CN101068804A

CN101068804A - Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use

Info

Publication number: CN101068804A
Application number: CN 200580036347
Authority: CN
Inventors: 阿德南·M·M·米亚里; 巴普·加德姆; 莫汉·饶; 穆拉利达尔·邦德雷拉; 拉梅什·高帕拉斯瓦米; 罗伯特·C·安德鲁斯; 斯蒂芬·戴维斯; 苏维·西米莱; 任坦
Original assignee: vTvx Holdings I LLC
Priority date: 2004-10-21
Filing date: 2005-10-20
Publication date: 2007-11-07
Also published as: ZA200702643B

Abstract

Embodiments of the present invention provide bissulfonamide compounds that are agonists of GalR1. The present invention further provides compositions comprising bissulfonamide compounds that are agonists of GalR1, and methods of use of such compounds and compositions.

Description

As two sulfonamide compoundss of GalR1 agonist, composition, and usage

The statement of related application

Present patent application requires the U.S. Provisional Patent Application No.60/620 of submission on October 21st, 2004, and 699, and the U.S. Provisional Patent Application No.60/670 that submitted on April 13rd, 2005,752 right of priority.

Invention field

The present invention relates to two sulfonamide compoundss as the GalR1 agonist, and composition, and use this compounds and method for compositions.

Background of invention

Galanin is 30 amino acid neuropeptides (being 29 amino acid in rodent) in the mankind, and it is distributed widely in tissue, comprises brain, in spinal cord and the intestines (1).Galanin is regulated various procedures, comprises nociception, and neurotization is ingested, memory, neuroendocrine, intestinal secretion and shrinkability (2,3).Three kinds of galanin receptors hypotypes (GalR1, GalR2 and GalR3) are cloned, and they belong to G albumen coupling 7-transmembrane receptor superfamily (4,5).These acceptors and the coupling of the active G protein system of various adjusting second messengers have now been shown.Galanin stimulates the effect of GalR1 to the Toxins, pertussis sensitivity, and this is consistent (6) with galanin and Gi/o type G albumen coupling.

All three kinds of galanin receptors hypotypes all are expressed in dorsal root ganglion (DRG) and spinal cord (7).The rise effect of the anatomy of galanin and acceptor thereof location and galanin reply nervous lesion has hinted galanin-GalR path may play an important role (8-10) in the adjusting of spinal cord nociception transmission.Give the anti-nociception of spinal cord that galanin can strengthen morphine in the sheath and alleviate sign (11,12) when cutting out opiate.GalR1 may be the important galanin receptors that anti-nociception transmits.Follow and give galanin the alternative threshold of pain (13,14) of improving the neuropathic pain model in the GalR1 sheath.

In the recent research, to the expression of GalR1, the research of mitogenesis effect and signaling mechanism is carried out in normal and pernicious mouth epithelial cells.Under the condition of competitive inhibition GalR1, the propagation of immortalization and pernicious keratinocyte is raised.Research shows that also GalR1 suppresses immortalization and pernicious keratinocyte propagation (15) by deactivation MAPK path.

Summary of the invention

The invention provides the compound of formula described herein (I), the compound of its Chinese style (I) is the GalR1 agonist.In another embodiment, the present invention also provides the method for the compound of preparation formula (I).

The present invention also provides the pharmaceutical composition of the compound that contains formula (I).In another embodiment, the invention provides the method for the pharmaceutical composition for preparing the compound that contains formula (I).This pharmaceutical composition comprises pharmaceutically acceptable carrier, vehicle, and/or thinner.

In another embodiment, the invention provides the method for the pharmaceutical composition of the compound of use formula (I) and the compound that use contains formula (I).Compound of the present invention and pharmaceutical composition can be used for the treatment of the disease of the mankind or animal.

When being used for the treatment of the disease of the mankind or animal, the compound of formula (I) can provide many advantages with the pharmaceutical composition that contains the compound of formula (I).In one embodiment, compound of the present invention and pharmaceutical composition provide multiple treatment to select.As the small molecules therapeutical agent, the representative embodiment of compound of the present invention and pharmaceutical composition can be oral, part or administered parenterally.Equally, compound of the present invention and pharmaceutical composition can comprise main therapeutical agent, and the subsidiary that perhaps can be used as other therapeutical agent uses.

