have prevented, alleviated or improved one or more symptoms of disease or medical condition effectively, and/or have prolonged by the life-span of treatment target.
[0161] term " PPAR " is meant peroxisome proliferation-activated receptors (peroxisomeproliferator-activated receptor), is familiar with as the present technique field.As top indicated, PPAR family comprises PPAR α (also being known as PPARa or PPARalpha), PPAR δ (also being known as PPARd or PPARdelta), PPAR γ (also being known as PPARg or PPARgamma).Each PPARs can be by their Sequence Identification, and wherein illustrative reference sequences registration number is as follows:
| Acceptor | Sequence | Registration number | SEQ ID NO： |
| hPPARa | cDNA | NM 005036 | |
| hPPARa | Protein | NP 005027 | |
| HPPARg isoform 2 | cDNA | NM 015869 | |
| HPPARg isoform 2 | Protein | NP 056953 | |
| hPPARd | cDNA | NM 006238 | |
| hPPARd | Protein | NP 006229 |
Those skilled in the art will recognize, because allelic variation, to there be sequence difference, and also will recognize, other animal, especially other Mammals has corresponding PPARs, and they have used sequence alignment, and (perhaps sequence alignment (sequence alignment) and active affirmation are identified, perhaps can easily be identified.Such homology PPARs also can be used among the present invention, homologous PPARs wherein, stride 50,100,150,200,250,300,350,400,450,500 or even the zone of the Nucleotide of more a plurality of proteinic amino acid or nucleic acid in, have such as at least 50%, 60%, 70%, 80%, 90%, 95%, 99% or even 100% sequence identity.Those of ordinary skills also will recognize, can introduce modification in the PPAR sequence, and can not destroy the PPAR activity.Such modification PPARs also can use in the present invention, for example, modifies the degree that PPAR lacks normal part keying action basically as long as modify the conformation that does not change binding site to quilt.
[0162] as used herein, relevant with the design or the exploitation of part, term " in conjunction with (bind) " and " keying action (binding) " and similar terms are meant association favourable on the energy non-covalent between the specific molecular (non-convalent energetically favorable association) (promptly, the bonding state score has lower free energy from state, and this can measure by calorimetry).For with the combining of target,, that is to say that with respect at the irrelevant proteinic non-specific binding that does not have similar binding site, compound preferentially combines at binding site with particular target or with the member of target family in conjunction with being optionally at least.For instance, BSA is normally used for estimating or the control non-specific binding.In addition, associate for being considered to bonded, the reduction of free energy from the separate stage to the bonding state must be can be detected so that associate in being suitable for the biochemical measurement method of related molecule fully.
[0163], means the generation of experiment condition and about the collection of the data of the particular result under the experiment condition with regard to " mensuration ".For instance, enzyme can act on the ability that can detect substrate based on it and measures.Similarly, for instance, compound or part can be measured with the active ability that combines and/or regulate target molecule of certain target molecules or a plurality of certain target molecules based on it.
[0164] about in conjunction with measuring, with regard to " background signal ", mean do not exist test compounds, molecular skeleton or with the situation of target molecule bonded part under, for particular assay, the signal that under standard conditions, is recorded to.Those skilled in the art will recognize and have acceptable method, and these methods can be used to measure background signal at large.
[0165] with regard to " clog P ", mean the calculating gained log P of compound, " P " is meant the partition ratio of compound between oleophylic phase and water, usually between hot alcohol and water.
[0166] with the context of target bonded compound in, term " higher affinity " is meant that compound is in conjunction with must promptly having lower dissociation constant than reference compound or than tighter with reference to compound same under the condition.In some embodiments, bigger affinity is at least 2,3,4,5,8,10,50,100,200,400,500,1000 or 10,000 times a affinity greatly.
[0167] with regard to " moderate affinity ", means bonded K
dUnder standard conditions, arrive between about 1 μ M at about 200nM.With regard to " appropriate high affinity ", mean bonded K
dUnder standard conditions, arrive between about 200nM at about 1nM.With regard to " high affinity ", mean bonded K
dUnder standard conditions, be lower than about 1nM.The bonded standard conditions are pH7.2, under 37 ℃, and 1 hour.For example, the typical combination condition in the volume in 100 μ l/ holes comprises HEPES 50mM damping fluid, NaCl 15mM, the ATP 2 μ M under PPAR, test compounds, the pH7.2, and under the bovine serum albumin (1ug/ hole), 37 ℃, 1 hour.
[0168] binding compounds also can be by them to the active influence sign of target molecule.Therefore, " low activity " compound has the inhibition concentration (IC greater than 1 μ M under standard conditions
50) (for inhibitor or antagonist) or effective concentration (EC
50) (being applicable to agonist).With regard to " moderate activity ", mean IC under standard conditions
50Or EC
50At 200nM between the 1 μ M.With regard to " appropriate high reactivity ", mean IC under standard conditions
50Or EC
50At 1nM between the 200nM.With regard to " high reactivity ", mean IC under standard conditions
50Or EC
50Be lower than 1nM.IC
50(or EC
50) being defined as this kind concentration of compound--the activity when not having compound, under this concentration, measured target molecule (for example enzyme or other protein) active 50% is active in loss (or acquisition).Activity can use the known method of those of ordinary skills to measure, for example, by measure enzymatic reaction generation produced any can detected product or signal, or by measuring measured proteinic other activity.For the PPAR agonist, activity can be determined as the next of embodiment description, or use other such measuring method known in the art to determine.
[0169] with regard to " protein ", means polymer of amino acid.Amino acid can be natural or non-natural exists.Protein also can contain modification, as being modified by glycosylation, phosphorylation or other routine.
[0170], means class protein based on structure and/or functional similarity with regard to " protein families ".For instance, kinases, Phosphoric acid esterase, proteolytic enzyme and proteinic similar grouping are protein familieses.Protein can be classified as protein families, classification based on have one or more total protein foldings, in Protein Folding in shape remarkable similarity, homology, or based on having the common function.In many cases, will describe littler family in detail, for example, PPAR family.
[0171], but means in the living things system, that cause detected result, significant biological chemistry variation in treatment with regard to " specific biological chemical effect ".This specific biological chemical effect can be, for example inhibition of enzyme or activation, and with expectation proteinic inhibition of target bonded or activation, or the variation of the similar type in the body biological chemistry.The specific biological chemical effect can cause the mitigation of disease or patient's condition symptom, or another kind of expectancy effect.But detected result also can be detected by intermediate steps.
[0172], means and measure to obtain the condition of significant data on science with regard to " standard conditions ".Standard conditions depend on special test, and normally subjective.Usually, the standard conditions of test will be for obtain optimal those conditions of useful data from particular experiment.Standard conditions will make background signal minimize usually, and make and seek the maximization of detected signal.
[0173] with regard to " standard deviation ", means the square root of variance.Variance is the unfolded observed value that how to distribute.Calculate with each numeral and the average variance of its average.For example, for numeral 1,2 and 3, average is 2, and variance is:
[0174] in the context of the present invention, with regard to " target molecule ", mean determined and its bonded molecule of compound, molecular skeleton or part.Target molecule has such activity, and promptly molecular skeleton or part will change or change with combining of target molecule.Compound, skeleton or part combine with target molecule, when it occurs in the living things system, can preferably cause the specific biological chemical effect." living things system " includes, but not limited to system alive, as people, animal, plant or insect.In most of the cases, but under the not all situation, target molecule will be protein or nucleic acid molecule.
[0175] " pharmacophore " means a representative of characterization of molecules, is considered to expecting active being responsible for, as with the interaction of acceptor or combine.Pharmacophore can comprise three-dimensional (hydrophobic grouping, charged/ionogenic group, hydrogen bond donor/acceptor), 2D (substructure) and 1D (physical or biological) characteristic.
[0176] as used herein, relevant with numerical value, term " general (approximately) " and " about (about) " be meant indicator value ± 10%.
The application of I.PPAR agonist
[0177] PPARs has been considered for the suitable targets of multiple various disease and illness.In those application some have simply been described below.Other application is known, and compound of the present invention also is used to those diseases and illness.
[0178] (a) insulin resistance and diabetes: relevant with insulin resistance and diabetes, PPAR γ is necessary and is enough concerning the differentiation of external and body fat cell.In adipocyte, PPAR γ has increased a plurality of expression of gene related in lipid metabolism and the lipid uptake.On the contrary, PPAR γ reduces RMETHU LEPTIN (leptin), RMETHU LEPTIN be a kind of demonstrated the secretor type that suppresses feed and increase the decomposability lipid metabolism, adipocyte protein optionally.Behind the PPAR gamma agonist treatment, active calorie intake and the storage that just can explain the increase of noticing in vivo of this receptor.Clinically, TZDs comprises troglitazone, rosiglitazone and Pa Gelie ketone and non-TZDs, comprises Fa Gelie ketone, has insulin sensitizing agent and anti-diabetic activity.(Berger, etc., Diabetes Tech.And Ther., 2002,4:163-174)
[0179] PPAR γ is relevant with the several genes that influence insulin action.TNF α, a kind of pro-inflammatory cytokine of expressing by adipocyte, relevant with insulin resistance.The PPAR gamma agonist suppresses the expression of the TNF α in the rodentine fatty tissue of endomorphy type, and eliminates the effect of TNF α in external adipocyte.The PPAR gamma agonist demonstrates and suppresses 11beta-Hydroxysteroid dehydrogenase (expression of 11 β-HSD-1), this enzyme is the enzyme that cortisone is converted into the glucocorticoid agonists hydrocortisone in the adipocyte of diabetes B mouse model and fatty tissue.This is noticeable, and reason is that high cortex-steroid mechanism (hypercortico-steroidism) aggravated insulin resistance.Lipocyte complement-associated protein of 30kDa (Acrp30 or adiponectin) is a kind of adipocyte-specific protein of secretor type, and it reduces glucose, triglyceride level and free fatty acids.Compare with normal people's individuality, the patient who suffers from diabetes B has the Acrp30 blood plasma level of reduction.Increased the blood plasma level of Acrp30 with PPAR gamma agonist treatment diabetic mice and ND human subjects.Therefore the PPAR gamma agonist may play keying action to inducing also of Acrp30 in the PPAR of diabetes gamma agonist insulin sensitizing agent mechanism.(people such as Berger, the same.)
[0180] PPAR γ is mainly expressed in fatty tissue.Therefore, think and render a service the direct effect that relates on the adipocyte in the clean body of PPAR gamma agonist, and in the insulin response tissue of key such as skeletal muscle and liver, second-order effect is arranged.This obtains following support: the glucose that lacks rosiglitazone in the mouse model of serious insulin resistance reduces effect, lacks white adipose tissue in these mouse models basically.Further, the interior therapeutic of insulin resistance rat has produced quick (＜24 hours) normalizing of fatty tissue insulin action; Although behind begin treatment several days, the glucose absorption of the insulin-mediated in the muscle just has improvement.This conforms to the following fact: after direct vitro culture, the PPAR gamma agonist can produce increase on the fatty tissue insulin action; Yet, use the skeletal muscle of isolating vitro culture, can confirm does not have such effect.The PPAR gamma agonist can be conditioned by their following ability the useful metabolic effects of muscle and liver: the fatty tissue that (a) strengthens the insulin-mediated of free fatty acids absorbs, stores (and potential katabolism); (b) induce the generation of the adipose-derived factor with potential insulin sensitizing agent activity (for example Acrp30); And/or (c) suppress to cause the adipose-derived factor of insulin resistance such as the cyclical level and/or the effect of TNF α or phylaxin.(people such as Berger, the same.)
[0181] (b) unusual lipidemia and atheronecrosis: relevant with atheronecrosis with unusual lipidemia is that PPAR α has demonstrated in the adjusting of cell absorption, activation and the β-Yang Hua of lipid acid and played keying action.The expression of the enzyme in the activation-inducing fatty acid transport protein of PPAR α and the β-Yang Hua approach of peroxysome.Several cyclophorases related in the energy capture katabolism of lipid acid are raised consumingly by the PPAR alfa agonists.Peroxisome proliferation also activates the expression of CYP4As, and CYP4As is a subclass of cytochrome P 450 enzymes, the ω-hydroxylation of its catalysis lipid acid, this be a kind of in fasting and diabetic disease states special valid approach.Generally speaking, very clear, PPAR α is a kind of important lipid sensor and the instrumentality that the metabolism of cellular energy results is decomposed.(people such as Berger, the same.)
[0182] atheronecrosis is very general disease in Western society.Except with the LDL cholesterol that raises very mutually outside the Pass, with the particle that is rich in triglyceride level that increases and low-level HDL cholesterol is that " the unusual lipidemia (dyslipidemia) " of feature is relevant with the others of metabolic syndrome usually, and these syndromess comprise the risk increase of obesity, insulin resistance, diabetes B and coronary artery disease.Therefore, in known 8500 male sex that suffer from coronary heart disease, find 38% have low HDL (＜35mg/dL) and 33% have the triglyceride level that increases (＞200mg/dL).In these patients, treat the HDL increase effect that causes significant triglyceride level reduction and appropriateness with Bei Te (fibrate).The more important thing is that a nearest very big test likely shows, can make cardiovascular event or dead reduction by 22% with gemfibrozil (gemfibrozil) treatment.Therefore, the PPAR alfa agonists can improve the cardiovascular risk factor effectively, and has a clean benefit to improve cardiovascular output exactly.In fact, fenofibrate gets permission to be used for the treatment of IIA type and IIB type hyperlipidaemia in the U.S. recently.PPAR α activates the mechanism that causes triglyceride level to reduce and may comprise: agonist suppresses the effect of liver apo-CIII genetic expression, equally also stimulates lipoprotein lipase genetic expression.Dual PPAR γ/alfa agonists comprises KRP-297 and DRF 2725, and is active and except the hyperglycemia in the animal model of diabetes and lipid imbalance, also has strong lipid change effect.
[0183] in the vascular cell type, comprise in scavenger cell, endotheliocyte and the vascular smooth muscle cell, exist PPAR α and/or PPAR γ to express, show that direct vascular effect has the potential of helping atherosclerosis effect.It is bonding that PPAR α and PPAR α activate the vascular cell that has demonstrated the inhibition cytokine induction, and suppress monocyte-macrophage migration.Several other researchs also show: PPAR γ-alternative cpd has the ability that reduces the arterial injury size in the atheronecrosis animal model, and has the ability of going back to the nest that weakening monocyte-scavenger cell arrives arterial injury.PPAR γ is present in the scavenger cell in people's atheromatous lesions, and can work aspect the expression that regulate matrix metalloproteinase-9 (MMP-9), this relates to arteriosclerosis plaque break (Marx etc., Am J Pathol.1998,153 (1): 17-23).Agonist for PPAR α and PPAR γ, also observe the downward modulation of the LPS secretion inducing of MMP-9, this can illustrate PPAR agonist viewed advantageous effects (Shu etc. in the atheronecrosis animal model, Biochem Biophys Res Commun.2000,267 (1): 345-9).PPAR γ also demonstrates intercellular adhesion molecule in endotheliocyte-1 (ICAM-1) protein expression (Chen etc., Biochem Biophys Res Commun.2001,282 (3): 717-22) with hemocyte adhesion molecule-1 (VCAM-1) protein expression (Jackson etc., ArteriosclerThromb Vase Biol.1999,19 (9): 2094-104) aspect has effect, and the both is worked aspect the sticking together of endotheliocyte at monocyte.
In addition, two nearest researchs show: PPAR α or the activation of PPAR γ in scavenger cell can induce cholesterol to flow out the expression of " pump " albumen (cholesterol efflux " pumb " protein).
[0184] have been found that: in the mouse model of diabetes B, compare with effective PPAR γ or PPAR alfa agonists, the PPAR delta agonists of relative selectivity has produced minimum, and--if present--glucose reduces activity or triglyceride level reduction activity.Therefore, in the db/db mouse, the appropriateness that detects the HDL-cholesterol levels for the PPAR delta agonists increases.Recently, people such as oliver (the same) report: effectively, the selective PPAR delta agonists can induce the remarkable increase of HDL-cholesterol levels, reduced triglyceride levels and the insulin resistance of fat rhesus monkey simultaneously.
[0185] therefore, by multifactorial mechanism, PPAR α, PPAR γ and PPAR delta agonists can be used to the treatment and the prevention of atheronecrosis, these mechanism are included in the improvement on circulation lipid, systematicness and the locality anti-inflammatory effect, and the vascular cell inhibition of proliferation.(people such as Berger, the same.)
[0186] (c) inflammation: known, monocyte and scavenger cell play an important role in inflammatory process, are to work by discharging inflammatory cytokine and utilizing the induction type nitric oxide synthase to produce nitrogen oxide.Rosiglitazone has demonstrated the apoptosis (apoptosis) of inducing scavenger cell, with it suitable concentration of affinity of PPAR γ is induced.This part has also demonstrated and blocked the synthetic of inflammatory cytokine in colon cell line.A kind of mechanistic view of life explanation of prompting is found in this back one, is used for explaining at the viewed TZDs anti-inflammatory action of the rodent model of colitis.
[0187] other research after deliberation the relation between scavenger cell, cytokine and PPAR γ and the agonist thereof (Jiang etc., Nature 1998,391 (6662): 82-6., Ricote etc., Nature 1998,391 (6662): 79-82, Hortelano etc., J Immunol 2000,165 (11): 6525-31 and Chawla etc., NatMed.2001,7 (1): 48-52), show the effect of PPAR gamma agonist aspect treatment inflammatory reaction such as autoimmune disease.
[0188] migration of monocyte and scavenger cell is also being worked aspect the development of inflammatory reaction.The PPAR part has demonstrated has effect to various chemokines.The monocytic migration that MCP-1 (MCP-1) guides is weakened (Kintscher etc., Eur J Pharmacol.2000,401 (3): 259-70) by PPAR γ and PPAR alpha ligands in monocytic leukemia cell is.MCP-1 genetic expression is presented at and is subjected to PPAR γ ligand 1 5-deoxidation-δ (12 in two monocytic seriess, 14) inhibition of PGJ2 (15d-PGJ2), this also shows (Zhang etc., J Immunol.2001,166 (12): 7104-11) of inducing of IL-8 genetic expression.
[0189] with regard to the PPAR alpha ligands, anti-inflammatory action has been described, it is very important in keeping vascular health.Adopt the PPAR alfa agonists to handle cytokine and activate human macrophage, induced the apoptosis (apoptosis) of these cells.According to reports, the PPAR alfa agonists suppresses the activation of Aorta unstriated muscle, as the response to inflammatory stimulus.(Staels etc., 1998, Nature 393:790-793.) in the patient of hyperlipidaemia, fenofibrate treatment has reduced the plasma concentration of inflammatory cytokine interleukin-6 (interleukin-6).
[0190] about PPAR α and PPAR γ, after deliberation the anti-inflammatory approach in airway smooth muscle cells (Patel etc., 2003, The Journal of Immunology, 170:2663-2669).This studies show that the antiphlogistic effects of PPAR γ part, and it can be used to treat COPD and the insensitive asthma of steroid.
[0191], also studies the anti-inflammatory effect of PPAR modulator about autoimmune disease such as chronic inflammation enteron aisle syndrome, sacroiliitis, Crohn's disease and multiple sclerosis and neuronal disease such as alzheimer's disease and parkinsonism.
[0192] (d) hypertension: hypertension is the syndrome of cardiovascular systems, and this disease has demonstrated relevant with insulin resistance.The diabetes B patient table reveals: compare with the general population, its hypertension has 1.5-2 increase doubly.Troglitazone (Troglitazone), rosiglitazone (rosiglitazone) and Pa Gelie ketone (pioglitazone) treatment have demonstrated the blood pressure that has reduced diabetic, and troglitazone (troglitazone) treatment has reduced blood pressure fat, the insulin resistance patient.Because it is relevant with the reduction of insulin level that these reductions of blood pressure demonstrate, so they can be regulated by the improvement on insulin sensitivity.Yet, because TZDs also brings high blood pressure down in (one-kidney one-clip) Sprague Dawley rat of a kidney one folder, this rat is not an insulin resistance, so propose: the ypotension effect of PPAR gamma agonist not only plays a role by the ability of their improvement insulin sensitivities.Be used to explain other mechanism of the hypertension effect of PPAR gamma agonist, the following ability that comprises them: (a) peptide of downward modulation control vascular tone is expressed, as PAI-I, endothelin (endothelin) and c type natriuretic peptide C, or (b) change the calcium concn of vascular cell and calcium sensitivity people such as (, the same) Berger.
[0193] (e) cancer: PPAR modulation is also relevant with cancer therapy.(Burstein, etc.; Breast CancerRes.Treat., 2003,79 (3): 391-7; Alderd, etc.; Oncogene, 2003,22 (22): 3412-6).
[0194] (f) weight management: using the PPAR alfa agonists can inducing satiation sense, and therefore lose weight or weight maintenance in be useful.Such PPAR alfa agonists can preferentially play a role to PPAR α, perhaps also can play a role to another kind of PPAR, perhaps can be the general agonist of PPAR.Therefore, the satiety inductive effect of PPAR alfa agonists can be used to weight management or alleviate.
[0195] (g) autoimmune disorder: the PPAR agonist can provide benefit aspect the treatment of autoimmune disorder.The agonist of PPAR isoform can relate to T cell and B cell transportation or active, the change of oligodendrocyte function or differentiation, and neuroprotective, and wherein some or all may be very important aspect various autoimmune disorders.
[0196] multiple sclerosis (MS) relates to the neurodegeneration autoimmune disorder of aixs cylinder demyelination and plaque formation.PPAR δ mRNA has demonstrated in the prematurity oligodendrocyte by great expression (Granneman etc., JNeurosci Res.1998,51 (5): 563-73).PPAR δ selective agonist or general agonist demonstrate the differentiation that promotes oligodendrocyte, and to not effect of the viewed differentiation of PPAR gamma selective agonist.In PPAR δ knock-out mice, observe change (Peters etc., Mol CellBiol.2000,20 (14): 5119-28) of corpus callosum myelinization.Show that also PPAR δ mRNA and protein are expressed in neurone and oligodendrocyte in whole brain, rather than at astroglia cell (Woods etc., Brain Res.2003,975 (1-2): 10-21).These observed results show the effect of PPAR δ in myelinization, the adjusting of wherein such effect can be used for treating multiple sclerosis, this is to realize by the differentiation that changes oligodendrocyte, and this also causes demyelination to slow down or even promotes the myelinization again of aixs cylinder.Also show, oligodendrocyte shape B12 cell, and isolating spinal cord oligodendrocyte has been subjected to the influence of PPAR gamma agonist from rat.Alkyl-otan phosphonate ester synthetase--relate to the important peroxidase of plasmogen synthetic, described plasmogen is myelinic key component--increase to some extent in the B12 cell that the PPAR gamma agonist is treated, the mature cell number increases along with the PPAR gamma agonist treatment in the isolating spinal cord oligodendrocyte simultaneously.
[0197] effect of PPAR can also provide curative effect such as MS to disease during B and T cell were regulated.For instance, show, the PPAR gamma agonist can suppress the secretion (Clark etc. of IL-2 by the T cell, JImmunol.2000,164 (3): 1364-71) or apoptosis (Harris etc. that can inducing T cell, Eur JImmunol.2001,31 (4): 1098-105), this has shown the vital role in cell-mediated immune responses.And antiproliferative and cytotoxin effect (Padilla etc., ClinImmunol.2002,103 (1): 22-33) of PPAR gamma agonist have been observed to the B cell.
[0198] discusses as this paper, the anti-inflammatory action of PPAR modulator also can be used for treating MS and various other autoimmune disorder, such as type i diabetes, psoriasis, vitiligo, uveitis (uveitis), sjogren syndrome (Sjogren ' s Syndrome), pemphigus foliaceus, inclusion body myositis, polymyositis, dermatomyositis, scleroderma, Exophthalmus goiter (Grave ' s disease), Hashimoto's disease (Hashimoto ' s disease), chronic graft versus host disease (chronic graft versus host disease), rheumatoid arthritis, inflammatory bowel (IBD) and Crohn's disease (Crohn ' s disease).By mouse model, PPAR alfa agonists gemfibrozil and fenofibrate demonstrate the clinical symptom that has suppressed experiment autoimmunization encephalomyelitis, this shows that the PPAR alfa agonists can be used for treating inflammation such as multiple sclerosis (Lovett-Racke etc., J Immunol.2004,172 (9): 5790-8).
[0199] shows the neuroprotective relevant and also can help to treat MS with PPARs.Be total to nutrient solution with cortical neuron-colloid and studied of the effect of PPAR agonist the death of LPS inductive neuronal cell.PPAR gamma agonist 15d-PGJ2, ciglitazone and troglitazone show and have suppressed the death of LPS inductive neuronal cell, and the release and iNOS and the COX-2 expression decreased (Kim etc. that have destroyed NO and PGE2, Brain Res.2002,941 (1-2): 1-10).
[0200] rheumatoid arthritis (RA) is the autoimmunization inflammation that causes the joint to be damaged.Except part because chronic inflammatory diseases that amboceptor such as IL-6 and TNF-α cause and joint damaged, the osteoclast differentiation also related to the damage to the joint.The PPAR agonist can be regulated these paths, and RA provides the treatment benefit to treatment.In these researchs--it uses PPAR gamma agonist troglitazone in isolating fibroblast sample synovial cell (FLS) from the rheumatoid arthritis patient, observe the inhibition (Yamasaki etc. of the inflammatory response of pair cell factor mediation, Clin Exp Immunol., 2002,129 (2): 379-84).The PPAR gamma agonist is also verified in the rat of RA or mouse model to have favourable effect (Kawahito etc., J Clin Invest.2000,106 (2): 189-97; Cuzzocrea etc., Arthritis Rheum.2003,48 (12): 3544-56).PPAR alpha ligands fenofibrate also demonstrates the inhibition that the pair cell factor produces and NF-KappaB activates and osteoclast breaks up to the effect from patient's RA similar rheumatism synovial membrane fibroblast.Fenofibrate also demonstrates and has suppressed arthritic development in the rat model (Okamoto etc., Clin Exp Rheumatol.2005,23 (3): 323-30).
[0201] psoriasis is the cell-mediated autoimmune disorder of T, and wherein t cell activation causes the release of cytokine and the hyperplasia of consequent keratinocyte.Except anti-inflammatory action, the differentiation of keratinocyte also can be the treatment target of PPAR agonist.Studies show that of PPAR δ knock-out mice model uses the PPAR 2-delta ligand optionally to induce the keratinocyte differentiation and to have suppressed hyperplasia (Kim etc., CellDeath differ.2005).PPAR γ thiazolidinedione part has demonstrated hyperplasia that has suppressed the organic nutrient solution heifer of individual layer tinea keratinocyte and the epidermal hyperplasia (Bhagavathula etc. that suppressed to be transplanted to the people's psoriasis skin on the SCID mouse when local the use, J Pharmacol Exp Titer.2005,315 (3) 996-1004).
[0202] (h) adjusting of neurodegenerative disease: PPARs can provide benefit to the treatment of neuronal disease.For instance, about neuronal disease such as alzheimer's disease and Parkinson's disease, also after deliberation the anti-inflammatory action of PPAR modulator discussed in this article.
[0203] except inflammatory process, alzheimer's disease is characterised in that the deposition and the neurofibrillary tangles of amyloid-β (Abeta) peptide.Along with the abduction delivering of PPAR γ or by using the activation of thiazolidinedione, observe reduction (Camacho etc., J Neurosci.2004,24 (48): 10908-17) of Abeta peptide level in neurone and the non-neuronal cell to PPAR γ.Use PPAR gamma agonist Pa Gelie ketone treatment APP7171 mouse to demonstrate several advantageous effects, be included in the reduction of interior little colloid of activated of hippocampus and cortex and reactive astrocytes, short scorching cyclo-oxygenase 2 and the reduction that can induce nitric oxide synthase, the reduction of beta-secretase-1mRNA and protein level, and the reduction (Heneka etc. of solubility Abeta1-42 peptide level, Brain.2005,128 (Pt 6): 1442-53).
[0204] relevant (Nagatsu etc., J Neural Transm Suppl.2000 (60): 277-90) of the degenerate region of dopamine neuron in the Parkinson's disease with the increase of inflammatory cells factor level.In Parkinsonian MPTP mouse model after deliberation dead the and neuroglia activated effect of PPAR gamma agonist Pa Gelie ketone to dopaminergic nerve cell, wherein the Pa Gelie ketone of oral administration causes the neuroglia activated to reduce and has prevented dopaminergic cell loss (Journal of Neurochemistry such as Breidert, 2002,82:615).
[0205] (i) other indication: the PPAR gamma modulators has demonstrated to the inhibition of VEGF-inductive train of thought vasculogenesis and to the inhibition of train of thought neovascularity nucleus formation, shows that the treatment to the retina imbalance is effective.PPAR δ has been presented in the transplanted sites of rat and the decidual cell and has been expressed, and shows the effect to pregnancy, such as having increased fertility.These are studied at Kota, etc., Pharmacological Research, 2005, summarized among the 51:85-94.
The treatment process of [0206] pain--neuropathy or inflammation--also shows it is the possible target of PPAR modulator.Burstein, S., Life Sci.2005,77 (14): 1674-84 shows that PPAR γ provides function of receptors for the activity of some cannaboids.Lo Verme etc., Mol Pharmacol.2005,67 (1): 15-9 thinks that the PPAR α as the target of being responsible for pain and inflammation has reduced palmityl thanomin (palmitoylethanolamide, effect PEA).PEA optionally activates external PPAR α, and the expression of having induced PPAR α mRNA when the part is used for mouse.In the animal model of carrageenan inductive paw edema and Fo Bo ester inductive ear edema, the inflammation of wild-type mice is weakened by PEA, the not effect of mouse that it lacks PPAR α.PPAR alfa agonists OEA, GW7647 and Wy-14643 show to have similar effect.Benani etc., Neurosci Lett.2004,369 (1): the PPAR that 59-63 uses the inflammation model of rat to estimate in the rat marrow of rear solid end injection complete Freund's adjuvant (completeFreund ' s adjuvant) back responds.It shows that PPAR α is activated, and shows the effect to pain pathways.
[0207] PPARs also relates to some infection, and can be as target in treating such infection.Reports such as Dharancy, HCV infects and relates to expression and the function that anti-inflammatory nuclear receptors PPAR's alpha changes, and liver PPARalpha is differentiated a kind of mechanism of pathogeny institute potential that infects for HCV, and discriminating is the new treatment target (Dharancy etc. in the traditional treatment of HCV inductive hepar damnification, Gastroenterology2005,128 (2): 334-42).J Raulin report, the variation of the infection induced cytolipin of HIV and other act on, and comprise imbalance (J.Raulin, the Prog Lipid Res 2002,41 (1): 27-65) of PPAR-gamma.Slomiany and Slomiany report, PPARgamma activates--it makes helicobacter pylori lipopolysaccharides (LPS) be hindered saliva mucoitin synthetic restraining effect--needs EGF-R ELISA (EGFR) to participate in.Further, they show by the obstruction of ciglitazone (ciglitazone) weakened in passing through the concentration dependent form of PPARgamma agonist.(Slomiany and Slomiany, Inflammopharmacology 2004,12 (2): 177-88).
[0208] (Human Molecular Genetics 2002,11 (15): 1731-1742) show such as Muto at Pkd1
-/-Observed molecular defect has been facilitated the pathogeny of autosomal dominant multicystic kidney disease (ADPKD) among the embryo, and the thiazolidinedione approach that minimizing is influenced to many capsules albumen-1 has compensating action.Therefore may provide the new treatment target of ADPKD (Muto etc., the same) by thiazolidinedione activated approach.Glintborg etc. show that the HGH level of object increases (Glintborg etc., J Clin Endocrinol Metab 2005,90 (10): 5605-12) along with treating polycystic ovarian syndrome with pioglitazone (pioglitazone).
[0209] according to top description, nuclear receptors PPAR's family isoform relates to obviously that the metabolic system of lipid regulates and as " sensor " of lipid acid, prostaglandin(PG) metabolite, prostaglandin(PG) and associated molecule.These acceptors play the effect of the gene of the very wide series of regulating equal type.Regulate that insulin action, lipid oxidation, lipid are synthetic, the important biochemical route of adipocyte differentiation, peroxidase function, apoptosis and inflammation can regulate by single PPAR isoform.Have been found that the strong effectively therapeutic action of PPAR α and PPAR gamma agonist recently, advantageously influenced system lipids level, glucose stable state and atherosclerosis risk (under people PPAR α activated situation).PPAR α and PPAR gamma agonist are used recently clinically, have advantageously changed system lipids level and glucose stable state respectively.The observed result that carries out with the PPARS part recently shows that same, this isoform also is the critical treatment target of hyperlipemia and insulin resistance.
[0210] therefore, the PPAR agonist is such as this paper through type I, Ia, Ib, Ic and Id described those, can be used to preventative and various disease of therapeutic treatment and illness, body weight disease (obesity for example for example, overweight state, Bulimia nerovsa and anorexia nervosa), lipoid dyscrasias (hyperlipidemia for example, the unusual lipidemia (dyslipidemia) that comprises unusual lipidemia of the property followed diabetes and the unusual lipidemia of Combination, slight alpha lipoprotein mass formed by blood stasis (hypoalphalipoproteinemia), hypertriglyceridemia (hypertriglyceridemia), hypercholesterolemia and low HDL (high-density lipoprotein (HDL) (high densitylipoprotein))), metabolic trouble (metabolism syndrome for example, type ii diabetes, type i diabetes, hyperinsulinemia (hyperinsulinemia), impaired glucose tolerance, insulin resistance, comprise neuropathy, ephrosis, retinopathy, diabetes type ulcer of foot and cataract are at interior diabetic complication, cardiovascular diseases (hypertension for example, coronary heart disease, in heart failure, congestive heart failure, atherosclerosis, arteriosclerosis, apoplexy, cerebrovascular disease, myocardial infarction, peripheral vascular disease), inflammation (for example, autoimmune disorder is such as vitiligo, uveitis (uveitis), pemphigus foliaceus, inclusion body myositis, polymyositis, dermatomyositis, scleroderma, Exophthalmus goiter (Grave ' s disease), Hashimoto's disease (Hashimoto ' s disease), chronic graft versus host disease (chronic graft versus host disease), rheumatoid arthritis, inflammatory bowel trace integration disease, Crohn's disease (Crohn ' s disease), systemic lupus erythematous, sjogren syndrome (Sjogren ' s Syndrome), and multiple sclerosis, disease such as the asthma and the chronic obstructive pulmonary disease that relate to airway inflammation, with other organ inflammation, such as multicystic kidney disease (PKD), polycystic ovarian syndrome, pancreatitis, ephritis and hepatitis), dermatosis (for example epithelium hyperplasia disease such as eczema and psoriasis, dermatitis, it comprises atopic dermatitis, contact dermatitis, allergic dermatitis and chronic dermatitis, with impaired wound healing), neurodegenerative disease (for example, alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Spinal injury and demyelinating disease, it comprises acute disseminated encephalomyelitis (acute disseminated encephalomyelitis) and guillain-Barre syndrome (Guillain-Barre syndrome)), blood coagulation disease (for example thrombus disease), gastrointestinal illness (for example big or little intestinal obstruction), urogenital disease (renal insufficiency for example, erective dysfunction, the urinary incontinence and neurogenic bladder), ophthalmic diseases is (as eye inflammation, macular degeneration and pathologic neovascularity generate), infect (HCV for example, HIV and Hp), nervosa or inflammatory pain, sterile and cancer.
