CN101627039A

CN101627039A - Spiro (furo [3, 2-c] pyridine-3-3 ' -indol) -2' (1'h)-one derivatives and related compounds for the treatment of sodium-channel mediated diseases, such as pain

Info

Publication number: CN101627039A
Application number: CN200780038272A
Authority: CN
Inventors: 琼-杰克库·卡迪厄; 苏鲁旦·乔德亨瑞; 傅建民; 雷杰德·坎柏; 谢瀚霄; 贾琦; 刘世峰; 孙建宇
Original assignee: Xenon Pharmaceuticals Inc
Current assignee: Xenon Pharmaceuticals Inc
Priority date: 2006-10-12
Filing date: 2007-10-12
Publication date: 2010-01-13

Abstract

This invention is directed to methods of using spiro-oxindole compounds of formula (I): wherein j, k, m, Q, X,, R<1>, R<2a>, R<2b>, R<2c>, R<2d> and R<3> are as defined herein, as a stereoisomer, enantiomer, tautomer thereof or mixtures thereof; or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof, for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.

Description

Be used for the treatment of spiral shell such as the disease of sodium channels such as pain mediations (furo [3,2-c] pyridine-3,3 '-indoles)-2 ' (1 ' H)-ketone derivatives and related compound

FIELD OF THE INVENTION

The present invention relates to spiro-oxindole compounds, and comprise the pharmaceutical composition of this compound, and the disease or the morbid state that use this compound and medicine composite for curing sodium channel to be mediated, pain for example, and other and the related disease of mediation of sodium channel and the method for morbid state.

Background of invention

Voltage-gated sodium channel, promptly the transmembrane protein of initiation action potential in nerve, muscle and other electrostimulation cell is essential component (Catterall, W.A., Nature (2001), the 409th volume: 988-990) of normal threshold of feeling, emotion, thinking and action.These passages are made up of the α subunit through highly handling relevant with auxiliary β subunit.For channel function, the α subunit that forms the hole is enough, modifies (people such as Goldin, Neuron (2000), the 28th volume: 365-368) but the kinetics of passage gate and voltage-dependent carry out part by this β subunit.Each α-subunit contains four homeodomains, I to IV, and each structural domain has the transmembrane segment of six predictions.The relative molecular mass that forms the ionic conduction hole and contain the sodium channel α-subunit of the voltage sensor of regulating the sodium ion conduction is 260,000.Electrophysiology record, biological chemistry purifying and molecular cloning have been differentiated ten kinds of different sodium channel α subunits and four kinds of β subunits (Yu, people such as F.H., Sci STKE (2004), 253; And Yu, people such as F.H., Neurosci. (2003), 20:7577-85).

The characteristics of sodium channel comprise: but quick active and inactivation when the voltage depolarize (voltage-dependent gate) of the plasma membrane that strides across the excitability cell; And the conduction hole of sodium ion by protein structure inside effectively and the selectivity conduction (Sato, people such as C., Nature (2001), 409:1047-1051).Under negative or hyperpolarization membrane potential, the sodium channel is closed.After the film depolarize, the open fast and subsequent inactivation in sodium channel.In case passage is conduction current and inactivation under open state only, then before can opening once more, it must return back to quiescent condition, and this quiescent condition is had a preference for by the film hyperpolarization.Different sodium channel hypotypes its activate with the voltage range of inactivation with and activation and deactivation kinetics aspect different.

The albumen of sodium channel family has been widely studied and has demonstrated the many important body functions of participation.The research in this field has identified and has caused channel function and the active main α subunit variant that changes that described main change can cause main physiopathology morbid state at last.With regard to function, the albumen of this family is regarded as therapeutic interventional main point, Na _v1.1 and Na _v1.2 express (Raymond, people such as C.K., J.Biol.Chem. (2004), 279 (44): 46234-41) and very important at the brain camber for the normal brain activity function.Na among the mankind _v1.1 and Na _v1.2 sudden change causes serious epilepsy state and can cause intelligence decline (Rhodes, people such as T.H., Proc.Natl.Acad.Sci.USA (2004), 101 (30) in some cases; 11147-52; Kamiya, people such as K., J.Biol.Chem. (2004), 24 (11): 2690-8; Pereira, people such as S., Neurology (2004), 63 (1): 191-2).Similarly, these two passages have been considered to treat the attested target spot (referring to No. 01/38564, the PCT patent disclosure WO that announces) of epilepsy.

Na _V1.3 the whole body wide expression (Raymond, people such as C.K., op.cit.).Verified after the rat nervous system damage, it is up-regulated (Hains, people such as B.D., J.Neurosc. (2003), 23 (26): 8881-92) in rat dorsal horn Sensory neurone.The expert in many these fields has thought Na _V1.3 be suitable target spot (Lai, people such as J., Curr.Opin.Neurobiol. (2003), (3): 291-72003 of pain therapy; Wood, people such as J.N., J.Neurobiol. (2004), 61 (1): 55-71; Chung, people such as J.M., Novartis Found.Symp. (2004), 261:19-27; Discuss 27-31,47-54).

Na _V1.4 expression be limited to basically muscle (Raymond, people such as C.K., op.cit.).Shown that the sudden change in this gene has far-reaching influence (Tamaoka A., Intern.Med. (2003), (9): 769-70) to the muscle function that comprises paralysis.Therefore, this passage is considered to treat the target spot of abnormal muscle contraction, spasm or paralysis.

Cardiac sodium channel Na _V(Raymond, people such as C.K. op.cit.), and can find and may find in the Purkinje cell in sinus node (sinovial), ventricle knot 1.5 mainly express in ventricle and atrium.The quick conduction of impulse of the fast rise of heart action potential and process heart tissue is owing to Na _V1.5 unlatching.Therefore, Na _V1.5 play an important role to ARR.People Na _V1.5 sudden change cause multiple irregular pulse syndrome, the sudden-death syndrome at night (SUNDS) and sudden infant death syndrome (SIDS) (the SIDS) (Liu that for example comprise long QT3 (LQT3), Brugada syndrome (BS), heredity cardiac conduction defective, sudden unknown cause, H. wait the people, Am.J.Pharmacogenomics (2003), 3 (3): 173-9).The sodium channel blockers therapy has been widely used in the treatment irregular pulse.First kind of antiarrhythmic drug-Quinidine (quinidine) of finding in 1914 is classified as sodium channel blockers.

Na _V1.6 be coded in the voltage gate control sodium channel (Caldwell a large amount of, that extensively distribute that spreads all in youth Fei Shi (Ranvier) knot of finding and accumulate in neural axon in maincenter and the peripheral nervous system, J.H. wait the people, Proc.Natl.Acad.Sci.USA (2000), 97 (10): 5616-20).Although in the people, do not detect sudden change as yet, think Na _V1.6 work in the performance of the symptom relevant with multiple sclerosis, and it has been considered to treat target spot (Craner, people such as M.J., Proc.Natl.Acad.Sci.USA (2004), 101 (21): 8168-73) of this disease.

Na _V1.7 at first from pheochromocytoma PC12 clone, clone (Toledo-Aral, people such as J.J., Proc.Natl.Acad.Sci.USA (1997), 94:1527-1532).It exists with high level in the neuronic growing tip of minor diameter and shows that it may work in the transmission in nociceptive information.This point has been subjected to this domain expert's query, because Na _V1.7 also in the neuroendocrine cell relevant, express (Klugbauer, people such as N., EMBO J. (1995), 14 (6): 1084-90), and similarly related to from main procedure by hint with autonomous system.By producing Na _V1.7 null mutation proved the effect of not explaining as yet in autonomic function; Na in deletion institute feeling and the sympathetic neuron _V1.7 cause lethality phenotype perinatal period.(people such as Nassar, Proc.Natl.Acad.Sci.USA (2004), 101 (34): 12706-11.).On the contrary, be mainly Na in the nocuous Sensory neurone subgroup by deletion _V1.7 express proved its effect in Theory of Pain Mechanism (people such as Nassar, op.cit.).Na _V1.7 blocker in the neurone subgroup active more supports from following discovery: these the two kinds of human inheritance's property pain disease states of primary erythromelalgia and familial proctalgia that demonstrated are positioned to Na _V1.7 (Yang, people such as Y., J.Med.Genet. (2004), 41 (3): 171-4).

Na _V1.8 expression be limited to basically DRG (Raymond, people such as C.K., op.cit.).For Na _V1.8, do not have the human mutant of determining.Yet, Na _V1.8-the inefficacy mutant mice can be survived, can be bred and outward appearance is normal.The obvious pain of harmful mechanical stimulus is felt that the little damaged and hyperalgesic delayed development of inflammatory of disappearance, harmful thermoreceptor hints Na to the investigator _V(Akopian, people such as A.N., Nat.Neurosci. (1999), 2 (6): 541-8) 1.8 in the pain signal transmission, play a major role.This carrier frequency channel break has been widely acknowledged to be potential treatment (Lai, people such as J, the above works of being quoted that is used for pain; Wood, people such as J.N., the above works of being quoted; Chung, people such as J.M., op.cit.).The PCT patent application WO that announces described for 03/037274A2 number by blocking-up with shown in morbid state outbreak or recur relevant sodium channel and treat the central or peripheral nervous system morbid state, especially be the pyrazole amide and the sulphonamide of pain and chronic pain.The PCT patent application WO that announces described for 03/037890A2 number by blocking-up with shown in morbid state outbreak or recur relevant sodium channel and treat the central or peripheral nervous system morbid state, especially be the piperidines of pain and chronic pain.The compound of these inventions, composition and method are by suppressing through comprising PN3 (Na _V1.8) subunit is particularly useful for treating neurogenic pain or inflammatory pain at the ionic flux of interior passage.

Dib-Hajj, people such as S.D. are disclosed to the insensitive sodium channel Na on every side of tetraodotoxin _V1.9 (referring to Dib-Hajj, people such as S.D., Proc.Natl.Acad.Sci.USA (1998), 95 (15): 8963-8) demonstrate and only be arranged in dorsal root ganglion.Proved Na _V1.9 be neurotrophic factor (the BDNF)-depolarize that causes and the basis of excitement, and show that it is unique through ligand-mediated member (Blum, R., Kafitz in the voltage-gated sodium channel superfamily, K.W., Konnerth, A., Nature (2002), 419 (6908): 687-93).The expression pattern of the limitation of this passage has made it become candidate's target spot (Lai, people such as J, the op.cit. of treatment pain; Wood, people such as J.N., op.cit.; Chung, people such as J.M., op.cit.).

NaX is the sodium channel of inferring, and it does not demonstrate to valtage-gated.Except that the expression in the Schwann of lung, heart, dorsal root ganglion and peripheral nervous system cell, NaX is found in the neurone and ependymocyte in the CNS limited area, especially (Watanabe in relating to the circumventricular organ official of body fluid homeostasis, E. wait the people, J.Neurosci. (2000), 20 (20): 7743-51).The invalid mouse of NaX-shows the unusual absorption to hypertonic saline under the condition of not only lack of water but also salt deficiency.These discoveries show that NaX plays an important role in the adjusting that the maincenter sensation and the salt of body fluid sodium level are taken in behavior.Its phraseology shows that with function it is that the treatment cystic fibrosis salt relevant with other is regulated the target spot of disease.

Use be used for reducing some zone of brain neuronal activity sodium channel blockers tetraodotoxin (TTX) studies show that its potential use aspect the treatment habituation.Companion's medicine (Drug-paired) stimulates and causes drug craving and make habituation and the recurrence of medicine pursuit behavior in rat.The recurrence that the functional completeness of substrate outside amygdala (BLA) is pursued behavior for the Cocaine that is caused by Cocaine-conditioned stimulus is necessary, but then also nonessential for what caused by Cocaine itself.BLA plays similar effect in the recurrence of heroine (heroin) pursuit behavior.In rat model, TTX inductive BLA inactivation is eliminated the heroine that is disappeared by conditioned disjunction heroine inductive and is pursued the recurrence of behavior (Psychopharmacology (2002) 160 (4): 425-33) for Fuchs, R.A. and see R.E..

This closely-related protein families is considered to therapeutic interventional target spot for a long time.The sodium channel is the target spot of different pharmacological agents.These comprise neurotoxin, anti-arrhythmic, anticonvulsive drug and local anesthetic (Clare, people such as J.J., Drug Discovery Today (2000) 5:506-520).The pharmacological agents of current all batrachotoxins all has acceptor site on the α subunit.At least six different acceptor sites of neurotoxin and an acceptor site of local anesthetic and related drugs (Cestele, people such as S., Biochimie (2000), the 82nd volume: 883-892) have been differentiated.

Small molecules sodium channel blockers or local anesthetic and relevant antiepileptic drug and antiarrhythmic drug and the overlapping acceptor site that is arranged in hole, sodium channel inner chamber interact (Catterall, W.A., Neuron (2000), 26:13-25).From the amino-acid residue in the S6 fragment of at least three structural domains in four structural domains this combination drug acceptor site is had effect, wherein the IVS6 fragment plays remarkable effect.These region height are conservative, and therefore known up to now most of sodium channel blockers interact with similar usefulness and all passage hypotypes.However, may produce the sodium channel blockers that is used for the treatment of epilepsy (for example lamotrigine (lamotrignine), Phenytoin Sodium Salt (phenytoin) and Carbamzepine (carbamazepine)) and some irregular pulse (for example lignocaine (lignocaine), appropriate card amine (tocainide), mexiletine (mexiletine)) that has the treatment selectivity and enough treat window.Yet the usefulness of these blockers and therapeutic index are not the best and have limited the purposes of these compounds in the multiple treatment field that is suitable for sodium channel blockers ideally.

Summary of the invention

The present invention relates to spiro-oxindole compounds and comprise the pharmaceutical composition of this compound and use compound of the present invention and medicine composite for curing and/or the disease of prevention such as sodium channels such as pain mediation or the method for morbid state.The invention still further relates to the disease of other sodium channel mediation of medicine composite for curing of using this compound and comprising this compound or the method for morbid state, include but not limited to the nervus centralis morbid state, as epilepsy, anxiety, depression and two-phase disease; The cardiovascular disorder state,, atrial fibrillation not normal and ventricular fibrillation as the rhythm of the heart; The neuromuscular disease state is as restless leg syndrome, essential tremor and muscular paralysis or tetanus; The neuroprotective of anti-palsy, glaucoma, nerve injury and multiple sclerosis; And the ionic channel disease, as erythromelalgia and familial rectum pain syndrome.The invention still further relates to the method for disease such as the medicine composite for curing that uses compound of the present invention and comprise this compound and/or prevention such as hypercholesterolemia, benign prostatic hyperplasia, pruritus and cancer or morbid state.

Therefore, an aspect of of the present present invention relates to general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Q is-C (R ^1a) ₂-,-O-,-S (O) _p-(wherein p is 0,1 or 2) ,-CF ₂-,-OC (O)-,-C (O) O-,-C (O) N (R ⁵)-,-N (R ⁵)-or-N (R ⁵) C (O)-,

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

R ¹For hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical ,-R ⁸-C (O) R ⁵,-R ⁸-C (O) OR ⁵,-R ⁸-C (O) N (R ⁴) R ⁵,-S (O) _t-R ⁵(wherein t is 1 or 2) ,-R ⁹-S (O) _p-R ⁵(wherein p is 0,1 or 2) ,-R ⁸-OR ⁵,-R ⁸-CN ,-R ⁹-P (O) (OR ⁵) ₂Or-R ⁹-O-R ⁹-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

R ⁷For hydrogen, alkyl, haloalkyl ,-R ⁹-CN ,-R ⁹-OR ⁵,-R ⁹-N (R ⁴) R ⁵, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl;

Or R ⁶And R ⁷Form heterocyclic radical or heteroaryl with the nitrogen that it connected;

And wherein for R ⁶With R ⁷, each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl can be randomly be selected from following substituting group and replace by one or more: alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl;

Or R ¹For randomly by one or more being selected from-R ⁸-OR ⁵,-C (O) OR ⁵, halogen, haloalkyl, alkyl, nitro, cyano group, aryl, aralkyl, heterocyclic radical and heteroaryl the aralkyl that replaces of substituting group;

Or R ¹For-R ⁹-N (R ¹⁰) R ¹¹,-R ⁹-N (R ¹²) C (O) R ¹¹,-R ⁹-C (O) N (R ¹²) R ¹¹Or-R ⁹-N (R ¹⁰) C (O) N (R ¹⁰) R ¹¹, wherein

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

Each R ¹¹For hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁹-OC (O) R ⁵,-R ⁹-C (O) OR ⁵,-R ⁹-C (O) N (R ⁴) R ⁵,-R ⁹-C (O) R ⁵,-R ⁹-N (R ⁴) R ⁵,-R ⁹-OR ⁵Or-R ⁹-CN;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

And wherein for R ¹⁰With R ¹¹, each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro ,-R ⁸-CN ,-R ⁸-OR ⁵,-R ⁸-C (O) R ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹Be heterocyclic radical alkyl or heteroarylalkyl, wherein heterocyclic radical alkyl or heteroarylalkyl be randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵, aryl and aralkyl substituting group replace;

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, halogen, haloalkyl, haloalkenyl group, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-N=C (R ⁴) R ⁵,-R ⁸-S (O) _pR ⁴,-R ⁸-OS (O) ₂CF ₃,-R ⁸-C (O) R ⁴-R ⁸-C (S) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-R ⁸-C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (O) R ⁴,-R ⁸-N (R ⁵) C (S) R ⁴,-R ⁸-N (R ⁵) C (O) OR ⁴,-R ⁸-N (R ⁵) C (S) R ⁴,-R ⁸-N (R ⁵) C (O) OR ⁴,-R ⁸-N (R ⁵) C (S) OR ⁴,-R ⁸-N (R ⁵) C (O) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) S (O) _tR ⁴,-R ⁸-N (R ⁵) S (O) _tN (R ⁴) R ⁵,-R ⁸-S (O) _tN (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-R ⁸-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each p independently is 0,1 or 2, and each t independently is 1 or 2;

And wherein for R ^2a, R ^2b, R ^2cAnd R ^2d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _pR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _tR ⁴Substituting group replace, wherein each p independently is 0,1 or 2, and each t independently is 1 or 2;

Or R ^2aAnd R ^2bWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, and R ^2cWith R ^2dAll define as preamble;

Or R ^2bAnd R ^2cWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, and R ^2aWith R ^2dAll define as preamble;

Or R ^2cAnd R ^2dWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, and R ^2aWith R ^2dAll define as preamble;

Each R ³Be independently selected from alkyl, thiazolinyl, alkynyl, halogen, haloalkyl, haloalkenyl group, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl, oxo ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-N=C (R ⁴) R ⁵,-R ⁸-S (O) _pR ⁴,-R ⁸-OS (O) ₂CF ₃,-R ⁸-C (O) R ⁴,-R ⁸-C (S) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-R ⁸-C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (O) R ⁴,-R ⁸-N (R ⁵) C (S) R ⁴,-R ⁸-N (R ⁵) C (O) OR ⁴,-R ⁸-N (R ⁵) C (S) OR ⁴,-R ⁸-N (R ⁵) C (O) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) S (O) _tR ⁴,-R ⁸-N (R ⁵) S (O) _tN (R ⁴) R ⁵,-R ⁸-S (O) _tN (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-R ⁸-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each p independently is 0,1 or 2, and each t independently is 1 or 2;

And wherein for R ³, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _pR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _tR ⁴Substituting group replace, wherein each p independently is 0,1 or 2, and each t independently is 1 or 2;

Each R ⁴With R ⁵Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, haloalkenyl group, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl;

Or work as R ⁴And R ⁵When all being connected to identical nitrogen-atoms, R then ⁴And R ⁵Can form heterocyclic radical or heteroaryl with the nitrogen-atoms that it connected; And

Each R ⁸Be direct key or the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched; And

Each R ⁹Be the alkylidene chain of straight or branched, the alkenylene chain or the straight or branched alkynylene chain of straight or branched.

It is mammiferous that the present invention provides treatment on the other hand, the method of preferred people's pain, wherein this method comprises compound aforesaid of the present invention, its steric isomer, enantiomer, tautomeric forms or its mixture of the Mammals that needs are arranged being treated significant quantity; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug; Or comprise above-mentioned The compounds of this invention, its steric isomer, enantiomer, tautomer or its mixture for the treatment of significant quantity, or the pharmaceutical composition of the acceptable salt of its medicine, N-oxide compound, solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provides treatment on the other hand or alleviates the method for the seriousness of mammiferous disease, morbid state or illness, wherein one or more Na _V1.1, Na _V1.2, Na _V1.3, Na _V1.4, Na _V1.5, Na _V1.6, Na _V1.7, Na _V1.8 or Na _V1.9 activation or hyperactivity hyperkinesia and this disease, morbid state or illness are relevant, wherein this method comprises the aforesaid The compounds of this invention of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the aforesaid The compounds of this invention for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provides the disease of the mammiferous multiple sodium channel mediation of treatment or the method for morbid state on the other hand; the pain that this disease or morbid state are for example relevant with HIV; the neuropathy that the HIV treatment is caused; trigeminal neuralgia; postherpetic neuralgia; eudynia; heat sensitivity; tosarcoidosis; irritable bowel syndrome; Crohn disease; with the relevant pain of multiple sclerosis (MS); amyotrophic lateral sclerosis (ALS); diabetic neuropathy; the peripheral nerve pathology; sacroiliitis; rheumatoid arthritis; osteoarthritis; atherosclerosis; the paroxysmal myodystonia; myasthenic syndrome; myotony; malignant hyperthermia; cystic fibrosis; pseudohyperaldosteronism; rhabdomyolysis; hypothyroidism; the two-phase dysthymia disorders; anxiety; schizophrenia; the sodium channel toxin-related diseases; the familial erythromelalgia; primary erythermalgia; familial rectum pain; cancer; epilepsy; locality grand mal and general grand mal; restless leg syndrome; irregular pulse; fibromyalgia; by palsy; neuroprotective under the ischemia state that glaucoma or neural wound caused; tachyarrhythmia; atrial fibrillation and ventricular fibrillation; wherein this method comprises the Mammals of needs is arranged; preferably be the people; treat the aforesaid The compounds of this invention of significant quantity; its steric isomer; enantiomer; tautomer or its mixture; or the acceptable salt of its medicine; the N-oxide compound; solvate or prodrug, or comprise the aforesaid The compounds of this invention for the treatment of significant quantity; its steric isomer; enantiomer; tautomer or its mixture; or the acceptable salt of its medicine; the N-oxide compound; the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provides on the other hand by suppressing mammiferous ionic current through the voltage-dependent sodium channel and treats the disease of mammiferous multiple sodium channel mediation or the method for morbid state, wherein this method comprises the aforesaid The compounds of this invention of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the aforesaid The compounds of this invention for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provides treatment on the other hand or prevents mammiferous, preferably be the people's, the method of hypercholesterolemia, wherein this method comprises the aforesaid The compounds of this invention of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the aforesaid The compounds of this invention for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provides treatment on the other hand or prevents mammiferous, it preferably is the method for people's benign prostatic hyperplasia, wherein this method comprises the aforesaid The compounds of this invention of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the aforesaid The compounds of this invention for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provides treatment on the other hand or prevents mammiferous, it preferably is the method for people's pruritus, wherein this method comprises the aforesaid The compounds of this invention of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the aforesaid The compounds of this invention for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provides treatment on the other hand or prevents mammiferous, it preferably is people's method for cancer, wherein this method comprises the aforesaid The compounds of this invention of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the aforesaid The compounds of this invention for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

The present invention provide on the other hand with the pharmacotherapy of one or more other The compounds of this invention or one or more other accepted therapy associating or its any combination with the effectiveness that increases existing or future pharmacotherapy or reduce and accepted the relevant adverse events of therapy.In one embodiment, the present invention relates to pharmaceutical composition that The compounds of this invention is combined with that established or the following therapy that is used for the cited indication of the present invention.

The present invention relates to above-mentioned The compounds of this invention on the other hand, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug are used for the treatment of purposes in the medicine of Mammals pain in preparation, or relate to and comprise pharmaceutically-acceptable excipients and aforesaid The compounds of this invention, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug is used for the treatment of purposes in the medicine of Mammals pain in preparation.

The present invention relates to above-mentioned The compounds of this invention on the other hand, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug be used for the treatment of purposes in the medicine of the disease of mammiferous sodium channel mediation or morbid state in preparation, or relate to and comprise pharmaceutically-acceptable excipients and aforesaid The compounds of this invention, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug is used for the treatment of purposes in the medicine of the disease of mammiferous sodium channel mediation or morbid state in preparation.

Detailed description of the invention

Definition

Indicate some chemical group of name herein in front by the contracted notation that shows the total number of carbon atoms of in specifying chemical group, finding.For example, C ₇-C ₁₂Alkyl is described has the alkyl as hereinafter defining of 7 to 12 carbon atoms altogether, and C ₄-C ₁₂The cyclic hydrocarbon radical alkyl is described has the cyclic hydrocarbon radical alkyl as hereinafter defining of 4 to 12 carbon atoms altogether.The total number of carbon atoms in the contracted notation does not comprise the carbon in the substituting group that may be present in described group.

Except that aforementioned, when being used for specification sheets and claims, except as otherwise noted, otherwise following term has implication as follows:

" amino " is meant-NH ₂Base.

" cyano group " is meant-the CN base.

" hydroxyl " is meant-the OH base.

" imido grpup " is meant=the NH substituting group.

" nitro " is meant-NO ₂Base.

" N-oxide compound " is meant the N → O of functional group.The N-oxide compound prepares by making tertiary amine (comprising aromatic amine, seen at pyridine) oxidation.

" oxo " is meant=the O substituting group.

" sulfo-" is meant=the S substituting group.

" trifluoromethyl " is meant-CF ₃Base.

" alkyl " only be meant by carbon atom and hydrogen atom form, do not contain unsaturated, have one to 12 carbon atom, be preferably one to eight carbon atom or to six carbon atom, and the hydrocarbon chain base of the straight or branched that is connected with the rest part of molecule by singly-bound, for example methyl, ethyl, just-propyl group, 1-methylethyl (sec.-propyl), just-butyl, just-amyl group, 1,1-dimethyl ethyl (tertiary butyl), 3-methyl hexyl, 2-methyl hexyl etc.Unless offer some clarification in addition in the specification sheets, otherwise alkyl can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, oxo, trimethyl silyl ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR ¹⁶,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" thiazolinyl " only is meant and is made up of carbon atom and hydrogen atom, contain at least one two key, have two to 12 carbon atoms, be preferably two to eight carbon atoms, and the hydrocarbon chain base of the straight or branched that is connected with the rest part of molecule by singly-bound, for example vinyl, third-1-thiazolinyl, but-1-ene base, penta-1-thiazolinyl, penta-1,4-dialkylene etc.Unless offer some clarification in addition in this specification sheets, otherwise thiazolinyl can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, oxo, trimethyl silyl ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR ¹⁶,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" alkynyl " only is meant and is made up of carbon atom and hydrogen atom, contain at least one three key, randomly contain at least one two key, have two to 12 carbon atoms, preferred two to eight carbon atoms, and the hydrocarbon chain base of the straight or branched that is connected with the rest part of molecule by singly-bound, for example ethynyl, proyl, butynyl, pentynyl, hexin base etc.Unless offer some clarification in addition in this specification sheets, otherwise alkynyl can randomly be replaced by one or more following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, oxo, trimethyl silyl ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR ¹⁶,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" alkylidene group " or " alkylidene chain " be meant that the rest part with molecule is connected with group, only form by carbon and hydrogen, do not contain unsaturated, and the bivalent hydrocarbon chain with straight or branched of one to 12 carbon atom, for example methylene radical, ethylidene, propylidene, inferior normal-butyl etc.Alkylidene chain is connected with the rest part of molecule by singly-bound and is connected with described group by singly-bound.Alkylidene chain and molecule rest part reach and the tie point of this group can be through carbon of this intrachain or any two carbon.Unless offer some clarification in addition in this specification sheets, otherwise alkylidene chain can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, oxo, trimethyl silyl ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR ¹⁶,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

That " alkenylene " and " alkenylene chain " are meant is that the rest part with molecule is connected with group, only be made up of carbon and hydrogen, contain at least one two key and have the bivalent hydrocarbon chain of the straight or branched of two to 12 carbon atoms, for example vinylidene, propenylidene, inferior n-butene base etc.The alkenylene chain is connected with the rest part of molecule by singly-bound and is connected with described group by two keys or singly-bound.The rest part of alkenylene chain and molecule reaches and the tie point of this group can be through carbon of intrachain or any two carbon.Unless offer some clarification in addition in this specification sheets, otherwise the alkenylene chain can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, oxo, trimethyl silyl ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR ¹⁶,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" alkynylene " or " alkynylene chain " be meant that the rest part with molecule is connected with group, only form by carbon and hydrogen, contain at least one three key and have the bivalent hydrocarbon chain of the straight or branched of two to 12 carbon atoms, for example inferior proyl, inferior positive butynyl etc.The alkynylene chain is connected with the rest part of molecule by singly-bound, and is connected with described group by two keys or singly-bound.The rest part of alkynylene chain and molecule reaches and the tie point of this group can be through carbon of intrachain or any two carbon.Unless offer some clarification in addition in this specification sheets, otherwise the alkynylene chain can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, oxo, trimethyl silyl ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR ¹⁶,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Independent is hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" alkoxyl group " is meant formula-OR _aGroup, wherein R _aBe to be the alkyl that contains one to 12 carbon atom as the preamble definition.The moieties of alkoxyl group can be optionally substituted about the definition of alkyl as preamble.

" alkoxyalkyl " is meant formula-R _b-O-R _aGroup, wherein R _bBe alkylidene chain as the preamble definition, and R _aBe alkyl as the preamble definition.Sauerstoffatom can with any bond with carbon in alkylidene chain and the alkyl.The moieties of alkoxyalkyl can be optionally substituted about the definition of alkyl as preamble.The alkylidene chain part of alkoxyalkyl can be optionally substituted about the definition of alkylidene group as preamble.

" aryl " is meant the hydrocarbon member ring systems that comprises hydrogen, 6 to 18 carbon atoms and at least one aromatic nucleus.With regard to purpose of the present invention, aryl can be monocycle, dicyclo, three ring or Fourth Ring systems, and can comprise fused rings or bridged-ring system.Aryl includes but not limited to by aceanthrylene, acenaphthene, the luxuriant and rich with fragrance alkene of vinegar, anthracene, Azulene, benzene, 1,2-benzophenanthrene, fluoranthene, fluorenes, asymmetric indacene (as-indacene), symmetrical indacene (s-indacene), indane, indenes, naphthalene, non-that alkene, phenanthrene, seven days of the week alkene, pyrene and triphenylene deutero-aryl.Unless offer some clarification in addition in this specification sheets, otherwise " aryl " or prefix " virtue-" (for example in " aralkyl ") mean and comprise randomly by one or more and independently be selected from the following aryl that substituting group replaced: alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR ¹⁶,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-N=C (OR ¹⁴) R ¹⁴,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-R ¹⁵-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; Each R ¹⁵Be the alkylidene group or the alkenylene chain of direct key or straight or branched independently; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" aralkyl " is meant formula-R _b-R _cGroup, wherein R _bBe alkylidene chain and R as the preamble definition _cBe the one or more aryl as the preamble definition, for example benzyl, diphenyl methyl etc.The alkylidene chain part of aralkyl can be optionally substituted by alkylidene chain as indicated above like that.The aryl moiety of aralkyl can be optionally substituted by aryl as indicated above like that.

" arylalkenyl " is meant formula-R _d-R _cGroup, wherein R _dBe alkenylene chain and R as the preamble definition _cBe one or more aryl as the preamble definition.The aryl moiety of arylalkenyl aryl as previously described is optionally substituted like that.The alkenylene chain portion of arylalkenyl can be optionally substituted about the definition of alkenylene as preamble.

" sweet-smelling alkynyl " is meant formula-R _e-R _cGroup, wherein R _eBe alkynylene chain and R as the preamble definition _cBe one or more aryl as the preamble definition.The aryl moiety of sweet-smelling alkynyl aryl as previously described is optionally substituted like that.The alkynylene chain branch of sweet-smelling alkynyl can be optionally substituted about the definition of alkynylene chain as preamble.

" cyclic hydrocarbon radical " is meant stable non-aromatic monocyclic or the multi-ring alkyl of only being made up of carbon and hydrogen atom, it can comprise fused rings system or bridged-ring system, have three to 15 carbon atoms, preferably have three to ten carbon atoms, and it is saturated or unsaturated and is connected with the rest part of molecule by singly-bound.Monocyclic groups comprises, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Many cyclic groups comprise, for example adamantyl, norcamphyl, decahydro naphthyl, 7,7-dimethyl-dicyclo [2.2.1] heptane base etc.Unless offer some clarification in addition in this specification sheets, otherwise " cyclic hydrocarbon radical " means and comprises randomly by one or more and independently be selected from the cyclic hydrocarbon radical that following substituting group replaces: alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, nitro, oxo, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR ¹⁶,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-N=C (OR ¹⁴) R ¹⁴,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-R ¹⁵-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; Each R ¹⁵Independent is the alkylidene group or the alkenylene chain of direct key or straight or branched; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" cyclic hydrocarbon radical alkyl " is meant formula-R _bR _gGroup, wherein R _bBe alkylidene chain and R as the preamble definition _gBe cyclic hydrocarbon radical as the preamble definition.Alkylidene chain and cyclic hydrocarbon radical all can be optionally substituted as the preamble definition.

" cyclic hydrocarbon radical thiazolinyl " is meant formula-R _dR _gGroup, wherein R _dBe alkenylene chain and R as the preamble definition _gBe cyclic hydrocarbon radical as the preamble definition.Alkenylene chain and cyclic hydrocarbon radical all can be optionally substituted as the preamble definition.

" cyclic hydrocarbon radical alkynyl " is meant formula-R _eR _gGroup, wherein R _eBe alkynylene and R as the preamble definition _gBe cyclic hydrocarbon radical as the preamble definition.Alkynylene chain and cyclic hydrocarbon radical all can optional replacements as the preamble definition.

" condense " be meant with compound of the present invention in ring structure condensed any ring structure described herein of both having deposited.When fused rings was heterocyclic ring or heteroaryl ring, any carbon atom both deposited on the ring structure that becomes the part of condensed heterocycle basic ring or condensed heteroaryl ring all can be replaced by nitrogen-atoms.

" halogen " is meant bromine, chlorine, fluorine or iodine.

" haloalkyl " is meant by one or more alkyl as the preamble definition that replace as the halogen of preamble definition, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-methyl fluoride-2-fluoro ethyl, 3-bromo-2-fluoropropyl, 1-brooethyl-2-bromotrifluoromethane etc.The moieties of haloalkyl can be optionally substituted about the definition of alkyl as preamble.

