CN101501009A - CGRP receptor antagonists - Google Patents

CGRP receptor antagonists Download PDF

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CN101501009A
CN101501009A CNA2007800297374A CN200780029737A CN101501009A CN 101501009 A CN101501009 A CN 101501009A CN A2007800297374 A CNA2007800297374 A CN A2007800297374A CN 200780029737 A CN200780029737 A CN 200780029737A CN 101501009 A CN101501009 A CN 101501009A
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base
alkyl
group
described compound
methyl
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C·古铁雷斯
A·特敏
S·哈迪达-鲁阿
P·乔希
D·贝热隆
俞尚嬉
H·宾奇
J·科姆
S·南塔库玛尔
曹景蓉
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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    • C07D513/10—Spiro-condensed systems

Abstract

The present invention relates to CGRP receptor antagonists, pharmaceutical compositions thereof, and methods therewith for treating CGRP receptor-mediated diseases and conditions. The present invention relates to CGRP receptor antagonists of formula 1, wherein: X is S, SO, or SO2; pharmaceutical compositions thereof, and methods therewith for treating CGRP receptor-mediated diseases and conditions.

Description

The CGRP receptor antagonist
Technical field
[0001] the present invention relates to the CGRP receptor antagonist, its pharmaceutical composition, and with the method for its treatment CGRP receptor-mediated diseases and the patient's condition.
Background technology
[0002] CGRP (calcitonin-gene-related peptide) is a kind of naturally occurring 37-amino acid peptide, and it is alternately to be processed and produced by the tissue specificity of thyrocalcitonin messenger RNA(mRNA), and is distributed widely in maincenter and the peripheral nervous system.CGRP mainly concentrates on and feels to import into and axoneuron, and regulates some biological actions, comprises vasorelaxation.CGRP is with α-and β-formal representation, and these two kinds of forms are changed by 1 and 3 amino acid respectively in rat and people.CGRP-α shows similar biological property with CGRP-β.When cell discharges, CGRP is by combining its biological respinse of beginning with the specific cell surface receptor, and described acceptor is main relevant with the activation of adenylate cyclase.The CGRP acceptor has been differentiated and pharmacological evaluation in comprising following some tissues and cell: brain, cardiovascular, endothelium and unstriated muscle initiating terminal.
[0003] CGRP is effective vasodilator, and it is relevant with pathology such as the cerebrovascular illness of migraine and cluster headache.In the clinical study, find the level that occurs CGRP in the jugular vein during the migraine raise (people such as Goadsby, Ann.Neurol., 1990,28,183-187).CGRP activates the acceptor on the intracranial vessel unstriated muscle, cause enhanced vasorelaxation, this is considered to the main origin (Lance that has a headache during the migraine, HeadachePathogenesis:Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997,3-9).Arteria meningea media, the main artery in the pachymeninx, by the Sensory fibre domination from gasserian ganglion, this neuroganglion contains some neuropeptides, comprises CGRP.Gasserian ganglion excitement in the cat causes the CGRP level to increase, and in the mankind, the activation of trigeminal system cause that the CGRP level increases in flush and the external jugular vein (people such as Goadsby, Ann.Neurol., 1988,23,193-196).Dural electricity irritation increases the diameter of arteria meningea media in the rat, and this effect is by using CGRP (8-37) earlier, and a kind of peptide CGRP antagonist blocking-up (people such as Williamson, Cephalalgia, 1997,17,525-531).The gasserian ganglion excitement increases facial blood flow in rat, this by CGRP (8-37) suppress (people such as Escott, Brain Res.1995,669,93-99).The electricity irritation of gasserian ganglion causes that facial blood flow increases in the marmoset monkey, this can by non-peptide CGRP antagonist BIBN4096BS blocking-up (people such as Doods, Br.J.Pharmacol., 2000,129,420-423).Therefore, the vascular effect of CGRP can be weakened, stop or reverse by the CGRP antagonist.Recently in the clinical trial of report, and the effectively migrainous acute attack of treatment of report CGRP receptor antagonist BIBN 4096 BS (people such as Olesen, N.Engl.J.Med.2004,350:1104-1110).
[0004] vasorelaxation of the CGRP-of rat arteria meningea media mediation shows the neurone sensitivity that makes the nuclei quintus tail (people such as Williamson, The CGRP Family:CalcitoninGene-Related Peptide (CGRP), Amylin, and Adrenomedullin, LandesBioscience, 2000,245-247).Similarly, the expansion of pachymeninx blood vessel can make trifacial neurone sensitivity during the migraine.More migrainous related symptoms comprise outer pain of cranium and facial allodynia, may be sensitization the neuronic result of trigeminal nerve (people such as Burstein, Ann.Neurol.2000,47,614-624).The CGRP antagonist can be of value to and weakens, stops or reverse neuronic sensitization.
[0005] The compounds of this invention makes it in the human and animal as the ability of CGRP antagonist, but particularly in the mankind, the illness relevant with CGRP is useful pharmacology medicine.This class illness comprises migraine and cluster headache (Doods, Curr.Opin.Inves.Drugs, 2001,2 (9), 1261-1268; People such as Edvinsson, Cephalalgia, 1994,14,320-327); Chronic tension-type headache (people such as Ashina, Neurology, 2000,14,1335-1340); Pain (people such as Yu, Eur.J.Pharm., 1998,347,275-282); Chronic pain (people such as Hulsebosch, Pain, 2000,86,163-175); Neurogenic inflammation and inflammatory pain (Holzer, Neurosci., 1988,24,739-768; People such as Delay-Goyet, Acta Physiol.Scanda.1992,146,537-538; People such as Salmon, Nature Neurosci., 2001,4 (4), 357-358); Ophthalmodynia (people Cephalalgia such as May, 2002,22,195-196), toothache (people such as Awawdeh, Int.Endocrin.J., 2002,35,30-36), non insulin dependent diabetes (people such as Molina, Diabetes, 1990,39,260-265); Vascular disorder; Inflammation (people such as Zhang, Pain, 2001,89,265), sacroiliitis, bronchial hyperreactivity, asthma, (people such as Foster, Ann.NY Acad.Sci., 1992,657,397-404; People such as Schini, Am.J.Physiol., 1994,267, H2483-H2490; People such as Zheng, J.Virol., 1993,67,5786-5791); Shock, and Sepsis (people such as Beer, Crit.Care Med., 2002,30 (8), 1794-1798); Refraining opium type material syndrome (people such as Salmon, Nature Neurosci., 2001,4 (4), 357-358); Morphine tolerance (people such as Menard, J.Neurosci., 1996,16 (7), 2342-2351); Hot flush in the masculinity and femininity (people such as Chen, Lancet, 1993,342,49; People such as Spetz, J.Urology, 2001,166,1720-1723); Allergic dermatitis (Wallengren, Contact Dermatitis, 2000,43 (3), 137-143); Psoriasis; Encephalitis, cerebral trauma, local asphyxia, apoplexy, epilepsy and neurodegenerative disease (people such as Rohrenbeck, Neurobiol.of Disease 1999,6,15-34); Dermatosis (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, Fla.), nervosa skin rubefaction, skin erythema (skin rosaceousness) and erythema; Tinnitus (people such as Herzog, J.Membrane Biology, 2002,189 (3), 225); Inflammatory bowel, irritable bowel syndrome, (people Scandinavian Journal ofGastroenterology such as Hoffman, 2002,37 (4) 414-422) and urocystitis.Wherein particularly importantly have a headache, comprise the acute or prophylactic treatment of migraine and cluster headache.
[0006] the present invention relates to compound as the CGRP receptors ligand, especially as the compound of CGRP receptor antagonist, its medical composition and its use.
Summary of the invention
[0007] the invention provides formula I compound:
Figure A200780029737D00321
Or its pharmacy acceptable salt.
Therefore these compounds treat the illness of CGRP-mediation as the CGRP receptor antagonist.The present invention also provides its pharmaceutical composition and purposes.
Detailed Description Of The Invention
[0008] 2. compound and definition:
[0009] The compounds of this invention comprises above those compounds of general description, and is further set forth by kind disclosed herein, group and kind.As used herein, unless otherwise noted, should use following definition.
[0010] for purposes of the present invention, the discriminating of chemical element is according to the PeriodicTable of the Elements, CAS version, Handbook of Chemistry andPhysics, the 75th edition.In addition, vitochemical rule is described in " OrganicChemistry ", Thomas Sorrell, University Science Books, Sausalito:1999 and " March ' s Advanced Organic Chemistry ", 5 ThEd., Ed.:Smith, M.B. and March, J., John Wiley ﹠amp; Sons, among the New York:2001, its full content is incorporated this paper by reference into.
[0011] as described herein, compound of the present invention is optional to be replaced by one or more substituting groups, and this class substituting group is set forth usually as mentioned, and perhaps kind, group and the kind that for example the present invention is special is described.Should be appreciated that phrase " optional being substituted " exchanges use with phrase " replacement or unsubstituted ".Usually, term " replacement " front has or not term " to choose " all expressions wantonly to the appointed substituting group replacement of the hydrogen atom in the fixed structure.Unless otherwise indicated, the optional group that replaces can have substituting group in each commutable position of this group, when can be selected from the substituting group of specifying group more than one for arbitrarily in the fixed structure an above position to replace, substituting group can be identical or different in each position.The substituting group of being contained by the present invention makes up the substituting group that preferably causes forming stable or chemically feasible compound.Term used herein " stable " expression be when being subjected to allowing its generation, detection, preferably reclaims, the condition of purifying and immovable basically compound when being used for one or more purposes disclosed herein.In some embodiments, stable compound or chemically feasible compound are the compounds that not have change when keeping at least one week under lacking moisture or other chemical reaction conditions, under 40 ℃ or following temperature basically.
[0012] as used herein, term " aliphatic series " or " aliphatic group " expression straight chain (promptly not ramose) or ramose, replacement or unsubstituted hydrocarbon chain, it is saturated fully or contains one or more unsaturated units, perhaps represent monocyclic hydrocarbon or bicyclic hydrocarbon, it is saturated fully or contains one or more unsaturated units, but its be not aromatic (this paper is also referred to as " carbocyclic ring ", " cyclic aliphatic " or " cycloalkyl "), it has the single point that links to each other with the molecule remainder.Unless otherwise indicated, aliphatic group contains 1-20 aliphatic carbon atom.In some embodiments, aliphatic group contains 1-10 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-8 aliphatic carbon atom.Also in other embodiments, aliphatic group contains 1-6 aliphatic carbon atom, and in other embodiments, aliphatic group contains 1-4 aliphatic carbon atom.In some embodiments, " cyclic aliphatic " (or " carbocyclic ring " or " cycloalkyl ") is meant monocycle C 3-C 8Hydrocarbon or two ring C 8-C 14Hydrocarbon or three ring C 8-C 14Hydrocarbon, it is fully saturated or contains one or more unsaturated units, but is not aromatic, and it has the single point that is connected with the molecule rest part, and any single ring is that 3-7 unit encircles in the wherein said bicyclic ring system.Suitable aliphatic group includes but not limited to, straight chain or branch, saturated or undersaturated alkyl, alkenyl and alkynyl group and combination thereof are as (cycloalkyl) alkyl, (cycloalkenyl group) alkyl or (cycloalkyl) alkenyl.Suitable cycloaliphatic groups comprises bicyclic alkyl such as norcamphane base or [2.2.2] two ring-octyl groups of cycloalkyl, bicyclic ring alkyl (for example naphthalane), bridge joint, and perhaps three of bridge joint rings are as adamantyl.
[0013] as used herein, term " heterolipid family " represents that one of them or two carbon atoms are independently by the displaced aliphatic group of one or more oxygen, sulphur, nitrogen, phosphorus or silicon.Heterolipid family group can be to replace or unsubstituted, branch or ramose ring-type or acyclic not, and comprises " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " group.
[0014] as used herein, " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " represent that wherein one or more annular atomses are independently selected from the monocyclic, bicyclic or tricyclic ring system of heteroatomic non-fragrance.In some embodiments, " heterocycle ", " heterocyclic radical ", " heterocycle aliphatic series " or " heterocyclic " group have 3-14 annular atoms, wherein one or more annular atomses are the heteroatomss that are independently selected from oxygen, sulphur, nitrogen or phosphorus, and each ring in the system contains 3-7 annular atoms.
[0015] term " heteroatoms " represents that one or more oxygen, sulphur or nitrogen (comprise its any oxidised form, for example S=O, SO 2Deng; Any basic nitrogen or heterocycle can replace the quaternary ammonium form of nitrogen, for example N (as 3, in the 4-dihydro-2 h-pyrrole base), NH (as in pyrrolidyl) or NR +(in the pyrrolidyl that replaces at N-)).
[0016] term " halogenated aliphatic base " and " halogenated alkoxy " expression is depended on the circumstances by aliphatic group or alkoxyl group that one or more halogen atoms replace.Term " halogen " or " halo " expression F, Cl, Br or I.The example of halogenated aliphatic base comprises-CHF 2,-CH 2F ,-CF 3,-CF 2-or whole haloalkyl as-CF 2CF 3
[0017] uses separately or be meant that as the term " aryl " of a part in " aralkyl ", " aralkoxy " or " aryloxy alkyl " having the monocycle, two rings and three that amount to 5-14 annular atoms encircles ring systems as major part, wherein at least one ring in the system is an aromatics, and wherein each ring of system contains 3-7 annular atoms.Term " aryl " can exchange with term " aryl rings " and use.Term " aryl " also is expressed as follows civilian defined heteroaryl ring system.
[0018] uses separately or be meant that as the term " heteroaryl " of a part in " heteroaralkyl " or " heteroaryl alkoxyl group " having the monocycle, two rings and three that amount to 5-14 annular atoms encircles ring systems as major part, wherein at least one ring in the system is an aromatics, at least one ring in the system contains one or more heteroatomss, and wherein the ring of each in the system contains 3-7 annular atoms.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or term " heteroaromatic base " and use.
[0019] aryl (comprising aralkyl, aralkoxy, aryloxy alkyl etc.) or heteroaryl (comprising heteroaralkyl and heteroaryl alkoxyl group etc.) group can contain one or more substituting groups.Suitable substituting group on the unsaturated carbon atom of aryl or heteroaryl groups be selected from halogen ,-R o,-OR o,-SR o, 1,2-methylene radical-dioxy, 1,2-ethylenedioxy, optional by R oThe phenyl (Ph) that replaces, optional by R oReplace-O (Ph), optional by R oReplace-(CH 2) 1-2(Ph), optional by R oReplace-CH=CH (Ph) ,-NO 2,-CN ,-N (R o) 2,-NR oC (O) R o,-NR oC (O) N (R o) 2,-NR oCO 2R o,-NR oNR oC (O) R o,-NR oNR oC (O) N (R o) 2,-NR oNR oCO 2R o,-C (O) C (O) R o,-C (O) CH 2C (O) R o,-CO 2R o,-C (O) R o,-C (O) N (R o) 2,-OC (O) N (R o) 2,-S (O) 2R o,-SO 2N (R o) 2,-S (O) R o,-NR oSO 2N (R o) 2,-NR oSO 2R o,-C (=S) N (R o) 2,-C (=NH)-N (R o) 2Or-(CH 2) 0-2NHC (O) R o, each R that independently occurs wherein oBe selected from hydrogen, the optional C that replaces 1-6Aliphatic group, unsubstituted 5-6 unit's heteroaryl or heterocyclic ring, phenyl ,-O (Ph) or-CH 2(Ph), although definition perhaps above, twice independent R that occurs on identical substituting group or the different substituents oWith each R oThe atom that group connects has 0-3 the first cycloalkyl of heteroatomic 3-8-, heterocyclic radical, aryl or heteroaryl ring that is independently selected from nitrogen, oxygen or sulphur in conjunction with forming together.R oSubstituting group optional on the aliphatic group is selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo C 1-4Aliphatic group, wherein R oAforementioned each C 1-4Aliphatic group is unsubstituted.
[0020] aliphatic group or heterolipid family group, perhaps the heterocycle of non-fragrance can contain one or more substituting groups.Suitable substituting group on the unsaturated carbon of aliphatic group or heterolipid family group or nonaromatic heterocycles is selected from the substituting group on the unsaturated carbon of above cited aryl or heteroaryl groups, and comprise in addition following group :=O ,=S ,=NNHR *,=NN (R *) 2,=NNHC (O) R *, NNHCO 2(alkyl) ,=NNHSO 2(alkyl) or=NR *, each R wherein *Be independently selected from hydrogen or the optional C that replaces 1-6Aliphatic group.R *Substituting group optional on the aliphatic group is selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo (C 1-4Aliphatic group), R wherein *Aforementioned each C 1-4Aliphatic group is unsubstituted.
[0021] optional substituting group is selected from-R on the nitrogen of nonaromatic heterocycles +,-N (R +) 2,-C (O) R +,-CO 2R +,-C (O) C (O) R +,-C (O) CH 2C (O) R +,-SO 2R +,-SO 2N (R +) 2,-C (=S) N (R +) 2,-C (=NH)-N (R +) 2Or-NR +SO 2R +R wherein +Be hydrogen, the optional C that replaces 1-6Aliphatic group is chosen the phenyl that replaces wantonly, optional replacement-O (Ph), optional replacement-CH 2(Ph), optional replace-(CH 2) 1-2(Ph), optional replacement-CH=CH (Ph), or have 1-4 heteroatomic unsubstituted 5-6 unit's heteroaryl or heterocycle that is independently selected from oxygen, nitrogen or sulphur, although definition perhaps above, twice independent R that occurs on identical substituting group or the different substituents +With each R +The atom that group connects has 0-3 the first cycloalkyl of heteroatomic 3-8-, heterocyclic radical, aryl or heteroaryl ring that is independently selected from nitrogen, oxygen or sulphur in conjunction with forming together.R +Aliphatic group or phenyl ring on optional substituting group be selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo (C 1-4Aliphatic group), R wherein +Aforementioned each C 1-4Aliphatic group is unsubstituted.
[0022] term " volution ring system " is meant the part that comprises two or more rings, and wherein at least one ring has two points that are connected with another ring by a common carboatomic ring atom.
[0023] described in detail as mentioned, in some embodiments, twice independent R that occurs o(or R +, or other have the variable of similar definition in this article arbitrarily) atom that connects with each variable has 0-3 heteroatomic 3-8-unit cycloalkyl, heterocyclic radical, aryl or heteroaryl ring that is independently selected from nitrogen, oxygen or sulphur in conjunction with forming.As twice independent R that occurs o(or R +, or other have the variable of similar definition in this article arbitrarily) atom that connects with each variable in conjunction with the time exemplary loop that forms include but not limited to following ring: the R that a) connects and combine the twice independent appearance that forms ring with this atom with same atoms o(or R +, or other have the variable of similar definition in this article arbitrarily), N (R for example o) 2, the R of twice appearance wherein oForm piperidines-1-base, piperazine-1-base or morpholine-4-base group with the nitrogen-atoms combination; With b) be connected with homoatomic not and combine the twice independent R that occurs that forms ring with those atoms o(or R +, or other have the variable of similar definition in this article arbitrarily), phenyl group for example worked as by the OR of twice appearance oReplace The time, the R of this twice appearance oConnected Sauerstoffatom is together in conjunction with forming fused 6-first ether ring:
Figure A200780029737D00372
Should be appreciated that as twice independent R that occurs o(or R +, or other have the variable of similar definition in this article arbitrarily) atom that connects with each variable in conjunction with the time can form many other rings, and be to be understood that it is restrictive that above-mentioned detailed example is not planned.
[0024] unless otherwise indicated, structure described herein also means all isomeric form (for example enantiomorph, diastereomer and geometrical isomer (or conformer)) that comprise described structure; The for example R of each asymmetric center and S configuration, (Z) and (E) double bond isomer, (Z) and (E) conformer.Therefore, the mixture of the single three-dimensional chemical isomer of The compounds of this invention and enantiomorph, diastereomer and geometrical isomer (or conformer) within the scope of the present invention.Unless otherwise indicated, all tautomeric forms of The compounds of this invention within the scope of the present invention.In addition, unless otherwise indicated, the structure that this paper described only is also intended to comprise compounds different in the existence of one or more isotopic enrichment atoms.For example, replaced or the carbon quilt by deuterium or tritium except hydrogen 13C-or 14The compound that has structure of the present invention beyond the carbon of C-enrichment replaces all within the scope of the invention.For example, this compounds can be used as analysis tool or the probe in the biological assay.
[0025] term " aryl-C1-C6 aliphatic group-" with represent that with the similar term of this class term aromatic yl group passes through C1-C6 aliphatic series linker and is connected with core element.For example, term " aryl-C2-alkyl-expression-CH 2CH 2The Ph group, perhaps styroyl is connected with core element.