The II.PPAR active compound
[0211] as indicated in the summary of the invention and relevant, many different PPAR agonists have been identified with disease applicatory and illness.In addition, the invention provides the PPAR agonist compound that through type I, Ia, Ib, Ic or Id describe, it is provided in the foregoing invention content.
[0212] use known method of those of ordinary skills and method described herein can assess the activity of compound.Screening is analyzed can comprise contrast, with the appropriate operation of calibration and validating analysis component.Generally include and contain all reactants but PPARs is not had a blank well of active compound.As another example, for its carry out the enzyme that conditioning agent seeks known inhibitor (or activator) can with a kind of sample cultivation of described analysis, and the minimizing of the enzymic activity that is produced (or increasing) is as a comparison or contrast.Should understand, conditioning agent also can with zymoexciter or inhibitor combined utilization finding out the conditioning agent that inhibitory enzyme activation or enzyme suppress, described enzyme activation or enzyme suppress to be because the existence of known enzyme conditioning agent causes in addition.Similarly, when seeking the part of target, the known ligand of target can be present in contrast/calibration analyte hole.
(a) enzymic activity test
[0213] can use a large amount of different tests to estimate the specificity of active and/or definite conditioning agent of PPAR conditioning agent to concrete PPAR.Except that mentioned in the following embodiments test, those of ordinary skills know other test that can be used, and can revise test at concrete application.For instance, this test can be used AlphaScreen (the luminous approximate homogeneous assay method of amplification (amplified luminescentproximity homogeneous assay)) mode, for example AlphaScreening system (PackardBioScience).AlphaScreen totally is described in Seethala and Prabhavathi, Homogenous Assays:AlphaScreen,
Handbook of Drug Screening, Marcel Dekkar Pub.2001, pp.106-110.PPAR receptors ligand binding analysis The Application of Technology is described in for example Xu, etc., Nature, 2002,415:813-817.
(b) evaluation of compound efficacy in the disease model system
[0214] formula I compounds for treating disease such as autoimmune disease and neuropathic application can use the known model system of those of ordinary skills easily to assess.For instance, the effect of PPAR conditioning agent can be recovered with use molecule and drug labelling measurement by the inflammatory injury of simulation to neuronal tissue in the model of alzheimer's disease, detects (Heneka, Deng, J.Neurosci., 2000,20:6862-6867).In multiple sclerosis the effect of PPAR conditioning agent by the accepted model of using experimental autoimmune encephalomyelitis (EAE) monitor (Storer, etc., J.Neuroimmunol., 2004,161:113-122.Also can be referring to Niino, etc., J.Neuroimmunol., 2001,116:40-48; Diab waits J.Immunol., and 2002,168:2508-2515; Natarajan, etc., Genes Immun., 2002,3:59-70; Feinstein, etc., Ann.Neurol., 2002,51:694-702).
(c) isomer, prodrug and active metabolite
[0215] compound of this paper consideration is described with reference to general formula and particular compound at this.In addition, The compounds of this invention can exist with many different forms or derivative, and all these within the scope of the invention.These comprise, for example, tautomer (tautomers), steric isomer (stereoisomers), racemic mixture, positional isomers (regioisomers), salt, prodrug (for example carboxylicesters), solvation form (solvated forms), different crystalline form or polymorphic form and active metabolite.
(d) tautomer, steric isomer, positional isomers and solvation form
Should be appreciated that [0216] some compounds can show tautomerism.In this case, the formula that is provided has herein just been described a kind of in the possible tautomeric form significantly.Therefore, should be appreciated that any tautomeric form of the described compound of described formula intention representative that is provided is not only limited to the concrete tautomeric form that structural formula figure is described herein.
[0217] same, can be used as steric isomer according in the compound of the present invention some and exist, that is, the same atoms that they have the covalent attachment atom connects, but atoms in space direction difference.For example, compound can be the optically-active steric isomer that comprises one or more chiral centres, therefore, can be used as two or more stereoisomeric forms in any ratio and has (for example, enantiomer or diastereomer).Therefore, such compound can be used as the mixture of single steric isomer (that is, being substantially free of other steric isomer), racemic modification and/or enantiomer and/or diastereomer and exists.Another example is that steric isomer comprises geometrical isomer, is cis or trans direction as the substituting group on the adjacent carbons of two keys.All these single stereoisomers, racemic modification and composition thereof intention comprises within the scope of the present invention.If do not indicate on the contrary, all these stereoisomeric forms in any ratio are comprised in the formula provided herein.
[0218] in some embodiments, chipal compounds of the present invention is in the form that contains at least 80% individual isomer (60% enantiomer excessive (" e.e. ") or diastereomer excessive (" d.e. ")), or at least 85% (70%e.e. or d.e.), 90% (80%e.e. or d.e.), 95% (90%e.e. or d.e.), 97.5% (95%e.e or d.e.) or 99% (98%e.e. or d.e.).As those skilled in the art, understand, optically pure compound with a chiral centre is basically by a kind of compound that constitutes in two kinds of possible enantiomers (promptly, enantiomer-pure), the optically pure compound with an above chiral centre is the compound of the pure and mild enantiomer-pure of non-enantiomerism.In some embodiments, compound exists with optically pure form.
[0219] for wherein the synthetic particularly compound of carbon-carbon double bond place addition separate base that relates at two keys place, described addition can occur in arbitrary doubly linked atom place.For this compounds, the present invention includes two kinds of such positional isomerss.
[0220] in addition, described formula intention comprises having solvation form and the non-solvent form of identifying structure.For example, specified structure comprises hydration and non-hydrated form.Other example of solvate comprises and suitable solvent such as Virahol, ethanol, methyl alcohol, DMSO, ethyl acetate, acetate or thanomin bonded structure.
(e) prodrug and metabolite
[0221] except formula of the present invention and compound as herein described, the present invention also comprises prodrug (generally being pharmaceutically acceptable prodrug), active metabolism derivative (active metabolite) and their pharmacy acceptable salt.
[0222] prodrug is metabolism or produce compound or its pharmacy acceptable salt of required active compound when being transformed by solvolysis under physiological condition.Prodrug includes but not limited to: the ester of active compound, acid amides, carbamate, carbonic ether, uride, solvate or hydrate.Usually, prodrug is that non-activity or its activity are lower than active compound, but one or more favourable processing, administration and/or metabolisming property can be provided.For example, some prodrugs are esters of active compound; Between metabilic stage, ester group is cut and produces active medicine.Simultaneously, some prodrugs are activated by enzymatic and produce active compound, or produce the compound of active compound when further chemical reaction.In the present context, common example is the alkyl ester of carboxylic acid.
[0223] as The Practice of Medicinal Chemistry, Ch.31-32 (Ed.Wermuth, Academic Press, San diego, CA, 2001) described in, conceptive, prodrug can be divided into the kind (non-exclusive categories) of two nonexcludabilities: bioprecursor prodrug (bioprecursorprodrugs) and precursor carrier medicine.Usually, the bioprecursor prodrug is such compound, its non-activity or to compare the active pharmaceutical compounds activity of answering low, and it contains one or more blocking groups and is converted into activity form by metabolism or solvolysis.Active medicine form and any d/d meta-bolites all should have acceptable low toxicity.Usually, the formation of active pharmaceutical compounds relates to the metabolic process or the reaction of one of following type:
[0224]
Oxidizing reaction: oxidizing reaction is not limited to following reaction by example: as alcohol, carbonyl and acid functionality's oxidation, the hydroxylation of aliphatic carbons, the hydroxylation of alicyclic ring carbon atom, the oxidation of aromatic carbon atom, the oxidation of carbon-carbon double bond, the oxidation of nitrogen-containing functional group, the oxidation of silicon, phosphorus, arsenic and sulphur, oxidisability N-dealkylation (delakylation), oxidisability O-and S-dealkylation, oxidisability deaminizating, and other oxidizing reaction.
[0225]
Reduction reaction: reduction reaction is not limited to following reaction by example: as carbonyl functionality's reduction, and the reduction of carbinol-functional degree and carbon-carbon double bond, the reduction of nitrogen-containing functional group and other reduction reaction.
[0226]
The reaction that does not change under the state of oxidation: the reaction example that does not change under the state of oxidation and be not limited to following reaction: as the hydrolysis of ester and ether, the single bonded hydrolytic cleavage of carbon nitrogen, the hydrolytic rupture of non-aromatic heterocyclic, a plurality of keys place carries out hydration and dehydration, new atomic bond by the dehydration reaction acquisition, the reaction of hydrolysis dehalogenation, the removal of hydrogen halide molecule and other this class reaction.
[0227] the precursor carrier medicine is the medical compounds that contains transport section (transport moiety), and described transport section is for example improved picked-up and/or carried to the part of site of action (one or more).The key that this precursor carrier medicine be it is desirable between drug moiety and the transport section is a covalent linkage, prodrug non-activity or to compare the medical compounds activity low, and the transport section of prodrug and any release is nontoxic acceptably.Strengthen the prodrug that absorbs for the transport section intention, typically, the release of transport section should be rapidly.In other cases, wish to utilize the part that slow release is provided, for example, some polymkeric substance or other parts are as cyclodextrin.(referring to, for example, Cheng etc., United States Patent (USP) publication 20040077595, application number 10/656,838 is incorporated this paper into as a reference).This precursor carrier medicine is favourable for the per os administered agents usually.For example, the precursor carrier medicine can be used to improve one or more in the following character: the toxicity of the pharmacological effect time length of the lipotropy of increase, increase, the site specific of increase, reduction and the improvement of adverse effect and/or pharmaceutical preparation (for example, the inhibition of stable, water-soluble, unwanted organ sensation or physico-chemical property).For example, by with lipotropy carboxylic esterification hydroxyl, or, can increase lipotropy with alcohol fatty alcohol esterification hydroxy-acid group for example.Wermuth, the same.
[0228] prodrug can become activity form from prodrug form in a step, perhaps can have one or more intermediate forms, and described intermediate forms itself can have activity or can not have activity.
[0229] metabolite, for example, active metabolite, overlapping with above-mentioned prodrug biological example precursor prodrug.Therefore, this metabolite be on the pharmacology active compound or further metabolism be the compound of pharmacologically active chemical compounds, described pharmacologically active chemical compounds is the derivative that obtains by in the intravital metabolic process of object.Wherein, active metabolite is these pharmacological activity derivative compounds.For prodrug, prodrug compound normally non-activity or active low than meta-bolites.For active metabolite, parent compound can be active compound or can be the prodrug of non-activity.Use conventional art known in the art can differentiate the metabolite of compound, and use those detections as described herein to determine their activity.For instance, in some compounds, one or more alkoxy bases can be metabolised to hydroxyl, keep pharmacological activity and/or the carboxyl can be esterified as glucuronic acid association reaction (glucuronidation) simultaneously.In some cases, more than one metabolites can be arranged, wherein the further metabolism of intermediate metabolites (one or more) quilt is to provide active metabolite.For instance, in some cases, the derivative compound that produces from metabolizable glucose aldehydic acid association reaction can be non-activity or low activity, and can be by further metabolism so that active metabolite to be provided.
[0230] uses routine techniques known in the art, can identify prodrug and active metabolite.Referring to, for example, Bertolini etc., 1997, JMed Chem 40:2011-2016; Shan etc., J Pharm Sci86:756-757; Bagshawe, 1995, Drug Dev Res 34:220-230; Wermuth, the same.
(f) pharmacy acceptable salt
[0231] compound can be configured to the form of pharmaceutically-acceptable salts or the form of pharmaceutically-acceptable salts.The form of the pharmaceutically-acceptable salts of considering includes but not limited to list, two, three, the fourth class.Pharmaceutically-acceptable salts is nontoxic under amount that they are applied and concentration.Owing to change the physical property of compound under the situation that does not stop its performance physiological effect, such salt pref can be so that the pharmacology application.Useful change comprises the reduction fusing point with the promotion mucosal on physical properties, and increases solubleness to promote to use the medicine of greater concn.Compound of the present invention can have enough tart functional group, enough functional group or two kinds of functional groups of alkalescence, and therefore with a large amount of inorganic or organic bases and inorganic or organic acid reactions arbitrarily, form pharmacy acceptable salt.
[0232] pharmacy acceptable salt comprises acid salt, those sulfur-bearing hydrochlorates for example, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, muriate, bromide, iodide, hydrochloride, fumarate, maleate, phosphoric acid salt, monohydric phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate salt, sulfamate, acetate, Citrate trianion, lactic acid salt, tartrate, sulfonate, mesylate, propanesulfonic acid salt, esilate, benzene sulfonate, tosilate, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, xylenesulfonate, cyclamate, quinate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1,4 diacid salt (dioates), hexin-1, the 6-diacid salt, benzoate, chloro-benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, phenylacetate, phenpropionate, benzenebutanoic acid salt, γ hydroxybutyric acid salt, the salt of glycollate and mandelate.Pharmacy acceptable salt can obtain from acid, and described acid is hydrochloric acid, toxilic acid, sulfuric acid, phosphoric acid, thionamic acid, acetate, citric acid, lactic acid, tartrate, propanedioic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid, cyclohexylsulfamic acid, fumaric acid and quinic acid for example.
[0233] when acidic functionality when for example carboxylic acid or phenol exist, pharmacy acceptable salt also comprises base addition salt, and for example those contain the salt of dibenzylethylenediamine dipenicillin G, chloroprocaine, choline, diethanolamine, thanomin, TERTIARY BUTYL AMINE, quadrol, meglumine, PROCAINE HCL, PHARMA GRADE, aluminium, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine and zinc.For example, referring to Remington ' s Pharmaceutical Sciences, 19
ThEd., Mack Publishing Co., Easton, PA, Vol.2, p.1457,1995.Use suitable corresponding alkali can prepare this type of salt.
[0234] by standard technique, can prepare pharmacy acceptable salt.For example, the compound dissolution of free alkali form in suitable solvent, is for example contained in suitable aqueous acid or the water-alcohol solution, evaporating solns separates then.In another example, can prepare salt by making free alkali and acid reaction in organic solvent.
[0235] therefore, for example, if specific compound is an alkali, then can prepare required pharmacy acceptable salt by any appropriate method that this area can get, for example, handle free alkali with mineral acid or organic acid, described mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid and class acidoid, described organic acid such as acetate, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, oxyacetic acid, Whitfield's ointment, pyranose thuja acid (pyranosidyl acid) is as glucuronic acid or galacturonic acid, alpha hydroxy acid such as citric acid or tartrate, amino acid such as aspartic acid or L-glutamic acid, aromatic acid such as phenylformic acid or styracin, sulfonic acid such as tosic acid or ethyl sulfonic acid or analogue.
[0236] same, if specific compound is acid, then can prepare required pharmacy acceptable salt by any appropriate method, for example, handle free acid with mineral alkali or organic bases, described mineral alkali or organic bases be amine (primary amine, secondary amine or tertiary amine), alkali metal hydroxide or alkaline earth metal hydroxides or analogue for example.The exemplary example of suitable salt comprises organic salt, it is derived from amino acid such as L-glycine, L-Methionin and L-arginine, ammonia, primary amine, secondary amine and tertiary amine, and cyclammonium, as hydroxyethyl hydroxyethyl, piperidines, morpholine or piperazine, and inorganic salt, it is derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium.
[0237] pharmacy acceptable salt of different compounds can be used as the complex compound existence.The example of complex compound comprise the 8-Chlorotheophyline complex compound (be similar to, for example, umine: diphenhydramine 8-Chlorotheophyline (1: 1) complex compound; Dimenhydrinate) and the various complex compound that comprises cyclodextrin.
[0238] if there is not opposite appointment, the detailed description of this paper compound is comprised the pharmacy acceptable salt of these compounds.
(g) polymorph form
[0239] when preparation is solid, it should be appreciated by those skilled in the art that compound can exist with different crystal or polymorph form with salt, all these are intended to be included in the scope of the present invention and specified formula.
III. administration
[0240] these methods and compound will be normally used for treating human subjects.Yet they also can be used for treating the similar or identical indication in other animal target.In the present context, term " object ", " animal target " and similar terms are meant people and non-human vertebrate, and for example, Mammals is such as non-human primates; Motion and commercial animal, for example ox, horse, pig, sheep, rodent; And pet, for example dog and cat.
[0241] suitable formulation partly depends on the approach of purposes or administration, for example per os, through skin, through mucous membrane, suction or by injection (parenteral).This type of formulation should make this compound can arrive target cell.Other factors is known in the art, and comprises consideration, such as toxicity with postpone compound or composition is brought into play the formulation of its effect.Technology and prescription generally can be in Remington:The Science andPractice of Pharmacy, 21
ThEdition., Lippincott, Williams and Wilkins, Philadelphia, PA finds in 2005 (being hereby incorporated by).
[0242] The compounds of this invention (that is, formula I comprises formula Ia-Im and all sub-embodiments disclosed herein) can be configured to pharmacy acceptable salt.
[0243] carrier or vehicle can be used to produce composition.Described carrier or vehicle can be selected to promote the administration of compound.The example of carrier comprises lime carbonate, calcium phosphate, various sugar for example lactose, glucose or sucrose or starch type, derivatived cellulose, gelatin, vegetables oil, polyoxyethylene glycol and physiological compatibility solvent.The example of physical compatibility solvent comprises water for injection (WFI) sterile solution, salt brine solution and glucose.
[0244] different path administered compounds be can pass through, intravenously, intraperitoneal, subcutaneous, intramuscular, per os comprised, through mucous membrane, rectum, through skin or suction.In some embodiments, preferred oral.For oral, for example, compound can be configured to conventional oral dosage form, for example capsule, tablet, and liquid preparation, for example syrup, elixir and concentrated drops.
[0245] pharmaceutical preparation that can following acquisition oral use, for example by active compound and solid excipient are made up, the formed mixture of optional grinding, and the mixture of processing granular, this carries out after adding suitable assistant agent, assistant agent if desired, thus tablet or drageeing obtained.Suitable vehicle particularly is that filler is sugar for example, comprises lactose, sucrose, mannitol or sorbyl alcohol; Cellulose preparation, for example W-Gum, wheat starch, Starch rice, yam starch, gelatin, Tragacanth, methylcellulose gum, Vltra tears, Xylo-Mucine (CMC) and/or polyvinylpyrrolidone (PVP: polyvidone (povidone)).If necessary, can add disintegrating agent, for example crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt, for example sodiun alginate.
[0246] drageeing (dragee core) is provided with suitable dressing.For this purpose, can use spissated sugar soln, it can be chosen wantonly and contain for example gum arabic, talcum, polyvinylpyrrolidone, the general gel of kappa, polyoxyethylene glycol (PEG) and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Dyestuff or pigment can be added in tablet or the drageeing sugar-coat, be used to discern or characterize the various combination of active compound doses.
[0247] pharmaceutical preparation of can oral administration using comprises push style (push-fit) capsule of being made by gelatin (" gelatine capsule (gelcaps) "), and by gelatin and the softening agent soft seal capsule made of glycerine or sorbyl alcohol for example.The capsule of slippaging can contain activeconstituents, and itself and filler be lactose, tackiness agent for example talcum or Magnesium Stearate of starch and/or lubricant for example for example, and optional stablizer mixes.In soft capsule, active compound can be dissolved or suspended in suitable liquid for example in fatty oil, whiteruss or the liquid macrogol (PEGs).In addition, can add stablizer.
[0248] alternatively, can use injection (administered parenterally), for example intramuscular, intravenous, endoperitoneal and/or subcutaneous.For injection, compound of the present invention is configured to sterile liquid solution, preferably in physiology compatible buffers or solution, and for example salt brine solution, hanks' solution or Ringer's solution.In addition, compound can be configured to solid form, and before using a moment dissolved again or suspended.Also can produce lyophilized form.
[0249] administration also can be by through mucous membrane, part, through skin or suction.For through mucous membrane, part or percutaneous dosing, in prescription, use the penetration agent that is fit to treat penetration barriers.Such penetration agent is generally known in the art, comprises, for example, and for mucosal, biliary salts and fusidic acid derivatives.In addition, washing agent can be used for promoting to penetrate.Mucosal for example, can pass through nasal spray or suppository (per rectum or vagina).
[0250] local component of the present invention can be preferably by selecting suitable carrier known in the art to be configured to oil, creme, lotion, paste etc.Suitable carriers comprises vegetables oil or mineral oil, white Vaseline (white soft wax), props up chain fatty or oil, animal tallow and high molecular weight alcohol (C
12More than).Preferred carrier is soluble those carriers of activeconstituents wherein.If desired, emulsifying agent, stablizer, wetting agent and antioxidant and give color or in the preparation of fragrance also can be included in.Preferably by the mixture preparation of mineral oil, self-emulsifying beeswax and water, in described mixture, the effective constituent that is dissolved in a small amount of solvent (for example oil) is mixed for the creme of topical application.In addition, use through the skin mode and to comprise, as the bandage of effective constituent and one or more carriers randomly known in the art or thinner is housed through skin patch or dressing.In order to use with the transdermal delivery system form, the application dosage during the whole dosage regimen will yes continues, rather than be interrupted.
[0251], compound of the present invention can be formulated as dry powder or suitable solution, suspension or aerosol for inhalation.Powder and solution can be prepared with suitable additive known in the art.For example, powder can comprise suitable powder matrix (powder base) as lactose or starch, and solution can comprise that propylene glycol, sterilized water, ethanol, sodium-chlor and other additive are as acid, alkali and buffering salt.Can give this solution or suspension by suction through spraying, pump, atomizer or spraying gun etc.Compound of the present invention also can with other anapnotherapy combined utilization, for example, reflunomide such as FLUTICASONE PROPIONATE, beclomethasone dipropionate, the third scorching pine (triamcinolone acetonide), Bu Desong and Sch-32088 (mometasone furoate); Beta receptor agonist such as salbutamol, Salmeterol and formoterol; Anticholinergic such as SCH 1000 (ipratropriumbromide) or thiophene holder (tiotropium); Vasodilator such as treprostinal and Iloprost (iloprost); Enzyme such as DNA enzyme; Human cytokines; Immune globulin antibody; Oligonucleotide such as strand or double-stranded DNA or RNA, siRNA; Microbiotic such as tobramycin; Muscarinic receptor antagonist; Leukotriene antagonist; Cytokine antagonist; Proteinase inhibitor; Sodium Cromoglicate (cromolyn sodium); Nedocril sodium and cromoglycate sodium (sodiumcromoglycate).
[0252] amount of all cpds that is applied can be considered that following factor determines by standard program, as compd E C
50, the biological half-life of compound, the age of object, size and body weight, and the illness relevant with object.The importance of these and other factor is known to those skilled in the art.Generally speaking, according to the body weight of the object of receiving treatment, dosage is between about 0.01 to 50mg/kg, preferably between 0.1 to 20mg/kg.Can use multiple dosage.
[0253] The compounds of this invention also can with the treatment same disease the other therapies combined utilization.This combined utilization is included in different time and gives compound and one or more other therapies, perhaps gives compound and one or more other therapies jointly.In some embodiments, use the method that those of ordinary skills know, the other therapies for one or more compounds of the present invention or combined utilization can change dosage, for example, and with respect to the compound or the therapy attenuating dosage of independent application.
[0254] should be appreciated that, combined utilization comprises with other therapies, medicine, medical procedure etc. to be used, wherein other therapies or process can (for example be used in the time different with using The compounds of this invention, at short notice, as (for example, 1,2,3,4-24 hour) in a few hours, or in a long time (for example, 1-2 days, 2-4 days, 4-7 days, 1-4 week)), or use in the time identical with using The compounds of this invention.Combined utilization also comprises with the therapy that gives once or frequently do not give or process to be used as operation, and The compounds of this invention before or after other therapies or process short period of time or the long period in use.In some embodiments, the present invention carries the conveying that The compounds of this invention and the treatment of one or more other medicines are provided by different way of administration or identical route of administration.The combined utilization of any route of administration comprises the conveying by the identical route of administration conveying The compounds of this invention in any preparation together and the treatment of one or more other medicines, comprises the preparation with two kinds of compounds that connect with the mode chemistry of keeping its therapeutic activity when using.On the one hand, the other medicines treatment can be used jointly with one or more compounds of the present invention.Comprise the preparation that gives common preparation or chemistry connection compound by the combined utilization of using jointly, or by identical or different approach, in the short period of time each other (for example, 1 hour, 2 hours, 3 hours, nearly in 24 hours) gives two or more compounds in the separate formulation.The co-administered of separate formulation comprises the co-administered of carrying through same equipment, for example, same inhalation device, same syringe etc., or in the short period of time each other from independent equipment administration.The common preparation of The compounds of this invention and one or more other pharmacological agenies of carrying by same approach is included in material pref together, so that they can pass through an equipment administration, be included in the independent compound that makes up in the preparation or be modified so that chemistry connects but still keep the compound of its biologic activity.This chemistry connects compound can have the connection that is kept basically in vivo, or described connection can rupture in vivo, makes two kinds of active compounds separately.
Embodiment
[0255] embodiment that is correlated with of the present invention is described below.Under most of situation, can use optional technology.These embodiment are intended to be exemplary and unqualified or to limit the scope of the invention.
The overall of embodiment 1 formula I compound synthesized
[0256] formula I compound is synthetic--R wherein
3Be-Ar
1-M-Ar
2--can realize as three steps as described in the scheme 1.
Scheme 1
Step 1: the preparation of compounds X XX
[0257] by inert solvent such as 2-butanone in the alkylated reaction of alkylogen and alkali such as salt of wormwood, perhaps the Mitsunobu reaction by utilize in such as THF activator such as DEAD (diethyl azodiformate) that hydroxyl and triphen are seen at inert solvent can prepare intermediate X XX from compounds X XIX.
Step 2: the preparation of compounds X XXI
[0258] by inert solvent such as pyridine in the reaction of trifluoromethanesulfanhydride anhydride (trifilic anhydride) or toluene sulfonyl chloride, make L-Ar
1Nucleophilic group replace unstable group, the hydroxyl of intermediate X XX is changed into more unstable group such as triflate, can prepare intermediate X XXI.Optional method is the hydroxyl that utilizes intermediate X XX at inert solvent in such as 2-butanone in the alkylated reaction of alkylogen and alkali such as salt of wormwood, perhaps by utilizing activator (activation reagent) such as DEAD to make hydroxyl alkane and triphen see at inert solvent in such as THF the Mitsunobu reaction takes place.Similarly, such as 1, utilize catalyzer such as cuprous iodide to make hydroxyl experience and the part of intermediate X XX such as N at inert solvent in the 4-diox, the Ullman of N-N-methylsarcosine reaction can prepare intermediate X XXI.In this scheme L be preferably-O-or-S (O)
2-.
Step 3: the preparation of compounds X XXII
[0259] produces aryl-linking compound or carry out SN by make intermediate X XXI and boric acid that the Suzuki coupling takes place with palladium catalyst
2The Ar reaction can prepare compounds X XXII to replace unstable functional group such as fluorochemical.Other introduces Ar
2Method can replace by the unstable group of assisting and realize with metal amino or that alcohol carries out.
[0260] alternatively, this fragment/substituting group can be assembled before being coupled to phenylacetic acid methyl esters core, as shown in scheme 2.
Scheme 2
Step 1: compound L-Ar
1-M-Ar
2Preparation
[0261] by the Suzuki coupling taking place to produce aryl-linking compound or to carry out SN with palladium catalyst and boric acid
2The Ar reaction can be from compound L-Ar to replace unstable functional group such as fluorochemical
1Middle preparation compound L-Ar
1-M-Ar
2Other introduces Ar
2Method can replace by the unstable group of assisting and realize with metal amino or that alcohol carries out.
Step 2: the preparation of compounds X XXII
[0262] by inert solvent such as pyridine in the reaction of trifluoromethanesulfanhydride anhydride or toluene sulfonyl chloride, make L-Ar
1-M-Ar
2Nucleophilic group replace unstable group, will change into more unstable group as the hydroxyl of intermediate X XX prepared in the scheme 1 such as the trichlorine methanesulfonates, can prepare compounds X XXII.Optional method is the hydroxyl that utilizes intermediate X XX at inert solvent in such as 2-butanone in the alkylated reaction of alkylogen and alkali such as salt of wormwood, perhaps activates reagent (activation reagent) such as DEAD and makes hydroxyl alkane and triphen see Mitsunobu takes place and react by utilizing in such as THF at inert solvent.Similarly, such as 1, utilize catalyzer such as cuprous iodide to make hydroxyl experience and the part of intermediate X XX such as N at inert solvent in the 4-diox, the Ullman of N-N-methylsarcosine reaction can prepare intermediate X XXII.
[0263] the compounds X XXII (formula I, the wherein R that advise have been illustrated in the scheme 3
3Be-Ar
1-M-Ar
2) optional synthetic route.From starting material XXXIII, can three steps preparation compounds X XXII.
Scheme 3
Step 1: the preparation of compounds X XXIV
[0264] by in inert solvent DMF or DMSO, utilizing catalyzer such as palladium or copper bromine (or iodine), can prepare intermediate X XXIV with hydroxyl or thiol replacement intermediate X XXIII.
Step 2: the preparation of compounds X XXI
[0265] by in inert solvent DMF or DMSO, utilizing catalyzer such as palladium or copper bromine (or iodine), can prepare intermediate X XXI with hydroxyl or thiol replacement intermediate X XXIV.
Step 3: the preparation of compounds X XXII
[0266] by makes intermediate X XXI and boric acid the Suzuki coupling take place with palladium catalyst to produce aryl-linking compound or to carry out SN
2The Ar reaction can prepare intermediate X XXII to replace unstable functional group such as fluorochemical.Other introduces Ar
2Method can replace by the unstable group of assisting and realize with metal amino or that alcohol carries out.
[0267] alternatively, this fragment/substituting group can be assembled before being coupled to phenylacetic acid methyl esters core, as shown in above-mentioned scheme 2.
[0268] formula I compound is synthetic--and wherein W is-CH
2-, X is-COOH R
1And R
2In one be OR
9With another is H, and L=-O---can produce with three synthesis steps from dihydroxyphenyl acetic acid ester II, and shown in scheme 4, wherein n, R and formula I are to R
3The definition unanimity.
Scheme 4
Step 1: the preparation of compound III
[0269] from II, by under heating at inert solvent such as N, alkylogen such as iodoethane and non-nucleophilicity alkali react such as salt of wormwood in the dinethylformamide (DMF), can prepare compound III.
Step 2: the preparation of compound IV
[0270] by similarly another takes turns alkylation with step 1, perhaps by under the room temperature inert solvent such as tetrahydrofuran (THF) in triphen see and reagent such as diisopropyl azodiformate is in the Mitsunobu reaction conditions, can prepare compound IV.
Step 3: the preparation of compound V
[0271] (for example, LiOH, NaOH or KOH 1M) carry out the deprotection of alkyl ester, can prepare compound V with 1: 1 inert organic solvents such as THF and hydroxide aqueous solution by utilizing standard saponification condition under the room temperature condition.
[0272] scheme 5 has shown the synthetic of formula I compound, and wherein W is-CR
4R
5-, X is-COOH R
1And R
2In one be OR
9With another is H, and L=-O-.The synthetic route that produces this series compound relates to five-step approach, and wherein n, R and formula I are to R
3The definition unanimity.
Scheme 5
The preparation of step 1: compound VI I
[0273] by in inert solvent such as DMF or dimethyl sulfoxide (DMSO) (DMSO), carrying out deprotonation and then uses alkylogen (or 1 with alkali (such as sodium hydride or sodium hydroxide), the 4-dibromobutane is to form the cyclopentyl ring) carry out alkylation, can prepare compound VI I.
Step 2: the preparation of compound VIII
[0274] compound VIII prepares by carrying out demethylation with acid such as boron tribromide down at 0 ℃.
The preparation of step 3: Compound I X
[0275] by heat down inert solvent such as DMF in alkylogen such as iodoethane react with non-nucleophilicity alkali such as salt of wormwood and can prepare Compound I X.
Step 4: the preparation of compounds X
[0276] by similarly another takes turns alkylation with step 1, perhaps by under the room temperature inert solvent such as THF in triphen see and reagent such as diisopropyl azodiformate is in the Mitsunobu reaction conditions, can prepare compounds X.
Step 5: the preparation of compounds X I
[0277] (for example, LiOH, NaOH or KOH 1M) carry out the deprotection of alkyl ester, can prepare compounds X I with 1: 1 inert organic solvents such as THF and hydroxide aqueous solution by utilizing standard saponification condition under the room temperature condition.
[0278] scheme 6 has shown the synthetic of formula I compound, and wherein W is-CH
2-, X is-COOH R
1And R
2In one be OR
9With another is H, L=-O-, and R
3Be optional substituted aryl or optional substituted heteroaryl.The synthetic route that produces this series compound relates to two-step approach, and wherein R is optional substituted aryl or optional substituted heteroaryl.
Scheme 6
Step 1: the preparation of compounds X II
[0279], is in the Ullman coupling condition of phenol (III of scheme 4 steps 1 preparation) and halo aromatic ring such as iodobenzene, preparation compounds X II by using catalyzer such as cuprous iodide under such as diox neutral and alkali condition at inert solvent.
Step 2: the preparation of compounds X III
[0280] (for example, LiOH, NaOH or KOH 1M), carry out the deprotection of alkyl ester XII, can prepare compounds X III with 1: 1 inert organic solvents such as THF and hydroxide aqueous solution by utilizing standard saponification condition under the room temperature condition.
[0281] scheme 7 has shown the synthetic of formula I compound, and wherein W is-CH
2-, X is-COOH R
1And R
2In one be OR
9With another is H, and L=-S (O)
2-, wherein R and formula I are to R
3The definition unanimity.Begin with compound III, can produce these compounds by three-step approach.
Scheme 7
Step 1: the preparation of compounds X IV
[0282] by from buffer solvent such as pyridine generation " trichlorine mesylate " in the reaction of hydroxylic moiety and trifluoromethyl sulfonic acid anhydride among the III, prepared compounds X IV.
Step 2: the preparation of compounds X V
[0283] under the alkaline environment of inert solvent such as toluene by catalyzer such as acid chloride, replace the trichlorine mesylate with-sulfinate, prepared compounds X V.
Step 3: the preparation of compounds X VI
[0284] (for example, LiOH, NaOH or KOH 1M) carry out the deprotection of alkyl ester, can prepare compounds X VI with 1: 1 inert organic solvents such as THF and hydroxide aqueous solution by utilizing standard saponification condition under the room temperature condition.