" haloalkenyl group " is meant by one or more thiazolinyls as the preamble definition that replace as the halogen of preamble definition.The alkenyl part of haloalkenyl group can be optionally substituted about the definition of thiazolinyl as preamble.

" halo alkynyl " is meant by one or more alkynyls as the preamble definition that replace as the halogen of preamble definition.The alkynyl part of alkynyl halide can be optionally substituted about the definition of alkynyl as preamble.

" heterocyclic radical " is meant by two to 12 carbon atoms and one to six and is selected from 3 yuan to the 18 yuan stable non-aromatics cyclic groups that the heteroatoms of nitrogen, oxygen and sulphur is formed.Unless offer some clarification in addition in this specification sheets, otherwise heterocyclic radical can be monocycle, dicyclo, three ring or Fourth Ring systems, it can comprise fused rings system or bridged-ring system; And the nitrogen in the heterocyclic radical, carbon or sulphur atom can be randomly oxidized; Nitrogen-atoms can be randomly by quaternized; And heterocyclic radical can be partially or completely saturated.The example of this heterocyclic radical includes but not limited to the dioxy cyclopentyl, thienyl [1,3] dithiane base, the Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidyl, isothiazole alkyl; isoxazole alkyl, morpholinyl, the octahydro indyl, the octahydro pseudoindoyl, 2-piperazine ketone group, the 2-piperidone base, 2-Pyrrolidone base oxazolidinyl, piperidyl, piperazinyl, the 4-piperidone base, pyrrolidyl, pyrazolidyl, the peaceful cyclic group of quinoline, thiazolidyl, tetrahydrofuran base, the trithian base, THP trtrahydropyranyl, thio-morpholinyl, the thiomorpholine base, 1-oxo-thio-morpholinyl and 1,1-dioxo-thio-morpholinyl.Unless offer some clarification in addition in this specification sheets, otherwise " heterocyclic radical " means and comprises randomly the heterocyclic radical as the preamble definition that is replaced by one or more following substituting groups: alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, oxo, sulfo-, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR ¹⁶,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-N=C (OR ¹⁴) R ¹⁴,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-R ¹⁵-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; Each R ¹⁵Independent is the alkylidene group or the alkenylene chain of direct key or straight or branched; And each R ¹⁶Be alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" N-heterocyclic radical alkyl " be meant contain at least one nitrogen and wherein the tie point of the rest part of heterocyclic radical and molecule be the heterocyclic radical as the preamble definition of the nitrogen-atoms in heterocyclic radical.N-heterocyclic radical heterocyclic radical as previously described is optionally substituted like that.

" heterocyclic radical alkyl " refers to formula-R _bR _hGroup, wherein R _bBe alkylidene chain and R as the preamble definition _hBe heterocyclic radical as the preamble definition, and if heterocyclic radical be nitrogenous heterocyclic radical, then heterocyclic radical can be connected with alkyl on this nitrogen-atoms.The alkylidene chain of heterocyclic radical alkyl can be optionally substituted defined about alkylidene chain as preamble.The heterocyclic radical of heterocyclic radical alkyl part can be optionally substituted defined about heterocyclic radical as preamble.

" heterocyclic radical thiazolinyl " refers to formula-R _dR _hGroup, wherein R _dBe alkenylene chain and R as the preamble definition _hBe heterocyclic radical as the preamble definition, and if heterocyclic radical be nitrogenous heterocyclic radical, then heterocyclic radical can be connected with the alkenylene chain on this nitrogen-atoms.The alkenylene chain of heterocyclic radical thiazolinyl can be optionally substituted defined about the alkenylene chain as preamble.The heterocyclic radical of heterocyclic radical thiazolinyl part can be optionally substituted defined about heterocyclic radical as preamble.

" heterocyclic radical alkynyl " refers to formula-R _eR _hGroup, wherein R _eBe alkynylene chain and R as the preamble definition _hBe heterocyclic radical as the preamble definition, and if heterocyclic radical be nitrogenous heterocyclic radical, then heterocyclic radical can be connected with alkynylene on this nitrogen-atoms.The alkynylene chain portion of heterocyclic radical alkynyl can be optionally substituted defined about the alkynylene chain as preamble.The heterocyclic radical of heterocyclic radical alkynyl part can be optionally substituted defined about heterocyclic radical as preamble.

" heteroaryl " be meant comprise hydrogen atom, one to 13 carbon atom, one to six be selected from nitrogen, oxygen and sulphur heteroatomic 5 yuan to 14-unit member ring systems group.With regard to purpose of the present invention, heteroaryl can be monocycle, dicyclo, three ring or Fourth Ring systems, and it can comprise fused rings system or bridged-ring system; And randomly oxidation of the nitrogen in the heteroaryl, carbon or sulphur atom; Nitrogen-atoms can be randomly by quaternized.Example includes but not limited to azepine Base, acridyl, benzimidazolyl-, benzothiazolyl, the benzindole base, the benzo dioxolyl, benzofuryl benzoxazolyl, benzothiazolyl, the diazosulfide base, benzo [b] [1,4] dioxane heptyl, 1,4-benzodioxan base, benzo aphthofurans base benzoxazolyl, the benzo dioxolyl, benzo dioxine base, benzopyranyl, the chromene ketone group, benzofuryl, the cumarone ketone group, benzothienyl (benzothienyl), the benzotriazole base, benzo [4,6] imidazo [1,2-a] pyridyl, carbazyl, the cinnolines base, dibenzofuran group, the dibenzothiophene base, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indyl, indazolyl, pseudoindoyl, indolinyl, iso-dihydro-indole-group, isoquinolyl, indolizine base isoxazolyl, naphthyridinyl oxadiazole base, 2-oxo azepine

Base oxazolyl, Oxyranyle, 1-oxo pyridine base, the 1-oxo-pyrimidine base, 1-Oxopyrazine base, 1-oxo pyridazinyl, 1-phenyl-1H-pyrryl, phenazinyl, phenothiazinyl phenoxazinyl, phthalazinyl, pteridine radicals, purine radicals, pyrryl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrryl, quinazolyl, quinoxalinyl, quinolyl, quinuclidinyl, isoquinolyl, tetrahydric quinoline group, thiazolyl, thiadiazolyl group, triazolyl, tetrazyl, triazinyl and thiophenyl (being thienyl).Unless offer some clarification in addition in this specification sheets, otherwise " heteroaryl " means and comprises randomly by one or more and be selected from the heteroaryls as the preamble definition that following substituting group replaces: alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, cyano group, oxo, sulfo-, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR ¹⁶,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-N=C (OR ¹⁴) R ¹⁴,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _pR ¹⁶(wherein p is 0 to 2) reaches-R ¹⁵-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Be hydrogen, alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl independently; Each R ¹⁵Be the alkylidene group or the alkenylene chain of direct key or straight or branched independently; And each R ¹⁶Be alkyl, thiazolinyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroarylalkyl.

" N-heteroaryl " be meant contain at least one nitrogen and wherein the tie point of the rest part of heteroaryl groups and molecule be the heteroaryl groups as the preamble definition of the nitrogen-atoms in heteroaryl groups.N-heteroaryl groups heteroaryl groups as previously described is optionally substituted like that.

" heteroarylalkyl " refers to formula-R _bR _iGroup, wherein R _bBe alkylidene chain and R as the preamble definition _iBe heteroaryl as the preamble definition.The heteroaryl moieties of heteroarylalkyl can be optionally substituted defined about heteroaryl as preamble.The alkylidene chain of heteroarylalkyl part can be optionally substituted defined about alkylidene chain as preamble.

" heteroaryl thiazolinyl " is meant formula-R _dR _iGroup, wherein R _dBe alkenylene chain and R as the preamble definition _iBe heteroaryl as the preamble definition.The heteroaryl moieties of heteroaryl thiazolinyl can be optionally substituted defined about heteroaryl as preamble.The alkenylene chain portion of heteroaryl thiazolinyl can be optionally substituted defined about the alkenylene chain as preamble.

" heteroaryl alkynyl " is meant formula-R _eR _iGroup, wherein R _eBe alkynylene chain and R as the preamble definition _iBe heteroaryl as the preamble definition.The heteroaryl moieties of heteroaryl alkynyl can be optionally substituted defined about heteroaryl as preamble.The alkynylene chain portion of heteroaryl alkynyl can be optionally substituted defined about the alkynylene chain as preamble.

" hydroxyalkyl " is meant the alkyl as the preamble definition that is replaced by one or more hydroxyls.

" analgesia " is meant that the pain that the stimulation to common misery responds does not exist.

" paralgesia " is meant harmless consciousness usually, such as pressure or slight contact, is perceived as painful terrifically morbid state.

" prodrug " is intended to represent can be under physiological conditions or be converted to the compound of bioactive compounds of the present invention by solvolysis.Therefore, term " prodrug " is meant the acceptable metabolic precursor thereof of medicine of The compounds of this invention.When being given need individual, prodrug can not have activity, but is converted to active compound of the present invention in vivo.Prodrug promptly transforms usually in vivo, and produces parent compound of the present invention, for example realizes by hydrolysis in blood.Preceding drug compound often provides the advantage of solubleness, histocompatibility or slowly-releasing (to consult Bundgard, H., the design of prodrug (1985), 7-9,21-24 page or leaf (Elsevier, Ams in mammalian organism _tErdam)).At Higuchi, T. wait the people, " prodrug is as the delivery system of novelty ", A.C.S. analects series, the 14th volume and " the biological reversible carrier in the medicinal design ", Edward B.Roche writes, united states drug association and Pergamon press publish, and the discussion of prodrug was provided in 1987, are incorporated herein these two pieces of documents for reference in full.

Term " prodrug " also means the carrier that comprises any covalent bonding, and when this prodrug was given mammalian subject, it disengaged active compound of the present invention in vivo.The prodrug of compound of the present invention can be modified by this way and prepares by being present in functional group in the The compounds of this invention: no matter be in routine operation or in vivo, make this modification be cracked into parent compound of the present invention.Prodrug comprises the wherein The compounds of this invention of hydroxyl, amino or sulfydryl and any group bonding, when the prodrug with The compounds of this invention gives mammalian subject, this prodrug can cracking to form free hydroxyl group, free amine group or free sulfhydryl groups respectively.The example of prodrug includes but not limited to acetic ester, manthanoate and the benzoate derivatives of the alcohol functional group in the The compounds of this invention, or the amide derivatives of amine functional group etc.

Invention disclosed herein also meaning contain have one or more by the acceptable general formula of all medicines (I) compound of the isotropic substance-mark of the displaced atom of atom of different mass or total mass number.Can be introduced in the isotropic substance that isotopic example in the disclosed compound comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, respectively as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I reaches ¹²⁵I.These radiolabeled compounds can be used for assisting to measure or measure the effectiveness of compound, for example act on site or pattern on the sodium channel by sign, or to acting on the binding affinity in important site on the pharmacology on the sodium channel.Some isotope-labeled general formula (I) compound is for example introduced radioisotopic general formula (I) compound, can be used for medicine and/or the research of substrate tissue distribution.The radio isotope tritium, promptly ³H and carbon- ¹⁴, promptly ¹⁴C, in view of it is easy to introduce and existing proofing unit, therefore particularly useful for this purpose.

With heavier isotopic replacement, deuterium for example, promptly ²H can obtain because than some treatment advantage that greater metabolic stability caused, the dosage demand of transformation period or reduction in the body of Zeng Jiaing for example, and so may be preferred in some cases.

Use the positron radiation isotropic substance, for example ¹¹C, ¹⁸F, ¹⁵O reaches ¹³The replacement of N can be used for positron emission computerized tomography imaging art (PET) research, captures with check substrate acceptor.Isotope-labeled general formula (I) compound can use the alternative previous unlabelled reagent that adopts of suitable isotope-labeled reagent to prepare by the known routine techniques of those skilled in the art or preparation and the method described in the embodiment by being similar to hereinafter statement.

Invention disclosed herein also is intended to contain the interior metabolism product of disclosed compound.This kind product may be because for example generations such as the oxygenizement of the compound of institute's administration, reductive action, hydrolytic action, amidation, esterification mainly be because enzyme process.Therefore, the present invention includes the compound that produces by following process, this process comprises makes compound of the present invention contact one period that is enough to produce its meta-bolites with Mammals.Such product is usually by confirming in the following manner, give animal with radiolabeled compound of the present invention with detectable dosage, for example rat, mouse, guinea pig, monkey or give the mankind, make the enough time of its experience generation metabolism, and separate its converted product from urine, blood or other biological material.

" stable compound " and " rock steady structure " be intended to represent enough strong and be separated to useful purity from reaction mixture, and retain the compound that gets off when being mixed with effective therapeutical agent.

" Mammals " comprises the animal of people and stable breeding, for example animal for research and household pet (for example cat, dog, pig, ox, sheep, goat, horse, rabbit), and non-captive animal, for example wildlife etc.

" optional " or " randomly " means incident or the situation described subsequently and may take place or may not take place, and narration is situation and the wherein nonevent situation that comprises that this incident wherein or situation take place.For example, " randomly substituted aryl " means aryl and is substituted or is not substituted, and narration is to comprise substituted aryl and unsubstituted aryl simultaneously.When describing functional group with " randomly being substituted " and the substituting group in the functional group also be " randomly being substituted " etc., then with regard to purpose of the present invention, this repeats to be limited to five times.

" medicine acceptable carrier, thinner or vehicle " includes but not limited to by any adjuvant, carrier, vehicle, glidant, sweetener, thinner, sanitas, dyestuff/tinting material, flavoring toughener, tensio-active agent, wetting agent, dispersion agent, suspending agent, stablizer, isotonic agent, solvent or the emulsifying agent of FDA's permission for acceptable people of being used for or livestock animals.

" the acceptable salt of medicine " comprises acid salt and base addition salt simultaneously.

" the acceptable acid salt of medicine " be meant the biological effectiveness that keeps free state alkali and character and can be not expect at biology or others, and salt with mineral acid and organic acid formation, this mineral acid is such as but not limited to hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc., this organic acid is such as but not limited to acetate, 2, the 2-dichloro acetic acid, hexanodioic acid, Lalgine, xitix, aspartic acid, Phenylsulfonic acid, phenylformic acid, the 4-acetaminobenzoic acid, dextrocamphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, sad, carbonic acid, styracin, citric acid, the cyclohexyl thionamic acid, dodecyl sulphate, ethane-1, the 2-disulfonic acid, ethane sulfonic acid, the 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, tetrahydroxyadipic acid, gentisinic acid, glucoheptonic acid, gluconic acid, glucuronic acid, L-glutamic acid, pentanedioic acid, 2-oxopentanedioic acid, Phosphoric acid glycerol esters, oxyacetic acid, urobenzoic acid, isopropylformic acid, lactic acid, lactobionic acid, lauric acid, toxilic acid, oxysuccinic acid, propanedioic acid, amygdalic acid, methanesulfonic, glactaric acid, naphthalene-1, the 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, oleic acid, vitamin B13, oxalic acid, palmitinic acid, pamoic acid, propionic acid, Pyrrolidonecarboxylic acid, pyruvic acid, Whitfield's ointment, the 4-aminosallcylic acid, sebacic acid, stearic acid, succsinic acid, tartrate, thiocyanic acid, right-toluenesulphonic acids, trifluoroacetic acid, undecylenic acid etc.

" the acceptable base addition salt of medicine " is meant the biological effectiveness that keeps free acid and character and salt that can not expect in biology or others.These salt are to be formed in free acid and to prepare by mineral alkali or organic bases are added.Salt derived from mineral alkali includes but not limited to sodium salt, sylvite, lithium salts, ammonium salt, calcium salt, magnesium salts, molysite, zinc salt, mantoquita, manganese salt, aluminium salt etc.Preferred inorganic salt are ammonium salt, sodium salt, sylvite, calcium salt and magnesium salts.Salt derived from organic bases includes but not limited to following salt: the primary amine class, secondary amine class and tertiary amines, substituted amine, comprise the natural amine that is substituted, cyclic amine and deacidite are as ammonia, Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, diethanolamine, thanomin, dimethylethanolamine, the 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexyl amine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming (hydrabamine), choline, trimethyl-glycine, benzene bright (benethamine), benzyl star (benzathine), quadrol, glucosamine, methyl glucoside amine, Theobromine, trolamine, tromethane, purine, piperazine, piperidines, N-ethylpiperidine, versamid 900 etc.Particularly preferred organic bases is Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexyl amine, choline and caffeine.

Usually, crystallization effect meeting produces the solvate of The compounds of this invention.Term used herein " solvate " is meant the aggregate that comprises one or more The compounds of this invention molecules and one or more solvent molecules.Solvent can be water, and the solvate under this situation can be hydrate.Perhaps, solvent can be organic solvent.Therefore, The compounds of this invention can hydrate exists, and comprises monohydrate, dihydrate, semihydrate, sesquialter hydrate, trihydrate, tetrahydrate etc., with and corresponding solvent chemical combination form.The compounds of this invention can be real solvate, but in other cases, The compounds of this invention can only just keep the mixture that indefinite water or water add the indefinite solvent in top.

" pharmaceutical composition " is meant that The compounds of this invention and being used for of usually accepting in the art be delivered to Mammals with bioactive compounds, people for example, the preparation of medium.This medium comprises all medicine acceptable carrier, thinner or vehicle for its use.

" the treatment significant quantity " be meant and the amount of The compounds of this invention, be preferably man-hour that this amount is enough to treat effectively mammiferous, preferred people's disease or morbid state as the sodium channel mediation of hereinafter definition when The compounds of this invention is given Mammals.The amount that constitutes the The compounds of this invention of " treatment significant quantity " is to depend on this compound, morbid state and seriousness thereof, administering mode and mammiferous age of waiting to be treated and changing, but but routine ground determine according to itself knowledge and present disclosure by those skilled in the art.

" treatment " used herein or " treatment " are contained and are had the disease paid close attention to or the Mammals of morbid state, preferably are people's the disease of being paid close attention to or the treatment of morbid state, and comprise:

(i) preventing disease or morbid state occur in Mammals, particularly work as this class Mammals and easily suffer from this morbid state, but be not diagnosed as yet when having suffered from this morbid state;

(ii) suppress disease or morbid state, promptly contain its development;

(iii) alleviate disease or morbid state, even this disease or morbid state disappear; Or

(iv) alleviate this disease or symptom that morbid state caused, promptly ease the pain but unresolved potential disease or morbid state.Term used herein " disease " is used interchangeably with " morbid state " or may be different, specific sick illness or morbid state may not have known cause of disease agent (so that not working out the cause of disease as yet), and therefore be not considered to disease as yet, and only be morbid state or the syndrome of not expecting, wherein specific symptom combination is more or less confirmed by clinician.

The compounds of this invention or the acceptable salt of its medicine can contain one or more asymmetric centers, and therefore can produce enantiomer, diastereomer and other stereoisomeric forms in any ratio, its can absolute stereo chemistry for viewpoint be defined as (R)-or (S)-, or for amino acid be defined as (D)-or (L)-.The present invention is intended to comprise all possible isomer, with and racemic modification and optical purity form.Optical activity (+) and (-), (R)-with (S)-or (D)-can use chiral synthon or chiral reagent preparation, or the fractionation of use routine techniques, for example chromatography and fractional crystallizaton with (L)-isomer.The routine techniques of the indivedual enantiomers of preparation/separation comprises by the chirality of suitable optical purity precursor synthetic, or uses for example chirality high pressure lipuid chromatography (HPLC) (HPLC) parsing racemic modification (or racemic modification of salt or derivative).When described compound herein contains the two keys of alkene or other how much asymmetric centers, and except as otherwise noted, otherwise this compounds is intended to comprise E and Z geometrical isomer.Similarly, in all tautomeric forms also will be included in.

" steric isomer " be meant by same atoms and form, by identical key bonding, but the compound with different three-dimensional structures, it is not interchangeable.The present invention will be contained various steric isomers and composition thereof, and comprise " enantiomer ", and it is meant that its molecule is two kinds of steric isomers of the mirror image that can not overlap each other.

" tautomer " is meant that proton is passed to another atom of same molecular from an atom of molecule.The present invention comprises the tautomer of any described compound.

The intermediate compound of general formula (I) also belongs in the scope of the invention, and all polymorphic forms of material mentioned above and crystal type thereof are also within the scope of the present invention.

Chemical name agreement used herein and structure iron are the correction form of I.U.P.A.C. naming system, use 9.07 editions software programs of ACD/ name and/or 10.0 editions software naming programs of ChemDraw (CambridgeSoft), wherein The compounds of this invention is called as the derivative of prostheses structure (for example imidazopyridine structure) in this article.With regard to the chemical name of the complexity that adopts with regard to this paper, at this substituting group of preceding name of the group that substituting group connected.For example, the cyclopropyl ethyl is to comprise having the substituent ethyl main chain of cyclopropyl.Except that following described, so key all in the chemical structural drawing of this paper, be identified, but to except some carbon atom, its be hypothesis with enough hydrogen atom bondings to finish valency.

About the chemical structure of the general formula in the following stated embodiment of the present invention (Ia) compound, following array structure is represented aromatic ring:

Therefore, for example general formula (Ia) compound (wherein j is 0; K is 1; M is 0; Q is-O-; R ¹Be n-pentyl; R ^2a, R ^2b, R ^2c, R ^2dAnd R ³Be hydrogen; A, B and E are C (H); And D is N), i.e. following formula: compound:

Be referred to herein as 1 '-amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

The working of an invention scheme

In the aforesaid each side of the present invention, some embodiment is preferred in summary of the invention.

In aforesaid general formula (I) compound, an embodiment is general formula (I) compound, wherein in summary of the invention

Be the condensed heterocycle basic ring.

In aforesaid general formula (I) compound, another embodiment is general formula (I) compound in summary of the invention, and wherein X is O, and

Be the condensed heteroaryl ring.

Embodiment in this embodiment relates to general formula (I) compound, and general formula (I) compound is following general formula (Ia) compound, its steric isomer, corresponding isomer, tautomer or its mixture; Or the acceptable salt of its medicine, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

Q is-C (R ^1a) H-,-C (O)-,-O-,-S-,-N (R ⁵)-,-CF ₂-,-C (O) O-,-C (O) N (R ⁵)-or-N (R ⁵) C (O)-;

A is C (R ^3a), N or N → O;

B is C (R ^3b), N or N → O;

D is C (R ^3d), N or N → O;

E is C (R ^3e), N or N → O; Precondition is that at least one is N or N → O among A, B, D and the E, and is no more than two among A, B, C and the D simultaneously for N or N → O;

Or A is C (R ^3a), B is C (R ^3b), E is that N (H) and D are C (O);

Or A is C (R ^3a), B is C (R ^3b), D is that N (H) and E are C (O);

R ^1aFor hydrogen or-OR ⁵

R ¹For hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical ,-R ⁸-C (O) R ⁵,-R ⁸-CN ,-R ⁹-P (O) (OR ⁵) ₂Or-R ⁹-O-R ⁹-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

And wherein for R ⁶With R ⁷, each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹Be the aralkyl that is randomly replaced :-R by following group ⁸-OR ⁵,-C (O) OR ⁵, halogen, haloalkyl, alkyl, nitro, cyano group, aryl (optional by cyano replaces), aralkyl (randomly being replaced), heterocyclic radical or heteroaryl by one or more alkyl;

Or R ¹For-R ⁹-N (R ¹⁰) R ¹¹,-R ⁹-N (R ¹²) C (O) R ¹¹,-R ⁹-C (O) N (R ¹²) R ¹¹Or-R ⁹-N (R ¹⁰) C (O) N (R ¹⁰) R ¹¹, wherein:

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹¹For hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁹-OC (O) R ⁵,-R ⁹-C (O) OR ⁵,-R ⁹-C (O) N (R ⁴) R ⁵,-R ⁹-C (O) R ⁵,-R ⁹-OR ⁵Or-R ⁹-CN;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

And wherein for R ¹⁰And R ¹¹, each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro ,-R ⁸-CN ,-R ⁸-OR ⁵,-R ⁸-C (O) R ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹Be heterocyclic radical alkyl or heteroarylalkyl, wherein heterocyclic radical alkyl or heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵, aryl and aralkyl substituting group replace;

R ^2a, R ^2b, R ^2cAnd R ^2dRespectively be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each m is 0,1 or 2 independently, and each n is 1 or 2 independently;

And wherein for R ^2a, R ^2b, R ^2cAnd R ^2d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaralkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m is 0,1 or 2 independently, and each n is 1 or 2 independently;

Or R ^2aAnd R ^2b, R ^2bAnd R ^2c, or R ^2cAnd R ^2dWith they direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl;

R ^3a, R ^3b, R ^3eAnd R ^3dRespectively be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

And wherein for R ^3a, R ^3b, R ^3eAnd R ^3d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3e, or R ^3eAnd R ^3dWith they direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl;

Each R ⁴With R ⁵Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl;

Or work as R ⁴And R ⁵When all connecting with identical nitrogen-atoms, R then ⁴And R ⁵Can form heterocyclic radical or heteroaryl with the nitrogen-atoms that it connected; And

Each R ⁹Be the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched.

Another embodiment is related to general formula (I) compound of above-mentioned general formula (Ia) compound, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b) or N;

E is C (R ^3e);

D is C (R ^3d) or N, precondition is that at least one is N among B and the D;

R ^1aFor hydrogen or-OR ⁵

R ¹For hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical ,-R ⁸-OR ⁵,-R ⁸-CN ,-R ⁹-P (O) (OR ⁵) ₂Or-R ⁹-O-R ⁹-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Or R ⁶And R ⁷Can form heterocyclic radical or heteroaryl with the nitrogen that it connected;

Or R ¹For chosen wantonly the aralkyl that replaces :-R by following group ⁸-OR ⁵,-C (O) OR ⁵, halogen, haloalkyl, alkyl, nitro, cyano group, aryl (optional by cyano replaces), aralkyl (randomly being replaced), heterocyclic radical or heteroaryl by one or more alkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

And wherein for R ^2a, R ^2b, R ^2cAnd R ^2d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

Or R ^2aAnd R ^2b, or R ^2bAnd R ^2c, or R ^2cAnd R ^2dWith they direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl;

R ^3a, R ^3b, R ^3eAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

Each R9 is the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched.

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3e, or R ^3eAnd R ^3dWith they direct-connected carboatomic ring atom form the fused rings that can be selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl;

Each R ⁴With R ⁵Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl;

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ^1aFor hydrogen or-OR ⁵

R ¹For hydrogen, alkyl, thiazolinyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical ,-R ⁸-OR ⁵,-R ⁸-CN ,-R ⁹-P (O) (OR ⁵) ₂Or-R ⁹-O-R ⁹-OR ⁵

Or R ¹For-R ⁹-C (O) N (R ¹²) R ¹¹, wherein:

R ¹¹Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

And wherein for R ¹¹, each aryl or aralkyl can randomly be replaced by one or more substituting groups that are selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen and haloalkyl;

R ^2a, R ^2b, R ^2cAnd R ^2dRespectively be independently selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴And-R ⁸-C (O) N (R ⁴) R ⁵

And wherein for R ^2a, R ^2b, R ^2cAnd R ^2d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m is 0,1 or 2, and each n is 1 or 2;

R ^3a, R ^3bAnd R ^3eEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴,

Wherein for R ^3a, R ^3bAnd R ^3e, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3eWith they direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl;

Each R ⁴With R ⁵Independently be selected from hydrogen, alkyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl;

Each R ⁸Alkylidene chain for direct key or straight or branched; And

Each R9 is the alkylidene chain of straight or branched.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹For hydrogen, alkyl, thiazolinyl, haloalkyl ,-R ⁸-OR ⁵Or-R ⁸-CN;

Or R ¹For-R ⁹-C (O) N (R ¹²) R ¹¹, wherein:

R ¹¹Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, heteroaryl ,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴And-R ⁸-C (O) N (R ⁴) R ⁵

R ^3a, R ^3bAnd R ^3eEach independently be selected from hydrogen, alkyl, alkoxyl group, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3eCan form the condensed heterocycle basic ring with their direct-connected carboatomic ring atoms;

Each R ⁴With R ⁵Independently be selected from hydrogen, alkyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl; And

Each R ⁸Alkylidene chain for direct key or straight or branched.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹Be hydrogen or heteroarylalkyl, wherein heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵Or-R ⁸-C (O) OR ⁵Substituting group replace;

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently is selected from hydrogen, alkyl, halogen, haloalkyl and heteroaryl;

R ^3a, R ^3bAnd R ^3eEach independently be selected from hydrogen, alkyl, alkoxyl group, halogen, haloalkyl and-R ⁸-OR ⁵

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3eWith they direct-connected carboatomic ring atom can form the fused rings that is selected from heterocyclic radical;

Each R ⁴With R ⁵Independently be selected from hydrogen, alkyl, haloalkyl, alkoxyalkyl, aryl and aralkyl; And

Each R ⁸Alkylidene chain for direct key or straight or branched.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹Be hydrogen;

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently is selected from hydrogen, alkyl, halogen and haloalkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is general formula (Ia) compound that is selected from following compound:

4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone; And

5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹Be heteroarylalkyl, wherein heteroarylalkyl be randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵And-R ⁸-C (O) OR ⁵Substituting group replace;

Each R ⁸Alkylidene chain for direct key or straight or branched.

4 '-bromo-5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

4 '-furans-3-base-5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [1, the 3-dioxole also [4,5-b] furo [2,3-e] pyridine-5,3 '-indoles]-2 ' (1 ' H)-ketone;

5 '-fluoro-5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

4 '-chloro-5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

1 '-[(5-chloro-1-methyl isophthalic acid H-imidazoles-2-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

5-methoxyl group-1 '-(pyridine-2-ylmethyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 (1 ' H)-ketone;

4 '-bromo-1 '-[(2-sec.-propyl-1,3-thiazoles-5-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

1 ' [(5-chlorothiophene-2-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles [2 (1 ' H)-ketone; And

5-methoxyl group-1 '-{ [2-(1-methylethyl)-1,3-thiazoles-4-yl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹Be the heterocyclic radical alkyl, wherein the heterocyclic radical alkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵And-R ⁸-C (O) OR ⁵Substituting group replace;

Each R ⁸Alkylidene chain for direct key or straight or branched.

5-methoxyl group-1 '-(piperidin-4-yl methyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

4-[(4 '-bromo-5-methoxyl group-2 '-oxo spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (2 ' H)-yl) methyl] piperidines-1-t-butyl formate; And

5-methoxyl group-1 '-[(1-methyl piperidine-4-yl) methyl] spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹For-R ⁹-C (O) N (R ¹²) R ¹¹, wherein:

R ¹¹Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3eWith they direct-connected carboatomic ring atom form the fused rings that is selected from heterocyclic radical;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is general formula (Ia) compound, this compound be N-(2-fluorophenyl)-2-(5-methoxyl group-2 '-oxo spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (2 ' H)-yl) ethanamides.

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Or R ¹For-R ⁹-N (R ¹⁰) R ¹¹,-R ⁹-N (R ¹²) C (O) R ¹¹Or-R ⁹-N (R ¹⁰) C (O) N (R ¹⁰) R ¹¹, wherein:

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Or R ¹Be heterocyclic radical alkyl or heteroarylalkyl, wherein this heterocyclic radical alkyl or heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵, aryl and aralkyl substituting group replace;

R ^3a, R ^3eAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

And wherein for R ^3a, R ^3eAnd R ^3d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

Or R ^3eAnd R ^3dWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl;

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴And-R ⁸-C (O) N (R ⁴) R ⁵

And wherein for R ^2a, R ^2b, R ^2cAnd R ^2d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

R ^3a, R ^3eAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

And wherein for R ^3a, R ^3eAnd R3d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

Each R ⁸Alkylidene chain for direct key or straight or branched; And

Each R ⁹Alkylidene chain for straight or branched.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹For hydrogen, alkyl, thiazolinyl, haloalkyl ,-R ⁸-OR ⁵Or-R ⁸-CN;

Or R ¹Be heterocyclic radical alkyl or heteroarylalkyl, wherein this heterocyclic radical alkyl or heteroarylalkyl be randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵, aryl and aralkyl substituting group replace;

R ^3a, R ^3eAnd R ^3dEach independently be selected from hydrogen, alkyl, alkoxyl group, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

Or R ^3eAnd R ^3dCan form the condensed heterocycle basic ring with its direct-connected carboatomic ring atom;

Each R ⁸Alkylidene chain for direct key or straight or branched.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be hydrogen;

R ^3a, R ^3eAnd R ^3dEach independently be selected from hydrogen, alkyl, alkoxyl group, halogen, haloalkyl and-R ⁸-OR ⁵

Or R ^3eAnd R ^3dWith its direct-connected carboatomic ring atom can form the fused rings that is selected from heterocyclic radical;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is the compound of general formula (Ia), and this compound is 5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be heteroarylalkyl, wherein heteroarylalkyl be randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵Substituting group replace;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is the compound of general formula (Ia), this compound be 5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be the heterocyclic radical alkyl, wherein this heterocyclic radical alkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵Substituting group replace;

Each R ⁸Alkylidene chain for direct key or straight or branched.

5-methoxyl group-1 '-(tetrahydrochysene-2H-pyrans-4-ylmethyl) spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone;

5-methoxyl group-1 '-[(2S)-tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone; And

5-methoxyl group-1 '-[(2R)-tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be aralkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is the compound of general formula (Ia), this compound is 1 '-(diphenyl methyl)-5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

E is N;

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Wherein for R ⁶With R ⁷, each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹Be aralkyl, it is randomly by-R ⁸-OR ⁵,-C (O) OR ⁵, halogen, haloalkyl, alkyl, nitro, cyano group, aryl (optional by cyano replaces), aralkyl (randomly being replaced by one or more alkyl), heterocyclic radical or heteroaryl replace;

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Wherein for R ¹⁰And R ¹¹, each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro ,-R ⁸-CN ,-R ⁸-OR ⁵,-R ⁸-C (O) R ⁵, heterocyclic radical and heteroaryl substituting group replace;

R ^3a, R ^3bAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

Or R ^3aAnd R ^3bWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl;

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is N;

D is C (R ^3d);

R ^3a, R ^3bAnd R ^3dEach independently be selected from hydrogen, alkyl, alkoxyl group, halogen, haloalkyl and-R ⁸-OR ⁵

Or R ^3aAnd R ^3bWith its direct-connected carboatomic ring atom can form the fused rings that is selected from heterocyclic radical;

Each R ⁴With R ⁵Independently be selected from hydrogen, alkyl, haloalkyl, alkoxyalkyl, aryl and aralkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched; And

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is N;

D is C (R ^3d);

R ¹Be hydrogen or alkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is general formula (Ia) compound, this compound is 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

D is C (R ^3d);

E is N → O;

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

And wherein for R ⁶With R ⁷, each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl substituting group replace;

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

And wherein to R ^2a, R ^2b, R ^2cAnd R ^2d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

And wherein for R ^3a, R ^3bAnd R ^3d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-,-C (O)-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is C (R ^3b);

D is C (R ^3d);

E is N → O;

R ^1aFor hydrogen or-OR ⁵

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) S (O) _nR ⁴, wherein n independently is 1 or 2;

And wherein for R ^2a, R ^2b, R ^2cAnd R ^2d, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2

R ^3a, R ^3bAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

D is C (R ^3d);

E is N → O;

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴And-R ⁸-C (O) N (R ⁴) R ⁵

R ^3a, R ^3bAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is general formula (Ia) compound, this compound is 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone 5-oxide compound.