In another embodiment, the invention provides the pharmaceutical composition of the compound that contains formula (I), the compound of its Chinese style (I) is the GalR1 agonist, and the compound of formula (I) is to be enough to improve measuring now of GalR1 receptor active.In another embodiment, pharmaceutical composition comprises the compound of formula (I), and the compound of its Chinese style (I) is the GalR1 agonist, and the compound of formula (I) is to be enough to stimulating experimenter's measuring of GalR1 to show.

In another embodiment, the invention provides a kind of method, it comprises: can give pharmaceutical composition by the experimenter who activates the disease that the GalR1 acceptor improves to suffering from, this pharmaceutical composition contains the compound of the formula (I) that is enough to improve the active amount of experimenter GalR1.For example, compound of the present invention and pharmaceutical composition can effectively be treated neuropathic pain or cancer.In addition, under the dosage that can observe analgesic effect, compound of the present invention can combine with at least a periphery GalR1, but almost can not pass through blood brain barrier.Compound of the present invention is partially or completely got rid of the risk or the severity that can reduce one or more the maincenter mediation side effects relevant with this compound or pharmaceutical composition outside brain.

Further feature of the present invention will be described below.Natural is, the invention is not restricted to its patent application in details illustrated above or in the explanation hereinafter, and it can have other embodiment, and can implement in many ways or carry out.

Describe in detail

In the whole application of this patent, a plurality of publications have been mentioned as a reference.Can find whole quoted passages of these publications in the claims front.

Pain is a kind of sensation and a kind of consciousness, and it is made of the mechanism of a series of complexity.In its simplest building process, pain is the nociception by periphery, the signal that sense of touch and pressure receptor send, and this signal is passed to spinal cord, arrives rudimentary and senior big mesencephalic centre at last.Yet this signal can be modified (16) in every way in each level of pain path.

Dysmenorrhea is a kind of important protection mechanism, and purpose is that the danger from the potential noxious stimulation of outside atmosphere is sounded a warning.System moves by one group of special elementary receptive neuron, and exclusively activates (16) by noxious stimulation by the periphery transduction mechanism.These Sensory fibres are considered to nociceptor, it is characterized in that axon diameter is less and conduction velocity is slow.Intensity, time length and the character of nociceptor coding noxious stimulation.Nociceptor also relies on the encode location of this stimulation of the myelopetal organized projection of its topology.Nociceptor finds that on the nociception nerve fiber nociception nerve fiber has two kinds of main types: A-δ fiber (medullated) and C fiber (unmyelinated).The activity that is produced by nociceptor input is through after the complicated processing of dorsal horn, directly transmits or is passed to the thalamus ventralis substrate through brain stem conduction relay nucleus, arrives cortex then, forms pain perception there.

Pain mainly contains three types.Acute pain, interim nociception is the moment outbreak of the pain perception of reply noxious stimulation.It is adaptive that acute pain is considered to, because it can stop organism injury self.For example, can avoid serious burn in case feel that pain is just removed hand from hot stove.

Second type of pain is rest pain.Different with acute pain, rest pain postpones outbreak usually but can continue a few hours to a couple of days.Majority think that rest pain is adaptive because after damage the generation of rest pain can stop to the tissue further injury.For example, the pain relevant with the ankle of spraining will stop the patient to use pin, thereby avoid further damage and help rehabilitation.

Last of pain type is chronic pain.Chronic pain is for postponing outbreak and can continuing the several months to the several years.Compare with rest pain with acute, it is unconformable that chronic pain is considered to, and with disease such as sacroiliitis, nerve injury, acquired immune deficiency syndrome (AIDS) is relevant with diabetes.

Chronic or neuropathic pain takes place with various forms, comprises spontaneous pain (pain perception that does not have outside stimulus), sense of touch pain (normally not having the pain perception that noxious stimulation causes) and hyperpathia (to the severe pain sensation of gentle pain stimulation).This symptom diversity has caused this disease to be difficult to treatment clinically.In fact, present treatment is at off-label use thymoleptic and anticonvulsive drug mostly.Thymoleptic and anticonvulsive drug all may have problems to the patient.