[0285] scheme 8 has shown the synthetic of formula I compound, and wherein W is-CH
2-, X is-COOH R
1And R
2In one be OR
9With another is H, L=-S (O)
2-, and R
3Be optional substituted aryl or optional substituted heteroaryl, wherein R is optional substituted aryl or optional substituted heteroaryl.The synthetic route that begins to produce this series compound from compound III relates to Six Steps, and wherein R is optional substituted aryl or optional substituted heteroaryl.
Scheme 8
Step 1: the preparation of compounds X VII
[0286] compound III N under inert solvent such as DMF neutral and alkali environment, the N-dimethyl sulphide is handled for urea chloride.
Step 2: the preparation of compounds X VIII
[0287] uses inert solvent such as DMSO or DMF, under the assistance of microwave synthesizer, reset thiocarbamate XVII, obtain compounds X VIII.
Step 3: the preparation of compounds X IX
[0288] hydrolysis by thiocarbamate XVII can prepare compounds X IX under inert solvent such as methyl alcohol neutral and alkali condition (for example KOH aqueous solution).
Step 4: the preparation of compounds X X
[0289] by using catalyzer such as cuprous iodide at inert solvent under such as diox neutral and alkali environment, the Ullman coupling condition of benzenethiol XIX and halo aromatic ring such as iodobenzene prepares compounds X X.
Step 5: the preparation of compounds X XI
[0290] inert solvent such as methylene dichloride in by being exposed to oxygenant such as a chloro peroxybenzoic acid, dibenzyl thiol ether XX can be converted to sulfone XXI.
Step 6: the preparation of compounds X XII
[0291] (for example, LiOH, NaOH or KOH 1M) carry out the deprotection of alkyl ester XXI, can prepare compounds X XII with 1: 1 inert organic solvents such as THF and hydroxide aqueous solution by utilizing standard saponification condition under the room temperature condition.
[0292] scheme 9 has shown the synthetic of formula I compound, and wherein W is-OCH
2-, X is-COOH R
1And R
2In one be OR
9With another is H, and L=-S (O)
2-, wherein R and formula I are to R
3The definition unanimity.These compounds can obtain by Six Steps.
Scheme 9
Step 1: the preparation of compounds X XIV
[0293] by under acidic conditions such as Indium-111 chloride, carrying out the Friedel-Craft sulfonylation, prepared compounds X XIV with dimethoxy benzene XXIII.
Step 2: the preparation of compounds X XV
[0294] compounds X XV prepares by carrying out demethylation with acid such as boron tribromide down at 0 ℃.
Step 3: the preparation of compounds X XVI
[0295] from XXV, by heat down inert solvent such as DMF in alkylogen such as iodoethane and non-nucleophilicity alkali react such as salt of wormwood, can prepare compounds X XVI.
Step 4: the preparation of compounds X XVII
[0296] from XXVI, by heat down inert solvent such as DMF in the monobromo-acetic acid ester react with non-nucleophilicity alkali such as salt of wormwood and can prepare compounds X XVII.
Step 5: the preparation of compounds X XVIII
[0297] (for example, LiOH, NaOH or KOH 1M) carry out the deprotection of alkyl ester, can prepare compounds X XVIII with 1: 1 inert organic solvents such as THF and hydroxide aqueous solution by utilizing standard saponification condition under the room temperature condition.
[0298] scheme 10 has shown the synthetic of formula I compound, and wherein W is-CH
2-, X is-COOH R
1And R
2In one be OR
9With another is H, L=-S (O)
2-, and R
3Be that (U is O, S or NH to optional imidazoles, the thiazole Huo oxazole that replaces, R
100And R
200Be independently hydrogen or as the optional described substituting group of substituted heteroaryl of this paper).Compounds X XXX can obtain by three-step approach.
Scheme 10
Step 1: the preparation of compounds X XXVII
[0299] compounds X XXVII can be prepared as follows: α-halogenation ethanoyl (XXXV, wherein V=chloro or bromo) and acid amides or thioamides (XXXVI, wherein U is O, S or OH) coupling, and heating is to produce cyclisation heterocycle XXXVII.
The preparation of step 2: intermediate X XXIX
[0300] compounds X XXVIX can prepare as follows: inert solvent such as THF in 5-proton on-78 ℃ of following heterocycles with highly basic such as the s-butyl lithium deprotonation, and then with electrophilic reagent XXXVIII coupling, to add thiol ether in heterocyclic 5-position.
The preparation of step 3: intermediate X XXLX
[0301] compounds X XXX can be prepared as follows: inert solvent such as methylene dichloride under the envrionment conditions this thiol ether carry out oxidation with oxygenant such as mCPBA.
Embodiment 2:2-{3-[3-(4-ethanoyl-3-hydroxyl-2-propyl group-phenoxy group)-propoxy-]-5-butoxy-phenyl }-2-methyl-propionic acid (P-0002) synthetic.
[0302] shown in scheme 11, Compound P-the 0002nd, from 3,5-dimethoxybenzeneacetonitrile 1 is with five step synthetic.
Scheme 11
The preparation of step 1:2-(3,5-dimethoxy-phenyl)-2-methyl-propionitrile (2)
[0303] in 5 minutes to-78 ℃ down 3, the 5-dimethoxybenzeneacetonitrile (1,500mg, (10mL 0.1mol) adds hexane (2.6mL) solution of the n-Butyl Lithium of 2.5M to tetrahydrofuran (THF) 0.003mol) in the solution.Stirred this mixture then 30 minutes.Methyl iodide in 10 minutes in the adding 5mL tetrahydrofuran (THF) (0.40mL, 0.0065mol).Allowing this mixture stir to the room temperature at 0 ℃ spends the night.Add entry (5mL), then add ether (10mL).The water extracted with diethyl ether.The merging organic phase is used the salt water washing and is dry on sodium sulfate.Flash chromatography (0-5% ethyl acetate in the hexane) obtains clarified oil (2,296mg, 50%).
The preparation of step 2:2-(3,5-dihydroxyl-phenyl)-2-methyl-propionitrile (3)
[0304] under the room temperature to 2-(3,5-dimethoxy-phenyl)-2-methyl-propionitrile (2,290mg, (6mL 0.09mol) adds 1M boron tribromide in the heptane (3.5mL) to methylene dichloride 0.0014mol) in the solution, and this mixture stirred 6 hours.This reaction water quencher and dilute with ethyl acetate.Be separated, and the water ethyl acetate extraction, it uses the salt water washing, with dried over sodium sulfate and concentrated.Rough material does not have further purification just to be used for next step.
The preparation of step 3:2-(3-butoxy-5-hydroxyl-phenyl)-2-methyl-propionitrile (4)
[0305] to 2-(3,5-dihydroxyl-phenyl)-2-methyl-propionitrile (3,0.257g, dimethyl formamide 0.00145mol) (10mL, 0.2mol) add in the solution salt of wormwood (0.6g, 0.004mol).This mixture be heated to 90 ℃ and be added dropwise to 1-butyl iodide in the dimethyl formamide (1mL) (0.100mL, 0.000878mol).Reaction is stirred 5 hours, removes dimethyl formamide then in a vacuum.Add entry and ethyl acetate, water carries out acidifying with 1M HCl and extracts with ethyl acetate.Organic phase is dry on sodium sulfate.Flash chromatography (0-5% ethyl acetate in the hexane) obtains expecting compound 4.
Step 4:2-{3-[3-(4-ethanoyl-3-hydroxyl-2-propyl group-phenoxy group)-propoxy-]-5-butoxy-phenyl }-preparation of 2-methyl-propionitrile (5)
[0306] to 2-(3-butoxy-5-hydroxyl-phenyl)-2-methyl-propionitrile (4,50mg, 0.0002mol) acetonitrile (5mL, 0.1mol) add salt of wormwood (89mg in the solution, 0.00064mol), then add 1-[4-(3-bromo-propoxy-)-2-hydroxyl-3-propyl group-phenyl]-ethyl ketone (100mg, 0.00032mol).This mixture is 80 ℃ of following heated overnight.This mixture is concentrated and adds entry and ethyl acetate.Water is with 1M HCl acidifying and use ethyl acetate extraction.The organic phase that merges also concentrates with dried over sodium sulfate.Purify with chromatography (25% ethyl acetate in the hexane).Obtain expecting compound oil (5,15mg, 10%).
Step 5:2-{3-[3-(4-ethanoyl-3-hydroxyl-2-propyl group-phenoxy group)-propoxy-]-5-butoxy-phenyl }-preparation of 2-methyl-propionic acid (P-2002)
[0307] to 2-{3-[3-(4-ethanoyl-3-hydroxyl-2-propyl group-phenoxy group)-propoxy-]-5-butoxy-phenyl }-2-methyl-propionitrile (5; 13mg; 0.000028mol) methyl alcohol (1mL; 0.02mol) add the 2M lithium hydroxide in the entry (0.2mL) in the solution, and this mixture stirred 2 days down at 80 ℃.This mixture is transferred in the microwave reactor and heated 5 minutes under 120 ℃ in microwave oven, then heats altogether under 160 ℃ 5 times 15 minutes.This mixture is used ethyl acetate extraction with 1M HCl acidifying, and is dry on sodium sulfate, and under reduced pressure removes solvent.Compound P-0002 usefulness normal phase chromatography (50% ethyl acetate in the hexane) is purified.Calculate molecular weight 486.60, MS (ESI) [M+H
+]
+=487.3, [M-H
+]
-=485.2.
[0308] additional compounds is to adopt to be prepared with scheme 11 described identical methods.P-0005 by in step 1 with 1,4-dibromobutane (1 equivalent) replacement 1, the 4-dibromobutane prepares.Compound P-0002 and P-0005 are isolating by products after step 5 hydrolysis of nitrile, and it also provides corresponding amide P-0003 and P-0004 respectively.The compound title of these other compounds, structure and experiment mass spectrum result are provided in the following table 1.
Table 1
Embodiment 3:{3-butoxy-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-acetate (P-0027) synthetic.
[0309] shown in scheme 12, Compound P-the 0027th is from 8 five step of (3,5-dihydroxyl-phenyl)-methyl acetate synthetic.
Scheme 12
Step 1:(3-butoxy-5-hydroxyl-phenyl)-preparation of methyl acetate (9)
[0310] to (3,5-dihydroxyl-phenyl)-methyl acetate (8,1.200g, dimethyl formamide 0.006587mol) (50mL, 0.7mol) add in the solution a salt of wormwood (2.73g, 0.0198mol).Be added dropwise to 1-butyl iodide in the dimethyl formamide (0.682mL, 0.00599mol) and reaction be heated to 90 ℃ and stir and spend the night.Remove dimethyl formamide in a vacuum and add entry and ethyl acetate.This mixture carries out acidifying with 1M HCl, and water extracts with ethyl acetate.The organic phase that merges is dry on the sodium sulfate and be placed on the silica.Flash chromatography (25% ethyl acetate in the hexane) obtains expecting compound oil (9,615mg, 43%)
Step 2:(3-butoxy-5-trifluoro-methanesulfonyl oxy-phenyl)-preparation of methyl acetate (10)
[0311] (3-butoxy-5-hydroxyl-phenyl)-methyl acetate in ice/water-bath (9,100mg, pyridine 0.0004mol) (0.4mL, 0.005mol) solution, dropwise add Trifluoromethanesulfonic anhydride (90.0 μ L, 0.000535mol).This mixture was followed cooling and stirring 15 minutes, at room temperature stirred then 2 hours.Add entry (5mL) and ether (5mL) and this solution and carry out acidifying with the dense HCl of 1mL.Ether is separated, washs with 1M HCl, and is dry and concentrated on sodium sulfate.Purify with flash chromatography (hexane/ethyl acetate 3: 1), obtain clarified oil (10,95mg, 60%)
Step 3:[3-butoxy-5-(4-fluoro-benzenesulfonyl)-phenyl]-preparation of methyl acetate (11)
[0312] under argon atmospher in sealed reactor, being dissolved in toluene (4mL, 0.04mol) in (3-butoxy-5-trifluoro-methanesulfonyl oxy-phenyl)-methyl acetate (10,198mg, 0.000535mol) and 4-fluoro-benzene sulfinic acid sodium salt (120mg, 0.00064mol) in the solution, add three (dibenzalacetones), two palladiums (0) (49mg, 0.000053mol), cesium carbonate (260mg, 0.00080mol) and 4,5-two (dimethyl phosphino-)-9,9-dimethyl xanthene (xanthphos) (60mg, 0.0001mol).With container sealing and this mixture 120 ℃ of following heated overnight.After the cooling, this reaction mixture dilutes with ethyl acetate, uses the salt water washing, and is dry on sodium sulfate, concentrates and is placed on the silica.Flash chromatography (hexane/ethyl acetate 9: 1) obtains expecting compound (11,65mg, 32%).
Step 4:{3-butoxy-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-preparation of methyl acetate (12)
[0313] to [3-butoxy-5-(4-fluoro-benzenesulfonyl)-phenyl]-methyl acetate (11; 25mg, (0.5mL 0.007mol) adds salt of wormwood (10mg to dimethyl sulfoxide (DMSO) 0.000066mol) in the solution; 0.000072mol) and 4-trifluoromethoxy-phenol (9.4 μ L, 0.000072mol).This mixture heated 10 minutes under 120 ℃ in microwave oven.This solvent is removed by lyophilized overnight.Add ethyl acetate and water and separately with these layers.This organic phase is used the salt water washing and is dry on sodium sulfate.Desired compounds is purified by silica gel chromatography (hexane/ethyl acetate 3: 1), obtains compound 12 (12mg, 34%).
Step 5:{3-butoxy-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-preparation of acetate (P-0027)
[0314] to { 3-butoxy-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-methyl acetate (12; 12mg; 0.000022mol) tetrahydrofuran (THF) (2mL, (1M 1mL) and at room temperature stirs and spends the night 0.02mol) to add potassium hydroxide in the solution.Add ethyl acetate (3mL) and this mixture and carry out acidifying with 1M HCl.This water extracts with ethyl acetate.This organic phase is washed with salt solution, and is dry and concentrated on sodium sulfate then.Expectation Compound P-0027 usefulness silica gel chromatography (5% methyl alcohol in the methylene dichloride) is purified.Calculate molecular weight 524.51, MS (ESI) [M+H
+]
+=525.2, [M-H
+]
-=523.2.
[0315] additional compounds is to adopt as with method preparation identical as described in the scheme 12.P-0158 is by replace (3,5-dihydroxyl-phenyl)-methyl acetate 8 and preparation with propyl iodide replacement 1-butyl iodide and with (3,5-dihydroxyl-phenyl)-methyl propionate in step 1.P-0293 begins by replacing (3-butoxy-5-hydroxyl-phenyl)-methyl acetate 9 to prepare with (3-hydroxyl-phenyl)-methyl acetate step 2 from step 2.Additional compounds is by replacing the 1-butyl iodide with suitable iodine alkylate alternatively in step 1, and/or prepares with suitable phenol or benzenethiol replacement 4-trifluoromethoxy-phenol in step 4 alternatively.Following table 2 has shown for specified compound number used reagent in step 1 and 4.
Table 2
| Compound number | Step 1 reagent | Step 4 reagent |
| P-0062 | Iodoethane | 4-trifluoromethoxy-phenol |
| P-0057 | Methyl iodide | 4-trifluoromethoxy-phenol |
| P-0058 | 1-iodo-2-methyl ethyl ether | 4-trifluoromethyl-phenol |
| P-0059 | 1-iodo-2-methyl ethyl ether | 4-trifluoromethoxy-phenol |
| P-0141 | Iodoethane | 3-oxyethyl group-phenol |
| P-0142 | Iodoethane | 6-methyl-pyridine-2-phenol |
| P-0143 | Iodoethane | 3-methyl-pyridine-2-phenol |
| P-0144 | Propyl iodide | 3-oxyethyl group-phenol |
| P-0145 | Propyl iodide | 6-methyl-pyridine-2-phenol |
| P-0146 | Propyl iodide | 3-methyl-pyridine-2-phenol |
| P-0114 | Iodoethane | 4-imidazoles-1-base-phenol |
| P-0115 | Iodoethane | 3,4-dimethoxy-phenol |
| P-0116 | Iodoethane | 3,4-two chloro-phenol |
| P-0117 | Propyl iodide | 4-imidazoles-1-base-phenol |
| Compound number | Step 1 reagent | Step 4 reagent |
| P-0118 | Propyl iodide | 3,4-dimethoxy-phenol |
| P-0119 | Propyl iodide | 3,4-two chloro-phenol |
| P-0235 | Iodoethane | 3-methoxyl group-benzenethiol |
| P-0236 | Iodoethane | 3-oxyethyl group-benzenethiol |
| P-0237 | Propyl iodide | 3,4-dimethoxy-benzenethiol |
| P-0238 | Propyl iodide | 3-methoxyl group-benzenethiol |
| P-0239 | Propyl iodide | 4-trifluoromethyl-benzenethiol |
| P-0240 | Propyl iodide | 3-oxyethyl group-benzenethiol |
| P-0241 | Propyl iodide | 4-methoxyl group-benzenethiol |
| P-0242 | Propyl iodide | 3-trifluoromethoxy-benzenethiol |
| P-0243 | Iodomethyl-cyclopropane | 3-methoxyl group-benzenethiol |
| P-0244 | Iodomethyl-cyclopropane | 4-trifluoromethyl-benzenethiol |
| P-0245 | Iodomethyl-cyclopropane | 3-oxyethyl group-benzenethiol |
| P-0246 | Iodomethyl-cyclopropane | 4-methoxyl group-benzenethiol |
| P-0247 | Iodomethyl-cyclopropane | 3-trifluoromethoxy-benzenethiol |
| P-0248 | 1-iodo-2-methyl ethyl ether | 3,4-dimethoxy-benzenethiol |
| P-0249 | 1-iodo-2-methyl ethyl ether | 3-methoxyl group-benzenethiol |
| P-0250 | 1-iodo-2-methyl ethyl ether | 3-oxyethyl group-benzenethiol |
| P-0251 | 1-iodo-2-methyl ethyl ether | 4-methoxyl group-benzenethiol |
| P-0252 | 1-iodo-2-methyl ethyl ether | 3-trifluoromethoxy-benzenethiol |
| P-0253 | Iodoethane | Pyridine-4-mercaptan |
| P-0254 | Propyl iodide | Pyridine-4-mercaptan |
| P-0255 | Iodomethyl-cyclopropane | Pyridine-4-mercaptan |
| P-0256 | 1-iodo-2-methyl ethyl ether | Pyridine-4-mercaptan |
| P-0281 * | Propyl iodide | 4-methylsulfonyl-phenol |
| P-0282 | Propyl iodide | 4-methylsulfonyl-phenol |
| P-0261 | 1-iodo-2-methyl ethyl ether | 4-methoxyl group-phenol |
| P-0262 | Iodoethane | 4-methoxyl group-phenol |
| P-0263 | Iodomethyl-cyclopropane | 4-methoxyl group-phenol |
| P-0264 | Propyl iodide | 4-methoxyl group-phenol |
| P-0265 | 1-iodo-2-methyl ethyl ether | 4-oxyethyl group-phenol |
| P-0266 | Iodoethane | 4-oxyethyl group-phenol |
| P-0267 | Iodomethyl-cyclopropane | 4-oxyethyl group-phenol |
| P-0268 | Propyl iodide | 4-oxyethyl group-phenol |
| P-0269 | 1-iodo-2-methyl ethyl ether | 4-propoxy--phenol |
| P-0270 | Iodoethane | 4-propoxy--phenol |
| P-0271 | Iodomethyl-cyclopropane | 4-propoxy--phenol |
| P-0272 | Propyl iodide | 4-propoxy--phenol |
| P-0273 | 1-iodo-2-methyl ethyl ether | Uncle 4--butoxy-phenol |
| P-0274 | Iodoethane | Uncle 4--butoxy-phenol |
| P-0275 | Iodomethyl-cyclopropane | Uncle 4--butoxy-phenol |
| P-0276 | Propyl iodide | Uncle 4--butoxy-phenol |
| P-0277 | Iodomethyl-cyclopropane | 4-trifluoromethoxy-phenol |
| P-0280 | Propyl iodide | 4-first sulfane base-phenol |
| P-0088 * | Iodoethane | 4-trifluoromethoxy-phenol |
| P-0207 | 1-iodo-2-methyl ethyl ether | 3-oxyethyl group-phenol |
| P-0208 | Iodomethyl-cyclopropane | 4-imidazoles-1-base-phenol |
| P-0212 | 1-iodo-2-methyl ethyl ether | 3,4-two chloro-phenol |
| P-0213 | Iodomethyl-cyclopropane | 3,4-two chloro-phenol |
| Compound number | Step 1 reagent | Step 4 reagent |
| P-0214 | 1-iodo-2-methyl ethyl ether | 3,4-dimethoxy-phenol |
| P-0215 | Iodomethyl-cyclopropane | 3,4-dimethoxy-phenol |
| P-0216 | Iodomethyl-cyclopropane | 3-oxyethyl group-phenol |
| P-0217 | 1-iodo-2-methyl ethyl ether | 4-imidazoles-1-base-phenol |
| P-0229 | Iodomethyl-cyclopropane | 6-methyl-pyridine-2-phenol |
| P-0230 | 1-iodo-2-methyl ethyl ether | 6-methyl-pyridine-2-phenol |
| P-0233 | 1-iodo-2-methyl ethyl ether | 3-methyl-pyridine-2-phenol |
*Methyl esters is isolated in step 4 back.
The compound structure of these compounds, title and mass spectrum result are provided in the following table 3.
Table 3
Embodiment 4:(3-butoxy-5-phenoxy group-phenyl)-acetate (P-0006) synthetic
[0316] shown in scheme 13, Compound P-the 0006th is from 9 liang of steps of (3-butoxy-5-hydroxyl-phenyl)-methyl acetate synthetic.
Scheme 13
Step 1:(3-butoxy-5-phenoxy group-phenyl)-preparation of methyl acetate (14)
[0317] to being dissolved in 1,4-diox (10mL, 0.1mol) in (3-butoxy-5-hydroxyl-phenyl)-methyl acetate (9,200mg, 0.0008mol, as preparation as described in the step 1 of embodiment 3 schemes 12) in the solution, add cesium carbonate (550mg, 0.0017mol), iodobenzene (140 μ L, 0.0012mol), levoproline (30mg, 0.0002mol) and cuprous iodide (I) (20mg, 0.00008mol).This mixture is 90 ℃ of following heated overnight.Add ethyl acetate and this mixture and carry out acidifying with 1M HCl.Ethyl acetate extraction 3 times of this water layer are with dried over sodium sulfate and concentrated.Purify with flash chromatography (10-20% ethyl acetate in the hexane), obtain expecting compound (14,19mg, 7%).
Step 2:(3-butoxy-5-phenoxy group-phenyl)-preparation of acetate (P-0006)
[0318] to (3-butoxy-5-phenoxy group-phenyl)-methyl acetate (14,18mg, (2mL, (1M, 0.6mL), and this mixture at room temperature stirs and spends the night tetrahydrofuran (THF) 0.000057mol) 0.02mol) to add potassium hydroxide in the entry in the solution.Add ethyl acetate and this mixture and carry out acidifying with 1M HCl.The water ethyl acetate extraction.Organic phase obtains expecting compound (P-0006,15mg, 84%) with salt water washing, dry and concentrated on sodium sulfate.Calculate molecular weight 300.35, MS (ESI) [M+H
+]
+=301.2, [M-H
+]
-=299.1.
Embodiment 5:[3-butoxy-5-(3-methoxyl group-benzenesulfonyl)-phenyl]-acetate (P-0025) synthetic
[0319] shown in scheme 14, Compound P-the 0025th is from 8 four step of (3,5-dihydroxyl-phenyl)-methyl acetate synthetic.
Scheme 14
Step 1:(3-butoxy-5-hydroxyl-phenyl)-preparation of methyl acetate (9)
[0320] at oven drying, then in the flame-dried round-bottomed flask, with (3,5-dihydroxyl-phenyl)-methyl acetate (8,5.0g, 0.027mol) and salt of wormwood (3.81g, 0.0276mol) be dissolved in 2-butanone (500mL, 5.55mol) in.Reaction vessel is with purification for argon and 97 ℃ of heating down.In feed hopper, mix 2-butanone (50mL, 0.55mol) and butyl iodide (4.59g, 0.0249mol).This feed hopper is connected on the reactor and inclusion was added in the reaction in 2 hours.After finally adding, funnel replaces with condenser and reacts to be heated and spend the night.The next morning, TLC (20% ethyl acetate/hexane) demonstrates three spot (R
f=0.8,0.3 and 0.02).Solid is filtered and removes solvent.Add entry and ethyl acetate.Solution neutralizes with 1M HCl, and the water ethyl acetate extraction.The organic phase that the merges (Na that is dried
2SO
4) and be absorbed on the silica.The flash chromatography of silicagel column is used, and with staged gradient organic solvent (4%, 7%, 10%, 20% ethyl acetate in the hexane), isolates the methyl esters (R of expectation
f=0.3), it is directly used in next step.
1HNMR (CDCl
3) consistent with compound structure.
Step 2:(3-butoxy-5-trifluoro-methanesulfonyl oxy-phenyl)-preparation of methyl acetate (10)
[0321] in round-bottomed flask with (3-butoxy-5-hydroxyl-phenyl)-methyl acetate (9,2.3g, 0.0096mol) be dissolved in pyridine (8mL, 0.1mol) in.This flask places on the ice bath and is cooled to 0 ℃.In 15 minutes, in solution, drip trifluoromethanesulfanhydride anhydride (3.3g, 0.012mol).Reaction is stirred 4 hours and makes it be warming up to envrionment conditions.This flask places on the new ice bath and to container and adds 40mL water, then adds ether (90mL) and dense HCl (6mL).In whole process, should react by vigorous stirring.After 40 minutes, isolate organic phase, with 1N HCl solution washing and at MgSO
4Last dry.Decompression goes down to desolventize, and obtains dark yellow oil.Silica plug (silica plug) is used to isolate the expectation compound, is yellow oil.
1HNMR is consistent with compound structure.
Step 3:[3-butoxy-5-(3-anisole alkylsulfonyl)-phenyl]-preparation of methyl acetate (15)
[0322] under argon gas stream, in dry round-bottomed flask, add (3-butoxy-5-trifluoro-methanesulfonyl oxy-phenyl)-methyl acetate (10,150mg, 0.00040mol).Add 3-p-methoxy-phenyl-sulfinic acid sodium salt (97mg, 0.00050mol) and toluene (8mL, 0.08mol), and this container purification for argon.Add cesium carbonate (205mg fast, 0.000629mol), three (dibenzalacetones), two palladiums (0) (4mg, 0.000004mol) and 4,5-two (dimethyl phosphino-)-9,9-dimethyl xanthene (4mg, 0.000007mol), and this is reflected at 110 ℃ of following heated overnight, and the TLC of this reaction after this analyzes (20% ethyl acetate/hexane) and shows that desired compounds forms (R
f=0.3).Make reaction cool to room temperature and dilute with water.With 3 times (3X) of ethyl acetate extraction reaction, the organic layer that merges with the salt water washing 2 times, dry and vapourisation under reduced pressure obtains thick compound on sodium sulfate, is brown oil.This oil is adsorbed on the silica, by flash chromatography, carry out purifying, isolates desired compounds with staged gradient (ethyl acetate in 5%, 7%, 10% hexane).
1H NMR is consistent with compound structure.
Step 4:[3-butoxy-5-(3-methoxyl group-benzenesulfonyl)-phenyl]-preparation of acetate (P-0025)
[0323] in flask, [3-butoxy-5-(3-methoxyl group-benzenesulfonyl)-phenyl]-methyl acetate 15 usefulness 5mL tetrahydrofuran (THF)s/handle, and vigorous stirring is spent the night by 1N KOH (4: 1) mixture.This reaction is carried out acidifying (by the pH test paper, being acidity) and is extracted (3 times of reaction volumes) and at MgSO with ethyl acetate by adding 1N HCl
4Last dry.Development: add hexanes/ch (each 3mL) and this flask and be stirred about one hour.This moment, solvent was removed by filtering.Canescence/brown solid is placed in the high vacuum one more than weekend.
1H NMR (CD
3OD) consistent with compound structure.Calculate molecular weight 378.44, MS (ESI) [M-H
+]
-=377.13.
[0324] additional compounds is passed through to replace the 1-butyl iodide with suitable iodine alkylate alternatively in step 1, and/or replaces 3-p-methoxy-phenyl-sulfinic acid sodium salt to prepare with suitable-sulfinic acid sodium salt in step 3 alternatively.Except these optional variations in step 1 or 3, Compound P-0149 to P-0157 be by in step 1 with (3,5-dihydroxyl-phenyl)-methyl propionate replacement (3,5-dihydroxyl-phenyl)-methyl acetate 8 and the preparation, Compound P-0147, P-0148 and P-0159 are by replacing (using (3 in the no step 1) in step 2 with (3-hydroxyl-phenyl)-methyl propionate, 5-dihydroxyl-phenyl)-methyl acetate 8 and the preparation, and Compound P-0258, P-0294 and P-0295 (use (3,5-dihydroxyl-phenyl)-methyl acetate 8 and prepare in step 2 by replacing with (3-hydroxyl-phenyl)-methyl acetate in the no step 1).Following table 4 shows for the compound of formulating used suitable iodine alkyl and-sulfinic acid reagent in step 1 and step 3 respectively.
Table 4
| Compound number | Step 1 iodine alkylate | Step 3-sulfinic acid sodium salt |
| P-0011 | The 1-butyl iodide | Phenyl |
| P-0022 | The 1-butyl iodide | The 4-trifluoromethyl |
| P-0023 | The 1-butyl iodide | The 4-p-methoxy-phenyl |
| P-0024 | The 1-butyl iodide | The 4-Trifluoromethoxyphen-l |
| P-0026 | The 1-butyl iodide | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0028 | Iodoethane | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0029 | Iodoethane | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0030 | Iodoethane | The 4-p-methoxy-phenyl |
| P-0050 | Propyl iodide | The 4-fluorophenyl |
| P-0051 | 1-iodo-2-methyl ethyl ether | The 4-p-methoxy-phenyl |
| P-0052 | 1-iodo-2-methyl ethyl ether | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0053 | Methyl iodide | The 4-p-methoxy-phenyl |
| P-0054 * | Propyl iodide | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0055 | Propyl iodide | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0056 | Propyl iodide | The 4-p-methoxy-phenyl |
| P-0060 | Methyl iodide | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0061 | Iodomethyl-benzene | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0063 | The 1-butyl iodide | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0065 | Methyl iodide | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0066 | Iodomethyl-benzene | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0067 | Propyl iodide | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0068 | Iodomethyl-cyclopropane | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0069 | Iodomethyl-benzene | The 4-p-methoxy-phenyl |
| P-0070 | Iodoethane | 4 '-methyl-biphenyl-2-base |
| P-0071 | Propyl iodide | 4 '-methyl-biphenyl-2-base |
| Compound number | Step 1 iodine alkylate | Step 3-sulfinic acid sodium salt |
| P-0072 | Propyl iodide | The 4-butoxy phenyl |
| P-0073 | Propyl iodide | The 4-butyl phenyl |
| P-0074 | Propyl iodide | 3-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0075 | Propyl iodide | 3-(4-methoxyl group-phenoxy group)-phenyl |
| P-0076 | Propyl iodide | 3-(2-methoxyl group-phenoxy group)-phenyl |
| P-0077 | Iodoethane | 4-(3-butyl-urea groups)-phenyl |
| P-0078 | Iodoethane | 3, the 4-dichlorophenyl |
| P-0084 | Iodoethane | 2-(4-methyl-phenoxy group)-phenyl |
| P-0085 * | Iodoethane | The 4-fluorophenyl |
| P-0086 | Iodoethane | The 4-fluorophenyl |
| P-0147 | No step 1 | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0148 | No step 1 | The 4-p-methoxy-phenyl |
| P-0149 | Propyl iodide | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0150 | Propyl iodide | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0151 | The 1-butyl iodide | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0152 | The 1-butyl iodide | The 4-p-methoxy-phenyl |
| P-0153 | The 1-butyl iodide | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0154 | Iodoethane | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0155 | Iodoethane | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0156 | Iodoethane | The 4-p-methoxy-phenyl |
| P-0157 | Propyl iodide | The 4-p-methoxy-phenyl |
| P-0159 | No step 1 | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
| P-0258 | No step 1 | 4 '-trifluoromethyl-biphenyl-3-base |
| P-0175 | Methyl iodide | 4 '-trifluoromethyl-biphenyl-3-base |
| P-0206 | Iodoethane | 2,5-dimethyl-thiene-3-yl- |
| P-0286 | Iodoethane | Thiophene-2-base |
| P-0294 | No step 1 | 5-(1-methyl-5-Trifluoromethyl-1 H-pyrazole-3-yl)-thiophene-2-base |
| P-0295 | No step 1 | 4-(4-trifluoromethyl-phenoxy group)-phenyl |
*Methyl esters is isolated in step 3 back.
The compound structure of these compounds, title and mass spectrum result are provided in the following table 5.
Table 5
Embodiment 6:[3-oxyethyl group-5-(4 '-trifluoromethyl-xenyl-3-alkylsulfonyl) phenyl]-acetate (P-0080) synthetic
[0325] shown in scheme 15, Compound P-the 0080th is from 8 four step of (3,5-dihydroxyl-phenyl)-methyl acetate synthetic.
Scheme 15
Step 1:(3-oxyethyl group 5-hydroxy phenyl)-preparation of methyl acetate (16)
[0326] in flask, with (3,5-dihydroxyl-phenyl)-methyl acetate (8,4g, 0.02mol) be dissolved in 2-butanone (80mL, 0.8mol) in.Salt of wormwood (9.10g, 0.0659mol) be added into portion and be added dropwise to iodoethane (1.60mL, 0.0200mol).This reaction is heated to 80 ℃ and allow it stir 5 hours.Solid filtering fallen and remove this solvent.Add entry and ethyl acetate.This solution extracts with ethyl acetate with 1M HCl neutralization and water.The organic phase that the merges (Na that is dried
2SO
4) and absorb on the silica.Flash chromatography--it obtains desired compounds with 20-40% eluent ethyl acetate in the hexane, is clarified yellow oil.
1H NMR is consistent with compound structure.
Step 2:(3-oxyethyl group-5-trifluoromethane sulfonyloxy-phenyl)-preparation of methyl acetate (17)
[0327] under 0 ℃ in round-bottomed flask with (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate (16,4g, 0.02mol) be dissolved in pyridine (60mL, 0.7mol) in.(7mL 0.04mol) is added by several parts Trifluoromethanesulfonic anhydride, and allows reaction stir 16 hours and make it reach envrionment conditions.This reaction is carried out acidifying with dense HCl and with extracted with diethyl ether 3 times.Bonded organic layer salt water washing 2 times then, dry on sodium sulfate, and evaporation obtains orange oil.Then should oil by on silica, purifying with the flash chromatography of ethyl acetate in the 20-35% hexane, obtain expecting compound, be yellow oil.
1H NMR is consistent with compound structure.