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

D is N → O;

E is C (R ^3e);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

And wherein for R ^3a, R ^3bAnd R ^3e, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is C (R ^3b);

D is N → O;

E is C (R ^3e);

R ^1aFor hydrogen or-OR ⁵

R ^3a, R ^3bAnd R ^3eEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

D is N → O;

E is C (R ^3e);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Or R ¹Be heteroarylalkyl, wherein this heterocyclic radical alkyl or heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵Substituting group replace;

R ^3a, R ^3bAnd R ^3eEach independently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is the compound of general formula (Ia), this compound be 5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone 4-oxide compound.

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a), B is C (R ^3b), E is that N (H) and D are C (O);

Or A is C (R ^3a), B is C (R ^3b), D is that N (H) and E are C (O);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^3aAnd R ^3bEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

And wherein for R ^3aAnd R ^3b, each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, and each n independently is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a), B is C (R ^3b), E is that N (H) and D are C (O);

Or A is C (R ^3a), B is C (R ^3b), D is that N (H) and E are C (O);

R ^1aFor hydrogen or-OR ⁵

R ^3aAnd R ^3bEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵And-N (R ⁵) C (O) R ⁴

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a), B is C (R ^3b), E is that N (H) and D are C (O);

Or A is C (R ^3a), B is C (R ^3b), D is that N (H) and E are C (O);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a), B is C (R ^3b), E is that N (H) and D are C (O);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is the compound of general formula (Ia), this compound is 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ', 4 (1 ' H, 5H)-diketone.

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a), B is C (R ^3b), D is that N (H) and E are C (O);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

Another embodiment is the compound of general formula (Ia), this compound is 1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ', 5 (1 ' H, 4H)-diketone.

K, j, m, R ¹, R ^2a, R ^2b, R ^2c, R ^2dAnd the embodiment of X with regard to general formula (I) compound wherein is

Heterocyclic radical and preamble are about the described k of general formula (Ia) compound, j, m, R ¹, R ^2a, R ^2b, R ^2c, R ^2dAnd the embodiment of X is identical.

Should understand any embodiment of above-mentioned general formula (Ia) compound and this paper about the R in above-mentioned general formula (Ia) compound ¹, R ^2a, R ^2b, R ^2c, R ^2d, R ^3a, R ^3b, R ^3c, R ^3d, A, B, D and the described j of E group, k, m or any specified substituent all can be independently with other embodiment and/or this paper about the R in general formula (Ia) compound ¹, R ^2a, R ^2b, R ^2c, R ^2d, R ^3a, R ^3b, R ^3c, R ^3d, A, B, D and the described any j of E group, k, m or the combination of any specific substituting group, form not in embodiment of the present invention of concrete statement above.In addition, in the cited a series of substituent situation of any specific R group in special embodiment and/or claim or A, B, D or E group, should be appreciated that and from this special embodiment and/or claim, to delete each independent substituting group, and think that the substituting group that residue is enumerated can be suggested in the present invention.

Another embodiment of the present invention is treatment, prevention or alleviate Mammals, preferably be people's the disease or the method for morbid state, wherein this disease or morbid state are selected from pain, depressed, cardiovascular disorder, respiratory disease and psychotic disorder, with and the combination, and wherein this method comprises the invention described above compound of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the above-mentioned The compounds of this invention for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

An embodiment of this embodiment is that wherein said disease or morbid state are selected from down neurogenic pain, inflammatory pain, internal organ pain, cancer pain, the pain of chemotherapy, wound pain, operation pain, post-operative pain, labor pains, throe, neurogenic bladder, ulcerative colitis, chronic pain, rest pain, the pain of periphery mediation, the pain of maincenter mediation, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury and combination thereof.

Another embodiment of this embodiment is that wherein said disease or morbid state are selected from the pain relevant with HIV; the neuropathy that the HIV treatment is caused; trigeminal neuralgia; postherpetic neuralgia; eudynia; heat sensitivity; tosarcoidosis; irritable bowel syndrome; Crohn disease; with the relevant pain of multiple sclerosis (MS); amyotrophic lateral sclerosis (ALS); diabetic neuropathy; the peripheral nerve pathology; sacroiliitis; rheumatoid arthritis; osteoarthritis; atherosclerosis; the paroxysmal myodystonia; myasthenic syndrome; myotony; malignant hyperthermia; Cysticfibrosis; pseudohyperaldosteronism; rhabdomyolysis; hypothyroidism; the two-phase dysthymia disorders; anxiety; schizophrenia; the sodium channel toxin-related diseases; the familial erythromelalgia; primary erythermalgia; familial rectum pain; cancer; epilepsy; locality grand mal and general grand mal; restless leg syndrome; irregular pulse; fibromyalgia; neuroprotective under the ischemia state that causes by palsy or neural wound; tachyarrhythmia; atrial fibrillation and ventricular fibrillation.

Another embodiment of the present invention is for treating mammiferous by the ionic flux that suppresses process voltage-dependent sodium channel in the Mammals, it preferably is the method for people's pain, wherein this method comprises the invention described above compound of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the invention described above compound for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

Another embodiment of the present invention is for treatment or prevent mammiferous, it preferably is the method for people's hypercholesterolemia, wherein this method comprises the invention described above compound of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the invention described above compound for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

Another embodiment of the present invention is for treatment or prevent mammiferous, it preferably is the method for people's benign prostatic hyperplasia, wherein this method comprises the invention described above compound of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the invention described above compound for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

Another embodiment of the present invention is for treatment or prevent mammiferous, it preferably is the method for people's pruritus, wherein this method comprises the invention described above compound of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the invention described above compound for the treatment of significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

Another embodiment of the present invention is for treatment or prevent mammiferous, it preferably is people's method for cancer, wherein this method comprises the invention described above compound of the Mammals that needs are arranged being treated significant quantity, its steric isomer, enantiomer, its tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, solvate or prodrug, or comprise the invention described above compound for the treatment of significant quantity, its steric isomer, enantiomer, its tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition of solvate or prodrug and pharmaceutically-acceptable excipients.

Another embodiment of the present invention is for reducing in the mammalian cell method through the ionic flux of voltage-dependent sodium channel, and wherein this method comprises cell is contacted with the invention described above compound, its steric isomer, enantiomer, its tautomer or its mixture or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug.

The particular of The compounds of this invention is specified in the preparation of following general formula (I) compound.

The application of The compounds of this invention and test

The compounds of this invention in Mammals, especially can regulate among the people, the preferred ionic flux that suppresses through the voltage-dependent sodium channel.Any should adjusting, no matter it is called as " blocking-up " and respective compound in this article sometimes and is called as " blocker " for partially or completely suppressing or preventing ionic flux.Generally speaking, The compounds of this invention regulates the activity of sodium channel downwards, by stoping sodium channel activity, suppresses the voltage-dependent activity of sodium channel and/or reduces or stop the sodium ion flux to stride across cytolemma as ionic flux.

The compounds of this invention suppresses the ionic flux through the voltage-dependent sodium channel.This compound is preferably the state or the frequency dependence conditioning agent of sodium channel, and it has low-affinity and inactivated state is had high-affinity tranquillization/closing condition.These compounds can interact with the overlapping site of the inner chamber of the sodium conduction hole that is arranged in passage equally (Cestele, S., et al., op.cit).These compounds also can interact with the site in the inner chamber outside equally, and have allosteric effect for the sodium ion conduction through the passage hole.

Any of these result finally may be the reason of the wholistic therapy benefit that provided by these compounds.

Therefore, The compounds of this invention be sodium channel blockers and therefore can be used for treating mammiferous, preferably for the people's and other organic disease or morbid state, comprise what unusual voltage-dependent sodium channel biological activity caused, maybe can lead to regulating voltage dependency sodium channel biological activity and all human diseasess and the morbid state that are enhanced.

As definition herein, the disease of sodium channel mediation or morbid state are meant can be enhanced mammiferous, preferably are people's disease or morbid state when regulating the sodium channel, it includes but not limited to pain, and the nervus centralis morbid state is as epilepsy, anxiety, depression and two-phase disease; The cardiovascular disorder state,, atrial fibrillation not normal and ventricular fibrillation as the rhythm of the heart; The neuromuscular disease state is as restless leg syndrome and muscular paralysis or tetanus; The neuroprotective of anti-palsy, neural wound and multiple sclerosis; And the passage disease, as erythromelalgia and familial rectum pain syndrome.

Therefore the present invention relates to compound, pharmaceutical composition and use described compound and pharmaceutical composition to be used for the treatment of the method for disease mammiferous, that preferably mediate for people's sodium channel, disease preferably relates to: pain, the nervus centralis morbid state is as epilepsy, anxiety, depression and two-phase disease; The cardiovascular disorder state,, atrial fibrillation not normal and ventricular fibrillation as the rhythm of the heart; The neuromuscular disease state is as restless leg syndrome and muscular paralysis or tetanus; The neuroprotective of anti-palsy, neural wound and multiple sclerosis; And the passage disease, as erythromelalgia and familial rectum pain syndrome, this method is by the Mammals of this treatment of needs, preferred behaviour being treated sodium channel blockers adjustment agent, the especially inhibitor of significant quantity.

Therefore, the invention provides treatment Mammals or prevention Mammals and develop into the disease of sodium channel mediation, especially pain method, this method comprises treats the The compounds of this invention of significant quantity or comprises the pharmaceutical composition of the The compounds of this invention for the treatment of significant quantity the Mammals that needs are arranged, and wherein this compound is regulated the activity of one or more voltage-dependent sodium channels.

The compounds of this invention is being regulated, and especially suppresses the general value of ionic flux aspect, sodium channel and can use the measuring method of hereinafter describing in biology is measured partly to determine.Perhaps, this compound can be used for proving that compound sets up the industry standard animal model of the effect of treatment pain in the general value of treatment people's morbid state and disease, the animal model of people's neurogenic pain morbid state is developed out, and this model causes the sensory defect (allodynia, hyperpathia and spontaneous pain) of reproduction that can be by sensory testing assessment after continuing for some time.Assess pharmacotherapy by setting up machinery, chemistry and thermoinducible allodynia and the hyperalgesic degree that exists, can simulate several pathologic, physiologic morbid states of in the people, observing with permission.

In the mouse models of peripheral nerve injury, the dystopy in the injured nerve is active corresponding with the behavior sign of pain.In these models, the intravenous administration of sodium channel blockers and local anesthetic lignocaine can under the concentration that does not influence general behavior and motor function, suppress dystopy active and make tactile allodynia reverse (Mao, J.and Chen, L.L, _PAin (2000), 87:7-17).In these rat models, the allimetric scale that effective dose is renderd a service convert to the people is shown the similar dosage of effective dosage ( _TAnelian, D.L.and Brose, W.G., Anes _tHesiology (1991), 74 (5): 949-951).In addition,

Lignocaine so that the transdermal patches form is used is the treatment that is used for postherpetic neuralgia (Devers, A.and Glaler, B.S., Xlin.J.Pain (2000), 16 (3): 205-8) of FDA approval at present.

Disease that the sodium channel is regulated or morbid state also comprise neuropathy, adiposis dolorosa, thalamic lesions, hypertension, autoimmune disorder, asthma, drug habit (for example opiate, the benzodiazepine of neuropathy that the pain relevant with HIV, HIV treatment caused, trigeminal neuralgia, glossopharyngeal neuralgia, transitivity infiltration secondary

Amphetamine; Cocaine; alcohol; butane sucks); the A Erzihaimo disease; dementia; the memory impairment relevant with the age; korsakoff's neurosis; restenosis; urinary dysfunction; incontinence; Parkinson's disease; cerebrovascular ischemia; neurosis; gastrointestinal illness; sicklemia; transplant rejection; in heart failure; myocardial infarction; reperfusion injury; intermittent claudication; stenocardia; faint from fear; respiratory disorder; brain or myocardial ischemia; for a long time-QT syndrome; catecholamine energy polytypism ventricular tachycardia; ophthalmic diseases; spasm; Spastic Paraplegia; myopathy; myasthenia gravis; paramyotonia congenita; hyperkalemic periodic paralysis; hypokalemia property in sexual cycle paralysis; baldness; the anxiety disease; psychosis; manic; the Paranoia; seasonal affective disorder; panic disorder; compulsive disorder (OCD); phobia; autism; Aspergers syndrome; the special Cotard of thunder; the collapse illness; attention deficit disorder; aggressive; impulse control disorder; thrombosis; preeclampsia; congestive heart failure; sudden cardiac arrest; the FreidrichShi dystaxia; spinal cord and cerebellar ataxia disease; myelopathy; radiculopathy; systemic lupus erythematous; granulomatosis; olivoponto-cerebellar atrophy; spinocebellar ataxia disease; ictal dystaxia; myokymia; carrying out property pallidal atrophy; paralysis and spasm on the carrying out property nuclear; traumatic brain injury; cerebral edema; the hydrocephalus damage; Spinal injury; anorexia nervosa; bulimia; Prader-Willi syndrome; obesity; optic neuritis; cataract; retinal hemorrhage; ischemic retinopathy; retinitis pigmentosa; acute and chronic glaucoma; maculopathy; retinal artery occlusion; tarantism; the Heng Tingdunshi chorea; cerebral edema; rectitis; postherpetic neuralgia; eudynia; heat sensitivity; sarcoidosis; irritable bowel syndrome; tourette's syndrome; Lay-Nissl syndromes; Brugado syndrome; Liddle syndrome; Crohn disease; multiple sclerosis reaches and the relevant pain of multiple sclerosis (MS); amyotrophic lateral sclerosis (ALS); diffuse sclerosis; diabetic neuropathy; the peripheral nerve pathology; peroneal muscular atrophy syndrome; sacroiliitis; rheumatoid arthritis; osteoarthritis; chondrocalcinosis; atherosclerosis; the paroxysmal myodystonia; myasthenic syndrome; myotony; myotonic dystrophy; muscular dystrophy; malignant hyperthermia; cystic fibrosis; pseudohyperaldosteronism; rhabdomyolysis; psychological disorders; hypothyroidism; the two-phase depression; anxiety; schizophrenia; the disease that the sodium channel toxin is relevant; the familial erythromelalgia; the primary erythromelalgia; rectum pain; cancer; epilepsy; locality grand mal and general grand mal; the heat generation outbreak; petit mal (petit mal epilepsy); myoclonic seizure; atonic seizure; grand mal; Lin-Ge syndrome; West syndrome (infantile spasm); the multidrug resistant outbreak; outbreak prevention (anti-epileptic outbreak); familial Mediterranean Sea heating syndrome; gout; restless leg syndrome; irregular pulse; fibromyalgia; because of the neuroprotective under the ischemia state that palsy or neural wound caused; tachy-arrhythmia; atrial fibrillation and ventricular fibrillation and because of anesthetic,general or local anesthetic.

Term used herein " pain " is meant the pain of all kinds, and be believed to comprise but be not limited to neurogenic pain, inflammatory pain, nociception pain, spontaneous pain, neuroglia pain, actinal surface pain, cusalgia, scorching hot oral area syndrome, body pain, visceral pain, flesh face pain, toothache, cancer pain, the pain of chemotherapy, wound pain, operation pain, post-operative pain, labor pains, throe, sympathetic reflection is malnutritive, brachial plexus is torn, neurogenic bladder, acute pain (for example flesh bone and postoperative pain), chronic pain, rest pain, the pain of periphery mediation, the pain of maincenter mediation, chronic headache, migraine, familial hemiplegia migraine, with the headache disease states associated, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, pain after the palsy, thalamic lesions, radiculopathy, HIV pain, pain after the bleb, non-heart trouble pectoralgia, irritable bowel syndrome and the pain relevant, and combination with intestinal disease and maldigestion.

Sodium channel blockers has the clinical application except that pain.Epilepsy and irregular pulse often are the target of sodium channel blockers.The nearest evidence that obtains from animal model shows that sodium channel blockers also can be under the ischemia state that causes because of palsy or neural wound and suffering from the patient of multiple sclerosis (MS) and be used for neuroprotective (Clare; J.J.et al.; op.cit.and Anger, T.etal., op.cit.).

The invention still further relates to compound, pharmaceutical composition and use this compound and the method for medicine composite for curing or prevention such as benign prostatic hyperplasia (BPH), hypercholesterolemia, cancer and itch diseases such as (itch) or morbid state.

Benign prostatic hyperplasia (BPH) is also referred to as benign prostatauxe, is one of modal disease that influences the elderly.BPH is progressive morbid state, and the node amplification that it is characterized by because of prostata tissue causes urethral obstruction.The result of BPH can comprise that smooth muscle of bladder hypertrophy, bladder lose compensatory, acute urinary retention and increase the incidence of urinary tract infection.

BPH has the public health impact of height and is to carry out one of the most general reason of surgical operation in the elderly men.Attempted to illustrate the cause of disease and pathogenesis and to develop experimental model at this purpose.Spontaneous animal model is limited to chimpanzee and dog.The BPH of the male sex and dog has many common features.In both, BPH development meeting is spontaneous with advancing age to be taken place and can be by in early days/and castrate pubescence and prevent.The adoptable method of medical science beyond the operation very needs and significant for treatment BPH.

The prostatic epithelium hyperplasia of the male sex and dog is the male hormone sensitivity, and experience committee contracts along with the male sex hormone disappearance and recover epithelial proliferation when the displacement male hormone.Be derived from prostatic cell indicator gauge and reveal high-caliber voltage-gated sodium channel.Immunostaining research clearly proves in the prostata tissue evidence (the Prostate Cancer ProstaticDis.2005 about valtage-gated logical sodium channel; 8 (3): 266-73).

Hypercholesterolemia, promptly the blood cholesterol of Sheng Gaoing such as fixed risk factors of disease such as atherosclerosis, coronary heart disease, hyperlipidaemia, palsy, hyperinsulinemia, hypertension, obesity, diabetes, cardiovascular disorder (CVD), myocardial ischemia and heart attacks for developing.Therefore, known reduction has the risk that total serum cholesterol levels in the individuality of elevated cholesterol can reduce these diseases.Reduce the basic step that low density lipoprotein cholesterol especially prevents CVD.Though various hypercholesterolemia therapy is arranged, need still to continue in this technical field and the research other therapies.

The invention provides the compound that can be used as the anti-hypercholesterolemiccompounds agent and be used for its relative disease state.Compound of the present invention can act in every way.Though do not wish to be subjected to the restriction of any particular mechanism of action; but described compound can be the enzyme acyl-CoA: the direct or indirect inhibitor of cholesterol acyltransferase (ACAT), cholesterol acyltransferase cause the esterification of cholesterol to be suppressed and to cross over the transhipment of small bowel.Another kind of possibility is that compound of the present invention can be the biosynthetic direct or indirect inhibitor of cholesterol in the liver.Some compound of the present invention might be simultaneously as ACAT and the biosynthetic direct or indirect inhibitor of cholesterol.

Pruritus is commonly referred to as itch, is the common skin morbid state.Though the definite reason of pruritus is complicated and understanding is not enough, come known for a long time and the pain interaction.Especially, think that the sodium channel may transmit or propagate itch signal along skin along neural axis.The transmission of itch pollex causes causing the expectation that scratches or the uncomfortable sensation of reflection.

By the neurobiology level, think the total complicacy of specific conditioning agent is arranged, the related neural path of itch and pain and main process, and nearest digital proof with pain and periphery conditioning agent relevant and/or acceptor with itch between overlapping widely (Ikoma et al. is arranged, Nature Reviews Neuroscience, 7:535-547,2006).Obviously, pain and itch have similar neurone sensitization mechanism in peripheral nervous system and central nervous system, but also present evident difference.

For example, the gentle pain stimulation that causes by scratching is effective for the sensation that alleviates itch.On the contrary, can produce serious pruritus such as opioid pain killer.Antagonism between pain and itch interacts and can be used for probing into the pruritus therapy, and present research focuses on the common target of confirming following pain management and antipruritic treatment.

Compound exhibits of the present invention has analgesic effect under 1 milligram/kilogram to 100 milligrams/kilogram the oral dosage in several animal models.The compounds of this invention also also is used for the treatment of pruritus.

The type of itch and skin irritation includes but not limited to:

A) psoriatic pruritus, the itch that causes because of hemodialysis, water (aguagenic) pruritus and the itch that causes because of tetter (for example contact dermatitis), systemic disease, neuropathy, psychological factor or its mixing;

B) itch, inflammatory diseases state or the damage that causes because of atopic reaction, sting, supersensitivity (for example xerosis cutis, acne, eczema, psoriatic);

C) itch relevant with vulvar vestibulitis; And

D) because of another kind treatment, the skin irritation or the inflammatory effects that cause of microbiotic, antiviral and antfhistamine administration for example.

Compound of the present invention also can be used for treating or prevent mammiferous, preferably be some hormone sensitive cancers of people, as prostate cancer (gland cancer), breast cancer, ovarian cancer, carcinoma of testis, thyrocele tumorigenesis.This voltage-gated sodium channel has been proved in prostate cancer cell and breast cancer cell and has expressed.Transfer moves past the integral part of journey as people's breast cancer, and (v) novel marker and treatment target (Clin.CancerRes.2005, the Aug.1 of metastatic phenotype raised and can be used as simultaneously in 1.5 generations to newborn Na; 11 (15): 5381-9).(the Na especially of voltage-gated sodium channel α-subunit _v1.7) functional expression and external prostate cancer (CaP) to shift potentiality strongly relevant.The antibody that use is special to this sodium channel α-subunit, voltage-gated sodium channel α-subunit's immunostaining proved occurred in the prostata tissue and with respect to non--CaP patient significantly stronger in CaP patient (Prostate Cancer Prostatic Dis., 2005; 8 (3): 266-73).

Compound of the present invention also can be used for treating or prevents the mammiferous symptom relevant with BPH, such as but not limited to acute urinary retention and urinary tract infection.

The compounds of this invention also can be used for treatment or prevents the unbalance or incretopathy of some internal secretion, and ((syndrome of Conn ' s), aldosteronism, hypogonadism, gonad function are hyperfunction, infertile, conceptual quotient and diabetes for the syndrome of Cushing ' s), Kang Shi as congenital congenital adrenal hyperplasia disease, hyperthyroidism, hypothyroidism, osteoporosis, osteomalacia, rickets, Ke Xing.

The present invention can be easy to provide multitude of different ways, to confirm the sodium channel modulators of useful as therapeutics.Sodium channel modulators is approved the multiple external and interior measuring method assessment of body of use really, for example, measure electric current, measure membrane potential, measure ionic flux (for example sodium or guanidinesalt), measure na concn, measure second messenger and transcriptional level, and use for example voltage sensitivity dyestuff, radioactive tracer and patch clamp electrophysiology.

A kind of such experimental design relates to the chemical reagent that screening has the ability of regulating sodium channel activity, thereby confirms that it is as conditioning agent.

Bean et a1., J.General Physiology (1983), 83:613-642 and Leuwer, M.etal., Br.J.Pharmacol (2004), 141 (1): the typical measuring method described in the 47-54 uses patch clamp technique, with the behavior of research passage.Such technology is known to those skilled in the art, and can use existing technology that it is developed into small throughput or middle isoflux mensuration, and it regulates the ability of sodium channel behavior with the assessment compound.

Use known sodium channel toxin, as the competitive binding assay of tetraodotoxin, α-scorpion toxin, napelline, BTX etc. applicable to differentiating the potential therapeutical agent that specific sodium channel is had highly selective.Is known at these in conjunction with using BTX in measuring, and at McNeal, E.T.et al., J.Med.Chem. (1985), 28 (3): 381-8 and Creveling, C.R.et al., Methods inNeuroscience (method on the neuroscience), Vol.8:Neurotoxins (neurotoxin) (Conn PMEd) (1992), pp.25-37, Academic Press is described among the New York.

These mensuration can the passage that the expression in the environment is paid close attention at natural endogenous environment or reorganization cell or the cell or tissue extract in implement.Spendable mensuration comprises dull and stereotyped mensuration, its by measure the surrogate markers thing as ¹⁴The influx of C-guanidine and measuring N a+ influx, or use fluorescence dye, as based on dyestuff and other fluorescence analysis of FRET or adopt the radio-labeling of radiolabeled napelline, BTX, TTX or STX to measure the cell depolarization effect in conjunction with measuring method.More direct measurement can be by using manually or the automatization electrophysiology system is implemented.Biology is hereinafter measured and has been explained guanidine influx mensuration in the part in more detail.

The flux (throughput) of handling testing compound is an important consideration when selecting screening assay method to be used.In some strategy, need to detect hundreds thousand of kinds of compounds, do not expect to use the small throughput mode.But in other situation, small throughput can be differentiated the significant differences between the compound of limited quantity satisfactorily.Often must regulate compound to differentiate specific sodium channel in conjunction with dissimilar mensuration.

Use the electrophysiology mensuration of patch clamp technique to be acknowledged as the interactional golden standard of detailed sign sodium channel compound, and at Bean et al., op.cit. and Leuwer, M.et al. is described among the op.cit..There is manual small throughput screening (LTS) method, can compares 2-10 compound its every day; The system of exploitation allows to carry out the medium flux screening of automatization (MTS) with 20-50 diaphragm every day (being compound) recently; And from molecular device company (Sunnyvale, CA) technology allows to carry out automatization high flux screening (HTS) with 1000-3000 diaphragm every day (being compound).

A kind of automatization patch clamp system utilizes the plane electrode technology to quicken the speed of drug discovery.High-resistance, cell sticking type sealing that plane electrode can reach, and subsequent the full cell record of stable lower noise that can compare with the routine record.The instrument that is fit to be PatchXpress 7000A (AxonInstruments Inc, Union City, CA).The cell that comprises adherent cell and spontaneous growth in suspension seals success ratio and stable classification in interior various kinds of cell system and culture technique according to providing.The immortalized cell of the high-caliber relevant sodium-ion channel of stably express (as HEK and CHO) is suitable in the high-density suspension culture.

Can select other to measure, it allows the investigator to differentiate the compound of the particular state of blocking-up passage, and as opened condition, closing condition or quiescent condition, or tranquillization or the tranquillization compound to the conversion of opening is closed, closed in blocking-up from being opened into.Those skilled in the art are familiar with these mensuration usually.

Also can adopt in conjunction with mensuration, but these have limited functional value and quantity of information.Design comprise based on traditional radioactivity filter in conjunction with detecting, or available from Evotec OAI consortium (Hamburg, Germany) based on confocal fluorescing system, both are HTS for this.

Also can use the radioactivity flux to measure.In this was measured, passage was stimulated by veratridine (veratridine) or napelline and opens, and remains on stable opened condition with toxin, and differentiates channel blocker by its ability that prevents that ion from flowing into.This mensuration can be used radioactivity ²²[Na] with ¹⁴[C] guanidinesalt ion is as tracer agent.FlashPlate﹠amp in viable cell; The Cytostar-T flat board is avoided separating step and is applicable to HTS.The flicker plate technique has also advanced to this method and has been applicable to HTS.Because the functional aspect of this mensuration is so quantity of information is reasonably good.

Also a kind of mode uses FLIPR system membranes current potential test kit (HTS) to measure the distribution again of membrane potential, this test kit can available from molecule dynamic (Molecular Dynamics) (department of AmershamBiosciences, Piscataway, NJ).This method is limited to slowly, and membrane potential changes.The fluorescence background of compound can produce some problem.Test compounds also can directly influence flowability of cell membranes, and causes the increase of cell inner dye concentration.However, because the functional aspect of measuring, so quantity of information is reasonably good.

Can use the sodium dyestuff to measure sodium ion and flow into speed or the quantity of passing through passage.This class is provided by the high quantity of information that provides about the potential channel blocker.This is determined as functional, and direct measuring N a+ influx.CoroNa red (Coro Red), SBFI and/or sodium green (sodiumgreen) (Molecular Probes, Inc.Eugene OR) can be used for measuring N a influx; All be Na responsiveness dyestuff.It can unite use with the FLIPR instrument.The application of these dyestuffs in screening do not described in the past in the literature.Calcium dyestuff also potentialization in this mode.

In another kind is measured, be used to measure test compounds based on the voltage sensor of FRET and directly block the ability that Na flows into.Commercially available HTS system comprises VIPR ^TMII FRET system (AuroraBiosciences Corporation, San Diego, CA, a department of Vertex pharmaceuticals), it can use in conjunction with the FRET dyestuff, and described dyestuff also can be available from Aurora Biosciences.This measuring method is measured the submicrosecond response to voltage change.Need not the channel function conditioning agent.This measuring method is measured depolarize and hyperpolarization, and is provided for quantized voltage percentage output (ratiometric output).The more not expensive a little MTS version of this mensuration adopts FLEXstation ^TM(molecular device company) combines with FRET dyestuff available from the Aurora bio-science.Other method of testing compound disclosed herein also is that those skilled in the art are easy to know and obtain.

These results provide the analysis foundation of the structure activity relationship (SAR) between test compounds and the sodium channel.Some substituting group on the nuclear structure of test compounds tends to provide more effective inhibition compound.One of instrument of the preferred embodiment of SAR the analyzes The compounds of this invention that to be the discriminating adopted at present of those skilled in the art use as therapeutical agent.

The conditioning agent that to so differentiate is tested in multiple body inner model then, to determine that it whether can alleviating pain, especially chronic pain or alleviate other morbid state, such as irregular pulse and epilepsy, benign prostatic hyperplasia (BHP), hypercholesterolemia, cancer and pruritus (itch) etc., and has minimum undesirable action.Hereinafter measure the biologic activity that the mensuration of describing in the part can be used for assessing The compounds of this invention at biology.

Usually, successful therapeutical agent of the present invention will meet part or all of following standard.Oral utilization ratio should be 20% or be higher than 20%.It is that 0.1 microgram is to about 100 milligrams/kg body weight, though also can be received in this extraneous dosage (" milligram/kilogram " is meant the compound milligram number of per kilogram body quality of the individuality of administration) that the animal model effect is lower than about 0.1 microgram to about 100 milligrams/kg body weight and target people dosage.Therapeutic index (or toxic dose is to ratio of therapeutic dose) should be greater than 100.Render a service (when by IC ₅₀Value representation) should be less than 10 μ M, preferably less than 1 μ M and most preferably less than 50nM.IC ₅₀(" inhibition concentration-50% ") is in measuring method of the present invention, in the specific period, for to realize the observed value of the compound amount that 50% restraining effect needs through the ionic flux of sodium channel.In the guanidine influx was measured, The compounds of this invention had confirmed that the IC-50 scope is lower than nanomolar concentration to being lower than 10 micro-molar concentrations.

In another kind of purposes of the present invention, The compounds of this invention can be used as the exemplary agents that is used for the comparison purpose and is used for external or the interior research of body, with the compound of finding that other also can be used for treating or preventing various diseases disclosed herein.

Another aspect of the present invention involves in biological material or the Mammals, be preferably philtrum and suppress Na _V1.1, Na _V1.2, Na _V1.3, Na _V1.4, Na _V1.5, Na _V1.6, Na _V1.7, Na _V1.8 or Na _V1.9 active method, this method comprise Mammals, are the people preferably, give compound of Formula I or comprise this compound compositions, or this biological material is in contact with it.Term used herein " biological material " includes but not limited to cell culture or its extract; Derive from the examination of living tissue material of Mammals or its extract; And blood, saliva, urine, ight soil, seminal fluid, tears or other body fluid or its extract.

To Na in the biological material _V1.1, Na _V1.2, Na _V1.3, Na _V1.4, Na _V1.5, Na _V1.6, Na _V1.7, Na _V1.8 or Na _V1.9 active inhibition can be used for various purpose well known by persons skilled in the art.The example of these purposes includes but not limited to the research of the sodium-ion channel in biology and the pathology phenomenon; And the comparative assessment of novel sodium-ion channel inhibitor.

The compounds of this invention described in the summary of the invention, its steric isomer, enantiomer, its tautomer or its mixture, or the acceptable salt of its medicine, solvate or prodrug, and/or comprise one or more The compounds of this invention described in general in pharmaceutically-acceptable excipients and the invention, its steric isomer, enantiomer, its tautomer or its mixture, or the acceptable salt of its medicine, the N-oxide compound, the pharmaceutical composition described herein of solvate or prodrug can be used for preparing the disease that is used for the treatment of the mediation of mammiferous sodium channel or the medicine of morbid state.

Pharmaceutical composition of the present invention and administration

The invention still further relates to the pharmaceutical composition that contains The compounds of this invention disclosed herein.In one embodiment, the present invention relates to composition, it comprises the The compounds of this invention that is present in medicine acceptable carrier, vehicle or the thinner, the amount of compound gives animal for working as, be preferably Mammals, most preferably during human patients, its amount can effectively be regulated, the preferred disease that suppresses the ionic flux of process voltage-dependent sodium channel with the mediation of treatment sodium channel is as pain.

Carry out with pure form or with any mode of administration of accepting of medicament that the administration of the The compounds of this invention of appropriate drug composition forms or the acceptable salt of its medicine can be by providing similar applications.Pharmaceutical composition of the present invention can be by preparing compound of the present invention and the acceptable supporting agent of appropriate drug, thinner or excipient composition, and can be mixed with solid-state, semi-solid state, liquid state or gaseous state preparation, as tablet, capsule, pulvis, granule, paste, solution, suppository, injection, inhalation, gelifying agent, microballoon and aerosol.That the typical approach that gives this pharmaceutical composition includes but not limited to is oral, local, in skin, suction, parenteral, hypogloeeis, rectum, vagina and nose.Term parenteral used herein comprises subcutaneous injection, intravenously, intramuscular, intrathoracic injection or infusion techniques.Pharmaceutical composition of the present invention is prepared thereby is made wherein contained activeconstituents available for biology when giving composition to the patient.The composition that gives individuality or patient can be taked the form of one or more dose units, and wherein for example tablet can be single dose unit, and the container of the The compounds of this invention of aerosol form can load a plurality of dose units.The practical methods known or understanding for preparing this class formulation for those skilled in the art, for example referring to The Science and Practice of Pharmacy (pharmacy science with put into practice), 20thEdition (Philadelphia College of Pharmacy and Science, 2000).The composition for the treatment of administration under any circumstance contains the The compounds of this invention or the acceptable salt of its medicine for the treatment of significant quantity, treats disease or the morbid state of being paid close attention to instruction according to the present invention.