[0026] in one embodiment, the invention provides formula I compound:
Figure A200780029737D00381
Wherein:
X is S, SO or SO 2
Z 1Be key or NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7, R wherein 7Be hydrogen, C1-C4 aliphatic group or C (O) C1-C4 aliphatic group;
Z 2Be key, O, CH 2O or C (O);
Ring A is phenyl or 4-7 unit's heterocycle or hetero-aromatic ring, or 10-14 unit two ring hetero-aromatic ring or heterocycles, and wherein said heterocycle or hetero-aromatic ring have 1-4 heteroatoms that is selected from O, N or S; Wherein encircle the optional quilt of A 5 R at the most 1Substituting group replaces;
Wherein:
Z 2Be key, Z 1Be key, NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7Perhaps
Wherein:
Z 1, Z 2And R 6Do not exist, ring A is not aromatic, and ring A forms the volution ring system with ring B;
R 6Be hydrogen or C1-C4 aliphatic group;
M is 1-3;
N is 1-3; Condition is m+n≤4;
R YBe aryl, heteroaryl, cyclic aliphatic base, C1-C6 aliphatic group, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, heterocyclic radical-C1-C6 aliphatic group-or cyclic aliphatic base-C1-C6 aliphatic group-; R wherein YOptional quilt is 5 R at the most 2Substituting group replaces;
R XBe hydrogen, aryl, heteroaryl, C1-C6 aliphatic group, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, R wherein XOptional quilt is 5 R at the most 3Substituting group replaces;
Perhaps, two R XIn conjunction with forming 3-9 unit monocycle, 9-14 unit's dicyclo or 12-14 unit three cyclophane bases, heteroaryl or heterocycle ring system, wherein each hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from O, S and N at the most with the carbon atom that connects them; Wherein said by two R XThe optional quilt of the ring system that forms is 5 R at the most 4Substituting group replaces;
R ZNot existing, is hydrogen, CN, C1-C6 aliphatic group, halo-C1-C6 aliphatic group, O-C1-C6 aliphatic group, O-(halo-C1-C6 aliphatic group), halogen, aryl-C1-C6 aliphatic group or heteroaryl-C1-C6 aliphatic group;
Figure A200780029737D0039094437QIETU
Be singly-bound or two key, condition is when it is two key, then R ZWith a R WDo not exist;
Each R WDo not exist independently, be hydrogen, halogen, oxo, C1-C6 aliphatic group, halo-C1-C6 aliphatic group ,-the O-C1-C6 aliphatic group ,-O-(halo-C1-C6 aliphatic group), aryl, aryl-C1-C6 aliphatic group-, C3-C7 cyclic aliphatic base; Perhaps
Two R WIn conjunction with forming optional C3-C7 cyclic aliphatic base or the heterocycle that replaces, wherein said heterocycle has 3 heteroatomss that are selected from O, S and N at the most together; Wherein said by two R WThe optional quilt of the ring that forms is 5 R at the most 5Substituting group replaces;
Wherein each R that occurs 1, R 2, R 3, R 4And R 5Be Q-R independently M
Wherein Q is a key, or the C1-C6 aliphatic chain, and wherein two non-adjacent MU (methylene unit) at the most of Q are optional and independently by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace;
Wherein each R that occurs MBe independently selected from R ', halogen, NO 2, CN, OR ', SR ', N (R ') 2, NR ' C (O) R ', NR ' C (O) N (R ') 2, NR ' CO 2R ', C (O) R ', CO 2R ', OC (O) R ', C (O) N (R ') 2, OC (O) N (R ') 2, SOR ', SO 2R ', SO 2N (R ') 2, NR ' SO 2R ', NR ' SO 2N (R ') 2, C (O) C (O) R ' or C (O) CH 2C (O) R ';
Wherein each R that occurs is independently selected from hydrogen or optional by the R of 0-5 appearance KThe C that replaces 1-6Aliphatic group; And each R that occurs KBe independently selected from-R V, halogen ,-NO 2,-CN ,-OR V,-SR V,-N (R V) 2,-NR VCOR V,-NR VCON (R V) 2,-NR VCO 2R V,-COR V,-CO 2R V,-OCOR V,-CON (R V) 2,-C (=N-CN) ,-OCON (R V) 2,-SOR V,-SO 2R V,-SO 2N (R V) 2,-NR VSO 2R V,-NR VSO 2N (R V) 2,-COCOR V, COCH 2COR V,-OP (O) (OR V) 2,-P (O) (OR V) 2,-OP (O) 2OR V,-P (O) 2OR V,-PO (R V) 2Or-OPO (R V) 2, R wherein VBe hydrogen or unsubstituted C 1-6Aliphatic group; And
Wherein each R ' that occurs is hydrogen independently, and is optional by the R of 0-5 appearance M1The C that replaces 1-6Aliphatic group; And each R that occurs M1Be independently selected from-R T, halogen ,-NO 2,-CN ,-OR T,-SR T,-N (R T) 2,-NR TCOR T,-NR TCON (R T) 2,-NR TCO 2R T,-COR T,-CO 2R T,-OCOR T,-CON (R T) 2,-C (=N-CN) ,-OCON (R T) 2,-SOR T,-SO 2R T,-SO 2N (R T) 2,-NR TSO 2R T,-NR TSO 2N (R T) 2,-COCOR T,-COCH 2COR T,-OP (O) (OR T) 2,-P (O) (OR T) 2,-OP (O) 2OR T,-P (O) 2OR T,-PO (R T) 2Or-OPO (R T) 2, R wherein TBe hydrogen or unsubstituted C 1-6Aliphatic group; Perhaps R ' is that 3-8-unit is saturated, part is unsaturated or the complete undersaturated 0-3 of having a heteroatomic monocycle that is independently selected from nitrogen, oxygen or sulphur, or 8-12 unit is saturated, part is unsaturated or the complete undersaturated 0-5 of having a heteroatomic dicyclo that is independently selected from nitrogen, oxygen or sulphur, and wherein said monocycle or dicyclo are optional by the R of 0-5 appearance UReplace; And each R that occurs UBe independently selected from that 3-8-unit is saturated, part is unsaturated or complete undersaturated monocycle, its optional by 0-3 appearance-R Q1Replacement also has 0-3 the heteroatoms that is independently selected from nitrogen, oxygen or sulphur, perhaps R UBe-R Q, halogen ,=O ,=NR Q,-NO 2,-CN ,-OR Q,-SR Q,-N (R Q) 2,-NR QCOR Q,-NR QCON (R Q) 2,-NR QCO 2R Q,-COR Q,-CO 2R Q,-OCOR Q,-CON (R Q) 2,-C (=N-CN) ,-OCON (R Q) 2,-SOR Q,-SO 2R Q,-SO 2N (R Q) 2,-NR QSO 2R Q,-NR QSO 2N (R Q) 2,-COCOR Q,-COCH 2COR Q,-OP (O) (OR Q) 2,-P (O) (OR Q) 2,-OP (O) 2OR Q,-P (O) 2OR Q,-PO (R Q) 2Or-OPO (R Q) 2, R wherein QAnd R Q1Be hydrogen or unsubstituted C 1-6Aliphatic group; Perhaps the R ' of the R of R and R ', twice appearance or twice appearance is saturated with the atom combination formation 3-12 unit that is connected them, part is unsaturated or the complete undersaturated 0-4 of having a heteroatomic monocycle or a dicyclo that is independently selected from nitrogen, oxygen or sulphur, and wherein said monocycle or dicyclo are optional by the R of 0-5 appearance T1Replace; And each R that occurs T1Be independently selected from-R S, halogen ,=O ,=NR S,-NO 2,-CN ,-OR S,-SR S,-N (R S) 2,-NR SCOR S,-NR SCON (R S) 2,-NR SCO 2R S,-COR S,-CO 2R S,-OCOR S,-CON (R S) 2,-C (=N-CN) ,-OCON (R S) 2,-SOR S,-SO 2R S,-SO 2N (R S) 2,-NR SSO 2R S,-NR SSO 2N (R S) 2,-COCOR S,-COCH 2COR S,-OP (O) (OR S) 2,-P (O) (OR S) 2,-OP (O) 2OR S,-P (O) 2OR S,-PO (R S) 2Or-OPO (R S) 2, R wherein SBe hydrogen or unsubstituted C 1-6Aliphatic group.
[0027] in the embodiment of formula I, Z 2Be key, R 6Be hydrogen, and Z 1It is key.
[0028] in another embodiment of formula I, Z 2Be key, R 6Be hydrogen, and Z 1Be NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7
[0029] in the embodiment of formula I, Z 2-R 6Not hydrogen and Z 1It is key.
[0030] in the embodiment of formula I, Z 2-R 6Not hydrogen and Z 1Be NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7
[0031] in the embodiment of formula I,
Figure A200780029737D0041095012QIETU
It is singly-bound.
[0032] in the embodiment of formula I,
Figure A200780029737D0041095012QIETU
Be singly-bound, and two R WAll be hydrogen.
[0033] in the embodiment of formula I, R ZIf existed would be C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
[0034] in the embodiment of formula I, R ZIf exist then be fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
[0035] in the embodiment of formula I, at least one R WBe C1-C6 alkyl, halo-C1-C6 alkyl or-the O-C1-C6 alkyl.
[0036] in the embodiment of formula I, at least one R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
[0037] in the embodiment of formula I, a R WBe hydrogen, and another R WBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
[0038] in the embodiment of formula I, a R WBe hydrogen, and another R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
[0039] in the embodiment of formula I, R YBe the optional C1-C6 aliphatic group that is replaced by one or more following groups: halogen, OH ,-the C1-C4 alkoxyl group ,-C1-C4 carbalkoxy or two-(C1-C4 alkyl) amino-.
[0040] in the embodiment of formula I, R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl group, 2-methoxyl group-ethyl, 3-ethoxy propyl group, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(methylol)-3-methyl-butyl, allyl group, ethynyl, 2-(diethylin) ethyl, 1-methyl-2-methoxyl group-ethyl, 3-hydroxyl-2,2-dimethyl-propyl group, 2,2,2-trifluoroethyl, 3,3,3-three fluoro-propyl group or 2,2,3,3,3-five fluoro-propyl group.
[0041] in the embodiment of formula I, R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl group.
[0042] in the embodiment of formula I, R YBe the C1-C6 aliphatic group that replaces of C3-C8 cyclic aliphatic base or C3-C8 cyclic aliphatic base-.
[0043] in the embodiment of formula I, R YBe the C3-C6 cycloalkyl or the C1-C6 alkyl of C3-C6 cycloalkyl substituted-.
[0044] in the embodiment of formula I, R YBe cyclopropyl, cyclohexyl, cyclohexyl methyl-, cyclopropyl methyl-or cyclohexyl ethyl-.
[0045] in the embodiment of formula I, R YBe pyridyl (C1-C6)-alkyl-, tetrahydrofuran base (C1-C6 alkyl)-or N-(C1-C4 alkyl)-pyrrolidyl-(C1-C6 alkyl)-.
[0046] in the embodiment of formula I, tetrahydrofuran (THF)-2-base-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridine-2-base-ethyl-, pyridin-4-yl-methyl-, 1H-indazole-5-base or 2-(N-methyl)-tetramethyleneimine-2-base-ethyl-.
[0047] in the embodiment of formula I, R YBe phenyl or (phenyl)-replace the C1-C6 aliphatic group-, each is optional by 5 R at the most 2Substituting group replaces, described R 2Substituting group is independently selected from halogen or has 1-3 the first heterocycle of heteroatomic 5-6 that is independently selected from N, O or S.
[0048] in the embodiment of formula I, R YBe phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyl methyl-, 4-morpholino phenyl-, 2-piperidyl phenyl-or styroyl-.
[0049] in the embodiment of formula I, a R XBe hydrogen, and another R XBe optional quilt 5 R at the most 3Aromatic ring or hetero-aromatic ring that substituting group replaces, described R 3Substituting group is selected from: C1-C6 aliphatic group, phenyl, halogen, C3-C6 cyclic aliphatic base, and perhaps 4-7 unit heterocycle, wherein said heterocycle is optional by 3 R at the most USubstituting group replaces, and wherein said hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from N, O or S at the most.
[0050] in the embodiment of formula I, a R XBe hydrogen, and another R XBe to have 2 R at the most 3Phenyl or pyridyl that substituting group replaces, described R 3Substituting group is independently selected from halogen or 4-7 unit heterocycle, and the optional quilt of wherein said heterocycle is 2 R at the most USubstituting group replaces, and wherein said heterocycle has 3 heteroatomss that are selected from N, O or S at the most.
[0051] in the embodiment of formula I, a R XBe hydrogen, and another R XBe by 4-7 unit's heterocyclic substituted and at 3 phenyl that replaced by halogen at 2.
[0052] in the embodiment of formula I, a R XBe hydrogen, and another R XIt is phenyl or the phenyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
[0053] in the embodiment of formula I, a R XBe hydrogen, and another R XIt is pyridyl or the pyridyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
[0054] in the embodiment of formula I, a R XBe hydrogen, and another R XBe optional phenyl or the heteroaryl that is replaced by one or more substituting groups, described substituting group be independently selected from C1-C6 aliphatic group, cyano group, halogen, halo-C1-C6 aliphatic group-, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, aralkoxy, two (C1-C6 aliphatic group) is amino-,-the O-C1-C6 aliphatic group ,-S (O)-C1-C6 aliphatic group or-S (O) 2-C1-C6 aliphatic group.
[0055] in the embodiment of formula I, a R XBe hydrogen, and another R XBe optional quilt 5 R at the most 3Substituting group replaces and has 3 heteroatomic C3-C7 cyclic aliphatic basic ring or heterocycle aliphatic series basic rings that are selected from O, N or S at the most, and wherein said ring is optional to condense with one or more phenyl ring or hetero-aromatic ring.
[0056] in the embodiment of formula I, described R XBe selected from cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, tetrahydrochysene-2H-pyranyl, tetrahydrochysene-2H-thiapyran base, 9H-fluorenes-9-base or piperidyl.
[0057] in the embodiment of formula I, two R XIn conjunction with forming 3-9 unit monocycle, 9-14 unit's dicyclo or 12-14 unit three cyclophane bases, heteroaryl or heterocycle ring system, wherein each hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from O, S and N at the most with the carbon atom that connects them; Wherein said by two R XThe optional quilt of the ring system that forms is 5 R at the most 4Substituting group replaces.
[0058] in the embodiment of formula I, described ring system is selected from 9H-fluorenes-9-base, tetrahydrochysene-2H-pyrans-4-base, tetrahydrochysene-2H-thiapyran-4-base, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclohexenyl, piperidyl or 1-benzyl-piperidin-4-yl.
[0059] in another embodiment of formula I, described compound is a formula I-A compound:
Wherein:
Ring A is by carbon atom C AWith the 4-7 unit heterocycle of described piperidine ring formation volution ring system, wherein encircle the optional and optional quilt of A 5 R at the most 1Phenyl ring or hetero-aromatic ring that substituting group replaces condense;
Wherein said ring A except the azo-cycle atom, has 2 other ring hetero atoms that are selected from O, N or S at the most;
Wherein encircle A, except oxo group, optional quilt is 5 R at the most 1Substituting group replaces;
R 1, R X, R Y, R Z, R WWith X as defined herein.
[0060] in the embodiment of formula I-A,
Figure A200780029737D0041095012QIETU
Be singly-bound, and R ZIf exist then be hydrogen.
[0061] in the embodiment of formula I-A,
Figure A200780029737D0041095012QIETU
Be singly-bound, and R ZBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
[0062] in the embodiment of formula I-A, R ZIf exist then be fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
[0063] in the embodiment of formula I-A, at least one R WBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
[0064] in the embodiment of formula I-A, at least one R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
[0065] in the embodiment of formula I-A,
Figure A200780029737D0041095012QIETU
Be singly-bound, a R WBe hydrogen, and another R WBe C1-C6 alkyl, halo-C1-C6 alkyl or-the O-C1-C6 alkyl.
[0066] in the embodiment of formula I-A, a R WBe hydrogen, and another R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
[0067] in the embodiment of formula I-A,
Figure A200780029737D0041095012QIETU
Be singly-bound, and each R WBe hydrogen.
[0068] in the embodiment of formula I-A, R YBe the optional C1-C6 aliphatic group that is replaced by one or more following groups: halogen, OH, C1-C4 alkoxyl group, C1-C4 carbalkoxy or two-(C1-C4 alkyl) amino-.
[0069] in the embodiment of formula I-A, R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl group, 2-methoxyl group-ethyl, 3-ethoxy propyl group, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(methylol)-3-methyl-butyl, allyl group, ethynyl, 2-(diethylin) ethyl, 1-methyl-2-methoxyl group-ethyl, 3-hydroxyl-2,2-dimethyl-propyl group, 2,2,2-trifluoroethyl, 3,3,3-three fluoro-propyl group or 2,2,3,3,3-five fluoro-propyl group.
[0070] in the embodiment of formula I-A, R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl group.
[0071] in the embodiment of formula I-A, R YBe the C1-C6 aliphatic group that replaces of C3-C8 cyclic aliphatic base or C3-C8 cyclic aliphatic base-.
[0072] in the embodiment of formula I-A, R YBe the C3-C6 cycloalkyl or the C1-C6 alkyl of C3-C6 cycloalkyl substituted-.
[0073] in the embodiment of formula I-A, R YBe cyclopropyl, cyclohexyl, cyclohexyl methyl-, cyclopropyl methyl-or cyclohexyl ethyl-.
[0074] in the embodiment of formula I-A, R YBe pyridyl (C1-C6) alkyl-, tetrahydrofuran base (C1-C6 alkyl)-, N-(C1-C4 alkyl)-pyrrolidyl-(C1-C6 alkyl)-.
[0075] in the embodiment of formula I-A, R YBe tetrahydrofuran (THF)-2-base-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridine-2-base-ethyl-, pyridin-4-yl-methyl-, 1H-indazole-5-base or 2-(N-methyl)-tetramethyleneimine-2-base-ethyl-.
[0076] in the embodiment of formula I-A, R YBe optional quilt 5 R at the most 2The C1-C6 aliphatic group of the phenyl that substituting group replaces or (phenyl)-replacement-, described R 2Substituting group is independently selected from halogen or 5-6 unit has 1-3 heteroatomic heterocycle that is selected from N, O or S.
[0077] in the embodiment of formula I-A, R YBe phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyl methyl-, 4-morpholino phenyl-, 2-piperidyl phenyl-or styroyl-.
[0078] in the embodiment of formula I-A,
Figure A200780029737D0041095012QIETU
Be singly-bound, a R XBe hydrogen, and another R XBe optional by at the most 5 be independently selected from following R 3Aromatic ring or hetero-aromatic ring that substituting group replaces: C1-C6 aliphatic group, phenyl, halogen, C3-C6 cyclic aliphatic base, or have 3 R at the most UThe first heterocycle of substituent 4-7, wherein said hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from N, O or S at the most.
[0079] in the embodiment of formula I-A, a R XBe hydrogen, and another R XBe to have 2 R at the most 5Substituent phenyl or pyridyl, described R 5Substituting group is independently selected from halogen or has 2 R at the most UThe first heterocycle of substituent 4-7, wherein said heterocycle has 3 heteroatomss that are selected from N, O or S at the most.
[0080] in the embodiment of formula I-A, a R XBe hydrogen, and another R XBe by 4-7 unit's heterocyclic substituted and at 3 phenyl that replaced by halogen at 2.
[0081] in the embodiment of formula I-A, a R XBe hydrogen, and another R XIt is phenyl or the phenyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
[0082] in the embodiment of formula I-A, a R XBe hydrogen, and another R XIt is pyridyl or the pyridyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base, 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
[0083] in the embodiment of formula I-A, a R XBe hydrogen, and another R XBe optional to be independently selected from phenyl or the heteroaryls that following substituting group replaces by one or more: C1-C6 aliphatic group, cyano group, halogen, halo-C1-C6 aliphatic group-, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, aralkoxy, two (C1-C6 aliphatic group) is amino-,-the O-C1-C6 aliphatic group ,-S (O)-C1-C6 aliphatic group or-S (O) 2-C1-C6 aliphatic group.
[0084] in the embodiment of formula I-A, at least one R XBe hydrogen, and another R XBe C3-C7 cyclic aliphatic or heterocycle aliphatic series ring, its optional quilt is 5 R at the most 3Substituting group replaces and has 3 heteroatomss that are selected from O, N or S at the most, and wherein said ring is optional to condense with one or more phenyl ring or hetero-aromatic ring.
[0085] in the embodiment of formula I-A, described R XBe selected from cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, tetrahydrochysene-2H-pyranyl, tetrahydrochysene-2H-thiapyran base, 9H-fluorenes-9-base or piperidyl.
[0086] in the embodiment of formula I-A,
Figure A200780029737D0041095012QIETU
Be singly-bound, two R XIn conjunction with forming 3-9 unit monocycle, 9-14 unit's dicyclo or 12-14 unit three cyclophane bases, heteroaryl or heterocycle ring system, wherein each hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from O, S and N at the most with the carbon atom that connects them; Wherein said by two R XThe optional quilt of the ring system that forms is 5 R at the most 4Substituting group replaces.
[0087] in the embodiment of formula I-A, described ring system is selected from 9H-fluorenes-9-base, tetrahydrochysene-2H-pyrans-4-base, tetrahydrochysene-2H-thiapyran-4-base, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclohexenyl, piperidyl or 1-benzyl-piperidin-4-yl.
[0088] in the embodiment of formula I or I-A, ring A is selected from:
Figure A200780029737D00481
A-iii or A-iv;
Wherein:
P is 0-2;
Q is 0-2; Condition is p+q≤2;
Each W AAnd W BBe independently selected from NR 1, O, S, SO, SO 2, C (R 1) 2Or=CR 1(when p or q are 2);
W EBe-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-;
W FDo not exist or be selected from-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-; Condition is W EAnd W FThe two is not simultaneously=N-or-N (R 1)-;
Ring B1 is optional quilt 5 R at the most 1Phenyl ring that substituting group replaces or 5-6 unit hetero-aromatic ring; And
R 1As defined herein.
[0089] in another embodiment of formula I or I-A, ring A has formula A-i.
[0090] in the embodiment of formula I or I-A, ring A has formula A-ii.
[0091] in the embodiment of formula I or I-A, ring A has formula A-iii.
[0092] in the embodiment of formula I or I-A, ring A has formula A-iv.
[0093] in the embodiment of formula I or I-A, W EAnd W FThe two all is=C (R 1).
[0094] in the embodiment of formula I or I-A, W EBe=C (R 1)-W FBe=N-.
[0095] in the embodiment of formula I or I-A, p be 0 and q be 0.
[0096] in the embodiment of formula I or I-A, p be 1 and q be 0.
[0097] in the embodiment of formula I or I-A, p be 0 and q be 2.
[0098] in the embodiment of formula I or I-A, W ABe NR 1
[0099] in the embodiment of formula I or I-A, W ABe O.
[00100] in the embodiment of formula I or I-A, W ABe C (R 1) 2
[00101] in the embodiment of formula I or I-A, W ABe C (R 1) 2And R 1Be hydrogen.
[00102] in the embodiment of formula I or I-A, W BBe NR 1
[00103] in the embodiment of formula I or I-A, W BBe O.
[00104] in the embodiment of formula I or I-A, W BBe C (R 1) 2.
[00105] in the embodiment of formula I or I-A, W BBe C (R 1) 2And R 1Be hydrogen.
[00106] in the embodiment of formula I or I-A, p is 2 and W ABe C (R 1) 2-C (R 1) 2Or-CR 1=CR 1-.
[00107] in the embodiment of formula I or I-A, q is 2 and W BBe C (R 1) 2-C (R 1) 2Or-CR 1=CR 1-.
[00108] in the embodiment of formula I or I-A, ring A is selected from:
Figure A200780029737D0050182237QIETU
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00109] in the embodiment of formula I or I-A, ring A is selected from:
Figure A200780029737D0050182312QIETU
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00110] in the embodiment of formula I or I-A, ring A is selected from:
Figure A200780029737D0051182124QIETU
The optional quilt of wherein said ring system is 4 R at the most 1Substituting group replaces.
[00111] in the embodiment of formula I or I-A, ring A is selected from:
The optional quilt of wherein said ring system is 4 R at the most 1Substituting group replaces.
[00112] in another embodiment of formula I or I-A, described compound is a formula I-B compound:
Figure A200780029737D00513
Wherein encircling A is optional and optional quilt 5 R at the most 1Phenyl ring that substituting group replaces or hetero-aromatic ring condensed 4-7 unit heterocycle;
Wherein said ring A except the azo-cycle atom, contains 2 other ring hetero atoms that are selected from O, N or S at the most;
Wherein encircle A, except oxo group, optional quilt is 5 R at the most 1Substituting group replaces;
R 1, R X, R YWith X as defined herein.
[00113] in the embodiment of formula I-B, R YBe optional C1-C6 aliphatic group, OH, C1-C4 alkoxyl group, C1-C4 carbalkoxy or two-(the C1-C4 alkyl) that is replaced by one or more halogens amino-.
[00114] in the embodiment of formula I-B, R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl group, 2-methoxyl group-ethyl, 3-ethoxy propyl group, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(methylol)-3-methyl-butyl, allyl group, ethynyl, 2-(diethylin) ethyl, 1-methyl-2-methoxyl group-ethyl, 3-hydroxyl-2,2-dimethyl-propyl group, 2,2,2-trifluoroethyl, 3,3,3-three fluoro-propyl group or 2,2,3,3,3-five fluoro-propyl group.