Step 3:[3-oxyethyl group-5-(4 '-trifluoromethyl-xenyl-3-alkylsulfonyl)-phenyl]-preparation of methyl acetate (18)
[0328] under argon gas stream in round-bottomed flask with 4 '-trifluoromethyl-xenyl-3--sulfinic acid sodium salt (71mg, 0.00023mol), (3-oxyethyl group-5-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (17,109mg, 0.000318mol), 4,5-two (dimethyl phosphino-)-9, and 9-dimethyl xanthene (12mg, 0.000021mol) and cesium carbonate (174mg, 0.000534mol) toluene (7mL, 0.06mol) the middle stirring.Add fast two (dibenzyl acetone) palladiums (0) (10mg, 0.000017mol), and this reaction is placed in the oil bath through 110 ℃ of heating 16 hours down, after this TLC (20% ethyl acetate/hexane) shows a plurality of spot and does not have raw material.Removing solvent and crude compound is placed on the silica plate.Isolate the expectation compound.
1H NMR is consistent with compound structure.
Step 4:[3-oxyethyl group-5-(4 '-trifluoromethyl-xenyl-3-alkylsulfonyl) phenyl]-preparation of acetate (P-0080)
[0329] saponification: crude reaction product is dissolved in the mixture of 2mL tetrahydrofuran (THF)/1N KOH (4: 1), and vigorous stirring spends the night, after this TLC (20% ethyl acetate/hexane) shows and does not have near new spot raw material and the baseline.This reaction is carried out acidifying (by the pH test paper, being acidity) by adding 1N HCl, extracts with ethyl acetate (3 times reaction volumes), and at MgSO
4Last dry.
1H NMR (CDCl
3) consistent with compound structure.Calculate molecular weight 426.48, MS (ESI) [M+H
+]
+=427.12, [M-H
+]
-=425.06.
[0330] other compound is the optional route by step 3-5, and the Suzuki coupling of dibenzyl coupling described in following proposal 15a of carrying out metal assistance prepares.
[0331] shown in scheme 15a, Compound P-the 0094th is from 8 four step of (3,5-dihydroxyl-phenyl)-methyl acetate synthetic.
Scheme 15a
Step 1 and step 2
[0332] referring to such scheme 15.
Step 3:[3-(3-chloro-benzenesulfonyl)-5-oxyethyl group-phenyl]-preparation of methyl acetate (69)
[0333] in round-bottomed flask, with (3-oxyethyl group-5-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (17,1.26g, 0.00368mol), 3-chloro-phenyl--sulfinic acid sodium salt (68,1.26g, 0.00634mol), toluene (30mL, 0.3mol), 4,5-two (dimethyl phosphino-)-9,9-dimethyl xanthene (0.30g, 0.00052mol), three (dibenzalacetones), two palladiums (0) (0.50g, 0.00055mol) and cesium carbonate (1.3g 0.0040mol) mixes and to be incorporated in 108 ℃ of heating 16 hours down.Allow reaction be cooled to room temperature and water dilutes.This reaction extracts 4 times with ethyl acetate.This blended organic phase washes 2 times, salt water washing with water 1 time, and dry on sodium sulfate.Evaporating solvent obtains orange oil.Should purify by flash chromatography (20-40% ethyl acetate in the hexane) by oil then, obtain expecting compound, be yellow oil.Using (workup) preceding should oil dissolved and processed 16 hours.This reaction is acidified to pH1-2 with 10%HCl, and extracts 4 times with ethyl acetate.Salt water washing 1 time of this blended organic layer, and dry on sodium sulfate.Evaporating solvent obtains yellow oil.Should pass through flash chromatography by oil then, it is purified with 9% methyl alcohol in the methylene dichloride, obtains expecting compound, is little yellow oil, and its drying under high vacuum obtains white solid.
1H NMR is consistent with compound structure.
Step 4:[3-(4 '-chloro-xenyl-3-alkylsulfonyl)-5-oxyethyl group-phenyl]-preparation of acetate (P-0094)
[0334] with 10mg[3-(3-chloro-benzenesulfonyl)-5-oxyethyl group-phenyl]-methyl acetate 69 is dissolved in the 400 μ L acetonitriles, and adds 2 normal 4-chlorophenylboronic acids.Add 200 μ L 1M K
2CO
3, and the Pd (AOc) of adding 0.2M
2/ di-t-butyl biphenyl phosphine solution 10 μ L.Reaction mixture heated 10 minutes under 160 ℃ in microwave oven.This solution neutralizes with acetate and goes down to desolventize in vacuum.Crude material is dissolved in the 500 μ L dimethyl sulfoxide (DMSO), and purifies with HPLC, HPLC employing water/0.1% trifluoroacetic acid and acetonitrile/0.1% trifluoroacetic acid gradient, 20-100% acetonitrile wash-out are more than 16 minutes.Calculate molecular weight 430.91, MS (ESI) [M-H
+]
-=429.03.
[0335] Compound P-0290 adopts the method for the step 2-5 of scheme 15a to be prepared, wherein in step 2, replace (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate 16, and in step 4, replace the 4-chlorophenylboronic acid with 2-methoxyl group-pyrimidine-5-boric acid with (3-hydroxyl-phenyl)-methyl acetate.Additional compounds adopts the method for scheme 15a to be prepared, and wherein randomly replaces iodoethane with suitable iodine alkylate in step 1, and/or replaces the 4-chlorophenylboronic acid with suitable boric acid alternatively in step 4.Following table 6 is illustrated in suitable iodine alkyl and the acid reagent that uses respectively in the step 1 and 4 of scheme 15a, so that the compound of indication to be provided.
Table 6
| Compound number | Step 1 iodine alkylate | Step 4 boric acid |
| P-0290 | No step 1 | 2-methoxyl group-pyrimidine-5-base |
| P-0095 | Propyl iodide | 4-fluoro-phenyl |
| P-0096 | Iodoethane | 4-fluoro-phenyl |
| P-0105 | Propyl iodide | 4-chloro-phenyl |
| P-0106 | Propyl iodide | 2-methoxyl group-phenyl |
| P-0107 | Propyl iodide | 4-methoxyl group-phenyl |
| P-0108 | Propyl iodide | 3-chloro-4-fluoro-phenyl |
| P-0109 | Propyl iodide | 2-trifluoromethyl-phenyl |
| P-0110 | Propyl iodide | 4-trifluoromethoxy-phenyl |
| P-0111 | Propyl iodide | 3-trifluoromethyl-phenyl |
| P-0112 | Propyl iodide | 6-methoxyl group-pyridin-3-yl |
| P-0113 | Propyl iodide | 3-fluoro-4-methoxyl group-phenyl |
| P-0134 | Iodoethane | 2-methoxyl group-phenyl |
| P-0135 | Iodoethane | 3-chloro-4-fluoro-phenyl |
| P-0136 | Iodoethane | 4-oxyethyl group-phenyl |
| P-0137 | Iodoethane | 3-trifluoromethoxy-phenyl |
| P-0138 | Iodoethane | 4-trifluoromethoxy-phenyl |
| P-0139 | Iodoethane | 6-methoxyl group-pyridin-3-yl |
| P-0140 | Iodoethane | 3-fluoro-4-methoxyl group-phenyl |
| Compound number | Step 1 iodine alkylate | Step 4 boric acid |
| P-0187 | Propyl iodide | 4-trifluoromethyl-phenyl |
| P-0188 | Propyl iodide | 1H-pyrazoles-4-base |
| P-0189 | Propyl iodide | 1-methyl isophthalic acid H-pyrazoles-4-base |
| P-0190 | Propyl iodide | 1-isobutyl--1H-pyrazoles-4-base |
| P-0191 | Propyl iodide | 1-(3-methyl-butyl)-1H-pyrazoles-4-base |
| P-0192 | Iodoethane | 1H-pyrazoles-4-base |
| P-0193 | Iodoethane | 1-isobutyl--1H-pyrazoles-4-base |
| P-0194 | 1-iodo-2-methyl ethyl ether | 4-chloro-phenyl |
| P-0195 | 1-iodo-2-methyl ethyl ether | 2-methoxyl group-phenyl |
| P-0196 | 1-iodo-2-methyl ethyl ether | 4-methoxyl group-phenyl |
| P-0197 | 1-iodo-2-methyl ethyl ether | 3-chloro-4-fluoro-phenyl |
| P-0198 | 1-iodo-2-methyl ethyl ether | 4-oxyethyl group-phenyl |
| P-0199 | 1-iodo-2-methyl ethyl ether | 3-trifluoromethoxy-phenyl |
| P-0200 | 1-iodo-2-methyl ethyl ether | 4-trifluoromethoxy-phenyl |
| P-0201 | 1-iodo-2-methyl ethyl ether | 3-trifluoromethyl-phenyl |
| P-0202 | 1-iodo-2-methyl ethyl ether | 4-trifluoromethyl-phenyl |
| P-0203 | 1-iodo-2-methyl ethyl ether | 6-methoxyl group-pyridin-3-yl |
| P-0204 | 1-iodo-2-methyl ethyl ether | 1H-pyrazoles-4-base |
| P-0205 | 1-iodo-2-methyl ethyl ether | 1-isobutyl--1H-pyrazoles-4-base |
| P-0259 | Propyl iodide | 4-oxyethyl group-phenyl |
| P-0260 | Propyl iodide | 3-trifluoromethoxy-phenyl |
| P-0081 | Iodoethane | 4-methoxyl group-phenyl |
The compound structure of these compounds, title and mass spectrum result are provided in the following table 7.
Table 7
Embodiment 7:[3-oxyethyl group-5-(4 '-trifluoromethyl-biphenyl-3-oxygen base)-phenyl]-acetate (P-0082) synthetic
[0336] shown in scheme 16, Compound P-the 0082nd is from (16) two step of (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate synthetic.
Scheme 16
Step 1:[3-oxyethyl group-5-(4 '-trifluoromethyl-biphenyl-3-oxygen base)-phenyl]-preparation of methyl acetate (19)
[0337] in flask, (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate (16,120mg, 0.00057mol, as through embodiment 6, the step 1 of scheme 15 is prepared) is dissolved in 1, the 4-diox (2mL, 0.02mol) in.Add cesium carbonate (370mg, 0.0011mol), 3-bromo-4 '-trifluoromethyl-biphenyl (260mg, 0.00086mol), dimethylamino-acetate (20mg, 0.0002mol) and cuprous iodide (I) (10mg, 0.00006mol).This mixture is 90 ℃ of heated overnight under argon atmospher, and after this TLC shows that raw material transforms fully.Adding ethyl acetate, then is the mixture (4: 1) of ammonium chloride/ammonium hydroxide.Separate these layers, and organic phase is dry on sodium sulfate.Crude material is absorbed on the silica, be used to separate the expectation compound with the flash chromatography of 10-20% ethyl acetate in the hexane, it is used to next step.
1H NMR is consistent with compound structure.
Step 2:[3-oxyethyl group-5-(4 '-trifluoromethyl-biphenyl-3-oxygen base)-phenyl]-preparation of acetate (P-0082)
[0338] with [3-oxyethyl group-5-(4 '-trifluoromethyl-biphenyl-3-oxygen base)-phenyl]-methyl acetate (19,20mg, 0.00005mol) be dissolved in tetrahydrofuran (THF) (4mL, 0.05mol) in.Add the lithium hydroxide in the 1M water (1mL), and mixture stirs at room temperature and spends the night.This mixture carries out acidifying with 1M HCl (pH1-2) and extracts with ethyl acetate.Organic layer separates with water layer, and dry on sodium sulfate.Decompression evaporating solvent down obtains oil.After purifying, isolate final compound with preparation property TLC (5% ethanol in the methylene dichloride).
1H NMR is consistent with compound structure.Calculate molecular weight 416.39, MS (ESI) [M+H
+]
+=417.2, [M-H
+]
--=415.0.
[0339] Compound P-0079, [3-oxyethyl group-5-(4 '-trifluoromethyl-biphenyl-4-oxygen base)-phenyl]-acetate,
The method of employing scheme 16 is prepared, and wherein replaces 3-bromo-4 '-trifluoromethyl-biphenyl with 4-bromo-4 '-trifluoromethyl-biphenyl in step 1.Calculate molecular weight 416.39, MS (ESI) [M+H
+]
+=417.2, [M-H
+]
--=415.0.
[0340] Compound P-0291, [3-methoxyl group-5-(4 '-trifluoromethyl-biphenyl-3-oxygen base)-phenyl]-acetate,
The method of employing scheme 16 is prepared, and wherein replaces (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate 16 with (3-hydroxy-5-methyl oxygen base-phenyl)-methyl acetate in step 1.Calculate molecular weight 402.37, MS (ESI) [M+H
+]
+=403.1, [M-H
+]
--=401.1.
[0341] Compound P-0292, [3-(4 '-trifluoromethyl-biphenyl-3-oxygen base)-phenyl]-acetate,
The method of employing scheme 16 is prepared, and wherein replaces (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate 16 with (3-hydroxyl-phenyl)-methyl acetate in step 1.Calculate molecular weight 372.34, MS (ESI) [M-H
+]
--=371.1.
Embodiment 8:{3-propoxy--5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-acetate (P-0064) synthetic
[0342] shown in scheme 17, Compound P-the 0064th is from 8 five step of (3,5-dihydroxyl-phenyl)-methyl acetate synthetic.
Scheme 17
Step 1:(3-hydroxyl-5-propoxy--phenyl)-preparation of methyl acetate (20)
[0343] in flask with (3,5-dihydroxyl-phenyl)-methyl acetate (8,10.376g, 0.056957mol) be dissolved in 2-butanone (200mL, 2mol) in.Add a salt of wormwood (21.5g, 0.155mol) and be added dropwise to propyl iodide (5.06mL, 0.0518mol).This reaction is heated to 80 ℃ and its stirring is spent the night.Filter out solid and remove solvent.Adding entry and ethyl acetate and solution neutralizes with 1M HCl.Water extracts with ethyl acetate.The organic phase that the merges (Na that is dried
2SO
4) and be absorbed on the silica.Flash chromatography, it carries out wash-out with 20-40% ethyl acetate in the hexane, obtains expecting compound, is clarified yellow oil.
1H NMR is consistent with compound structure.
Step 2:(3-propoxy--5-trifluoromethane sulfonyloxy-phenyl)-preparation of methyl acetate (21)
[0344] be cooled in 0 ℃ the round-bottomed flask, with (3-hydroxyl-5-propoxy--phenyl)-methyl acetate (20,2.36g, 0.0105mol) be dissolved in pyridine (35mL, 0.43mol) in.(4mL 0.02mol) divides a plurality of parts to add by syringe to Trifluoromethanesulfonic anhydride.Allow this reaction continue 16 hours before use.This reaction is carried out acidifying with the 2-3mL concentrated hydrochloric acid, and with extracted with diethyl ether 4 times.The ether layer that merges 1N HCl washing 1 time, water washing 1 time, salt water washing 1 time, and dry on sodium sulfate.Evaporating solvent obtains brown oil, and it is used to next step.TLC shows that the expectation compound is a primary product.
1H NMR analysis revealed triflate 21 is primary product (＞90%).
Step 3:[3-(4-fluoro-benzenesulfonyl)-5-propoxy--phenyl]-preparation of methyl acetate (22)
[0345] (3-propoxy--5-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (21,129.4mg, 0.0003633mol), (4-fluorophenyl)-sulfinic acid sodium salt (116mg, 0.36mmol), toluene (2.7090mL, 0.025432mol), three (dibenzalacetone)-two palladium (0) (20mg, 0.00002mol), cesium carbonate (177.56mg, 5.4497E-4mol) and 4,5-two (dimethyl phosphino-)-9, (21.02mg 3.633E-5mol) is added in the high pressure pipe and uses nitrogen purge before with the sealing of tetrafluoroethylene plug 9-dimethyl xanthene.This is reflected at 120 ℃ of following heated overnight.This reaction is cooled and dilutes with ethyl acetate.With these layers separately and organic layer with the saturated sodium bicarbonate washing and at MgSO
4Last dry.Under reduced pressure remove solvent to obtain crude material, it is with preparing column plate chromatography (7: 3 hexanes: ethyl acetate) purify.Isolate the expectation compound and
1HNMR is consistent with compound structure.MS(ESI)[M+H
+]
+＝367.2。
Step 4:3-propoxy--5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-preparation of phenyl-acetic acid methyl esters (23)
[0346] with [3-(4-fluoro-benzenesulfonyl)-5-propoxy--phenyl]-methyl acetate (22; 24mg; 0.000066mol) be dissolved in dimethyl sulfoxide (DMSO) (0.5mL; 0.007mol) in; and in microwave reactor, add salt of wormwood (10mg; 0.000072mol) and 4-trifluoromethoxy-phenol (9.4 μ L, 0.000072mol).This mixture heated 10 minutes down at 120 ℃.Solvent is removed by lyophilized overnight.Ethyl acetate and water are joined in the crude material, and with these layers separately.Organic phase is with the salt water washing and use dried over sodium sulfate.Crude material is by preparation property TLC (hexane: ethyl acetate 7: 3) purify.
1H NMR is consistent with compound structure.MS(ESI)[M+H
+]
+＝525.2。
Step 5:{3-propoxy--5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-preparation of acetate (P-0064)
[0347] with 3-propoxy--5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl-acetic acid methyl esters (23; 20.000mg; 3.813E-5mol), lithium hydroxide (1M; 0.30mL) and tetrahydrofuran (THF) (1.0mL 0.012mol) adds in the bottle and reaction mixture is stirred 3 days under envrionment conditions.This reaction is carried out acidifying and water and ethyl acetate with 1M HCl and is diluted.Organic layer is separated and at MgSO
4Last dry, and under reduced pressure concentrate, pale solid (11mg) obtained.
1HNMR is consistent with compound structure.Calculate molecular weight 510.48, MS (ESI) [M+H
+]
+=511.2.
Embodiment 9:{3-butoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl }-acetate (P-0009) synthetic
[0348] shown in scheme 18, Compound P-the 0009th is from 9 liang of steps of (3-butoxy-5-hydroxyl-phenyl)-methyl acetate synthetic.
Scheme 18
Step 1:{3-butoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl }-preparation of methyl acetate (24)
[0349] in flask, (3-butoxy-5-hydroxyl-phenyl)-methyl acetate (9,103mg, 0.000432mol, as through embodiment 5, the step 1 of scheme 14 is prepared) is dissolved in N, dinethylformamide (4mL, 0.05mol) in.Add salt of wormwood (180mg, 0.0013mol) and 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl) phenyl]-1,3-thiazoles (0.21g, 0.00073mol).Reaction mixture stirred 5 hours down at 90 ℃.This mixture under reduced pressure concentrates and water and ethyl acetate are diluted.This mixture carries out acidifying with 1M HCl.Water extracts with ethyl acetate and organic layer carries out drying with sodium sulfate, and under reduced pressure evaporates.Crude material is absorbed on the silica and with flash chromatography and purifies, and described flash chromatography adopts 100% hexane solvent, then 10% ethyl acetate in the hexane.
1H NMR is consistent with compound structure.
Step 2:{3-butoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl }-preparation of acetate (P-0009)
[0350] in flask, will { 3-butoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-phenyl }-methyl acetate (24,101mg, 0.000205mol) be dissolved in tetrahydrofuran (THF) (5mL, 0.06mol) in.Add the potassium hydroxide in the 1M water (2mL), and this mixture stirs at room temperature and spends the night.This mixture carries out acidifying with 1M HCl and water carries out 3 extractions with ethyl acetate.Organic phase is washed with salt solution, with dried over sodium sulfate and concentrated.By
1H NMR sees small amount of impurities.This product is further purified on preparation property TLC column plate, described preparation TLC column plate 5% methanol-eluted fractions in the methylene dichloride.
1H NMR is consistent with compound structure.Calculate molecular weight 479.52, MS (ESI) [M+H
+]
+=480.2; [M-H
+]
-=478.2.
[0351] additional compounds is prepared as follows: by replacing 5-(chloromethyl)-4-methyl-2-[4-(trifluoromethyl) phenyl in step 1 with suitable chloroalkyl cpd alternatively]-1, the 3-thiazole, and/or replace (3-butoxy-5-hydroxyl-phenyl)-methyl acetate 9 in step 1 with suitable methyl acetate alternatively, wherein said methyl acetate is by replacing the 1-butyl iodide with suitable iodine alkylate, according to embodiment 5, the described preparation of step 1 of scheme 14.Following table 8 expression is for appointed compound used suitable methyl acetate and chloroalkyl cpd in step 1.
Table 8
| Compound number | Methyl acetate | Chloroalkyl cpd |
| P-0001 | 3-butoxy-5-hydroxyl-phenyl | 1-[4-(3-chloro-propoxy-)-2-hydroxyl-3-propyl group-phenyl]-ethyl ketone |
| P-0007 | 3-butoxy-5-hydroxyl-phenyl | Chloromethyl-benzene |
| P-0008 | 3-butoxy-5-hydroxyl-phenyl | 2-chloro-ethyl-benzene |
| P-0010 | 3-butoxy-5-hydroxyl-phenyl | 4-(2-chloro-ethyl)-5-methyl-2-phenyl-azoles |
| P-0012 | 3-butoxy-5-hydroxyl-phenyl | 5-chloromethyl-2-phenoxy group-pyridine |
| P-0013 | 3-butoxy-5-hydroxyl-phenyl | 4-chloromethyl-3-(2,6-two chloro-phenyl)-5-sec.-propyl-isoxazole |
| P-0014 | 3-butoxy-5-hydroxyl-phenyl | 1-(2-chloro-ethyl)-4-trifluoromethyl-benzene |
| P-0015 | 3-butoxy-5-hydroxyl-phenyl | 1-(2-chloro-ethyl)-3-trifluoromethyl-benzene |
| P-0016 | 3,5-dihydroxyl-phenyl | 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole |
| P-0017 | 3-butoxy-5-hydroxyl-phenyl | 1-chloromethyl-4-(4-trifluoromethyl-phenoxy group)-benzene |
| P-0018 | 3-cyclo propyl methoxy-5-hydroxyl-phenyl | 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole |
| P-0019 | 3-oxyethyl group-5-hydroxyl-phenyl | 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole |
| P-0020 | 3-hydroxyl-5-isopropoxy-phenyl | 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole |
| P-0021 | 3-hydroxyl-5-(2-methoxyl group-oxyethyl group)-phenyl | 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole |
| P-0046 * | 3-hydroxyl-4-methoxyl group-phenyl | 1-[4-(3-chloro-propoxy-)-2-hydroxyl-3-propyl group-phenyl]-ethyl ketone |
| P-0047 | 3-hydroxyl-4-methoxyl group-phenyl | 1-[4-(3-chloro-propoxy-)-2-hydroxyl-3-propyl group-phenyl]-ethyl ketone |
* methyl esters is isolated in step 1 back.
The compound structure of these compounds, title and mass spectrum result are provided in the following table 9.
Table 9
Embodiment 10:{3-oxyethyl group-5-[3-(6-methoxyl group-pyridin-3-yl)-phenoxy group]-phenyl }-acetate (P-0089) synthetic
[0352] shown in scheme 19, Compound P-the 0089th is from 16 3 step of (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate synthetic.
Scheme 19
Step 1:[3-(3-bromo-phenoxy group)-5-methoxyl group-phenyl]-preparation of methyl acetate (25)
[0353] to being dissolved in 1,4-diox (3mL, 0.04mol) in (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate (16,200mg, 0.001mol, as embodiment 6, the preparation of the step 1 of scheme 15) add in the solution cesium carbonate (620mg, 0.0019mol), 1-bromo-3-iodo-benzene (180 μ L, 0.0014mol), dimethylamino-acetate (30mg, 0.0003mol) and cuprous iodide (I) (20mg, 0.0001mol).This mixture is 90 ℃ of following heated overnight under argon atmospher.This reaction ammonium chloride: 4: 1 mixture of ammonium hydroxide dilutes, and carries out 3 extractions with ethyl acetate.The organic layer that merges is dry on sodium sulfate, under reduced pressure concentrates, and is absorbed on the silica, to carry out flash chromatography.Adopt the gradient of 10-20% ethyl acetate in the hexane, isolate pure compound 25.
1H NMR is consistent with compound structure.MS(ESI)[M+H
+]
+＝417.2；[M-H
+]
-＝365.1、367.1。
Step 2:{3-oxyethyl group-5-[3-(6-methoxyl group-pyridin-3-yl)-phenoxy group]-phenyl }-preparation of methyl acetate (26)
[0354] to [3-(3-bromo-phenoxy group)-5-methoxyl group-phenyl]-methyl acetate (25,71mg, 0.00019mol) tetrahydrofuran (THF) (5mL, 0.007mol) add 2-methoxypyridine ylboronic acid (44mg in the solution, 0.00029mol) and [1,1 '-two (diphenyl phosphine)-ferrocene] dichloro palladium (II) and methylene dichloride complex compound (1: 1) (16mg, 0.000019mol) and the salt of wormwood in the 1M water (0.6mL).Stir under this is reflected at 90 ℃ and spend the night.After the cooling, add entry so that this reaction dilution.This reaction is carried out 3 extractions with ethyl acetate.The organic layer that merges salt water washing 1 time, and dry on sodium sulfate.After under reduced pressure concentrating, raw product is absorbed on the silica and by flash chromatography and purifies, and described flash chromatography adopts the gradient of 10-20% ethyl acetate in the hexane, isolates the expectation compound, is clarified oil.
1HNMR is consistent with compound structure.
Step 3:{3-oxyethyl group-5-[3-(6-methoxyl group-pyridin-3-yl)-phenoxy group]-phenyl }-preparation of acetate (P-0089)
[0355] in flask, { 3-oxyethyl group-5-[3-(6-methoxyl group-pyridin-3-yl)-phenoxy group]-phenyl }-methyl acetate 26 is dissolved in THF (3mL) lining, also add 1mL LiOH (1M), and this is reflected to stir under the envrionment conditions and spends the night.This reaction is acidified to pH1-2 with 1M HCl.These reaction ethyl acetate extraction 2 times, and the organic layer that merges is at Na
2SO
4Last dry, under reduced pressure concentrate, and on preparation TLC column plate, purify, adopt 5% methyl alcohol in the methylene dichloride.
1H NMR is consistent with compound structure.Calculate molecular weight 379.41, MS (ESI) [M-H
+]
+=380.2; [M-H
+]
-=379.1.
[0356] additional compounds is prepared as follows: by replacing 2-methoxypyridine ylboronic acid with suitable boronic acid compounds alternatively in step 2, and/or in step 1, replace (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate 16 alternatively with suitable methyl acetate, wherein said methyl acetate is by replacing iodoethane with suitable iodine alkylate, according to embodiment 6, the preparation of the step 1 of scheme 15.Suitable methyl acetate and boronic acid compounds that following table 10 expressions are used respectively in step 1 and 2 for appointed compound.
Table 10
| Compound number | Methyl acetate | Boric acid |
| P-0087 | 3-oxyethyl group-5-hydroxyl-phenyl | 4-oxyethyl group-phenyl |
| P-0090 | “ ” | 3-fluoro-4-methoxyl group-phenyl |
| P-0091 | “ ” | 2,6-dimethoxy-pyridin-3-yl |
| P-0097 | “ ” | 4-chloro-phenyl |
| P-0098 | “ ” | 2-methoxyl group-phenyl |
| P-0099 | “ ” | 4-methoxyl group-phenyl |
| P-0100 | “ ” | 3-chloro-4-fluoro-phenyl |
| P-0101 | “ ” | 2-trifluoromethyl-phenyl |
| P-0102 | “ ” | 3-trifluoromethoxy-phenyl |
| P-0103 | “ ” | 4-trifluoromethoxy-phenyl |
| P-0104 | “ ” | 3-trifluoromethyl-phenyl |
| P-0122 | 3-hydroxyl-5-propoxy--phenyl | 4-chloro-phenyl |
| P-0123 | “ ” | 2-methoxyl group-phenyl |
| P-0124 | “ ” | 4-methoxyl group-phenyl |
| P-0125 | “ ” | 3-chloro-4-fluoro-phenyl |
| P-0126 | “ ” | 2-trifluoromethyl-phenyl |
| P-0127 | “ ” | 4-oxyethyl group-phenyl |
| P-0128 | “ ” | 3-trifluoromethoxy-phenyl |
| P-0129 | “ ” | 4-trifluoromethoxy-phenyl |
| P-0130 | “ ” | 3-trifluoromethyl-phenyl |
| P-0131 | “ ” | 6-methoxyl group-pyridin-3-yl |
| P-0132 | “ ” | 3-fluoro-4-methoxyl group-phenyl |
| P-0133 | “ ” | 2,4-dimethoxy-pyrimidine-5-base |
| P-0234 | 3-hydroxyl-5-(2-methoxyl group-oxyethyl group)-phenyl | 1,3,5-trimethylammonium-1H-pyrazoles-4-base |
| P-0257 | “ ” | 2,4-dimethoxy-pyrimidine-5-base |
| P-0160 | 3-cyclo propyl methoxy-5-hydroxyl-phenyl | 2-methoxyl group-phenyl |
| P-0161 | “ ” | 4-methoxyl group-phenyl |
| P-0162 | “ ” | 4-chloro-phenyl |
| P-0163 | “ ” | 3-chloro-4-fluoro-phenyl |
| P-0164 | “ ” | 2-trifluoromethyl-phenyl |
| P-0165 | “ ” | 4-oxyethyl group-phenyl |
| P-0166 | “ ” | 3-trifluoromethoxy-phenyl |
| P-0167 | “ ” | 4-trifluoromethoxy-phenyl |
| Compound number | Methyl acetate | Boric acid |
| P-0168 | “ ” | 3-trifluoromethyl-phenyl |
| P-0169 | “ ” | 4-trifluoromethyl-phenyl |
| P-0170 | “ ” | 6-methoxyl group-pyridin-3-yl |
| P-0171 | “ ” | 3-fluoro-4-methoxyl group-phenyl |
| P-0172 | “ ” | 1-methyl isophthalic acid H-pyrazoles-4-base |
| P-0173 | “ ” | 1,3,5-trimethylammonium-1H-pyrazoles-4-base |
| P-0174 | “ ” | 1-(3-methyl-butyl)-1H-pyrazoles-4-base |
| P-0176 | 3-oxyethyl group-5-hydroxyl-phenyl | 1H-pyrazoles-4-base |
| P-0177 | “ ” | 1-methyl isophthalic acid H-pyrazoles-4-base |
| P-0178 | “ ” | 1,3,5-trimethylammonium-1H-pyrazoles-4-base |
| P-0179 | “ ” | 1-isobutyl--1H-pyrazoles-4-base |
| P-0180 | “ ” | 1-(3-methyl-butyl)-1H-pyrazoles-4-base |
| P-0181 | 3-hydroxyl-5-propoxy--phenyl | 4-trifluoromethyl-phenyl |
| P-0182 | “ ” | 1H-pyrazoles-4-base |
| P-0183 | “ ” | 1-methyl isophthalic acid H-pyrazoles-4-base |
| P-0184 | “ ” | 1,3,5-trimethylammonium-1H-pyrazoles-4-base |
| P-0185 | “ ” | 1-isobutyl--1H-pyrazoles-4-base |
| P-0186 | “ ” | 1-(3-methyl-butyl)-1H-pyrazoles-4-base |
| P-0209 | 3-hydroxyl-5-(2-methoxyl group-oxyethyl group)-phenyl | 1-(3-methyl-butyl)-1H-pyrazoles-4-base |
| P-0210 | “ ” | 1-isobutyl--1H-pyrazoles-4-base |
| P-0211 | “ ” | 6-methoxyl group-pyridin-3-yl |
| P-0218 | “ ” | 4-chloro-phenyl |
| P-0219 | “ ” | 2-methoxyl group-phenyl |
| P-0220 | “ ” | 4-methoxyl group-phenyl |
| P-0221 | “ ” | 3-chloro-4-fluoro-phenyl |
| P-0222 | “ ” | 2-trifluoromethyl-phenyl |
| P-0223 | “ ” | 4-oxyethyl group-phenyl |
| P-0224 | “ ” | 3-trifluoromethoxy-phenyl |
| P-0225 | “ ” | 4-trifluoromethoxy-phenyl |
| P-0226 | “ ” | 3-trifluoromethyl-phenyl |
| P-0227 | “ ” | 4-trifluoromethyl-phenyl |
| P-0228 | “ ” | 3-fluoro-4-methoxyl group-phenyl |
| P-0231 | “ ” | 1H-pyrazoles-4-base |
| P-0232 | “ ” | 1-methyl isophthalic acid H-pyrazoles-4-base |
The compound structure of these compounds, title and mass spectrum result are provided in the following table 11.
Table 11
Embodiment 11:{3-oxyethyl group-5-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiophene-2-alkylsulfonyl]-phenyl }-acetate (P-0093) synthetic
[0357] shown in scheme 20, Compound P-0093 is five step synthetic.
Scheme 20
The preparation of step 1:2-methyl-3-(4-trifluoromethyl-phenyl)-thiophene (28)
[0358] in the microwave test tube, 2-methyl-3 bromo thiophene (27,130.0mg, 0.0007342mol), 4-(trifluoromethyl) phenyl-boron dihydroxide (189mg, 0.000995mol), four (triphen is seen) palladium (0) (10mg, 0.000009mol) and 1N K
2CO
3(0.3mL) 1 (3mL, 0.05mol) the middle stirring.This reaction vessel heated 30 minutes down at 98 ℃, heated other 20 minutes under 300 watts of power then.This reaction is transferred in the round-bottomed flask and by removing solvent with the ethyl acetate azeotropic, obtains oil.This crude material is absorbed on the silica then, and purifies by flash chromatography, isolates the expectation compound, and described flash chromatography adopts 10-20% ethyl acetate gradient in the hexane.
1H NMR is consistent with compound structure.
The preparation of step 2:5-methyl-4-(4-trifluoromethyl-phenyl)-thiophene-2-SULPHURYL CHLORIDE (29)
[0359] in the exsiccant round-bottomed flask, with chlorsulfonic acid (620mg, 0.0053mol) be dissolved in methylene dichloride (10mL, 0.2mol) in.This flask is placed on the ice bath and cooled off 10-15 minute under small argon gas stream.Add phosphorus pentachloride (410mg, 0.0020mol) and should reaction by vigorous stirring.Stirred solution is dissolved fully until phosphorus pentachloride, and (28,4.00E2mg 0.00165mol) joins in the reaction with portion after this to be dissolved in 2-methyl-3-(4-trifluoromethyl) thiophene in the 3mL methylene dichloride.The color of reaction becomes sap green from yellow.After 3 hours, reaction is introduced in ice/water mixture, and stirs until all ice-outs.Reaction is introduced in the separatory funnel, and reaction extracts with methylene dichloride (2x30mL).The organic phase water (2x10mL), 1 salt solution (15mL) that merge wash, and at MgSO
4Last dry.The vapourisation under reduced pressure solvent, and be absorbed on the silica.Flash chromatography, it adopts the feasible expectation of the gradient compound separation of 0-30% ethyl acetate in the hexane.
1H NMR is consistent with compound structure.