The pharmaceutical composition that can be used for herein also contains the medicine acceptable carrier, comprise any suitable dilution agent or vehicle, it comprises any medicament that can not induce generation to the individual deleterious antibody of accepting said composition itself, and it can not had unsuitable toxicity by administration.The medicine acceptable carrier includes but not limited to liquid, for example water, salt solution, glycerine and ethanol etc.Discussing fully of medicine acceptable carrier, thinner and other vehicle referring to REMINGTON ' S PHARMACEUTICAL SCIENCES (Lei Mingdun pharmaceutical science) (Mack Pub.Co., N.J, current edition).

Pharmaceutical composition of the present invention can be solid or liquid form.On the one hand, carrier is a particulate, thereby makes composition be for example tablet or powder form.Carrier can be liquid, and making composition is that for example oral syrup, injectable liquid maybe can be used for for example aerosol of inhalation.

When being intended to oral administration, pharmaceutical composition is preferably solid or liquid form, and wherein half-solid, half-liquid, suspension and gel form are included in the scope that is considered as solid or liquid form herein.

As the solids composition that is used for oral administration, pharmaceutical composition can be mixed with tablet, pill, capsule, Chewing gum, thin slice or the similar type of pulvis, granule, compacting.This solids composition contains one or more inert diluents or edible carrier usually.In addition, can contain following one or more: tackiness agent, as carboxymethyl cellulose, ethyl cellulose, Microcrystalline Cellulose, tragacanth gum or gelatin; Vehicle is as starch, lactose or dextrin; Disintegrating agent is as alginic acid, sodiun alginate, Primogel, W-Gum etc.; Lubricant is as Magnesium Stearate or Sterotex; Glidant is as colloid silica; Sweeting agent is as sucrose or asccharin; Correctives is as peppermint, wintergreen oil or orange seasonings; And tinting material.

When pharmaceutical composition is a capsule form, for example gelatine capsule then also can contain liquid carrier except that the material of the above-mentioned type, as polyoxyethylene glycol or oil.

Pharmaceutical composition can be liquid form, for example elixir, syrup, solution, emulsion or suspension.Liquid is lifted two examples and be can be that oral administration is used or use through injection delivery.When oral administration, preferred compositions promotes except that also containing one or more sweeting agents, sanitas, dyestuff/tinting material and taste this compound.Be intended to comprise one or more tensio-active agents, sanitas, wetting agent, dispersion agent, suspending agent, buffer reagent, stablizer and isotonic agent in the composition of drug administration by injection.

Composition of liquid medicine of the present invention, no matter be solution, suspension or other similar form, all can comprise one or more following adjuvants: the thinner of sterilization, as water for injection, salt brine solution, preferred physiological saline, Ringer ' s solution, isotonic sodium chloride can be used as the fixed oil of solvent or suspension medium, as synthetic glycerine monoesters or triglyceride, polyoxyethylene glycol, glycerine, propylene glycol or other solvent; Antiseptic-germicide is as benzylalcohol or para methyl paraben; Antioxidant is as xitix or sodium bisulfite; Sequestrant is as ethylenediamine tetraacetic acid (EDTA); Buffer reagent is as the reagent of acetate, Citrate trianion or phosphoric acid salt and adjusting osmotic pressure, as sodium-chlor or dextrose.Parenteral preparation can be contained in ampoule, disposable syringe or the multiple doses medicine bottle of being made by glass or plastics.Normal saline solution is a preferred adjuvants.Injectable pharmaceutical composition is preferably sterilization.

The composition of liquid medicine of the present invention that is intended to parenteral or oral administration should contain a certain amount of The compounds of this invention, makes to obtain proper dosage.Usually, this amount is at least 0.01% for The compounds of this invention in composition.When being intended to oral administration, this amount can the weight of said composition 0.1% to about 70% between change.Preferred combination of oral medication contains 4% to about 50% the The compounds of this invention of having an appointment.Before preferred pharmaceutical composition of the present invention and preparation were prepared as feasible dilution, parenteral dosage units contained the compound of 0.01 weight % to 10 weight %.

Pharmaceutical composition of the present invention can be used for topical, and the carrier under this situation can suitably comprise solution, emulsion, ointment or gel matrix.This matrix can for example comprise one or more following ingredients: Vaseline, lanolin, polyoxyethylene glycol, beeswax, mineral oil, thinner, and as water and alcohol, and emulsifying agent and stablizer.The pharmaceutical composition that is used for topical can contain thickening material.If be intended to percutaneous dosing, then said composition can comprise percutaneous plaster or iontophoresis device.Topical formulations can contain the The compounds of this invention that concentration is about 0.1 to about 10%w/v (weight per unit volume).

For example the form of suppository is by rectal administration for pharmaceutical composition of the present invention, and this suppository can be melted in the rectum and discharge medicine.The composition that is used for rectal administration can contain oleaginous bases as suitable nonirritant excipient.This matrix includes but not limited to lanolin, theobroma oil and polyoxyethylene glycol.

Pharmaceutical composition of the present invention can comprise the various materials of improvement solid or the unitary physical form of liquid dosages.For example, said composition can comprise the external coating (EC) that forms the coating activeconstituents.The material that forms external coating (EC) is generally inert substance and can be selected from for example sugar, shellac and other enteric coating agent.Perhaps, activeconstituents can be packed in the gelatine capsule.

The pharmaceutical composition of the present invention of solid or liquid form can comprise with the The compounds of this invention bonded and the reagent that therefore helps compound to carry.The suitable reagent that can this ability works comprises mono-clonal or polyclonal antibody, protein or liposome.

Pharmaceutical composition of the present invention can be made up of the dose unit that carries out administration as aerosol.The term aerosol is used to represent the various systems of its scope from system to the system that is made up of pressurized package of colloidal property.Conveying can be passed through liquefaction or pressurized gas, or is undertaken by the suitable pump system that distributes activeconstituents.The aerosol of The compounds of this invention can be single-phase, two-phase or three-phase system form are carried, with conveying active.Aerocolloidal conveying comprises required container, starter, valve, less important container etc., and it forms test kit together.Those skilled in the art need not can determine preferred aerosol through complicated experiment.

Pharmaceutical composition of the present invention can be by the preparation of the known method in the pharmacy field.For example, the pharmaceutical composition that is intended to drug administration by injection can make up by the distilled water with compound of the present invention and sterilization and prepare thereby form solution.Can add tensio-active agent to promote to form homogeneous solution or suspension.Tensio-active agent is following compound, itself and The compounds of this invention noncovalent interaction thereby promote the dissolving of compound in the water-based delivery system or evenly suspend.

Compound of the present invention or the acceptable salt of its medicine be with the treatment significant quantity by administration, this significant quantity can change along with various factors, comprises the activity of used specific compound; The metabolic stability of compound and action time; Patient age, body weight, general health situation, sex and diet; Mode of administration and time; Secreting rate; Drug regimen; The target of the seriousness of specified disease or morbid state and experience treatment.Usually, treating effective per daily dose is that (for 70 kilograms Mammals) about 0.001mg/kg (promptly 0.07 milligram) is to about 100mg/kg (i.e. 7.0 grams); The preferred therapeutic effective dose is that (for 70 kilograms Mammals) about 0.01mg/kg (promptly 7 milligrams) is to about 50mg/kg (i.e. 3.5 grams); Preferred treatment effective dose is that (for 70 kilograms Mammals) about 1mg/kg (promptly 70 milligrams) is to about 25mg/kg (i.e. 1.75 grams).

The scope of the effective dose that is provided not is the intention restriction but represents the preferred dosage scope herein.But most preferred dose is to adjust at individual one, and it is that those skilled in the art understand and decidablely (for example consult people such as Berkow and write Merck handbook, the 16th edition, Merck company, Rahway, N.J., 1992; Goodmanetna writes, the therapeutic pharmacological basis of Goodman and CilmanShi, the 10th edition, Pergamon publishing company, Elmsford, N.Y., (2001); AveryShi pharmacological agent: clinical pharmacology and therapeutic principle and practice, the 3rd edition, ADIS publishing company, Williams and Wilkins, Baltimore, MD. (1987), Ebadi pharmacology, Little, Brown company, Boston (1985); Osolci al. writes, the RemingtonShi pharmaceutical science, and the 18th edition, Mack publishing company (Easton, _PA) (1990); Katzung, basis and clinical pharmacology, Appleton and Lange, Norwalk, CT (1992)).

If desired, can with every kind the treatment needed total dose during one day in multidose or with the single dose administration.Generally speaking, treat from the smaller dose of the optimum dosage that is lower than described compound.Subsequently, increase this dosage, till reaching the optimum effect in this case with little increment.Diagnosis medicinal compound or composition can be individually dosed or with at these pathology or at other diagnostic reagent and/or the medication combined administration of this pathological other symptom.The recipient of The compounds of this invention and/or composition administration can be any vertebrates, as Mammals.In Mammals, preferred recipient is primate (comprising people, ape and monkey), cloven-hoofed animal (comprising horse, goat, ox, sheep, pig), rodent (comprising mouse, rat, rabbit and hamster) and carnivorous animal (comprising cat and dog).In birds, preferred recipient is other member of turkey, chicken and identical type.Most preferred recipient behaves.

For topical application, the pharmaceutical composition of the present invention that preferably gives significant quantity is to the target area adjacent with peripheral neurons to be treated, for example skin surface, mucous membrane etc.Generally speaking, the scope of this amount is each about 0.0001 milligram of The compounds of this invention to about 1 gram of using, and this depends on the area of being treated, and no matter whether its purposes is the character of the seriousness of diagnosis, prevention or treatment, symptom and the local medium that adopted.Preferred topical formulations is an ointment, and wherein every cc ointment base uses about 0.001 to about 50 milligrams activeconstituents.Pharmaceutical composition can be formulated into through the composition of skin or dermal delivery device (" patch ").This composition comprises for example liner, active compound reservoir, controlling diaphragm, liner and contact adhesive.This kind can be used for providing the successive pulsation through the patch of skin, or carries required The compounds of this invention on demand.

Composition of the present invention can be prepared by adopting program as known in the art so that after to patient's administration, provide activeconstituents fast, continue or postpone to discharge.The delivery system of controlled release drug comprises osmotic pump system and contains the reservoir of polymer coating or the dissolution system of drug-polymer matrix formulations.The example of controlled release system is shown in United States Patent (USP) 3,845, and in 770 and 4,326,525, and people such as P.J.Kuzma, Regional Anesthesia 22 (6): among the 543-551 (1997), during the mode by reference is incorporated herein its full content.

Composition of the present invention also can be by delivery system transmission in the nose, to be used for the pharmacotherapy to brain of part, whole body and nose.Controlled particle as well known to those skilled in the art is disperseed (CPD) ^TMTechnology, traditional nasal spray bottle, sucker or spraying gun are carried with effective part and whole body that medicine is provided by target regio olfactoria and paranasal sinus.

The invention still further relates to and be fit to the intravaginal shell of women or jenny administration or the delivery device of nuclear.The active pharmaceutical ingredients that this device can be included in the polymeric matrix and be centered on by sheath (sheath), and it can be basically serve as that the basis discharges this compound with the every day in the zero level mode, its be similar to described in the PCT patent WO 98/50016 in order to apply the device of testosterone.

Be used for method that eye carries at present and comprise topical (eye drops), subconjunctival injection, periocular injections, intravitreal injection, surgery implant and iontophoresis (utilizing little electric current) to carry ionized drugs and enter and pass through bodily tissue.Those skilled in the art can combine optimal vehicle with this compound, so that safe and efficient eye drops to be provided.

The most suitable approach depends on the character and the seriousness of the morbid state of being treated.Those skilled in the art also be familiar with to determine medication (oral cavity, intravenously, suction, subcutaneous, rectum etc.), formulation, suitable drug excipient and are delivered to other relevant items of individuality of needs with compound.

Conjoint therapy

The compounds of this invention can be with other therapeutical agent associating of one or more other The compounds of this invention or one or more or as its any being used in combination, with the disease and the morbid state of treatment sodium channel mediation.For example, compound of the present invention can be united with other therapeutical agent and carried out simultaneously, in succession or administration respectively, and described other therapeutical agent includes but not limited to:

The opiate anodyne, for example morphine, heroine, Cocaine, oxydimorphine, levorphan, levallorphan, oxycodone, morphine monomethyl ether, paracodin, the third oxygen sweet smell, Nalmefene, fentanyl, hydrocodone, hydromorphone, Mei Lipiding (meripidine), methadone, nalorphine, naloxone, TREXUPONT, buprenorphine, butorphanol, nalbuphine and penta azoles are new;

Non-opiate anodyne, for example beautiful Buddhist nun's fen (acetomeniphen) of acetyl, salicylate (for example acetylsalicylic acid);

NSAID (non-steroidal anti-inflammatory drug) (NSAID), for example Ibuprofen BP/EP, Na Puluosen, Lip river, Fino sweet smell, Ketoprofen, celecoxib, diclofenac, the new promise of difluoro (diflusinal), R-ETODOLAC, fenbufen, fenoprofen, flufenisal, flurbiprofen, Ibuprofen BP/EP, indomethacin, Ketoprofen, ketorolac, meclofenamic acid, vialidon, meloxicam, nabumetone, Na Puluosen, nimesulide, nitro flurbiprofen, olsalazine, Evil promazine, phenylbutazone, piroxicam, sulfasalazine, sulindac, pain are gone out and are reached zomepirac surely;

Anticonvulsive drug, for example Karma is uncommon flat, Ao Kaxiping, lamotrigine, valproic acid ester, topiramate, gabapentin and lyrica

Antidepressive, for example tricyclic antidepressants, for example amitriptyline, clomipramine, desmethylimipramine, imipramine and nortriptyline

The COX-2 selective depressant, for example Sai Lakao former times, rofecoxib, Parecoxib, dimension penta ground former times cloth, SC 59046, support are examined former times and Luo Mei former times cloth

The alpha-adrenergic medicine, for example Doxazosin, Tamsulosin, clonidine, guanfacine, right beautiful Tommy decide (dexmetatomidine), modafinil and 4-amino-6,7-dimethoxy-2-(5-sulfonyl methane amido-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl) quinazoline;

Barbiturate(s) tranquilizer, for example Amobarbital, somnifen, neo-barb, butalbital, Mephogarbital, metharbital, Methohexitone, Sodital, phenylethyl barbituric acid, secobarbital, Talbutal, Xi Ermila (theamylal) and Thiothal;

Tachykinin (NK) antagonist, NK-3 particularly, NK-2 or NK-1 antagonist, (α R for example, 9R)-7-[3, two (trifluoromethyl) benzyls of 5-]-8,9,10,11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[1,4] diazocine [2,1-g] [1,7] naphthyridines-6-13-diketone (TAK-637) also, 5-[[(2R, 3S)-2-[(1R)-1-[3, two (trifluoromethyl) phenyl of 5-] oxyethyl group-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone (MK-869), A Rui smooth, lanepitant, Dapitant and 3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl] methylamino]-2-phenyl-piperidines (2S, 3S);

The coal tar pain killer is particularly caught heat breath pain;

Serotonin reuptake inhibitor, for example paroxetine, Sertraline, Norfluoxetine (fluoxetine demethylation metabolite), metabolite demethyl Sertraline, ' 3-fluvoxamine, paroxetine, citalopram, citalopram metabolite demethylation citalopram, escitalopram, d, the 1-sweet smell is Lamine, femoxetine, ifoxetine, cyano group dothiepin, Litoxetine, dapoxetine, nefazodone, Cericlamine, trazodone and fluoxetine not;

Norepinephrine (norepinephrine) reuptake inhibitor, for example maprotiline, Tymelvt, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, Bupropion, bupropion metabolites hydroxyl Bupropion, nomifensine and viloxazine (

)), selectivity NRI especially, as Reboxetine, particularly (S, S)-Reboxetine, and Venlafaxine, the neural lax tranquilizer/anxiolytic of Du Luoxiting;

Dual serotonin-NRI, but for example Venlafaxine, Venlafaxine metabolite O-demethylation Venlafaxine, clomipramine, clomipramine metabolite demethylation clomipramine, Du Luoxiting, Midalcipran and imipramine;

Acetylcholinesterase depressant, for example E2020;

5-HT ₃Antagonist, for example ondansetron;

Metabotropic glutamate receptor (mGluR) antagonist;

Local anesthetic, for example mexiletine and lignocaine;

Corticosteroid hormone, for example dexamethasone;

Anti-arrhythmic, for example mexiletine and Phenytoin Sodium Salt;

Muscarinic type antagonist, for example tolterodine, propiverine, trospium chloride, darifenacin, plain Li Fenxin, temiverine and Ipratropium Bromured;

Cannaboid;

Capsaicin receptor agonist (for example resinferatoxin) or antagonist (for example capsazepine);

Tranquilizer, for example glutethimide, meprobamate, methaqualone and Dichloralphenazone;

Antianxiety agent, for example the benzene phenodiazine is flat,

Antidepressive, mirtazapine for example,

Local application's agent (for example lignocaine, capsacin and resiniferotoxin);

Muscle relaxant, for example the benzene phenodiazine is flat, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;

Antihistamine or H1 antagonist;

Nmda receptor antagonist;

5-HT receptor stimulant/antagonist;

The PDEV inhibitor;

·

Cholinergic (nicotine) anodyne;

α-2-δ ligand;

The prostaglandin E2 subtype antagonist;

Leukotriene B4 antagonist;

5-fats oxidn enzyme inhibitors; And

5-HT ₃Antagonist.

Can use the disease and the morbid state of the sodium channel mediation of these combined therapies and/or prevention to include but not limited to pain, the mediation of maincenter and periphery, acute, chronic, neuropathy originality and other disease with the property followed pain, and other nervus centralis illness, for example epilepsy, anxiety, depression and two-phase disease; Or cardiovascular disorder, for example irregular pulse, atrial fibrillation and ventricular fibrillation; Neuromuscular illness, for example restless leg syndrome and muscular paralysis or tetanus; The neuroprotective of anti-palsy, neural wound and multiple sclerosis; And passage disease, for example erythromelalgia and familial rectum pain syndrome.

" combination " used herein is meant any mixture or the replacement of one or more The compounds of this invention and one or more other The compounds of this invention or one or more other therapeutical agents.Unless clarify content in addition, otherwise " combination " can comprise the while or one after the other carry The compounds of this invention and one or more therapeutical agents.Unless clarify content in addition, otherwise " combination " can comprise the formulation of The compounds of this invention and another kind of therapeutical agent.Unless clarify content in addition, otherwise " combination " can comprise the route of administration of The compounds of this invention and another kind of therapeutical agent.Unless clarify content in addition, otherwise " combination " can comprise the preparation of The compounds of this invention and another kind of therapeutical agent.Formulation, route of administration and pharmaceutical composition include but not limited to described formulation, route of administration and pharmaceutical composition herein.

The accessory test kit

The present invention also provides test kit, and it contains the pharmaceutical composition that comprises one or more The compounds of this invention.This test kit also comprises about using this pharmaceutical composition to regulate the specification sheets of ion channel activity, treatment pain and other purposes disclosed herein.Commercial package preferably contains the pharmaceutical composition of one or more unitary doses.For example, such unitary dose can be the amount that is enough to prepare the intravenous injection agent.For those of ordinary skills, it is evident that the compound to light and/or air-sensitive may need extra package and/or preparation.For example, can use light tight and/or through sealing in order to avoid contact with ambient air and/or with packing that suitable dressing or vehicle are prepared.

The preparation of The compounds of this invention

Following reaction scheme exemplary illustration prepares The compounds of this invention, i.e. the method for the general formula described in the summary of the invention (I) compound.Especially following reaction scheme exemplary illustration preparation has the method for general formula (I) compound of following general formula (Ia):

Wherein j, k, Q, A, B, D, E, R ¹, R ^2a, R ^2b, R ^2cAnd R ^2dAll such as above-mentioned in about the embodiment of the present invention of general formula (Ia) compound, its steric isomer, enantiomer, its tautomer or its mixture or the acceptable salt of its medicine, solvate or prodrug definition, it is to be used for method of the present invention.

Should be appreciated that those skilled in the art can prepare compound of the present invention by similar method or by method known to those skilled in the art.Also answer those skilled in the art to prepare other compound of the present invention that does not hereinafter specify by using suitable starting ingredient and changing synthetic parameters as required with similar fashion as described below.Usually, starting ingredient can be by such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, MatrixScientific, TCI and Fluorochem USA etc. the acquisition of originating, or (consult according to the synthetic starting ingredient in source well known by persons skilled in the art, Smith for example, M.B.and J.March, Advanced Organic Chemistry:Reactions, Mechanisms, and Structure (Advanced Organic Chemistry: reaction, mechanism and structure), or preparation starting ingredient as described herein 5th edition (Wiley, December 2000)).

Should be appreciated that in the following description to have only when the variant of substituent combination and/or described general formula can obtain stable compound, the variant of substituent combination of this class and/or described general formula is only permission.

Those skilled in the art should also be clear that in the described hereinafter method that the functional group of intermediate compound may be by suitable protecting group protection.Such functional group comprises hydroxyl, amino, sulfydryl and carboxylic acid.Suitable hydroxyl protecting group comprises trialkylsilkl or alkyl diaryl silyl (for example t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl, benzyl etc.The protecting group of suitable amino, amidino groups and guanidine radicals comprises tertbutyloxycarbonyl, benzyloxycarbonyl etc.Suitable sulfhydryl protected base comprises-C (O)-R " (wherein R " is alkyl, aryl or aralkyl), right-methoxy-benzyl, trityl etc.Suitable carboxylic acid protecting group comprises alkyl, aryl or aryl alkane ester class.

Protecting group can be introduced or remove according to standard technique well known by persons skilled in the art and as described herein.

The use of protecting group is specified in Greene, T.W. and P.G.M.Wuts, and ProtectiveGroups in Organic Synthesis (protecting group in the organic synthesis) (1999), the 4th edition, among the Wiley.Protecting group also can be fluoropolymer resin, for example Wang resin or 2-chlorine trityl chloride resin.

Though those skilled in the art should also be clear that these protected derivatives itself of The compounds of this invention and may not have pharmacological activity, to the Mammals administration, and metabolism in vivo subsequently is to form the The compounds of this invention of tool pharmacological activity with it.Therefore such derivative can be called as " prodrug ".All prodrugs of The compounds of this invention include within the scope of the invention.

In the following reaction scheme, j, k, Q, A, B, D, E, R ¹, R ^2a, R ^2b, R ^2c, R ^2d, R ^3a, R ^3b, R ^3cAnd R ^3dAll as in summary of the invention about defined in general formula (Ia) compound, except as otherwise noted.X is a chlorine or bromine; And R " is an alkyl.

A. the preparation of general formula (Ia) compound, general formula (Ib) compound and general formula (Ic) compound

General formula (Ia-1) compound is that A is C (R ^3a), B is C (R ^3b), E is N, D is C (R ^3d), Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.General formula (Ia-2) compound is that A is C (R ^3a), B is C (R ^3b), E is N → O, D is C (R ^3d), Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.General formula (Ia-3) compound is that A is C (R ^3a), B is C (R ^3b), E is N (H), D is C (O), Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.These compounds can be synthetic according to the general procedure described in the following reaction scheme 1, and wherein Pg represents oxygen-protecting group:

Reaction scheme 1

General formula (101), general formula (102) and general formula (103) compound are all commercially available, maybe can prepare by method known to those skilled in the art.

By and large, general formula (Ia-1) compound, general formula ([a-2) compound and general formula (Ia-3) compound can be by in the programs described in the above-mentioned reaction scheme 1, at first handle the bromine compounds of general formula (102) down with Grignard reagent (103) at low temperature (0 ℃), make it to take place metal-halogen exchange, to form negatively charged ion, its in such as, but not limited to the solvent of tetrahydrofuran (THF) with the ketone-carbonyl reaction of isatin (isatin) compound of general formula (101), obtain general formula (104) compound oxindole compounds.Remove the hydroxyl of the C-3 position of general formula (104) compound and can use silane reagent, realize as triethyl-silicane processing general formula (104) compound by in the presence of such as, but not limited to acid such as trifluoroacetic acid.The hydroxyl of removing the C-3 position of general formula (104) compound also can be by using SOCl ₂/ NEt ₃Handle general formula (104) compound,, obtain general formula (105) compound and realize subsequently with the reduction of Zn powder.Use alkali then,,, produce the hydroxymethyl midbody compound of general formula (106) with formaldehyde reaction such as but not limited to Diisopropylamine, lithium diisopropylamine or sodium-hydroxide treatment general formula (105) compound.Through the Mitsunobu reaction conditions, as adopt phosphonate reagent, such as but not limited to triphenylphosphine or tributylphosphine, and azo agents, such as but not limited to diethyl azodiformate, diisopropyl azodiformate or tert-butyl azodicarboxylate, at solvent,, obtain general formula (Ia-1) compound such as but not limited to making general formula (107) compound in tetrahydrofuran (THF), methylene dichloride or the ethyl acetate by intramolecular cyclization.In addition, use such as, but not limited between-the oxidizer treatment compound (Ia-1) of chloroperoxybenzoic acid, obtain the oxide compound of general formula (Ia-2).General formula (Ia-2) compound (R wherein ^3dBe H) with cause forming the pyridinone compounds of general formula (Ia-3) such as but not limited to the reaction of the acid anhydrides of trifluoroacetic anhydride by rearrangement, it can separate with reaction mixture by the standard isolation technique.

B. the preparation of general formula (Ia-4) compound, general formula (Ia-5) compound, general formula (Ia-6) compound, general formula (Ia-7) compound and general formula (Ia-8) compound

General formula (Ia-4) compound is that A is C (R ^3a), B is C (R ^3b), E is C (R ^3e), D is N, Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.General formula (Ia-5) compound is that A is C (R ^3a), B is C (R ^3b), E is C (R ^3e), D is N → O, Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.General formula (Ia-6) compound is R ^2aBe H, A is C (R ^3a), B is C (R ^3b), E is C (R ^3e), D is N, Q is-O-, j be 0 and k be 1 general formula of the present invention (I) compound.General formula (Ia-7) compound is R ^2aBe aryl, A is C (R ^3a), B is C (R ^3b), E is C (R ^3e), D is N, Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.General formula (Ia-8) compound is that A is C (R ^3a), B is C (R ^3b), E is C (O), D is N, Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.These compounds can be synthetic according to the general procedure described in the following reaction scheme 2, and wherein Ar is an aryl.

Reaction scheme 2

General formula (101) and general formula (103) compound are and are purchased or can prepare according to method known to those skilled in the art.

By and large, general formula (Ia-4) compound, general formula (Ia-5) compound, general formula (Ia-6) compound, general formula (Ia-7) compound and general formula (Ia-8) compound, can be by at first handling general formula (202) compound with Grignard reagent (103) down at low temperature (0 ℃), make it to form pyridyloxy magnesium halogenide intermediate, it is at solvent, such as but not limited in methylene dichloride, tetrahydrofuran (THF) or the toluene with the ketone-carbonyl reaction of the isatin compound of general formula (101), obtain the oxindole compounds of general formula (204).The hydroxyl of removing the C-3 position of general formula (204) compound can be by use silicomethane reagent in the presence of such as, but not limited to the acid of trifluoroacetic acid, as triethyl-silicane processing general formula (204) compound and realize.The hydroxyl of removing the C-3 position of general formula (204) compound also can be by using SOCl ₂/ NEt ₃Handle general formula (204) compound,, obtain general formula (205) compound and realize subsequently with the reduction of Zn powder.Use alkali,,, produce the hydroxymethyl midbody compound of general formula (206) then with formaldehyde reaction such as but not limited to Diisopropylamine, lithium diisopropylamine or sodium-hydroxide treatment general formula (205) compound.Through the Mitsunobu reaction conditions, for example adopt phosphonate reagent, such as but not limited to triphenylphosphine or tributylphosphine, and azo agents, such as but not limited to diethyl azodiformate, diisopropyl azodiformate or tert-butyl azodicarboxylate, at solvent, through intramolecular cyclization, obtain general formula (Ia-4) compound such as but not limited to the compound that makes general formula (206) in tetrahydrofuran (THF), methylene dichloride or the ethyl acetate.

In addition, use oxygenant, such as but not limited to-chloroperoxybenzoic acid handles general formula (Ia-4) compound, obtains the oxide compound of general formula (Ia-5).

General formula (Ia-4) compound (R wherein ^2aBe bromo) can be under the hydrogenolysis condition, as adopting palladium catalyst, such as but not limited to tetrakis triphenylphosphine palladium (0), use hydride source, be further processed such as but not limited to formic acid and triethylamine,, obtain general formula (Ia-6) compound to remove the bromo of general formula (Ia-4) compound.

In addition, make general formula (Ia-4) compound (R wherein ^2aBe bromo) at palladium catalyst, such as but not limited to acid chloride, under the existence of tetrakis triphenylphosphine palladium (0) or three (dibenzalacetones), two palladiums (0), contain or do not contain ligand, such as but not limited to triphenylphosphine, three (neighbour-tolyl) phosphine, 1,1 '-two (diphenylphosphino) ferrocene or 2-(di-t-butyl phosphino-) biphenyl, and alkali, such as but not limited to yellow soda ash, cesium carbonate or sodium bicarbonate are at solvent, in glycol dimethyl ether diox or tetrahydrofuran (THF), react with aryl boric acid (210), acquisition general formula (Ia-7) compound (referring to Kotha, S., et al., Tetrahedron (2002), 58:9633and Miyaura, N., et al., Chem.Rev. (1995), 95:2457).

In addition, for general formula (Ia-4) compound (R wherein ^3eBe methoxyl group), can use such as but not limited to using TMSCl/NaI/H ₂O/CH ₃The method that CN handles is carried out the demethylation process, obtains the pyridinone compounds of general formula (Ia-8).

C. the preparation of general formula (Ia-9) compound and general formula (Ia-10) compound

General formula (Ia-9) compound and general formula (Ia-10) compound are that A is C (R ^3a), B is C (R ^3b), E is C (R ^3e), D is N, Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.It can adopt the general procedure described in the following reaction scheme 3 synthetic, wherein w and y each independently be 1,2 or 3, and Pg ¹Be nitrogen-protecting group.

Reaction scheme 3

General formula (301) compound is R ¹General formula (Ia-4) compound for H.General formula (302) compound is commercially available or can prepare according to method known to those skilled in the art.

By and large, general formula (Ia-9) compound and general formula (Ia-10) compound prepare by the program described in the above-mentioned reaction scheme 3, at first at solvent, such as but not limited to N, in dinethylformamide, tetrahydrofuran (THF), acetonitrile or the acetone, use alkali, such as but not limited to sodium hydride, cesium carbonate or salt of wormwood, with general formula (302) compound, wherein X is bromine or right-toluenesulphonic acids base, handles general formula (301) compound.After removing nitrogen-protecting group in general formula (303) compound with standard program, obtain general formula (Ia-9) compound.Under standard program, make the amination of being reduced property of general formula (Ia-9), obtain general formula (Ia-10) compound.

D. the preparation of general formula (Ia-11) compound

General formula (Ia-11) compound is that A is C (R ^3a), B is N, E is C (R ^3e), D is C (R ^3d), Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.It can adopt the general procedure described in the following reaction scheme 4 synthetic, and wherein Pg represents oxygen-protecting group:

Reaction scheme 4

General formula (101), general formula (402) and general formula (403) compound can commercially obtain maybe can prepare by method known to those skilled in the art.

By and large; general formula (Ia-11) compound is to prepare by the program described in the above-mentioned reaction scheme 4; at first use highly basic (403) down at low temperature (78 ℃); handle the protected hydroxyl pyridine compounds of general formula (402) such as but not limited to tert-butyl lithium; make it provide protection to form negatively charged ion; negatively charged ion is at solvent, such as but not limited in the tetrahydrofuran (THF) with the ketone-carbonyl reaction of the isatin compound of general formula (101), obtain general formula (404) compound indolone.The hydroxyl of removing the C-3 position of general formula (404) compound can be by use silicomethane reagent in the presence of such as, but not limited to the acid of trifluoroacetic acid, as triethyl-silicane processing general formula (404) compound and realize.The hydroxyl of removing general formula (404) Compound C-3 position also can be by using SOCl ₂/ NEt ₃Handle general formula (404) compound,, obtain general formula (405) compound and realize subsequently with the reduction of Zn powder.Remove protecting group and obtain general formula (406) compound, use alkali then,,, produce the hydroxymethyl midbody compound of general formula (407) subsequently with formaldehyde reaction such as but not limited to Diisopropylamine, lithium diisopropylamine or sodium-hydroxide treatment.General formula (407) compound is through the Mitsunobu reaction conditions, as adopt phosphonate reagent, such as but not limited to triphenylphosphine or tributylphosphine, and azo agents, such as but not limited to diethyl azodiformate, diisopropyl azodiformate or tert-butyl azodicarboxylate, at solvent,, obtain general formula (Ia-11) compound such as but not limited to carrying out intramolecular cyclization in tetrahydrofuran (THF), methylene dichloride or the ethyl acetate.

E. the preparation of general formula (Ia-12) compound, general formula (Ia-13) compound and general formula (Ia-14) compound

General formula (Ia-12) compound, general formula (Ia-13) compound and general formula (Ia-14) compound are that A is C (R ^3a), B is N, E is C (R ^3e), D is C (R ^3d), Q is-O-, j be 0 and k be 1 general formula of the present invention (Ia) compound.It can be synthetic by the universal program described in the following reaction scheme 5, and wherein Pg is oxygen-protecting group, Pg ¹Be nitrogen-protecting group:

Reaction scheme 5

The compound of general formula (501), general formula (502) and general formula (503) is and is purchased maybe and can prepares by method known to those skilled in the art.

By and large; general formula (Ia-12) compound is by the program described in the above-mentioned reaction scheme 5; be subjected to logical highly basic (503) under low temperature (78 ℃) earlier; handle the protected hydroxyl pyridine compounds of general formula (502) such as but not limited to tert-butyl lithium; make it provide protection to form negatively charged ion; negatively charged ion is at solvent, such as but not limited in the tetrahydrofuran (THF) with the ketone-carbonyl reaction of the isatin compound of general formula (501), obtain the oxindole compounds of general formula (504).When oxygen-protecting group (Pg) was methoxymethyl, it can be removed under acidic conditions, to obtain general formula (505) compound.Use SOCl ₂/ NEt ₃Handle general formula (505) compound, with the reduction of Zn powder, obtain general formula (506) compound subsequently, use alkali then,, handle, obtain the spiral shell oxindole compounds of general formula (Ia-12) such as but not limited to chloroiodomethane such as but not limited to cesium carbonate and dihalo reagent.Nitrogen-protecting group (Pg when general formula (Ia-12) compound ¹) when being diphenyl methyl, it can such as but not limited to trifluoroacetic acid and silicomethane reagent, be removed such as but not limited to triethyl-silicane with acid, obtains general formula (Ia-13) compound.At solvent, such as but not limited to tetrahydrofuran (THF), N, dinethylformamide or acetone are used alkali, such as but not limited to cesium carbonate or sodium hydride and electrophilic reagent (R ¹X) handle general formula (Ia-13) compound, obtain general formula (Ia-14) compound.