Tricyclic antidepressant has the longest history that is used for the treatment of neuropathic pain.This class medicine is a target with serotonergic systems and noradrenergic system generally, improves the outer level of available born of the same parents of thrombotonin and norepinephrine.Existing proposal is thought by norepinephrine postsynaptic activation α ₂-adrenoceptor may be the mechanism of these compounds for reducing neuropathic pains.Because thymoleptic can easily pass through blood brain barrier, its ability that improves thrombotonin and noradrenaline levels also can cause the unexpected activation of other acceptor, thereby causes the excessive risk of maincenter mediation side effect.The scope of the side effect of thymoleptic can be from symptom such as dry and calmness slight but that stimulate, to serious life-threatening side effect such as postural hypotension and irregular pulse.Represented the elderly of many neuropathic pain patients that the side effect of more serious thymoleptic takes place especially easily.

Anticonvulsive drug comprises that at the various pain statuses of treatment the effectiveness of neuropathic pain aspect has obtained assessment (17) recently.Similar to thymoleptic, side effect usually takes place simultaneously with these pharmacological agenies.

Because with thymoleptic and the usually simultaneous side effect of anticonvulsive drug, and these side effects may limit the purposes of these compounds, therefore need a kind of medicine that can avoid the treatment neuropathic pain of maincenter mediation side effect.

In one aspect, the invention provides the compound of formula (I): Ar ₂-SO ₂NH-Ar ₁-NHSO ₂-Ar ₃(I), its pharmacy acceptable salt or prodrug, the compound of its Chinese style (I) is the GalR1 agonist.

A) Ar ₁Comprise the optional arylidene that replaces 1-4 time, heteroarylidene, fused rings alkyl arylene, annelated heterocycles base arylidene, fused rings alkyl heteroarylidene, or annelated heterocycles base heteroarylidene.In one embodiment, Ar ₁Comprise the optional arylidene that replaces 1-4 time.In a plurality of embodiments, Ar ₁Substituting group can comprise: hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-whole haloalkyl;

F)-alkyl;

G)-aryl;

H)-heteroaryl;

I)-cycloalkyl;

J)-the L-aryl;

K)-L-arylidene-aryl;

L)-L-arylidene-alkyl;

M)-the Q-alkyl;

N)-the Q-aryl;

O)-Q-alkylidene group-aryl;

P)-Q-arylidene-alkyl;

Q)-L-Q-alkylidene group-aryl;

R)-arylidene-Q-alkyl;

S)-the L-Q-alkyl;

T)-the L-Q-aryl;

U)-the L-Q-heteroaryl;

V)-the L-Q-cycloalkyl;

W)-L-Q-arylidene-alkyl;

X)-D ₄-alkylidene group-NR ₁R ₂

y)-D ₄-NR ₁R ₂；

Z)-D ₄-alkyl; Or

aa)-D ₄-H；

Wherein,

D ₄Comprise direct key ,-CH ₂-,-O-,-N (R ₄)-,-C (O)-,-CON (R ₄)-,-N (R ₄) C (O)-,-N (R ₄) CON (R _{4 '})-,-N (R ₄) C (O) O-,-CO (O) N (R ₄)-,-N (R ₄) SO ₂-, SO ₂N (R ₄)-,-C (O)-O-,-O-C (O)-,-S-,-S (O)-,-S (O) ₂-,-N (R ₄) SO ₂N (R _{4 '})-, or-N=N-;

R wherein ₄And R _{4 '}Comprise independently-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl, or-alkylidene group-aryl;

R ₁And R ₂Comprise hydrogen independently, alkyl, or aryl, wherein R ₁And R ₂Can combine to form and have formula-(CH ₂) _o-Z ₄-(CH ₂) _P-ring and R ₁And R ₂Institute's azine atomic linkage;

Wherein

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₄Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂NH-,-OC (O)-,-N (R ₃₁)-,-N (C (O) R ₃₁)-,-N (C (O) NHR ₃₁)-,-N (C (O) NR ₃₁R ₃₂)-,-N (S (O) ₂NHR ₃₁)-,-N (SO ₂R ₃₁)-, or-N (C (O) OR ₃₁)-;

Wherein

R ₃₁And R ₃₂Comprise independently-hydrogen ,-alkyl ,-aryl, or-alkylidene group-aryl;

L comprises direct key ,-alkylidene group, and-alkenylene (alkenylene), or-alkynylene (alknylene); And

Q comprises direct key ,-CH ₂-,-O-, or-S-.