The preparation of step 3:5-methyl-4-(4-trifluoromethyl)-thiophene-2--sulfinic acid sodium salt (30)
[0360] in round-bottomed flask, with S-WAT (308mg, 0.00244mol) be dissolved in water (13mL, 0.72mol) in.This flask is placed in the oil bath, 90 ℃ of following preheatings.This reaction be stirred 20 minutes dissolved up to all S-WATs.(105mg, 0.00125mol) (29,356.0mg 0.001045mol), and heated 4 hours under being reflected at 103 ℃ with 5-methyl-4-(4-trifluoromethyl) thiophene-2-SULPHURYL CHLORIDE to add sodium bicarbonate in flask simultaneously.This flask is cooled to room temperature and by freeze-drying 2 days.In this salt, add methyl alcohol (40mL) and this container 100 ℃ of heating 40 minutes and process thermogravimetric filtrations (hot gravityfiltration) down.This salt washes in a large number with the ethanol of heat.Vapourisation under reduced pressure filtrate to obtain 5-methyl-4-(4-trifluoromethyl)-thiophene-2--sulfinic acid sodium salt 30, is white solid.
Step 4:{3-oxyethyl group-5-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of methyl acetate (31)
[0361] in screw-topped reactor, with 3-oxyethyl group-5-trifluoromethane sulfonyloxy-phenyl-acetic acid methyl esters (17,110mg, 0.00032mol, as embodiment 6, the step 2 of scheme 15 preparation), 5-methyl-4-(4-trifluoromethyl)-thiophene-2--sulfinic acid sodium salt (30,130mg, 0.00041mol), 4,5-two (dimethyl phosphino-)-9, and 9-dimethyl xanthene (10mg, 0.00002mol) and cesium carbonate (245mg, 0.000752mol) be dissolved in toluene (6mL, 0.06mol) in.This reaction vessel is with purification for argon 3-5 minute, and (10mg, 0.00001mol), and this reaction is covered and places in the oil bath, 120 ℃ of following preheatings to add three (dibenzalacetone)-two palladiums (0).Reaction is heated spends the night.Under reduced pressure remove solvent.Raw product is purified by preparation property TLC column plate, and it adopts 20% ethyl acetate in the hexane, isolates the expectation compound, is oil.
1H NMR is consistent with compound structure.
Step 5:{3-oxyethyl group-5-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of acetate (P-0093)
[0362] in flask, { 3-oxyethyl group-5-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiophene-2-alkylsulfonyl]-phenyl }-methyl acetate 31 is dissolved in the mixture of 3mL tetrahydrofuran (THF)/1N LiOH (4: 1), and should reaction by vigorous stirring 4 hours.Reaction is carried out acidifying (pH1-2) by adding 1N HCl, and reaction extracts (3 times) with ethyl acetate.Organic layer is at MgSO
4Last dry, and the vapourisation under reduced pressure solvent.This raw product is purified through preparation property TLC column plate, with 3% methanol-eluted fractions in the chloroform, isolates the expectation compound.
1H NMR is consistent with compound structure.Calculate molecular weight 484.51, MS (ESI) [M-H
+]
-=484.21.
Embodiment 12:[3-oxyethyl group-5-(5-phenyl-thiophene-2-oxygen base)-phenyl]-acetate (P-0083) synthetic
[0363] shown in scheme 21, Compound P-0083 is two step synthetic.
Scheme 21
Step 1:[3-oxyethyl group-5-(5-phenyl-thiophene-2-oxygen base)-phenyl]-preparation of methyl acetate (31)
[0364] in flask, (3-oxyethyl group-5-hydroxyl-phenyl)-methyl acetate (16,120mg, 0.00057mol, as embodiment 6, the step 1 of scheme 15 preparation) is dissolved in 1, the 4-diox (2mL, 0.02mol) in.Under argon atmospher with cesium carbonate (370mg, 0.0011mol), 2-bromo-5-phenyl-thiophene (2.0E2mg, 0.00086mol), dimethylamino-acetate (20mg, 0.0002mol) and cuprous iodide (I) (10mg, 0.00006mol) mix, and under 90 ℃, stir and spend the night.After the cooling, this reaction is diluted with ethyl acetate, then is to use ammonium chloride: 4: 1 mixture of ammonium hydroxide.With these layers separately, the organic layer dried over sodium sulfate, and under reduced pressure remove solvent.Crude material is absorbed on the silica, purifies by flash chromatography, and it adopts 10-20% ethyl acetate gradient in the hexane, obtains expecting compound.
1H NMR is consistent with compound structure.
Step 2:[3-oxyethyl group-5-(5-phenyl-thiophene-2-oxygen base)-phenyl]-preparation of acetate (P-0083)
[0365] in flask, with [3-oxyethyl group-5-(5-phenyl-thiophene-2-oxygen base)-phenyl]-methyl acetate (31,20mg, 0.00005mol) be dissolved in tetrahydrofuran (THF) (4mL, 0.05mol) in.Add the lithium hydroxide in the 1M water (1mL), and this mixture stirs at room temperature and spends the night.This mixture at first dilutes with ethyl acetate, and is acidified to pH1-2 with 1M HCl.With these layers separately.Organic phase is dry on sodium sulfate, and under reduced pressure removes solvent.Crude compound P-0083 purifies through preparation TLC column plate, with 5% methanol-eluted fractions in the methylene dichloride, isolates the expectation compound.
1H NMR is consistent with compound structure.Calculate molecular weight 354.42, MS (ESI) [M+H
+]
+=355.1, [M-H
+]
-=353.0.
Embodiment 13:3-[4-methyl-2-(4-trifluoromethyl-phenyl)-phenyl]-azoles-5-alkylsulfonyl]-phenyl-acetic acid (P-0284) synthetic
[0366] shown in scheme 22, Compound P-0284 is three step synthetic.
Scheme 22
The preparation of step 1:4-methyl-2-(4-trifluoromethyl-phenyl)-azoles (34)
[0367] 4-trifluoromethyl-benzamide (33,1.00g, 0.00529mol) (13,20mL 0.2mol) is placed in the microwave reaction container together with monochloroacetone.This mixture heated 40 minutes under 120 ℃ in microwave.Surplus stock still.Evaporating solvent and rough reaction product are placed on the silica, and purify by flash chromatography (ethyl acetate in the hexane), and compound 34 is provided.
1H NMR is consistent with compound structure.
Step 2:3-[4-methyl-2-(4-trifluoromethyl-phenyl)-phenyl]-azoles-5-base sulfane base]-preparation of phenyl-acetic acid (36)
[0368] with 4-methyl-2-(4-trifluoromethyl-phenyl)-azoles (34,200mg, 0.0009mol) be dissolved in tetrahydrofuran (THF) (5mL, 0.06mol) in.This mixture is cooled to-76 ℃.Hexane solution (1.4M, 2200 μ L) and this mixture of being added dropwise to s-butyl lithium are stirred 20 minutes.In solution, slowly add [3-(3-carboxymethyl-phenyl disulphanes base)-phenyl]-acetate in the tetrahydrofuran (THF) (35,210mg, 0.00063mol).Allowing this mixture reach room temperature and to be stirred spends the night.Reaction mixture is with ethyl acetate dilution and with 1M HCl acidifying.These are separated and water extracts with ethyl acetate.The organic extract liquid that merges concentrates with dried over sodium sulfate and in vacuum.Reaction product is purified with flash chromatography (ethyl acetate in the hexane), and compound 36 is provided.
1H NMR is consistent with compound structure.MS(ESI)[M+H
+]
+＝394.1，[M-H
+]
-＝392。
Step 3:3-[4-methyl-2-(4-trifluoromethyl-phenyl)-phenyl]-azoles-5-alkylsulfonyl]-preparation of phenyl-acetic acid (P-0284)
[0369] with 3-[4-methyl-2-(4-trifluoromethyl-phenyl)-azoles-5-base sulfane base]-phenyl-acetic acid (36,20mg, 0.00005mol) be dissolved in methylene dichloride (1mL, 0.02mol) in.Add metachloroperbenzoic acid (m-Chloroperbenzoic acid) (29mg, 0.00017mol) and this mixture at room temperature stir and spend the night.TLC shows a spot, and it has the R identical with raw material
f, mass spectrum has shown the quality of expectation compound.This mixture is concentrated and is dissolved in the methyl alcohol.To expect that compound utilizes anti-phase preparation HPLC to purify.
1H NMR is consistent with compound structure.Calculate molecular weight 425.38, MS (ESI) [M+H
+]
+=426.0, [M-H
+]
-=424.0.
Embodiment 14:{3-[1-(4-trifluoromethyl-phenyl)-1H-pyrazoles-4-alkylsulfonyl]-phenyl }-acetate (P-0287) and related compound synthetic
[0370] shown in scheme 23, Compound P-0287 is three step synthetic.
Scheme 23
The preparation of step 1:4-bromo-1-(4-trifluoromethyl)-1H-pyrazoles (39)
[0371] in round-bottomed flask (flame dry and under inert conditions) lining, with 1-bromo-4-trifluoromethylbenzene (38,2.0g, 0.0089mol), salicylaldoxime (40mg, 0.0003mol), cesium carbonate (6g, 0.02mol), Red copper oxide (44mg, 0.00031mol) and 4-bromine pyrazoles (37,2.0g, 0.013mol) be blended in acetonitrile (15mL, 0.21mol) in.The mixture that merges heated 3 days down at 110 ℃.The crude reaction thing filters with B (Buchner funnel).Filtrate is reduced to half of original volume and adds silica, adopts rotary evaporation (roto evaporation) that solvent is removed fully then.Adopt gradient solvent (0 to 35% ethyl acetate/hexane) to carry out flash chromatography, obtain expecting compound.Intermediate uses without further characterizing.
1H NMR is consistent with compound structure.
Step 2:3-[1-(4-trifluoromethyl) 1H-pyrazoles-4-base alkylsulfonyl]-preparation of phenylacetic acid (40)
[0372] in round-bottomed flask (flame dry and under inert conditions) lining, with 4-bromo-1-(4-trifluoromethyl)-1H-pyrazoles (39,180.00mg, 6.184E-4mol) be dissolved in tetrahydrofuran (THF) (8mL, 0.1mol) in.This flask is placed in acetone-the dry ice bath and stirred 10 minutes, and lithiumation pyrazoles (lithiatedpyrazole) solution is provided.Add s-butyl lithium (0.063mL, 0.00074mol) and reaction be stirred 10 minutes.In another dry flask, argon purifies down, and (35,206.8mg 0.0006184mol) is dissolved in tetrahydrofuran (THF) (10mL) lining with [3-(3-carboxymethyl-phenyl disulphanes base)-phenyl]-acetate.Add s-butyl lithium (0.126mL, 0.00148mol) and reaction be stirred 10 minutes, disulfide solution is provided.Lithiumation pyrazoles solution is joined in the disulfide solution and this is reflected to stir under the inert atmosphere and spends the night with intubate, after this TLC (20% ethyl acetate/hexane) shows and does not have phenylpyrazole, and the mass spectrum of this rough reaction with expect that compound is consistent.Add methyl alcohol (3mL) with this butyllithium of quencher, and solvent be rotated be evaporated to dried.This crude compound is absorbed on the silica, and adopts gradient solvent condition (0 to 8% ethanol/methylene), purifies by flash chromatography.
1H NMR structural characterization shows methylene peak.This compound is used to next step, and does not further purify.
Step 3:{3-[1-(4-trifluoromethyl-phenyl)-1H-pyrazoles-4-alkylsulfonyl]-phenyl } preparation of acetate (P-0287)
[0373] will be dissolved in the 4mL methylene dichloride from the crude compound 40 of step 2 and adding m-CPBA (4 equivalent).This reaction was at room temperature stirred 6 hours, and the aliquot that got this moment has shown the expectation product by mass spectrum.In crude mixture, add silica and evaporating solvent.Adopt the gradient condition of 0 to 8% ethanol/methylene to carry out flash chromatography.The suitable fraction that shows by mass spectrum is merged and is evaporated.Be dissolved in this in acetonitrile again and carry out reversed-phase HPLC, isolate the expectation compound.
1H NMR (CD
3OD) consistent with compound structure, purity＞90%.Calculate molecular weight 410.37, MS (ESI) [M-H
+]
-=409.01.
[0374] additional compounds adopts the method preparation of scheme 23.P-0284 is by replacing 4-bromine pyrazoles to prepare with 5-bromo-4-methyl-azoles in step 1.P-0285 is by replacing 4-bromine pyrazoles and replace 1-bromo-4-trifluoromethylbenzene to prepare with 1-bromo-4-chloro-benzene with 5-bromo-thiazole in step 1.P-0288 is by replacing 4-bromine pyrazoles and replace 1-bromo-4-trifluoromethylbenzene to prepare with 1-bromo-4-trifluoromethoxy-benzene with 5-bromo-4-methyl-azoles in step 1.Compound title, structure and test mass spectrum result are provided in the following table 12.
Table 12
Embodiment 15:(3-{4-[2-(5-methyl-2-phenyl-azoles-4-yl)-oxyethyl group]-benzenesulfonyl }-phenyl)-acetate (P-0289) synthetic
[0375] shown in scheme 24, Compound P-0289 is six step synthetic.
Scheme 24
Step 1:(3-trifluoromethane sulfonyloxy-phenyl)-preparation of jasmal (42)
[0376] with (3-hydroxyl-phenyl)-jasmal (41,2000mg, 0.008mol) be dissolved in pyridine (9mL, 0.1mol).Down (1.77mL 0.0105mol) is added drop-wise in the solution with Trifluoromethanesulfonic anhydride in cooling.This mixture is stirred 30 minutes under cooling, be allowed to condition at then to stir under the room temperature to spend the night.This mixture is cooled and adds entry and then adds ether.This mixture is acidified to pH1 with 6M HCl.This ether is separated and with 1M HCl washed twice, uses the salt water washing then, with dried over sodium sulfate and concentrate so that oil to be provided.This is used, and does not further purify.
1H NMR is consistent with compound structure.
Step 2:(3-trifluoromethane sulfonyloxy-phenyl)-preparation of methyl acetate (43)
[0377] to (3-trifluoromethane sulfonyloxy-phenyl)-jasmal (42,1.13g, methyl alcohol 0.00302mol) (4mL, 0.1mol) add in the solution sulfuric acid (0.2mL, 0.004mol).This mixture at room temperature stirs and spends the night.This mixture is concentrated under vacuum.Add ethyl acetate and water and separately with these layers.The saturated NaHCO of organic phase
3Washed twice and being concentrated.
1H NMR is consistent with compound structure.
Step 3:[3-(4-benzyloxy-benzenesulfonyl)-phenyl]-preparation of methyl acetate (45)
[0378] in reaction flask with (3-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (43,630mg, 0.0021mol) and 4-benzyloxy-benzene sulfinic acid sodium salt (44,856mg, 0.00317mol) be placed on toluene (10mL, 0.1mol) in.Add three (dibenzalacetones), two palladiums (0) (190mg, 0.00021mol), cesium carbonate (1.0E3mg, 0.0032mol) and 4,5-two (dimethyl phosphino-)-9,9-dimethyl xanthene (200mg, 0.0004mol).Under argon atmospher, this mixture is 120 ℃ of following heated overnight.After the cooling, this reaction mixture dilutes with ethyl acetate, uses the salt water washing, and is dry on sodium sulfate, concentrates and is placed on the silica.This product is gone up separated and is isolated the expectation compound at Isco 40g post (10-30% ethyl acetate in the hexane).
1H NMR is consistent with compound structure.
Step 4:[3-(4-hydroxyl-benzenesulfonyl)-phenyl]-preparation of methyl acetate (46)
[0379] with [3-(4-benzyloxy-benzenesulfonyl)-phenyl]-methyl acetate (45,220mg, 0.00055mol) be dissolved in tetrahydrofuran (THF) (10mL, 0.1mol) in and add 5%Pd/C (5: 95 palladiums: carbon, 100mg).This mixture stirs under the room temperature under nitrogen atmosphere and spends the night.Catalyzer is filtered out and evaporating solvent, the expectation compound is provided, it is used and does not further purify.
1H NMR is consistent with compound structure.
Step 5:(3-{4-[2-(5-methyl-2-phenyl-azoles-4-yl)-oxyethyl group]-benzenesulfonyl }-phenyl)-preparation of methyl acetate (48)
[0380] tetrahydrofuran (THF) (3mL; 0.04mol) in [3-(4-hydroxyl-benzenesulfonyl)-phenyl]-methyl acetate (46; 100mg; 0.0003mol), 2-(5-methyl-2-phenyl-azoles-4-yl)-ethanol (47,73.0mg, 0.000359mol) and the triphen (128mg that sees; 0.000490mol) stirred solution; by dripping, (96.4 μ L 0.000490mol) handle with the diisopropyl azodiformate in the 1mL tetrahydrofuran (THF).This mixture at room temperature stirs and spends the night.It is mutually separated with water and these to add ethyl acetate, and water is further used ethyl acetate extraction.The organic phase that merges is with the salt water washing and use dried over sodium sulfate.Reactive material is loaded on the silica and on Isco Companion 12g post (10-30% ethyl acetate in the hexane) and purifies, and the expectation compound is provided.
1H NMR is consistent with compound structure.
Step 6:(3-{4-[2-(5-methyl-2-phenyl-azoles-4-yl)-oxyethyl group]-benzenesulfonyl }-phenyl)-preparation of acetate (P-0289)
[0381] (3-{4-[2-(5-methyl-2-phenyl-azoles-4-yl)-oxyethyl group]-benzenesulfonyl }-phenyl)-methyl acetate 48 usefulness 1ml KOH (1M) and 3mL tetrahydrofuran (THF)s, and at room temperature stir and spend the night and be hydrolyzed.In this mixture, add ethyl acetate, use 1M HCl acidifying then.Organic phase is with the salt water washing and be dried.The expectation compound is gone up separated at preparation TLC (5% methyl alcohol in the methylene dichloride).
1H NMR is consistent with compound structure.Calculate molecular weight 477.53, MS (ESI) [M+H
+]
+=478.1, [M-H
+]
-=476.1.
Embodiment 16:{3-oxyethyl group-5-[5-methyl-4-(4-Trifluoromethoxyphen-l)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of acetate (P-0120)
[0382] shown in scheme 25, Compound P-0120 is five step synthetic.
Scheme 25
The preparation of step 1:2-methyl-3-(4-Trifluoromethoxyphen-l) thiophene (49)
[0383] in circular microwave test-tube reaction device, add 1 (3mL, 0.05mol) the 2-methyl-3 bromo thiophene in (27,2.40E2mg, 0.00136mol), 4-Trifluoromethoxyphen-l boric acid (590mg, 0.0028mol) and 1N K
2CO
3(0.2mL).This container purifies 2-3 minute with argon, add then four (triphen is seen) palladium (0) (4mg, 0.000003mol).This is reflected at 120 ℃ of following microwaves 30 minutes.TLC analyzes (hexane solvent) and shows and formed the expectation compound.This reactant is adsorbed on the silica and the expectation compound uses the straight chain hexane to separate by flash chromatography, and is used to next step and does not further purify.
1HNMR is consistent with compound structure.
The preparation of step 2:5-methyl-4-(4-Trifluoromethoxyphen-l)-thiophene-2-SULPHURYL CHLORIDE (50)
[0384] in the round-bottomed flask of oven drying, with chlorsulfonic acid (330mg, 0.0028mol) be dissolved in methylene dichloride (6mL, 0.09mol) in.This flask is placed on the ice bath and was cooled 10-15 minute under small argon gas stream.Add phosphorus pentachloride (340mg, 0.0016mol) and should reaction by vigorous stirring, cause producing a large amount of gases.This solution be stirred 20-35 minute dissolved until the solid bulk of pentachloride.(49,350mg 0.0014mol) is drawn in syringe, and is joined in the mixture with portion dissolved 2-methyl-3-(4-Trifluoromethoxyphen-l) thiophene in the 3mL methylene dichloride, makes the color of this reaction become sap green from yellow in time.The process of reaction is monitored 3 hours by TLC.This reaction is poured in the ice and is stirred until ice-out.This reaction is poured in the separatory funnel and with methylene dichloride (2x30mL) and is extracted.This organic layer water (2x10mL) and salt solution (15mL) wash and at MgSO
4Last dry.Solvent under reduced pressure is concentrated, and reaction product is absorbed on the silica.The expectation compound separates by flash chromatography, and it adopts the gradient solvent condition of 0 to 30% ethyl acetate/hexane, carries out more than 25 minutes.
1H NMR (CDCl
3) consistent with compound structure, purity＞90%.
The preparation of step 3:5-methyl-4-(4-Trifluoromethoxyphen-l)-thiophene-2--sulfinic acid sodium salt (51)
[0385] in round-bottomed flask, with S-WAT (4.0E2mg, 0.0031mol) be dissolved in water (15mL, 0.83mol) in.This reaction is positioned in the oil bath of 98 ℃ of following preheatings.After about 20 minutes, this salt is dissolved fully, and with sodium bicarbonate (99mg, 0.0012mol) and 5-methyl-4-(4-Trifluoromethoxyphen-l)-thiophene-2-SULPHURYL CHLORIDE (50,3.50E2mg, combined mixture 0.000981mol) adds with portion.The process of this reaction per hour monitors by TLC (20% ethyl acetate/hexane).This reaction is heated spends the night, and after this TLC shows and do not have raw material.Reaction vessel is cooled to room temperature and content is frozen in acetone-the dry ice bath.Water is removed by lyophilized overnight.Sulphite is dissolved in ethanol (40mL) lining and descends heating 30 minutes, heat filterings then at 98 ℃.The white salt resistates carries out a large amount of drip washing with the ethanol (40mL) of heat.The filtrate of collecting is rotated evaporation, obtains expecting compound, is white viscous solid, and it is used and does not further purify.
1H NMR (CD
3OD) consistent with compound structure.
Step 4:{3-oxyethyl group-5-[5-methyl-4-(4-Trifluoromethoxyphen-l)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of methyl acetate (52)
[0386] in flame-dried 40mL bottle, with (3-oxyethyl group-5-[-5-methyl-4-(4-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (17,116mg, 0.000339mol, as embodiment 6, step 2 preparation of scheme 15), 5-methyl-4-(4-Trifluoromethoxyphen-l)-thiophene-2-sodium sulfite salt (51,195mg, 0.000566mol), cesium carbonate (289mg, 0.000887mol) and 4,5-two (dimethyl phosphino-)-9,9-dimethyl xanthene (8mg, 0.00001mol) (5mg 0.00005mol) adds together with toluene.This container then with argon purge and add fast three (dibenzalacetones), two palladiums (0) (8mg, 0.000009mol).This was reflected under the argon atmospher by restir 3-4 minute.This moment, reaction vessel is transferred on the heat block that is preset in 117 ℃ and heated overnight.This bottle is cooled to room temperature, and TLC (20% ethyl acetate/hexane) shows and do not have raw material.This crude reaction mixture is transferred in the flask and under reduced pressure removes solvent.This material dilutes with ethyl acetate (60mL) and water (30mL).Isolating organic layer and water layer washs with ethyl acetate (2x40mL).Organic fraction is merged, use the salt water washing, at MgSO
4Last dry and be filtered.Filtrate is concentrated and is adsorbed onto on the silica to carry out chromatography.The expectation compound separated by flash chromatography in 40 minutes, and described flash chromatography adopts the gradient solvent condition of 0 to 35% ethyl acetate/hexane, carries out 40 minutes, and is used for following step.
1H NMR is consistent with compound structure.
Step 5:{3-oxyethyl group-5-[-5-methyl-4-(4-Trifluoromethoxyphen-l)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of acetate (P-0120)
[0387] methyl esters 52 is dissolved in 5mL tetrahydrofuran (THF)/1N LiOH mixture (4: 1) lining and vigorous stirring is spent the night.This reaction by add 1N HCl carry out acidifying (by the pH test paper, pH0-1), with ethyl acetate extraction (3 times of reaction volumes) and at MgSO
4Last dry.The expectation compound separates by flash chromatography, and described flash chromatography adopts 2% methyl alcohol/chloroform.
1H NMR (CDCl
3) consistent with compound structure, purity＞96%.
[0388] additional compounds adopts the method for scheme 25 to be prepared.P-0121 be by in step 4 with (3-propoxy--5-trifluoromethane sulfonyloxy-phenyl)-(it is as embodiment 6 for methyl acetate, the step 2 of scheme 15 is described, by replacing iodoethane to prepare in step 1 with propyl iodide) (3-oxyethyl group-5-[-5-methyl-4-(4-trifluoromethane sulfonyloxy-phenyl)-methyl acetate 17 prepares in replacement.P-0092 uses (3-propoxy--5-trifluoromethane sulfonyloxy-phenyl)-methyl acetate in step 4, and further replaces 4-Trifluoromethoxyphen-l boric acid to prepare in step 1 with the 4-trifluoromethyl phenyl boronic acid.The compound structure of these compounds, name and mass spectrum result are provided at 13 li of following tables.
Table 13
Embodiment 17:{3-oxyethyl group-5-[2-methyl-5-(4-trifluoromethyl)-thiophene-3-alkylsulfonyl]-phenyl }-preparation of acetate (P-0283)
[0389] shown in scheme 26, Compound P-0283 is five step synthetic.
Scheme 26
The preparation of step 1:2-methyl-5-(4-trifluoromethyl-phenyl)-thiophene (54)
[0390] in microwave tube, with 2-bromo-5-methyl-thiophene (53,400mg, 0.002mol), 4-(trifluoromethyl) phenyl-boron dihydroxide (640mg, 0.0034mol) and 1N K
2CO
3Be incorporated in tetrahydrofuran (THF) (3mL, 0.04mol) in.This container purifies with argon, add fast then four (triphen is seen) palladium (0) (10mg, 0.000009mol).Reaction vessel is placed in the microwave office and at 110 ℃ and heated 30 minutes down, and after this TLC analyzes the fluorescent spot that (hexane) still shows raw material and close raw material.Solvent is partly removed, and this crude reaction mixture is absorbed on the silica.The expectation compound separates by the flash chromatography that adopts 100% hexane and is used for next step.
1H NMR is consistent with compound structure.
The preparation of step 2:2-methyl-5-(4-trifluoromethyl-phenyl) thiophene-2-SULPHURYL CHLORIDE (55)
[0391] the dry and round-bottomed flask that be under the inert conditions of flame is placed on the ice bath, and with chlorsulfonic acid (250mg, 0.0021mol) and dry methylene chloride (6mL, 0.09mol) mixing.This reaction flask cleans with argon gas and is stirred 10-15 minute, after this add phosphorus pentachloride (210mg, 0.00099mol) and stir this reaction and dissolve until solid phosphorus.(54,200mg 0.0008mol) slowly joins in the reaction of stirring with being dissolved in 2-methyl-5-(4-trifluoromethyl)-thiophene in the 5mL methylene dichloride.After final reinforced the finishing, allow be reflected under the argon atmospher and stirred 4 hours.TLC analyzes (5% ethyl acetate/hexane) and shows and have raw material hardly and at slower R
fTwo new spot appear in the place.This reaction is introduced in the ice and is stirred.Behind the ice-out, organic phase 30mL dichloromethane extraction is with salt solution (2x) washing and at MgSO
4Last dry and with its filtration.This solvent is evaporated to half of its original volume and adds silica, goes down to desolventize in vacuum then.The expectation compound separates by flash chromatography, and it adopts the gradient solvent condition of 0 to 5% ethyl acetate/hexane to carry out more than 18 minutes, is that 5 to 20% ethyl acetate was carried out more than 5 minutes then, and is used to next step.
1H NMR is consistent with compound structure.Calculate molecular weight 322.32, MS (ESI) [M-H
+]
-=321.33.
The preparation of step 3:2-methyl-5-(4-trifluoromethyl)-thiophene-3--sulfinic acid sodium salt (56)
[0392] in round-bottomed flask, with S-WAT (100mg, 0.0008mol) be dissolved in water (9mL, 0.5mol) in.This reaction flask 98 ℃ down heating 30 minutes dissolve fully until this solid.With sodium bicarbonate (33mg, 0.00039mol) and 2-methyl-5-(4-trifluoromethyl) thiophene-2-SULPHURYL CHLORIDE (55,112mg 0.000329mol) joins in the reaction simultaneously, and this reaction is heated and spends the night, and it is connected to condenser.After 16 hours, TLC analyzes (20% ethyl acetate/hexane) and shows and do not have raw material.This reaction is cooled to room temperature, and removes this solvent by lyophilize.The gained solid is dissolved in the 30mL ethanol, and this container was refluxed 30 minutes, and this mixture is by heat filtering.This salt is collected and is dissolved in the ethanol, and repeat said process.Collect filtrate and under reduced pressure it is evaporated the-sulfinate that obtains expecting.1H NMR (CD
3OD) result is consistent with compound structure.Calculate molecular weight 306.00, MS (ESI) [M-H
+]
-=305.01.
Step 4:{3-oxyethyl group-5-[2-methyl-5-(4-trifluoromethyl)-thiophene-3-alkylsulfonyl]-phenyl }-preparation of methyl acetate (57)
[0393] in flame-dried bottle, with (3-oxyethyl group-5-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (17,102mg, 0.000298mol, as embodiment 6, the described preparation of the step 2 of scheme 15), 2-methyl-5-(4-trifluoromethyl)-thiophene-3--sulfinic acid sodium salt (56,75mg, 0.00023mol), 4,5-two (dimethyl phosphino-)-9,9-dimethyl xanthene (6mg, 0.00001mol), cesium carbonate (150mg, 0.00046mol) and three (dibenzyl acetone) two palladiums (0) (5mg, 0.000005mol) (6mL mixes in 0.06mol) at toluene.This bottle cleaned 2-3 minute with argon gas, and this reaction is placed in last 5 hour of oil bath of 117 ℃ of following preheatings.Use the TLC analysis revealed of 10% ethyl acetate/hexane that desired compounds is arranged.This bottle be cooled to room temperature and this appearance agent be rotated be evaporated to dried.This crude mixture extracts with ethyl acetate (3x30mL) and water (20mL), and organic layer is separated, uses the salt water washing, at MgSO
4Last dry and with its filtration.The vapourisation under reduced pressure solvent.The gained solid is dissolved in the ethyl acetate of minimum again, and this is placed on the silica column plate.The expectation compound separates by plate chromatography, and it adopts 10% ethyl acetate/hexane solvent elution.
1H NMR is consistent with compound structure.
Step 5:{3-oxyethyl group-5-[2-methyl-5-(4-trifluoromethyl)-thiophene-3-alkylsulfonyl]-phenyl }-preparation of acetate (P-0283)
[0394] methyl esters 57 is dissolved in 5mL tetrahydrofuran (THF)/1N LiOH mixture (4: 1) lining and spent the night by vigorous stirring, after this TLC (20% ethyl acetate/hexane) shows and does not have raw material and a new spot is arranged near baseline.This reaction is carried out acidifying and (by the pH test paper, pH0-1), is extracted (3 times of reaction volumes) and at MgSO with ethyl acetate by adding 1N HCl
4Last dry.The expectation compound separates by flash chromatography, and it adopts the gradient solvent condition of 0 to 3% ethanol/methylene to carry out more than 25 minutes.
1H NMR (CDCl
3) consistent with compound structure, purity＞96%.
Embodiment 18:{3-propoxy--5-[3-(4-Trifluoromethoxyphen-l)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of acetate (P-0279)
[0395] shown in scheme 27, Compound P-0279 is five step synthetic.
Scheme 27
The preparation of step 1:3-(4-Trifluoromethoxyphen-l)-thiophene (59)
[0396] in the 40mL reactor, with 3-bromo-thiophene (58,4.50E2mg, 0.00276mol), 4-Trifluoromethoxyphen-l boric acid (683mg, 0.00332mol), 1N K
2CO
3(0.4mL), tetrabutylammonium iodide (4mg, 0.00001mol) and tetrahydrofuran (THF) (8mL 0.1mol) mixes.This mixture is stirred 2-5 minute under argon atmospher, add then four (triphen is seen) palladium (0) (8mg, 0.000007mol).This container is positioned in the oil bath of 87 ℃ of following preheatings and is stirred 2 days.TLC analysis (hexane) shows and has raw material and have two to move slower spot.This reaction under reduced pressure is filtered and concentrates.This crude reaction mixture is absorbed on the silica, and the expectation compound separates by flash chromatography, and it is with 100% hexane wash-out, and it is used to next step and not further purification.
1H NMR is consistent with compound structure.
The preparation of step 2:3-(4-Trifluoromethoxyphen-l) thiophene-2-SULPHURYL CHLORIDE (60)
[0397] in the flame-dried round-bottomed flask that is under the inert conditions, with chlorsulfonic acid (480mg, 0.0042mol) be dissolved in methylene dichloride (5mL, 0.08mol) in.This flask under argon gas stream, be transferred in the ice bath and add phosphorus pentachloride (340mg, 0.0016mol).Stir the mixture until this solid dissolving.(59,328mg 0.00134mol) is dissolved in the 4mL methylene dichloride, and is added in cold pentachloride-chlorsulfonic acid mixture with 3-(4-Trifluoromethoxyphen-l)-thiophene.This is reflected under the inert atmosphere to stir and spends the night, and after this TLC analyzes (hexane) and shows and do not have raw material to have the new spot that occurs under the solvent condition of 20% ethyl acetate/hexane.This reaction mixture is introduced in the ice and with methylene dichloride (2x20mL) and extracts.MgSO is washed and used to the organic phase of separating with salt solution (3x20mL)
4Dry.This crude mixture is filtered, and solvent under reduced pressure is evaporated and this crude compound is absorbed on the silica, and purifies by flash chromatography, and it adopts the gradient of 0 to 25% ethyl acetate/hexane to carry out more than 20 minutes.
1HNMR is consistent with compound structure, and it has 2 of expectation, and 3-replaces form.
The preparation of step 3:3-(4-Trifluoromethoxyphen-l) thiophene-2--sulfinic acid sodium salt (61)
[0398] in round-bottomed flask, with S-WAT (220mg, 0.0017mol) be dissolved in water (15mL, 0.83mol) in and 107 ℃ of down heating 10-12 minute.Solid progresses in the solution.With 3-(4-Trifluoromethoxyphen-l) thiophene-2-SULPHURYL CHLORIDE (60,223mg, 0.000651mol) and sodium bicarbonate (62mg 0.00074mol) mixes on pan paper and the solid that merges is added in the reflux solution.After 4 hours, TLC analyzes (20% ethyl acetate/hexane) and shows and have raw material.The nitrogen capsule is connected on the reaction flask, and this reaction refluxed and spend the night, after this TLC shows and does not have raw material.This reaction is cooled to room temperature and solvent and carries out freezingly with acetone-the dry ice bath, and this solvent is removed by lyophilize.After 16 hours, this solid salt mixes with 40mL ethanol, and quilt was refluxed 40 minutes and was filtered.Be dissolved in the solid of collecting in the ethanol again and repeat this process.Filtrate is merged, and remove solvent in a vacuum, the sulphite that obtains expecting.This white powder is used to next step.