Prepared above-mentioned all compounds that exist with free alkali or sour form can be by changing into the acceptable salt of its medicine with suitable inorganic or organic bases or acid.The salt of the compound of above-mentioned preparation can change into its free alkali or sour form general formula by standard technique.All polymorphs, amorphous form, anhydride, hydrate, solvate and the salt that need to understand general formula (I) compound all are included in the scope of the present invention.In addition, all general formulas (I) compound that contains acid groups or ester group can change into corresponding ester or acid respectively by method known to those skilled in the art or with method as herein described.

Providing following concrete synthetic preparation embodiment (preparation initiator and intermediate) and synthetic example (preparation general formula (I) compound, especially general formula (Ia) compound) as the guiding example, to help putting into practice the present invention, but is not that intention limits the scope of the invention.Wherein provide one or more NMR ' s to specific compound, but but the racemic mixture of the non-racemic mixture of the single stereoisomers of each NMR representation compound, steric isomer or steric isomer.

Synthetic preparation embodiment 1

Synthesizing of 4-(benzyl oxygen base)-3-bromopyridine

Under 0 ℃,, add sodium hydride (0.13 gram, 3.10 mmoles) in dinethylformamide (20.0 milliliters) stirred solution in the N of 3-bromo-4-pyridine alcohol (0.45 gram, 2.60 mmoles).Mixture was stirred 30 minutes down at 0 ℃, then slowly add bromotoluene (0.38 milliliter, 3.10 mmoles).Mixture is stirred at ambient temperature spend the night and react with saturated ammonium chloride (50.0 milliliters) cancellation.With ethyl acetate (3 * 30.0 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate.Make residue with the eluent ethyl acetate that contains 2% methyl alcohol,, obtain 4-(benzyl oxygen base)-3-bromopyridine (0.48 gram, 69%) through column chromatography. ¹H?NMR(300MHz，CDCl ₃)δ7.78(d，J＝2.3Hz，1H)，7.41-7.34(m，4H)，7.21-7.14(m，2H)，6.42(d，J＝7.6Hz，1H)，4.79(s，2H)；MS(ES+)m/z?264.3(M+1)，266.3(M+1)。

Synthetic preparation embodiment 2

1-amyl group-1H-indoles-2,3-diketone synthetic

Under 0 ℃,, slowly add sodium hydride (4.24 grams, 60% dispersion liquid in the Dormant oils, 106 mmoles) in dinethylformamide (120.0 milliliters) stirred solution in the N of isatin (12.0 grams, 81.6 mmoles).Mixture was stirred 30 minutes down at 0 ℃, slowly add 1-bromo pentane silane (13.1 milliliters, 106 mmoles) subsequently.Mixture is stirred at ambient temperature spend the night, under agitation in the impouring frozen water (500.0 milliliters).With ethyl acetate (3 * 100.0 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate obtains 1-amyl group-1H-indoles-2, the orange solid of 3-diketone (17.5 grams, 99%). ¹H?NMR(300MHz，CDCl ₃)δ7.60-7.52(m，2H)，7.08(ddd，J＝7.6，7.6，0.6Hz，1H)，6.87(d，J＝7.6Hz，1H)，3.69(t，J＝7.3Hz，2H)，1.74-1.61(m，2H)，1.40-1.28(m，4H)，0.88(t，J＝7.0Hz，3H)。

Synthetic preparation embodiment 3

3-(hydroxymethyl)-3-(4-pyridone-3-yl)-1-amyl group-1,3-dihydro-2H-indol-2-one synthetic

A.3-[4-(benzyl oxygen base) pyridin-3-yl]-3-hydroxyl-1-amyl group-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃, in anhydrous tetrahydro furan (30.0 milliliters) stirred solution of 4-(benzyl oxygen base)-3-bromopyridine (0.85 gram, 3.20 mmoles), slowly add isopropylmagnesium chloride (1.61 milliliters, the tetrahydrofuran solution of 2M, 3.50 mmoles).Make mixture stir 1h at ambient temperature, add 1-amyl group-1H-indoles-2 then, 3-diketone (0.77 gram, 0.54 mmole).Mixture is stirred at ambient temperature spend the night and react with saturated ammonium chloride (50.0 milliliters) cancellation.With ethyl acetate (3 * 50.0 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate.Make residue with the eluent ethyl acetate that contains 2% methyl alcohol, implement column chromatography, obtain 3-[4-(benzyl oxygen base) pyridin-3-yl]-3-hydroxyl-1-amyl group-1,3-dihydro-2H-indol-2-one (0.52 gram, 40%): ¹H NMR (300MHz, CDCl ₃) δ 7.47 (d, J=7.3Hz, 1H), 7.42 (s, 1H), 7.39-7.25 (m, 5H), and 7.17-7.11 (m, 2H), 6.98 (ddd, J=7.6,7.6,0.8Hz, 1H), 6.82 (d, J=7.6Hz, 1H), 6.43 (d, J=7.3Hz, 1H), 4.92 (s, 2H), and 3.80-3.58 (m, 2H), 1.74-1.59 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, J=7.0Hz, 3H); ¹³C NMR (75MHz, CDCl ₃) δ 175.2,143.0,139.6,137.6,134.1,131.0,130.0,129.8,129.4,129.1,128.6,127.7,124.4,123.0,118.5,108.6,60.7,40.2,29.1,26.9,22.3,14.0; MS (ES+) m/z 403.5 (M+1).

B.3-[4-(benzyl oxygen base) pyridin-3-yl]-1-amyl group-1,3-dihydro-2H-indol-2-one synthetic

Make 3-[4-(benzyl oxygen base) pyridin-3-yl]-3-hydroxyl-1-amyl group-1,3-dihydro-2H-indol-2-one (0.20 gram, 0.50 mmole), the mixture of triethyl-silicane (1.6 milliliters, 10.0 mmoles), trifluoroacetic acid (0.74 milliliter, 10.0 mmoles) heated two days down at 100 ℃.Mixture washes with water with ethyl acetate (100.0 milliliters) dilution, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate.Make residue with the eluent ethyl acetate that contains 2% methyl alcohol, implement column chromatography, obtain 3-[4-(benzyl oxygen base) pyridin-3-yl]-1-amyl group-1,3-dihydro-2H-indol-2-one (0.17 gram, 95%): ¹H NMR (300MHz, CDCl ₃) δ 7.44-7.11 (m, 9H), 6.95 (t, J=7.6Hz, 1H), 6.83 (d, J=7.9Hz, 1H), 6.50 (d, J=7.6Hz, 1H), 4.92 (s, 2H), 4.81 (s, 1H), 3.73 (t, J=7.3Hz, 1H), and 1.75-1.61 (m, 2H), 1.40-1.27 (m, 4H), 0.87 (t, J=7.0Hz, 1H); MS (ES+) m/z 387.5 (M+1).

C.3-[4-(benzyl oxygen base) pyridin-3-yl]-3-(hydroxymethyl)-1-amyl group-1,3-dihydro-2H-indol-2-one synthetic

Feeding under the argon gas, make 3-[4-(benzyl oxygen base) pyridin-3-yl]-1-amyl group-1, degasification 1h in anhydrous tetrahydro furan (15.0 milliliters) solution of 3-dihydro-2H-indol-2-one (0.07 gram, 0.18 mmole) and Paraformaldehyde 96 (0.057 gram, 1.80 mmoles).Reach the slow lithium diisopropylamine (0.54 milliliter, freshly prepd 0.5M solution, 0.27 mmole) that adds under the stirring down at-78 ℃.Mixture is stirred at ambient temperature spend the night and react with saturated ammonium chloride (30.0 milliliters) cancellation.With ethyl acetate (3 * 50.0 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate obtains 3-[4-(benzyl oxygen base) pyridin-3-yl]-3-(hydroxymethyl)-1-amyl group-1, the solid of 3-dihydro-2H-indol-2-one (0.075 gram, 100%).MS(ES+)m/z?417.5(M+1)。

D.3-(hydroxymethyl)-3-(4-pyridone-3-yl)-1-amyl group-1,3-dihydro-2H-indol-2-one synthetic

To 3-[4-(benzyl oxygen base) pyridin-3-yl]-3-(hydroxymethyl)-1-amyl group-1, add 10%Pd/C (0.04 gram, 0.036 mmole) in methyl alcohol (10.0 milliliters) solution of 3-dihydro-2H-indol-2-one (0.075 gram, 0.18 mmole).Make mixture hydrogenation 4h under normal pressure.Make reaction mixture pass through bed of diatomaceous earth.Vacuum concentrated filtrate.Make residue with the eluent ethyl acetate that contains 5% methyl alcohol, implement column chromatography, obtain 3-(hydroxymethyl)-3-(4-pyridone-3-yl)-1-amyl group-1,3-dihydro-2H-indol-2-one (0.03 gram, 51%): MS (ES+) m/z 327.5 (M+1).

Synthetic preparation embodiment 4

[1,3] dioxole is synthesizing of [4,5-b] pyridine-6-alcohol also

A.[1,3] dioxole [4,5-b] pyridine-6-ylboronic acid synthetic also

Under-78 ℃ in 6-bromine [1,3] dioxole also [4,5-b] pyridine (Dallacker, F.et al., Z.Naturforsch.B Anorg.Chem.Org.Chem. (1979) 34:1729) adds (1.5 milliliters of n-butyllithium solutions in anhydrous diethyl ether (8.0 milliliters) stirred solution of (0.32 gram, 1.60 mmoles), 1.6M in hexane, 2.40 mmoles).Make reaction mixture stir 1h down, add triisopropyl borate ester (0.73 milliliter, 3.20 mmoles) subsequently fast at-78 ℃.After stirring 1h under-78 ℃, add water (20.0 milliliters).Mixture is stirred at ambient temperature to spend the night.Slowly add sodium hydroxide solution (2M) pH is adjusted to 10.With diethyl ether (3 * 10.0 milliliters) extraction mixture.Adding hydrobromic acid solution (〉=33% in Glacial acetic acid) makes water layer be acidified to pH 4.With ethyl acetate (3 * 50.0 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate.Make residue with the eluent ethyl acetate that contains 5% methyl alcohol, implement column chromatography, obtain also [4,5-b] pyridine-6-ylboronic acid (0.15 gram, 50%) of [1,3] dioxole: MS (ES+) m/z 168.2 (M+1).

B.[1,3] dioxole [4,5-b] pyridine-6-alcohol synthetic also

Under 0 ℃, also add superoxol (0.22 milliliter, 30%w/w, 2.00 mmoles) in anhydrous methylene chloride (5.0 milliliters) stirred solution of [4,5-b] pyridine-6-ylboronic acid (0.11 gram, 0.70 mmole) in [1,3] dioxole.Mixture is diluted at 0 ℃ of following 1h of stirring and with methylene dichloride (50.0 milliliters).Separate organic layer, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate.Make residue with the hexane wash-out that contains 30% ethyl acetate, implement column chromatography, obtain also [4,5-b] pyridine-6-alcohol (0.05 gram, 49%) of [1,3] dioxole: ¹H NMR (300MHz, CD ₃CN) δ 7.14 (d, J=2.9Hz, 1H), 6.71 (d, J=2.9Hz, 1H), 5.99 (s, 2H); MS (ES+) m/z 140.1 (M+1).

Synthetic preparation embodiment 5

1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2,3-diketone synthetic

Under 0 ℃,, slowly add sodium hydride (0.88 gram, 60% dispersion liquid in the mineral oil, 22.0 mmoles) in dinethylformamide (50.0 milliliters) stirred solution in the N of isatin (3.0 grams, 20.0 mmoles).Mixture was stirred 30 minutes down at 0 ℃, slowly add 2-(brooethyl)-5-(trifluoromethyl) furans (4.95 milliliters, 21.0 mmoles) subsequently.Mixture is stirred at ambient temperature spend the night, stir in the following impouring frozen water (200.0 milliliters).Filtering mixt and make gained solid 1-{[5-(trifluoromethyl)-2-furyl] methyl-1H-indoles-2, the vacuum-drying of 3-diketone, up to constant weight (6.02 gram, 100%): ¹H NMR (300MHz, CDCl ₃) δ 7.66-7.56 (m, 2H), 7.15 (dd, J=7.6,7.6Hz, 1H), 7.03 (d, J=7.9Hz, 1H), 6.74 (d, J=3.5Hz, 1H), 6.44 (d, J=3.5Hz, 1H), 4.92 (s, 2H).

Synthetic preparation embodiment 6

3-(6-hydroxyl [1,3] dioxole is [4,5-b] pyridine-5-yl also)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

A.3-hydroxyl-3-(6-hydroxyl [1,3] dioxole is [4,5-b] pyridine-5-yl also)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

At 0 ℃ in [1,3] dioxole also slowly adds (1.61 milliliters of isopropylmagnesium chlorides in anhydrous tetrahydro furan (50.0 milliliters) stirred solution of [4,5-b] pyridine-6-alcohol (0.26 gram, 1.87 mmoles), the tetrahydrofuran solution of 2M, 3.54 mmoles).Make mixture stir 1h at ambient temperature, add 1-{[5-(trifluoromethyl)-2-furyl subsequently] methyl }-1H-indoles-2,3-diketone (0.61 gram, 0.54 mmole).Mixture is stirred at ambient temperature spend the night and react with saturated ammonium chloride (50.0 milliliters) cancellation.With ethyl acetate (3 * 50.0 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate.Make the residue hexane wash-out that contains 30% ethyl acetate, implement column chromatography, obtain 3-hydroxyl-3-(6-hydroxyl [1,3] dioxole also [4,5-b] pyridine-5-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one (0.67 gram, 73%): mp＞250 ℃; ¹H NMR (300MHz, CD ₃OD) δ 7.30 (t, J=7.6Hz, 1H), 7.19 (d, J=7.6Hz, 1H), 7.07-6.99 (m, 2H), 6.91 (d, J=3.5Hz, 1H), 6.67 (s, 1H), 6.57 (d, J=3.5Hz, 1H), 6.04-6.00 (m, 2H), 5.11-4.95 (m, 2H); ¹³C NMR (75MHz, CD ₃OD) δ 178.3,154.4, and 151.7,148.6,143.9,142.4,132.9,131.5,130.7,125.1,124.5,114.1 (m), 110.3,110.2,107.5,102.4,78.9,37.7; MS (ES+) m/z457.1 (M+23).

B.3-(6-hydroxyl [1,3] dioxole is [4,5-b] pyridine-5-yl also)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Make 3-hydroxyl-3-(6-hydroxyl [1,3] dioxole also [4,5-b] pyridine-5-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one (0.33 gram, 0.75 mmole), triethyl-silicane is (0.60 milliliter, 3.74 mmole), the mixture of trifluoroacetic acid (0.29 milliliter, 3.74 mmoles) and anhydrous methylene chloride (12.0 milliliters) stirs 2h at ambient temperature.The vacuum concentration reaction mixture.Residue grinds and filters with ether (5.0 milliliters), obtain 3-(6-hydroxyl [1,3] dioxole is [4,5-b] pyridine-5-yl also)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one (0.27 gram, 87%): mp 161-163 ℃; ¹H NMR (300MHz, CD ₃OD) δ 7.25 (t, J=7.6Hz, 1H), 7.08 (d, J=7.6Hz, 1H), 7.05-6.98 (m, 2H), 6.90 (d, J=3.5Hz, 1H), 6.76 (s, 1H), 6.55 (d, J=3.5Hz, 1H), 6.03-5.98 (m, 2H), 5.06 (s, 2H), 5.03 (s, 1H); ¹³C NMR (75MHz, CD ₃OD) δ 178.2,154.5, and 152.3,148.9,144.2,141.9,132.0,130.4,129.1,125.1,124.1,114.1 (m), 110.2,110.0,106.9,102.3,37.7; MS (ES+) m/z 419.1 (M+1).

C.3-(6-hydroxyl [1,3] dioxole is [4,5-b] pyridine-5-yl also)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃, make argon gas feed 3-(6-hydroxyl [1,3] dioxole also [4,5-b] pyridine-5-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one (0.32 gram, 0.78 mmole) and Paraformaldehyde 96 (0.23 the gram, 7.8 degasification 1h in anhydrous tetrahydro furan mmole) (25.0 milliliters) mixture slowly adds lithium diisopropylamine (3.9 milliliters, the solution of the tetrahydrofuran (THF) of freshly prepd 0.5M) subsequently.Mixture was stirred two hours at ambient temperature and react with saturated ammonium chloride (20.0 milliliters) cancellation.With ethyl acetate (3 * 50 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate, obtain 3-(6-hydroxyl [1,3] dioxole [4,5-b] pyridine-5-yl also)-and 3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the solid of 3-dihydro-2H-indol-2-one: MS (ES+) m/z449.1 (M+1).

Synthetic preparation embodiment 7

5-fluoro-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2,3-diketone synthetic

Under 0 ℃,, add sodium hydride (1.74 grams, 60% dispersion liquid in mineral oil, 45.4 mmoles) in dinethylformamide (50 milliliters) solution in the anhydrous N of the full diketone of 5-fluoro indole (5.00 grams, 30.3 mmoles).Brown reaction mixture was stirred 30 minutes, add the anhydrous N of 2-(brooethyl)-5-(trifluoromethyl) furans (7.25 grams, 31.8 mmoles) subsequently, dinethylformamide (7.0 milliliters) solution.Make reaction mixture at ambient temperature in the wet diethyl ether (200 milliliters) of restir 6h and impouring.Separate organic layer, water (5 * 100 milliliters) washing is with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Residue grinds with ether, obtains 5-fluoro-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2, the orange solid of 3-diketone (5.62 grams, 59%): ¹HNMR (300MHz, DMSO-d ₆) δ 7.54-7.50 (m, 1H), 7.47-7.44 (m, 1H), 7.20 (dd, J=8.7,3.9Hz, 1H), 7.14-7.13 (m, 1H), 6.75 (d, J=3.6Hz, 1H), 4.99 (s, 2H); ¹³C NMR (75MHz, DMSO-d ₆) δ 182.4,160.7,158.5,157.5,153.0,146.5,140.4 (m), 124.3,119.3,114.5 (m), 112.7,112.0,110.5,36.8.

Synthetic preparation embodiment 8

4-bromo-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2,3-diketone synthetic

Adopt the program described in the synthetic preparation embodiment 7, and carry out nonessential variation, promptly replace the full diketone of 5-fluoro indole, obtain 4-bromo-1-{[5-(trifluoromethyl)-2-furyl with the full diketone of 4-bromo indole] methyl }-1H-indoles-2, the orange solid of 3-diketone (70%): ¹H NMR (300MHz, CDCl ₃) δ 7.41 (dd, J=8.0,8.0Hz, 1H), 7.25 (dd, J=3.3,3.3Hz, 1H), 7.00 (d, J=7.9Hz, 1H), 6.74 (d, J=3.3Hz, 1H), 6.45 (d, J=3.3Hz, 1H), 4.93 (s, 2H); ¹³C NMR (75MHz, CDCl ₃) δ 179.9,156.8,151.5,150.7,142.2,141.8,138.6,129.0,122.0,116.4,112.8,110.2,109.3,36.6.

Synthetic preparation embodiment 9

4-chloro-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2,3-diketone synthetic

Adopt synthetic preparation embodiment 7 described programs, and carry out nonessential variation, promptly replace the full diketone of 5-fluoro indole, obtain 4-chloro-1-{[5-(trifluoromethyl)-2-furyl with the full diketone of 4-chloro-indole] methyl }-1H-indoles-2, the orange solid of 3-diketone (90%): mp 148-150 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 7.60 (dd, J=8.1,8.1Hz, 1H), 7.15-7.10 (m, 3H), 6.76 (d, J=3.4Hz, 1H), 4.99 (s, 2H); ¹³C NMR (75MHz, DMSO-d ₆) δ 179.9,157.7,152.9 (m), 151.6,140.1 (d, ¹J _CF=167Hz), 138.9,131.5,124.9,121.2,117.7,114.5 (m), 110.5,110.0,36.9.

Synthetic preparation embodiment 10

4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

A.4-bromo-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃ in 6-methoxypyridine-3-alcohol (Van de Poel et al., Heterocycles2002; 57:55-71) add isopropylmagnesium chloride (6.40 milliliters, the diethyl ether solution of 2.0M, 12.8 mmoles) in anhydrous tetrahydro furan (20.0 milliliters) solution of (1.60 grams, 12.8 mmoles).Make reaction mixture stir 30 minutes and removal of solvent under reduced pressure.Colourless residue is dissolved in anhydrous methylene chloride (20.0 milliliters) and the anhydrous tetrahydro furan (20.0 milliliters), and add gained solution to 4-bromo-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2, in anhydrous tetrahydro furan (20.0 milliliters) solution of 3-diketone (3.19 grams, 8.53 mmoles).The yellow reaction mixture was stirred 2 days at ambient temperature and react with saturated aqueous ammonium chloride (40 milliliters) cancellation.Reaction mixture also filters with anhydrous sodium sulfate drying with the layer of methylene dichloride (3 * 100 milliliters) extraction and merging.Vacuum concentrated filtrate is to doing.Make the residue ethyl acetate: hexane (35% to 50% gradient) wash-out, by the silica gel column chromatography purifying, obtain 4-bromo-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the colourless cotton-shaped solid of 3-dihydro-2H-indol-2-one (2.75 grams, 65%): R _f=0.44 (ethyl acetate: hexane, 1: 1); ¹H NMR (300MHz, CDCl ₃) δ 7.24 (s, 1H), 7.17-7.11 (m, 1H), 6.98 (d, J=8.8Hz, 1H), 6.89-6.84 (m, 1H), 6.67 (s, 1H), 6.54 (d, J=8.8Hz, 1H), 4.88 (ABq, 2H), 3.78 (s, 3H); ¹³C NMR (75MHz, CDCl ₃) δ 175.5,156.6,151.4,144.7,141.9,141.3,135.7,131.2,129.6,128.8,127.6,119.8,112.7,112.6,112.1,109.5,108.0,77.2,53.7,37.1.

B.4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃ in 4-bromo-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl-1,3-dihydro-2H-indol-2-one (2.33 grams, 4.68 add triethylamine (1.42 grams in anhydrous methylene chloride mmole) (47.0 milliliters) solution, 1.9 milliliter, 14.0 mmole), add thionyl chloride (1.11 grams, 9.36 mmoles) then.Make reaction mixture stir 1h and removal of solvent under reduced pressure.Residue is dissolved in tetrahydrofuran (THF) (33 milliliters) and the acetate (20 milliliters) again, adds Zn powder (3.10 grams, 46.8 mmoles) down at 0 ℃ then.Make the gained mixture stir 16h at ambient temperature and filter out solid.Vacuum concentrated filtrate is to doing, and residue ethyl acetate (100 milliliters) dilution is with saturated aqueous ammonium chloride (3 * 25 milliliters), water (3 * 25 milliliters) washing, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Make the residue ethyl acetate: hexane (50%) wash-out, by the silica gel column chromatography purifying, obtain 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the colorless solid of 3-dihydro-2H-indol-2-one (1.10 grams, 49%): R _f=0.56 (ethyl acetate: hexane, 1: 1); MS (ES+) m/z 485.3 (M+1), 483.2 (M+1).

C.4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃ in 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl-1,3-dihydro-2H-indol-2-one (0.99 gram, 2.04 mmole) and in methylene dichloride (35 milliliters) suspension of Paraformaldehyde 96 (0.25 gram, 8.29 mmoles) add Diisopropylamine (6.16 mmole).Make the gained mixture stir 16h at ambient temperature and react with saturated aqueous ammonium chloride (40 milliliters) cancellation.Separate organic layer, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.With ether solid residue is ground, obtains 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the colorless solid of 3-dihydro-2H-indol-2-one (0.79 gram, 71%): ¹H NMR (300MHz, DMSO-d ₆) δ 9.13 (s, 1H), 7.15-6.92 (m, 5H), 6.58 (d, J=8.7Hz, 1H), 6.48 (d, J=8.7Hz, 1H), 5.02 (q, J=9.5Hz, 2H), 4.87-4.74 (m, 2H), 4.36-4.26 (m, 1H), 3.77 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.7,155.6,154.1 (m), 146.6,146.0,140.0,139.5,139.0,129.8,129.6,127.4,126.2,117.8,114.5 (m), 109.9,109.1,107.6,63.3,59.9,53.4,37.2.

Synthetic preparation embodiment 11

5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

A.5-fluoro-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃, in anhydrous tetrahydro furan (20.0 milliliters) solution of 6-methoxypyridine-3-alcohol (1.56 grams, 12.5 mmoles), add isopropylmagnesium chloride (7.8 milliliters, the tetrahydrofuran solution of 2.0M, 15.6 mmoles).Make reaction mixture stir 0.5h, add 5-fluoro-1-{[5-(trifluoromethyl)-2-furyl then] methyl }-1H-indoles-2, anhydrous tetrahydro furan (10.0 milliliters) solution of 3-diketone (3.13 grams, 10.0 mmoles).Make the yellow reaction mixture stir 16h and vacuum concentration at ambient temperature to doing.Residue is dissolved in the ethyl acetate (100.0 milliliters), with saturated aqueous ammonium chloride (15 milliliters), water (3 * 15 milliliters), salt solution (15 milliliters) washing.Organic layer also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate is to doing.Make residue hexane (1: the 1) wash-out that contains ethyl acetate, by the silica gel column chromatography purifying, obtain 5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the yellow solid of 3-dihydro-2H-indol-2-one (3.67 grams, 84%): mp 110-113 ℃; ¹H NMR (300MHz, CDCl ₃) δ 7.22 (br, 1H), 6.96-6.86 (m, 3H), 6.82-6.78 (m, 1H), 6.67-6.61 (m, 1H), 6.47 (m, 1H), 6.37-6.28 (m, 1H), 5.00 (br, 1H), 4.94 (d, J=16.5Hz, 1H), 4.70 (d, J=16.5Hz, 1H), 3.74 (s, 3H); ¹³C NMR (75MHz, CDCl ₃) δ 176.7,161.4,158.2,155.6,151.4,144.8,141.6 (d), 137.9,132.1 (m), 129.6,120.5,117.0,116.1,112.6 (m), 111.9,109.8,109.3,77.2,53.6,37.2; MS (ES+) m/z 439.2 (M+1), 421.1 (M-17).

B.5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃ in 5-fluoro-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl-1,3-dihydro-2H-indol-2-one (3.67 grams, 8.38 anhydrous tetrahydro furan/anhydrous methylene chloride mmole) (1: 1,100.0 milliliter) add triethylamine (1.27 grams in the solution, 1.8 milliliter, 12.6 mmoles), add thionyl chloride (1.09 grams then, 1.3 milliliter, 9.22 mmoles).Make reaction mixture stirring 1h and vacuum concentration to doing.Residue is dissolved in tetrahydrofuran (THF) (100 milliliters) and the acetate (30 milliliters) again, adds Zn powder (1.10 grams, 16.8 mmoles) down at 0 ℃ then.Make reaction mixture stir 1h at ambient temperature and filter out solid.Behind the vacuum concentrated filtrate, residue, also filters with anhydrous sodium sulfate drying with saturated aqueous ammonium chloride (3 * 50 milliliters), salt solution (3 * 25 milliliters) washing with ethyl acetate (100 milliliters) dilution.Vacuum concentrated filtrate is to doing.Make residue hexane (30%) wash-out that contains ethyl acetate, by the silica gel column chromatography purifying, obtain 5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the light yellow solid of 3-dihydro-2H-indol-2-one (2.94 grams, 83%): ¹³C NMR (75MHz, CDCl ₃) δ 177.4,158.0,157.5,151.6,147.9,146.4,138.4,137.5,132.3,129.5,128.8,128.1,114.6,112.6 (m), 110.8,110.5,109.5,53.4,50.1,37.1; MS (ES+) m/z 423.2 (M+1).

C.5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃ in 5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl-1,3-dihydro-2H-indol-2-one (2.70 grams, 6.40 mmole) and Paraformaldehyde 96 (1.92 the gram, 64.0 add water (2.00 milliliters) solution of lithium hydroxide monohydrate (0.81 gram, 19.2 mmoles) in tetrahydrofuran (THF) mmole) (100.0 milliliters) suspension.Make reaction mixture stir 2h at ambient temperature and with saturated aqueous ammonium chloride (40.0 milliliters) cancellation reaction, and extract with ethyl acetate (3 * 50.0 milliliters).The organic layer that merges anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.With ether solid residue is ground, obtain 5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the gluing material of 3-dihydro-2H-indol-2-one (quantitative yield): MS (ES+) m/z 453.2 (M+1).

Synthetic preparation embodiment 12

4-chloro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

A.4 '-chloro-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Adopt program described in the synthetic preparation embodiment 11A, and carry out nonessential variation, with 4-chloro-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2, the 3-diketone replaces 5-fluoro-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1H-indoles-2, the 3-diketone, acquisition 4 '-chloro-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the light yellow solid of 3-dihydro-2H-indol-2-one (87%): mp 185-188 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 9.44 (s, 1H), 7.30 (dd, J=8.0,8.0Hz, 1H), 7.15-7.08 (m, 3H), 7.00 (br, 1H), 6.94 (d, J=8.1Hz, 1H), 6.69 (d, J=8.7Hz, 1H), 6.62 (d, J=8.6Hz, 1H), 5.02 (s, 2H), 3.71 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 174.8,155.7,153.6,149.1,145.4,140.3,132.8,131.5,130.3,129.1,127.7,123.8,114.5,111.4,110.9,110.1,108.3,77.1,53.7,36.9; MS (ES+) m/z 457.3 (M+1), 455.3 (M+1).

B.4-chloro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Adopt program described in the synthetic preparation embodiment 11B, and carry out nonessential variation, with 4 '-chloro-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one replaces 5-fluoro-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one, obtain 4-chloro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the light yellow solid of 3-dihydro-2H-indol-2-one (35%): mp 151-152 ℃; ¹HNMR (300MHz, DMSO-d ₆) δ 9.47 (br, 1H), 7.26 (dd, J=8.0,8.0Hz, 1H), and 7.18-7.12 (m, 2H), 7.08 (d, J=7.8Hz, 1H), 6.96 (d, J=8.1Hz, 1H), 6.59 (d, J=3.1Hz, 1H), 6.56 (d, J=8.7Hz, 1H), 5.16 (s, 1H), 5.02 (ABq, J=16.6Hz, 2H), 3.41 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 174.8; MS (ES+) m/z 441.2 (M+1), 439.2 (M+1).

C.4-chloro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃ in 4-chloro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1-{[5-(trifluoromethyl)-2-furyl] methyl-1,3-dihydro-2H-indol-2-one (1.25 grams, 2.85 mmole) and Paraformaldehyde 96 (0.34 the gram, 11.4 add water (2.00 milliliters) solution of sodium hydroxide (0.46 gram, 11.4 mmoles) in water/tetrahydrofuran (THF) mmole) (15.0/5.0 milliliter) suspension.Reaction mixture was stirred 30 minutes at ambient temperature, extract with 10% aqueous hydrochloric acid (25.0 milliliters) cancellation reaction and with ethyl acetate (3 * 50.0 milliliters).The organic layer that merges anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.With diethyl ether solid residue is ground, obtain 4-chloro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1, the colorless solid of 3-dihydro-2H-indol-2-one (1.25 grams, 94%): mp 191-193 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 9.15 (s, 1H), 7.18 (dd, J=8.0,8.0Hz, 1H), 7.13 (dd, J=3.3,1.1Hz, 1H), 6.98 (d, J=8.7Hz, 1H), 6.92 (d, J=7.8Hz, 1H), 6.88 (d, J=8.2Hz, 1H), 6.58 (d, J=8.6Hz, 1H), 6.49 (d, J=3.3Hz, 1H), 5.02 (ABq, J=16.9Hz, 2H), 4.88 (t, J=4.9Hz, 1H), 4.77 (dd, J=10.4,4.7Hz, 1H), 4.33 (dd, J=10.4,5.2Hz, 1H), 3.76 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.8,155.7,154.1,146.5,145.9,140.0,139.1,129.6,129.3,127.9,127.5,123.1,121.3,117.8,114.5,109.8,109.1,107.2,59.2,53.3,37.3; MS (ES+) m/z 471.3 (M+1), 469.3 (M+1).

Synthetic preparation embodiment 13

4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1, two (hydroxymethyl)-1 of 3-, 3-dihydro-2H-indol-2-one synthetic

A.4-bromo-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃, in anhydrous tetrahydro furan (100 milliliters) pale yellow solution of 6-methoxypyridine-3-alcohol (7.16 grams, 57.2 mmoles), add isopropylmagnesium chloride (28.6 milliliters, 57.2 mmoles, the tetrahydrofuran solution of 2.0M).Reaction soln was stirred 30 minutes, add the full diketone of solid 4-bromo indole (10.3 grams, 45.8 mmoles) one by one with many parts then.Reaction mixture was stirred 2 days at ambient temperature.Reaction extracts with (100 milliliters) cancellation of 10% aqueous hydrochloric acid and with ethyl acetate (3 * 100 milliliters).The organic layer that merges anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Grind residue with ether, obtain 4-bromo-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1, the light yellow solid of 3-dihydro-2H-indol-2-one (10.7 grams, 67%): mp 172-175 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 10.61 (s, 1H), 9.41 (s, 1H), 7.10 (d, J=8.0Hz, 2H), 6.99 (d, J=8.1Hz, 1H), 6.81 (d, J=7.6Hz, 1H), 6.77 (br, 1H), 6.68 (d, J=8.6Hz, 1H), 3.77 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.5,155.5,145.9,139.4,131.6,128.9,127.2,125.6,118.9,111.8,111.1,109.3,53.8; MS (ES+) m/z 353.2 (M+1), 351.2 (M+1).