In another embodiment ,-NHSO ₂-Ar ₂With-NHSO ₂-Ar ₃Group is positioned at Ar ₁On the adjacent atom in the ring.In another embodiment, Ar ₁Be

Wherein J and K comprise independently:

A) hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-whole haloalkyl;

F)-alkyl;

G)-aryl;

H)-heteroaryl;

I)-cycloalkyl;

J)-the L-aryl;

K)-L-arylidene-aryl;

L)-L-arylidene-alkyl;

M)-the Q-alkyl;

N)-the Q-aryl;

O)-Q-alkylidene group-aryl;

P)-Q-arylidene-alkyl;

Q)-L-Q-alkylidene group-aryl;

R)-arylidene-Q-alkyl;

S)-the L-Q-alkyl;

T)-the L-Q-aryl;

U)-the L-Q-heteroaryl;

V)-the L-Q-cycloalkyl;

W)-L-Q-arylidene-alkyl;

X)-D ₄-alkylidene group-NR ₁R ₂

y)-D ₄-NR ₁R ₂；

Z)-D ₄-alkyl; Or

aa)-D ₄-H；

Wherein,

D ₄Comprise direct key ,-CH ₂-,-O-,-N (R ₄)-,-C (O)-,-CON (R ₄)-,-N (R ₄) C (O)-,-N (R ₄) CON (R _{4 '})-,-N (R ₄) C (O) O-,-OC (O) N (R ₄)-,-N (R ₄) SO ₂-,-SO ₂N (R4 ')-,-C (O)-O-,-O-C (O)-,-S-,-S (O)-,-S (O) ₂-,-N (R ₄) SO ₂N (R _{4 '})-, or-N=N-;

Wherein, R ₄And R _{4 '}Comprise independently-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl, or-alkylidene group-aryl;

Wherein

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

R wherein ₃₁And R ₃₂Comprise independently-hydrogen ,-alkyl ,-aryl, or-alkylidene group-aryl;

Q comprises direct key ,-CH ₂-,-O-, or-S-.

In another embodiment, J and K comprise hydrogen, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, cyano group, carboxyl, amide group ,-D independently ₄-alkyl ,-D ₄-alkylidene group-NR ₁R ₂,-D4-NR ₁R ₂,-D ₄-alkyl;-D ₄-H, wherein D ₄Comprise-C (O)-,-CON (R ₄)-,-SO ₂N (R ₄)-,-C (O)-O-, wherein R ₄Comprise-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl, or-alkylidene group-aryl;

Wherein

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

One of at least be group beyond the hydrogen among J and the K wherein.

In another embodiment, Ar ₁Be

Wherein J and K be with defined above consistent, and Ar wherein ₂And Ar ₃It is unsubstituted benzothienyl.

In another embodiment, Ar ₁Comprise unsubstituted phenylene.In another embodiment, Ar ₁Comprise unsubstituted phenylene, and-NHSO ₂-Ar ₂With-NHSO ₂-Ar ₃Group is positioned at Ar ₁On the adjacent carbons on the ring.

In another embodiment, the compound of formula (I) be with respect to by at this planar opposite side with Ar ₁With Ar ₂And Ar ₃Plane right and wrong C2 separately is symmetric.

Ar ₂And Ar ₃Comprise being optionally substituted 1 to 5 time aryl heteroaryl, fused rings alkylaryl, fused rings miscellaneous alkyl aryl, annelated heterocycles Ji Fangji, or annelated heterocycles base heteroaryl, wherein Ar independently ₂And Ar ₃In contain one of at least and-NHSO ₂-the tie point ortho position or the Sauerstoffatom or the sulphur atom of geminal.In a plurality of embodiments, Ar ₂And Ar ₃Substituting group comprise independently:

A) hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-alkyl;

F)-aryl;

G)-cycloalkyl;

H)-heterocyclic radical;

I)-alkylidene group-cycloalkyl;

J)-whole haloalkyl;

K) heteroaryl;