Step 4:{3-propoxy--5-[3-(4-Trifluoromethoxyphen-l)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of methyl acetate (63)
[0399] in the flame-dried round-bottomed flask that is under the inert conditions, with (3-propoxy--5-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (62,106mg, 0.000298mol, as embodiment 6, the step 2 of scheme 15 is described, by in step 1, replacing iodoethane to prepare) with iodopropane, 3-(4-Trifluoromethoxyphen-l) thiophene-2--sulfinic acid sodium salt (61,221mg, 0.000669mol), cesium carbonate (295mg, 0.000905mol), 4,5-two (dimethyl phosphino-)-9, and 9-dimethyl xanthene (10mg, 0.00002mol), three (dibenzyl acetone) two palladiums (0) (10mg, 0.00001mol) and toluene (15mL, 0.14mol) mixing.This reaction vessel cleaned 5 minutes with argon gas, and 117 ℃ of heating 5 hours down, and after this TLC (20% ethyl acetate/hexane) shows and do not have raw material and a plurality of new spot are arranged.The vapourisation under reduced pressure solvent, and this crude reaction mixture is directed on the preparation property silica column plate.The expectation compound separates by plate chromatography, and it adopts 20% ethyl acetate/hexane.
1H NMR is consistent with compound structure.
Step 5:{3-propoxy--5-[3-(4-Trifluoromethoxyphen-l)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of acetate (P-0279)
[0400] methyl esters 63 is dissolved in 5mL tetrahydrofuran (THF)/1N LiOH mixture (4: 1) lining and spent the night by vigorous stirring, after this TLC (20% ethyl acetate/hexane) shows and does not have raw material and a new spot is arranged near baseline.This reaction is carried out acidifying and (by the pH test paper, pH0-1), is extracted (3 times of reaction volumes) and at MgSO with ethyl acetate by adding 1N HCl
4Last dry.The expectation compound separates by flash chromatography, and it adopts the gradient solvent condition of 0 to 3% ethanol/methylene to carry out more than 25 minutes.
1H NMR (CDCl
3) consistent with compound structure, purity＞96%.
Embodiment 19:{3-oxyethyl group-5-[4-(4-trifluoromethyl)-thiophene-2-alkylsulfonyl]-phenyl }-preparation of acetate (P-0278)
[0401] shown in scheme 28, Compound P-0278 is five step synthetic.
Scheme 28
The preparation of step 1:3-(4-trifluoromethyl)-thiophene (64)
[0402] in the 40mL reactor, with 3-bromo-thiophene (58,4.50E2mg, 0.00276mol), the 4-trifluoromethyl phenyl boronic acid (6.30E2mg, 0.00332mol), 1N K
2CO
3(0.4mL), tetrabutylammonium iodide (4mg, 0.00001mol) and tetrahydrofuran (THF) (8mL 0.1mol) mixes.This mixture is stirred 2-5 minute under argon atmospher, add then four (triphen is seen) palladium (0) (8mg, 0.000007mol).This container is positioned in the oil bath of 87 ℃ of following preheatings and is stirred 2 days, and after this TLC analyzes (hexane) and shows and have raw material and have two to move slower spot.This reaction is filtered and concentrates with silica.The expectation compound separates by flash chromatography, described flash chromatography hexane wash-out, and it is used to next step.
1HNMR is consistent with compound structure.
The preparation of step 2:4-(4-trifluoromethyl) thiophene-2-SULPHURYL CHLORIDE (65)
[0403] under argon atmospher, in flame-dried round-bottomed flask, with chlorsulfonic acid (480mg, 0.0042mol) be dissolved in methylene dichloride (8mL, 0.1mol) in.This container is put on the ice bath and is stirred 4-5 minute.Slowly add phosphorus pentachloride (340mg 0.0016mol), continues more than 2 minutes, and stirs this reaction until the solid dissolving, after this will be dissolved in 3-(4-trifluoromethyl)-thiophene in the 3mL methylene dichloride (64,306mg, 0.00134mol) adding.This is reflected to be stirred under the nitrogen air bag and spends the night.After 16 hours, TLC analyzes (hexane) and shows and do not have raw material, and 20% ethyl acetate/hexane elutriant shows that three new spot are arranged.This reaction is slowly poured in the beaker that ice is housed and is stirred until ice-out.This material extracts with the 30mL methylene dichloride, and it waits for this emulsion layer dispersion then with salt solution (10mL) washed twice after adding salt.Organic layer is collected and uses MgSO
4Dry up hill and dale, it is rotated half that is evaporated to its original volume then.In mixture, add silica and remove solvent.The expectation compound is purified by flash chromatography, and described flash chromatography adopts the gradient of 0 to 25% ethyl acetate/hexane to carry out more than 25 minutes, and it is used to next step.
1H NMR is consistent with compound structure.
The preparation of step 3:4-(4-trifluoromethyl)-thiophene-2--sulfinic acid sodium salt (66)
[0404] in round-bottomed flask, (240mg 0.0019mol) is dissolved in the water with S-WAT.This reactor is positioned in the oil bath of 102 ℃ of following preheatings, heats 20-23 minute.With 4-(4-trifluoromethyl) thiophene-2-SULPHURYL CHLORIDE (65,250mg, 0.00076mol) and sodium bicarbonate (77mg 0.00092mol) mixes on pan paper and is slowly joined in the reaction.This reaction is heated spends the night, and after this TLC analyzes (20% ethyl acetate/hexane) and shows and do not have raw material.This reaction is cooled to room temperature and solvent carries out freezing with acetone-the dry ice bath.This solvent is removed by lyophilize.This rough white solid mixes with ethanol and was refluxed 20 minutes, then by filtered while hot, and the abundant drip washing of ethanol of heat of this salt.Collect filtrate and the sulphite of vapourisation under reduced pressure to obtain expecting.1H NMR is consistent with compound structure.Calculate molecular weight 291.98, MS (ESI) [M-H
+]
-=291.21.
Step 4:{3-oxyethyl group-5-[4-(4-trifluoromethyl) thiophene-2-alkylsulfonyl]-phenyl }-preparation of methyl acetate (67)
[0405] in flame-dried scintillation vial, with (3-oxyethyl group-5-trifluoromethane sulfonyloxy-phenyl)-methyl acetate (17,102mg, 0.000298mol, as embodiment 6, the described preparation of the step 2 of scheme 15), 4-(4-trifluoromethyl)-thiophene-2--sulfinic acid sodium salt (66,112mg, 0.000356mol) and cesium carbonate (210mg, 0.00064mol) be dissolved in toluene (4mL, 0.04mol) in.This mixture cleans several minutes with argon gas, then with 4, and 5-two (dimethyl phosphino-)-9, (5mg, 0.000009mol) (5mg 0.000005mol) adds 9-dimethyl xanthene with three (dibenzyl acetone) two palladiums (0).Bottle is covered, and this mixture is 117 ℃ of down heating 5 hours, after this TLC analyzes (20% ethyl acetate/hexane) and shows raw material that trace is arranged and the spot (fluorescence) that mobile is new under raw material.This reaction is cooled to room temperature and vapourisation under reduced pressure solvent.This crude mixture is absorbed on the silica.The expectation compound separates by flash chromatography, and it adopts 0 to 20% ethyl acetate/hexane to carry out more than 25 minutes.
1H NMR is consistent with compound structure.
Step 5:{3-oxyethyl group-5-[4-(4-trifluoromethyl) thiophene-2-alkylsulfonyl]-phenyl }-preparation of acetate (P-0278)
[0406] methyl esters 67 is dissolved in 4mL tetrahydrofuran (THF)/1N LiOH mixture (4: 1) lining and by vigorous stirring 3 hours, after this TLC analyzes (20% ethyl acetate/hexane) and shows and do not have raw material and a new spot is arranged near baseline.This reaction is carried out acidifying and (by the pH test paper, pH0-1), is extracted (3 times of reaction volumes) and at MgSO with ethyl acetate by adding 1N HCl
4Last dry.The expectation compound separates by flash chromatography, and it adopts the gradient of 0 to 3% ethanol/methylene.
1H NMR (CDCl
3) consistent with compound structure, purity＞96%.Calculate molecular weight 470.49, MS (ESI) [M-H
+]
-=468.24.
Embodiment 20:{3-oxyethyl group-5-[4-(4-trifluoromethyl-phenoxy group) benzenesulfonyl]-phenyl } preparation of acetate (P-0029)
[0407] Compound P-the 0029th, following four step synthetic.
The preparation of step 1:2-(3-oxyethyl group-5-hydroxyphenyl) methyl acetate
[0408] 500mL be equipped with that thermometer, stopper, nitrogen inlet are taken over and 3 neck flasks of magnetic stirring bar in, put into 2-(3, the 5-dihydroxyphenyl) methyl acetate (5.33g, 29.3mmol) and N, dinethylformamide (100mL).This reaction mixture is placed under the nitrogen and is cooled to internal temperature-50 ℃.This moment, (60% dispersion in the mineral oil, 2.34g 58.5mmol) added with four parts, and internal temperature rises to-22 ℃ during this period with sodium hydride during 15 minutes.The gained slurries at room temperature stirred 40 minutes.To clarify the green reaction mixture and be cooled to internal temperature-50 ℃ once more, and (2.36mL 29.2mmol) all adds at once with iodoethane.This reaction mixture is placed in-24 ℃ of baths then.In 20 minutes, internal temperature rises to-24 ℃ from-57 ℃.Internal temperature was kept 75 minutes at-24 ℃ to-14 ℃, during 95 minutes, make then its be warming up to+11 ℃.This reaction mixture is with formic acid (15mL) quencher and at room temperature stirred 20 minutes.With the gained dope filtration, with ethyl acetate drip washing thriftily, and under reduced pressure concentrate to obtain the viscosity orange oil, it is loaded onto on the silica gel plug (Silica Gel plug).With 20% ethyl acetate in the hexane, use 30% eluent ethyl acetate in the hexane then, obtain a kind of oil, by
1H NMR is accredited as 2-(3-oxyethyl group-5-hydroxyphenyl) methyl acetate (2.84g, 46%).
1H NMR(CDCl
3)：δ6.38(s，1H)，6.33(s，1H)，6.29(s，1H)，3.97(q，J＝7Hz，2H)，3.68(s，3H)，3.50(s，2H)，1.37(t，J＝7Hz，3H)。
The preparation of step 2:2-(3-oxyethyl group-5-(trifluoromethyl sulfonyloxy) phenyl) methyl acetate
[0409] be equipped with in the round-bottomed flask that feed hopper and nitrogen inlet take over to 1L, add 2-(3-oxyethyl group-5-hydroxyphenyl) methyl acetate (2.1g, 9.99mmol) and methylene dichloride (19.98mL).This reaction mixture is cooled in-78 ℃ of baths under nitrogen.Add N, the N-diisopropylethylamine (2.44mL, 13.98mmol), then during 6 minutes, be added dropwise to Trifluoromethanesulfonic anhydride in the methylene dichloride (10mL) (2.02mL, 11.99mmol).This pale yellow syrup is stirred in-78 ℃ of baths.This reaction mixture is introduced in water (100mL) and the methylene dichloride (100mL) and is extracted after 40 minutes.This emulsus dichloromethane layer is loaded on the silica gel plug (SilicaGel plug), and with the methylene dichloride wash-out until having collected 500mL.Dichloromethane layer is under reduced pressure concentrated obtaining 3.12g (91%) water white oil, by
1H NMR is accredited as 2-(3-oxyethyl group-5-(trifluoromethyl sulfonyloxy) phenyl) methyl acetate.
1H NMR(DMSO-d6)：δ6.94(m，1H)，6.92(m，2H)，4.02(q，J＝7Hz，2H)，3.72(s，2H)，3.58(s，3H)，1.28(t，J＝7Hz，3H)。
The preparation of step 3:2-(3-oxyethyl group-5-(4-(4-(trifluoromethyl) phenoxy group) phenyl sulfonyl) phenyl) methyl acetate
[0410] 2-(3-oxyethyl group-5-(trifluoromethyl sulfonyloxy) phenyl) methyl acetate (3.48g, 10.17mmol) reacted as follows with two portions: with 2-(3-oxyethyl group-5-(trifluoromethyl sulfonyloxy) phenyl) methyl acetate (1.74g, 5.08mmol), Cs
2CO
3(2.49g, 7.64mmol), 4-(4-(trifluoromethyl) phenoxy group) benzene sulfinic acid sodium salt dihydrate (2.09g, 5.80mmol), three (dibenzalacetones), two palladiums (0) (0.465g, 0.5mmol), 4, two (hexichol is seen)-9 of 5-, 9-dimethyl xanthene (0.588g, 1.0mmol) He diox (26mL) in the 80mL container, mix and fully stirred.(Matthews NC) carried out microwave radiation 5 minutes among the Discover (300 watts) at 160 ℃ of following CEM.Pour the effluent that merges into same C salt pad (celite pad) gone up and with eluent methylene chloride 3-4 time.40 ℃ of following concentrating under reduced pressure obtain orange oil (8.33g); it is purified by silica gel chromatography; described chromatography adopts 20% ethyl acetate in the hexane, produces 3.05g (60.6%) 2-(3-oxyethyl group-5-(4-(4-(trifluoromethyl) phenoxy group) phenyl sulfonyl) phenyl) methyl acetate.
1H NMR(DMSO-d6)：δ7.97(d，J＝9Hz，2H)，7.76(d，J＝8.5Hz，2H)，7.41(brs，1H)，7.28-7.26(m，3H)，7.21(d，J＝9Hz，2H)，7.11(br s，1H)，4.05(q，J＝7Hz，2H)，3.75(s，2H)，3.57(s，3H)，1.28(t，J＝7Hz，3H)。
Step 4:{3-oxyethyl group-5-[4-(4-trifluoromethyl-phenoxy group) benzenesulfonyl]-phenyl } preparation of acetate (P-0029)
[0411] in the 2L round-bottomed flask, with 2-(3-oxyethyl group-5-(4-(4-(trifluoromethyl) phenoxy group) phenyl sulfonyl) phenyl) methyl acetate (29.9g, 60.4mmol) and tetrahydrofuran (THF) (201mL) mix.With 1N potassium hydroxide (72.4mL 72.4mmol) added during 5 minutes, then add methyl alcohol until this reaction mixture evenly (～75mL).This solution at room temperature stirred 2 hours, under reduced pressure was concentrated then until removing all trace carbinols.Gained light brown solid is distributed between 2N HCl (350mL) and ethyl acetate (1.3L), and fully extracted.Separated and the dry (Na of this ethyl acetate layer
2SO
4).Under reduced pressure concentrate to produce foam (26.76g, 91%), it was with 1: 1 toluene: hexane carries out recrystallization.With gained solid dried overnight in the vacuum oven at room temperature, obtain 22.5g (84%) { 3-oxyethyl group-5-[4-(4-trifluoromethyl-phenoxy group) benzenesulfonyl]-phenyl } acetate (P-0029).
1H NMR(DMSO-d6)：δ12.43(br s，1H)，7.97(d，J＝8.9Hz，2H)，7.75(d，J＝8.5Hz，2H)，7.4(br s，1H)，7.28-7.26(m，3H)，7.20(d，J＝8.9Hz，2H)，7.10(br s，1H)，4.05(q，J＝7Hz，2H)，3.63(s，2H)，1.28(t，J＝7Hz，3H)。
Embodiment 21: the expression and the purifying that are used for the PPARs in biochemical analysis and the cell analysis
Genetic engineering
[0412] uses conventional polymerase chain reaction (PCR) method, coding PPAR α, PPAR γ and PPAR 2-delta ligand are carried out genetically engineered (pGal4-PPAR α-LBD, pGal4-PPAR γ-LBD, pGal4-PPAR δ-LBD) in conjunction with the plasmid of territory (LBDs).Associated dna sequence that uses in the analysis and encoded protein matter sequence illustrate (vide infra) separately.Available from Invitrogen, these are used as the substrate in the PCR reaction from various human tissue clone's complementary DNA.The synthetic oligonucleotide primer thing (Invitrogen vide infra) of special customization is designed to cause the PCR product, also is used to provide the suitable Restriction Enzyme that is used for being connected with plasmid and cuts the site.
[0413] plasmid that is connected of insertion fragment that is used for the coding acceptor is the derivative of pET28 (Novagen) or pET28, pET-BAM6, so that express with intestinal bacteria.Under all these situations, acceptor LBD all be transformed into contain histidine-tagged so that the applied metal affinity chromatography is carried out purifying.
The protein expression of PPAR and purifying
[0414] in order to carry out protein expression, the plasmid that will contain goal gene is transformed among coli strain BL21 (DE3) RIL (Invitrogen), selects transformant containing on the suitable antibiotic LB agar plate, with growth.Single bacterium colony was grown 4 hours in 37 ℃ in 200ml LB substratum.For PPAR α and PPAR γ, all protein expressions are all used the 30L bio-reactor and are undertaken by large scale fermentation.The starting culture of 400ml is added in the 30L TB culture, make it, reach 2-5 until OD600nm 37 ℃ of growths.Culture is cooled to 20 ℃, adds 0.5mM IPTG, made the culture regrowth 18 hours.
[0415] for PPAR δ protein expression, single bacterium colony was grown 4 hours in 37 ℃ in the 200m1LB substratum.With the fresh TB culture medium inoculated of 10ml starting culture, and under 37 ℃, constantly shake middle growth to the 16x1L in the 2.8L flask., after the absorbancy of 600nm reaches 1.0, the additive that improves PPAR δ solubleness is joined in this culture at culture, after 30 minutes, add 0.5mM IPTG, make culture at 20 ℃ of following regrowth 12-18 hours.By centrifugal collecting cell, and with the cell precipitation thing-80 ℃ freezing, up to preparing to be used for cracking/purifying.
[0416] for protein purification, all operations are all carried out at 4 ℃.The mechanical means of application standard is resuspended in refrigerated Bacillus coli cells throw out in the lysis buffer and makes its cracking.Applying immobilized metal affinity purification (IMAC) is by polyhistidyl label purification of soluble protein.For each PPAR that describes all is to use 3 step purge process purifying, and it uses IMAC, size exclusion chromatography method and ion exchange chromatography.For PPAR α, randomly use zymoplasm (Calbiochem) and remove the polyhistidyl label.Under the situation of PPAR δ, during protein purification, exist solubleness to increase additive so that keep proteinic stability.During final purification step, before concentrating, make solubleness increase the additive desalination.
Plasmid sequence and PCR primer information:
PPAR α: (nucleic acid SEQ ID NO:__) (protein s EQ ID NO:__)
P332.pET28 PPARA E199-Y468-X
taatacgactcactataggggaattgt
gagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatatacc
atgggcagcagccatcatcatcatcatcacagcagcggcctggtgccgcgcggcagccat
M G S S H H H H H H S S G L V P R G S H
atggaaactgcagatctcaaatctctggccaagagaatctacgaggcctacttgaagaac
M E T A D L K S L A K R I Y E A Y L K N
ttcaacatgaacaaggtcaaagcccgggtcatcctctcaggaaaggccagtaacaatcca
F N M N K V K A R V I L S G K A S N N P
ccttttgtcatacatgatatggagacactgtgtatggctgagaagacgctggtggccaag
P F V I H D M E T L C M A E K T L V A K
ctggtggccaatggcatccagaacaaggaggcggaggtccgcatctttcactgctgccag
L V A N G I Q N K E A E V R I F H C C Q
tgcacgtcagtggagaccgtcacggagctcacggaattcgccaaggccatcccaggcttc
C T S V E T V T E L T E F A K A I P G F
gcaaacttggacctgaacgatcaagtgacattgctaaaatacggagtttatgaggccata
A N L D L N D Q V T L L K Y G V Y E A I
ttcgccatgctgtcttctgtgatgaacaaagacgggatgctggtagcgtatggaaatggg
F A M L S S V M N K D G M L V A Y G N G
tttataactcgtgaattcctaaaaagcctaaggaaaccgttctgtgatatcatggaaccc
F I T R E F L K S L R K P F C D I M E P
aagtttgattttgccatgaagttcaatgcactggaactggatgacagtgatatctccctt
K F D F A M K F N A L E L D D S D I S L
tttgtggctgctatcatttgctgtggagatcgtcctggccttctaaacgtaggacacatt
F V A A I I C C G D R P G L L N V G H I
gaaaaaatgcaggagggtattgtacatgtgctcagactccacctgcagagcaaccacccg
E K M Q E G I V H V L R L H L Q S N H P
gacgatatctttctcttcccaaaacttcttcaaaaaatggcagacctccggcagctggtg
D D I F L F P K L L Q K M A D L R Q L V
acggagcatgcgcagctggtgcagatcatcaagaagacggagtcggatgctgcgctgcac
T E H A Q L V Q I I K K T E S D A A L H
ccgctactgcaggagatctacagggacatgtactgagtcgacaagcttgcggccgcactc
P L L Q E I Y R D M Y -
gagcaccaccaccaccaccactgagat
The PCR primer:
PPARA PPARA-S GCTGACACATATGGAAACTGCAGATCTCAAATC (SEQ ID NO：__)
PPARA-A GTGACTGTCGACTCAGTACATGTCCCTGTAGA (SEQ ID NO：__)
PPAR γ: (nucleic acid SEQ ID NO:__) (protein s EQ ID NO:__)
P333.pET28 PPARG E205-Y475-X
taatacgactcactataggggaattgt
gagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatatacc
atgggcagcagccatcatcatcatcatcacagcagcggcctggtgccgcgcggcagccat
M G S S H H H H H H S S G L V P R G S H
atggagtccgctgacctccgggccctggcaaaacatttgtatgactcatacataaagtcc
M E S A D L R A L A K H L Y D S Y I K S
ttcccgctgaccaaagcaaaggcgagggcgatcttgacaggaaagacaacagacaaatca
F P L T K A K A R A I L T G K T T D K S
ccattcgttatctatgacatgaattccttaatgatgggagaagataaaatcaagttcaaa
P F V I Y D M N S L M M G E D K I K F K
cacatcacccccctgcaggagcagagcaaagaggtggccatccgcatctttcagggctgc
H I T P L Q E Q S K E V A I R I F Q G C
cagtttcgctccgtggaggctgtgcaggagatcacagagtatgccaaaagcattcctggt
Q F R S V E A V Q E I T E Y A K S I P G
tttgtaaatcttgacttgaacgaccaagtaactctcctcaaatatggagtccacgagatc
F V N L D L N D Q V T L L K Y G V H E I
atttacacaatgctggcctccttgatgaataaagatggggttctcatatccgagggccaa
I Y T M L A S L M N K D G V L I S E G Q
ggcttcatgacaagggagtttctaaagagcctgcgaaagccttttggtgactttatggag
G F M T R E F L K S L R K P F G D F M E
cccaagtttgagtttgctgtgaagttcaatgcactggaattagatgacagcgacttggca
P K F E F A V K F N A L E L D D S D L A
atatttattgctgtcattattctcagtggagaccgcccaggtttgctgaatgtgaagccc
I F I A V I I L S G D R P G L L N V K P
attgaagacattcaagacaacctgctacaagccctggagctccagctgaagctgaaccac
I E D I Q D N L L Q A L E L Q L K L N H
cctgagtcctcacagctgtttgccaagctgctccagaaaatgacagacctcagacagatt
P E S S Q L F A K L L Q K M T D L R Q I
gtcacggaacatgtgcagctactgcaggtgatcaagaagacggagacagacatgagtctt
V T E H V Q L L Q V I K K T E T D M S L
cacccgctcctgcaggagatctacaaggacttgtactaggtcgacaagcttgcggccgca
H P L L Q E I Y K D L Y -
ctcgagcaccaccaccaccaccactgagat
The PCR primer:
PPARG PPARG-S GCTCAGACATATGGAGTCCGCTGACCTCCGGGC (SEQ ID NO：__)
PPARG-A GTGACTGTCGACCTAGTACAAGTCCTTGTAGA (SEQ ID NO：__)
PPAR δ: (nucleic acid SEQ ID NO:__) (protein s EQ ID NO:__)
P1057.pET BAM6 PPARD G165-Y441-X
taatacgactcactataggggaattgt
gagcggataacaattcccctctagaaataattttgtttaactttaagaaggagatatacc
atgaaaaaaggtcaccaccatcaccatcacggatcccagtacaacccacaggtggccgac
M K K G H H H H H H G S Q Y N P Q V A D
ctgaaggccttctccaagcacatctacaatgcctacctgaaaaacttcaacatgaccaaa
L K A F S K H I Y N A Y L K N F N M T K
aagaaggcccgcagcatcctcaccggcaaagccagccacacggcgccctttgtgatccac
K K A R S I L T G K A S H T A P F V I H
gacatcgagacattgtggcaggcagagaaggggctggtgtggaagcagttggtgaatggc
D I E T L W Q A E K G L V W K Q L V N G
ctgcctccctacaaggagatcagcgtgcacgtcttctaccgctgccagtgcaccacagtg
L P P Y K E I S V H V F Y R C Q C T T V
gagaccgtgcgggagctcactgagttcgccaagagcatccccagcttcagcagcctcttc
E T V R E L T E F A K S I P S F S S L F
ctcaacgaccaggttacccttctcaagtatggcgtgcacgaggccatcttcgccatgctg
L N D Q V T L L K Y G V H E A I F A M L
gcctctatcgtcaacaaggacgggctgctggtagccaacggcagtggctttgtcacccgt
A S I V N K D G L L V A N G S G F V T R
gagttcctgcgcagcctccgcaaacccttcagtgatatcattgagcctaagtttgaattt
E F L R S L R K P F S D I I E P K F E F
gctgtcaagttcaacgccctggaacttgatgacagtgacctggccctattcattgcggcc
A V K F N A L E L D D S D L A L F I A A
atcattctgtgtggagaccggccaggcctcatgaacgttccacgggtggaggctatccag
I I L C G D R P G L M N V P R V E A I Q
gacaccatcctgcgtgccctcgaattccacctgcaggccaaccaccctgatgcccagtac
D T I L R A L E F H L Q A N H P D A Q Y
ctcttccccaagctgctgcagaagatggctgacctgcggcaactggtcaccgagcacgcc
L F P K L L Q K M A D L R Q L V T E H A
cagatgatgcagcggatcaagaagaccgaaaccgagacctcgctgcaccctctgctccag
Q M M Q R I K K T E T E T S L H P L L Q
gagatctacaaggacatgtactaagtcgaccaccaccaccaccaccactgagatccggct
E I Y K D M Y -
ggccctactggccgaaaggaattcgaggccagcagggccaccgctgagcaataactagca
taaccccttggggcctctaaacgggtcttgaggggttttttg
The PCR primer:
PPARD PPARD-G165 GTTGGATCCCAGTACAACCCACAGGTGGC (SEQ ID NO：__)
PPARD-A GTGACTGTCGACTTAGTACATGTCCTTGTAGA (SEQ ID NO：__)
Embodiment 22: the biological chemistry screening
[0417] in the agonist pattern, uses even α screening assay method (homogenous Alpha screenassay), to determine PPARs (α, δ is γ) with coactivator vitamin H-PGC-1 peptide (vitamin H-AHX-DGTPPPQEAEEPSLLKKLLLAPANT-CONH
2(SEQ ID NO:__) provided by Wyeth) between ligand-dependent interact.The compound of all detections is gone into DMSO, whole 8 concentration point with dilution in 1: 3 continuously.Use the His-label PPAR-LBD of embodiment 21 preparations, the preparation sample.Add the Ni-chelating acceptor bead (bead) that is attached to His-label PPAR-LBD, and add the streptavidin donor bead (Perkin-Elmer #6760619M) be attached to the coactivator vitamin H, so that the activity of agonist is closely related with signal from donor and acceptor bead.By mixing extremely body/peptide mixt of 1 μ l compound and 15 μ l 1.33, prepare each sample, each sample incubation 15 minutes at room temperature wherein, 4 times of pearls that add 4 μ l then are in analysis buffer.Described analysis buffer is 50mM HEPES, 50mM KCl, 1mM DTT and the 0.8%BSA of pH7.5.The ultimate density of each sample is 25nM vitamin H-PGC-1 peptide, 20nM PPAR γ or 10nMPPAR α or δ, and each pearl concentration is 5 μ g/ml, and compound is joined the expection concentration that produces 5% final DMSO.Sample is analyzed in contrast for WY-14643 (PPAR α), Fa Gelie ketone (PPAR γ) and bezafibrate (PPAR δ).Before in Fusion α or Alpha Quest reader (reader), carrying out reading, at room temperature in dark place incubation sample 1 hour.Signal vs compound concentration is used to determine EC
50Data are represented with μ Mol/L.The data point that obtains from Fusion α instrument is transferred to Assay Explorer
(MDL), with the generation curve, and according to EC
50The flex point of calculated curve (inflection point).
Embodiment 23: the cotransfection assay method
[0418] this assay method is used for confirming in the viewed chemical-biological activities (embodiment 22) that expection target molecule (one or more) is regulated of cell levels.With 293T cell (ATCC) with every hole 1-2x10 in 6 orifice plates (Corning 3516)
6The concentration shop cell of individual cell, and wherein every hole 3ml growth medium (Dulbecco ' s eaglemedium, Mediatech contains 10%FBS).These plate incubations are converged degree (confluent) to 80-90%, remove substratum by absorption.With PPAR LBD and these cells of luciferase transfection, so that agonist activation biotin enzyme.Measure activity, it directly is associated with agonist activity with the luciferase of compound cells transfected.To 100 μ l do not contain add in the growth medium of serum 1 μ g pFR-Luc (Stratagene catalog number (Cat.No.) 219050), 6 μ l Metafectene (Biontex, Inc.) and 1mg pGal4-PPAR-LBD (alpha, gamma or the δ that obtain from embodiment 21).By upset, mix, at room temperature incubation 15-20 minute then, the growth medium that does not contain serum with 900 μ l diluted it.It is covered on the 293T cell, and at 37 ℃, CO
2In the incubator incubation 4-5 hour.Remove transfection media by absorption, add growth medium then, incubation cell 24 hours.Then with cell suspension in the 5ml growth medium, and dilute with other 15ml growth medium.For the sample of each detection, 95 μ l cells transfected are transferred in each hole of 96 well culture plates.Detection compound is diluted 200 times in DMSO, reach the ultimate density of expectation., with 10 times of its dilutions its 5 μ l is joined in the 95 μ l cells transfected with growth medium.At 37 ℃, CO
2This plate of incubation is 24 hours in the incubator.By mixing 1ml lysis buffer, substrate and the 3ml reaction buffer of 1ml in lysis buffer, prepare luciferase reaction mixture (Roche diagnosis luciferase assay kit (Roche DiagnosticsLuciferase assay kit) #1814036).For each sample well, replace growth medium with the 50ml reaction mixture, swing plate 15-20 minute then, and by Victor2 V plate reader (Perkin Elmer) measurement fluorescence.Use signal that compound concentration is determined EC
50
[0419] the biological chemistry of embodiment 22 detect or detection based on this cell in, at least a to PPAR α, PPAR γ and PPAR δ has the EC that is less than or equal to 1 μ M
50Compound shown in the table 14.
Table 14 has the EC that is less than or equal to 1 μ M at least a activation analysis of PPAR α, PPAR γ and PPAR δ
50The compounds of this invention.
| P-0001，P-0002，P-0005，P-0009，P-0010，P-0011，P-0017，P-0018，P-0019，P-0021，P-0025， P-0027，P-0029，P-0050，P-0056，P-0057，P-0058，P-0059，P-0060，P-0061，P-0062，P-0064， P-0067，P-0068，P-0073，P-0074，P-0075，P-0076，P-0077，P-0078，P-0080，P-0081，P-0082， P-0087，P-0089，P-0090，P-0091，P-0092，P-0093，P-0094，P-0095，P-0096，P-0097，P-0098， P-0099，P-0100，P-0101，P-0102，P-0103，P-0104，P-0105，P-0106，P-0107，P-0108，P-0109， P-0110，P-0111，P-0112，P-0113，P-0114，P-0115，P-0117，P-0118，P-0121，P-0126，P-0127， P-0129，P-0132，P-0133，P-0134，P-0135，P-0136，P-0137，P-0138，P-0139，P-0140，P-0150， P-0152，P-0155，P-0156，P-0157，P-0158，P-0164，P-0165，P-0167，P-0174，P-0175，P-0178， P-0180，P-0186，P-0187，P-0188，P-0190，P-0191，P-0193，P-0194，P-0195，P-0196，P-0197， P-0198，P-0200，P-0201，P-0202，P-0205，P-0208，P-0209，P-0210，P-0215，P-0217，P-0218， P-0220，P-0223，P-0224，P-0225，P-0226，P-0227，P-0228，P-0229，P-0239，P-0244，P-0247， P-0257，P-0258，P-0259，P-0260，P-0262，P-0266，P-0267，P-0270，P-0271，P-0272，P-0273， P-0274，P-0275，P-0276，P-0277，P-0280，P-0281，P-0282，P-0284，P-0285，P-0287，P-0288， P-0293，P-0295 |
[0420] all patents of quoting in this specification sheets and other reference have been pointed out those skilled in the art's level, and incorporate this paper into as a reference with integral body, comprise any table and figure, the degree of incorporating into is incorporated this paper into as a reference with integral body individually as each reference.
[0421] those skilled in the art should be easy to recognize, the present invention is well suited for result and the advantage that acquisition is mentioned, and wherein inherent result of institute and advantage.Method as herein described, variation and combination are exemplary as the present representative of preferred embodiment, and being not intended to becomes limitation of the scope of the invention.Those skilled in the art will expect variation and other application wherein, and this is included in the spirit of the present invention, limits as the scope of claims.
[0422] for a person skilled in the art, should be easy to recognize, without departing from the scope and spirit of the present invention, can make various substituting and modification the present invention disclosed herein.For instance, can change so that the other compound of formula I to be provided, and/or various medication can be used.Therefore, so other embodiment is also within the scope of the present invention and claim.
[0423] invention of describing herein suitably illustratively can lack the concrete disclosed arbitrary element of this paper perhaps multielement, limit under perhaps situations about limiting more and be implemented.Therefore, for instance, under each situation of this paper, term " comprises (comprising) ", " basically by ... form (consisting estentiallyof) " and " by ... composition (consisting of) " in any one can replace with one of two other terms.Term that has used and statement are used as descriptive term rather than limited term; and be not intended to and when using these terms and statement, get rid of demonstration and the feature of describing or any equivalent of its part, but recognize that various modifications are possible in the claimed invention scope.Therefore, should be appreciated that, although the present invention is open particularly by embodiment preferred and optional feature quilt, but those skilled in the art can make amendment and change notion disclosed herein, and these modifications and variations are contemplated as falling with within the scope of the present invention, as defined by the appended claims.
[0424] in addition, when feature of the present invention or aspect are described according to Ma Kushi group or other selection group, those skilled in the art will know that the present invention thereby also be that any single member or subgroup member according to this Ma Kushi group or other group is described.
[0425] simultaneously, if do not indicate on the contrary, when embodiment is provided each numerical value,, other embodiment has been described by adopting the end points of any two different values as scope.Such scope is also contained in the described scope of invention.
[0426] therefore, other embodiment comprises within the scope of the present invention in the scope with claims.