[00115] in the embodiment of formula I-B, R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl group.
[00116] in the embodiment of formula I-B, R YBe the C1-C6 aliphatic group that replaces of C3-C8 cyclic aliphatic base or C3-C8 cyclic aliphatic base-
[00117] in the embodiment of formula I-B, R YBe the C3-C6 cycloalkyl or the C1-C6 alkyl of C3-C6 cycloalkyl substituted-.
[00118] in the embodiment of formula I-B, R YBe cyclopropyl, cyclohexyl, cyclohexyl methyl-, cyclopropyl methyl-or cyclohexyl ethyl-.
[00119] in the embodiment of formula I-B, R YBe pyridyl (C1-C6) alkyl-, tetrahydrofuran base (C1-C6 alkyl)-, N-(C1-C4 alkyl)-pyrrolidyl-(C1-C6 alkyl)-.
[00120] in the embodiment of formula I-B, R YBe tetrahydrofuran (THF)-2-base-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridine-2-base-ethyl-, pyridin-4-yl-methyl-, 1H-indazole-5-base or 2-(N-methyl)-tetramethyleneimine-2-base-ethyl-.
[00121] in the embodiment of formula I-B, R YBe the C1-C6 aliphatic group of phenyl or (phenyl)-replacement, optional separately quilt is 5 R at the most 2Substituting group replaces, described R 2Substituting group is independently selected from halogen or has 1-3 the first heterocycle of heteroatomic 5-6 that is selected from N, O or S.
[00122] in the embodiment of formula I-B, R YBe phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyl methyl-, 4-morpholino phenyl-, 2-piperidyl phenyl-or styroyl-.
[00123] in the embodiment of formula I-B, R XBe optional by at the most 5 be independently selected from following R 3Aromatic ring or hetero-aromatic ring that substituting group replaces: C1-C6 aliphatic group, phenyl, halogen, C3-C6 cyclic aliphatic base, or have 3 R at the most UThe first heterocycle of substituent 4-7, wherein said hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from N, O or S at the most.
[00124] in the embodiment of formula I-B, R XBe to have 2 R at the most 3Phenyl or pyridyl that substituting group replaces, described R 3Substituting group is independently selected from halogen or 4-7 unit heterocycle, and the optional quilt of wherein said heterocycle is 2 R at the most USubstituting group replaces, and wherein said heterocycle has 3 heteroatomss that are selected from N, O or S at the most.
[00125] in the embodiment of formula I-B, R XBe by 4-7 unit's heterocyclic substituted and at 3 phenyl that replaced by halogen at 2.
[00126] in the embodiment of formula I-B, R XIt is pyridyl, phenyl or the phenyl that is replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
[00127] in the embodiment of formula I-B, R XBe optional phenyl or the heteroaryl that is replaced by one or more substituting groups, described substituting group be independently selected from C1-C6 aliphatic group, cyano group, halogen, halo-C1-C6 aliphatic group-, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, aralkoxy, two (C1-C6 aliphatic group) is amino-,-the O-C1-C6 aliphatic group ,-S (O)-C1-C6 aliphatic group or-S (O) 2-C1-C6 aliphatic group.
[00128] in the embodiment of formula I-B, R XBe C3-C7 cyclic aliphatic or heterocycle aliphatic series ring, its optional quilt is 5 R at the most 3Substituting group replaces and has 3 heteroatomss that are selected from O, N or S at the most, and wherein said ring is optional to condense with one or more phenyl ring or hetero-aromatic ring.
[00129] in the embodiment of formula I-B, described condensed ring is selected from cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, tetrahydrochysene-2H-pyranyl, tetrahydrochysene-2H-thiapyran base, 9H-fluorenes-9-base or piperidyl.
[00130] in the embodiment of formula I-B, ring A is selected from:
Wherein:
W CBe-C (R 1) 2, C (O) or=CR 1-;
R is 0-2;
W DBe N or=C-;
W EBe-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-;
W FDo not exist or be selected from-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-; Condition is W EAnd W FThe two is not simultaneously=N-or-N (R 1)-;
Y is C (O), S (O) or S (O) 2
Ring B1 is optional quilt 5 R at the most 1Phenyl ring that substituting group replaces or 5-6 unit hetero-aromatic ring; And
Figure A200780029737D0041095012QIETU
Be singly-bound or two key;
R 1As defined herein.
[00131] in the embodiment of formula I-B, W CBe-C (R 1) 2
[00132] in another embodiment of formula I-B, W CBe=CR 1
[00133] in the embodiment of formula I-B, W CBe C (O).
[00134] in the embodiment of formula I-B, r is 0.
[00135] in the embodiment of formula I-B, r is 1.
[00136] in the embodiment of formula I-B, r is 2.
[00137] in the embodiment of formula I-B, W DBe N.
[00138] in the embodiment of formula I-B, W DBe=C-.
[00139] in the embodiment of formula I-B, Y is C (O).
[00140] in the embodiment of formula I-B, Y is S (O).
[00141] in the embodiment of formula I-B, Y is S (O) 2
[00142] in the embodiment of formula I-B, ring A is selected from:
Figure A200780029737D0055174544QIETU
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00143] in the embodiment of formula I-B, ring A is selected from:
Figure A200780029737D0055174624QIETU
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00144] in the embodiment of formula I-B, ring A optional by at the most 5 be selected from following substituting group and replace: C1-C6 aliphatic group, C1-C6 aliphatic group-oxygen base, C1-C6 halogenated aliphatic base, CN, halogen, oxo, the optional C3-C7 cyclic aliphatic base that replaces, or optional replace be selected from following ring: phenyl, furyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl (imadazolyl), imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, pyridyl, pyrimidyl, piperidyl, piperazinyl or morpholinyl.
[00145] in the embodiment of formula I-B, at R 1In, Q is a key.
[00146] in the embodiment of formula I-B, at R 1In, Q-R MBe Q-R '.
[00147] in the embodiment of formula I-B, Q exists and R is a hydrogen.
[00148] in the embodiment of formula I-B, Q exists and R is the C1-C6 aliphatic group.
[00149] in the embodiment of formula I-B, R is methyl, ethyl, propyl group or butyl.
[00150] in the embodiment of formula I-B, R ' is a hydrogen.
[00151] in the embodiment of formula I-B, R ' is the C1-C8 aliphatic group, and it is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3Or OCHF 2, two MU (methylene unit) at the most of wherein said C1-C8 aliphatic group are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00152] in the embodiment of formula I-B, R ' is that 3-8 unit is saturated, part is unsaturated or the complete undersaturated 0-3 of having a heteroatomic monocycle that is independently selected from nitrogen, oxygen or sulphur, wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO--CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00153] in the embodiment of formula I-B, R ' is the heteroatomic dicyclo ring system that 8-12 unit is saturated, part is unsaturated or the undersaturated 0-5 of having is independently selected from nitrogen, oxygen or sulphur fully; Wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00154] in the embodiment of formula I-B, the optional 3-12 unit that replaces is saturated, part is unsaturated or the complete undersaturated 0-4 of having a heteroatomic monocycle or a dicyclo that is independently selected from nitrogen, oxygen or sulphur in conjunction with forming with their atom of connection for the R ' of twice appearance, wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00155] in one embodiment, compound of the present invention comprises those compounds among table 1 and the table 1A.
[00156] in another embodiment, compound of the present invention comprises those compounds in the table 1.
[00157] in another embodiment, compound of the present invention comprises those compounds among the table 1A.
[00158] in another embodiment, compound of the present invention comprises those compounds except that compound 85,97 and 105 in table 1A and the table 1.
[00159] in another embodiment, compound of the present invention comprises those compounds except that compound 85,97 and 105 in the table 1.
[00160] in one embodiment, the invention provides formula I ' compound:
Figure A200780029737D00581
Wherein:
X is S, SO or SO 2
Z exists or does not exist;
Wherein:
When Z exists, then encircle A and be connected with ring B by singly-bound;
When Z does not exist, then encircle A and form the volution ring system with ring B;
Ring A is 4-7 unit's heterocycle or hetero-aromatic ring or 10-14 unit bicyclic heterocycle, wherein encircles A and has 1-4 heteroatoms that is selected from O, N or S;
Wherein encircle the optional quilt of A 5 R at the most 1Substituting group replaces;
M is 1-3;
N is 1-3; Condition is m+n≤4;
R YBe aryl, heteroaryl, cyclic aliphatic base, C1-C6 aliphatic group, aryl-aliphatic group or cyclic aliphatic base-aliphatic group; R wherein YOptional quilt is 5 R at the most 2Substituting group replaces;
R XBe hydrogen, halogen, aryl, heteroaryl, C1-C6 aliphatic group, aryl-C1-C6 aliphatic group, heteroaryl-C1-C6 aliphatic group, wherein R XOptional quilt is 5 R at the most 3Substituting group replaces;
Perhaps, two R XIn conjunction with forming 3-9 unit's cyclic aliphatic base or heterocycle, wherein said heterocycle has 3 heteroatomss that are selected from O, S and N at the most with the carbon atom that connects them; The optional quilt of wherein said ring is 3 R at the most 3Substituting group replaces;
Wherein said by two R XThe optional quilt of the ring that forms is 5 R at the most 4Substituting group replaces;
R ZNot existing, is hydrogen, CN, C1-C6 aliphatic group, halo-C1-C6 aliphatic group, O-C1-C6 aliphatic group, O-(halo-C1-C6 aliphatic group), halogen, aryl-C1-C6 aliphatic group or heteroaryl-C1-C6 aliphatic group;
Figure A200780029737D0059174847QIETU
Be singly-bound or two key, condition is as its R then when being two key ZWith a R WDo not exist;
R WBe hydrogen, halogen, oxo, C1-C6 aliphatic group, halo-C1-C6 aliphatic group, O-C1-C6 aliphatic group, O-(halo-C1-C6 aliphatic group), aryl, aryl-C1-C6 aliphatic group, C3-C7 cyclic aliphatic base independently; Perhaps
Two R WIn conjunction with forming optional C3-C7 cyclic aliphatic base or the heterocycle that replaces, wherein said heterocycle has 3 heteroatomss that are selected from O, S and N at the most together; Wherein said by two R WThe optional quilt of the ring that forms is 5 R at the most 5Substituting group replaces;
Wherein each R that occurs 1, R 2, R 3, R 4And R 5Be Q-R independently M
Wherein Q is a key, or C 1-C 6Aliphatic chain, wherein two non-adjacent MU (methylene unit) at the most of Q are chosen wantonly and are replaced by following group: CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR;
Wherein each R that occurs MBe independently selected from R ', halogen, NO 2, CN, OR ', SR ', N (R ') 2, NR ' C (O) R ', NR ' C (O) N (R ') 2, NR ' CO 2R ', C (O) R ', CO 2R ', OC (O) R ', C (O) N (R ') 2, OC (O) N (R ') 2, SOR ', SO 2R ', SO 2N (R ') 2, NR ' SO 2R ', NR ' SO 2N (R ') 2, C (O) C (O) R ' or C (O) CH 2C (O) R ', wherein each R that occurs is independently selected from hydrogen or the optional C that replaces 1-6Aliphatic group;
Wherein each R ' that occurs be independently selected from hydrogen or optional replace be selected from following group: C 1-8Aliphatic group, C 6-10Aryl, have the hetero-aromatic ring of 5-10 annular atoms or have the heterocycle of 3-10 annular atoms, perhaps wherein R and R ' with the atom that is connected them in conjunction with or the R ' of twice appearance have 0-3 heteroatomic 5-8 unit cycloalkyl, heterocyclic radical, aryl or heteroaryl ring that is independently selected from nitrogen, oxygen or sulphur with the atom that connects them in conjunction with forming.
[00161] in one embodiment,
Figure A200780029737D0041095012QIETU
Be a two key, and R ZWith a R WDo not exist.
[00162] in another embodiment,
Figure A200780029737D0041095012QIETU
It is singly-bound.In another embodiment, R WBe hydrogen, and another not.In another embodiment, two R WAll be hydrogen.
[00163] in one embodiment, m be 1 and n be 1.In another embodiment, m be 1 and n be 2.Perhaps, m be 2 and n be 1.Perhaps, m be 2 and n be 2.
[00164] in another embodiment, R ZIt is C1-C6 alkyl or halo-C1-C6 alkyl.Perhaps, R ZBe-the O-C1-C6 alkyl.Exemplary R ZComprise fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe, OEt etc.
[00165] in another embodiment, R WIt is C1-C6 alkyl or halo-C1-C6 alkyl.Perhaps, R WBe-the O-C1-C6 alkyl.Exemplary R WComprise fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe, OEt etc.
[00166] in another embodiment, two R WChoose C3-C9 cycloalkyl or the 3-9 unit heterocycle that replaces with the carbon atom that connects them wantonly in conjunction with forming.This exemplary class ring comprises cyclopropyl, cyclopentyl or cyclohexyl.
[00167] in one embodiment, R YBe optional C1-C6 aliphatic group, OH, C1-C4 alkoxyl group, the C1-C4 carbalkoxy or two-(C1-C4 alkyl) amino that is replaced by one or more halogens.Exemplary embodiment comprises methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl group, 2-methoxyl group-ethyl, 3-ethoxy propyl group, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(methylol)-3-methyl-butyl, allyl group, ethynyl, 2-(diethylin) ethyl, 1-methyl-2-methoxyl group-ethyl, 3-hydroxyl-2,2-dimethyl-propyl group, 2,2,2-trifluoroethyl, 3,3,3-three fluoro-propyl group or 2,2,3,3,3-five fluoro-propyl group.
[00168] in another embodiment, R YIt is the C1-C6 aliphatic group that C3-C8 cyclic aliphatic base or C3-C8 cyclic aliphatic base replace.In one embodiment, R YIt is the C1-C6 alkyl of C3-C6 cycloalkyl or C3-C6 cycloalkyl substituted.Illustrative embodiments comprises cyclopropyl, cyclohexyl, cyclohexyl methyl, cyclopropyl methyl or cyclohexyl ethyl.
[00169] in another embodiment, R YBe pyridyl (C1-C6) alkyl, tetrahydrofuran base (C1-C6 alkyl), N-(C1-C4 alkyl)-pyrrolidyl-(C1-C6 alkyl).Illustrative embodiments comprises tetrahydrofuran (THF)-2-ylmethyl, pyridin-3-yl-methyl, pyridin-4-yl-ethyl, pyridine-2-base-ethyl, pyridin-4-yl-methyl, 1H-indazole-5-base or 2-(N-methyl)-tetramethyleneimine-2-base-ethyl.
[00170] in another embodiment, R YIt is the C1-C6 aliphatic group of the optional phenyl that replaces or (the optional phenyl that replaces)-replacement.Illustrative embodiments comprises phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyl methyl or styroyl.
[00171] in one embodiment, two R XAll be hydrogen.
[00172] in one embodiment, R XBe phenyl or as the heteroaryl of pyridyl, wherein said phenyl or heteroaryl be optional be optionally substituted have at the most that 3 heteroatomic 3-7 unit's heterocycle or hetero-aromatic rings that are selected from O, S or N replace.Exemplary R XComprise phenyl, pyridyl or the phenyl that is replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, 1-H-pyrazol-1-yl, imidazoles-1-base or pyridyl.
[00173] in another embodiment, R XBe optional: C1-C6 aliphatic group, cyano group, halogen, halo-C1-C6 aliphatic group, aryl-C1-C6 aliphatic group, heteroaryl-C1-C6 aliphatic group, aralkoxy, two (C1-C6 aliphatic group) amino, O-C1-C6 aliphatic group, S (O)-C1-C6 aliphatic group or S (O) by one or more phenyl or heteroaryls that are independently selected from following substituting group replacement 2-C1-C6 aliphatic group.
[00174] in another embodiment, R XBe to choose the C3-C7 cyclic aliphatic base that replaces wantonly or have 3 heteroatomic heterocycle aliphatic series basic rings that are selected from O, N or S at the most, wherein said ring is optional to condense with one or more phenyl ring or hetero-aromatic ring.Exemplary ring comprises cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, tetrahydrochysene-2H-pyranyl, tetrahydrochysene-2H-thiapyran base, 9H-fluorenes-9-base, piperidyl etc.
[00175] in another embodiment, two R XChoose 3-9 unit's cyclic aliphatic base or the heterocyclic radical that replaces, monocycle, two rings or three rings with the carbon atom that connects them wantonly in conjunction with forming.Illustrative embodiments comprises 9H-fluorenes-9-base, tetrahydrochysene-2H-pyrans-4-base, tetrahydrochysene-2H-thiapyran-4-base, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclohexenyl, piperidyl or 1-benzyl-piperidin-4-yl.
[00176] in another embodiment, the invention provides formula I '-A compound:
Figure A200780029737D00621
Wherein:
Ring A is by carbon atom C AWith the 4-7 unit heterocycle of described piperidine ring formation volution ring system, optional phenyl ring or the hetero-aromatic ring with optional replacement of wherein said heterocycle condenses;
Wherein said ring A except the azo-cycle atom, contains 2 other ring hetero atoms that are selected from O, N or S at the most;
Wherein encircle A, except oxo group, optional quilt is 5 R at the most 1Substituting group replaces;
R 1, R X, R Y, R Z, R WWith X as hereinbefore defined.
[00177] in one embodiment,
Figure A200780029737D0041095012QIETU
Be a two key, and R ZWith a R WDo not exist;
[00178] in another embodiment,
Figure A200780029737D0041095012QIETU
It is singly-bound.
[00179] in another embodiment, R ZIt is C1-C6 alkyl or halo-C1-C6 alkyl.Perhaps, R ZBe-the O-C1-C6 alkyl.Exemplary R ZComprise methyl, ethyl, n-propyl, CF 3, CHF 2, OMe, OEt etc.
[00180] in another embodiment, R WIt is C1-C6 alkyl or halo-C1-C6 alkyl.Perhaps, R WBe-the O-C1-C6 alkyl.Exemplary R WComprise methyl, ethyl, n-propyl, CF 3, CHF 2, OMe, OEt etc.
[00181] in another embodiment, two R WConnected carbon atom combines and forms optional C3-C9 cycloalkyl that replaces or 3-9 unit heterocycle.This exemplary class ring comprises cyclopropyl, cyclopentyl or cyclohexyl.
[00182] in one embodiment, ring A is selected from:
Figure A200780029737D0063175127QIETU
Wherein:
P is 0-2;
Q is 0-2; Condition is p+q≤2;
Each W AAnd W BBe independently selected from NR 1, O, S, SO, SO 2, C (R 1) 2Or=CR 1(when p or q are 2);
W EBe-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-
W FDo not exist or be selected from-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-; Condition is W EAnd W FThe two is not simultaneously=N-or-N (R 1)-;
Ring B1 is optional phenyl ring that replaces or 5-6 unit hetero-aromatic ring;
R 1As hereinbefore defined.
[00183] in one embodiment, ring A has formula A-i.In another embodiment, ring A has formula A-ii.Perhaps, ring A has formula A-iii.Perhaps, ring A has formula A-iv.
[00184] in one embodiment, W EAnd W FThe two all is=C (R 1).In another embodiment, W EBe=C (R 1)-and W FBe=N-.
[00185] in one embodiment, p be 0 and q be 0.In another embodiment, p be 1 and q be 0.In another embodiment, p be 0 and q be 1.In another embodiment again, the two is 1 for p and q.Perhaps, p be 0 and q be 2.Perhaps, p be 2 and q be 0.
[00186] in one embodiment, W ABe NR 1In another embodiment, W ABe O.Perhaps, W ABe C (R 1) 2In one embodiment, R 1Be hydrogen.
[00187] in one embodiment, W BBe NR 1In another embodiment, W BBe O.Perhaps, W BBe C (R 1) 2In one embodiment, R 1Be hydrogen.
[00188] in another embodiment, p is 2 and W ABe C (R 1) 2-C (R 1) 2Or-CR 1=CR 1-.
[00189] in another embodiment, q is 2 and W BBe C (R 1) 2-C (R 1) 2Or-CR 1=CR 1-.
[00190] in one embodiment, ring A is selected from:
Figure A200780029737D0064175301QIETU
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00191] in another embodiment, ring A is selected from:
Figure A200780029737D0064175335QIETU
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00192] in another embodiment, ring A is selected from:
The optional quilt of wherein said ring system is 4 R at the most 1Substituting group replaces.
[00193] in another embodiment, ring A is selected from:
Figure A200780029737D0065175456QIETU
The optional quilt of wherein said ring system is 4 R at the most 1Substituting group replaces.
[00194] in another embodiment, compound of the present invention has formula I '-B:
Figure A200780029737D00653
Wherein said ring A except the azo-cycle atom, contains 2 other ring hetero atoms that are selected from O, N or S at the most;
Wherein encircle A, except oxo group, optional quilt is 5 R at the most 1Substituting group replaces;
R 1, R X, R YWith X as hereinbefore defined.
[00195] in one embodiment, ring A is selected from:
Figure A200780029737D0066175547QIETU
Wherein:
W CBe-C (R 1) 2, C (O) or=CR 1-;
R is 0-2;
W DBe N or=C-;
W EBe-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-;
W FDo not exist, or be selected from-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-; Condition is W EAnd W FThe two is not simultaneously=N-or-N (R 1)-;
Y is C (O), S (O) or S (O) 2
Ring B1 is optional phenyl ring or the hetero-aromatic ring that replaces;
Figure A200780029737D0041095012QIETU
Be singly-bound or two key;
R 1As hereinbefore defined.
[00196] in one embodiment, W CBe-C (R 1) 2Perhaps, W CBe=CR 1Perhaps, W CBe C (O).
[00197] in one embodiment, r is 0.Perhaps, r is 1.Perhaps, r is 2.
[00198] in another embodiment, W DBe N.Perhaps, W DBe=C-.
[00199] in one embodiment, Y is C (O).Perhaps, Y is S (O).Perhaps, Y is S (O) 2
[00200] in one embodiment, ring A is selected from:
Figure A200780029737D00662
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00201] in one embodiment, ring A is selected from:
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
[00202] in one embodiment, ring A optional by at the most 5 be selected from following substituting group and replace: C1-C6 aliphatic group, C1-C6 aliphatic group-oxygen base, C1-C6 halogenated aliphatic base, CN, halogen, oxo, the optional C3-C7 cyclic aliphatic base that replaces, or optional replace be selected from following ring: phenyl, furyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, pyridyl, pyrimidyl, piperidyl, piperazinyl or morpholinyl.
[00203] in one embodiment, Q does not exist.In another embodiment, Q-R MBe R '.
[00204] in one embodiment, R is a hydrogen.Perhaps, R is the C1-C6 aliphatic group.Exemplary R comprises the C1-C6 alkyl, for example methyl, ethyl, propyl group or butyl.
[00205] in one embodiment, R ' is a hydrogen.