L)-alkylidene group-aryl;

m)-D ₁-H；

n)-D ₁-R ₃；

O)-D ₁-alkyl;

P)-D ₁-aryl;

Q)-D ₁-whole haloalkyl;

R)-D ₁-alkylidene group-R ₃

S)-D ₁-alkylidene group-aryl;

T)-D ₁-alkylidene group-D ₂-R ₃

U)-D ₁-cycloalkyl;

V)-D ₁-heterocyclic radical;

W)-D ₁-aryl;

X)-D ₁-heteroaryl;

Y)-D ₁-arylidene-D ₂-R ₃

Z)-D ₁-heteroarylidene-D ₂-R ₃

Aa)-D ₁-alkylidene group-heteroaryl;

Bb)-D ₁-alkylidenyl-heterocyclic base;

Cc)-D ₁-alkylidene group-aryl;

Dd)-D ₁-alkylidene group-arylidene-D ₂-R ₃

Ee)-D ₁-alkylidene group-heteroarylidene-D ₂-R ₃

Ff)-D ₁-alkylidene group-NR ₅R ₆

Gg)-D ₁-arylidene-NR ₅R ₆Or

Hh)-acid isostere;

Wherein,

D ₁Comprise direct key ,-CH ₂-,-O-,-N (R ₇)-,-C (O)-,-CON (R ₇)-,-N (R ₇) C (O)-,-N (R ₇) CON (R ₈)-,-N (R ₇) C (O) O-,-OC (O) N (R ₇)-,-N (R ₇) SO ₂-,-SO ₂N (R ₇)-,-C (O)-O-,-O-C (O)-,-S-,-S (O)-,-S (O) ₂-,-N (R ₇) SO ₂N (R ₈)-, or-N=N-;

Wherein, R ₇And R ₈Comprise independently-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl ,-alkylidene group-aryl, or-alkylidene group-arylidene-alkyl;

R ₃Comprise :-hydrogen ,-alkyl ,-aryl ,-heterocyclic radical, or-heteroaryl; And

R ₅And R ₆Comprise hydrogen independently, alkyl, or aryl, wherein R ₅And R ₆Can combine to form and have formula-(CH ₂) _o-Z ₁-(CH ₂) _P-ring and R ₅And R ₆Institute's azine atomic linkage,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₄Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂NH-,-OC (O)-,-N (R ₉)-,-N (C (O) R ₉)-,-N (C (O) NHR ₉)-,-N (C (O) NR ₉R ₁₀)-,-N (S (O) ₂NHR ₉)-,-N (SO ₂R ₉)-, or-N (C (O) OR ₉)-;

Wherein,

R ₉And R ₁₀Comprise independently-hydrogen ,-alkyl ,-aryl, or-alkylidene group-aryl;

D ₂Comprise-alkylidene group-,-alkenylene-,-alkylidene group-S-,-S-alkylidene group-,-alkylidene group-O-,-O-alkylidene group-,-alkylidene group-S (O) ₂-,-S (O) ₂-alkylidene group ,-O-,-N (R ₁₁)-,-C (O)-,-CON (R ₁₁)-,-N (R ₁₁) C (O)-,-N (R ₁₁) CON (R ₁₂)-,-N (R ₁₁) C (O) O-,-OC (O) N (R ₁₁)-,-N (R ₁₁) SO ₂-,-SO ₂N (R ₁₁)-,-C (O)-O-,-O-C (O)-,-S-,-S (O)-,-S (O) ₂-, or-N (R ₁₁) SO ₂N (R ₁₂)-,

Wherein,

R ₁₁And R ₁₂Comprise independently :-hydrogen ,-alkyl, or-aryl.

In one embodiment, Ar ₂And Ar ₃Comprise being optionally substituted 1 to 5 time aryl heteroaryl, fused rings alkylaryl, fused rings miscellaneous alkyl aryl, annelated heterocycles Ji Fangji, or annelated heterocycles base heteroaryl, wherein Ar independently ₂And Ar ₃In contain one of at least and-NHSO ₂-the tie point ortho position or the Sauerstoffatom or the sulphur atom of geminal, and Ar ₂And Ar ₃Be different.