B.4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1,3-dihydro-2H-indol-2-one synthetic

Under 0 ℃ in 4-bromo-3-hydroxyl-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1,3-dihydro-2H-indol-2-one (4.20 grams, 12.0 add triethylamine (3.64 grams in anhydrous methylene chloride mmole) (100.0 milliliters) and anhydrous tetrahydro furan (10.0 milliliters) solution, 36.0 mmole) and thionyl chloride (4.28 gram, 36.0 mmoles).Reaction soln was stirred 30 minutes and react with 10% aqueous hydrochloric acid (50.0 milliliters) cancellation.The gained mixture extracts with ethyl acetate (3 * 50.0 milliliters).The organic layer that merges is with saturated ammonium chloride (3 * 50.0 milliliters), hydrochloric acid (50.0 milliliters) washing, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Residue is dissolved in tetrahydrofuran (THF) (70.0 milliliters) and the acetate (30.0 milliliters), adds zinc powder (7.84 grams, 120 mmoles) then.Make reaction mixture stir 3h and filtration at ambient temperature.Vacuum concentrated filtrate is to doing.Residue is dissolved in the ethyl acetate (100 milliliters), with saturated ammonium chloride (3 * 50.0 milliliters), salt solution (50.0 milliliters) washing, with anhydrous sodium sulfate drying and filtration.Make the residue eluent ethyl acetate,, obtain 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1, the light yellow solid of 3-dihydro-2H-indol-2-one (2.58 grams, 64%): mp 149-152 ℃ by the column chromatography purifying; ¹H NMR (300MHz, DMSO-d ₆) δ 10.61 (s, 1H), 9.34 (br, 1H), 7.15-7.06 (m, 2H), 6.99 (d, J=7.8Hz, 1H), 6.81 (d, J=7.4Hz, 1H), 6.55 (d, J=8.5Hz, 1H), 4.90 (s, 1H), 3.52 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.2,156.5,147.4,147.2,145.7,138.9,130.1,127.7,124.7,118.5,109.7,108.7,53.3,49.4; MS (ES+) m/z 337.2 (M+1), 335.2 (M+1).

C.4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1, two (hydroxymethyl)-1,3 dihydros of 3--2H-indol-2-one synthetic

Under 0 ℃ in 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1,3-dihydro-2H-indol-2-one (1.67 grams, 5.00 mmole) and Paraformaldehyde 96 (0.60 the gram, 20.0 add water (10.0 milliliters) solution of sodium hydroxide (0.80 gram, 20.0 milliliters) in tetrahydrofuran (THF) mmole) (20.0 milliliters) mixture.Make reaction soln stir 1h and react with 10% aqueous hydrochloric acid (50.0 milliliters) cancellation.With ethyl acetate (3 * 50.0 milliliters) extractive reaction mixture.The organic layer that merges is with saturated ammonium chloride (3 * 50.0 milliliters), salt solution (50.0 milliliters) washing, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Make residue pass through column chromatography, come purifying with the hexane that contains ethyl acetate (50%) wash-out, obtain 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1, two (hydroxymethyl)-1 of 3-, the colorless solid of 3 dihydros-2H-indol-2-one (1.83 grams, 81%): mp 142-145 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 9.08 (s, 1H), 7.11 (d, J=7.8Hz, 1H), 7.05 (d, J=6.7Hz, 1H), 7.00 (dd, J=7.8,1.0Hz, 1H), 6.93 (d, J=8.7Hz, 1H), 6.55 (d, J=8.6Hz, 1H), 6.23 (br, 1H), 5.05 (q, J=10.7Hz, 2H), 4.64 (br, 1H), 4.52 (ABq, 2H), 3.76 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.8,155.5,147.2,146.1,139.5,129.6,129.5,127.2,125.8,117.7,109.7,108.2,78.3,63.5,63.3,53.3; MS (ES+) m/z 419.2 (M+23), 417.2 (M+23).

Synthetic preparation embodiment 14

Synthesizing of 3-(5-hydroxyl-2-methoxypyridine-4-yl)-3-(hydroxymethyl)-1-((5-(trifluoromethyl) furans-2-yl) methyl) indole-2-ketone

A.3-hydroxyl-3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

-78 ℃ down and in 15 minutes in 2-methoxyl group-5-(methoxymethoxy) pyridine (Van dePoel et al., Heterocycles 2002; 57:55-71) (12.0 grams, 71.0 add the pentane solution (1.0M of tert-butyl lithium in anhydrous tetrahydro furan mmole) (250 milliliters) solution, 71.0 milliliter, 71.0 mmole), then add 1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1H-indoles-2, anhydrous tetrahydro furan (80 milliliters) solution of 3-diketone (22.0 grams, 74.1 mmoles).Make reaction mixture be warming up to surrounding temperature and stirring 16h.Adding saturated aqueous ammonium chloride (50 milliliters) and reaction mixture stirred 10 minutes.Reaction mixture dilutes and makes with ethyl acetate (400 milliliters) and water (200 milliliters) and is separated.With ethyl acetate (4 * 100 milliliters) aqueous phase extracted.Anhydrous sodium sulfate drying is used in organic extract liquid water (3 * 100 milliliters) that merges and salt solution (100 milliliters) washing, filters and vacuum concentration.Make raw product through column chromatography, come purifying with hexane/ethyl acetate (2/1) wash-out, obtain 3-hydroxyl-3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1, the orange microcrystalline solids of 3-dihydro-2H-indol-2-one (6.61 grams, 20%): ¹H NMR (300MHz, CDCl ₃) δ 7.81 (s, 1H), 7.38-7.30 (m, 1H), 7.23 (s, 1H), and 7.12-7.00 (m, 3H), 6.79-6.75 (m, 1H), 6.51-6.47 (m, 1H), 5.06 (d, J=16.1Hz, 1H), 4.82 (d, J=16.1Hz, 1H), 4.66 (d, J=6.7Hz, 1H), 4.29 (d, J=6.7Hz, 1H), 3.90 (s, 3H), 3.52 (br s, 1H), 2.92 (s, 3H); MS (ES+) m/z465.2 (M+1).

B.3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

In 3-hydroxyl-3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1,3-dihydro-2H-indol-2-one (6.61 grams, 14.2 drip (6.0 milliliters of triethylamines in anhydrous methylene chloride mmole) (100 milliliters) ice-cold (0 ℃) solution, 43 mmoles), add thionyl chloride (2.1 milliliters, 29 mmoles) then.Make reaction mixture stir 1h and vacuum concentration down at 0 ℃.Residue is distributed in water (100 milliliters) and ethyl acetate (250 milliliters).Organic phase is used anhydrous sodium sulfate drying with salt solution (100 milliliters) washing, filters and vacuum concentration.Residue is dissolved in the anhydrous tetrahydro furan (210 milliliters).Add Glacial acetic acid (30 milliliters), then add zinc (10 μ m powder, 9.25 grams, 142 mmoles).Make reaction mixture refluxed heating 44h and make it to be cooled to surrounding temperature.Mixture is filtered by Celite pad and wash this pad with ethyl acetate (250 milliliters).Vacuum concentrated filtrate is to doing, and make residue pass through the column chromatography purifying, with hexane/ethyl acetate (5/2), then with hexane/ethyl acetate (2/1) and hexane/ethyl acetate (3/2) wash-out, obtain 3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1, the amber foam of 3-dihydro-2H-indol-2-one (2.97 grams, 47%): ¹H NMR (300MHz, CDCl ₃) δ 7.95 (s, 1H), 7.37-7.28 (m, 1H), 7.08-6.92 (m, 4H), 6.78-6.72 (m, 1H), 6.56 (s, 1H), 6.46-6.41 (m, 1H), 5.09-4.62 (m, 4H), 3.87 (s, 3H), 3.15 (s, 3H); MS (ES+) m/z 449.4 (M+1).

C.3-(5-hydroxyl-2-methoxypyridine-4-yl)-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1,3-dihydro-2H-indol-2-one synthetic

In 3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1, add trifluoroacetic acid (10 milliliters) in methylene dichloride (40 milliliters) ice-cold (0 ℃) solution of 3-dihydro-2H-indol-2-one (2.85 grams, 6.35 mmoles).Make reaction mixture be warming up to surrounding temperature and stirring 7h.Vacuum concentration reaction mixture and the residue thing is distributed in methylene dichloride (100 milliliters) and saturated sodium bicarbonate aqueous solution (100 milliliters).Anhydrous sodium sulfate drying is used in organic phase water (50 milliliters) and salt solution (50 milliliters) washing, filters and vacuum concentration.Make residue through column chromatography, gradient elution with the hexane that contains 15 to 70% ethyl acetate carries out purifying, obtain 3-(5-hydroxyl-2-methoxypyridine-4-yl)-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1, the yellow foam of 3-dihydro-2H-indol-2-one (1.80 grams, 70%): MS (ES+) m/z405.3 (M+1).

D.3-(5-hydroxyl-2-methoxypyridine-4-yl)-3-(hydroxymethyl)-1-((5-(trifluoromethyl) furans-2-yl) methyl)-1,3-dihydro-2H-indol-2-one synthetic

In anhydrous tetrahydro furan (5 milliliters) ice-cold (0 ℃) solution of diisopropylamine (0.21 milliliter, 1.5 mmoles), drip the hexane solution (1.2M, 1.2 milliliters, 1.4 mmoles) of n-Butyl Lithium.Reaction mixture was stirred 30 minutes down at 0 ℃, then be cooled to-78 ℃.Add 3-(5-hydroxyl-2-methoxypyridine-4-yl)-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1, anhydrous tetrahydro furan (5 milliliters) solution of 3-dihydro-2H-indol-2-one (0.27 gram, 0.67 mmole) and reaction mixture was stirred 15 minutes.Once add p-polyoxymethylene (0.20 gram, 6.7 mmoles) and make reaction mixture be warming up to surrounding temperature.1.5h after, with saturated aqueous ammonium chloride (15 milliliters) and ethyl acetate (30 milliliters) diluted reaction mixture.Water extracts with ethyl acetate (3 * 20 milliliters).The organic phase that merges is used anhydrous sodium sulfate drying with salt solution (20 milliliters) washing, filters and vacuum concentration.Make residue through column chromatography, with the hexane wash-out purifying that contains ethyl acetate of 20 to 80% gradients, obtain the yellow foam (0.23 gram) of 3-(5-hydroxyl-2-methoxypyridine-4-yl)-3-(hydroxymethyl)-1-((5-(trifluoromethyl) furans-2-yl) methyl) indole-2-ketone: MS (ES+) m/z 417 (M-17).

Synthetic preparation embodiment 15

1-(diphenyl methyl)-3-(5-hydroxyl-2-methoxypyridine-4-yl)-1,3-dihydro-2H-indol-2-one synthetic

A.1-(diphenyl methyl)-3-hydroxyl-3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1,3-dihydro-2H-indol-2-one synthetic

-78 ℃ down and in 15 minutes to 2-methoxyl group-5-(methoxymethoxy) pyridine (Van dePoel et al., Heterocycles 2002; 57:55-71) the pentane solution (1.2M, 30.0 milliliters, 35.4 mmoles) of interpolation tert-butyl lithium in anhydrous tetrahydro furan (200 milliliters) solution of (6.00 grams, 35.4 mmoles).After stirring 0.5h under-78 ℃, once add 1-(diphenyl methyl)-1H-indoles-2,3-diketone (Schoenberg, A.et al., Chem.Ber.1963; 96:3328-3337) (13.3 grams, 42.5 millis are ear not).Make reaction mixture be warming up to surrounding temperature and stirring 16h.Adding saturated aqueous ammonium chloride (50 milliliters) and reaction mixture stirred 10 minutes.Reaction mixture dilutes and makes with ethyl acetate (200 milliliters) and water (200 milliliters) and is separated.Anhydrous sodium sulfate drying is used in organic phase water (50 milliliters) and salt solution (50 milliliters) washing, filters and vacuum concentration.Make raw product through column chromatography, with hexane/ethyl acetate (5/2) wash-out purifying, obtain 1-(diphenyl methyl)-3-hydroxyl-3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1, the shallow orange microcrystalline solids of 3-dihydro-2H-indol-2-one (10.9 grams, 64%): ¹H NMR (300MHz, CDCl ₃) δ 7.86 (s, 1H), 7.52-7.23 (m, 11H), 7.11-6.90 (m, 4H), 6.54 (d, J=7.8Hz, 1H), 4.53 (d, J=6.9Hz, 1H), 4.22 (d, J=6.9Hz, 1H), 3.90 (s, 3H), 3.79 (brs, 1H), 2.88 (s, 3H); MS (ES+) m/z 483.1 (M+1).

B.1-(diphenyl methyl)-3-hydroxyl-3-(5-hydroxyl-2-methoxypyridine-4-yl)-1,3-dihydro-2H-indol-2-one synthetic

In 1-(diphenyl methyl)-3-hydroxyl-3-[2-methoxyl group-5-(methoxymethoxy) pyridin-4-yl]-1, add trifluoroacetic acid (40 milliliters) in methylene dichloride (40 milliliters) solution of 3-dihydro-2H-indol-2-one (10.57 gram, 21.9 mmoles) and reaction mixture stirs 16h at ambient temperature.The vacuum concentration reaction mixture obtains 1-(diphenyl methyl)-3-hydroxyl-3-(5-hydroxyl-2-methoxypyridine-4-yl)-1, the colourless foam of 3-dihydro-2H-indol-2-one (9.32 grams, 97%): ¹H NMR (300MHz, DMSO-d ₆) δ 9.40 (br s, 1H), 7.50 (s, 1H), 7.42-7.23 (m, 11H), 7.19 (s, 1H), 6.99-6.76 (m, 4H), 6.32 (d, J=7.8Hz, 1H), 3.77 (s, 3H); MS (ES+) m/z 439.1 (M+1).

C.1-(diphenyl methyl)-3-(5-hydroxyl-2-methoxypyridine-4-yl)-1,3-dihydro-2H-indol-2-one synthetic

In 1-(diphenyl methyl)-3-hydroxyl-3-(5-hydroxyl-2-methoxypyridine-4-yl)-1,3-dihydro-2H-indol-2-one (10.1 grams, 23.1 mmole) 1, add (9.6 milliliters of triethylamines in 2-ethylene dichloride ice-cold (0 ℃) suspension, 69 mmoles), then add thionyl chloride (3.7 milliliters, 46 mmoles).Make reaction mixture in 0.5h, be warming up to surrounding temperature, then under refluxing, heat 1.5h.Make reaction mixture be cooled to surrounding temperature and water (2 * 50 milliliters) and salt solution (50 milliliters) washing, use anhydrous sodium sulfate drying, filtration and vacuum concentration and high vacuum drying obtain colourless foam.In tetrahydrofuran (THF) (210 milliliters) solution of the foam of this generation (11 gram), add Glacial acetic acid (30 milliliters), then add zinc powder (15.1 grams, 231 mmoles).Make reaction mixture stir 16h at ambient temperature.Add extra zinc powder (7.55 grams, 115 mmoles) and make reaction mixture heat 24h down at 50 ℃.Make reaction mixture be cooled to surrounding temperature and filter through Celite pad.Wash this pad and vacuum concentration with ethyl acetate (200 milliliters).Make residue through the column chromatography purifying, with hexane/ethyl acetate (2/1), then with hexane/ethyl acetate (1/1) wash-out, obtain 1-(diphenyl methyl)-3-(5-hydroxyl-2-methoxypyridine-4-yl)-1, the colorless solid of 3-dihydro-2H-indol-2-one (3.33 grams, 34%): MS (ES+) m/z 423.3 (M+1).

Synthetic embodiment 1

1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Under 0 ℃ in 3-(hydroxymethyl)-3-(4-pyridone-3-yl)-1-amyl group-1,3-dihydro-2H-indol-2-one (0.03 gram, 0.09 add triphenylphosphine (0.047 gram in anhydrous tetrahydro furan mmole) (5.0 milliliters) solution, 0.18 mmole) and diethyl azodiformate (0.028 milliliter, 0.18 mmole).Make mixture stir 16h at ambient temperature and react with saturated ammonium chloride (20.0 milliliters) cancellation.Mixture extracts with ethyl acetate (3 * 30.0 milliliters).The organic layer that merges anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate.Make residue with the hexane wash-out that contains 30% ethyl acetate, implement column chromatography, acquisition 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.02 gram, 71%): ¹H NMR (300MHz, CDCl ₃) δ 8.36 (d, J=5.6Hz, 1H), 7.89 (s, 1H), 7.33 (ddd, J=7.3,7.3,1.8Hz, 1H), 7.13-7.00 (m, 2H), 6.97-6.87 (m, 2H), 5.00 (d, J=9.1Hz, 1H), 4.74 (d, J=9.1Hz, 1H), 3.89-3.62 (m, 2H), 1.79-1.66 (m, 2H), 1.41-1.30 (m, 4H), 0.89 (t, J=7.0Hz, 3H); ¹³C NMR (75MHz, CDCl ₃) δ 176.3,167.2,151.0,145.0,142.57,131.6,129.4,123.9,123.4,109.0,106.6,80.9,56.0,40.5,29.0,27.1,22.3,14.0; MS (ES+) m/z 309.5 (M+1).

Synthetic embodiment 2

1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone 5-oxide compound

Under 0 ℃ in 1 '-amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (between adding in anhydrous methylene chloride (2.0 milliliters) solution of 1 ' H)-ketone (0.045 gram, 0.15 mmole)-chloroperoxybenzoic acid (0.049 gram, 0.22 mmole).Make mixture stir 16h at ambient temperature and neutralize with saturated sodium bicarbonate (10.0 milliliters).In mixture, add methylene dichloride (20.0 milliliters).Separate organic layer, use the salt water washing, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate.Make residue with the eluent ethyl acetate that contains 2% methyl alcohol, implement column chromatography, acquisition 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone 5-oxide compound (0.04 gram, 85%): ¹HNMR (300MHz, CDCl ₃) δ 8.10 (d, J=6.7Hz, 1H), 7.62 (s, 1H), 7.32 (ddd, J=7.6,7.6,1.8Hz, 1H), 7.18-7.05 (m, 2H), 6.97-6.86 (m, 2H), 5.10 (d, J=9.1Hz, 1H), 4.84 (d, J=9.1Hz, 1H), 3.86-3.59 (m, 2H), 1.79-1.66 (m, 2H), 1.41-1.30 (m, 4H), 0.89 (t, J=7.0Hz, 3H); MS (ES+) m/z 325.5 (M+1).

Synthetic embodiment 3

1 '-amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ', 4 (1 ' H, 5H)-diketone synthetic

Under 0 ℃ in 1 '-amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (add trifluoroacetic anhydride (0.19 milliliter, 1.40 mmoles) in anhydrous tetrahydro furan (5.0 milliliters) solution of 1 ' H)-ketone 5-oxide compound (0.045 gram, 0.14 mmole) and triethylamine.Make mixture stir 5h at ambient temperature, then add methyl alcohol (1.0 milliliters) and sodium hydroxide (2N, 1.0 milliliters).Make mixture stir 16h at ambient temperature and react with 25% ammonium acetate (10.0 milliliters) cancellation.With ethyl acetate (3 * 30.0 milliliters) extraction mixture.The organic layer that merges also filters with anhydrous sodium sulfate drying.Vacuum concentrated filtrate.Make residue with the hexane wash-out that contains 50% ethyl acetate, implement column chromatography, acquisition 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ', 4 (1 ' H, 5H)-diketone (0.015 gram, 33%): ¹H NMR (300MHz, CDCl ₃) δ 11.64 (br, 1H), 7.30-7.22 (m, 1H), 7.09 (d, J=7.3Hz, 1H), 7.03-6.94 (m, 2H), 6.85 (d, J=7.6Hz, 1H), 6.03 (d, J=7.3Hz, 1H), 4.91 (d, J=9.4Hz, 1H), 4.67 (d, J=9.4Hz, 1H), and 3.82-3.61 (m, 2H), 1.77-1.62 (m, 2H), 1.42-1.28 (m, 4H), 0.87 (t, J=7.0Hz, 3H); ¹³C NMR (75MHz, CDCl ₃) δ 176.1,170.5,161.2,142.9,137.5,131.0,128.9,123.3,122.9,111.7,108.5,95.2,81.9,55.9,40.5,28.9,26.9,22.4,14.0; MS (ES+) m/z 325.4 (M+1).

Synthetic embodiment 4

4 '-bromo-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Under 0 ℃ in 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl-1,3-dihydro-2H-indol-2-one (0.72 gram, 1.37 add (0.51 milliliter of tributylphosphine in ethyl acetate mmole) (25 milliliters) solution, 2.06 mmole), then in 5 minutes, slowly add ethyl acetate (25 milliliters) solution of tert-butyl azodicarboxylate (0.47 gram, 2.05 mmoles).Make the gained mixture stir 10 minutes down and react with saturated aqueous ammonium chloride (40 milliliters) cancellation at 0 ℃.Separate organic layer, with hydrochloric acid (1.0N, 3 * 50 milliliters) washing, with dried over sodium sulfate and filtration.Vacuum concentrated filtrate.Make brown residual oily matter hexane (20-50%) wash-out that contains ethyl acetate, by the silica gel column chromatography purifying, acquisition 4 '-bromo-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (0.59 gram, 87%): ¹H NMR (300MHz, CDCl ₃) δ 7.20-7.13 (m, 3H), 6.94-6.86 (m, 1H), 6.69 (s, 1H), 6.58 (d, J=8.8Hz, 1H), 6.45 (s, 1H), 5.01 (ABq, J=9.5Hz, 2H), 4.98 (ABq, J=16.6Hz, 2H), 3.63 (s, 3H); MS (ES+) m/z 497.2 (M+1), 495.2 (M+1).

Synthetic embodiment 5

5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Make 4 '-bromo-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.25 gram, 0.51 tetrakis triphenylphosphine palladium (0) (0.12 gram mmole),, 0.10 mmole), formic acid is (0.20 milliliter, 5.22 mmole), triethylamine (0.75 milliliter, 5.38 mmoles) 1,4-diox (7.0 milliliters) mixture heating up is to the 16h that refluxes.After being cooled to surrounding temperature, with ethyl acetate (40 milliliters) diluted reaction mixture and make it to pass through bed of diatomaceous earth.With salt solution (3 * 50 milliliters) wash filtrate, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate.Make brown residual oily matter ethyl acetate: hexane (20-35%) wash-out, by the silica gel column chromatography purifying, acquisition 5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (0.21 gram, 98%): mp145-147 ℃; ¹H NMR (300MHz, CD ₃CN) δ 7.32 (dd,, J=7.7Hz, 1H), 7.30 (d, J=3.0Hz, 1H), 7.18 (d, J=7.6Hz, 1H), 7.12-7.03 (m, 2H), 6.91 (s, 1H), 6.61 (d, J=8.9Hz, 1H), 6.56 (d, J=8.9Hz, 1H), 4.99 (ABq, 2H), 4.85 (ABq, 2H), 3.56 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.0,159.9,153.8,153.7,149.7,146.0,142.5,139.8 (m), 131.2,129.4,124.3,123.7,122.2,114.5 (m), 110.8,109.8,109.7,79.1,58.5,53.6,37.0; MS (ES+) m/z 417.2 (M+1).

Synthetic embodiment 6

4 '-(3-furyl)-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

4 '-bromo-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.072 gram, 0.15 3-furans boric acid (0.027 gram mmole),, 0.24 mmole) and the mixture of tetrakis triphenylphosphine palladium (0) (0.026 gram, 0.022 mmole) with nitrogen flushing 5 minutes.Add diox (7.0 milliliters) and sodium carbonate solution (2M, 1.0 milliliters).Make reaction mixture reflux 16h.After being cooled to surrounding temperature, vacuum concentrated mixture.Residue extracts and makes the organic layer of merging to pass through Celite pad with ethyl acetate (4 * 15 milliliters).Vacuum concentrated filtrate is to doing.Make brown residue ethyl acetate: hexane (20-35%) wash-out, by the silica gel column chromatography purifying, acquisition 4 '-(3-furyl)-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (0.052 gram, 74%): ¹H NMR (300MHz, CD ₃CN) δ 7.40-7.32 (m, 2H), 7.12 (d, J=8.8Hz, 1H), 7.06 (d, J=7.8Hz, 1H), 6.99 (d, J=7.8Hz, 1H), 6.92 (d, J=2.9Hz, 1H), 6.85 (s, 1H), 6.62 (d, J=8.8Hz, 1H), 6.57 (d, J=3.2Hz, 1H), 5.94 (s, 1H), 5.00 (ABq, 2H), 4.67 (ABq, 2H), 3.60 (s, 3H); MS (ES+) m/z 483.2 (M+1).

Synthetic embodiment 7

1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ', 5 (1 ' H, 4H)-diketone synthetic

In 5-methoxyl group-1 '-((5-(trifluoromethyl) furans-2-yl) methyl)-2H-spiral shell [furo [3,2-b] pyridine-3,3 '-indoline]-2 '-ketone (0.02 gram, 0.48 add (0.2 milliliter of trimethylchlorosilane in acetonitrile mmole) (12 milliliters) solution, 1.59 mmole), water of catalytic amount (6) and sodium iodide (0.20 gram, 1.33 mmoles).Gained solution was stirred 2 days down at 65 ℃.Reaction is then added salt solution (25 milliliters) with the 5% saturated sodium sulfite aqueous solution (25 milliliters) cancellation reaction.The gained mixture extracts with ethyl acetate (3 * 50 milliliters).The organic layer that merges anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Make residue hexane (40%) wash-out that contains ethyl acetate, by the silica gel column chromatography purifying, acquisition 1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ', 5 (1 ' H, 4H)-colorless solid of diketone (0.12 gram, 60%): mp 175-177 ℃; ¹H NMR (300MHz, CDCl ₃) δ 7.38-7.26 (m, 2H), 7.14-6.96 (m, 3H), 6.70 (d, J=2.5Hz, 1H), 6.49 (d, J=9.4Hz, 1H), 6.44 (d, J=3.3Hz, 1H), 4.99 (ABq, 2H), 4.88 (ABq, 2H), 3.20-2.20 (br, 1H); MS (ES+) m/z 403.2 (M+1).

Synthetic embodiment 8

1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [1, the 3-dioxole also [4,5-b] furo [2,3-e] pyridine-5,3 '-indoles]-2 ' (1 ' H)-ketone synthetic

Make 3-(6-hydroxyl [1,3] dioxole also [4,5-b] pyridine-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one (0.35 gram, 0.78 triphenylphosphine (0.31 gram mmole),, 1.2 mmole), anhydrous tetrahydro furan (20.0 milliliters) mixture of diethyl azodiformate (0.19 milliliter, 1.2 mmoles) stirs at ambient temperature and spend the night, and the vacuum-evaporation organic solvent.Make the residue hexane wash-out that contains 20% ethyl acetate, implement column chromatography, acquisition 1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [1,3-dioxole also [4,5-b] furo [2,3-e] pyridine-5,3 '-indoles]-2 ' (1 ' H)-ketone (0.19 gram, 58%): mp 175-177 ℃; ¹H NMR (300MHz, CDCl ₃) δ 7.28 (ddd, J=7.6,7.6,1.2Hz, 1H), 7.16 (dd, J=7.6,1.2Hz, 1H), 7.06 (ddd, J=7.6,7.6,0.9Hz, 1H), 6.94 (d, J=8.1Hz, 1H), 6.73 (s, 1H), 6.72-6.68 (m, 1H), 6.42 (d, J=3.2Hz, 1H), 5.98 (s, 2H), 5.04 (d, J=9.3Hz, 1H), 5.04-4.88 (m, 2H), 4.76 (d, J=9.3Hz, 1H); ¹³C NMR (75MHz, CDCl ₃) δ 176.3,153.3,151.9,151.0,141.8,141.2,135.2,131.0,129.2,123.8,123.7,112.7 (m), 109.2,101.0,80.1,58.0,37.2; MS (ES+) m/z 431.3 (M+1).

Synthetic embodiment 9

5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone 4-oxide compound

Make 5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.07 gram, 0.17 mmole) ,-methylene dichloride (15 milliliters) mixture of chloroperoxybenzoic acid (0.18 gram, 1.04 mmoles) reaches at ambient temperature in the nitrogen and stirs a week.Reaction is reacted with saturated sodium bicarbonate aqueous solution (15 milliliters) cancellation.Separate organic layer and with methylene dichloride (2 * 20 milliliters) aqueous layer extracted.The organic layer that merges anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Make residue preparation of lamina chromatogram purification, and use ethyl acetate: hexane (20%) launches, acquisition 5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone 4-oxide compound (0.02 gram, 15%) solid: MS (ES+) m/z 433.2 (M+1), 455.2 (M+23).

Synthetic embodiment 10

5 '-fluoro-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Under 0 ℃ in 5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl-1,3-dihydro-2H-indol-2-one (2.89 grams, 6.40 add tributylphosphine (1.62 grams in anhydrous tetrahydro furan mmole) (100.0 milliliters) solution, 1.9 milliliter, 8.00 mmole), then add diethyl azodiformate (1.39 milliliters, 1.3 milliliters, 8.00 mmoles).Reaction mixture is reacted at 0 ℃ of following 1h of stirring and with saturated ammonium chloride solution (50 milliliters) cancellation.After vacuum is removed organic solvent, with ethyl acetate (3 * 50 milliliters) extraction water-based residue.The organic layer that merges dried over sodium sulfate and filtration.Vacuum concentrated filtrate is to doing.Make residue hexane (30%) wash-out that contains ethyl acetate, by the silica gel column chromatography purifying, acquisition 5 '-fluoro-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (0.15 gram, 5.4%): mp 158-160 ℃; ¹HNMR (300MHz, CDCl ₃) δ 7.20 (d, J=8.7Hz, 1H), 6.99 (ddd, J=9.0,9.0,2.7Hz, 1H), and 6.91-6.84 (m, 1H), 6.69 (d, J=2.4Hz, 1H), 6.57 (d, J=8.7Hz, 1H), 6.45 (d, J=3.0Hz, 1H), 5.15 (d, J=16.5Hz, 1H), 5.04 (d, J=9.3Hz, 1H), 4.81 (d, J=16.5Hz, 1H), 4.74 (d, J=9.3Hz, 1H), 3.64 (s, 3H); ¹³CNMR (75MHz, CDCl ₃) δ 175.8,160.3,158.1,151.8,149.3,144.7,137.6,132.7,121.5,115.6,115.3,112.6 (m), 112.2,111.8,111.0,109.6,108.9,78.8,59.1,53.7,37.3; MS (ES+) m/z 435.2 (M+1).

Synthetic embodiment 11

4 '-chloro-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt synthetic embodiment 10 described programs, and carry out nonessential variation, promptly use 4-chloro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one replaces 5-fluoro-3-(3-hydroxyl-6-methoxypyridine-2-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl] methyl }-1,3-dihydro-2H-indol-2-one, acquisition 4 '-chloro-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (78%): mp 106-108 ℃; ¹HNMR (300MHz, DMSO-d ₆) δ 7.38 (d, J=8.8Hz, 1H), 7.35 (dd, J=8.0,8.0Hz, 1H), 7.19 (dd, J=7.8,7.8Hz, 1H), 7.16 (dd, J=3.3,1.1Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 6.67-6.64 (m, 2H), 5.08 (ABq, J=16.6Hz, 2H), 4.89 (ABq, J=10.1Hz, 2H), 3.49 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 175.7,159.8,153.5,150.7,144.5,143.3,131.2,130.2,127.7,124.0,121.8,114.5,111.1,109.9,109.2,108.8,76.6,59.0,53.6,37.4; MS (ES+) m/z 453.18 (M+1), 451.20 (M+1).

Synthetic embodiment 12

4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Under 0 ℃ in 4-bromo-3-(3-hydroxyl-6-methoxypyridine-2-yl)-1, two (hydroxymethyl)-1 of 3-, 3-dihydro-2H-indol-2-one (3.48 grams, 8.83 add tributylphosphine in anhydrous tetrahydro furan mmole) (80.0 milliliters) solution, then add anhydrous tetrahydro furan (10.0 milliliters) solution of tert-butyl azodicarboxylate (2.54 grams, 11.0 mmoles).Make reaction soln stir 1h, then add ammonium hydroxide (5.0 milliliters) and continue to stir 0.5h.Vacuum concentrated mixture is to doing.Residue is dissolved in the ethyl acetate (100.0 milliliters) and with 10% aqueous hydrochloric acid (2 * 50.0 milliliters), saturated ammonium chloride (30.0 milliliters), salt solution (30.0 milliliters) washs, with anhydrous sodium sulfate drying and filtration.Vacuum concentrated filtrate is to doing.Make residue with ethyl acetate (100%) wash-out, by the column chromatography purifying, acquisition 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (light yellow solid of 1 ' H)-ketone (1.28 grams, 42%): mp 265-268 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 10.86 (s, 1H), 7.33 (d, J=8.8Hz, 1H), 7.18 (dd, J=7.6,7.6Hz, 1H), 7.10 (d, J=8.2Hz, 1H), 6.91 (d, J=7.5Hz, 1H), 6.64 (d, J=8.8Hz, 1H), 4.84 (ABq, J=9.9Hz, 2H), 3.54 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 177.4,159.7,151.1,144.9,143.9,131.2,130.1,126.0,121.4,119.1,110.4,109.8,76.7,60.3,53.9; MS (ES+) m/z 349.2 (M+1), 347.2 (M+1).

Synthetic embodiment 13

5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt synthetic embodiment 5 described programs, and carry out nonessential variation, promptly use 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone replacement 4 '-bromo-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone, obtain 5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (69%): mp 199-200 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 10.62 (s, 1H), 7.38 (d, J=8.8Hz, 1H), 7.21 (dd, J=7.7,7.7Hz, 1H), 7.08 (d, J=7.2Hz, 1H), 6.94 (d, J=7.5Hz, 1H), 6.89 (d, J=8.0Hz, 1H), 6.63 (d, J=8.8Hz, 1H), 4.77 (ABq, J=9.5Hz, 2H), 3.53 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 177.8,159.9,149.8,146.5,142.6,132.1,129.3,124.3,122.7,121.8,110.3,110.2,79.4,59.0,53.9; MS (ES+) m/z 269.3 (M+1), 241.3 (M-17).

Synthetic embodiment 14

4 '-bromo-1 '-[(2-sec.-propyl-1,3-thiazoles-5-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Make 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.16 gram, 0.46 4-chloromethyl-2-sec.-propyl thiazole (0.12 gram mmole),, 0.69 mmole) and acetone (2.0 milliliters) mixture of cesium carbonate (0.23 gram, 0.69 mmole) stir 16h at ambient temperature.Cross filter solid and with ethyl acetate (5.0 milliliters) wash residual thing.Vacuum concentrated filtrate is to doing.Make residue hexane (30%) wash-out that contains ethyl acetate, by the column chromatography purifying, acquisition 4 '-bromo-1 '-[(2-sec.-propyl-1,3-thiazole-5-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (0.02 gram, 7.6%): mp 158-160 ℃; ¹HNMR (300MHz, DMSO-d ₆) δ 7.37 (d, J=8.8Hz, 1H), 7.26-7.24 (m, 2H), 7.21 (d, J=3.9Hz, 1H), 7.10 (dd, J=7.2,1.5Hz, 1H), 6.67 (d, J=8.8Hz, 1H), 5.10-4.93 (m, 3H), 4.82 (d, J=10.1Hz, 1H), 3.55 (s, 3H); ¹³CNMR (75MHz, DMSO-d ₆) δ 178.4,175.8,159.8,151.1,150.3,145.2,143.5,131.4,129.3,126.9,121.7,119.0,114.3,111.0,109.4,76.5,59.9,53.9,41.0,32.9,23.2; MS (ES+) m/z 490.4 (M+1), 488.3 (M+1).