[00206] in one embodiment, R ' is the C1-C8 aliphatic group, its optional by at the most 3 be selected from following substituting group and replace: halogen, CN, CF 3, CHF 2, OCF 3Or OCHF 2, two MU (methylene unit) at the most of wherein said C1-C8 aliphatic group are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00207] in one embodiment, R ' is that 3-8 unit is saturated, part is unsaturated or the complete undersaturated 0-3 of having a heteroatomic monocycle that is independently selected from nitrogen, oxygen or sulphur, wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00208] in one embodiment, R ' is that 8-12 unit is saturated, part is unsaturated or the complete undersaturated 0-5 of having a heteroatomic bicyclic ring that is independently selected from nitrogen, oxygen or sulphur is; Wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00209] in one embodiment, the optional 3-12 unit that replaces is saturated, part is unsaturated or the complete undersaturated 0-4 of having a heteroatomic monocycle or a dicyclo that is independently selected from nitrogen, oxygen or sulphur in conjunction with forming with their atom of connection for the R ' of twice appearance, wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
[00210] exemplary The compounds of this invention is shown in following table 1 and table 1A.
Table 1:
Figure A200780029737D00701
Figure A200780029737D00711
Figure A200780029737D00721
Figure A200780029737D00731
Figure A200780029737D00741
Figure A200780029737D00771
Figure A200780029737D00791
Figure A200780029737D00801
Figure A200780029737D00811
Figure A200780029737D00841
Figure A200780029737D00851
Figure A200780029737D00861
Figure A200780029737D00871
Figure A200780029737D00891
Figure A200780029737D00901
Figure A200780029737D00921
Table 1A:
Figure A200780029737D00941
Figure A200780029737D00951
Figure A200780029737D00961
Figure A200780029737D00971
Figure A200780029737D00981
Figure A200780029737D00991
Figure A200780029737D01001
Figure A200780029737D01011
Figure A200780029737D01021
Figure A200780029737D01031
Figure A200780029737D01041
Figure A200780029737D01051
Figure A200780029737D01061
Figure A200780029737D01071
Figure A200780029737D01081
Figure A200780029737D01091
[00211] compound of the present invention preparation easily by means commonly known in the art.The synthetic schemes of preparation The compounds of this invention shows below, and is used for illustration purpose.
[00212] scheme 1: the preparation of formula I compound:
Figure A200780029737D0110180233QIETU
A) HATU, D iPEA, DMF, RT, 16 hours.
[00213] preparation I compound shown in the scheme 1 as mentioned wherein contains the amine nuclear that encircles A and examines under suitable condition with the thiazolidine ketone acid that chemical combination obtains formula I compound.
[00214] scheme 1A: the preparation of formula I compound:
Figure A200780029737D0110180305QIETU
[00215] scheme 2: thiazolidone nucleic acid (preparation of acid-I):
Figure A200780029737D0110180346QIETU
A) DMF or toluene or benzene,
Figure A200780029737D01104
Molecular sieve, 80 ℃, 1-2 hour
B) mercaptosuccinic acid, 80 ℃, 16 hours
[00216] scheme 3: thiazolidone nucleic acid (preparation of acid-II):
Figure A200780029737D0111102157QIETU
A) EtOH/H 2SO 4, 80 ℃, 24 hours
B) LiHMDS, THF, 15 minutes, R then W-LG, 0 ℃ to room temperature, 16 hours NaOH (aq.), MeOH; Wherein LG is suitable leavings group.
[00217] scheme 4: thiazolidone nucleic acid (preparation of acid-III):
A) BOP, D iPEA, THF, 6 hours, NaBH then 4, room temperature
B) LiCl, LiHMDS, R Z-LG ,-78 ℃ to-40 ℃; Wherein LG is suitable leavings group
C) Jones reagent oxidation, 0 ℃
[00218] scheme 5: thiazolidone nucleic acid (preparation of acid-IV):
Figure A200780029737D0112102536QIETU
A) THF/ trimethoxy ortho-formiate, thioacetic acid, 80 ℃, 16 hours or DMF, 2 hours, 80 ℃, thioacetic acid then, 80 ℃, 16 hours.
B) LDA ,-78 ℃ to room temperature, glyoxylic acid ethyl ester then, room temperature, 16 hours
c)NaOH(aq.)，MeOH。
[00219] scheme 6: the preparation of thiazolidone nucleic acid (sour V):
Figure A200780029737D0112102512QIETU
A) mCPBA, CHCl 3, 0 ℃ to room temperature, 16 hours
[00220] scheme 7: the preparation of amine nuclear (C-A-i-d):
Figure A200780029737D01123
A) 4-methoxybenzyl chlorine, TEA, DMF
B) two (2-chloroethyl) t-butyl carbamate, LDA, THF
c)TFA/DCM
[00221] wherein encircle A be A-i-e (referring to above) but the method preparation of amine nuclear C-A-i-e operational version 7.
[00222] scheme 8: the preparation of amine nuclear C-A-ii-c:
Figure A200780029737D01131
A) polyphosphoric acid, 100 ℃, phenylurea then, 150 ℃
b)MeOH，HCl，Pd/C，H 2
[00223] scheme 9: the preparation of amine nuclear C-A-ii-d:
Figure A200780029737D01132
a)LiHMDS
b)TFA/DCM
[00224] scheme 10: the preparation of amine nuclear C-A-ii-e:
Figure A200780029737D01133
a)NaHMDS
b)H 2，Pd/C
c)HCl
[00225] scheme 11: the preparation of amine nuclear C-A-v-e:
Figure A200780029737D01141
a)NaBH 4CN
B) CDI or SOCl 2Or 1,1 '-the alkylsulfonyl diimidazole
c)TFA/DCM
[00226] contain the amine nuclear that encircles A embodiment A-v-a, A-v-c and A-v-f and be respectively C-A-v-a, C-A-v-c and C-A-v-f, the method for operational version 11 prepares easily.
[00227] scheme 12: the another kind preparation of amine nuclear C-A-v-e:
a)COCl 2
B) aminoacetaldehyde dimethyl-acetal
c)TFA/DCM
[00228] scheme 13: the preparation of amine nuclear C-A-vi-a:
A) TEA, DCM, RT, 16 hours
B) CDI, THF/DCM, 16 hours.
c)TFA/DCM
[00229] scheme 14: the preparation of amine nuclear C-A-vi-c:
Figure A200780029737D0115102719QIETU
a)TEA，DCM，RT，16h
B) 1,1 '-alkylsulfonyl diimidazole, THF/DCM.
c)TFA/DCM
[00230] scheme 15: the preparation of amine nuclear C-A-vi-f:
Figure A200780029737D01152
A) PPh 3, CBr 4, DCM, spends the night by O ℃～RT
b)NaN 3，H 2O，CH 3CN
C) 1) PPh 3, toluene, RT, 16 hours;
2) acetic acid solution of acetate/48% HBr, 100 ℃ of 1h.
D) 4-Oxypertine-1-t-butyl formate, NaBH (OAc) 3, AcOH, DMF
e)CDI，THF
f)TFA/DCM
[00231] scheme 16: the preparation of amine nuclear A-v-e:
Figure A200780029737D01153
a)DCM，D iPEA
b)NaOCN，AcOH，
c)TFA/DCM
[00232] scheme 17: the preparation of amine nuclear A-v-f:
Figure A200780029737D01161
a)H 2，Pd/C，MeOH
[00233] scheme 18: the preparation of amine nuclear A-v-g:
Figure A200780029737D01162
a)H 2NNHBoc，EtOH
b)PtO 2，AcOH，H 2
c)TFA
d)D iPEA，THF
e)Et 2NH，THF
[00234] scheme 19: the preparation of amine nuclear A-vi-h:
Figure A200780029737D01163
a)NaBH(OAc)3，DCE
b)CDI，CH 3CN
c)HCl，Et 2O
[00235] scheme 20: the preparation of amine nuclear A-vi-i:
Figure A200780029737D01171
A) 2,4-dimethoxybenzylamine, DMA, TEA
b)LiAlH 3，THF
C) 4-Oxypertine-1-t-butyl formate, NaBH (OAc) 3, AcOH, DCE
d)CDI，DMF
e)TFA/DCM
[00236] scheme 21: the preparation of amine nuclear A-ii-h:
a)NaH，SEM-Cl，DMF
B) pyridine hydrogen bromine salt perbromate ， diox
c)Zn，AcOH
D) suitable-1,4-dichloro but-2-ene, Cs 2CO 3, DMF
e)TFA/DCM
f)OsO 4，Me 3N-O，DCM
g)NaIO 4，EtOH，H 2O
h)NH 4OH，H 2，Pd/C
[00237] scheme 22: the preparation of amine nuclear A-ii-i:
Figure A200780029737D01181
a)NaHMDS，BOC 2O，THF
B) nBuLi, TMEDA, 4-Oxypertine-1-benzyl formate, THF
c)H 2，Pd/C
d)EtOH
[00238] scheme 23: the preparation of amine nuclear A-i-h:
Figure A200780029737D01182
A) KHMDS, allyl bromide 98, THF
B) O 3, MeOH, DCM, Me then 2S
c) tBuSONH 2，CuSO 4，DCE
d)PhLi，Et 2O
e)HCl，MeOH
[00239] scheme 24: the preparation of amine nuclear A-ii-j:
Figure A200780029737D01191
A) (2-methoxyl group-2-oxygen ethyl) (triphenyl) chlorination, benzene
b)DBU，DMF
C) 3-bromo-2-aminopyridine, AlMe 3, DCE
d)NaH，SEM-Cl，THF
E) Pd ( tBu 3) 2, dicyclohexyl methylamine ， diox
f)TFA
g)H 2，Pd/C
[00240] scheme 25: the preparation of amine nuclear A-i-i:
Figure A200780029737D01192
a)EDC，HOBt，NH 3，TEA，DMF
b)H 2，Pd/C，EtOH
C) 1-(trimethoxy methyl) benzene, toluene
d)TFA/DCM
[00241] scheme 26: the preparation of amine nuclear A-i-j:
A) 2,4-dimethoxybenzylamine, TMSCN
B) H 2, the Rh/ aluminum oxide
c)CDI
d)TFA/DCM
e)H 2，Pd/C
[00242] scheme 27: the preparation of amine nuclear A-i-k:
Figure A200780029737D01211
A) 2,4-dimethoxybenzylamine, TMSCN
b)H 2SO 4
c)1)KOH
2)H 2SO 4，KOH
d)LiAlH 4
e)CDI
f)1)TFA/DCM
2)H 2，Pd/C
[00243] scheme 28: the preparation of amine nuclear A-i-l:
Figure A200780029737D01221
a)TMSCN
b)LiAlH 4
c)COCl 2
d)1)TFA/DCM
2)H 2，Pd/C
[00244] amine nuclear A-i-a can be according to disclosed method preparation among the WO2005097795.Amine nuclear A-ii-a can be according to disclosed method preparation among the US2006293281.Wherein condensed 6-unit ring is that the amine nuclear A-ii-a of pyridyl can be according to disclosed method preparation among the WO2007016087.Amine nuclear A-v-b can be according to disclosed method preparation among the WO2006044504.Amine nuclear A-v-i can be according to disclosed method preparation among the WO2006044504.Amine nuclear A-vi-b as HCI salt can be according to disclosed method preparation among the WO2005056550.Amine nuclear A-vi-d can be according to Chem.Pharm.Bull., and 34 (5), disclosed method preparation among the pp.1907-1916 (1986).Amine nuclear A-vi-e is available commercially.Amine nuclear A-v-h can be according to disclosed method preparation among the WO2007016087.Other amine of not describing in the scheme of this paper, experiment or the reference is endorsed by method known to those skilled in the art and is prepared.
[00245] should be appreciated that some The compounds of this invention can exist with free form and is used for the treatment of that perhaps suitable words exist with its pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates includes but not limited to the salt of pharmacy acceptable salt, ester, this class ester or other adductss or derivative arbitrarily, and its patient who in a single day needs promptly can directly or indirectly provide compound or its meta-bolites or resistates as described herein.
[00246] as used herein, the following salt of term " pharmacy acceptable salt " expression, in rational medical judgment scope, they are applicable to human body and contact with the lower animal tissue, do not have unsuitable toxicity, pungency, transformation reactions etc., match with rational interests/risk ratio.Any non-toxic salts or the ester salt of " pharmacy acceptable salt " expression The compounds of this invention in case give the recipient, promptly can directly or indirectly provide The compounds of this invention or its active metabolite or resistates.As used herein, term " its active metabolite or resistates " represents that its meta-bolites or resistates also are the CGRP antagonists.
[00247] pharmacy acceptable salt is well known in the art.For example, S.M.Berge waits the people at J.Pharmaceutical Sciences, and 1977,66, describe pharmacy acceptable salt among the 1-19 in detail, incorporate this paper by reference into.The pharmacy acceptable salt of The compounds of this invention comprises from inorganic and organic acid and the alkali deutero-salt that are fit to.The example of pharmaceutically acceptable non-toxic acid addition salt is the amide that generates with mineral acid or organic acid, mineral acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid for example, organic acid is acetate, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid for example, the additive method that perhaps utilizes this area to use, for example salt of ion-exchange formation.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, glucoheptose salt, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, the 2-isethionate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin resin acid salt, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, right-tosylate, the undecane hydrochlorate, valerate etc.Comprise an alkali metal salt, alkaline earth salt, ammonium salt and N from suitable alkali deutero-salt +(C 1-4Alkyl) 4Salt.The quaternization of any alkaline nitrogen-containing group of compound is as disclosed herein also contained in the present invention.Can obtain water or the molten or dispersive product of oil by this class quaternization.Representative basic metal or alkaline earth salt comprise sodium salt, lithium salts, sylvite, calcium salt, magnesium salts etc.Suitable words, other pharmacy acceptable salt comprises nontoxic ammonium salt, quaternary ammonium salt and the amine cationic salts that utilizes counter ion to form, for example halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, low-grade alkane sulfonate and arylsulphonate.
[00248] as indicated above, pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, auxiliary agent or vehicle in addition, described in the present invention, they comprise be suitable for required particular dosage form arbitrarily and all solvents, thinner or other liquid excipients, dispersion agent or suspension aids, tensio-active agent, isotonic agent, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc.Remington ' s Pharmaceutical Sciences, the 16th edition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1980) known technology that is used to prepare the various carriers of pharmaceutically acceptable composition and is used for its preparation is disclosed.Except any conventional mounting medium is incompatible with The compounds of this invention, for example produce any unwanted biological effect or with any other component interaction of harmful mode and pharmaceutically acceptable composition, the use of other conventional mounting medium is contained within the scope of the invention.Some examples that can serve as the material of pharmaceutically acceptable carrier include but not limited to ion-exchanger; Aluminum oxide; Aluminum stearate; Yelkin TTS; Serum protein, for example human serum albumin; Buffer substance, for example phosphoric acid salt; Glycine; Sorbic Acid or potassium sorbate; The partial glyceride mixture of saturated vegetable fatty acid; Water; Salt or ionogen, for example protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt; Colloid silica; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylic ester; The wax class; Polyethylene-polyoxytrimethylene-block polymer; Lanolin; Carbohydrate, for example lactose, dextrose plus saccharose; Starch, for example W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and rhodia; The tragacanth gum of pulverizing; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle, for example theobroma oil and suppository wax; Oils, for example peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycols, for example propylene glycol or polyoxyethylene glycol; Ester class, for example ethyl oleate and Laurate ethyl; Agar; Buffer reagent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol and phosphate buffer soln; And other nontoxic compatible lubricant, for example Sodium Lauryl Sulphate BP/USP and Magnesium Stearates; According to preparation personnel's judgement, in composition, also can exist toner, releasing agent, Drug coating, sweeting agent, correctives and spices, sanitas and antioxidant.
[00249] but in the pharmaceutically acceptable composition per os of the present invention, rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (with pulvis, ointment or drops), cheek, with mouth with or administration of human and other animal such as nasal spray, depend on the severity of infection to be treated.In certain embodiments, The compounds of this invention can per os or parenteral admin, dosage level be every day about 0.01mg/kg to about 50mg/kg, preferred about 1mg/kg about 25mg/kg experimenter's body weight extremely, once a day or repeatedly, to obtain required result of treatment.
[00250] liquid dosage form of oral administration includes but not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active compound, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent, fatty acid ester of ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, wheat germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and anhydro sorbitol and composition thereof for example.Except inert diluent, oral compositions can also comprise auxiliary agent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and spices.
[00251] uses dispersion or wetting agent and the suspension agent that is fit to, can prepare injectable formulation according to known technique, for example the water-based of sterile injectable or oil-based suspension.Sterile injectable preparation also can be at nontoxic parenteral acceptable diluent or sterile injectable solution, suspension or the emulsion in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, conventionally adopt aseptic fixed oil as solvent or suspension medium.For this reason, can adopt the fixed oil of any gentleness, comprise synthetic list-or two-glyceryl ester.In addition, in the preparation of injection, also can use lipid acid, for example oleic acid.
[00252] injectable formulation can be sterilized, and for example filters by the bacterium property held back filter, perhaps mixes the disinfectant of aseptic solid composite form, can be before use with its dissolving be dispersed in aseptic water or other sterile injectable medium in.
[00253] in order to prolong the effect of The compounds of this invention, often need delay the absorption of compound after subcutaneous or intramuscularly.This can utilize the crystallinity of poorly water-soluble or the liquid suspension of amorphous substance to realize.The uptake rate of compound depends on its dissolution rate, and the latter may be depended on crystallographic dimension and crystal formation again successively.Perhaps, with compound dissolution or be suspended in the oils carrier, realize that the delay of parenteral admin compound form absorbs.Injectable depot forms prepares by the microencapsulation matrix that generates compound in Biodegradable polymeric such as polylactide-polyglycolide.According to the ratio of compound and polymkeric substance and the attribute of the particular polymers that adopts, can control the rate of release of compound.The example of other biological degradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).The depot injectable formulation also can prepare the compound inclusion in liposome compatible with body tissue or micro emulsion.
[00254] rectum or vagina administration composition suppository preferably, they can be by being mixed with The compounds of this invention and the nonirritant excipient that is fit to or carrier such as theobroma oil, polyoxyethylene glycol or suppository with wax, they are solid at ambient temperature, but under body temperature, be liquid, therefore in rectum or vaginal canal, melt, discharge active compound.
[00255] solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granule.In this class solid dosage, active compound is mixed with pharmaceutically acceptable vehicle of at least a inert or carrier, for example Trisodium Citrate or Lin Suanergai, and/or a) weighting agent or expanding material, starch for example, lactose, sucrose, glucose, mannitol and silicic acid, b) tackiness agent, carboxymethyl cellulose for example, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) wetting agent, glycerine for example, d) disintegrating agent, for example agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash, e) dissolving retarding agent, paraffin for example, f) absorption enhancer, for example quaternary ammonium compound, g) wetting agent, for example hexadecanol and Zerol, h) absorption agent, for example kaolin and wilkinite, and i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and composition thereof.For capsule, tablet and pill, described formulation can also comprise buffer reagent.
[00256] solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft or hard filling, and the capsule used excipient is lactose or toffee and macromolecule polyethylene glycol etc. for example.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example other dressings of knowing of enteric coating and medicine formulation art.They can be chosen wantonly and contain opalizer, also can choose wantonly in the mode that postpones only or preferentially at the composition of a part of release of active ingredients of enteron aisle.The example of operable embedding composition comprises polymeric material and wax class.The solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft and hard filling, and the capsule used excipient is lactose or toffee and macromolecule polyethylene glycol etc. for example.
[00257] active compound also can be the form of microencapsulation, wherein contains one or more above-mentioned vehicle.Tablet, lozenge, capsule, pill and granule solid dosage can have dressing and shell, for example enteric coating, discharge other dressings that controlled dressing and medicine formulation art are known.In this class solid dosage, active compound can be mixed with at least a inert diluent, for example sucrose, lactose or starch.Under normal circumstances, this class formulation can also comprise other materials except that inert diluent, for example compressing tablet lubricant and other compression aids, for example Magnesium Stearate and Microcrystalline Cellulose.For capsule, tablet and pill, formulation can also comprise buffer reagent.They can be chosen wantonly and contain opalizer, also can choose wantonly in the mode that postpones only or preferentially at the composition of a part of release of active ingredients of enteron aisle.The example of operable embedding composition comprises polymeric material and wax class.
[00258] part of The compounds of this invention or transdermal administration formulation comprise ointment, paste, creme, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.As required, active ingredient is mixed with pharmaceutically acceptable carrier and any essential sanitas or buffer reagent under aseptic condition.Ophthalmic preparation, ear drop and eye drops also covered in the scope of the present invention.In addition, the use of transdermal patch is contained in the present invention, and they have the attendant advantages that the control compound is sent to body.This class formulation can be by with compound dissolution or be dispersed in the appropriate medium and prepare.Can also use the absorption enhancement agent to increase the flux that compound passes skin.Can control speed by rate controlling membranes being provided or compound being dispersed in polymeric matrix or the gel.
[00259] it should also be understood that, compound of the present invention and pharmaceutically acceptable composition can be used in the conjoint therapy, that is to say, compound and pharmaceutically acceptable composition can one or more other required therapeutical agent or medical program simultaneously, before or administration subsequently.Be used in that specific therapy combination (therapeutical agent or program) in the scheme for combining will be considered required therapeutical agent and/or program and the tolerability of the required result of treatment that will reach.It is also understood that used therapy can reach required effect (for example, The compounds of this invention can be used for the treatment of the medicine administration simultaneously of same illness with another kind) to same illness, perhaps they can reach different effects (for example controlling any side effect).As used herein, administration under normal circumstances is called as " be suitable for treated disease or illness " with the other therapeutical agent of treatment or prevention specified disease or illness.For example, exemplary other medicine includes, but are not limited to: (indoles are as R-ETODOLAC, indomethacin, sulindac, tolmetin for nonopioid analgesic; Naphthyl alkane ketone (naphthylalkanones) is as nabumetone; Former times health class such as piroxicam; The p-aminophenol derivative is as paracetamol; Propionic acid class such as fenoprofen, flurbiprofen, Ibuprofen BP/EP, Ketoprofen, Naproxen Base, naproxen sodium, Taisho); Salicylic acid such as acetylsalicylic acid, choline magnesium trisalicylate, diflunisal; Fragrant that esters of gallic acid such as meclofenamic acid, mefenamic acid; And pyrazoles such as Phenylbutazone); Perhaps opium (narcotic) agonist (as morphine monomethyl ether, fentanyl, hydromorphone, levorphanol, Pethidine, methadone, morphine, oxycodone, oxymorphone, Propoxyphene, buprenorphine, butorphanol, Wy-16225, nalbuphine and pentazocine).In addition, in conjunction with one or more compounds of the present invention, can use the pain relieving method of non-medicine.For example, also can use anesthesia (intraspinal injection, nerve block), Neurological Surgery method (neurolysis of CNS approach), nerve stimulation method (transcutaneous electric nerve stimu lation, backbone stimulates), physical therapy (physiotherapy, orthopedic instrument, transthermia) or psychological method (cognitive approach-hypnosis, biofeedback or behavioral approach).In addition suitable medicine and method are described in The MerckManual usually, and 17 editions, Mark H.Beers and Robert Berkow edit, MerckResearch Laboratories, 1999 and Food and Drug Admistraton's webpage Www.fda.govIn, its full content is incorporated this paper by reference into.