In another embodiment, Ar ₂And Ar ₃Comprise being optionally substituted 1 to 5 time aryl heteroaryl, or annelated heterocycles base heteroaryl, wherein Ar independently ₂And Ar ₃In comprise one of at least and-NHSO ₂-the tie point ortho position or the Sauerstoffatom or the sulphur atom of geminal.

In another embodiment, Ar ₂And Ar ₃Comprise being optionally substituted 1 to 5 time aryl heteroaryl, or annelated heterocycles base heteroaryl, wherein Ar independently ₂And Ar ₃In comprise one of at least and-NHSO ₂-the tie point ortho position or the Sauerstoffatom or the sulphur atom of geminal, and Ar wherein ₂And Ar ₃Be different.

In another embodiment, Ar ₂And Ar ₃Comprise optional the replacement or unsubstituted phenyl independently, benzothienyl, benzofuryl, or 4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridyl, wherein Ar also ₂And Ar ₃In comprise one of at least and-NHSO ₂-the tie point ortho position or the Sauerstoffatom or the sulphur atom of geminal.

In another embodiment, Ar ₂And Ar ₃Comprise being optionally substituted 1 to 5 time aryl heteroaryl, fused rings alkylaryl, fused rings miscellaneous alkyl aryl, annelated heterocycles Ji Fangji, or annelated heterocycles base heteroaryl, wherein Ar independently ₂And Ar ₃In comprise one of at least

Perhaps

Wherein,

R ₁₃Comprise alkyl, alkylidene group-cycloalkyl, haloalkyl, whole haloalkyl, or cycloalkyl;

R ₁₄Comprise:

A)-halogen;

B)-cyano group;

C)-nitro;

D)-whole haloalkyl;

e)-D ₁-R ₁₇；

F)-D ₁-alkyl;

G)-D ₁-alkylidene group-R ₁₇

H)-D ₁-alkylidene group-D ₂-R ₁₇

I)-D ₁-aryl;

J)-D ₁-heteroaryl;

K)-D ₁-arylidene-D ₂-R ₁₇

L)-D ₁-heteroarylidene-D ₂-R ₁₇

M)-D ₁-alkylidene group-heteroaryl;

N)-D ₁-alkylidenyl-heterocyclic base;

O)-D ₁-alkylidene group-aryl;

P)-D ₁-alkylidene group-arylidene-D ₂-R ₁₇

Q)-D ₁-alkylidene group-heteroarylidene-D ₂-R ₁₇

R)-D ₁-alkylidene group-NR ₁₈R ₁₉

S)-D ₁-arylidene-NR ₁₈R ₁₉Or

T)-acid isostere;

Wherein,

D ₁Comprise direct key ,-S (O) ₂-,-CON (R ₂₀)-,-SO ₂N (R ₂₀)-,-C (O)-O-,-S-,-S (O)-;

R wherein ₂₀Comprise-hydrogen ,-alkyl ,-aryl ,-heterocyclic radical, or-heteroaryl;

R ₁₇Comprise :-hydrogen ,-alkyl ,-aryl ,-heterocyclic radical, or-heteroaryl;

R ₁₈And R ₁₉Comprise hydrogen independently, aryl, or alkyl, wherein R ₁₈And R ₁₉Can combine to form and have formula-(CH ₂) _o-Z ₂-(CH ₂) _P-ring and R ₁₈And R ₁₉Institute's azine atomic linkage,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₂Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂N (H)-,-OC (O)-,-N (R ₂₀)-,-N (C (O) R ₂₀)-,-N (C (O) NHR ₂₀)-,-N (C (O) NR ₂₀R ₂₁)-,-N (S (O) ₂NHR ₂₀)-,-N (SO ₂R ₂₀)-, or-N (C (O) OR ₂₀)-;

Wherein,

R ₂₀And R ₂₁Comprise independently-hydrogen ,-alkyl ,-aryl, or-alkylidene group-aryl;

D ₂Comprise-alkylidene group-,-alkenylene-,-alkylidene group-S-,-S-alkylidene group-,-alkylidene group-O-,-O-alkylidene group-,-alkylidene group-S (O) ₂-,-S (O) ₂-alkylidene group ,-O-,-N (R ₂₂)-,-C (O)-,-CON (R ₂₂)-,-N (R ₂₂) C (O)-,-N (R ₂₂) CON (R ₂₃)-,-N (R ₂₂) C (O) O-,-OC (O) N (R ₂₂)-,-N (R ₂₂) SO ₂-,-SO ₂N (R ₂₂)-,-C (O)-O-,-O-C (O)-,-S-,-S (O)-,-S (O) ₂-, or-N (R ₂₂) SO ₂N (R ₂₃)-,

Wherein,

R ₂₂And R ₂₃Comprise independently :-hydrogen ,-alkyl, or-aryl.