Synthetic embodiment 15

1 '-[(5-chloro-2-thienyl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt embodiment 14 described programs and carry out nonessential variation, promptly use 5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone replacement 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone, and replace 4-chloromethyl-2-sec.-propyl thiazole with 5-chloromethyl-2-chlorothiophene, acquisition 1 '-[(5-chloro-2-thienyl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (78%): mp 130-132 ℃; ¹HNMR (300MHz, DMSO-d ₆) δ 7.41 (d, J=8.8Hz, 1H), 7.28 (dd, J=7.7,7.7Hz, 1H), 7.18 (d, J=4.3Hz, 1H), 7.16 (d, J=4.5Hz, 1H), 7.07 (d, J=3.8Hz, 1H), 7.01 (d, J=7.6Hz, 1H), 6.94 (d, J=3.8Hz, 1H), 6.65 (d, J=8.8Hz, 1H), 5.07 (ABq, J=16.1Hz, 2H), 4.83 (ABq, J=9.7Hz, 2H), 3.52 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.0,159.9,149.7,146.1,142.3,138.4,131.3,129.4,128.1,127.1,126.8,124.257,123.7,122.1,110.8,109.9,79.0,58.5,53.7,38.9; MS (ES+) m/z 401.2 (M+1), 399.2 (M+1).

Synthetic embodiment 16

1 '-[(2-sec.-propyl-1,3-thiazoles-4-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt embodiment 14 described programs and carry out nonessential variation, promptly use 5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone replacement 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone, acquisition 1 '-[(2-sec.-propyl-1,3-thiazole-4-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (64%): mp 136-138 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 7.42 (d, J=8.8Hz, 1H), 7.29-7.23 (m, 2H), 7.19 (d, J=6.8Hz, 1H), 7.06-6.99 (m, 2H), 6.65 (d, J=8.8Hz, 1H), 5.01 (ABq, 2H), 4.86 (ABq, 2H), 3.54 (s, 3H), 3.27-3.18 (m, 1H), 1.28 (d, J=6.9Hz, 6H); ¹³C NMR (75MHz, DMSO-d ₆) δ 178.3,176.1,159.9,150.7,149.7,146.2,142.9,131.3,129.4,124.2,123.6,122.2,114.2,110.8,109.9,79.1,58.6,53.9,40.7,33.0,23.2; MS (ES+) m/z 408.31 (M+1).

Synthetic embodiment 17

5-methoxyl group-1 '-(pyridine-2-ylmethyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt embodiment 14 described programs and carry out nonessential variation, promptly use 5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone replacement 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone, and replace 4-chloromethyl-2-sec.-propyl thiazole with the 2-bromo methyl cycloheptapyridine, acquisition 5-methoxyl group-1 '-(pyridine-2-ylmethyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (75%): mp 168-171 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 8.57 (d, J=4.8Hz, 1H), 7.72 (dt, J=7.7,1.8Hz, 1H), 7.46 (d, J=8.8Hz, 1H), 7.37 (d, J=7.8Hz, 1H), and 7.33-7.23 (m, 3H), 7.05 (dt, J=7.5,0.8Hz, 1H), 6.94 (d, J=7.7Hz, 1H), 6.70 (d, J=8.8Hz, 1H), 5.19 (d, J=16.7Hz, 1H), 4.97-4.86 (m, 3H), 3.62 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 175.8,159.4,155.4,149.4,149.1,145.7,142.5,137.0,130.8,128.9,123.7,123.0,122.6,121.7,120.3,110.2,109.3,78.5,58.1,53.3,44.9; MS (ES+) m/z 360.4 (M+1).

Synthetic embodiment 18

N-(2-fluorophenyl)-2-(5-methoxyl group-2 '-the oxo spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (synthesizing of 2 ' H)-yl) ethanamides

Adopt embodiment 14 described programs and carry out nonessential variation, promptly use 5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone replacement 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone, and replace 4-chloromethyl-2-sec.-propyl thiazole with 2-chloro-N-(2-fluorophenyl) ethanamide, acquisition N-(2-fluorophenyl)-2-(5-methoxyl group-2 '-oxo spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (colorless solid of 2 ' H)-yl) ethanamides (56%): mp＞170 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 10.17 (s, 1H), 7.93-7.87 (m, 1H), 7.45 (d, J=8.8Hz, 1H), 7.37-7.04 (m, 7H), 6.70 (d, J=8.8Hz, 1H), 4.85 (d, J=20.6,9.5Hz, 2H), 4.72 (s, 2H), 3.58 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.1,165.4,159.4,153.4 (d, ¹J _C-F=245Hz), 149.4,145.4,143.1,130.3,128.9,125.8,125.6,125.5 (d, J _C-F=7Hz), 124.4 (d, J _C-F=3Hz), 123.7,123.0,121.5,115.5 (d, ²J _C-F=19.3Hz), 109.9,109.2,79.0,58.0,53.5,43.0; MS (ES+) m/z420.2 (M+1).

Synthetic embodiment 19

1 '-[(5-chloro-1-methyl isophthalic acid H-imidazoles-2-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt embodiment 14 described programs and carry out nonessential variation, promptly use 5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone replacement 4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone, and replace 4-chloromethyl-2-sec.-propyl thiazole with 5-chloro-(2-chloromethyl)-1-methyl isophthalic acid H-imidazoles, acquisition 1 '-[(5-chloro-1-methyl isophthalic acid H-imidazoles-2-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (76%): mp 169-171 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 7.46 (d, J=8.8Hz, 1H), 7.33-7.18 (m, 3H), 7.04 (ddd, J=7.3Hz, J=7.3Hz, J=1.1Hz, 1H), 6.99 (s, 1H), 6.69 (d, J=8.8Hz, 1H), 5.28 (d, J=15.8Hz, 1H), 4.91 (d, J=9.7Hz, 1H), 4.90 (d, J=15.8Hz, 1H), 4.80 (d, J=9.7Hz, 1H), 3.55 (s, 3H), 3.54 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 175.3,159.4,149.3,145.4,142.3,142.1,130.7,128.7,123.8,123.5,123.1,121.6,117.6,110.2,110.0,78.9,58.1,53.3,37.4,30.4; MS (ES+) m/z 397.2 (M+1), 399.2 (M+1).

Synthetic embodiment 20

4-[(4 '-bromo-5-methoxyl group-2 '-oxo spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (2 ' H)-yl) methyl] piperidines-1-t-butyl formate synthetic

Adopt embodiment 14 described programs and carry out nonessential variation; promptly use 4-({ [(4-aminomethyl phenyl) alkylsulfonyl] oxygen base } methyl) piperidines-1-t-butyl formate to replace 4-chloromethyl-2-sec.-propyl thiazole; acquisition 4-[(4 '-bromo-5-methoxyl group-2 '-oxo spiral shell [furo [3; 2-b] pyridine-3; 3 '-indoles]-1 ' (2 ' H)-yl) methyl] the tackiness solid of piperidines-1-t-butyl formate (1.80 gram, quantitatively output): R _f=0.5 (hexane that contains ethyl acetate, 50%).

Synthetic embodiment 21

5-methoxyl group-1 '-(piperidin-4-yl methyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Make 4-[(4 '-bromo-5-methoxyl group-2 '-oxo spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (2 ' H)-yl) methyl] piperidines-1-t-butyl formate (2.10 grams, 3.85 tetrakis triphenylphosphine palladium (0) (1.10 grams mmole),, 0.96 mmole), formic acid is (2.31 milliliters, 50.1 mmole) and no Shui diox (50.0 milliliters) mixture of triethylamine (5.07 milliliters, 50.1 mmoles) under refluxing, heat 16h.Reaction soln filters through Celite pad.Vacuum concentrated filtrate is to doing.Make residue be dissolved in the ethyl acetate (100.0 milliliters) and filtering precipitate.Vacuum concentrated filtrate is to doing.Residue is dissolved in the anhydrous methylene chloride (20.0 milliliters) again, then adds trifluoroacetic acid (10.0 milliliters).Make reaction mixture stirring 1.5h and vacuum concentration to doing.Make residue methyl alcohol (10%) and ammonium hydroxide (0.10%) wash-out that contains methylene dichloride, by the column chromatography purifying, acquisition 5-methoxyl group-1 '-(piperidin-4-yl methyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.40 gram, 28%) cotton-shaped solid: MS (ES+) m/z 388.1 (M+23), 366.1 (M+1).

Synthetic embodiment 22

5-methoxyl group-1 '-[(1-methyl piperidine-4-yl) methyl] spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

In sealed tube, make 5-methoxyl group-1 '-(piperidin-4-yl methyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.30 gram, 0.82 formaldehyde solution (0.50 gram mmole),, 16.4 mmole, 37wt% is in water) and water (2.0 milliliters) mixture of formic acid (1.52 gram, 32.8 mmoles) at 100 ℃ of heating 7h down.Make reaction mixture alkalization and with methylene dichloride (3 * 25 milliliters) extraction, with anhydrous sodium sulfate drying and filtration with ammonium hydroxide.Vacuum concentrated filtrate is to doing.Make residue methyl alcohol (5.0%) and ammonium hydroxide (0.10%) wash-out that contains methylene dichloride, by the column chromatography purifying, acquisition 5-methoxyl group-1 '-[(1-methyl piperidine-4-yl) methyl] spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (0.20 gram, 42%): mp 58-62 ℃; ¹H NMR (300MHz, DMSO-d ₆) δ 7.43 (d, J=8.8Hz, 1H), 7.33 (dd, J=7.7Hz, J=7.7Hz, 1H), 7.18 (d, J=7.8Hz, 2H), 7.03 (dd, J=7.5Hz, J=7.5Hz, 1H), 6.66 (d, J=8.8Hz, 1H), 4.83 (q, J=9.7Hz, 2H), 3.73 (dd, J=13.8Hz, J=8.0Hz, 1H), 3.56-3.50 (m, 1H), 3.52 (s, 3H), 2.73 (t, J=11.4Hz, 2H), 2.12 (s, 3H), 1.83-1.68 (m, 5H), 1.35-1.16 (m, 2H); ¹³C NMR (75MHz, DMSO-d ₆) δ 175.7,159.3,149.0,145.8,143.0,130.9,128.8,123.4,122.6,121.5,110.2,109.2,78.5,58.0,54.8,54.8,53.0,46.0,44.8,33.5,29.3,29.1; MS (ES+) m/z 380.1 (M+1).

Synthetic embodiment 23

5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

In 3-(5-hydroxyl-2-methoxypyridine-4-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl) furans-2-yl] methyl }-1,3-dihydro-2H-indol-2-one (0.23 gram, 0.53 add triphenylphosphine (0.16 gram in anhydrous tetrahydro furan mmole) (5 milliliters) ice-cold (78 ℃) solution, 0.63 mmole) and azoformic acid N, N-diethyl ester (0.12 milliliter, 0.74 mmole).Make reaction mixture be warming up to surrounding temperature.After stirring 3h, the vacuum concentration reaction mixture, and make residue through the column chromatography purifying, the hexane wash-out that contains ethyl acetate with 10 to 50% gradients, acquisition 5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (the colourless colloid of 1 ' H)-ketone (0.057 gram, 26%): ¹H NMR (300MHz, CDCl ₃) δ 7.86 (s, 1H), 7.38-7.32 (m, 1H), 7.18-6.99 (m, 3H), 6.78-6.74 (m, 1H), 6.43-6.38 (m, 1H), 6.13 (s, 1H), 5.11-4.86 (m, 3H), 4.70 (d, J=9.0Hz, 1H), 3.83 (s, 3H); ¹³C NMR (75MHz, CDCl ₃) δ 175.6,159.2,153.0,151.8,142.3,141.5,130.8,129.6,127.1,124.2,124.1,120.6,117.1,112.8,109.5,109.3,105.5,80.0,57.8,54.9,37.1; MS (ES+) m/z 417.2 (M+1).

Synthetic embodiment 24

1 '-(diphenyl methyl)-5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Make 1-(diphenyl methyl)-3-(5-hydroxyl-2-methoxypyridine-4-yl)-1 with dry argon gas, anhydrous tetrahydro furan (50 milliliters) the solution degasification 1h of 3-dihydro-2H-indol-2-one (3.33 grams, 7.88 mmoles).Once add cesium carbonate (9.00 grams, 27.6 mmoles), then add chloroiodomethane (1.7 milliliters, 24 mmoles).Make reaction mixture stir 16h at ambient temperature and filter through Celite pad.Wash this pad and vacuum concentrated filtrate with ethyl acetate (50 milliliters).Make residue through the column chromatography purifying, the hexane wash-out that contains ethyl acetate with 5 to 50% gradients, acquisition 1 '-(diphenyl methyl)-5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (1.37 grams, 40%): mp 177-178 ℃ (hexane/ether); ¹H NMR (300MHz, CDCl ₃) δ 7.86 (s, 1H), 7.43-7.27 (m, 10H), 7.15-6.96 (m, 4H), 6.52 (d, J=7.6Hz, 1H), 6.13 (s, 1H), 5.00 (d, J=9.0Hz, 1H), 4.75 (d, J=9.0Hz, 1H), 3.81 (s, 3H); ¹³C NMR (75MHz, CDCl ₃) δ 176.2,159.1,153.1,142.9,141.9,137.5,137.3,131.2,129.0,128.9,128.5,128.4,128.2 (2C), 127.1,123.9,123.5,112.6,105.6,80.3,59.0,57.7,54.0; MS (ES+) m/z435.0 (M+1).

Synthetic embodiment 25

5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

In 1 '-(diphenyl methyl)-5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.91 gram, 2.1 add triethyl-silicane (1.7 milliliters, 10 mmoles) in trifluoroacetic acid mmole) (20 milliliters) solution and make reaction mixture refluxed heating 24h.Make reaction mixture be cooled to surrounding temperature and vacuum concentration.Residue is distributed in ethyl acetate (25 milliliters) and sodium hydroxide (1M, 25 milliliters).Make and be separated and with ethyl acetate (3 * 25 milliliters) aqueous phase extracted.Anhydrous sodium sulfate drying is used in organic phase water (2 * 25 milliliters) that merges and salt solution (25 milliliters) washing, filters and vacuum concentration.Grind raw product with diethyl ether (20 milliliters).Vacuum filtration is collected solid and is washed with ice-cold diethyl ether (20 milliliters), carry out dry air and high vacuum drying, obtain 5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (pale solid of 1 ' H)-ketone (0.281 gram, 50%): mp 231-232 ℃ (ethyl acetate); ¹H NMR (300MHz, DMSO-d ₆) δ 10.76 (br s, 1H), 7.87 (s, 1H), 7.32-7.25 (m, 1H), 7.15 (d, J=7.3Hz, 1H), 7.02-6.91 (m, 2H), 6.24 (s, 1H), 4.85 (d, J=9.3Hz, 1H), 4.72 (d, J=9.3Hz, 1H), 3.71 (s, 3H); ¹³C NMR (75MHz, DMSO-d ₆) δ 176.9,158.3,152.9,143.3,132.0,131.1,129.2,126.2,123.9,122.5,110.0,105.0,79.6,57.6,53.5; MS (ES+) m/z 268.7 (M+1).

Synthetic embodiment 26

5-methoxyl group-1 '-(tetrahydrochysene-2H-pyrans-4-ylmethyl) spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Make 5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone (0.134 gram, 0.50 cesium carbonate (0.488 gram mmole),, 1.50 the heterogeneous mixture reflux 1.5h of 4-(brooethyl) tetrahydropyrans (0.447 gram, 2.50 mmoles) and 2-butanone (10 milliliters) mmole).Make reaction mixture be cooled to surrounding temperature and filtration.Vacuum concentrated filtrate.Make raw product through the column chromatography purifying, the hexane wash-out that contains ethyl acetate with 10 to 50% gradients, acquisition 5-methoxyl group-1 '-(tetrahydrochysene-2H-pyrans-4-ylmethyl) spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (0.162 gram, 89%): mp 84-85 ℃ (hexane/ethyl acetate); ¹H NMR (300MHz, CDCl ₃) δ 7.85 (s, 1H), 7.37-7.30 (m, 1H), 7.17-7.03 (m, 2H), 6.93 (d, J=7.9Hz, 1H), 6.12 (s, 1H), 4.93 (d, J=9.0Hz, 1H), 4.68 (d, J=9.0Hz, 1H), 4.04-3.95 (m, 2H), 3.82 (s, 3H), 3.79-3.69 (m, 1H), 3.62-3.52 (m, 1H), 3.42-3.31 (m, 2H), and 2.16-2.05 (m, 1H), 1.65-1.41 (m, 4H); ¹³C NMR (75MHz, CDCl ₃) δ 176.1,159.0,142.8,142.5,131.0,129.4,126.9,124.0,123.6,109.0,105.4,80.2,67.4,57.8,53.8,46.2,33.9,30.8,30.7; MS (ES+) m/z 367.1 (M+1).

Synthetic embodiment 27

5-methoxyl group-1 '-[(2S)-tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt synthetic embodiment 26 described programs and carry out nonessential variation, promptly use (2S)-tetrahydrofuran (THF)-2-ylmethyl 4-toluene sulfonic acide ester replacement 4-(brooethyl) tetrahydropyrans, acquisition 5-methoxyl group-1 '-[(2S)-and tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (27%): mp＞250 ℃ (methylene dichloride); ¹H NMR (300MHz, CDCl ₃) δ 7.85 (s, 1H), 7.32 (t, J=7.5Hz, 1H), 7.14-7.02 (m, 3H), 6.19 (d, J=3.9Hz, 1H), 4.94 (d, J=9.0Hz, 1H), 4.69 (d, J=9.0Hz, 1H), 4.27 (m, 1H), 3.99-3.84 (m, 2H), 3.82 (s, 3H), 3.79-3.68 (m, 2H), 2.11-2.00 (m, 1H), and 1.97-1.85 (m, 2H), 1.76-1.67 (m, 1H); ¹³C NMR (75MHz, CDCl ₃) δ 176.5,176.3,159.1,153.1,153.0,143.0,142.9,142.8,131.1,130.9,129.4,129.3,126.9,123.7,123.7,123.6,110.1,109.9,105.6,105.5,80.2,76.9,68.4,68.3,57.9,57.8,53.9,44.9,44.8,29.4,29.1,25.9,25.7; MS (ES+) m/z 353.1 (M+1).

Synthetic embodiment 28

5-methoxyl group-1 '-[(2R)-tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (synthesizing of 1 ' H)-ketone

Adopt synthetic embodiment 26 described programs and carry out nonessential variation, promptly use (2R)-tetrahydrofuran (THF)-2-ylmethyl 4-toluene sulfonic acide ester replacement 4-(brooethyl) tetrahydropyrans, acquisition 5-methoxyl group-1 '-[(2R)-and tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (colorless solid of 1 ' H)-ketone (50%): mp＞250 ℃ (hexane/ethyl acetate); ¹H NMR (300MHz, CDCl ₃) δ 7.84 (s, 1H), 7.35-7.29 (m, 1H), 7.14-7.00 (m, 4H), 6.19 (d, J=3.9Hz, 1H), 4.94 (d, J=3.9Hz, 1H), 4.69 (d, J=3.9Hz, 1H), 6.87 (s, 1H), 6.36 (s, 1H), 4.81 (d, J=9.0Hz, 1H), 4.70 (d, J=9.0Hz, 1H), 4.33-4.21 (m, 1H), 3.99-3.69 (m, 8H), and 2.11-1.85 (m, 4H), 1.76-1.67 (m, 1H); ¹³C NMR (75MHz, CDCl ₃) δ 159.0,153.0,142.9,131.0,129.3,129.2,126.8,123.6,123.5,123.4,110.0,109.8,105.5,105.4,80.1,68.3,68.2,57.8,57.7,53.8,44.8,44.7,29.3,29.0,25.7,25.6; MS (ES+) m/z353.1 (M+1).

Biology is measured

Active various technology in order to the test The compounds of this invention are known in this field.For invention as herein described can be understood more fully, therefore propose following biology and measure.Should be appreciated that these embodiment only are used for the exemplary illustration purpose and should be interpreted as limiting by any way the present invention.

Biological Examples 1

Guanidine flows into measures (external test)

This embodiment has described and has been used for testing and analyze test reagent and resists at the people of the cell stably express of interior endogenous source or recombinant sources or the external test of rat sodium channel.This measuring method also can be used for measuring the IC-50 of sodium channel blocking compound.This mensuration is with Reddy, people such as N.L., and pharmaceutical chemistry periodical (J.Med.Chem.) (1998), 41 (17): the described guanidine flow analysis of 3298-302 is the basis.

This guanidine flows into and is determined as the active radioactive tracer flow analysis of ion-flow rate that is used for measuring based on the mode of microplate with high-throughput the sodium channel.This analyzes use and various known sodium channel adjusting control agents and usefulness ¹⁴The C-Guanidinium hydrochloride is with the effectiveness of determination test reagent.Effectiveness is calculated by IC-50 and is measured.By comparative compound the effectiveness of the passage paid close attention to and the effectiveness of its anti-other sodium channel are measured selectivity (being also referred to as " selectivity analysis ").

Analyze the anti-cell of expressing the sodium channel of being paid close attention to of each test reagent.Voltage-gated sodium channel is that TTX is responsive or insensitive.When the passage of being paid close attention to be present in other sodium channel mix among the group time, this character is particularly useful when sodium channel that assessment is paid close attention to active.Following table 1 has been summed up in the TTX existence or some clone that is used to screen specific sodium channel activity not.

Table 1

Clone	MRNA expresses	Functional character
Clone	MRNA expresses	Functional character	CHO-K1 (Chinese hamster ovary; The host cell system of recommending) ATTC preserving number CCL-61	??·Na _V1.4 having been shown by RT-PCR, performance do not detect other Na _VExpress	Use TTX, blocking-up fully [ ¹⁴C] 18-20 that flows into of guanidine doubly increases (Na _v1.4 be the passage of TTX sensitivity)

L6 (rat myoblasts) ATTC preserving number CRL-1458	Na _V1.4 and 1.5 expression	Only part blocking-up of TTX [ ¹⁴C] 10-15 that flows into of guanidine doubly increases (Na _v1.5 be that TTX is drug-fast)
L6 (rat myoblasts) ATTC preserving number CRL-1458	Na _V1.4 and 1.5 expression		SH-SY5Y (human neuroblastoma) ATTC preserving number CRL-2266	Na _V1.9 and Na _V1.7 announcement express people such as () Blum	Only part blocking-up of TTX [ ¹⁴C] 10-16 that is higher than background that flows into of guanidine doubly increases (Na _v1.9 be that TTX is drug-fast)
SK-N-BE2C (human neuroblastoma clone ATCC preserving number CRL-2268)	Na _V1.8 expression	With pyrethroid stimulate the BE2C cell cause [ ¹⁴C] 6 times of increases that are higher than background of flowing into of guanidine.TTX partly blocks inflow (NaV1.8 is that TTX is drug-fast)
	Na _V1.8 expression		PC12 (rat pheochromocytoma) ATTC preserving number CRL-1721	Na _V1.2 expression	Use TTX block fully [ ¹⁴C] 8-12 that flows into of guanidine doubly increases (Na _v1.2 be the passage of TTX sensitivity)

Also may use the reconstitution cell of expressing these sodium channels.The clone of reconstitution cell and propagation (are for example seen Klugbauer, people such as N, EMBO J. (1995), 14 (6): 1084-90 for those skilled in the art are known; And Lossin, people such as C., Neuron (2002), 34, pp.877-884).

According to the supplier, the clone of the passage that culture expression is paid close attention to, or under the situation of reconstitution cell, then at the selective growth substratum, cultivate down as the existence of G418 (Gibco/Invitrogen).With enzyme solution (1X) trypsinase/EDTA (Gibco/Invitrogen) this cell is dissociated from culture dish, and use hemocytometer (Neubauer) analytic density and viability.Resuspending then is laid on Scintiplates (Beckman CoulterInc.) and goes up (about 100,000 cells/well) in its substratum dissociated cell through washing also, and at 37 ℃/5%CO ₂Under hatched 20-24 hour.After the strong washing of low sodium HEPES-buffered saline solution (LNHBSS) (150mM choline chloride 60,20nMHEPES (Sigma), 1mM calcium chloride, 5mM Repone K, 1mM magnesium chloride, 10mM glucose), in each hole, add reagent (can use the test reagent of different concns) with the LNHBSS dilution.Activation/radiolabeled mixture contains napelline (Sigma) and reaches ¹⁴C-Guanidinium hydrochloride (ARC).

After being added on test reagent and activation/radiolabeled mixture in the cell, Scintiplates is hatched at ambient temperature.After hatching, thoroughly wash Scintiplates with the LNHBSS that is supplemented with guanidine (Sigma).Dry Scintiplates uses Wallac MicroBetaTriLux (Perkin-Elmer Life Sciences) counting then.By what exist in the cell of relatively expressing different sodium channels ¹⁴The amount of C-guanidine is come the ability of determination test reagent blocking-up sodium channel activity.According to these data, can use as the various calculating of listing in addition in this specification sheets and come confirmed test reagent whether specific sodium channel is had a selectivity.

Can use the IC-50 value of above-mentioned general method determination test reagent to specific sodium channel.Can make and measure IC-50 with the following method: use repetition twice or 3,8,10,12 or 16 point curves of triplicate, initial concentration is 1,5 or 10 μ M, and serial dilution is to reach the ultimate density of inferior nmole, nmole and low micro-molar range.Usually the mid point concentration of test reagent is set at 1 μ M, and uses continuous concentration (for example 0.5 μ M, 5 μ M and the 0.25 μ M of half greater or lesser dilution; 10 μ M and 0.125 μ M; 20 μ M etc.).(fit=(A+ ((B-A)/(1+ ((C/x) ^D)))) calculates the IC-50 curve to use 4 parameter L ogistic models or S type (Sigmoidal) dose-response model equation.

By IC with the test sodium channel ₅₀Value is divided by the sodium channel of reference Na for example _v1.5 calculate multiple selectivity, optionally factor or multiple optionally.

Representative compounds of the present invention when using the known clone of expressing the sodium channel to test in said determination, confirms as IC listed in the following table 2 ₅₀(nM) activity level, wherein " A " is meant the IC of 1nM to 10nM ₅₀Activity level, " B " is meant the IC of 10nM to 100nM ₅₀Activity level, " C " is meant the IC of 100nM to 1000nM ₅₀Activity level, and " D " is meant the IC that is equal to or greater than 1000nM ₅₀Activity level.The synthetic embodiment that provides in the table 2 numbers the synthetic embodiment corresponding to this paper:

Table 2

Synthetic embodiment	The compound title	??IC ₅₀Activity level
Synthetic embodiment	The compound title	??IC ₅₀Activity level	??1	1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C
??2	1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone 5-oxide compound	??D	??1		??C
??2		??D	??3	1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-Yin	??D

	Diindyl]-2 ', 4 (1 ' H, 5H)-diketone
	Diindyl]-2 ', 4 (1 ' H, 5H)-diketone		??4	4 '-bromo-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??B
??5	5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C	??4		??B
??5		??C	??7	1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ', 5 (1 ' H, 4H)-diketone	??C
??8	1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [1, the 3-dioxole also [4,5-b] furo [2,3-e] pyridine-5,3 '-indoles]-2 ' (1 ' H)-ketone	??A	??7		??C
??8		??A	??10	5 '-fluoro-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??D
??11	4 '-chloro-5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C	??10		??D
??11		??C	??12	4 '-bromo-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C
??13	5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??D	??12		??C
??13		??D	??14	4 '-bromo-1 '-[(2-sec.-propyl-1,3-thiazoles-5-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??B
??15	1 '-[(5-chloro-2-thienyl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??B	??14		??B
??15		??B	??16	1 '-[(2-sec.-propyl-1,3-thiazoles-4-yl) methyl]-5-first	??B

	Oxygen base spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone
			??17	5-methoxyl group-1 '-(pyridine-2-ylmethyl) spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C
??18	N-(2-fluorophenyl)-2-(5-methoxyl group-2 '-oxo spiral shell furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (2 ' H)-yl) ethanamides	??C	??17		??C
??18		??C	??19	1 '-[(5-chloro-1-methyl isophthalic acid H-imidazoles-2-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C
??22	5-methoxyl group-1 '-[(1-methyl piperidine-4-yl) methyl] spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??D	??19		??C
??22		??D	??23	5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??A
??24	1 '-(diphenyl methyl)-5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??D	??23		??A
??24		??D	??25	5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C
??26	5-methoxyl group-1 '-(tetrahydrochysene-2H-pyrans-4-ylmethyl) spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??C	??25		??C
??26		??C	??27	5-methoxyl group-1 '-[(2S)-tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??B
??28	5-methoxyl group-1 '-[(2R)-tetrahydrofuran (THF)-2-ylmethyl] spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone	??B	??27		??B

Biological Examples 2

Electrophysiology is measured (external test)

Reach 5%CO down at 37 ℃ ₂In, contain 0.5mg/mL G418 ,+/-the DMEM growth medium (Gibco) of 1%PSG and 10% heat-inactivated fetal bovine serum in the clone of culture expression purpose passage.For the electrophysiology record, cell is placed on the 10mm ware.

Full cell record is that ((Bean et al. op.cit.) detects the establishment method of full cell voltage pincers CA) for Axon Instruments, Union City by using Axopatch 200B amplifier and Clampex software.All experiments are all carried out at ambient temperature.Electrode is a 2-4 Mohm (unit of measure) voltage error through flame polish to resistance, and comes the minimum capacitance illusion by continuous resnstance transformer and capacitance compensation respectively.Under 40kHz, obtain data and under 5kHz, filter.Outside (bath) solution is made up of following: NaCl (140mM), KCl (5mM), CaCl ₂(2mM), MgCl ₂(1mM), the HEPES of pH 7.4 (10mM).Inner (transfer pipet) solution is by following the composition (mM): NaCl (5), CaCl ₂(0.1), MgCl ₂(2), CsCl (10), CsF (120), HEPES (10), EGTA (10), pH 7.2.

In order to assess compound the tranquillization and the inactivated state of passage (is respectively K _rAnd K _i) the stable state affinity, use 12.5ms test pulse from-110mV CONTROLLED POTENTIAL to make voltage from-60mV depolarize to+90mV, to set up current-voltage relation (I-V curve).Use runs through the test pulse of the rest part of this experiment near voltage (30 to the 0mV) conduct at IV-curve peak.Set up stable state inactivation (operability) curve by the activation electric current of measuring during scope is for-110 8.75ms test pulses to the 1s regulating impulse of-10mV current potential then.Be the passage under the monitoring stable state, foundation has-single " diary " experimental program of 110mV CONTROLLED POTENTIAL, with record quiescent condition electric current (10ms test pulse), electric current behind the rapid deactivation (80 to-50mV 5ms prepulsing, and the electric current during various CONTROLLED POTENTIAL (35ms is gradually to the test pulse level) 10ms test pulse then).During " diary " experimental program, use compound, and monitoring blocking-up under the 15s interval.

After compound reaches balance, be determined at compound and have the voltage-dependent of stable state inactivation down.The electric current that causes by all CONTROLLED POTENTIAL during the compound reduction test pulse of blocking-up passage quiescent condition, and mainly block the electric current that under more unpolarized current potential, causes during the compound reduction test pulse of inactivated state.Electric current (I under the quiescent condition _{Tranquillization}) with inactivated state during electric current (I _Inactivation) be used to the stable state avidity of computerized compound.Suppress model, K based on Michaelis-Menton _rWith K _iBe calculated as respectively and caused I _{Tranquillization}Or I _Inactivation50% suppress needed compound concentration.

V _MaxFor suppressing speed, h is Hill coefficient (for an interaction sites), K _mBe the Michaelis-Menten constant, and [medicine] is the concentration of test compounds.At I _{Tranquillization}Or I _Inactivation50% suppress (1/2V _Max) under, drug level equals K in number _m, and approximate respectively K _rWith K _i

Biological Examples 3

The analgesia that sodium channel blockers brings out

The TFL that heat is brought out (Tail Flick Latency) test

In this test, observe the analgesia effect that produces by the The compounds of this invention administration by the whipping that heat in the mouse is brought out.This test comprises the thermal source of being made up of the projecting lamp with focused beam and tried mouse tail with the single-point irradiation.In the time of 40,80,120 and 160 minutes, measure and be recorded in pharmacological agent before the TFL evaluated and the TFL of the harmful thermal stimulus of response, promptly apply radiant heat to the latent period that whipping takes place from dorsal surface to tail.

For example, can design following research, wherein to the first part of this research, to the animal of some amount to continue to carry out in two days the assessment of baseline TFL once a day.Then these animals are randomized to either in the treatment group in a plurality of different treatment groups (depending on that what compounds are tested), comprise that medium contrast, morphine contrast and with the compound of 30mg/Kg intramuscular administration.After the dosed administration, the toxicity sign of close supervision animal comprises and trembles or outbreak, hyperaction, shallow breathing, breathe or the breathing that suppresses and can not cleaning fast.Determine the best incubation time of each compound by regression analysis.Represent the active and use following formula calculating of analgesia of test compounds with the per-cent (%MPE) of maximum possible effect:

Wherein:

After the medication latent period=each single animal removes (whipping) preceding latent period with tail from thermal source after accepting medicine.

Before the medication latent period=each single animal throws away tail the latent period before the thermal source before accepting medicine.

The maximum time of thermal source dead line (10s)=be exposed to.

Acute pain (gate-Papacostas' tests)

Use the animal model of gate-Papacostas' tests as acute pain.In gate-Papacostas' tests, in the resin glass test cabinet, be accustomed to 20 minutes simply the last angel animal of test.Test same day is with animal test injection product at random.Behind the drug administration 30 minutes, with the 10% formalin subcutaneous injection of 50 μ L sole of the foot face to the left back pawl of rat.Begin the capture video data after the formalin administration immediately, continue 90 minutes.

Use Actimetrix Limelight software collection image, and file is kept under the * .IIii extension name, then make it to change into the MPEG-4 coding.Usage behavior analysis software " TheObserver 5.1 " then, (Version 5.0, Noldus Information Technology, Wageningen, The Netherlands) analyze video.By observe animal behavior and according to type to each behavior scoring, and the time length of define behavior is carried out video analysis (Dubuisson and Dennis, 1977).The behavior of scoring comprises: (1) normal behaviour; (2) do not apply weight on pawl; (3) pawl is lifted; (4) lick/sting or scratch pawl.Lift, like or exceedingly lick, sting the pawl demonstration pain reaction that food and scratching were injected.If two pawls all are placed on and significantly do not like, excessively lick, sting that the pawl of eating or scratch this injection promptly means analgesia or from the provide protection of compound on the floor.