[00260] the other content of therapeutical agent in the present composition will be no more than comprise this therapeutical agent as unique composition of active components in common dosage.Preferably, the other amount of therapeutical agent in present disclosed composition will be the common about 50%-100% of this medicine as the content in the composition of unique therapeutic activity composition that comprise.
[00261] The compounds of this invention or its pharmaceutically acceptable composition also can be incorporated in the composition that applies implantable medical devices, for example artificial limb, artificial valve, vascular graft, Si Tengtemo (support) and conduit.Therefore, the present invention comprises the composition that applies implantable device on the other hand, and it comprises as above general describe and at big class and the The compounds of this invention described in the group of this paper be suitable for applying the carrier of described implantable device.On the other hand, the present invention includes the implantable device that scribbles composition, described composition comprises as above general describe and at the The compounds of this invention described in big class of this paper and the group be suitable for applying the carrier of described implantable device.Coating that is fit to and the general preparation method who applies implantable device are described in United States Patent (USP) 6,099, in 562,5,886,026 and 5,304,121.Coating is the polymeric material of bio-compatible normally, for example aquogel polymer, poly-methyl sily oxide, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), vinyl-vinyl acetate copolymer and composition thereof.Coating can be chosen wantonly further and be covered by the top coat of the fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination that are fit to, to give the release characteristics of composition.
[00262] compound of the present invention is used for the method for antagonism CGRP acceptor in the mammiferous patient such as this class antagonistic action of needs, and described method comprises the compound of using significant quantity.The present invention relates to the purposes of the compound as the CGRP receptor antagonist disclosed herein.Except that the primates especially mankind, various other Mammalss can be according to method treatment of the present invention.
[00263] another embodiment of the invention relate to a kind ofly be used for the treatment of, disease or illness that control, improvement are relevant with the CGRP acceptor or reduce the method for its risk, described method comprises the compound to the CGRP receptor antagonist of significant quantity on described patient's administering therapeutic.
[00264] the invention further relates to a kind of method that is used at the medicine of humans and animals antagonism CGRP receptor active that is used for making, described medicine comprises the combination of compound of the present invention and pharmaceutical carrier or thinner.
[00265] individuality for the treatment of in the inventive method Mammals normally, for example human, sex needs the antagonistic action of CGRP receptor active therein.Term " significant quantity in the treatment " expression will produce the amount of the test-compound of biology or medical response to tissue, system, animal or human by what investigator, animal doctor, doctor or other clinicians sought.As used herein, term ＂ treatment ＂ is meant above-mentioned treatment of conditions and prevention or prophylactic treatment, especially in the patient to this class disease or illness susceptible.
[00266] compound of the present invention makes it in the human and animal as the ability of CGRP antagonist, in the mankind, is the useful pharmacology factor for the illness relevant with CGRP especially.
[00267] compound of the present invention have in treatment, prevention, improvement, the following patient's condition of control or the disease one or more or reduce the function of its risk: headache; Migraine; Cluster headache; Chronic tension-type headache; Pain; Chronic pain; Neurogenic inflammation and inflammatory pain; Neuropathic pain; Ophthalmodynia; Toothache; Diabetes; Non insulin dependent diabetes; Vascular disorder; Inflammation; Sacroiliitis; Bronchial hyperreactivity, asthma; Shock; Sepsis; Refraining opium type material syndrome; The morphine tolerance; Hot flush in the masculinity and femininity; Allergic dermatitis; Encephalitis; Cerebral trauma; Epilepsy; Neurodegenerative disease; Dermatosis; The nervosa skin rubefaction, skin erythema and erythema; Tinnitus; Inflammatory bowel, irritable bowel syndrome, urocystitis; Can pass through the illness of treatment of antagonism CGRP acceptor or prevention with other.Wherein particularly importantly have a headache, comprise the acute or prophylactic treatment of migraine and cluster headache.
[00268] compound of the present invention is further used for preventing, treat, control, improve in disease, obstacle and illness that this paper points out or the method that reduces its risk.
[00269] compound of the present invention is further used for uniting prevention with other medicines, treats, controls, improves above-mentioned disease, obstacle and illness or reduce in the method for its risk.
[00270] compound of the present invention can be united with one or more other medicines and is used for the treatment of, prevent, control, improve its Chinese style I compound or other medicines can have the disease or the illness of effect or reduce its risk, and this of medicine united than the medicine list with safer or more effective simultaneously.Other medicine of this class can be by its approach of using usually and amount and formula I compound simultaneously or sequential application.When formula I compound and one or more other medicines use simultaneously, the preferred pharmaceutical composition in the unit dosage that comprises these other medicines and formula I compound.Yet combination therapy also can comprise wherein with the not treatment of negative lap scheme use formula I compound and one or more other medicines.Also should be taken into account, when uniting when using with one or more other activeconstituentss, compound of the present invention and other activeconstituents in the time of can using more separately low dosage use.Therefore, pharmaceutical composition of the present invention comprises that those contain one or more other activeconstituentss except that formula I compound.
[00271] for example, The compounds of this invention can be united use with anti-inflammatory or anodyne or antimigraine drug, described medicine such as Ergotamine or 5-HT.sub.1 agonist, especially 5-HT.sub.1B/1D agonist, for example sumatriptan, naratriptan, Zomitriptan, eletriptan, almotriptan, frovatriptan, many Buddhist nuns Qu Putan and risatriptan; Cyclooxygenase-2 inhibitors such as selectivity COX-2 inhibitors, for example rofecoxib, L-791456, celecoxib, valdecoxib or parecoxib (paracoxib); NSAID (non-steroidal anti-inflammatory drug) or cytokine-inhibition antiphlogiston, for example: acetylsalicylic acid, Ibuprofen BP/EP, Ketoprofen, fenoprofen, Naproxen Base, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, R-ETODOLAC, mefenamic acid, meclofenamic acid, Flufenamic Acid, tolfenamic acid, diclofenac, Taisho), Azapropazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, Phenylbutazone, Tacote, diflunisal, salsalate, olsalazine or sulfasalazine etc.; Perhaps steroidal pain killer.Similarly, The compounds of this invention can be with using such as following pain relief agents: paracetamol, phenacetin, morphine monomethyl ether, fentanyl, sufentanil, methadone, Methadyl Acetate, buprenorphine or morphine.
[00272] in addition, The compounds of this invention can with following medication combined use: interleukin inhibitors, as the interleukin 1 inhibitor; Nk 1 receptor antagonist, for example aprepitant; Nmda antagonist; The NR2B antagonist; Bradykinin-1 receptor antagonist; Adenosine a1 receptor agonists; Sodium channel inhibitor, for example lamotrigine; Opiate agonist such as Levomethadyl Acetate or Methadyl Acetate; Lipoxidase inhibitor is as the 5-lipoxidase inhibitor; α receptor antagonist, for example Indoramine; α receptor stimulant, vanilloid receptor antagonist, mGluR5 agonist, antagonist or reinforcer, GABA A receptor modulators, for example calcium bisacetyl homotaurine; Nicotinic antagonists or agonist comprise Nicotine; Muscarinic agonist or antagonist; Selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, Sertraline, duloxetine, escitalopram or citalopram; Tricyclic antidepressants, for example amitriptyline, doxepin, protriptyline, Desipramine, Trimipramine or imipramine; Leukotriene antagonist, for example Singulair or Zafirlukast; Nitric oxide inhibitor or nitrogen protoxide synthetic inhibitor.
[00273] simultaneously, The compounds of this invention can be united use with for example following Ergot alkaloids: Ergotamine, ergotocine, ergotocine, methylergobasine, metergoline, dihydroergotoxine methanesulfonate, dihydroergotamine, two hydrogen ergot Ke Ning, Dihydroergocristine, dihydroergocryptine, two hydrogen-I-ergomolline, dihydro-θ-ergomolline, Ecboline, ergocornine, ergot spit of fland, ergomolline, I-ergomolline, θ-ergomolline, ergosine, ergot alkane, bromocriptine or methysergide.
[00274] in addition, The compounds of this invention can with following medication combined use: the beta-adrenergic antagonist, as timolol, Proprasylyte, atenolol USP 23 or nadolol etc.; MAO inhibitor, for example Phenelzine; Calcium channel blocker, for example flunarizine, nimodipine, lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin; Nerve sedative is as olanzapine and Quetiapine; Anticonvulsive agent such as topiramate, zonisamide, tonabersat, carabersat or Sodium hydrogen divalproate; Angiotensin II antagonist, for example losartan and candesartan cilexetil; Angiotensin-convertion enzyme inhibitor is as lisinopril; Or botulinum toxin type A.
[00275] The compounds of this invention can with following medication combined use: synergistic agent, as caffeine, H2-antagonist, Simethicone, aluminium hydroxide or magnesium hydroxide; Separate congested agent such as synephrine, Phenylpropanolamine, pseudoephedrine, oxymetazoline, suprarenin, naphazoline, xylometazoline, propylhexedrine or a left side-deoxidation-ephedrine; Anti-tussive agents is as morphine monomethyl ether, hydrocodone, caramiphen, pentoxyverine or Dextromethorphane Hbr; Diuretic(s); Short motion agent, as metoclopramide or domperidone, and calmness or non-sedating antihistaminic agent.
In particularly preferred embodiments, The compounds of this invention with unite use such as following anti-migraine agent: Ergotamine; 5-HT.sub.1 agonist, especially 5-HT.sub.1B/1D agonist, particularly sumatriptan, naratriptan, Zomitriptan, eletriptan, almotriptan, frovatriptan, many Buddhist nuns Qu Putan and risatriptan; And with unite use such as following cyclooxygenase-2 inhibitors: selective epoxidation enzyme-2 inhibitor, particularly rofecoxib, L-791456, celecoxib, meloxicam, valdecoxib or parecoxib.
[00276] above combination comprises that The compounds of this invention not only makes up with other active compound but also with two or more other active compounds.And compound of the present invention can be united with the other medicines that the present invention uses and is used to prevent, treat, control, improve that The compounds of this invention is useful disease or illness or reduces its risk for it.These class other medicines can be by its normally used approach and amount and compound of the present invention while or sequential application.When compound of the present invention and one or more other medicines use simultaneously, preferably contain the pharmaceutical composition of these other medicines except that The compounds of this invention.Therefore, pharmaceutical composition of the present invention comprises that those also contain one or more other composition of active components except that The compounds of this invention.
[00277] the compound weight ratio of The compounds of this invention and other activeconstituents is transformable, and will depend on the effective dose of each composition.Usually, the effective dose of each composition will be used.Therefore, for example, when The compounds of this invention and another kind of drug regimen, the compound weight ratio scope of The compounds of this invention and another kind of medicine is generally about 1000:1～about 1:1000, perhaps about 200:1～about 1:200.The combination of The compounds of this invention and other activeconstituents also will still in all cases, should be used each activeconstituents of significant quantity usually within above-mentioned scope.
[00278] in this class combination, The compounds of this invention can separate with other activeconstituents or be co-administered.In addition, using of a kind of composition can be before other medicines be used, simultaneously or use subsequently, and by identical or different route of administration.
[00279] but compound per os of the present invention, parenteral (for example, intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implantation) use, through sucking spraying, nose, vagina, rectum, sublingual administration, perhaps local approach is used, and can be separately or be formulated in together in the suitable dosage unit preparations, it contains conventional nontoxic various pharmaceutically acceptable carrier, auxiliary agent and the vehicle of using route of administration that are suitable for.Except that the treatment warm-blooded animal, The compounds of this invention can be effective among the mankind.
[00280] in order to understand invention described herein more fully, provides the following example.Should be appreciated that these embodiment only supply purposes of illustration, are not interpreted as limiting in any way the present invention.
Embodiment
[00281] General LC/MS method
[00282] uses PESciex API-150-EX LC/MS, Shimadzu LC-8A pump, Gilson 215 automatic samplers, Gilson 819 injecting assemblies, 3.0mL/min flow velocity, 10-99% CH 3CN (0.035% TFA)/H 2O (0.05% TFA) gradient, PhenomenexLuna 5u C18 post (50 x 4.60mm), Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSD detectors obtain the LC/MS data.
[00283] Be used to separate the mass spectroscopy of non-enantiomer mixture:
[00284] Semi-Prep Gilson HPLC is used for the various the present invention's of purifying non-enantiomer mixture, uses Gilson 322 pumps, Gilson 215 liquid processors, Gilson 819 injecting assemblies.At Agilent Zorbax with the detection of Gilson 156 UV/Vis detectors, the SB-C18 post (21.2 x 100mm, 5um) in, flow velocity is 15.0mL/min, uses gradient to be 20-70% CH3CN (0.1% TFA)/H2O (0.1% TFA).
[00285] 4-(1,2-dihydro-2-oxygen-5-phenylimidazole-3-yl) piperidines-1-t-butyl formate
[00286]
Figure A200780029737D01341
[00287] 4-(1,2-dihydro-2-oxygen-5-phenylimidazole-3-yl) piperidines-1-t-butyl formate such as J.Med.Chem., 2005,48, synthetic described in 5921.To the 4-amino piperidine-1-t-butyl formate that stirs (6g, 30mmol) and D iPEA (9.84ml, in DCM 57.5ml) (50ml) solution, dropwise add 2-bromo-1-methyl phenyl ketone (5g, DCM 25mmol) (10ml) solution was gone through 1 hour, then with reaction mixture in stirring at room 16 hours.(3.41g 52.5mmol), is cooled to reaction mixture 0 ℃ then, with acetate pH is transferred to pH4, and reaction mixture is stirred to RT from 0 ℃, goes through 16 hours to add Zassol.Reaction mixture is toppled in the entry, and extract (3x) with DCM.Organic phase merges, water (3x), salt water washing, dry (MgSO 4), and be evaporated to drying.Resistates and ether grind, and filter, and solid washs with ether, obtains faint yellow solid (4.04g, 47%).LC/MS(10％-99％)：M/Z(M+H) +(obs)＝344；t R＝3.01.
[00288] 5-phenyl-3-(piperidin-4-yl)-1H-imidazoles-2 (3H)-ketone
[00289]
Figure A200780029737D01342
[00290] in DCM (20ml) solution of 4-(1,2-dihydro-2-oxygen-5-phenylimidazole-3-yl) piperidines-1-t-butyl formate (4g), adds TFA (4ml), and reaction mixture was stirred 4 hours in RT.Evaporation needing to obtain the tfa salt (Quant.) of product.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝244；t R＝1.06.
[00291] 4-(2-nitrobenzyl amino) piperidines-1-t-butyl formate
[00292]
Figure A200780029737D01343
[00293] with 1-(brooethyl)-2-oil of mirbane (13.2g, DCM 61mmol) (60ml) solution dropwise joins 4-amino piperidine-1-t-butyl formate (14.6g, 73mmol) and TEA (13.4ml, in DCM 91mmol) (100ml) solution, subsequently reaction mixture was stirred other 16 hours.Then, reaction mixture is toppled in the entry, and separate each layer.Then, water layer is extracted (2x) with DCM.Organic layer is merged water (2x), salt water washing, dry (MgSO 4), and be evaporated to drying.Resistates places EtOAc, and filters by the silica gel huge pillar.Silica gel washs with EtOAc, analyzes until TLC to show do not have other material wash-out to come out.Evaporation obtains the product (24g, 74%) into orange.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝336；t R＝2.23.
[00294] 4-(2-aminobenzyl amino) piperidines-1-t-butyl formate
[00295]
Figure A200780029737D01351
[00296] (24g, MeOH 71.6mmol) (150ml) solution stirred 24 hours under nitrogen atmosphere 4-(2-nitrobenzyl amino) piperidines-1-t-butyl formate.Reaction mixture is filtered and evaporation, obtain crude product amine, it need not to be further purified promptly and uses.
[00297] 4-(1,2-dihydro-2-oxygen quinazoline-3 (4H)-yl) piperidines-1-t-butyl formate
[00298]
Figure A200780029737D01352
[00299] to 4-(2-nitrobenzyl amino) piperidines-1-t-butyl formate (13.2g, 43.2mmol) THF (400ml) solution in, dropwise add CDI (7.7g, 47.5mmol) solution in 1:1DCM:THF (100ml), went through 1 hour, subsequently reaction mixture was stirred other 16 hours.The reaction mixture evaporation is obtained oily matter, when it is handled with EtOAc, the product that precipitation needs.This throw out obtains yellow solid (3.5g) with cold EtOAc washing and dry.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝332；t R＝3.01.
[00300] 3,4-dihydro-3-(piperidin-4-yl) quinazoline-2 (1H)-ketone
[00301]
Figure A200780029737D01353
[00302] (1, (3.5g in DCM 10.6mmol) (20ml) solution, adds TFA (15ml), and reaction mixture is stirred 2h in RT 2-dihydro-2-oxygen quinazoline-3 (4H)-yl) piperidines-1-t-butyl formate to 4-.Evaporation reaction mixture then with EtOH coevaporation (2x), needing to obtain the tfa salt (Quant.) of compound.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝232；t R＝0.38.
[00303] 1-(2-bromotrifluoromethane)-2-oil of mirbane
[00304]
[00305] in 0 ℃ to 1-(2-hydroxyethyl)-2-oil of mirbane (21ml, 150mmol) and triphenylphosphine (39.2g is among DCM 150mmol) (400ml), by part adding a CBr 4(49.5g 150mmol), is stirred to RT with reaction mixture from 0 ℃ and spends the night.The saturated Na of reaction mixture 2CO 3Aqueous solution quencher separates each layer, organic layer salt water washing, dry (MgSO 4), and be evaporated to drying.Resistates is handled with EtOAc, and with sedimentary Ph 3O filters, and removes and desolvates.This operation repeats more than twice.Through column chromatography (the 0%-10% EtOAc in Hx) purifying, obtain oily matter, it leaves standstill and solidifies.
[00306] 2-(2-nitrophenyl) ethamine
[00307]
Figure A200780029737D0136103515QIETU
[00308] to 1-(2-bromotrifluoromethane)-2-oil of mirbane (6.96g, CH 30.5mmol) 3Add NaN in the CN solution 3(6g, water 91.6mmol) (20ml) solution, and with reaction mixture refluxed 20 hours.Extract (3x) with the solution cooling and with DCM.Organic phase is merged, use the salt water washing, dry (MgSO 4), and be evaporated to drying.Resistates is placed toluene (160ml), and in this solution, add PPh 3(8g 30.5mmol), and stirs reaction mixture 16 hours in RT.Evaporating solvent is to dry, and resistates is handled 1h with acetate (30ml) solution of acetate (30ml) and 48% HBr in 100 ℃.With the reaction mixture cooling, concentrate and extract with DCM.Water is adjusted to pH～10 with NaOH (aq.), and extracts (3x) with EtOAc.Organic phase is merged, use the salt water washing, dry (MgSO 4), and be evaporated to drying (4.2g).
[00309] 4-(2-oil of mirbane ethylamino) piperidines-1-t-butyl formate
[00310]
Figure A200780029737D01371
[00311] (4g, 24mmol) (4.8g, MeOH 24mmol) (48ml) solution is adjusted to pH5 with 4-Oxypertine-1-t-butyl formate with 2-(2-nitrophenyl) ethamine by adding acetate.(2.3g 36mmol), and stirs reaction mixture 3 hours in RT to add NaBH3CN.Evaporating solvent, and resistates placed EtOAc and saturated Na 2CO 3In the aqueous solution.Separate each layer, and with organic layer salt water washing, dry (Na 2SO 4), and be evaporated to drying.Through column chromatography (the 0%-7% MeOH in DCM) purifying, obtain the product that needs.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝350；t R＝2.22.
[00312] 4-(2-amino-benzene ethylamino) piperidines-1-t-butyl formate
[00313]
Figure A200780029737D01372
[00314] in EtOH (180ml) solution of 4-(2-oil of mirbane ethylamino) piperidines-1-t-butyl formate (10.5g), add 10% Pd/C (1.05g), and with reaction mixture in RT at H 2Stir under the atmosphere and spend the night.Filter reaction mixture, and the solution evaporation that obtains is extremely dry, obtain the product (9.6g) that needs.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝320；t R＝2.06.
[00315] 4-(1,2,4,5-tetrahydrochysene-2-oxygen benzo [d] [1,3] diaza
Figure A200780029737D0137103558QIETU
-3-yl) piperidines-1-t-butyl formate
[00316]
[00317] to 4-(2-amino-benzene ethylamino) piperidines-1-t-butyl formate (6.9g, in DMF 30mmol) (110ml) solution by part add a CDI (4.86g, 30mmol), subsequently in RT stirred reaction mixture 2h.The reaction mixture dilute with water, and extract with EtOAc.Organic phase is merged, water, salt water washing, and be evaporated to drying, obtain the product that needs.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝346；t R＝3.24.
[00318] 4,5-dihydro-3-(piperidin-4-yl)-1H-benzo [d] [1,3] diaza
Figure A200780029737D0137103558QIETU
-2 (3H)-ketone
[00319]
Figure A200780029737D0138103629QIETU
[00320] to 4-(1,2,4,5-tetrahydrochysene-2-oxygen benzo [d] [1,3] diaza -3-yl) (10g adds TFA (5ml) in DCM 2.89mmol) (5ml) solution, and reaction mixture is stirred 1h in RT piperidines-1-t-butyl formate.Evaporation reaction mixture then with EtOH coevaporation (2x), needing to obtain the tfa salt (Quant.) of product.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝246；t R＝1.75.
[00321] 4-(2-aminopyridine-3-base is amino) piperidines-1-t-butyl formate
[00322]
Figure A200780029737D01382
[00323] (3.0g, (5.75g 28.8mmol), and stirs 5min with reaction mixture in RT, afterwards by part adding a NaBH (Oac) to add 4-Oxypertine-1-t-butyl formate in DCE 27.5mmol) (45ml) solution to 2,3 diamino pyridine 3(8.7g 41.7mmol), and continues stirring in RT and finishes until judging to react by LCMS.The reaction with 5% NaOH quencher, separate each layer, and with organic layer through Na 2SO 4Dry.Evaporation obtains the product of needs, is brown solid (4.96g).LC/MS(10％-99％)：M/Z(M+H) +(obs)＝293；t R＝2.31.
[00324] 4-(2,3-dihydro-2-oxygen imidazo [4,5-b] pyridine-1-yl) piperidines-1-t-butyl formate
[00325]
Figure A200780029737D01383
[00326] in RT to 4-(2-aminopyridine-3-base amino) piperidines-1-t-butyl formate (3.0g, CH 10.3mmol) 3(4.2g 25.7mmol), and stirs reaction mixture 16 hours in RT by part adding a CDI in CN (206ml) solution.Reaction mixture is evaporated to drying, and resistates is placed DCM and water.Separate each layer, and with organic layer salt water washing, dry (Na 2SO 4), and be evaporated to drying.Through column chromatography (1-10%MeOH in DCM) purifying, obtain the solid of needs, be beige solid (3.55g).LC/MS(10％-99％)：M/Z(M+H) +(obs)＝319；t R＝2.31.