R ₁₅And R ₁₆Comprise independently:

A)-hydrogen

B)-halogen;

C)-cyano group;

D)-alkyl;

E)-aryl;

F)-alkylidene group-aryl;

g)-D ₃-H；

H)-D ₃-alkyl;

I)-D ₃-aryl;

J)-D ₃-alkylidene aryl;

K)-the Y-alkyl;

L)-the Y-aryl;

M)-Y-alkylidene group-aryl;

N)-Y-alkylidene group-NR ₂₄R ₂₅Or

O)-Y-alkylidene group-W-R ₂₆

Wherein,

D ₃Comprise-O-,-C (O)-O-,-C (O)-NH-,-SO2-,-SO2-NH-, or-C (O)-;

Y and W comprise-CH independently ₂-,-O-,-N (H) ,-S-, SO ₂-,-CON (H)-,-NHC (O)-,-NHCON (H)-,-NHSO ₂-,-SO ₂N (H)-,-C (O)-O-,-NHSO ₂NH-and-O-CO-,

R ₂₆Comprise aryl, alkyl, alkylidene group-aryl, alkoxyl group, and alkoxy aryl;

R ₂₄And R ₂₅Comprise hydrogen independently, aryl, and alkyl, hydrogen wherein, aryl, or alkyl, wherein R ₂₄And R ₂₅Can combine to form and have formula-(CH ₂) _o-Z ₃-(CH ₂) _P-ring and R ₂₄And R ₂₅Institute's azine atomic linkage,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₃Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂N (H)-,-OC (O)-,-N (R ₂₉)-,-N (C (O) R ₂₉)-,-N (C (O) NHR ₂₉)-,-N (C (O) NR ₂₉R ₃₀)-,-N (S (O) ₂NHR ₂₉)-,-N (SO ₂R ₂₉)-, or-N (C (O) OR ₂₉)-;

Wherein,

R ₂₉And R ₃₀Comprise hydrogen independently, aryl, alkyl, or-alkylaryl;

R ₂₆Comprise hydrogen, alkyl, aryl, and alkylidene group-aryl;

X comprises sulphur or oxygen; And

M and n are 0,1 or 2 independently.

In another embodiment,

Ar ₂Comprise

Wherein,

R ₁₄Comprise:

A)-D ₁-perhalogeno-C ₂-C ₆Alkyl;

B)-D ₁-alkylidene group-heteroaryl;

C)-D ₁-alkylidenyl-heterocyclic base;

D)-D ₁-alkylidene group-NR ₁₈R ₁₉Or

E)-acid isostere;

Wherein,

R ₁₃, R ₁₅, R ₁₈, R ₁₉And D ₁With defined above consistent.

In another embodiment, Ar ₂Comprise

And Ar ₃Comprise

R wherein ₁₃, R ₁₄, R ₁₅, R ₁₆, X, m and n are with defined above consistent.

In another embodiment, Ar ₂Comprise

And Ar ₃The phenyl that comprises substituted 11 to 5 time, wherein Ar ₂And Ar ₃Be different, and R ₁₃, R ₁₄, R ₁₅With m with defined above consistent.In another embodiment, Ar ₃Comprise the phenyl that is replaced by at least one halogen.

In another embodiment, Ar ₂Comprise And Ar ₃Comprise and be optionally substituted 1 to 5 time phenyl, benzothienyl, or benzofuryl, wherein Ar ₂And Ar ₃Be identical or different, and R ₁₆With n with defined above consistent.

In another embodiment, Ar ₂Comprise unsubstituted benzothienyl.

In another embodiment, Ar ₂And Ar ₃Be different.