The analysis of gate-Papacostas' tests data is carried out according to two factors: (1) maximum potential restraining effect per-cent (%MPIE) and (2) pain score.Calculate %MPIE by series of steps, wherein first step is the time that adds with the irregularities (behavior 1,2,3) of each animal.By all scorings in the media processes group being averaged the single value that obtains media pack.Following column count can obtain the MPIE value of each animal:

MPIE (%)=100-[(treats summation/average medium value) * 100%]

Calculate pain score by above-mentioned weighted rating.The behavior time length be multiply by weighted value (grade of reaction seriousness), and divided by the total time of observing, to measure the pain grade of each animal.This is calculated as follows formula and represents:

Pain grade=[0 (To)+1 (T1)+2 (T2)+3 (T3)]/(To+T1+T2+T3)

The chronic inflammatory pain that CFA brings out

Use von Frey filament method assessment to touch different pain (tactileallodynia) in this test through calibration.After the environmental adaptation of process to the complete cycle of animal raising equipment, with 150 μ L " Freund's complete adjuvant " (CFA) emulsion (be suspended in the CFA in oil/salt solution (1: 1) emulsion, concentration is 0.5mg/mL) be subcutaneously injected into sole of the foot face through the left back pawl of rat of slight isoflurane anesthesia.Animal is recovered from anesthesia, and the baseline heat injury of all animals of week assessment is experienced threshold values and the baseline mechanical wounding is experienced threshold values after the CFA administration.Be accustomed to experimental installations 20 minutes all animals of the last angel of experiment beginning.Give test article and reference substance to animal, and after administration, measure the nociception threshold values, to measure analgesia reaction each treatment in six kinds of adoptable treatments at the time point place that limits.Determine used time point in advance, to show the highest analgesia effect of each test compounds.

Use the heat injury of Hargreaves test assessment animal to experience threshold values.Animal is placed the resin glass box on the glass platform of rising with heating unit.This glass platform to all the test all by thermostatic control in about 30 ℃ temperature.Animal is placed in this box, make it adapt to 20 minutes till all exploratory behaviors stop.(IITC, Woodland Hills CA) will put on the sole of the foot face of rear solid end from the radiant heat bundle of glass platform below to use 226 types vola/afterbody stimulator analgesia meter (Model 226Plantar/Tail Stimulator Analgesia Meter).All duration of test, the invalid intensity and the activity intensity of thermal source are set at 1 and 45 respectively, and use dead line of 20 seconds to avoid tissue damaged.

Use 2290 type Electrovonfrey anesthesimeters (IITC Life Science, Woodland Hills CA) measure the reaction threshold values of animal to haptic stimulus in Hargreaves test back.Animal is placed the resin glass box that is absorbed in the lip-deep rising of net (mire mesh).Adapt to after 10 minutes, begin precalibrated Von Frey hair vertically to be put on the sole of the foot face of two pawls of animal by the order that increases with the 0.1g hair, and the hair slight bending of using enough power to make to withstand pawl.Continue test up to determine to have the hair that brings out the minimum force that pawl gets out of the way fast or reach about 20 grams till power.Using this to end power is because it represents about 10% the weight of animals, and it has prevented that this can change the character of stimulation owing to using harder hair to cause whole limbs to be raised.

When representative compounds of the present invention is tested in said determination, confirm to compare with the contrast analgesic compounds, its lenitive % activity is in the 23%-98% scope.

Model after the operation of injury sensation

In this model, up to withdrawing its pawl from the stimulation that applies till, animal comes the hyperalgesia (hypealgesia) that causes by the in-plane mouth in the measuring claw by the haptic stimulus that applies increase to pawl.When animal after anesthesia under 3.5% isoflurane of carrying through nose cone, use 10 trumpeter's art blades transdermal and manadesma on the sole of the foot face of left back pawl, from the longitudinal cut that begins and extend to form 1cm to toes near 0.5cm place, rear foot edge.After the incision, use 2, the aseptic suture of 3-0 is with skin closure.The injury covers with Polysporin and excellent iodine (Betadine).Animal is got back to recover in the cage to spend the night.

Use 2290 type Electrovonfrey anesthesimeters (IITC Life Science, Woodland Hills, CA) measure (homonymy) of animal via operation and not (offside) pawl of underwent operative to the sufficient threshold value of contracting of haptic stimulus.Animal is placed the resin glass box of the rising that is absorbed on the net surface.Adapt to after at least 10 minutes, begin precalibrated Von Frey hair vertically to be put on the sole of the foot face of two pawls of animal by the order that increases with the 10g hair, and the hair slight bending of using enough power to make to withstand pawl.Continue test up to determine to have the hair that brings out the minimum force that pawl gets out of the way fast or reach about 20 grams till power.Using this to end power is because it represents about 10% the weight of animals, and it has prevented that this can change the character of stimulation owing to the whole limbs that use harder hair to cause are raised.

Neurogenic pain model: chronic constriction injury

In brief, use 10 trumpeter's art blades to form about 3cm otch at the big midleg transdermal and the manadesma of the left back leg of animal.Expose left sciatic nerve by blunt dissection through biceps muscle of thigh, careful operation reduces hemorrhage as far as possible.Using the nondegradable sterile suture of 4-0 is four untwistings along sciatic nerve with 1 to 2mm at interval.The pressure of this untwisting needs enough tight so that be enough to bring out sciatic slight shrinkage during observation under amplifying 4 times dissecting microscope.In the animal of sham-operation, expose left sciatic nerve and further do not operate.Antibiotic ointment directly is applied in the wound, and uses the sterile suture suture muscles.Be applied in excellent iodine on the muscle and all around, then clamp skin with operating forceps.

(IITC Life Science, Woodland Hills CA) measure the reaction threshold values of animal to haptic stimulus to use 2290 type Electrovonfrey anesthesimeters.Animal is placed the resin glass box of the rising that is absorbed on the net surface.Adapt to after 10 minutes, begin precalibrated Von Frey hair vertically to be put on the sole of the foot face of two pawls of animal, use enough power to make the hair slight bending of withstanding pawl by the order that increases with the 0.1g hair.Continue test up to determine to have the hair that brings out the minimum force that pawl gets out of the way fast or reach about 20 grams till power.Using this to end power is because it represents about 10% the weight of animals, and it has prevented that this can change the character of stimulation owing to the whole limbs that use harder hair to cause are raised.The compounds of this invention is effective in 30mg/kg to 0.1mg/kg scope shows.

Use the heat injury of Hargreaves test assessment animal to experience threshold value.After the measurement of sense of touch threshold values, animal is placed the resin glass box that is placed on the rising glass platform with heating unit.This glass platform is tested equal thermostatic control in about 24 ℃ to 26 ℃ temperature to all.After placing animal in this box, make it adapt to 10 minutes till all exploratory behaviors stop.(IITC, Woodland Hills CA) will put on the sole of the foot face of rear solid end from the radiant heat bundle of glass platform below to use 226 types vola/afterbody stimulator analgesia meter (Model 226Plantar/TailStimulator Analgesia Meter).All duration of test, the idle intensity and the activity intensity of thermal source are set at 1 and 55 respectively, and use dead line of 20 seconds to avoid tissue damaged.

Biological Examples 4

The irregular pulse test that napelline brings out

Antiarrhythmic activity by following evidence The compounds of this invention.Cause irregular pulse by the intravenously administrable that is dissolved in the napelline (2.0 μ g/kg) in the normal saline solution.After the napelline administration 5 minutes with test compounds intravenously administrable of the present invention.Be administered to time that additional shrinkage (ES) takes place and the time assessment antiarrhythmic activity that is administered to generation ventricular tachycardia (VT) from napelline by measuring from napelline.

To rat through isoflurane (2% 1/4 to 1/3) anesthesia, by cutting a kerf at neck earlier, then separate tracheae and cut the 2mm otch, trachea cannula is inserted 2cm in the tracheae, tracheotomy is implemented at the top that makes the opening of pipe just in time be positioned at mouth.Fix this intubate and be connected with ventilation breather (ventilator) with suture line at experimental session.

Then in femur portion, form otch (2.5cm) and use blunt dissection probe separates Femur blood vessel.Conduit is inserted two femoral vein, and one keeps anesthesia (0.02-0.05mL) with Sodital, and another root is then imported and injectable drug and medium.Femoral artery is carried out intubate with the blood pressure gel conduit of forwarder.

The ECG lead is located to stick on the chest muscle in lead II (Lead II) position (heart upper right side-white wire and heart lower left-red lead).Lead is fixed with suture.

All operative regions all use the gauze through 0.9% salt water-wet to cover.Provide salt solution (0.9% solution of 1-1.5mL) with wetting operation rear region.Make ECG and the ventilation balance at least 30 minutes of animal.

Brought out irregular pulse in 5 minutes with 2 μ g/Kg/ minute infusion napelline.Record and lasting monitoring ECG during this.Intravenous injection test compounds (10,30 or 100 μ g/Kg) causes returning to fully normal baseline ECG.

Biological Examples 5

The irregular pulse test that local asphyxia is brought out

The rodent model of ventricle arrhythmia all has been used to test the atrium property that is used for the people and the potential therapy of ventricle arrhythmia in the example in acute cardiac conversion and prevention.It is the common cause of sickness rate and mortality ratio that cardiac ischemia causes myocardial infarction.Ventricle tachycardia that compound prevention local asphyxia is brought out and fibrillar ability are for determining that compound is clinically to the model accepted of atrium property and ventricle tachycardia and fibrillar validity.

At first use Sodital (i.p.) to bring out and anaesthetize and inject maintenance with i.v. and anaesthetize.The tracheae of male SD rat is by intubate, so as with room air with the cardiac output of stroke volume, 60 of the 10mL/Kg artificial ventilation of beating/minute carry out.Right femoral artery and vein with the PE50 intubation catheter so that write down mean arterial blood pressure (MAP) respectively and carry out the intravenous administration of compound.

Between the 4th and the 5th root bone, open the thoracic cavity, and produce the opening of 1.5cm so that can see heart.Each rat placed on the jagged platform and with buckle be buckled on the thorax to open the thoracic cavity.Use sewing needle below near the atrium that promotes, to penetrate ventricle, and pass ventricle, therefore obtain＞30% to＜50% block section (OZ) along downward diagonal.The outlet position be below aorta and left ventricle junction～0.5cm.With the suture line tension, make to form loose ring (plugging device) in bifurcation around artery.Then, the chest that closes makes this plugging device terminal accessible outside chest.

Placing lead II position (right atrium is to the top) to sentence the just following ECG of carrying out at electrode measures: an electrode is inserted right front pawl and another electrode inserts left back pawl.

Omnidistance record body temperature, MAP, ECG and the heart rate of continuing of experiment.After important parameter is stable, obtain 1-2 minute record to set up baseline value.After in case baseline value is set up, beginning infusion compound or contrast material.Infusion The compounds of this invention or contrast be after 5 minutes, with the suture line tension with ligation LCA and make left ventricle produce local asphyxia.Continue record important parameter 20 minutes after the ligation,, stop record this moment because animal will be by the declaration of death and then is condemned to death unless MAP reaches the critical level at least 3 minutes of 20-30mmHg.To compound prevention irregular pulse and keep that the ability that is close to normal MAP and HR is marked and with compare.

Biological Examples 6

Measure in the body of benign prostatic hyperplasia (BPH)

The effectiveness of The compounds of this invention treatment BPH can confirm by measuring in the following body.

To dog orally give The compounds of this invention, lasted for 4 weeks with 0 milligram/kilogram to 100 milligrams/kilogram oral dosage.Control group is accepted placebo.Kill animals and separate and cut prostate gland gently press dry dry and weighs.When comparing with the control group of medium treatment (0 milligram/kilogram), the weight of prostate of dog obviously reduces, and shows that The compounds of this invention is effective in the dose-dependently mode 5 milligrams/kilogram to 100 milligrams/kilogram scope.

Biological Examples 7

Measure in the effectiveness of anti-hypercholesterolemiccompounds and the body of antiatherogenic effectiveness

The effectiveness of the anti-hypercholesterolemiccompounds of The compounds of this invention can prove by measuring in the following body.

Dog has the anthropoid cardiovascular systems of class, makes aspect the validity of its medical compounds that is designed to treat cardiovascular disorder in research very desirable.

Dog lasts 2-4 week with 5 milligrams of/kilogram per daily dose orally give The compounds of this invention to 100 milligrams of/kilogram scopes.After 2 weeks and 4 weeks, make the animal bloodletting and collect its serum to be used for the total cholesterol analysis and to compare with the animal that only gives medium (0 milligram/kilogram).

Cholesterol be measured as one of test that clinical experiment the most generally carries out in setting.Generally use in blood plasma or serum the quantitative total cholesterol of induction simple fluorescence survey method.In one measured, cholesteryl ester was earlier by the cholesteryl ester enzymic hydrolysis in the sample.No matter in advance esterification or exist with free state in circulation, all cholesterol all are oxidized to corresponding ketone and hydrogen peroxide by rCO subsequently.Utilize the super-sensitive stable probe of ADHP (10-ethanoyl-3,7-dihydroxyl phenoxazine) as hydrogen peroxide.The reaction of horseradish peroxidase catalysis ADHP and hydrogen peroxide and produce the product hydroxyl Yi Fen azolactone (resorufin) of high fluorescence, it can use the excitation wavelength of 565-580nm and the emission wavelength of 585-595nm to be followed the trail of.

Biological Examples 8

Measure in the body of treatment itch

Its activity of assessment during The compounds of this invention can be measured in vivo by use rodents model as the antipruritic agent.A kind of model of having set up that is used for the itch of periphery initiation is to set up by serotonin being injected the mouth side dorsal area (neck) that does not have the hair rat.Serotonin injection (as 2 mg/ml, 50 microlitres) is preceding, but the dosage oral administration of The compounds of this invention, intravenously or the general administration of intraperitoneal approach or local border circular areas (as 18mm) administration to fixed diameter.After the administration, give the serotonin injection in this topical zone.After the serotonin injection, followed the trail of animal behavior in 20 minutes to 1.5 hours by photorecording, and the animal of this moment and the media processes number of times that relatively scratches.Therefore, use The compounds of this invention and can in rat, suppress scratching of serotonin initiation.

*****

All United States Patent (USP)s of quoting in this specification sheets, U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and non-patent publication are in all by reference its full content being incorporated herein.

Though be described in previously described the present invention in more detail to help understanding, should be understood that obviously and can in appended claim scope, carry out some change and modification.Therefore, described embodiment should be considered to exemplary illustration, and unrestricted, and the details that the present invention is not subjected to this paper and is provided limits, and can modify in claims scope and equivalency range thereof.

Claims

1. general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Q is-C (R ^1a) ₂-,-O-,-S (O) _p-(wherein p is 0,1 or 2) ,-CF ₂-,-OC (O)-,-C (O) O-,-C (O) N (R ⁵)-,-N (R ⁵)-or-N (R ⁵) C (O)-;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo group with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

R wherein ⁶With R ⁷Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl randomly be selected from following substituting group and replace by one or more: alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl;

Or R ¹Be aralkyl, described aralkyl is randomly by one or more being selected from-R ⁸-OR ⁵,-C (O) OR ⁵, halogen, haloalkyl, alkyl, nitro, cyano group, aryl, aralkyl, heterocyclic radical and heteroaryl substituting group replace;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

And R wherein ¹⁰With R ¹¹Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro ,-R ⁸-CN ,-R ⁸-OR ⁵,-R ⁸-C (O) R ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹Be heterocyclic radical alkyl or heteroarylalkyl, wherein said heterocyclic radical alkyl or heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵, aryl and aralkyl substituting group replace;

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, halogen, haloalkyl, haloalkenyl group, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-NO2 ,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-N=C (R ⁴) R ⁵,-R ⁸-S (O) _pR ⁴,-R ⁸-OS (O) ₂CF ₃,-R ⁸-C (O) R ⁴,-R ⁸-C (S) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-R ⁸-C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (O) R ⁴,-R ⁸-N (R ⁵) C (S) R ⁴,-R ⁸-N (R ⁵) C (O) OR ⁴,-R ⁸-N (R ⁵) C (S) OR ⁴,-R ⁸-N (R ⁵) C (O) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) S (O) _tR ⁴,-R ⁸-N (R ⁵) S (O) _tN (R ⁴) R ⁵,-R ⁸-S (O) _tN (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-R ⁸-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each p independently is 0,1 or 2, each t independently is 1 or 2;

R wherein ^2a, R ^2b, R ^2cAnd R ^2dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _pR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _tR ⁴, wherein each p independently is 0,1 or 2, each t independently is 1 or 2;

Or R ^2aAnd R ^2bWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, R ^2cWith R ^2dAs above definition;

Or R ^2bAnd R ^2cWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, R ^2aWith R ^2dAll as above definition;

Or R ^2cAnd R ^2dWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, R ^2aWith R ^2bAll as above definition;

Each R ³Independently be selected from alkyl, thiazolinyl, alkynyl, halogen, haloalkyl, haloalkenyl group, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl, oxo ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-N=C (R ⁴) R ⁵,-R ⁸-S (O) _pR ⁴,-R ⁸-OS (O) ₂CF ₃,-R ⁸-C (O) R ⁴,-R ⁸-C (S) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-R ⁸-C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (O) R ⁴,-R ⁸-N (R ⁵) C (S) R ⁴,-R ⁸-N (R ⁵) C (O) OR ⁴,-R ⁸-N (R ⁵) C (S) OR ⁴,-R ⁸-N (R ⁵) C (O) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) S (O) _tR ⁴,-R ⁸-N (R ⁵) S (O) _tN (R ⁴) R ⁵,-R ⁸-S (O) _tN (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-R ⁸-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each p independently is 0,1 or 2, each t independently is 1 or 2;

R wherein ³Each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _pR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _tR ⁴, wherein each p independently is 0,1 or 2, each t independently is 1 or 2;

Each R ⁴With R ⁵Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, haloalkenyl group, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl;

Or work as R ⁴And R ⁵When all being connected to identical nitrogen-atoms, R ⁴And R ⁵Can form heterocyclic radical or heteroaryl with the nitrogen-atoms that it connected; And

2. compound as claimed in claim 1, wherein X is O, and

Be the condensed heteroaryl ring.

3. compound as claimed in claim 2, wherein said general formula (I) compound are general formula (Ia) compound, its steric isomer, corresponding isomer, tautomer or its mixture; Or its drug acceptable salt, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a), N or N → O;

B is C (R ^3b), N or N → O;

D is C (R ^3d), N or N → O;

Or A is C (R ^3a), B is C (R ^3b), E is N (H), D is C (O);

Or A is C (R ^3a), B is C (R ^3b), D is N (H), E is C (O);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

R wherein ⁶With R ⁷Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹Be aralkyl, described aralkyl is randomly by-R ⁸-OR ⁵,-C (O) OR ⁵, halogen, haloalkyl, alkyl, nitro, cyano group, aryl (optional by cyano replaces), aralkyl (randomly being replaced by one or more alkyl), heterocyclic radical or heteroaryl replace;

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R wherein ¹⁰And R ¹¹Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro ,-R ⁸-CN ,-R ⁸-OR ⁵,-R ⁸-C (O) R ⁵, heterocyclic radical and heteroaryl substituting group replace;

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

R wherein ^2a, R ^2b, R ^2cAnd R ^2dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaralkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

Or R ^2aAnd R ^2b, R ^2bAnd R ^2c, or R ^2cAnd R ^2dWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl;

R ^3a, R ^3b, R ^3eAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

R wherein ^3a, R ^3b, R ^3eAnd R ^3dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3e, or R ^3eAnd R ^3dWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl;

Or work as R ⁴And R ⁵When all connecting with identical nitrogen-atoms, R ⁴And R ⁵Can form heterocyclic radical or heteroaryl with the nitrogen-atoms that it connected; And

4. compound as claimed in claim 3, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b) or N;

E is C (R ^3e);

D is C (R ^3d) or N, precondition is that at least one is N among B and the D;

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

R wherein ⁶With R ⁷Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl substituting group replace;

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R wherein ^2a, R ^2b, R ^2cAnd R ^2dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

Or R ^2aAnd R ^2b, or R ^2bAnd R ^2c, or R ^2cAnd R ^2dWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl;

5. compound as claimed in claim 4, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ^1aFor hydrogen or-OR ⁵

Or R1 is quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Or as R and R ⁵When all connecting with identical nitrogen-atoms, R ⁴And R ⁵Can form heterocyclic radical or heteroaryl with the nitrogen-atoms that it connected; And

6. compound as claimed in claim 5, wherein:

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ^1aFor hydrogen or-OR ⁵

Or R ¹For-R ⁹-C (O) N (R ¹²) R ¹¹, wherein:

R ¹¹Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R wherein ¹¹Each aryl or aralkyl can be randomly replaced by one or more substituting groups that are selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen and haloalkyl;

R wherein ^2a, R ^2b, R ^2cAnd R ^2dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m is 0,1 or 2, each n is 1 or 2;

R wherein ^3a, R ^3bAnd R ^3eEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3eWith its direct-connected carboatomic ring atom can form the fused rings that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl;

Each R ⁸Alkylidene chain for direct key or straight or branched; And

Each R ⁹Alkylidene chain for straight or branched.

7. compound as claimed in claim 6, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹For hydrogen, alkyl, thiazolinyl, haloalkyl ,-R ⁸-OR ⁵Or-R ⁸-CN;

Or R ¹For-R ⁹-C (O) N (R ¹²) R ¹¹, wherein:

R ¹¹Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3eCan form the condensed heterocycle basic ring with its direct-connected carboatomic ring atom;

Each R ⁸Alkylidene chain for direct key or straight or branched.

8. compound as claimed in claim 7, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹Be hydrogen or heteroarylalkyl, wherein heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵And-R ⁸-C (O) OR ⁵Substituting group replace;

Or R ^3aAnd R ^3b, or R ^3bAnd R ^3eWith its direct-connected carboatomic ring atom can form the fused rings that is selected from heterocyclic radical;

Each R ⁸Alkylidene chain for direct key or straight or branched.

9. compound as claimed in claim 8, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹Be hydrogen;

Each R ⁸Alkylidene chain for direct key or straight or branched.

10. compound as claimed in claim 9, it is selected from following compound:

11. compound as claimed in claim 8, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹Be heteroarylalkyl, wherein heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵And-R ⁸-C (O) OR ⁵Substituting group replace;

Each R ⁸Alkylidene chain for direct key or straight or branched.

12. as the compound of claim 11, it is selected from:

1 ' [(5-chlorothiophene-2-yl) methyl]-5-methoxyl group spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 (1 ' H)-ketone; And

13. compound as claimed in claim 7, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

Each R ⁸Alkylidene chain for direct key or straight or branched.

14. as the compound of claim 13, it is selected from:

15. compound as claimed in claim 7, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N;

R ¹For-R ⁹-C (O) N (R ¹²) R ¹¹, wherein:

R ¹¹Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Each R ⁸Alkylidene chain for direct key or straight or branched.

16. as the compound of claim 15, its be N-(2-fluorophenyl)-2-(5-methoxyl group-2 '-oxo spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-1 ' (2 ' H)-yl) ethanamides.

17. compound as claimed in claim 4, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^3a, R ^3eAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

R wherein ^3a, R ^3eAnd R ^3dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

Each R ⁴And R ⁵Independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl;

18. as the compound of claim 17, wherein:

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

R ^2a, R ^2b, R ^2cAnd R ^2dIndependently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴And-R ⁸-C (O) N (R ⁴) R ⁵

R wherein ^2a, R ^2b, R ^2cAnd R ^2dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

Each R ⁸Alkylidene chain for direct key or straight or branched; And

Each R ⁹Alkylidene chain for straight or branched.

19. as the compound of claim 18, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹For hydrogen, alkyl, thiazolinyl, haloalkyl ,-R ⁸-OR ⁵Or-R ⁸-CN;

Or R ^3eAnd R ^3dCan form the annelated heterocycles basic ring with its direct-connected carboatomic ring atom;

Each R ⁸Alkylidene chain for direct key or straight or branched.

20. as the compound of claim 19, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be hydrogen;

Each R ⁸Alkylidene chain for direct key or straight or branched.

21. as the compound of claim 20, it is 5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

22. as the compound of claim 19, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be heteroarylalkyl, wherein heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵, and-R ⁸-C (O) OR ⁵Substituting group replace;

Each R ⁸Alkylidene chain for direct key or straight or branched.

23. as the compound of claim 22, its be 5-methoxyl group-1 '-{ [5-(trifluoromethyl) furans-2-yl] methyl } spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

24. as the compound of claim 19, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be the heterocyclic radical alkyl, wherein this heterocyclic radical alkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵And-R ⁸-C (O) OR ⁵Substituting group replace;

Each R ⁸Alkylidene chain for direct key or straight or branched.

25. as the compound of claim 24, it is selected from:

26. as the compound of claim 19, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is N;

E is C (R ^3e);

D is C (R ^3d);

R ¹Be aralkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

27. as the compound of claim 26, it is 1 '-(diphenyl methyl)-5-methoxyl group spiral shell [furo [2,3-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

28. compound as claimed in claim 3, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

E is N;

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^3a, R ^3bAnd R ^3dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

29. as the compound of claim 28, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is N;

D is C (R ^3d);

Each R ⁸Alkylidene chain for direct key or straight or branched; And

30. as the compound of claim 29, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is N;

D is C (R ^3d);

R ¹Be hydrogen or alkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

31. as the compound of claim 30, it is 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone.

32. compound as claimed in claim 3, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

E is N → O;

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R wherein ^3a, R ^3bAnd R ^3dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

33. as the compound of claim 32, wherein:

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is C (R ^3b);

E is N → O;

D is C (R ^3d);

R ^1aFor hydrogen or-OR ⁵

34. as the compound of claim 33, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is N → O;

D is C (R ^3d);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

35. as the compound of claim 34, it is 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone 5-oxide compound.

36. compound as claimed in claim 3, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N → O;

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^3a, R ^3bAnd R ^3eEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

37. as the compound of claim 36, wherein:

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N → O;

R ^1aFor hydrogen or-OR ⁵

38. as the compound of claim 37, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a);

B is C (R ^3b);

E is C (R ^3e);

D is N → O;

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Or R ¹Be heteroarylalkyl, wherein heterocyclic radical alkyl or heteroarylalkyl randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵And-R ⁸-C (O) OR ⁵Substituting group replace;

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴And-R ⁸-C (O) N (R ⁴) R;

Each R ⁸Alkylidene chain for direct key or straight or branched.

39. as the compound of claim 38, its be 5-methoxyl group-1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ' (1 ' H)-ketone 4-oxide compound.

40. compound as claimed in claim 3, wherein:

Each independently is 0,1,2 or 3 for j and k;

A is C (R ^3a), B is C (R ^3b), E is N (H), D is C (O);

Or A is C (R ^3a), B is C (R ^3b), D is N (H), E is C (O);

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^3aAnd R ^3bEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) _nR ⁴,-N (R ⁵) S (O) _nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

R wherein ^3aAnd R ^3bEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly be selected from following substituting group and replace by one or more: alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _nR ⁴, wherein each m independently is 0,1 or 2, each n independently is 1 or 2;

41. as the compound of claim 40, wherein:

J be 0 and k be 1;

Q is-C (R ^1a) H-,-O-,-S-or-N (R ⁵)-;

A is C (R ^3a), B is C (R ^3b), E is N (H), D is C (O);

Or A is C (R ^3a), B is C (R ^3b), D is N (H), E is C (O);

R ^1aFor hydrogen or-OR ⁵

42. as the compound of claim 41, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a), B is C (R ^3b), E is N (H), D is C (O);

Or A is C (R ^3a), B is C (R ^3b), D is N (H), E is C (O);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

43. as the compound of claim 42, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a), B is C (R ^3b), E is N (H), D is C (O);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Each R ⁸Alkylidene chain for direct key or straight or branched.

44. as the compound of claim 43, it is 1 '-the amyl group spiral shell [furo [3,2-c] pyridine-3,3 '-indoles]-2 ', 4 (1 ' H, 5H)-diketone.

45. as the compound of claim 42, wherein:

J be 0 and k be 1;

Q is-O-;

A is C (R ^3a), B is C (R ^3b), D is N (H), E is C (O);

R ¹Be hydrogen, alkyl, thiazolinyl or haloalkyl;

Or work as R ⁴And R ⁵When all connecting with identical nitrogen-atoms, R ⁴With and R ⁵Can form heterocyclic radical or heteroaryl with the nitrogen-atoms that it connected; And

Each R ⁸Alkylidene chain for direct key or straight or branched.

46. as the compound of claim 45, it is 1 '-{ [5-(trifluoromethyl)-2-furyl] methyl } spiral shell [furo [3,2-b] pyridine-3,3 '-indoles]-2 ', 5 (1 ' H, 4H)-diketone.

47. treat, prevent or alleviate the method for mammiferous disease or morbid state, described disease or morbid state be selected from pain, depression, cardiovascular disorder, respiratory tract disease and mental disorder with and the combination, wherein said method comprises general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture of the Mammals that needs are arranged being treated significant quantity; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

R wherein ⁶With R ⁷Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl can be randomly be selected from following substituting group and replace by one or more: alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ^2a, R ^2b, R ^2cAnd R ^2dEach independently be selected from hydrogen, alkyl, thiazolinyl, alkynyl, halogen, haloalkyl, haloalkenyl group, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-N=C (R ⁴) R ⁵,-R ⁸-S (O) _pR ⁴,-R ⁸-OS (O) ₂CF ₃,-R ⁸-C (O) R ⁴,-R ⁸-C (S) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-R ⁸-C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (O) R ⁴,-R ⁸-N (R ⁵) C (S) R ⁴,-R ⁸-N (R ⁵) C (O) OR ⁴,-R ⁸-N (R ⁵) C (S) OR ⁴,-R ⁸-N (R ⁵) C (O) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) S (O) _tR ⁴,-R ⁸-N (R ⁵) S (O) _tN (R ⁴) R ⁵,-R ⁸-S (O) _tN (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-R ⁸-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each p independently is 0,1 or 2, each t independently is 1 or 2;

R wherein ^2a, R ^2b, R ^2cAnd R ^2dEach cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroarylalkyl can be randomly by one or more be selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl ,-R ⁸-CN ,-R ⁸-N (O) ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) _pR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) _tR ⁴Substituting group replace, wherein each p independently is 0,1 or 2, each t independently is 1 or 2;

Each R ³Independently be selected from alkyl, thiazolinyl, alkynyl, halogen, haloalkyl, haloalkenyl group, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, arylalkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroarylalkyl, oxo ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-R ⁸-N=C (R ⁴) R ⁵,-R ⁸-S (O) _pR ⁴,-R ⁸-OS (O) ₂CF ³,-R ⁸-C (O) R ⁴,-R ⁸-C (S) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-R ⁸-C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (O) R ⁴,-R ⁸-N (R ⁵) C (S) R ⁴,-R ⁸-N (R ⁵) C (O) OR ⁴,-R ⁸-N (R ⁵) C (S) OR ⁴,-R ⁸-N (R ⁵) C (O) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (S) N (R ⁴) R ⁵,-R ⁸-N (R ⁵) S (O) _tR ⁴,-R ⁸-N (R ⁵) S (O) _tN (R ⁴) R ⁵,-R ⁸-S (O) _tN (R ⁴) R ⁵,-R ⁸-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-R ⁸-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each p independently is 0,1 or 2, each t independently is 1 or 2;

48. as the method for claim 47, wherein said disease or morbid state are selected from pain, wound pain, operation pain, post-operative pain, labor pains, throe, neurogenic bladder, ulcerative colitis, chronic pain, the rest pain of neurogenic pain, inflammatory pain, internal organ pain, cancer pain, chemotherapy, the pain of periphery mediation, pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury and the combination thereof of maincenter mediation.

49. as the method for claim 47, wherein said disease or morbid state are selected from the pain relevant with HIV; the neuropathy that the HIV treatment causes; trigeminal neuralgia; postherpetic neuralgia; eudynia; heat sensitivity; tosarcoidosis; irritable bowel syndrome; Crohn disease; with the relevant pain of multiple sclerosis (MS); amyotrophic lateral sclerosis (ALS); diabetic neuropathy; the peripheral nerve pathology; sacroiliitis; rheumatoid arthritis; osteoarthritis; atherosclerosis; the paroxysmal myodystonia; myasthenic syndrome; myotony; malignant hyperthermia; cystic fibrosis; pseudohyperaldosteronism; rhabdomyolysis; hypothyroidism; the two-phase dysthymia disorders; anxiety; schizophrenia; the sodium channel toxin-related diseases; the familial erythromelalgia; the primary erythromelalgia; familial rectum pain; cancer; epilepsy; locality grand mal and general grand mal; restless leg syndrome; irregular pulse; fibromyalgia; neuroprotective under the ischemia state that palsy or neural wound cause; tachy-arrhythmia; atrial fibrillation and ventricular fibrillation.

50. by suppressing to treat by the ion-flow rate of voltage-dependent sodium channel in the Mammals method of Mammals pain, wherein said method comprises general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture of the Mammals that needs are arranged being treated significant quantity; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

51. pass through the method for the ion-flow rate of voltage-dependent sodium channel in the minimizing mammalian cell, wherein said method comprises makes cell and general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug contact:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

52. treat the method for mammiferous hypercholesterolemia, wherein said method comprises general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture of the Mammals that needs are arranged being treated significant quantity; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

53. treat the method for mammiferous benign prostatic hyperplasia, wherein said method comprises general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture of the Mammals that needs are arranged being treated significant quantity; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

R ¹For hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical ,-R ⁸-C (O) R ⁵,-R ⁸-C (O) OR ⁵,-R ⁸-C (O) N (R ⁴) R ⁵,-S (O) _t-R ⁵(wherein t is 1 or 2) ,-R ⁹-S (O) ^p-R ⁵(wherein p is 0,1 or 2) ,-R ⁸-OR ⁵,-R ⁸-CN ,-R ⁹-P (O) (OR ⁵) ₂Or-R ⁹-O-R ⁹-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

54. treat the method for mammiferous pruritus, wherein said method comprises general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture of the Mammals that needs are arranged being treated significant quantity; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

55. treat mammiferous method for cancer, wherein said method comprises general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture of the Mammals that needs are arranged being treated significant quantity; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

56. pharmaceutical composition, it comprises pharmaceutically-acceptable excipients and general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture; Or the acceptable salt of its medicine, N-oxide compound, solvate or prodrug:

Wherein:

Each independently is 0,1,2 or 3 for j and k;

M is 0,1,2 or 4;

X is O or S;

Be annelated heterocycles basic ring or condensed heteroaryl ring;

Each R ^1aFor hydrogen or-OR ⁵

Or two R ^1aForm oxo with the carbon that it connected;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl;

Each R ¹⁰Be hydrogen, alkyl, aryl, aralkyl or heteroaryl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