[00327] 1-(piperidin-4-yl)-1H-imidazo [4,5-b] pyridines-2 (3H)-ketone
[00328]
[00329] with the 4-among the 2N HCl (2,3-dihydro-2-oxygen imidazo [4,5-b] pyridine-1-yl) piperidines-1-t-butyl formate (3.39g, Et 10.7mmol) 2O (20ml) solution is stirred to RT from 0 ℃, goes through 2h.Evaporating solvent, and with resistates Et 2O grinds, and filters, and uses Et 2The O washing is also dry, needing to obtain two-HCl salt (2.62g) of product.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝219；t R＝0.36.
[00330] 2-(2,4-dimethoxy-benzyl amino) pyridine-3-nitrile
[00331]
Figure A200780029737D01392
[00332] to 2-chloro-3-cyanopyridine (4.0g adds 2 in DMA 28.9mmol) (58ml) solution, the 4-dimethoxy benzaldehyde (5.2ml, 34.6mmol) and TEA (4.8ml 34.6mmol), and stirs reaction mixture 4 hours in 80 ℃.Reaction mixture is toppled in the entry, and use Et 2The O extraction.Organic phase is merged dry (Na 2SO 4), and be evaporated to drying.Column chromatography (the 0.5%-5% EtOAc in DCM (containing 0.1% TEA)) obtains the product that needs.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝270；t R＝3.05.
[00333] N-(2, the 4-dimethoxy-benzyl)-3-(aminomethyl) pyridine-2-amine
[00334]
Figure A200780029737D01393
[00335] with 2-(2,4-dimethoxy-benzyl amino) pyridine-3-nitrile (0.55g, 2.04mmol) and LiAlH 4(2.2ml of 1N, solution 4.4mmol) stir until judging to react through LCMS in RT and finish.The saturated Na of reaction 2CO 3Aqueous solution quencher, and separate each layer.With organic layer drying (Na 2SO 4), and under reduced pressure remove and desolvate, obtaining the product of needs, it need not to be further purified promptly and uses.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝274；t R＝0.28.
[00336] 4-((2-(2,4-dimethoxy-benzyl amino) pyridin-3-yl) methylamino-) piperidines-1-t-butyl formate
[00337]
Figure A200780029737D01401
[00338] to the N-(2 that stirs, the 4-dimethoxy-benzyl)-3-(aminomethyl) pyridine-2-amine (2.04mmol) and 4-Oxypertine-1-t-butyl formate (0.41g, 2.04mmol) (115 μ L 2.04mmol) add NaBH (OAc) in the solution at DCE (8ml) and AcOH 3(0.43g, 2.04mmol), and in the RT stirring reaction until judging that through LCMS reaction finishes.Reaction mixture DCM and saturated Na 2CO 3Aqueous solution dilution separates each layer, and with organic layer drying (Na2SO3), and be evaporated to drying.Through column chromatography (MeOH/DCM) purifying, obtain the product (0.64g, 69%) that needs.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝457；t R＝2.19.
[00339] (1-(2, the 4-dimethoxy-benzyl)-1,2-dihydro-2-oxy picolinate is [2,3-d] pyrimidines-3 (4H)-yl) piperidines-1-t-butyl formate also for 4-
[00340]
[00341] ((2-(2 to 4-, 4-dimethoxy-benzyl amino) piperidines-1-t-butyl formate (2.89g methylamino-pyridin-3-yl)), 6.33mmol) DMF (42ml) solution in (1.23g 7.6mmol), and stirs reaction mixture 2 hours in 120 ℃ by part adding a CDI.Add another part CDI (0.82g), and reaction mixture was stirred 6 hours, stirred 16 hours in RT subsequently in 130 ℃.To react dilute with water, and extract with DCM.Organic phase is merged, dry (NaSO4), and be evaporated to drying.Through column chromatography (the 10-80% EtOAc in Hx) purifying, obtain the product (1.17g) that needs.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝483；t R＝3.58.
[00342] 3,4-dihydro-3-(piperidin-4-yl) pyrido [2,3-d] pyrimidines-2 (1H)-ketone
[00343]
Figure A200780029737D01411
[00344]
[00345] 2-(4-oxygen-2-phenyl-3-((pyridin-4-yl) methyl) thiazolidine-5-yl) acetate
[00346]
[00347] phenyl aldehyde (0.75mmol, 79.6mg) and 2-(pyridin-4-yl) ethamine (97.3mg, DMF solution (0.5ml) 0.9mmol) and
Figure A200780029737D0141181311QIETU
Molecular sieve was in 80 ℃ of heating 2 hours.The adding mercaptosuccinic acid (1.13mmol, DMF 168mg) (0.2ml) solution, and will react on other 16 hours of 80 ℃ of heating.The reaction mixture dilute with water also extracts with EtOAc.Organic layer usefulness 1N HCl, water washing, and be evaporated to drying, obtaining the product of needs, it need not to be further purified promptly and uses.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝329；t R＝1.95.
[00348] 1-(1-(2-(4-oxygen-2-phenyl-3-((pyridin-4-yl) methyl) thiazolidine-5-yl) ethanoyl) piperidin-4-yl)-1H-benzo [d] imidazoles-2 (3H)-ketone (compound #45)
[00349]
Figure A200780029737D01413
[00350] to 2-(4-oxygen-2-phenyl-3-((pyridin-4-yl) methyl) thiazolidine-5-yl) acetate (0.15mmol, 49mg), 1-(piperidin-4-yl)-1H-benzo [d] imidazoles-2 (3H)-ketone (0.15mmol, 33mg) and D IPEA (0.375mmol, 65.3 μ l) is at 4:1 CH 3(0.18m mol 68mg), and stirs 16h in room temperature with reaction mixture to add HATU in the solution among the CN:DMF (0.5ml).Use 10%-99% CH3CN (0.035%TFA)/H 2O (0.05%TFA) through preparation type reversed-phase HPLC purifying, obtains title compound.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝528.1；t R＝2.28.H?NMR(400MHz，CDCl3)δ?9.00(s，1H)，8.60(d，J＝6.3Hz，2H)，7.40-7.38(m，2H)，7.33-7.29(m，5H)，7.06-6.92(m，4H)，5.55-5.53(m，1H)，4.55(d，J＝4.4Hz，2H)，4.45-4.42(m，3H)，4.07(d，m，2H)，3.42-3.41(m，1H)，3.20-3.15(m，1H)，3.01-2.90(m，1H)，2.66(m，2H)，1.88(m，2H)ppm.
[00351] 2-(3-methyl-4-oxygen-2-phenyl thiazole alkane-5-yl) acetate
[00352]
Figure A200780029737D01421
[00353] with phenyl aldehyde (0.75mmol, 79.6mg) and methylamine hydrochloride (60.8mg, DMF 0.9mmol) (0.5ml) solution and
Figure A200780029737D0141181311QIETU
Molecular sieve was in 80 ℃ of heating 2 hours.(1.13mmol, DMF 168mg) (0.2ml) solution will react on other 16 hours of 80 ℃ of heating to add mercaptosuccinic acid.The reaction mixture dilute with water, and extract with EtOAc.Organic layer usefulness 1N HCl, water washing, and be evaporated to drying, obtaining the product of needs, it need not to be further purified promptly and uses.
[00354] 3,4-dihydro-3-(1-(2-(3-methyl-4-oxygen-2-phenyl thiazole alkane-5-yl) ethanoyl) piperidin-4-yl) quinazoline-2 (1H)-ketone (compound #273)
[00355]
[00356] to 2-(3-methyl-4-oxygen-2-phenyl thiazole alkane-5-yl) acetate (0.2mmol, 50mg), 3,4-dihydro-3-(piperidin-4-yl) quinazoline-2 (1H)-ketone tfa salt (0.15mmol, 49mg) and D IPEA (0.375mmol, 65.3 μ l) is at 4:1 CH 3Add in the solution among the CN:DMF (0.5ml) HATU (0.18mmol, 68mg), and with reaction mixture in stirring at room 16h.Use 10%-99% CH 3CN (0.035% TFA)/H 2O (0.05% TFA) obtains title compound through preparation type reversed-phase HPLC purifying.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝465.5；t R＝2.18. 1H?NMR(400MHz，CDCl3)δ?7.34-7.22(m，5H)，7.12(t，J＝7.5Hz，1H)，7.00(d，J＝7.5Hz，2H)，6.95-6.89(m，2H)，6.61(d，J＝7.8Hz，2H)，5.46-5.41(m，1H)，4.70(m，1H)，4.56(m，1H)，4.26(m，3H)，3.86(m，1H)，3.50(m，1H)，3.32(m，1H)，3.12-3.08(m，1H)，2.89-2.73(m，1H)，1.69(m，3H)ppm.
[00357] 2-(3-sec.-propyl-4-oxygen-2-phenyl thiazole alkane-5-yl) acetate
[00358]
[00359] with phenyl aldehyde (0.75mmol, 79.6mg and Isopropylamine (53.1mg, DMF 0.9mmol) (0.5ml) solution and
Figure A200780029737D0141181311QIETU
Molecular sieve was in 80 ℃ of heating 2 hours.The adding mercaptosuccinic acid (1.13mmol, DMF 168mg) (0.2ml) solution, and will react on other 16 hours of 80 ℃ of heating.The reaction mixture dilute with water, and extract with EtOAc.Organic layer usefulness 1N HCl, water washing, and be evaporated to drying, obtaining the product of needs, it need not to be further purified promptly and uses.
[00360] 3,4-dihydro-3-(1-(2-(3-sec.-propyl-4-oxygen-2-phenyl thiazole alkane-5-yl) ethanoyl) piperidin-4-yl) quinazoline-2 (1H)-ketone (compound #255)
[00361]
Figure A200780029737D01432
[00362] to 2-(3-sec.-propyl-4-oxygen-2-phenyl thiazole alkane-5-yl) acetate (0.2mmol, 56mg), 1-(piperidin-4-yl)-1H-benzo [d] imidazoles-2 (3H)-ketone (0.15mmol, 33mg) and D IPEA (0.375mmol, 65.3 μ l) is at 4:1 CH 3(0.18mmol 68mg), and stirs 16h in room temperature with reaction mixture to add HATU in the solution among the CN:DMF (0.5ml).
Use 10%-99% CH 3CN (0.035% TFA)/H 2O (0.05% TFA) obtains title compound through preparation type reversed-phase HPLC purifying.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝493.5；t R＝3.1.H?NMR(400MHz，CDCl3)δ?7.31-7.25(m，5H)，7.14-7.10(m，1H)，7.05(s，1H)，7.00(m，1H)，6.93-6.89(m，1H)，6.62(d，J＝7.8Hz，1H)，5.56(m，1H)，4.72(m，1H)，4.47-4.41(m，2H)，4.27-4.19(m，2H)，4.02-3.96(m，1H)，3.87(m，1H)，3.36-3.29(m，1H)，3.13-3.10(m，1H)，2.70(m，2H)，1.70-1.60(m，3H)，1.20(dd，J＝2.0，6.9Hz，3H)，0.94(m，3H)。
[00363] 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) acetate
[00364]
[00365] phenyl aldehyde (5.06ml, 50mmol) and isobutylcarbylamine (5.82ml, solution 50mmol) stirred 2 hours in 80 ℃, add afterwards mercaptosuccinic acid (7.51g, 50mmol), and in 80 ℃ of restir 16 hours.Reaction mixture is toppled in the entry, and extract with EtOAc.Organic phase is merged, drying, and be evaporated to drying.Through column chromatography (EtOAc/Hx) purifying, obtain the product of needs, be yellow oil (11.3g).
[00366] 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) ethyl acetate
[00367]
[00368] with 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) acetate (2.2g, EtOH 7.2mmol) (20ml) and H 2SO 4(1ml) solution refluxed 16 hours.Solution evaporation to dry, and is placed EtOAc with resistates, and use saturated Na 2CO 3The aqueous solution (3x), salt water washing, and evaporation obtain the oily product that needs.
[00369] 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) ethyl propionate
[00370]
Figure A200780029737D01451
[00371] in 0 ℃ of 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) ethyl acetate (84mg to stirring, 0.25mmol) THF solution in dropwise add the LiHMDS (0.28ml of 1N, 0.28m mol), and reaction mixture is stirred to RT from 0 ℃, went through 16 hours.Reaction mixture is poured among the 1N HCl, and extract (4x) with EtOAc.Organic phase is merged dry (MgSO 4), and be evaporated to drying.Through preparation type TLC (7:1; Hx:EtOAc) purifying obtains the oily product (12mg) that needs.
[00372] 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) propionic acid
[00373]
Figure A200780029737D01452
[00374] (12mg, 0.034mmol) (MeOH 0.068mmol) (0.2ml) solution stirred 16 hours in 60 ℃ 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) propionic acid for 1N, 0.068ml with NaOH aq..(except that desolvating, the crude product product need not to be further purified promptly and uses this solution for 1N, 0.068ml) neutralization with 1N HCl.
[00375] 3-(1-(2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) propionyl) piperidin-4-yl)-3,4-dihydroquinazoline-2 (1H)-ketone (compound #156)
[00376]
Figure A200780029737D01453
[00377] to 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-yl) propionic acid (11mg, 0.034mmol), 3,4-dihydro-3-(piperidin-4-yl) quinazoline-2 (1H)-ketone TFA (17mg, 0.051mmol) and D i(24ul, (17mg 0.044mmol), and stirs reaction mixture 16 hours in RT PEA to add HATU in DMF 0.14mmol) (0.2ml) solution.Use 10%-99% CH 3CN (0.035% TFA)/H 2O (0.05% TFA) obtains title compound through preparation type reversed-phase HPLC purifying.
[00378] 3-isopentyl-2-phenyl thiazole alkane-4-ketone
[00379]
Figure A200780029737D01461
[00380] with isobutylcarbylamine (0.58ml, 5mmol), phenyl aldehyde (1ml, 10mmol) and the solution of Thiovanic acid (1.05ml g, 15m mol) in THF (7ml) and trimethoxy ortho-formiate (2ml) stirred 16 hours in 75 ℃.RM is toppled in the entry, and extract (3x) with EtOAc.Organic phase is merged, with 1N HCl (2x), salt water washing, dry (MgSO 4), and be evaporated to drying.Through column chromatography purifying (the 10-25% EtOAc in Hx), obtain the oily product (1.07g, 86%) that needs.
[00381] 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-base subunit) ethyl acetate
[00382]
Figure A200780029737D01462
[00383] (0.25g adds LDA (the THF solution of 1.1ml～1M in THF solution 1mmol) to the 3-isopentyl-2-phenyl thiazole alkane-4-ketone that stirs in-78 ℃; By nBuLi and the fresh preparation of Diisopropylamine), and make reaction mixture be warmed to room temperature.Add glyoxylic acid ethyl ester (0.24ml in toluene～50% w/v, 1.2mmol), and with reaction mixture in stirring at room 16 hours.Reaction mixture is poured among the 1N HCl, and extract (3x) with EtOAc.Organic phase is merged, use the salt water washing, dry (MgSO 4), and be evaporated to drying. through column chromatography purifying (5 to 15% EtOAc in Hx), obtain the oily product that needs.
[00384] 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-base subunit) acetate
[00385]
Figure A200780029737D01463
[00386] with 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-base subunit) ethyl acetate (0.031g, 0.1mmol) and aq.NaOH (1N, MeOH solution 0.3ml) was in 40 ℃ of stirrings 2 hours.Add HCl (0.5ml of 1N), and evaporation MeOH.Add entry and EtOAc, and separate each layer.Water layer merges all organic layers with EtOAc extraction (2x), dry (MgSO 4), and be evaporated to drying, and obtain the product of needs, be orange (11mg, 36%).
[00387] 3,4-dihydro-3-(1-(2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-base subunit) ethanoyl) piperidin-4-yl) quinazoline-2 (1H)-ketone
[00388]
[00389] to 2-(3-isopentyl-4-oxygen-2-phenyl thiazole alkane-5-base subunit) acetate (11mg, 0.036mmol), 3,4-dihydro-3-(piperidin-4-yl) quinazoline-2 (1H)-ketone TFA (18mg, 0.054mmol) and D i(22ul, (16mg 0.043mmol), and stirs reaction mixture 16 hours in RT PEA to add HATU in DMF 0.14mmol) (0.2ml) solution.Use 10%-99% CH 3CN (0.035% TFA)/H 2O (0.05% TFA) obtains title compound through preparation type reversed-phase HPLC purifying.
[00390] Preparation A: 1 ' H-spiral shell [piperidines-4,4 '-quinoline]-2 ' (synthesizing of 3 ' H)-ketone
[00391] with 3-oxygen-2,3-dihydro spiral shell [indenes-1,4 '-piperidines]-1 '-t-butyl formate (20g, 66.4mmol) and MeOH/HCl (2.5mol/L, mixture 100mL) stir and spend the night.After the evaporation, the resistates petroleum ether obtains spiral shell [indenes-1,4 '-piperidines]-3 (2H)-keto hydrochlorides (15.4g, 97.6%).
[00392] to spiral shell [indenes-1,4 '-piperidines]-3 (2H)-keto hydrochlorides (5.0g, 24.84mmol) and Et 3N (7.54g, CH 74.53mol) 2Cl 2(50mL) in the solution in 0 ℃ dropwise add Cbz-Cl (4.66g, 27.33mmol).Making reaction be warmed to room temperature and stir spends the night.With sedimentation and filtration, use Et 2The O washing is also dry, obtains 3-oxygen-2,3-dihydro spiral shell [indenes-1,4 '-piperidines]-1 '-benzyl formate (6.1g, yield 99%).
[00393] will contain NH 2OH.HCl (1.43g, 20.6mmol) and NaOAc (1.52g, 3-oxygen-2 18.53mmol), 3-dihydro spiral shell [indenes-1,4 '-piperidines]-1 '-benzyl formate (3g, EtOH 10.3mmol) (30mL) the solution heating 1.5h down that refluxes.Except that desolvating, resistates is allocated in CH by evaporation 2Cl 2In water.Organic phase salt water washing is through Na 2SO 4Drying, and concentrate, obtain 3-(oximido)-2,3-dihydro spiral shell [indenes-1,4 '-piperidines]-1 '-benzyl formate (3.14g, yield 99%), it is directly used in the next step.
[00394] with 2,4, (1.32g 7.16mmol) adds among the DMF (9.6mL) that is maintained at 25 ℃ 6-three chloro-[1,3,5]-triazine.Through the TLC monitoring reaction, consumed until TCT.Then, add 3-(oximido)-2,3-dihydro spiral shell [indenes-1,4 '-piperidines]-1 '-benzyl formate (1.6g, DMF 4.77mmol) (17mL) solution.After the adding, with mixture in stirred overnight at room temperature.Add entry.Mixture extracts with EtOAc.The saturated Na of organic layer that merges 2CO 3Washing is used 1N HCl and salt water washing, subsequently through Na 2SO 4Dry and concentrated.Resistates is through the preparation HPLC purifying, obtain 2 '-oxygen-2 ', 3 '-dihydro-1 ' H-spiral shell [piperidines-4,4 '-quinoline]-1-benzyl formate (260mg, yield 16%).
[00395] 2 '-oxygen-2 ', 3 '-dihydro-1 ' H-spiral shell [piperidines-4,4 '-quinoline]-1-benzyl formate (1.2g, 3.4mmol) and MeOH (20mL) solution of Pd/C (200mg) mixture under atmospheric pressure in room temperature hydrogenation 3h.Filtering catalyst, and filtrate is under reduced pressure concentrated.Resistates is through preparation HPLC purifying twice, obtains 1 ' H-spiral shell [piperidines-4,4 '-quinoline]-2 ' (3 ' the H)-ketone (110mg, 11%) into tfa salt. 1H?NMR(CDCl 3)δ?7.65(d，J＝7.5Hz，1H)，7.29-7.45(m，3H)，3.45(d，J＝12.3Hz，2H)，3.20(t，J＝12.3Hz，2H)，2.96(s，2H)，2.10-2.21(m，2H)，1.70(d，J＝14.1Hz，2H)。MS(ESI)m/z217.06[M+H] +。
[00396] Preparation B: spiral shell [4H-3,1-benzoxazine-4,4 '-piperidines]-2 (1H)-ketone
Figure A200780029737D01491
[00397] N-Boc-aniline (16.12g, 83.4m mol) is dissolved in the anhydrous tetrahydro furan (120mL), and is cooled to-70 ℃.In-70 ℃ under nitrogen, in this solution, dropwise add pentane (110mL, 187mmol) solution of the tert-butyl lithium of 1.7M.Behind-70 ℃ of 30min, this solution is warmed to-20 ℃, and under this temperature, keeps 2h.Solution is cooled to once more-70 ℃, and (15.98g, anhydrous tetrahydro furan 80.2mmol) (50mL) solution is handled dropwise with the N-Boc-4-piperidone.Solution slowly is warmed to room temperature, handles with potassium tert.-butoxide (25mg), and under nitrogen in stirred overnight at room temperature.This solution is with ether (300mL) dilution, at ice-H 2O cools off in bathing, and is adjusted to pH 7 with 1.0N HCl (aq).Separate each layer, water layer with ether (100mL) extraction once.With the organic layer H that merges 2O and saturated brine washing are then through Na 2SO 4Dry also filtration.Filtrate under reduced pressure concentrates and obtains 39.09g crude product product, is the faint yellow oily thing of heavy-gravity.The crude product product obtains 2-oxygen-1 by the hurried chromatography of silica gel (hexane solution of 25-50% ethyl acetate) purifying, 2-dihydro spiral shell [benzo [d] [1,3] oxazine-4,4 '-piperidines]-1 '-t-butyl formate, be faint yellow solid (8.687g, yield are 34%).LC/MS m/z319.0[M+H] +, retention time 2.72 min (RP-C 18, 10-99% CH 3CN/0.05%TFA); 1H-NMR (400MHz, CDCl 3) δ 9.06 (br s, 1H), 7.28 (m, 1H), 7.12 (m, 2H), 6.91 (d, J=8.5Hz, 1H), 4.12 (br d, J=9.9Hz, 2H), 3.36 (br t, J=12.4Hz, 2H), 2.13 (br d, J=13.1Hz, 2H), 1.98 (m, 2H), 1.51 (s, 9H).
[00398] with 2-oxygen-1,2-dihydro spiral shell [benzo [d] [1,3] oxazine-4,4 '-piperidines]-1 '-t-butyl formate (6.71g 21.1mmol) is dissolved in the methylene dichloride (50mL), handles with trifluoroacetic acid (20mL), and in stirring at room 45min.To react under reduced pressure and concentrate, be dissolved in the acetonitrile again, and reconcentration under reduced pressure.With the crude product tfa salt at ice-H 2Cooling was dissolved in ice-cold saturated brine (20mL) and H during O bathed 2Among the O (50mL), and alkalize with ice-cold 35%NaOH (aq).A spot of product (being obtained by the 50mL ethyl acetate extraction) is joined in the water layer, with the beginning crystallization.The suspension that obtains is at ice-H 2Cooling during O bathes is filtered, with ice-cold H 2O flushing is also dry, and [benzo [d] [1,3] oxazine-4,4 '-piperidines]-2 (1H)-ketone free alkalis are white crystalline solid to obtain the 3.071g spiral shell.Other 800mg free alkali grinds the crude product free alkali with acetonitrile subsequently and obtains (total recovery=84%) by with ethyl acetate (10 x 50mL) extracting mother liquid.LC/MS m/z 219.2[M+H] +, retention time 0.58min (RP-C 18, 10-99% CH 3CN/0.05% TFA); 1H-NMR (400MHz, DMSO-d 6) δ 10.17 (brs, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.87 (dd, J=8.2,1.2Hz, 1H), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H).