The PPAR sequence
PPARA registration number NM_005036 (SEQ ID NO:__)
gcgccgcctc cttcggcgtt cgccccacgg accggcaggc ggcggaccgc ggcccaggct
gaagctcagg gccctgtctg ctctgtggac tcaacagttt gtggcaagac aagctcagaa
ctgagaagct gtcaccacag ttctggaggc tgggaagttc aagatcaaag tgccagcaga
ttcagtgtca tgtgaggacg tgcttcctgc ttcatagata agagtagctt ggagctcggc
ggcacaacca gcaccatctg gtcgcgatgg tggacacgga aagcccactc tgccccctct
ccccactcga ggccggcgat ctagagagcc cgttatctga agagttcctg caagaaatgg
gaaacatcca agagatttcg caatccatcg gcgaggatag ttctggaagc tttggcttta
cggaatacca gtatttagga agctgtcctg gctcagatgg ctcggtcatc acggacacgc
tttcaccagc ttcgagcccc tcctcggtga cttatcctgt ggtccccggc agcgtggacg
agtctcccag tggagcattg aacatcgaat gtagaatctg cggggacaag gcctcaggct
atcattacgg agtccacgcg tgtgaaggct gcaagggctt ctttcggcga acgattcgac
tcaagctggt gtatgacaag tgcgaccgca gctgcaagat ccagaaaaag aacagaaaca
aatgccagta ttgtcgattt cacaagtgcc tttctgtcgg gatgtcacac aacgcgattc
gttttggacg aatgccaaga tctgagaaag caaaactgaa agcagaaatt cttacctgtg
aacatgacat agaagattct gaaactgcag atctcaaatc tctggccaag agaatctacg
aggcctactt gaagaacttc aacatgaaca aggtcaaagc ccgggtcatc ctctcaggaa
aggccagtaa caatccacct tttgtcatac atgatatgga gacactgtgt atggctgaga
agacgctggt ggccaagctg gtggccaatg gcatccagaa caaggaggcg gaggtccgca
tctttcactg ctgccagtgc acgtcagtgg agaccgtcac ggagctcacg gaattcgcca
aggccatccc aggcttcgca aacttggacc tgaacgatca agtgacattg ctaaaatacg
gagtttatga ggccatattc gccatgctgt cttctgtgat gaacaaagac gggatgctgg
tagcgtatgg aaatgggttt ataactcgtg aattcctaaa aagcctaagg aaaccgttct
gtgatatcat ggaacccaag tttgattttg ccatgaagtt caatgcactg gaactggatg
acagtgatat ctcccttttt gtggctgcta tcatttgctg tggagatcgt cctggccttc
taaacgtagg acacattgaa aaaatgcagg agggtattgt acatgtgctc agactccacc
tgcagagcaa ccacccggac gatatctttc tcttcccaaa acttcttcaa aaaatggcag
acctccggca gctggtgacg gagcatgcgc agctggtgca gatcatcaag aagacggagt
cggatgctgc gctgcacccg ctactgcagg agatctacag ggacatgtac tgagttcctt
cagatcagcc acaccttttc caggagttct gaagctgaca gcactacaaa ggagacgggg
gagcagcacg attttgcaca aatatccacc actttaacct tagagcttgg acagtctgag
ctgtaggtaa ccggcatatt attccatatc tttgttttaa ccagtacttc taagagcata
gaactcaaat gctgggggta ggtggctaat ctcaggactg ggaagattac ggcgaattat
gctcaatggt ctgattttaa ctcacccgat gttaatcaat gcacattgct ttagatcaca
ttcgtgattt accatttaat taactggtaa cctcaaaatt cgtggcctgt cttcccattc
accccgcttt tgactattgt gctcctttat aattctgaaa actaatcagc actttttaac
aatgtttata atcctataag tctagatgta tccaaaggtg aagtatgtaa aaagcagcaa
aatatttatt tcaaagactt cacttctgtt tcctgaatct aaagaaagac aacatgctgc
tttttaatca taggatggag aattttaaag aactgtttgg gccaggcaca gtcgctcata
cttgtaatcc cagcactttg ggaggccgag gcgggtggat cacaaggtca gcagatcgag
accatcctgg ccaacatggt gaaaccctgt ctctactaaa aatacaaaaa ttagccgggt
gtggtggcac atgcctgtaa tcccagctac tcgggaagct gaggcaggag aattgcttga
accagggagt tggaggttgc agtgagctaa gactgcacca ctgcactcca gcctggtgac
agaacgagac tctgtcttaa aaacaaacaa acaaaaaaaa aatctgttag ataagctatc
aaaatgcagc tgttgttttg tttttggctc actgttttcg tggttgtaac taatatgtgg
aaaggcccat ttccaggttt gcgtagaaga gcccagaaaa cagagtctca agacccccgc
tctggactgt cataagctag cacccgtggt aagcgggacg agacaagctc ccgaagcccg
ccagcttcct gctccactca gctccgtcca gtcaacctga acccacccag tccagctgtc
tgtgggaatg gtggtgttct tagggacaga ctgacacctt acttgtcagt gttcctccgg
gccccatttg gcagctcccg tatcttttgt tatgttgctt ttaaagatat gatgttttat
tgttttaact cttggtgaca gtagatgctc tctggagcgc agacgaggca catgtgtctt
catagcctgg gctgggtggg agccagtcac cctgcggatc gagagagggg gtagagtctt
cttcaaatgg cagttttact tcaaatggca gatttcacaa gagttggtta ttttttacaa
tggtttaggt tgttaagtct cctttgtatg taaggtagtt ttttcaacat ctaaaatttt
tgttttagcc ttcaaaacca acttaccaac ctcagtccag ctgggaaggc agcgttgatt
atggtagttt gtcaagaata tatggacctg gaaacacttt ctctctctgt ccacctggta
gataaattgt cctgttgaga atttttagat ctggactgga actgccagga ccaccgcctc
cagggagtcg ctgggcacct ggaggtatcg tcgatgcctc tcccccatct ttagaaaatt
tggctcttct gaggtcatta ttattttaag aatgattagg attgataagg gtcccatgac
cagcattatg aaaatgcgag agtgggaagg acacagtgtg agacttccac tagaaaaaag
tgaaagttag ggttaggaca tcctttttta aaaattacaa atttagtccg ttttggtttt
tgtaatcagg ctaggcacag tggctcacac atggaatccc agcactttgg gaggccgagg
tgggaggatc acttgagccc aggagttcga gaccagccta ggcaacatag caagaccctg
tctgtacaca aaatttaaaa attagttcat cggggtggca cacatcagta gtcccagcta
ctctgcaggc tgaggtggga ggattgcttg aacccaggag gtcgaggctg cagtgagctg
tgatctcacc actgcattcc agcctgggtg acagagttag attccaccct ctcccacccc
ggcaaaaaaa aaaaaaaaag atgcaatcaa aggggctgtt ggccagcaat ggcagcagca
gcggcgggca gtctgcccaa gtgtcttagg aaccaaaagc aaataaaagt gtttccatat
atgccaccag ccaagtggcc atcctaattc agaaagaagc tagcctttga gtgtctgtca
tggtgcatcc gtttcagtat tatttcctaa aatgagaagc ccctgtgtca acaagatcca
ggggctggag cccaatgcca agcctgtgtt gtccccagcg accctgcagc tgctcgctct
gatgtaccct gtgccattca aggagatgtg gtccaggaaa gtgagcctca tggttttcag
agaagtcatt gttctgttta cattttcata aaacctgttt aaaatagctc cccgtctcag
gctttcagca gtaacagtga gctgactggc aagttcgatg ttagctcccg ggacactcag
cagcgatggt gagcattttg gtttccttaa ggcccagcaa gacttccagg gacatctctg
gtgaagccag aatggagaca cccgtgacct caggctgaaa gtcactcgac attggtctct
tgtgttgata gggaaggaaa tcaggcattc ctatttcttt aaataacaaa accactaatt
gccactcaat gctggaatat tttgggtcac ctaatcatag atttctcagg gcatcaatac
tcaaatatag gctgattatg ccccagttca aatgggaact attaacagag tgcatttctt
gcttgctggg tttcaacaga catcagccaa aagaacaaaa gagatgtcag gacagattcc
aggagtgtcg gagcacatgt gtggcacccg ctccctctgg cagcgaatgt aggaagtcgc
caaatttacc cactcttcaa caagtcattg tttaaacacg gtttttcatt ttctcaactt
ttaatagcaa aaagtgccaa agtcctcaga gacctaacag ccttggtcta ccgtgctgac
cagggtgaag gcacggcgag ggactcctcc cagacgtgcc tcttgtgtgc cagctggctg
tggctcggga gcagacgcag gcctctccat tgtccagggg agcctggcgg cgcatccctc
ctctcccacc tcctggcact tccagctggg tgtcccacat gttggattcc gtccccacca
cacttccaga gaccggagaa ctgtgcaggg cctaaggccg tttggatgaa ttgtcaaaac
aagatgcttc cagttacagc ggcaggagcg ggactgggag cacgggctga cggctgctgg
tgcctttctt cccacctcgc ttgcctgttt ccgcttgacc cttcctccag ctccgatgag
aagagtataa agcatcttcc taacgggtgt gtttgctata cgaacataat ggacgtgaag
tggggcagaa acccagaact cagcattcaa ggatgcccag gagagctgtc cctgttttaa
agagctgtgt tttgttttgt ttcgcattta gagagcagac aaggcaccct tctgctgcgc
tgatacgttt cttacactgg gccattttag acccccaggg aaacagcctt cctggagcgt
tgtctggagg ttccagggac agggcagcct cccagagccg agcaagagct caaggtacaa
atgagagatt tgctataccg tgagaagtca acaacttagc caccacttcc ccgcaatgga
ccatgtaaca aatacctcag caggccctgc aaaaggccat gctagagctg aggcgcacag
cctgtggcct ctgtagttag ggcaggtggg atggagactc cttgagtgca cacacctgag
cctgcccaca cacaggggag cagcatctcg tatgacgtct ggaaggaact tcggttgtgt
aaagggagcc ttgaagatac gtgcaaaagg tgctacccca atttggtgaa actgacattg
ggcacgtctt gggcttagga gaagcggccg atggtcccgg cctgcagtga caaacccccc
tccccgcacc gcccccagca ccccctctcc tcttcacctc ttcctgctgg ccacgaggaa
gccacttcct cagagagacc ctaccagatg cggatggaaa cagatgcacc aaagcaagcc
ctgatgaaac cgcgacttcc taaggtctgt ctcctctgaa cttgcacctg ggcctctctg
tgtttggttc caagcacttc ccacctcaaa ctcccatttt caaaccactg tatctctgcg
cacatctgct acttaccagc cgcatacatg atggagggtt ttttggtcct gatccagtgg
ccacacctgt ctttgaaatg tctcactgaa ctccagtttt aaaatagatt cattgcttca
acacagcaag cccaatgcac ccagctaaga ctggcttgac cgacagcctg gcctttggtg
gggggcttcc tggggcctgg ggaaagctgg ccaccttcaa cagctggtac ctcttcaaca
gtgtggcctt tcaaaatgca gatgccacca ggagaacatg cccacagctc accacctatg
gatgccatgg ctctgggcag ctttcaaagc aggttcctgt ggtctcctca gctgtttgag
ggggtaacag caaatcagcc tccattttaa aatgaaaaca ccagcctcca gatgtagggc
ctgctgggtg ttgctagccg ctggtcccca ggcacggtgc actttctcca cctcctgcag
cctccctgtt gtttctagac tcttgcacct ggtgagtgca aggataggtg acccaggggc
ctgcagcctt gtcctcagct cccatctcct ggactgccag cctcaccctc tgcagttagc
atggttggcc tgatgcaggg atcccgaggg attacttttt agaccttctt tcacattcag
aaaagtagta tagattcagg agaggcaaga aaattatgct gtccatagaa gtcacccatg
aagactgatg ccaccacctg aaggctcatg attgttaaaa atgtccacgg gaacctctcg
tccacaggag gtttgtctca acacttccca tttttacggc attggcattg ccaagcatgg
ggaagtatct gctcttctca tgttaaaagt ggcccagctt ttcttaactc agtccaagct
gacttgttta gctgcactgg aatttcttac caaccaaata tttgcatcga gcaaaggggg
ctgtgtgcac ctccctaatg gcagcgatga tggctgctgt cattcaagcc catcttcaga
cgtcacagtc tggaagtgaa atgtccacaa acatctgtgg cagaaaaggc tatacggacc
acccagttgt gctgcagctt tacagagcaa ggaagggttg tggcaaataa atgattaacc
tgcctcgact gtgctgaggg caacaaaggc catctcacca aaggattatt cgatgccatt
aaatcatccc gtgaccttcc tgcttccgag tccatggcct ttgcccaggg catgtactcc
cctgagaggc cttctgccta gaaagatcta tgactgggtt ccaaagttga ggcctaggtt
tttgctggga tttagatatt ttcaggcacc attttgacag cattcaggaa aacggttatt
gaccccatag actagggtaa gaataaaggc aataaatttg gtctgactca gaatatagga
gatccatata tttctctgga aaccacagtg tacactaaaa tgtgaaattg aaggttttgt
taaaaagaaa aagataatga gcttcatgct ttgtttaatt acataatgat ttccattacg
ctatttctgt gaaatgcagc aggttcttaa acgttatttc agtggcatgg gctggaagct
tatcacaaaa agccatgtgt gtggccttat cagaacagaa agagacaggc tggtgcccaa
ggctgctgcc tgctccacct tttgccagct ctggacatct gaggacgtcc cggcagatct
ggaatggggc cctcaactga ccatttgctt ctcagaattt cagtttgaga catgagaggt
ataatcagtt acttttctcc ccccagagaa acccttttgt gaggggagag gagctatggt
atgtggttca gctgaaacac atacaactgc atccttttgg agtcctttgc caacaaaaac
agaccaacag accagatggt gtccatgttc aatatcatgt cttgatggac gcagctgatg
acctcaaata cttgagtggt ctcatggctg ttagatggat tatttgaaaa aaaaaaaaaa
aaaagagaga aaaaataatt gatttttaca tcagagatag caaactaaga cctggggagg
ggggtcagct tttattttat tttatttttt ttaagtttgc tagttgggtc aaatgtgagg
aggagggagt ctacctgcca cctcttctct tgcccctctt ctgcccacac atccagcatc
caaaatccat tcatttaatg aattgataaa gtgccgtgca aactggtgca caaacaggcc
cccagtccac gcagcctggc tcctaggaaa agtggtgacc gggcgtgggg gggcatgccg
cagccctggg acacagtcgg gcaccttccc cggaccccca ggccttggct gtgcctcaag
tcagagaggg tcagccttca ggccccggag acgagtgact ggccgatcat ttcacaataa
aatcactcac ttttggcaac ttcacttttt ttaaggcaca gtcagttcct tttctcatgt
acctcacaaa agatgaagac catgtagtac tctttttggt aaagttacag tgttcatgtt
aaatatcact tttttctaca ttgtgtggta aaaagaacta cgttaatagc tatatcttaa
atactgtgat ttgacttttt gaaaaatatc ctaatacaaa tattttacta acttacaatc
actcatttaa taagaaacat ttggattctt ttgaaatcag tgttaattga ctcatattct
taaaagcctg gctcttgacc ctattggaaa cacaaaggaa gctgaaatca aacatctaaa
atacactgcg tacacgtgtg cgtgcacaca cacacacaca cacacacaca cacagctctt
catttctcct gagccatgca gaatttactt tcaatgtgga aatctgttcc ctttaccaca
ctgtatatgc acagagcaca agagaggcta tctctagtca cttccaccag cgaggcctta
gactccgtat tagaggccac cgatttcata caacagtgtt tcgctaaaga cccttcacta
ttcttgttta gtaaatagct gtctgctctt cagggaactg ttacctatgg gttattacca
aagaacgctg gcaattggaa atgtcctgat ggaaattctt tgcacgtgcc ggttctctgg
catcctccag gtggcccaac ccaaagcaga aagcagaaac cacagacccc gtgagtctcc
ccataccttg tttccaataa cttggcaaaa cttcttggtg catattggtt acaccctctg
ggattcataa tgccattagg ctaaaaccct aagagagagg gttgacagaa acacacgcga
gaatgaggca gatcccagag caaggactgg gcccagactc tccacatgtg ctctactagt
gagtgcctta tactctcagt attttggggc ttacagcttc ttatttgtgc taaaaaggtg
cagttccaaa gtaggaactg ccacacaggc cccagcatcc tctctccaac ttcatacctc
tctcctggtg gggggagcgg gcatccagga cctccggaat caaggatgtg cagagaagag
cgaaagtaat ttttctagtc acatgaactg attggttcca ggcaattaga aaatggctat
aaaataacct taattttaaa aaaaaatctt gggtcttcgt tttcctatta ggagactgaa
ctgaccacat gtattgattt atatcctgaa tatatgggaa cttctgtgtt tgggatgtcc
tactgtaaga ctgatgaatg tacagagtta atttcagggt acagttttgc cttaatggtt
ttaaaaaata aactattttt taaaatttt
PPARA registration number NP_005027 (SEQ ID NO:__)
MVDTESPLCP LSPLEAGDLE SPLSEEFLQE MGNIQEISQS IGEDSSGSFG FTEYQYLGSC
PGSDGSVITD TLSPASSPSS VTYPVVPGSV DESPSGALNI ECRICGDKAS GYHYGVHACE
GCKGFFRRTI RLKLVYDKCD RSCKIQKKNR NKCQYCRFHK CLSVGMSHNA IRFGRMPRSE
KAKLKAEILT CEHDIEDSET ADLKSLAKR IYEAYLKNFNM NKVKARVILS GKASNNPPFV
IHDMETLCMA EKTLVAKLVA NGIQNKEAEV RIFHCCQCTS VETVTELTEF AKAIPGFANL
DLNDQVTLLK YGVYEAIFAM LSSVMNKDGM LVAYGNGFIT REFLKSLRKP FCDIMEPKFD
FAMKFNALEL DDSDISLFVA AIICCGDRPG LLNVGHIEKM QEGIVHVLRL HLQSNHPDDI
flfpkllqkm adlrqlvteh aqlvqiikkt esdaalhpll qeiyrdmy
PPARG registration number NM_015869 (SEQ ID NO:__)
actgatgtct tgactcatgg gtgtattcac aaattctgtt acttcaagtc tttttctttt
aacggattga tcttttgcta gatagagaca aaatatcagt gtgaattaca gcaaacccct
attccatgct gttatgggtg aaactctggg agattctcct attgacccag aaagcgattc
cttcactgat acactgtctg caaacatatc acaagaaatg accatggttg acacagagat
gccattctgg cccaccaact ttgggatcag ctccgtggat ctctccgtaa tggaagacca
ctcccactcc tttgatatca agcccttcac tactgttgac ttctccagca tttctactcc
acattacgaa gacattccat tcacaagaac agatccagtg gttgcagatt acaagtatga
cctgaaactt caagagtacc aaagtgcaat caaagtggag cctgcatctc caccttatta
ttctgagaag actcagctct acaataagcc tcatgaagag ccttccaact ccctcatggc
aattgaatgt cgtgtctgtg gagataaagc ttctggattt cactatggag ttcatgcttg
tgaaggatgc aagggtttct tccggagaac aatcagattg aagcttatct atgacagatg
tgatcttaac tgtcggatcc acaaaaaaag tagaaataaa tgtcagtact gtcggtttca
gaaatgcctt gcagtgggga tgtctcataa tgccatcagg tttgggcgga tgccacaggc
cgagaaggag aagctgttgg cggagatctc cagtgatatc gaccagctga atccagagtc
cgctgacctc cgggccctgg caaaacattt gtatgactca tacataaagt ccttcccgct
gaccaaagca aaggcgaggg cgatcttgac aggaaagaca acagacaaat caccattcgt
tatctatgac atgaattcct taatgatggg agaagataaa atcaagttca aacacatcac
ccccctgcag gagcagagca aagaggtggc catccgcatc tttcagggct gccagtttcg
ctccgtggag gctgtgcagg agatcacaga gtatgccaaa agcattcctg gttttgtaaa
tcttgacttg aacgaccaag taactctcct caaatatgga gtccacgaga tcatttacac
aatgctggcc tccttgatga ataaagatgg ggttctcata tccgagggcc aaggcttcat
gacaagggag tttctaaaga gcctgcgaaa gccttttggt gactttatgg agcccaagtt
tgagtttgct gtgaagttca atgcactgga attagatgac agcgacttgg caatatttat
tgctgtcatt attctcagtg gagaccgccc aggtttgctg aatgtgaagc ccattgaaga
cattcaagac aacctgctac aagccctgga gctccagctg aagctgaacc accctgagtc
ctcacagctg tttgccaagc tgctccagaa aatgacagac ctcagacaga ttgtcacgga
acacgtgcag ctactgcagg tgatcaagaa gacggagaca gacatgagtc ttcacccgct
cctgcaggag atctacaagg acttgtacta gcagagagtc ctgagccact gccaacattt
cccttcttcc agttgcacta ttctgaggga aaatctgaca cctaagaaat ttactgtgaa
aaagcatttt aaaaagaaaa ggttttagaa tatgatctat tttatgcata ttgtttataa
agacacattt acaatttact tttaatatta aaaattacca tattatgaaa aaaaaaaaaa
aaa
PPARG registration number NP_056953 (SEQ ID NO:__)
MGETLGDSPI DPESDSFTDT LSANISQEMT MVDTEMPFWP TNFGISSVDL SVMEDHSHSF
DIKPFTTVDF SSISTPHYED IPFTRTDPVV ADYKYDLKLQ EYQSAIKVEP ASPPYYSEKT
QLYNKPHEEP SNSLMAIECR VCGDKASGFH YGVHACEGCK GFFRRTIRLK LIYDRCDLNC
RIHKKSRNKC QYCRFQKCLA VGMSHNAIRF GRMPQAEKEK LLAEISSDID QLNPESADLR
ALAKHLYDSY IKSFPLTKAK ARAILTGKTT DKSPFVIYDM NSLMMGEDKI KFKHITPLQE
QSKEVAIRIF QGCQFRSVEA VQEITEYAKS IPGFVNLDLN DQVTLLKYGV HEIIYTMLAS
LMNKDGVLIS EGQGFMTREF LKSLRKPFGD FMEPKFEFAV KFNALELDDS DLAIFIAVII
LSGDRPGLLN VKPIEDIQDN LLQALELQLK LNHPESSQLF AKLLQKMTDL RQIVTEHVQL
LQVIKKTETD MSLHPLLQEI YKDLY
PPARD registration number NM_006238 (SEQ ID NO:__)
gcggagcgtg tgacgctgcg gccgccgcgg acctggggat taatgggaaa agttttggca
ggagcgggag aattctgcgg agcctgcggg acggcggcgg tggcgccgta ggcagccggg
acagtgttgt acagtgtttt gggcatgcac gtgatactca cacagtggct tctgctcacc
aacagatgaa gacagatgca ccaacgaggc tgatgggaac caccctgtag aggtccatct
gcgttcagac ccagacgatg ccagagctat gactgggcct gcaggtgtgg cgccgagggg
agatcagcca tggagcagcc acaggaggaa gcccctgagg tccgggaaga ggaggagaaa
gaggaagtgg cagaggcaga aggagcccca gagctcaatg ggggaccaca gcatgcactt
ccttccagca gctacacaga cctctcccgg agctcctcgc caccctcact gctggaccaa
ctgcagatgg gctgtgacgg ggcctcatgc ggcagcctca acatggagtg ccgggtgtgc
ggggacaagg catcgggctt ccactacggt gttcatgcat gtgaggggtg caagggcttc
ttccgtcgta cgatccgcat gaagctggag tacgagaagt gtgagcgcag ctgcaagatt
cagaagaaga accgcaacaa gtgccagtac tgccgcttcc agaagtgcct ggcactgggc
atgtcacaca acgctatccg ttttggtcgg atgccggagg ctgagaagag gaagctggtg
gcagggctga ctgcaaacga ggggagccag tacaacccac aggtggccga cctgaaggcc
ttctccaagc acatctacaa tgcctacctg aaaaacttca acatgaccaa aaagaaggcc
cgcagcatcc tcaccggcaa agccagccac acggcgccct ttgtgatcca cgacatcgag
acattgtggc aggcagagaa ggggctggtg tggaagcagt tggtgaatgg cctgcctccc
tacaaggaga tcagcgtgca cgtcttctac cgctgccagt gcaccacagt ggagaccgtg
cgggagctca ctgagttcgc caagagcatc cccagcttca gcagcctctt cctcaacgac
caggttaccc ttctcaagta tggcgtgcac gaggccatct tcgccatgct ggcctctatc
gtcaacaagg acgggctgct ggtagccaac ggcagtggct ttgtcacccg tgagttcctg
cgcagcctcc gcaaaccctt cagtgatatc attgagccta agtttgaatt tgctgtcaag
ttcaacgccc tggaacttga tgacagtgac ctggccctat tcattgcggc catcattctg
tgtggagacc ggccaggcct catgaacgtt ccacgggtgg aggctatcca ggacaccatc
ctgcgtgccc tcgaattcca cctgcaggcc aaccaccctg atgcccagta cctcttcccc
aagctgctgc agaagatggc tgacctgcgg caactggtca ccgagcacgc ccagatgatg
cagcggatca agaagaccga aaccgagacc tcgctgcacc ctctgctcca ggagatctac
aaggacatgt actaacggcg gcacccaggc ctccctgcag actccaatgg ggccagcact
ggaggggccc acccacatga cttttccatt gaccagccct tgagcacccg gcctggagca
gcagagtccc acgatcgccc tcagacacat gacacccacg gcctctggct ccctgtgccc
tctctcccgc ttcctccagc cagctctctt cctgtctttg ttgtctccct ctttctcagt
tcctctttct tttctaattc ctgttgctct gtttcttcct ttctgtaggt ttctctcttc
ccttctccct tgccctccct ttctctctcc accccccacg tctgtcctcc tttcttattc
tgtgagatgt tttgtattat ttcaccagca gcatagaaca ggacctctgc ttttgcacac
cttttcccca ggagcagaag agagtggggc ctgccctctg ccccatcatt gcacctgcag
gcttaggtcc tcacttctgt ctcctgtctt cagagcaaaa gacttgagcc atccaaagaa
acactaagct ctctgggcct gggttccagg gaaggctaag catggcctgg actgactgca
gccccctata gtcatggggt ccctgctgca aaggacagtg ggcaggaggc cccaggctga
gagccagatg cctccccaag actgtcattg cccctccgat gctgaggcca cccactgacc
caactgatcc tgctccagca gcacacctca gccccactga cacccagtgt ccttccatct
tcacactggt ttgccaggcc aatgttgctg atggccccct gcactggccg ctggacggca
ctctcccagc ttggaagtag gcagggttcc ctccaggtgg gcccccacct cactgaagag
gagcaagtct caagagaagg aggggggatt ggtggttgga ggaagcagca cacccaattc
tgcccctagg actcggggtc tgagtcctgg ggtcaggcca gggagagctc ggggcaggcc
ttccgccagc actcccactg cccccctgcc cagtagcagc cgcccacatt gtgtcagcat
ccagggccag ggcctggcct cacatccccc tgctcctttc tctagctggc tccacgggag
ttcaggcccc actccccctg aagctgcccc tccagcacac acacataagc actgaaatca
ctttacctgc aggctccatg cacctccctt ccctccctga ggcaggtgag aacccagaga
gaggggcctg caggtgagca ggcagggctg ggccaggtct ccggggaggc aggggtcctg
caggtcctgg tgggtcagcc cagcacctgc tcccagtggg agcttcccgg gataaactga
gcctgttcat tctgatgtcc atttgtccca atagctctac tgccctcccc ttccccttta
ctcagcccag ctggccacct agaagtctcc ctgcacagcc tctagtgtcc ggggaccttg
tgggaccagt cccacaccgc tggtccctgc cctcccctgc tcccaggttg aggtgcgctc
acctcagagc agggccaaag cacagctggg catgccatgt ctgagcggcg cagagccctc
caggcctgca ggggcaaggg gctggctgga gtctcagagc acagaggtag gagaactggg
gttcaagccc aggcttcctg ggtcctgcct ggtcctccct cccaaggagc cattctgtgt
gtgactctgg gtggaagtgc ccagcccctg cccctacggg cgctgcagcc tcccttccat
gccccaggat cactctctgc tggcaggatt cttcccgctc cccacctacc cagctgatgg
gggttggggt gcttcctttc aggccaaggc tatgaaggga cagctgctgg gacccacctc
cccctccccg gccacatgcc gcgtccctgc cccgacccgg gtctggtgct gaggatacag
ctcttctcag tgtctgaaca atctccaaaa ttgaaatgta tatttttgct aggagcccca
gcttcctgtg tttttaatat aaatagtgta cacagactga cgaaacttta aataaatggg
aattaaatat ttaa
PPARD registration number NP_006229 (SEQ ID NO:__)
meqpqeeape vreeeekeev aeaegapeln ggpqhalpss sytdlsrsss ppslldqlqm
gcdgascgsl nmecrvcgdk asgfhygvha cegckgffrr tirmkleyek cersckiqkk
nrnkcqycrf qkclalgmsh nairfgrmpe aekrklvagl tanegsqynp qvadlkafsk
hiynaylknf nmtkkkarsi ltgkashtap fvihdietlw qaekglvwkq lvnglppyke
isvhvfyrcq cttvetvrel tefaksipsf sslflndqvt llkygvheai famlasivnk
dgllvangsg fvtreflrsl rkpfsdiiep kfefavkfna lelddsdlal fiaaiilcgd
rpglmnvprv eaiqdtilra lefhlqanhp daqylfpkll qkmadlrqlv tehaqmmqri
kktetetslh pllqeiykdm y
Claims (76)
1. compound, it has chemical structure:
Its all salt, prodrug, tautomer and isomers,
Wherein:
X is selected from-C (O) OR
16,-C (O) NR
17R
18With the carboxylic acid isostere;
W be selected from covalent linkage ,-NR
51(CR
4R
5)
1-2-,-O-(CR
4R
5)
1-2-,-S-(CR
4R
5)
1-2-,-(CR
4R
5)
1-3-and-CR
6=CR
7-;
R
1And R
2Be independently selected from hydrogen, halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl ,-SR
9With-OR
9, wherein said low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
3Be selected from-[(CR
4R
5)
m-(Y)
p]
r-R
10With-[(CR
4RV (Y)
P]
1-Ar
1-M-Ar
2
L is selected from-O-,-S-,-NR
52-,-C (Z)-,-S (O)
n-,-C (Z) NR
52-,-NR
52C (Z)-,-NR
52S (O)
2-,-S (O)
2NR
52-,-NR
52C (Z) NR
52-and-NR
52S (O)
2NR
52-;
Y is selected from-O-,-S-,-NR
53-,-C (Z)-,-S (O)
n-,-C (Z) NR
54-,-NR
54C (Z)-,-NR
54S (O)
2-,-S (O)
2NR
54-,-NR
54C (Z) NR
54-and-NR
54S (O)
2NR
54-;
Ar
1Be selected from optional arylidene that replaces and the optional heteroarylidene that replaces;
M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-,-NR
53-,-C (Z)-and-S (O)
n-;
Ar
2Be selected from optional aryl that replaces and the optional heteroaryl that replaces;
In all cases, R
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
A R
4Or R
5Be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R on the identical or different carbon
4And R
5In any two in conjunction with forming 3-7 unit's monocyclic cycloalkyls or 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl are randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
6And R
7Be independently selected from hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In one be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and R
6And R
7In another is hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In conjunction with forming 5-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
9Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
9Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-OR
9O or-SR
9S go up, C
3-6Yet alkynyl--condition is to work as R
9Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-OR
9O or-SR
9S go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups--described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace--yet condition is, with-OR
9O or-SR
9S bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein alkyl, C
3-6Alkenyl and C
3-6The cycloalkyl of alkynyl, Heterocyclylalkyl, aryl and heteroaryl substituting group randomly replace with one or more substituting groups--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
10Be selected from the optional cycloalkyl that replaces, the optional Heterocyclylalkyl that replaces, the optional aryl that replaces and the optional heteroaryl that replaces;
In all cases, R
51And R
52Be independently selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein low-carbon alkyl is randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is, with-NR
51-or-NR
52-N bonded alkyl carbon on any substituting group be fluorine, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
53Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
53Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-NR
53-N go up, C
3-6Yet alkynyl--condition is to work as R
53Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-NR
53-N go up, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-C (Z) NR
11R
12,-S (O)
2NR
11R
12,-S (O)
2R
13,-C (Z) R
13With-C (Z) OR
15, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
53-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl further randomly with one or more substituting groups replacements and described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
54Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
54Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-NR
54-N go up, C
3-6Yet alkynyl--condition is to work as R
54Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-NR
54-N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
54-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl further randomly with one or more substituting groups replacements and described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
11And R
12Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
11And/or R
12Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, C
3-6Alkynyl--right condition is to work as R
11And/or R
12Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements--described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
11And R
12Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
In all cases, R
13Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
13Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, C
3-6Yet alkynyl--condition is to work as R
13Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl further randomly with one or more substituting groups replacements and described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
15Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
15Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to (O) R
15O go up, C
3-6Yet alkynyl--condition is to work as R
15Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to (O) R
15O go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any OR
15O bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements--described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
R
16Be selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly with one or more substituting groups replacements--described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
16When being low-carbon alkyl, with OR
16O bonded alkyl carbon on any substituting group be fluorine;
R
17And R
18Be independently selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly with one or more substituting groups replacements--described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
17And/or R
18When being low-carbon alkyl, with NR
17R
18N bonded alkyl carbon on any substituting group be fluorine; Or
R
17And R
18Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
19And R
20Be independently selected from hydrogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein any cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl further randomly with one or more substituting groups replacements and described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
19And R
20In conjunction with forming 3-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein monocyclic cycloalkyl or monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
21, R
22And R
23Be independently selected from hydrogen or low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group is selected from low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace, yet condition is and OR
21, SR
21, NR
21, NR
22Or NR
23In any one O, S or any substituting group on the low-carbon alkyl carbon that combines of N be fluorine, yet and further condition be and S, S (O), S (O)
2Or C (Z) bonded R
21Not hydrogen; Or
R
22And R
23Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
Z is O or S;
M is 1,2,3 or 4;
N is 1 or 2;
P is 0 or 1, yet, condition be when p is 1, m be 1 and L be-O-,-S-,-NR
52-,-C (Z) NR
52-,-S (O)
2NR
52-,-NR
52C (Z) NR
52-or-NR
52S (O)
2NR
52-time, so Y be not-O-,-S-,-NR
53-,-NR
54C (Z)-,-NR
54S (O)
2-,-NR
54C (Z) NR
54-or-NR
54S (O)
2NR
54-; With
R is 0 or 1.
2. compound according to claim 1, wherein L is-S (O)
2-and R
3Be R
10, R wherein
10It is the optional phenyl that replaces.
3. compound according to claim 2, wherein R
10Be phenyl, described phenyl replaces with one or more substituting groups are optional, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkoxy that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy and the fluorine that replace.