[00399] 1-benzyl-4-(2-chloroquinoline-3-yl) piperidines-4-alcohol
Figure A200780029737D01501
In-78 ℃ to LDA (3.4ml, 2M in Hept/THF) THF (10ml) solution that dropwise adds 2-chloroquinoline (1.0g.6.11mmol) in THF (5ml) solution, and reaction mixture was stirred 1 hour in-78 ℃, dropwise add 1-benzyl piepridine-4-ketone (1.22g, THF 6.22mmol) (2ml) solution afterwards.Reaction mixture is stirred to RT from-78 ℃, went through 2 hours, be cooled to-20 ℃, the water quencher, and extract with EtOAc.Organic phase is merged dry (Na 2SO 4), and be evaporated to drying.Through column chromatography (the DCM solution of 1-15% MeOH) purifying, obtain the product that needs.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝353；t R＝2.24.
[00400] 3-(1-benzyl-1,2,3,6-tetrahydropyridine-4-yl) quinoline-2 (1H)-ketone
(1g, 6N HCl (9ml) solution 2.84mmol) is in 100 ℃ of heating 8h with 1-benzyl-4-(2-chloroquinoline-3-yl) piperidines-4-alcohol.With the reaction mixture cooling, add entry, and precipitated product is filtered and dry (0.27g).LC/MS(10％-99％)：M/Z(M+H) +(obs)＝317；t R＝2.18.
[00401] 3-(piperidin-4-yl) quinoline-2 (1H)-ketone
MeOH (20ml) solution of 3-(1-benzyl-1,2,3,6-tetrahydropyridine-4-yl) quinoline-2 (1H)-ketone (0.25g.0.29mmol) and 10% Pd/C (130mg) was stirred 6 hours in 40 ℃.Catalyzer is filtered, and evaporating solvent, the product that needs obtained.LC/MS(10％-99％)：M/Z(M+H) +(obs)＝229；t R＝1.27.
[00402] analytical data of some The compounds of this invention is shown in the following table 2.
[00403] Table 2
Figure A200780029737D01521
Figure A200780029737D01531
Figure A200780029737D01541
Figure A200780029737D01551
Figure A200780029737D01561
Figure A200780029737D01571
Figure A200780029737D01581
[00404] use SK-N-MC-BLA (4C10) to measure the CGRP functional antagonism:
[00405] using the sign CGRP functional antagonism in the test of transcribing based on cell of reorganization SK-N-MC system.For reporting system is transcribed in introducing, SK-N-MC clone is transduceed with the retroviral vector of the β-Nei Xiananmei gene catchment of containing the responsive promotor of cAMP.The expression of β-Nei Xiananmei is increased by cAMP to be brought out, and it is the catchment incident of endogenous CGRP receptor activation that described cAMP increases.According to the beta-lactam enzymic activity that CGRP brings out, use the cell sorting (FACS) of fluorescent activation to separate mono-clonal.The beta-lactam enzymic activity is used fluorescence energy transfer (FRET) dyestuff, and CCF4 measures.CCF4 is the substrate (Zlokarnik G waits the people, Science, 279 (5347): 84-88,1998) of β-Nei Xiananmei, and is split into the product with fluorescent signal different with the fluorescent signal of parent.According to the dose-dependently beta-lactam expression of enzymes of the CGRP of different concns with the consistent pharmacology of previous disclosed numerical value, select the 4C10 clone.For estimate SK-N-MC (4C10) is in the compound functions antagonistic activity, assessing compound in the presence of CGRP to the restraining effect of beta-lactam expression of enzymes.
[00406] SK-N-MC (4C10) cultivates in (Invitrogen) at the MEM (MEM) that has replenished 1mM non-essential amino acid solution (Invitrogen), 100 units/ml penicillin-Streptomycin sulphate (Invitrogen), 1mM Sodium.alpha.-ketopropionate (Invitrogen) and 10% foetal calf serum.For the beta-lactam enzymatic determination, use lower concentration serum, the 1%FBS in MEM.With 30,000 cells in each hole of measuring the 384-orifice plate (Becton Dickinson) of implanting poly--D-Methionin coating the day before yesterday.Before adding 200pM CGRP, SK-N-MC (4C10) and compound preincubate 30min.This assay method is hatched 3 hours in 37 ℃, so that the beta-lactam expression of enzymes.Add the CCF4 dyestuff, and in incubated at room 2 hours.Use the fluorescent plate reader, Topology Compensatory plate reader (tcPR) locates to read fluorescent signal in excitation wavelength 400nm and emission wavelength 460nm (product) and 535nm (parent).460 and the numerical value ratio of 535nm be used for the percentage ratio of computing activation.Fitting of a curve and IC50 calculate and use MOD3 to carry out.
[00407] is used for the K of computerized compound iI 125-CGRP is in conjunction with the displacement test.
[00408] the SK-N-MC film of purifying is available from Perkin Elmer.Film is melted fast, and place on ice.Compound dilutes with CGRP binding soln (25mM Tris-HCl, pH7.4,5mM MgCl2,0.1% BSA and 0.05% Tween).Film is 1:20 with binding soln dilution, and with Tissue Matster-50 homogenizer (Omni International) homogenize 30sec.The film of homogenize is joined in the compound in the binding soln.After hatching 10 minutes under the room temperature, with final concentration 46pM, I125-iodine tyrosyl-calcitonin-gene-related peptide (GEhealthcare) joins in film and the compound.After hatching 2 hours under the room temperature, the GF/C filter plate (Perkin Elmer) of reaction through handling by 0.5% PEI filters fast and stops, and use cell harvestor (Tomtec) to wash the filter plate with ice-cold washing lotion (50mM Tris HCl, pH7.4,5mM MgCl2 and 0.1% BSA).The radioactive intensity of filter plate is read on Topcount (Packard).Non-specific binding is measured in control reaction, in the described control reaction, the unlabelled CGRP of 1uM before I125-CGRP adds with the film preincubate.Total not being combined in when compound does not exist measured in the control reaction of film and I125-CGRP.The combined thing metathetical of I125-CGRP percentage ratio uses non-specific and total calculating in conjunction with contrast.Fitting of a curve uses MOD3 to carry out.The Ki of compound is by the equation (ChengY., Prusoff W.H., Biochem.Pharmacol.22:3099-3108,1973) of Cheng and Prusoff, and the amount of the Kd of the CGRP of use film and the I125-CGRP that is used to measure is calculated.
[00409] at above-described I 125-CGRP is in conjunction with in mensuration and the CGRP functional antagonism mensuration, and the exemplary The compounds of this invention in the table of discovery 1 is the CGRP antagonist.
[00410] IC of the The compounds of this invention of Xuan Zeing 50With the Ki data presentation in following table 3.In the table 3, for IC 50Row and Ki row, the symbol of the two has following implication: " A " represents＜1 μ M; " B " represents 1 μ M～5 μ M; " C " expression〉5 μ M, and " ND " statement No data.
[00411] table 3
Figure A200780029737D01611
Figure A200780029737D01621
Figure A200780029737D01631
Figure A200780029737D01641
Figure A200780029737D01651

Claims (140)

1. the compound of formula I:
Figure A200780029737C00021
Wherein:
X is S, SO or SO 2
Z 1Be key or NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7, R wherein 7Be hydrogen, C1-C4 aliphatic group or C (O) C1-C4 aliphatic group;
Z 2Be key, O, CH 2O or C (O);
Ring A is phenyl or 4-7 unit's heterocycle or hetero-aromatic ring, or 10-14 unit two ring hetero-aromatic ring or heterocycles, and wherein said heterocycle or hetero-aromatic ring have 1-4 heteroatoms that is selected from O, N or S; Wherein encircle the optional quilt of A 5 R at the most 1Substituting group replaces;
Wherein:
Z 2Be key, Z 1Be key, NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7Perhaps
Wherein:
Z 1, Z 2And R 6Do not exist, ring A is not aromatic, and ring A forms the volution ring system with ring B;
R 6Be hydrogen or C1-C4 aliphatic group;
M is 1-3;
N is 1-3; Condition is m+n≤4;
R YBe aryl, heteroaryl, cyclic aliphatic base, C1-C6 aliphatic group, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, heterocyclic radical-C1-C6 aliphatic group-or cyclic aliphatic base-C1-C6 aliphatic group-; R wherein YOptional quilt is 5 R at the most 2Substituting group replaces;
R XBe hydrogen, aryl, heteroaryl, C1-C6 aliphatic group, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, R wherein XOptional quilt is 5 R at the most 3Substituting group replaces;
Perhaps, two R XIn conjunction with forming 3-9 unit monocycle, 9-14 unit's dicyclo or 12-14 unit three cyclophane bases, heteroaryl or heterocycle ring system, wherein each hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from O, S and N at the most with the carbon atom that connects them; Wherein said by two R XThe optional quilt of the ring system that forms is 5 R at the most 4Substituting group replaces;
R ZNot existing, is hydrogen, CN, C1-C6 aliphatic group, halo-C1-C6 aliphatic group, O-C1-C6 aliphatic group, O-(halo-C1-C6 aliphatic group), halogen, aryl-C1-C6 aliphatic group or heteroaryl-C1-C6 aliphatic group;
Figure A200780029737C0003103243QIETU
Be singly-bound or two key, condition is when it is two key, then R zWith a R WDo not exist;
Each R WDo not exist independently, be hydrogen, halogen, oxo, C1-C6 aliphatic group, halo-C1-C6 aliphatic group ,-the O-C1-C6 aliphatic group ,-O-(halo-C1-C6 aliphatic group), aryl, aryl-C1-C6 aliphatic group-, C3-C7 cyclic aliphatic base; Perhaps
Two R WIn conjunction with forming optional C3-C7 cyclic aliphatic base or the heterocycle that replaces, wherein said heterocycle has 3 heteroatomss that are selected from O, S and N at the most together; Wherein said by two R WThe optional quilt of the ring that forms is 5 R at the most 5Substituting group replaces;
Wherein each R that occurs 1, R 2, R 3, R 4And R 5Be Q-R independently M
Wherein Q is a key, or the C1-C6 aliphatic chain, and wherein two non-adjacent MU (methylene unit) at the most of Q are optional and independently by CO, CO 2, COCO, CONR, OCONR, NRNR, NRNRCO, NRCO, NRCO 2, NRCONR, SO, SO 2, NRSO 2, SO 2NR, NRSO 2NR, O, S or NR replace;
Wherein each R that occurs MBe independently selected from R ', halogen, NO 2, CN, OR ', SR ', N (R ') 2, NR ' C (O) R ', NR ' C (O) N (R ') 2, NR ' CO 2R ', C (O) R ' CO 2R ', OC (O) R ', C (O) N (R ') 2, OC (O) N (R ') 2, SOR ', SO 2R ', SO 2N (R ') 2, NR ' SO 2R ', NR ' SO 2N (R ') 2, C (O) C (O) R ' or C (O) CH 2C (O) R ';
Wherein each R that occurs is independently selected from hydrogen or optional by the R of 0-5 appearance KThe C that replaces 1-6Aliphatic group; And each R that occurs KBe independently selected from-R V, halogen ,-NO 2,-CN ,-OR V,-SR V,-N (R V) 2,-NR VCOR V,-NR VCON (R V) 2,-NR VCO 2R V,-COR V,-CO 2R V,-OCOR V,-CON (R V) 2,-C (=N-CN) ,-OCON (R V) 2,-SOR V,-SO 2R V,-SO 2N (R V) 2,-NR VSO 2R V,-NR VSO 2N (R V) 2,-COCOR V, COCH 2COR V,-OP (O) (OR V) 2,-P (O) (OR V) 2,-OP (O) 2OR V,-P (O) 2OR V,-PO (R V) 2Or-OPO (R V) 2, R wherein VBe hydrogen or unsubstituted C 1-6Aliphatic group; And
Wherein each R ' that occurs is hydrogen, optional by the R of 0-5 appearance independentlyM1The C that replaces1-6Aliphatic group; And each R that occursM1Be independently selected from-RT, halogen ,-NO2、- CN、-OR T、-SR T、-N(R T) 2、-NR TCOR T、- NR TCON(R T) 2、-NR TCO 2R T、-COR T、-CO 2R T、-OCOR T、- CON(R T) 2、-C(＝N-CN)、-OCON(R T) 2、-SOR T、-SO 2R T、- SO 2N(R T) 2、-NR TSO 2R T、-NR TSO 2N(R T) 2、-COCOR T、- COCH 2COR T、-OP(O)(OR T) 2、-P(O)(OR T) 2、-OP(O) 2OR T、- P(O) 2OR T、-PO(R T) 2Or-OPO (RT) 2, R whereinTHydrogen or unsubstituted C1-6Aliphatic group; Perhaps R ' is that 3-8-unit is saturated, part is unsaturated or the complete undersaturated 0-3 of having a heteroatomic monocycle that is independently selected from nitrogen, oxygen or sulphur, or 8-12 unit is saturated, part is unsaturated or the complete undersaturated 0-5 of having a heteroatomic dicyclo that is independently selected from nitrogen, oxygen or sulphur, and wherein said monocycle or dicyclo are optional by the R of 0-5 appearanceUReplace; And each R that occursUBe independently selected from that 3-8-unit is saturated, part is unsaturated or complete undersaturated monocycle, its optional by 0-3 appearance-RQ1Replace and have 0-3 and be independently selected from the hetero atom of nitrogen, oxygen or sulphur, perhaps RUBe-RQ, halogen ,=O ,=NRQ、-NO 2、-CN、-OR Q、- SR Q、-N(R Q) 2、-NR QCOR Q、- NR QCON(R Q) 2、-NR QCO 2R Q、-COR Q、-CO 2R Q、-OCOR Q、- CON(R Q) 2、-C(＝N-CN)、-OCON(R Q) 2、- SOR Q、-SO 2R Q、-SO 2N(R Q) 2、-NR QSO 2R Q、-NR QSO 2N(R Q) 2、- COCOR Q、-COCH 2COR Q、-OP(O)(OR Q) 2、-P(O)(OR Q) 2、- OP(O) 2OR Q、-P(O) 2OR Q、-PO(R Q) 2Or-OPO (RQ) 2, R whereinQAnd RQ1Hydrogen or unsubstituted C1-6Aliphatic group; Perhaps R is connected with R, the R ' of the R of twice appearance or twice appearance is in conjunction with forming that 3-12 unit is saturated, part is unsaturated or the undersaturated 0-4 of having heteroatomic monocycle or dicyclo that is independently selected from nitrogen, oxygen or sulphur fully together with the atom that connects them, and wherein said monocycle or dicyclo are optional by the R of 0-5 appearanceT1Replace; And each R that occursT1Be independently selected from-RS, halogen ,=O ,=NRS、-NO 2、-CN、- OR S、-SR S、-N(R S) 2、-NR SCOR S、-NR SCON(R S) 2、-NR SCO 2R S、- COR S、-CO 2R S、-OCOR S、-CON(R S) 2、-C(＝N-CN)、- OCON(R S) 2、-SOR S、-SO 2R S、-SO 2N(R S) 2、- NR SSO 2R S、-NR SSO 2N(R S) 2、-COCOR S、-COCH 2COR S、- OP(O)(OR S) 2、-P(O)(OR S) 2、-OP(O) 2OR S、-P(O) 2OR S、-PO(R S) 2Or-OPO (RS) 2, R whereinSHydrogen or unsubstituted C1-6Aliphatic group.
2. compound according to claim 1, wherein Z 2Be key, R 6Be hydrogen, and Z 1It is key.
3. compound according to claim 1, wherein Z 2Be key, R 6Be hydrogen, and Z 1Be NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7
4. compound according to claim 1, wherein Z 2-R 6Not hydrogen and Z 1It is key.
5. according to the described compound of claim, wherein Z 2-R 6Not hydrogen and Z 1Be NR 7, O, S, CH 2, C (O) or NR 7C (O) NR 7
6. compound according to claim 1, wherein
Figure A200780029737C0003103243QIETU
It is singly-bound.
7. compound according to claim 1, wherein
Figure A200780029737C0003103243QIETU
Be singly-bound, and two R WAll be hydrogen.
8. according to claim 1-7 each described compound, wherein R ZIf existed would be C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
9. compound according to claim 8, wherein R ZIf exist then be fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
10. according to each described compound of claim 1-6, wherein at least one R WBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
11. compound according to claim 10, wherein at least one R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
12. according to each described compound of claim 1-8, one of them R WBe hydrogen, and another R WBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
13. compound according to claim 12, one of them R WBe hydrogen, and another R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
14. according to claim 1-13 each described compound, wherein R YBe the optional C1-C6 aliphatic group that is replaced by one or more halogens, OH ,-the C1-C4 alkoxyl group ,-C1-C4 carbalkoxy or two-(C1-C4 alkyl) be amino-.
15. compound according to claim 14, wherein R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl group, 2-methoxyl group-ethyl, 3-ethoxy propyl group, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(methylol)-3-methyl-butyl, allyl group, ethynyl, 2-(diethylin) ethyl, 1-methyl-2-methoxyl group-ethyl, 3-hydroxyl-2,2-dimethyl-propyl group, 2,2,2-trifluoroethyl, 3,3,3-three fluoro-propyl group or 2,2,3,3,3-five fluoro-propyl group.
16. compound according to claim 15, wherein R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl group.
17. according to claim 1-13 each described compound, wherein R YBe the C1-C6 aliphatic group that replaces of C3-C8 cyclic aliphatic base or C3-C8 cyclic aliphatic base-.
18. compound according to claim 17, wherein R YBe the C3-C6 cycloalkyl or the C1-C6 alkyl of C3-C6 cycloalkyl substituted-.
19. compound according to claim 18, wherein R YBe cyclopropyl, cyclohexyl, cyclohexyl methyl-, cyclopropyl methyl-or cyclohexyl ethyl-.
20. according to claim 1-13 each described compound, wherein R YBe pyridyl (C1-C6)-alkyl-, tetrahydrofuran base (C1-C6 alkyl)-or N-(C1-C4 alkyl)-pyrrolidyl-(C1-C6 alkyl)-.
21. compound according to claim 20, wherein tetrahydrofuran (THF)-2-base-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridine-2-base-ethyl-, pyridin-4-yl-methyl-, 1H-indazole-5-base or 2-(N-methyl)-tetramethyleneimine-2-base-ethyl-.
22. according to claim 1-13 each described compound, wherein R YBe phenyl or (phenyl)-replace the C1-C6 aliphatic group-, it is optional by 5 R at the most 2Substituting group replaces, this R 2Substituting group is independently selected from halogen or has 1-3 the first heterocycle of heteroatomic 5-6 that is selected from N, O or S.
23. compound according to claim 22, wherein R YBe phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyl methyl-, 4-morpholino phenyl-, 2-piperidyl phenyl-or styroyl-.
24. according to each described compound of claim 1-23, one of them R XBe hydrogen, and another R XBe aromatic ring or hetero-aromatic ring, its optional quilt is 5 R at the most 3Substituting group replaces, this R 3Substituting group is independently selected from C1-C6 aliphatic group, phenyl, halogen, C3-C6 cyclic aliphatic base, or 4-7 unit heterocycle, and the optional quilt of wherein said heterocycle is 3 R at the most USubstituting group replaces, and wherein said hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from N, O or S at the most.
25. compound according to claim 24, one of them R XBe hydrogen, and another R XBe phenyl or pyridyl, it has 2 R at the most 3Substituting group, this R 3Substituting group is independently selected from halogen or 4-7 unit heterocycle, and the optional quilt of wherein said heterocycle is 2 R at the most USubstituting group replaces, and wherein said heterocycle has 3 heteroatomss that are selected from N, O or S at the most.
26. compound according to claim 25, one of them R XBe hydrogen, and another R XBe phenyl, this phenyl is replaced by halogen by 4-7 unit's heterocycle and at 3 at 2.
27. compound according to claim 24, one of them R XBe hydrogen, and another R XIt is phenyl or the phenyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
28. compound according to claim 24, one of them R XBe hydrogen, and another R XIt is pyridyl or the pyridyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
29. according to each described compound of claim 1-23, one of them R XBe hydrogen, and another R XBe optional phenyl or the heteroaryl that is replaced by one or more substituting groups, described substituting group be independently selected from C1-C6 aliphatic group, cyano group, halogen, halo-C1-C6 aliphatic group-, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, aralkoxy, two (C1-C6 aliphatic group) is amino-,-the O-C1-C6 aliphatic group ,-S (O)-C1-C6 aliphatic group or-S (O) 2-C1-C6 aliphatic group.
30. according to each described compound of claim 1-23, one of them R XBe hydrogen, and another R XBe C3-C7 cyclic aliphatic or heterocycle aliphatic series ring, its optional quilt is 5 R at the most 3Substituting group replaces and has 3 heteroatomss that are selected from O, N or S at the most, and wherein said ring is optional to condense with one or more phenyl ring or hetero-aromatic ring.
31. compound according to claim 30, wherein said R XBe selected from cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, tetrahydrochysene-2H-pyranyl, tetrahydrochysene-2H-thiapyran base, 9H-fluorenes-9-base or piperidyl.
32. according to each described compound of claim 1-23, wherein two R XIn conjunction with forming 3-9 unit monocycle, 9-14 unit's dicyclo or 12-14 unit three cyclophane bases, heteroaryl or heterocyclic radical ring system, wherein each hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from O, S and N at the most with the carbon atom that connects them; Wherein said by two R XThe optional quilt of the ring system that forms is 5 R at the most 4Substituting group replaces.
33. compound according to claim 32, wherein said ring system are selected from 9H-fluorenes-9-base, tetrahydrochysene-2H-pyrans-4-base, tetrahydrochysene-2H-thiapyran-4-base, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclohexenyl, piperidyl or 1-benzyl-piperidin-4-yl.
34. compound according to claim 1, wherein said compound has formula I-A:
Figure A200780029737C00101
Wherein:
Ring A is a 4-7 unit heterocycle, and it is by carbon atom C AForm the volution ring system with described piperidine ring, encircle wherein that A is optional to condense with phenyl ring or hetero-aromatic ring, described phenyl ring or hetero-aromatic ring are optional by 5 R at the most 1Substituting group replaces;
Wherein said ring A except the azo-cycle atom, also has 2 other ring hetero atoms that are selected from O, N or S at the most; And
Wherein encircle A, except oxo group, optional quilt is 5 R at the most 1Substituting group replaces.
35. compound according to claim 34, wherein
Figure A200780029737C0003103243QIETU
Be singly-bound, and R ZIf exist then be hydrogen.
36. compound according to claim 34, wherein
Figure A200780029737C0003103243QIETU
Be singly-bound, and R ZBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
37. compound according to claim 36, wherein R ZIf exist then be fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
38. according to each described compound of claim 34-37, wherein at least one R WBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
39. according to the described compound of claim 38, wherein at least one R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
40. according to each described compound of claim 37, wherein
Figure A200780029737C0003103243QIETU
Be singly-bound, a R WBe hydrogen, and another R WBe C1-C6 alkyl, halo-C1-C6 alkyl-or-the O-C1-C6 alkyl.
41. according to the described compound of claim 40, one of them R WBe hydrogen, and another R WBe fluorine, methyl, ethyl, n-propyl, CF 3, CHF 2, OMe or OEt.
42. according to each described compound of claim 37, wherein
Figure A200780029737C0003103243QIETU
Be singly-bound, and each R WBe hydrogen.
43. according to claim 34-42 each described compound, wherein R YBe optional C1-C6 aliphatic group, OH, C1-C4 alkoxyl group, C1-C4 carbalkoxy or two-(the C1-C4 alkyl) that is replaced by one or more halogens amino-.
44. according to the described compound of claim 43, wherein R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl group, 2-methoxyl group-ethyl, 3-ethoxy propyl group, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(methylol)-3-methyl-butyl, allyl group, ethynyl, 2-(diethylin) ethyl, 1-methyl-2-methoxyl group-ethyl, 3-hydroxyl-2,2-dimethyl-propyl group, 2,2,2-trifluoroethyl, 3,3,3-three fluoro-propyl group or 2,2,3,3,3-five fluoro-propyl group.
45. according to the described compound of claim 44, wherein R YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl group.
46. according to claim 34-42 each described compound, wherein R YBe the C1-C6 aliphatic group that replaces of C3-C8 cyclic aliphatic base or C3-C8 cyclic aliphatic base-.
47. according to the described compound of claim 46, wherein R YBe the C3-C6 cycloalkyl or the C1-C6 alkyl of C3-C6 cycloalkyl substituted-.
48. according to the described compound of claim 47, wherein R YBe cyclopropyl, cyclohexyl, cyclohexyl methyl-, cyclopropyl methyl-or cyclohexyl ethyl-.
49. according to claim 34-42 each described compound, wherein R YBe pyridyl (C1-C6) alkyl-, tetrahydrofuran base (C1-C6 alkyl)-or N-(C1-C4 alkyl)-pyrrolidyl-(C1-C6 alkyl)-.
50. according to the described compound of claim 49, wherein R YBe tetrahydrofuran (THF)-2-base-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridine-2-base-ethyl-, pyridin-4-yl-methyl-, 1H-indazole-5-base or 2-(N-methyl)-tetramethyleneimine-2-base-ethyl-.
51. according to claim 34-42 each described compound, wherein R YBe the C1-C6 aliphatic group of phenyl or (phenyl)-replacement, its optional quilt is 5 R at the most 2Substituting group replaces, this R 2Substituting group is independently selected from halogen or 5-6 unit has 1-3 heteroatomic heterocycle that is selected from N, O or S.
52. according to the described compound of claim 51, wherein R YBe phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyl methyl-, 4-morpholino phenyl, 2-piperidyl phenyl-or styroyl-
53. according to each described compound of claim 43-52, wherein
Figure A200780029737C0003103243QIETU
Be singly-bound, a R XBe hydrogen, and another R XBe aromatic ring or hetero-aromatic ring, its optional quilt is 5 R at the most 3Substituting group replaces, this R 3Substituting group is independently selected from C1-C6 aliphatic group, phenyl, halogen, C3-C6 cyclic aliphatic base or 4-7 unit heterocycle, and the optional quilt of wherein said heterocycle is 3 R at the most USubstituting group replaces, and wherein said hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from N, O or S at the most.
54. according to the described compound of claim 53, one of them R XBe hydrogen, and another R XBe to have 2 R at the most 5Substituent phenyl or pyridyl, this R 5Substituting group is independently selected from halogen or has 2 R at the most UThe first heterocycle of substituent 4-7, wherein said heterocycle has 3 heteroatomss that are selected from N, O or S at the most.
55. according to the described compound of claim 54, one of them R XBe hydrogen, and another R XBe by 4-7 unit's heterocyclic substituted and at 3 phenyl that replaced by halogen at 2.
56. according to the described compound of claim 54, one of them R XBe hydrogen, and another R XIt is phenyl or the phenyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
57. according to the described compound of claim 54, one of them R XBe hydrogen, and another R XIt is pyridyl or the pyridyl that replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base, 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
58. according to each described compound of claim 34-52, one of them R XBe hydrogen, and another R XBe optional phenyl or the heteroaryl that is replaced by one or more substituting groups, described substituting group be independently selected from C1-C6 aliphatic group, cyano group, halogen, halo-C1-C6 aliphatic group-, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, aralkoxy, two (C1-C6 aliphatic group) is amino-,-the O-C1-C6 aliphatic group ,-S (O)-C1-C6 aliphatic group or-S (O) 2-C1-C6 aliphatic group.
59. according to each described compound of claim 34-52, wherein at least one R XBe hydrogen, and another R XBe C3-C7 cyclic aliphatic or heterocycle aliphatic series ring, its optional quilt is 5 R at the most 3Substituting group replaces and has 3 heteroatomss that are selected from O, N or S at the most, and wherein said ring is optional to condense with one or more phenyl ring or hetero-aromatic ring.
60. according to the described compound of claim 59, wherein said R XBe selected from cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, tetrahydrochysene-2H-pyranyl, tetrahydrochysene-2H-thiapyran base, 9H-fluorenes-9-base or piperidyl.
61. according to each described compound of claim 34-52, wherein
Figure A200780029737C0003103243QIETU
Be singly-bound, two R XIn conjunction with forming 3-9 unit monocycle, 9-14 unit's dicyclo or 12-14 unit three cyclophane bases, heteroaryl or heterocyclic radical ring system, wherein each hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from O, S and N at the most with the carbon atom that connects them; Wherein said by two R XThe optional quilt of the ring system that forms is 5 R at the most 4Substituting group replaces.
62. according to the described compound of claim 61, wherein said ring system is selected from 9H-fluorenes-9-base, tetrahydrochysene-2H-pyrans-4-base, tetrahydrochysene-2H-thiapyran-4-base, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclohexenyl, piperidyl or 1-benzyl-piperidin-4-yl.
63., wherein encircle A and be selected from according to each described compound of claim 34-62:
Figure A200780029737C00151
Figure A200780029737C00152
Or
Figure A200780029737C00153
Wherein:
P is 0-2;
Q is 0-2; Condition is p+q≤2;
Each W AAnd W BBe independently selected from NR 1, O, S, SO, SO 2, C (R 1) 2Or=CR 1(when p or q are 2);
W EBe-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-;
W FDo not exist, or be selected from-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-; Condition is W EAnd W FThe two is not simultaneously=N-or-N (R 1)-;
Ring B1 is optional quilt 5 R at the most 1Phenyl ring that substituting group replaces or 5-6 unit hetero-aromatic ring; And
R 1Such as in the claim 34 definition.
64., wherein encircle A and have formula A-i according to the described compound of claim 63.
65., wherein encircle A and have formula A-ii according to the described compound of claim 63.
66., wherein encircle A and have formula A-iii according to the described compound of claim 63.
67., wherein encircle A and have formula A-iv according to the described compound of claim 63.
68. according to claim 64 or 66 described compound, wherein W EAnd W FThe two all is=C (R 1).
69. according to claim 64 or 66 described compound, wherein W EBe=C (R 1)-and W FBe=N-.
70. according to each described compound of claim 63-69, wherein p be 0 and q be 0.
71. according to each described compound of claim 63-69, wherein p be 1 and q be 0.
72. according to each described compound of claim 63-69, wherein p be 0 and q be 2.
73. according to claim 63-72 each described compound, wherein W ABe NR 1
74. according to claim 63-72 each described compound, wherein W ABe O.
75. according to claim 63-72 each described compound, wherein W ABe C (R 1) 2
76. according to claim 63-72 each described compound, wherein W ABe C (R 1) 2And R 1Be hydrogen.
77. according to claim 63-72 each described compound, wherein W BBe NR 1
78. according to claim 63-72 each described compound, wherein W BBe O.
79. according to claim 63-72 each described compound, wherein W BBe C (R 1) 2
80. according to claim 63-72 each described compound, wherein W BBe C (R 1) 2And R 1Be hydrogen.
81. according to each described compound of claim 63-72, wherein p is 2 and W ABe C (R 1) 2-C (R 1) 2Or-CR 1=CR 1
82. according to each described compound of claim 63-72, wherein q is 2 and W BBe C (R 1) 2-C (R 1) 2Or-CR 1=CR 1-.
83., wherein encircle A and be selected from according to the described compound of claim 63:
Figure A200780029737C00181
Or
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
84., wherein encircle A and be selected from according to the described compound of claim 63:
Figure A200780029737C00184
Or
Figure A200780029737C00185
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
85., wherein encircle A and be selected from according to the described compound of claim 63:
Figure A200780029737C00186
Or
Figure A200780029737C00187
The optional quilt of wherein said ring system is 4 R at the most 1Substituting group replaces.
86., wherein encircle A and be selected from according to the described compound of claim 63:
Figure A200780029737C00191
Figure A200780029737C00192
The optional quilt of wherein said ring system is 4 R at the most 1Substituting group replaces.
87. compound according to claim 1, wherein said compound has formula I-B:
Figure A200780029737C00193
Wherein encircling A is optional and phenyl ring or hetero-aromatic ring condensed 4-7 unit heterocycle, and the optional quilt of described phenyl ring or hetero-aromatic ring is 5 R at the most 1Substituting group replaces;
Wherein said ring A except the azo-cycle atom, contains 2 other ring hetero atoms that are selected from O, N or S at the most; And
Wherein encircle A, except oxo group, optional quilt is 5 R at the most 1Substituting group replaces.
88. 7 described compound, wherein R according to Claim 8 YBe optional C1-C6 aliphatic group, OH, C1-C4 alkoxyl group, C1-C4 carbalkoxy or two-(the C1-C4 alkyl) that is replaced by one or more halogens amino-.
89. 8 described compound, wherein R according to Claim 8 YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl, 2-methyl-propyl group, 2-methoxyl group-ethyl, 3-ethoxy propyl group, 1-(methoxycarbonyl)-3-methyl-butyl, 1-(methylol)-3-methyl-butyl, allyl group, ethynyl, 2-(diethylin) ethyl, 1-methyl-2-methoxyl group-ethyl, 3-hydroxyl-2,2-dimethyl-propyl group, 2,2,2-trifluoroethyl, 3,3,3-three fluoro-propyl group or 2,2,3,3,3-five fluoro-propyl group.
90. 9 described compound, wherein R according to Claim 8 YBe methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, 3,3-dimethyl-butyl, 3-methyl-butyl or 2-methyl-propyl group.
91. 7 described compound, wherein R according to Claim 8 YBe the C1-C6 aliphatic group that replaces of C3-C8 cyclic aliphatic base or C3-C8 cyclic aliphatic base-.
92. 7 described compound, wherein R according to Claim 8 YBe the C3-C6 cycloalkyl or the C1-C6 alkyl of C3-C6 cycloalkyl substituted-.
93. according to the described compound of claim 92, wherein R YBe cyclopropyl, cyclohexyl, cyclohexyl methyl-, cyclopropyl methyl-or cyclohexyl ethyl-.
94. 7 described compound, wherein R according to Claim 8 YBe pyridyl (C1-C6) alkyl-, tetrahydrofuran base (C1-C6 alkyl)-or N-(C1-C4 alkyl)-pyrrolidyl-(C1-C6 alkyl)-.
95. according to the described compound of claim 94, wherein R YBe tetrahydrofuran (THF)-2-base-methyl-, pyridin-3-yl-methyl-, pyridin-4-yl-ethyl-, pyridine-2-base-ethyl-, pyridin-4-yl-methyl-, 1H-indazole-5-base or 2-(N-methyl)-tetramethyleneimine-2-base-ethyl-.
96. 7 described compound, wherein R according to Claim 8 YBe optional quilt 5 R at the most 2The C1-C6 aliphatic group of the phenyl that substituting group replaces or (phenyl)-replacement, described R 2Substituting group is independently selected from halogen or has 1-3 the first heterocycle of heteroatomic 5-6 that is selected from N, O or S.
97. according to the described compound of claim 96, wherein R YBe phenyl, 2,6-difluorophenyl, benzyl, 4-fluorophenyl methyl-, 4-morpholino phenyl-, 2-piperidyl phenyl-or styroyl-.
98. each described compound, wherein R of 7-97 according to Claim 8 XBe optional quilt 5 R at the most 3Aromatic ring or hetero-aromatic ring that substituting group replaces, described R 3Substituting group is independently selected from C1-C6 aliphatic group, phenyl, halogen, C3-C6 cyclic aliphatic base or 4-7 unit heterocycle, and the optional quilt of wherein said heterocycle is 3 R at the most USubstituting group replaces, and wherein said hetero-aromatic ring or heterocycle have 3 heteroatomss that are selected from N, O or S at the most.
99. according to the described compound of claim 98, wherein R XBe to have 2 R at the most 3Phenyl or pyridyl that substituting group replaces, described R 3Substituting group is independently selected from halogen or 4-7 unit heterocycle, and the optional quilt of wherein said heterocycle is 2 R at the most USubstituting group replaces, and wherein said heterocycle has 3 heteroatomss that are selected from N, O or S at the most.
100. according to the described compound of claim 99, wherein R XBe by 4-7 unit's heterocyclic substituted and at 3 phenyl that replaced by halogen at 2.
101. according to the described compound of claim 99, wherein R XIt is pyridyl, phenyl or the phenyl that is replaced by following group: piperazine, 4-methyl-piperazine-1-base, 4-ethyl-piperazine-1 base, 4-propyl group-piperazine-1 base, 4-butyl-piperazine-1 base, 4-sec.-propyl-piperazine-1 base, 4-tertiary butyl piperazine-1 base, 4-cyclopropyl piperazine-1-base, 4-tert-butoxycarbonyl-piperazine-1-base, 4-hydroxy-piperdine base, 4-ethoxycarbonyl-piperidines-1-base, morpholine-4-base, the 1-H-pyrazol-1-yl, imidazoles-1-base, tetramethyleneimine-1-base, 3-dimethylamino-tetramethyleneimine-1-base, 4-(piperidines-1-yl) piperidines, pyridyl (1-methyl piperidine-4-yl) piperazine-1-base or 1-(2,2, the 2-trifluoroethyl) piperazine-1-base.
102. each described compound, wherein R of 7-97 according to Claim 8 XBe optional phenyl or the heteroaryl that is replaced by one or more substituting groups, described substituting group be independently selected from C1-C6 aliphatic group, cyano group, halogen, halo-C1-C6 aliphatic group-, aryl-C1-C6 aliphatic group-, heteroaryl-C1-C6 aliphatic group-, aralkoxy, two (C1-C6 aliphatic group) is amino-,-the O-C1-C6 aliphatic group ,-S (O)-C1-C6 aliphatic group or-S (O) 2-C1-C6 aliphatic group.
103. each described compound, wherein R of 7-97 according to Claim 8 XBe C3-C7 cyclic aliphatic or heterocycle aliphatic series ring, its optional quilt is 5 R at the most 3Substituting group replaces and has 3 heteroatomss that are selected from O, N or S at the most, and wherein said ring is optional to condense with one or more phenyl ring or hetero-aromatic ring.
104. according to the described compound of claim 103, wherein said R XBe selected from cyclopentyl, cyclohexyl, cyclohexenyl, suberyl, tetrahydrochysene-2H-pyranyl, tetrahydrochysene-2H-thiapyran base, 9H-fluorenes-9-base or piperidyl.
105. 7 described compounds according to Claim 8 wherein encircle A and are selected from:
Figure A200780029737C00221
Wherein:
W CBe-C (R 1) 2, C (O) or=CR 1-;
R is 0-2;
W DBe N or=C-;
W EBe-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-;
W FDo not exist, or be selected from-C (R 1) 2,=C (R 1)-,=N-or-N (R 1)-; Condition is W EAnd W FThe two is not simultaneously=N-or-N (R 1)-;
Y is C (O), S (O) or S (O) 2And
Ring B1 is optional quilt 5 R at the most 1Phenyl ring that substituting group replaces or 5-6 unit hetero-aromatic ring; And
Figure A200780029737C0003103243QIETU
Be singly-bound or two key.
106. according to the described compound of claim 105, wherein W CBe-C (R 1) 2
107. according to the described compound of claim 105, wherein W CBe=CR 1
108. according to the described compound of claim 105, wherein W CBe C (O).
109. according to each described compound of claim 105-108, wherein r is 0.
110. according to each described compound of claim 105-108, wherein r is 1.
111. according to each described compound of claim 105-108, wherein r is 2.
112. according to claim 105-111 each described compound, wherein W DBe N.
113. according to claim 105-111 each described compound, wherein W DBe=C-.
114. according to each described compound of claim 105-113, wherein Y is C (O).
115. according to each described compound of claim 105-113, wherein Y is S (O).
116. according to each described compound of claim 105-113, wherein Y is S (O) 2
117., wherein encircle A and be selected from according to the described compound of claim 105:
Figure A200780029737C00241
Figure A200780029737C00242
Or
Figure A200780029737C00243
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
118., wherein encircle A and be selected from according to the described compound of claim 105:
Figure A200780029737C00244
The optional quilt of wherein said ring is 4 R at the most 1Substituting group replaces.
119. according to the described compound of claim 105, it is optional by 5 substituting groups replacements at the most wherein to encircle A, described substituting group is selected from C1-C6 aliphatic group, C1-C6 aliphatic group-oxygen base, C1-C6 halogenated aliphatic base, CN, halogen, oxo, the optional C3-C7 cyclic aliphatic base that replaces or the optional ring that replaces, and this ring is selected from phenyl, furyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl, pyridyl, pyrimidyl, piperidyl, piperazinyl or morpholinyl.
120. according to each described compound of claim 105-119, wherein at R 1Middle Q is a key.
121. according to each described compound of claim 105-119, wherein at R 1Middle Q-R MBe Q-R '.
122. according to each described compound of claim 105-119, wherein Q existence and R are hydrogen.
123. according to each described compound of claim 105-119, wherein Q existence and R are the C1-C6 aliphatic groups.
124. according to the described compound of claim 123, wherein R is methyl, ethyl, propyl group or butyl.
125. according to the described compound of claim 121, wherein R ' is a hydrogen.
126. according to the described compound of claim 121, wherein R ' is the C1-C8 aliphatic group, it is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3Or OCHF 2, two MU (methylene unit) at the most of wherein said C1-C8 aliphatic group are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
127. according to the described compound of claim 121, wherein R ' is that 3-8 unit is saturated, part is unsaturated or the complete undersaturated 0-3 of having a heteroatomic monocycle that is independently selected from nitrogen, oxygen or sulphur, wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
128. according to the described compound of claim 121, wherein R ' is that 8-12 unit is saturated, part is unsaturated or the complete undersaturated 0-5 of having a heteroatomic dicyclo that is independently selected from nitrogen, oxygen or sulphur; Wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
129. according to the described compound of claim 121, wherein the optional 3-12 unit that replaces is saturated, part is unsaturated or the complete undersaturated 0-4 of having a heteroatomic monocycle or a dicyclo that is independently selected from nitrogen, oxygen or sulphur in conjunction with forming with their atom of connection for the R ' of twice appearance, wherein R ' is optional by 3 substituting groups replacements at the most, and described substituting group is selected from halogen, CN, CF 3, CHF 2, OCF 3, OCHF 2Or the C1-C6 alkyl, two MU (methylene unit) at the most of wherein said C1-C6 alkyl are chosen wantonly and are replaced by following group :-CO-,-CONH (C1-C4 alkyl)-,-CO 2-,-OCO-,-N (C1-C4 alkyl) CO 2-,-O-,-N (C1-C4 alkyl) CON (C1-C4 alkyl)-,-OCON (C1-C4 alkyl)-,-N (C1-C4 alkyl) CO-,-S-,-N (C1-C4 alkyl)-,-SO 2N (C1-C4 alkyl)-, N (C1-C4 alkyl) SO 2-or-N (C1-C4 alkyl) SO 2N (C1-C4 alkyl)-.
130. be selected from the compound of table 1 or table 1A.
131. pharmaceutical composition, it comprises according to each described compound of claim 1-130 and pharmaceutically acceptable carrier, assistant agent or vehicle.
132. according to the described pharmaceutical composition of claim 131, it further comprises other therapeutical agent.
133. in the experimenter, treat, prevent, alleviate, control one or more in the following patient's condition or the disease for one kind, or reduce the method for its risk: headache; Migraine; Cluster headache; Chronic tension-type headache; Pain; Chronic pain; Neurogenic inflammation and inflammatory pain; Neuropathic pain; Ophthalmodynia; Toothache; Diabetes; Non insulin dependent diabetes; Vascular disorder; Inflammation; Sacroiliitis; Bronchial hyperreactivity, asthma; Shock; Sepsis; Refraining opium type material syndrome; The morphine tolerance; Hot flush in the masculinity and femininity; Allergic dermatitis; Encephalitis; Cerebral trauma; Epilepsy; Neurodegenerative disease; Dermatosis; The nervosa skin rubefaction, skin erythema and erythema; Tinnitus; Inflammatory bowel, irritable bowel syndrome or urocystitis, described method comprise and give the described experimenter that these needs are arranged with what significant quantity was gone up in treatment according to the compound of claim 1 or the pharmaceutically acceptable composition that comprises described compound.
134. according to the described method of claim 133, wherein said method is used for headache, comprises the acute or prophylactic treatment of migraine and cluster headache.
135. according to claim 133 or the described method of claim 134, it further comprises other medicine.
136. according to the described method of claim 135, wherein said other medicine is selected from anti-inflammatory agent, pain killer or antimigraine drug.
137. according to the described method of claim 136, wherein said other medicine is selected from interleukin inhibitors, the nk 1 receptor antagonist, nmda antagonist, the NR2B antagonist, bradykinin-1 receptor antagonist, adenosine a1 receptor agonists, sodium channel inhibitor, opiate agonist, lipoxygenase inhibitor, the α receptor antagonist, the α receptor stimulant, vanilloid receptor antagonist, the mGluR5 agonist, antagonist or reinforcer, GABA A receptor modulators, nicotinic antagonists or agonist, muscarinic agonist or antagonist, selective serotonin reuptake inhibitor, tricyclic antidepressants, leukotriene antagonist, nitric oxide inhibitor or nitrogen protoxide synthetic inhibitor.
138. according to the described method of claim 135, wherein said other medicine is selected from Ergot alkaloids.
139. according to the described method of claim 135, wherein said other medicine is selected from beta-adrenaline antagonist, MAO inhibitor, calcium channel blocker, anticonvulsive agent, Angiotensin II antagonist, angiotensin-convertion enzyme inhibitor or botulinum toxin type A.
140. according to the described method of claim 135, wherein said other medicine is selected from reinforcer such as caffeine, H2-antagonist, separates congested agent, anti-tussive agents, diuretic(s), short motion agent or calmness or non-sedating antihistaminic agent.
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