4. compound according to claim 1, wherein L is-O-and R
3Be R
10, R wherein
10It is the optional phenyl that replaces.
5. compound according to claim 4, wherein R
10Be phenyl, described phenyl replaces with one or more substituting groups are optional, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkoxy that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy and the fluorine that replace.
6. according to each described compound, wherein R among the claim 1-5
1And R
2In at least one is-OR
9
7. compound according to claim 6, wherein R
1And R
2In one be-OR
9And R
1And R
2In another is hydrogen or halogen.
8. compound according to claim 7, wherein R
2Be-OR
9And R
1Be hydrogen.
9. compound according to claim 8, wherein R
9It is low-carbon alkyl, described low-carbon alkyl replaces with one or more substituting groups are optional, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.
10. according to each described compound among the claim 7-9, wherein X is-C (O) OR
16
11. compound according to claim 10, wherein R
16Be H.
12. compound according to claim 11, wherein W is-(CR
4R
5)
1-3-.
13. compound according to claim 12, wherein W is-CH
2-or-CH
2CH
2-.
14. compound according to claim 13, wherein R
9Be low-carbon alkyl, described low-carbon alkyl replaces with one or more substituting groups are optional, described substituting group be selected from fluorine ,-OH, low-carbon alkoxy and low-carbon alkyl sulfo-.
15. compound according to claim 1, it has chemical structure:
Its all salt, prodrug, tautomer and isomers,
Wherein:
X is selected from-C (O) OR
16,-C (O) NR
17R
18With the carboxylic acid isostere;
W be selected from covalent linkage ,-NR
51(CR
4R
5)
1-2-,-O-(CR
4R
5)
1-2-,-S-(CR
4R
5)
1-2-,-(CR
4R
5)
1-3-and-CR
6=CR
7-;
Y is selected from-O-,-S-,-NR
53-,-C (Z)-,-S (O)
n-,-C (Z) NR
54-,-NR
54C (Z)-,-NR
54S (O)
2-,-S (O)
2NR
54-,-NR
54C (Z) NR
54-and-NR
54S (O)
2NR
54-;
M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-,-NR
53-,-C (Z)-and-S (O)
n-;
Ar
1aBe selected from arylidene and heteroarylidene;
Ar
2aBe selected from aryl and heteroaryl;
R
1And R
2Be independently selected from hydrogen, halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl ,-SR
9With-OR
9, wherein said low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl are randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
A R
4Or R
5Be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R on the identical or different carbon
4And R
5In any two in conjunction with forming 3-7 unit's monocyclic cycloalkyls or 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl are randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
6And R
7Be independently selected from hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In one be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and R
6And R
7In another is hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly with one or more substituting groups replacements--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In conjunction with forming 5-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
9Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
9Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-OR
9O or-SR
9S go up, C
3-6Yet alkynyl--condition is to work as R
9Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-OR
9O or-SR
9S go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups--described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace--yet condition is, with-OR
9O or-SR
9S bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein alkyl, C
3-6Alkenyl and C
3-6The cycloalkyl of alkynyl, Heterocyclylalkyl, aryl and heteroaryl substituting group randomly replace with one or more substituting groups--described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
51Be selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein low-carbon alkyl is randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is, with-NR
51-N bonded alkyl carbon on any substituting group be fluorine, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups and described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
53Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
53Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-NR
53-N go up, C
3-6Yet alkynyl--condition is to work as R
53Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-NR
53-N go up, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-C (Z) NR
11R
12,-S (O)
2NR
11R
12,-S (O)
2R
13,-C (Z) R
13With-C (Z) OR
15, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
53-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl further randomly with one or more substituting groups replacements and described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
54Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
54Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-NR
54-N go up, C
3-6Yet alkynyl--condition is to work as R
54Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-NR
54-N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
54-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl further randomly with one or more substituting groups replacements and described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
11And R
12Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
11And/or R
12Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, C
3-6Yet alkynyl--condition is to work as R
11And/or R
12Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl further randomly with one or more substituting groups replacements and described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
11And R
12Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
In all cases, R
13Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
13Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, C
3-6Yet alkynyl--condition is to work as R
13Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
15Be independently selected from hydrogen, low-carbon alkyl, C
3-6Alkenyl--yet right condition is to work as R
15Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to (O) R
15O go up, C
3-6Yet alkynyl--condition is to work as R
15Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to (O) R
15O go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any OR
15O bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
R
16Be selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
16When being low-carbon alkyl, with OR
16O bonded alkyl carbon on any substituting group be fluorine;
R
17And R
18Be independently selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
17And/or R
18When being low-carbon alkyl, with NR
17R
18N bonded alkyl carbon on any substituting group be fluorine; Or
R
17And R
18Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
19And R
20Be independently selected from hydrogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein any cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
19And R
20In conjunction with forming 3-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein monocyclic cycloalkyl or monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
21, R
22And R
23Be independently selected from hydrogen or low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group is selected from low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace, yet condition is and OR
21, SR
21, NR
21, NR
22Or NR
23In any one O, S or any substituting group on the low-carbon alkyl carbon that combines of N be fluorine, yet and further condition be and S, S (O), S (O)
2Or C (Z) bonded R
21Not hydrogen; Or
R
22And R
23Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
In all cases, R
24Be independently selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl ,-NO
2,-CN-OR
26,-SR
26,-OC (O) R
26,-OC (S) R
26,-C (O) R
26,-C (S) R
26,-C (O) OR
26,-C (S) OR
26,-S (O) R
26,-S (O)
2R
26,-C (O) NR
27R
28,-C (S) NR
27R
28,-S (O)
2NR
27R
28,-C (NH) NR
27R
28,-NR
26C (O) R
26,-NR
26C (S) R
26,-NR
26S (O)
2R
26, NR
26C (O) NR
27R
28, NR
26C (S) NR
27R
28,-NR
26S (O)
2NR
27R
28With-NR
27R
28, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
25Be independently selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NO
2,-CN ,-OR
29,-SR
29,-OC (O) R
29,-OC (S) R
29,-C (O) R
29,-C (S) R
29,-C (O) OR
29,-C (S) OR
29,-S (O) R
29,-S (O)
2R
29,-C (O) NR
29R
29,-C (S) NR
29R
29,-S (O)
2NR
29R
29,-C (NH) NR
30R
31,-NR
29C (O) R
29,-NR
29C (S) R
29,-NR
29S (O)
2R
29,-NR
29C (O) NR
29R
29,-NR
29C (S) NR
29R
29,-NR
29S (O)
2NR
29R
29With-NR
29R
29, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
32, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38,-R
35With-R
32, and wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
36,-SR
36,-NR
37R
38,-R
35,-R
33With-R
34
In all cases, R
26, R
27And R
28Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is that it does not have olefinic carbon to be attached to R
24O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, C
3-6Yet alkynyl--condition is that it does not have alkynes carbon to be attached to R
24O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35Yet further condition is and S, C (O), C (S), S (O) or S (O)
2Bonded R
26Not hydrogen, or
R
27And R
28With the nitrogen that is connected them in conjunction with forming cycloalkyl amino;
In all cases, R
29, R
30And R
31Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is that it does not have olefinic carbon to be attached to R
25O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, C
3-6Yet alkynyl--condition is that it does not have alkynes carbon to be attached to R
25O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, or
R
30And R
31With the nitrogen that is connected them in conjunction with forming 5-7 unit's monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle, wherein low-carbon alkyl is randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
32, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38,-R
35With-R
32, and wherein cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, 5-7 unit's monocyclic heterocycles alkyl and 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OH ,-NH
2,-OR
36,-SR
36,-NHR
36,-NR
37R
38,-R
33,-R
34With-R
35Yet further condition is and S, C (O), C (S), S (O) or S (O)
2Bonded R
29Not hydrogen;
In all cases, R
32Be independently selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
36,-SR
36,-NR
37R
38,-R
33,-R
34With-R
35
In all cases, R
33Be the low carbon chain thiazolinyl independently, described low carbon chain thiazolinyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
34Be the low-carbon (LC) alkynyl independently, described low-carbon (LC) alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
35Be low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38
In all cases, R
36, R
37And R
38Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace or-NR
37R
38Be cycloalkyl amino, yet condition is and OR
36, SR
36, NR
36, NR
37Or NR
38In any one O, S or any substituting group on the low-carbon alkyl carbon that combines of N be fluorine, yet and further condition be and S bonded R
36Not hydrogen;
Z is O or S;
N is 1 or 2;
U is 0,1,2,3 or 4;
V is 0,1,2,3,4 or 5;
P is 1 or 2; With
T is 0,1,2,3 or 4, yet condition is when t=0, so p=0.
16. compound according to claim 15, wherein R
1And R
2In at least one is-OR
9
17. compound according to claim 16, wherein R
1And R
2In one be-OR
9And R
1And R
2In another is hydrogen or halogen.
18. compound according to claim 17, wherein R
2Be-OR
9And R
1Be hydrogen.
19. compound according to claim 18, wherein R
9It is low-carbon alkyl, described low-carbon alkyl replaces with one or more substituting groups are optional, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.
20. compound according to claim 1, it has chemical structure:
21. compound according to claim 20, wherein R
1And R
2In at least one is-OR
9
22. compound according to claim 21, wherein R
1And R
2In one be-OR
9And R
1And R
2In another is hydrogen or halogen.
23. compound according to claim 22, wherein R
2Be-OR
9And R
1Be hydrogen.
24. compound according to claim 23, wherein R
9It is low-carbon alkyl, described low-carbon alkyl replaces with one or more substituting groups are optional, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.
25. according to each described compound, wherein Ar among the claim 20-24
1aBe that phenyl and M are at S (O)
2Contraposition be attached to Ar
1a
26. compound according to claim 25, wherein Ar
2aIt is phenyl.
27. compound according to claim 26, wherein v is 1 and R
25Contraposition combination at M.
28. compound according to claim 27, wherein M be covalent linkage or-O-.
29. compound according to claim 28, wherein X is C (O) OR
16
30. compound according to claim 29, wherein R
16Be H.
31. compound according to claim 30, wherein W is-(CR
4R
5)
1-3-.
32. compound according to claim 31, wherein W is-CH
2-or-CH
2CH
2-.
33. compound according to claim 24, wherein R
9Be low-carbon alkyl, described low-carbon alkyl replaces with one or more substituting groups are optional, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-, Ar
1aBe phenyl, M be covalent linkage or-O-and at S (O)
2Contraposition be attached to Ar
1aOn, u is 0, v is 1, Ar
2aBe phenyl, W is-CH
2-, X is-COOH, and R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-replace with one or more substituting groups are optional, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
34. compound according to claim 33, wherein R
9Be low-carbon alkyl, M is-O-and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine.
35. compound according to claim 34, wherein R
25Contraposition at M is incorporated into Ar
2aOn.
36. compound according to claim 34, wherein R
25The position is incorporated into Ar between M
2aOn.
37. compound according to claim 24, wherein R
9Be low-carbon alkyl, described low-carbon alkyl replaces with one or more substituting groups are optional, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-, Ar
1aBe phenyl, M be covalent linkage or-O-and at S (O)
2Between the position be incorporated into Ar
1aOn, u is 0, v is 1, Ar
2aBe phenyl, W is-CH
2-, X is-COOH, and R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-replace with one or more substituting groups are optional, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
38. according to the described compound of claim 37, wherein R
9Be low-carbon alkyl and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine.
39. according to the described compound of claim 38, wherein R
25Contraposition at M is incorporated into Ar
2aOn.
40. according to the described compound of claim 38, wherein R
25The position is incorporated into Ar between M
2aOn.
41. compound according to claim 1, it has chemical structure:
Its all salt, prodrug, tautomer and isomers,
Wherein:
X is selected from-C (O) OR
16,-C (O) NR
17R
18With the carboxylic acid isostere;
W be selected from covalent linkage ,-NR
51(CR
4R
5)
1-2-,-O-(CR
4R
5)
1-2-,-S-(CR
4R
5)
1-2-,-(CR
4R
5)
1-3-and-CR
6=CR
7-;
Y is selected from-O-,-S-,-NR
53-,-C (Z)-,-S (O)
n-,-C (Z) NR
54-,-NR
54C (Z)-,-NR
54S (O)
2-,-S (O)
2NR
54-,-NR
54C (Z) NR
54-and-NR
54S (O)
2NR
54-;
M be selected from covalent linkage ,-CR
19R
20-,-O-,-S-,-NR
53-,-C (Z)-and-S (O)
n-;
Ar
1aBe selected from arylidene and heteroarylidene;
Ar
2aBe selected from aryl and heteroaryl;
R
1And R
2Be independently selected from hydrogen, halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl ,-SR
9With-OR
9, wherein said low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
A R
4Or R
5Be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R on the identical or different carbon
4And R
5In any two in conjunction with forming 3-7 unit's monocyclic cycloalkyls or 5-7 unit monocyclic heterocycles alkyl, and other R arbitrarily
4And R
5Be independently selected from hydrogen, fluorine and low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
6And R
7Be independently selected from hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In one be selected from phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, and R
6And R
7In another is hydrogen or low-carbon alkyl, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace; Or
R
6And R
7In conjunction with forming 5-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein said monocyclic cycloalkyl and monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
9Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
9Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-OR
9O or-SR
9S go up, C
3-6Yet alkynyl--condition is to work as R
9Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-OR
9O or-SR
9S go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-, the fluorine that replace the low-carbon alkyl sulfo-, cycloalkyl, Heterocyclylalkyl, aryl and the heteroaryl that replace--yet condition is, with-OR
9O or-SR
9S bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein alkyl, C
3-6Alkenyl and C
3-6The cycloalkyl of alkynyl, Heterocyclylalkyl, aryl and heteroaryl substituting group randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low carbon chain thiazolinyl, the fluorine that replace the low carbon chain thiazolinyl, low-carbon (LC) alkynyl, the fluorine that replace the low-carbon (LC) alkynyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
51Be selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein low-carbon alkyl is randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is, with-NR
51-N bonded alkyl carbon on any substituting group be fluorine, and wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
53Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
53Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-NR
53-N go up, C
3-6Yet alkynyl--condition is to work as R
53Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-NR
53-N go up, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-C (Z) NR
11R
12,-S (O)
2NR
11R
12,-S (O)
2R
13,-C (Z) R
13With-C (Z) OR
15, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
53-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
54Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
54Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-NR
54-N go up, C
3-6Yet alkynyl--condition is to work as R
54Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-NR
54-N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-NR
54-N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
11And R
12Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
11And/or R
12Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, C
3-6Yet alkynyl--condition is to work as R
11And/or R
12Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any-C (Z) NR
11R
12Or-S (O)
2NR
11R
12N bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
11And R
12Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
In all cases, R
13Be independently selected from low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
13Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, C
3-6Yet alkynyl--condition is to work as R
13Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to-C (Z) R
13C (Z) or-S (O)
2R
13S (O)
2Upward, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
In all cases, R
15Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is to work as R
15Be C
3-6During alkenyl, it does not have olefinic carbon to be attached to (O) R
15O go up, C
3-6Yet alkynyl--condition is to work as R
15Be C
3-6During alkynyl, it does not have alkynes carbon to be attached to (O) R
15O go up, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, C
3-6Alkenyl and C
3-6Alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, yet condition is and any OR
15O bonded alkyl, C
3-6Alkenyl or C
3-6Any substituting group on the alkynyl carbon is selected from fluorine, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein arbitrarily cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23
R
16Be selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
16When being low-carbon alkyl, with OR
16O bonded alkyl carbon on any substituting group be fluorine;
R
17And R
18Be independently selected from hydrogen, low-carbon alkyl, phenyl, 5-7 unit bicyclic heteroaryl, 3-7 unit's monocyclic cycloalkyl and 5-7 unit monocyclic heterocycles alkyl, wherein phenyl, bicyclic heteroaryl, monocyclic cycloalkyl and monocyclic heterocycles alkyl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, and wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkoxy, the fluorine low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace, yet condition is to work as R
17And/or R
18When being low-carbon alkyl, with NR
17R
18N bonded alkyl carbon on any substituting group be fluorine; Or
R
17And R
18Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
R
19And R
20Be independently selected from hydrogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
21,-SR
21,-NR
22R
23, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, and wherein any cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
21,-SR
21,-S (O) R
21,-S (O)
2R
21,-C (Z) R
21,-C (Z) OR
21,-NR
22R
23,-C (Z) NR
22R
23,-S (O)
2NR
22R
23,-C (NH) NR
22R
23,-NR
21C (Z) R
21,-NR
21S (O)
2R
21,-NR
21C (Z) NR
22R
23,-NR
21S (O)
2NR
22R
23, low-carbon alkyl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl, wherein the optional substituting group of the low-carbon alkyl of cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, low carbon chain thiazolinyl and low-carbon (LC) alkynyl is further randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
21,-SR
21With-NR
22R
23Or
R
19And R
20In conjunction with forming 3-7 unit's monocyclic cycloalkyl or 5-7 unit monocyclic heterocycles alkyl, wherein monocyclic cycloalkyl or monocyclic heterocycles alkyl be randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2, the low-carbon alkyl sulfo-that replaces of low-carbon alkyl, the fluorine low-carbon alkyl, low-carbon alkoxy, the fluorine that the replace low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine that replace;
In all cases, R
21, R
22And R
23Be independently selected from hydrogen or low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group is selected from low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and the cycloalkyl amino that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace, yet condition is and OR
21, SR
21, NR
21, NR
22Or NR
23In any one O, S or any substituting group on the low-carbon alkyl carbon that combines of N be fluorine, yet and further condition be and S, S (O), S (O)
2Or C (Z) bonded R
21Not hydrogen; Or
R
22And R
23Form 5-7 unit monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle with the nitrogen that they connected, wherein the nitrogenous heteroaryl of monocyclic heterocycles alkyl or monocycle is randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-OH ,-NH
2,-NO
2Low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that the low-carbon alkoxy that the low-carbon alkyl that ,-CN, low-carbon alkyl, fluorine replace, low-carbon alkoxy, fluorine replace, low-carbon alkyl sulfo-, fluorine replace;
In all cases, R
24Be independently selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl ,-NO
2,-CN-OR
26,-SR
26,-OC (O) R
26,-OC (S) R
26,-C (O) R
26,-C (S) R
26,-C (O) OR
26,-C (S) OR
26,-S (O) R
26,-S (O)
2R
26,-C (O) NR
27R
28,-C (S) NR
27R
28,-S (O)
2NR
27R
28,-C (NH) NR
27R
28,-NR
26C (O) R
26,-NR
26C (S) R
26,-NR
26S (O)
2R
26, NR
26C (O) NR
27R
28, NR
26C (S) NR
27R
28,-NR
26S (O)
2NR
27R
28With-NR
27R
28, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
25Be independently selected from halogen, low-carbon alkyl, low carbon chain thiazolinyl, low-carbon (LC) alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-NO
2,-CN ,-OR
29,-SR
29,-OC (O) R
29,-OC (S) R
29,-C (O) R
29,-C (S) R
29,-C (O) OR
29,-C (S) OR
29,-S (O) R
29,-S (O)
2R
29,-C (O) NR
29R
29,-C (S) NR
29R
29,-S (O)
2NR
29R
29,-C (NH) NR
30R
31,-NR
29C (O) R
29,-NR
29C (S) R
29,-NR
29S (O)
2R
29,-NR
29C (O) NR
29R
29,-NR
29C (S) NR
29R
29,-NR
29S (O)
2NR
29R
29With-NR
29R
29, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
32, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38,-R
35With-R
32, and wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
36,-SR
36,-NR
37R
38,-R
35,-R
33With-R
34
In all cases, R
26, R
27And R
28Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is that it does not have olefinic carbon to be attached to R
24O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, C
3-6Yet alkynyl--condition is that it does not have alkynes carbon to be attached to R
24O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, wherein low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35Yet further condition is and S, C (O), C (S), S (O) or S (O)
2Bonded R
26Not hydrogen, or
R
27And R
28With the nitrogen that is connected them in conjunction with forming cycloalkyl amino;
In all cases, R
29, R
30And R
31Be independently selected from hydrogen, low-carbon alkyl, C
3-6Yet alkenyl--condition is that it does not have olefinic carbon to be attached to R
25O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, C
3-6Yet alkynyl--condition is that it does not have alkynes carbon to be attached to R
25O, S, N, C (O), C (S), S (O) or S (O)
2Any one on, cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, or
R
30And R
31With the nitrogen that is connected them in conjunction with forming 5-7 unit's monocyclic heterocycles alkyl or 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle, wherein low-carbon alkyl is randomly with one or more substituting groups replacements, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
32, and wherein low carbon chain thiazolinyl and low-carbon (LC) alkynyl randomly replace with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38,-R
35With-R
32, and wherein cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, 5-7 unit's monocyclic heterocycles alkyl and 5 yuan or 7 yuan of nitrogenous heteroaryls of monocycle randomly with one or more substituting groups replacements, described substituting group be selected from halogen ,-NO
2,-CN ,-OH ,-NH
2,-OR
36,-SR
36,-NHR
36,-NR
37R
38,-R
33,-R
34With-R
35Yet further condition is and S, C (O), C (S), S (O) or S (O)
2Bonded R
29Not hydrogen;
In all cases, R
32Be independently selected from cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl, wherein cycloalkyl, Heterocyclylalkyl, aryl and heteroaryl randomly replace with one or more substituting groups, described substituting group be selected from halogen ,-NO
2,-CN ,-OR
36,-SR
36,-NR
37R
38,-R
33,-R
34With-R
35
In all cases, R
33Be the low carbon chain thiazolinyl independently, described low carbon chain thiazolinyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
34Be the low-carbon (LC) alkynyl independently, described low-carbon (LC) alkynyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36,-NR
37R
38With-R
35
In all cases, R
35Be low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from fluorine ,-OR
36,-SR
36With-NR
37R
38
In all cases, R
36, R
37And R
38Be hydrogen or low-carbon alkyl independently, described low-carbon alkyl randomly replaces with one or more substituting groups, described substituting group be selected from low-carbon alkyl sulfo-, alkyl monosubstituted amino, dialkyl amido and cycloalkyl amino that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace or-NR
37R
38Be cycloalkyl amino, yet condition is and OR
36, SR
36, NR
36, NR
37Or NR
38In any one O, S or any substituting group on the low-carbon alkyl carbon that combines of N be fluorine, yet and further condition be and S bonded R
36Not hydrogen;
Z is O or S;
N is 1 or 2;
U is 0,1,2,3 or 4;
V is 0,1,2,3,4 or 5;
P is 0 or 1; With
S is 0,1,2,3 or 4, yet condition is when s=0, so p=0 and when s be 0,1,2,3 or 4 and during p=0, Ar so
1aNot pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl or isothiazolyl, and work as s=0, p=0 and Ar
1aWhen being phenyl,
Be not
Wherein
Expression and the tie point of O and
Expression and Ar
1aTie point.
42. according to the described compound of claim 41, wherein R
1And R
2In at least one is-OR
9
43. according to the described compound of claim 42, wherein R
1And R
2In one be-OR
9And R
1And R
2In another is hydrogen or halogen.
44. according to the described compound of claim 43, wherein R
2Be-OR
9And R
1Be hydrogen.
45. according to the described compound of claim 44, wherein R
9It is low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.
46. according to the described compound of claim 41, it has chemical structure:
47. according to the described compound of claim 46, wherein R
1And R
2In at least one is-OR
9
48. according to the described compound of claim 47, wherein R
1And R
2In one be-OR
9And R
1And R
2In another is hydrogen or halogen.
49. according to the described compound of claim 48, wherein R
2Be-OR
9And R
1Be hydrogen.
50. according to the described compound of claim 49, wherein R
9It is low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from the cycloalkyl that low-carbon alkyl sulfo-, cycloalkyl and fluorine that low-carbon alkoxy, low-carbon alkyl sulfo-, fluorine that fluorine, low-carbon alkoxy, fluorine replace replace replace.
51. according to each described compound, wherein Ar among the claim 46-50
1aBe that phenyl and M are at S (O)
2Contraposition be attached to Ar
1a
52. according to the described compound of claim 51, wherein Ar
2aIt is phenyl.
53. according to the described compound of claim 52, wherein v is 1 and R
25Contraposition combination at M.
54. according to the described compound of claim 53, wherein M be covalent linkage or-O-.
55. according to the described compound of claim 54, wherein X is C (O) OR
16
56. according to the described compound of claim 55, wherein R
16Be H.
57. according to the described compound of claim 56, wherein W is-(CR
4R
5)
1-3-.
58. according to the described compound of claim 57, wherein W is-CH
2-or-CH
2CH
2-.
59. according to the described compound of claim 50, wherein R
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-, Ar
1aBe phenyl, M be covalent linkage or-O-and be incorporated into Ar in the contraposition of-O-
1aOn, u is 0, v is 1, Ar
2aBe phenyl, W is-CH
2-, X is-COOH, and R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
60. according to the described compound of claim 59, wherein R
9Be low-carbon alkyl, M is-O-and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine.
61. according to the described compound of claim 60, wherein R
25Contraposition at M is incorporated into Ar
2aOn.
62. according to the described compound of claim 60, wherein R
25The position is incorporated into Ar between M
2aOn.
63. according to the described compound of claim 50, wherein R
9Be low-carbon alkyl, described low-carbon alkyl randomly replaces with one or more substituting groups, and described substituting group is selected from fluorine, low-carbon alkoxy and low-carbon alkyl sulfo-, Ar
1aBe phenyl, the M covalent linkage or-O-and between-O-the position be incorporated into Ar
1aOn, u is 0, v is 1, Ar
2aBe phenyl, W is-CH
2-, X is-COOH, and R
25Be selected from halogen, low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-, wherein low-carbon alkyl, low-carbon alkoxy and low-carbon alkyl sulfo-randomly replace with one or more substituting groups, and described substituting group is selected from the low-carbon alkyl sulfo-of low-carbon alkoxy, low-carbon alkyl sulfo-and the fluorine replacement of fluorine, low-carbon alkoxy, fluorine replacement.
64. according to the described compound of claim 63, wherein R
9Be low-carbon alkyl and R
25Be the randomly low-carbon alkyl that replaces of fluorine or the randomly low-carbon alkoxy that replaces of fluorine.
65. according to the described compound of claim 64, wherein R
25Contraposition at M is incorporated into Ar
2aOn.
66. according to the described compound of claim 64, wherein R
25The position is incorporated into Ar between M
2aOn.
67. compound according to claim 1, wherein said compound is selected from:
3-butoxy-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-methoxyl group-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-(2-methoxyl group-oxyethyl group)-5-[4-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-(2-methoxyl group-oxyethyl group)-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-methoxyl group-5-[4-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-benzyloxy-5-[4-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-butoxy-5-[4-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-oxyethyl group-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-propoxy--5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
3-propoxy--5-[3-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl }-acetate,
[3-oxyethyl group-5-(4 '-trifluoromethyl-xenyl-3-alkylsulfonyl) phenyl]-acetate,
3-oxyethyl group-5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-methyl acetate,
3-oxyethyl group-5-[4-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl }-acetate
[3-oxyethyl group-5-(4 '-trifluoromethoxy-xenyl-3-alkylsulfonyl) phenyl]-acetate,
3-{3-propoxy--5-[4-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl }-propionic acid,
3-{3-oxyethyl group-5-[4-(4-trifluoromethyl-phenoxy group)-benzenesulfonyl]-phenyl-propionic acid or
3-{3-propoxy--5-[4-(4-trifluoromethoxy-phenoxy group)-benzenesulfonyl]-phenyl }-propionic acid.
68. compound according to claim 1, wherein said compound is selected from:
[3-butoxy-5-(4-trifluoromethyl-benzenesulfonyl)-phenyl]-acetate,
[3-butoxy-5-(4-methoxyl group-benzenesulfonyl)-phenyl]-acetate,
[3-butoxy-5-(4-trifluoromethoxy-benzenesulfonyl)-phenyl]-acetate or
[3-butoxy-5-(3-methoxyl group-benzenesulfonyl)-phenyl]-acetate.
69. composition comprises:
Pharmaceutically acceptable carrier; With
According to each described compound among the claim 1-68.
The method that 70. treatment suffers or risky trouble PPAR regulates the object of disease that the treatment benefit is provided or illness, comprise to described object use significant quantity according to each described compound among the claim 1-68 or according to the described composition of claim 69.
71. according to the described method of claim 70, wherein said compound goes through to be administered to the people.
72. according to claim 70 or 71 described methods, wherein said disease or illness are the disease or the illnesss of PPAR-mediation.
73. according to each described method among the claim 70-72, wherein said disease or illness are selected from obesity, overweight state, Bulimia nerovsa, anorexia nervosa, hyperlipidemia, unusual lipidemia, slight alpha lipoprotein mass formed by blood stasis, hypertriglyceridemia and hypercholesterolemia, low HDL, metabolic syndrome, type ii diabetes, type i diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, the neuropathy diabetic complication, the ephrosis diabetic complication, the retinopathy diabetic complication, diabetic foot ulcer or cataract, hypertension, coronary heart disease, in heart failure, congestive heart failure, atheronecrosis, arteriosclerosis, apoplexy, cerebro-vascular diseases, myocardial infarction, peripheral vascular disease, vitiligo, uveitis, pemphigus foliaceus, inclusion body myositis, polymyositis, dermatomyositis, scleroderma, Exophthalmus goiter, Hashimoto's disease, chronic graft versus host disease, rheumatoid arthritis, the inflammatory bowel trace integration is levied, Crohn's disease, systemic lupus erythematosis, dry syndrome, multiple sclerosis, asthma, chronic obstructive pulmonary disease, multicystic kidney disease, polycystic ovarian syndrome, pancreatitis, ephritis, hepatitis, eczema, psoriasis, dermatitis, the damage wound healing, alzheimer's disease, parkinsonism, amyotrophic lateral sclerosis, vertebra Spinal injury, acute disseminated encephalomyelitis, guillain-Barre syndrome, thrombosis, large intestine or small intestinal obstruction, renal insufficiency, erectile dysfunction, the urinary incontinence, neurogenic bladder, eye inflammation, macular degeneration, the pathologic neovascularization, HCV infects, HIV infects, helicobacter pylori infection, nervosa or inflammatory pain, sterile or cancer.
74. test kit, it comprises according to the described pharmaceutical composition of claim 69.
75. according to the described test kit of claim 74, it further comprises written explanation: described composition goes through to be administered to the people.
76. according to the described test kit of claim 75, wherein said composition is approved for medical indications, and described indication is selected from obesity, overweight state, Bulimia nerovsa, anorexia nervosa, hyperlipidemia, unusual lipidemia, slight alpha lipoprotein mass formed by blood stasis, hypertriglyceridemia and hypercholesterolemia, low HDL, metabolic syndrome, type ii diabetes, type i diabetes, hyperinsulinemia, impaired glucose tolerance, insulin resistance, the neuropathy diabetic complication, the ephrosis diabetic complication, the retinopathy diabetic complication, diabetic foot ulcer or cataract, hypertension, coronary heart disease, in heart failure, congestive heart failure, atheronecrosis, arteriosclerosis, apoplexy, cerebro-vascular diseases, myocardial infarction, peripheral vascular disease, vitiligo, uveitis, pemphigus foliaceus, inclusion body myositis, polymyositis, dermatomyositis, scleroderma, Exophthalmus goiter, Hashimoto's disease, chronic graft versus host disease, rheumatoid arthritis, the inflammatory bowel trace integration is levied, Crohn's disease, systemic lupus erythematosis, dry syndrome, multiple sclerosis, asthma, chronic obstructive pulmonary disease, multicystic kidney disease, polycystic ovarian syndrome, pancreatitis, ephritis, hepatitis, eczema, psoriasis, dermatitis, the damage wound healing, alzheimer's disease, parkinsonism, amyotrophic lateral sclerosis, vertebra Spinal injury, acute disseminated encephalomyelitis, guillain-Barre syndrome, thrombosis, large intestine or small intestinal obstruction, renal insufficiency, erectile dysfunction, the urinary incontinence, neurogenic bladder, eye inflammation, macular degeneration, the pathologic neovascularization, HCV infects, HIV infects, helicobacter pylori infection, nervosa or inflammatory pain, sterile or cancer.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71521405P | 2005-09-07 | 2005-09-07 | |
| US60/715,214 | 2005-09-07 | ||
| US60/789,387 | 2006-04-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101296892A true CN101296892A (en) | 2008-10-29 |
Family
ID=40066536
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200680040053XA Pending CN101296892A (en) | 2005-09-07 | 2006-09-06 | PPAR active compounds |
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| Country | Link |
|---|---|
| CN (1) | CN101296892A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933580A (en) * | 2010-06-18 | 2013-02-13 | 浙江海正药业股份有限公司 | Compounds having activating effect on subtypes of peroxisome proliferator-activated receptors and its preparation method and uses |
| CN109843857A (en) * | 2016-10-05 | 2019-06-04 | 米托布里奇公司 | The crystallization of PPAR agonist compound and salt form |
| CN113209071A (en) * | 2021-05-20 | 2021-08-06 | 郑州大学第一附属医院 | Application of fibrate drugs in preparation of drugs for preventing or treating chronic inflammation of old people |
| CN114392266A (en) * | 2022-01-22 | 2022-04-26 | 暨南大学附属第一医院（广州华侨医院） | Pharmaceutical composition containing PPAR gamma inhibitor and application thereof |
-
2006
- 2006-09-06 CN CNA200680040053XA patent/CN101296892A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102933580A (en) * | 2010-06-18 | 2013-02-13 | 浙江海正药业股份有限公司 | Compounds having activating effect on subtypes of peroxisome proliferator-activated receptors and its preparation method and uses |
| CN102933580B (en) * | 2010-06-18 | 2015-07-01 | 浙江海正药业股份有限公司 | Compounds having activating effect on subtypes of peroxisome proliferator-activated receptors and its preparation method and uses |
| CN109843857A (en) * | 2016-10-05 | 2019-06-04 | 米托布里奇公司 | The crystallization of PPAR agonist compound and salt form |
| US11530192B2 (en) | 2016-10-05 | 2022-12-20 | Mitobridge, Inc. | Crystalline and salt forms of PPAR agonist compounds |
| CN109843857B (en) * | 2016-10-05 | 2023-01-06 | 米托布里奇公司 | Crystalline and salt forms of PPAR agonist compounds |
| US11912681B2 (en) | 2016-10-05 | 2024-02-27 | Mitobridge, Inc. | Crystalline and salt forms of PPAR agonist compounds |
| CN113209071A (en) * | 2021-05-20 | 2021-08-06 | 郑州大学第一附属医院 | Application of fibrate drugs in preparation of drugs for preventing or treating chronic inflammation of old people |
| CN114392266A (en) * | 2022-01-22 | 2022-04-26 | 暨南大学附属第一医院（广州华侨医院） | Pharmaceutical composition containing PPAR gamma inhibitor and application thereof |
| CN114392266B (en) * | 2022-01-22 | 2022-11-15 | 暨南大学附属第一医院（广州华侨医院） | Pharmaceutical composition containing PPAR gamma inhibitor and application thereof |
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