At J, K, Ar ₂, Ar ₃And R ₁To R ₃₂In alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylidene group, cycloalkylidene, inferior heterocyclic radical, arylidene, and heteroaryl can be substituted that base is optional to be replaced 1 to 4 time, this substituting group comprises:

A)-hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-whole haloalkyl;

F)-the A-whole haloalkyl;

g)-A-R ₄₀；

H)-the A-alkyl;

I)-the A-aryl;

J)-A-alkylidene group-aryl;

K)-A-alkylidene group-NR ₄₁R ₄₂Or

L)-A-alkylidene group-E-R ₄₃

Wherein,

A and E comprise independently :-CH ₂-,-O-,-N (R ₄₄)-,-C (O)-,-CON (R ₄₄)-,-N (R ₄₄) C (O)-,-N (R ₄₄) CON (R ₄₅)-,-N (R ₄₄) C (O) O-,-OC (O) N (R ₄₄)-,-N (R ₄₄) SO ₂-,-SO ₂N (R ₄₄)-,-C (O)-O-,-O-C (O)-, or-N (R ₄₄) SO ₂N (R ₄₅)-,

R wherein ₄₄And R ₄₅Comprise independently :-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl ,-alkylidene group-aryl and-alkylidene group-arylidene-alkyl;

R ₄₀And R ₄₃Comprise independently :-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl ,-alkylidene group-aryl and-alkylidene group-arylidene-alkyl; And

R ₄₁And R ₄₂Comprise hydrogen independently, aryl, or alkyl, wherein R ₄₁And R ₄₂Can combine to form and have formula-(CH ₂) _o-Z ₄-(CH ₂) _P-ring and R ₄₁And R ₄₂Institute's azine atomic linkage,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₄Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂N (H)-,-OC (O)-,-N (R ₄₆)-,-N (C (O) R ₄₆)-,-N (C (O) NHR ₄₆)-,-N (C (O) NR ₄₆R ₄₇)-,-N (S (O) ₂NHR ₄₆)-,-N (SO ₂R ₄₆)-, or-N (C (O) OR ₄₆)-;

Wherein,

R ₄₆And R ₄₇Comprise hydrogen independently, aryl, alkyl, or-alkylidene group-aryl;

The example of the compound of formula of the present invention (I) sees Table 1 and the embodiment part.

Table 1

Except as otherwise noted, the structure of embodiment of compound with formula (I) of heteroatoms such as oxygen and nitrogen room connectivity (vacantconnectivity) supposes that all that hydrogen atom is arranged is coupled.

Term used herein " rudimentary " is meant that a group contains one to six carbon.

Term used herein " alkyl " is meant the straight or branched hydrocarbon that contains one to ten carbon atom, and it is selected from optional replacement of substituting group of following groups, and allows repeatedly to replace: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; rudimentary alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silylation that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Like this " alkyl " can comprise one or more O, S, S (O), or S (O) ₂Atom.The example of " alkyl " used herein includes, but are not limited to methyl, normal-butyl, the tertiary butyl, n-propyl, isobutyl-and sec.-propyl etc.

Term used herein " alkylidene group " is meant the straight or branched bivalent hydrocarbon radical that contains one to ten carbon atom, and it is selected from optional replacement of substituting group of following groups, and allows repeatedly to replace: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; rudimentary alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Like this " alkylidene group " can comprise one or more O, S, S (O), or S (O) ₂Atom.The example of " alkylidene group " used herein includes, but are not limited to methylene radical, ethylidene etc.

Term used herein " thiazolinyl " is meant the alkyl that contains two to ten carbon and at least one carbon-to-carbon double bond, and it is selected from optional replacement of substituting group of following groups, and allows the replacement of multiple degree: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; rudimentary alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Like this " thiazolinyl " can comprise one or more O, S, S (O), or S (O) ₂Atom.

Term used herein " alkenylene " is meant the straight or branched bivalent hydrocarbon radical that contains two to ten carbon atoms and one or more carbon-to-carbon double bonds; it is selected from optional replacement of substituting group of following groups; and allow the replacement of multiple degree: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Like this " alkenylene " can comprise one or more O, S, S (O), or S (O) ₂Atom.The example of " alkenylene " used herein includes, but are not limited to ethene-1,2-two bases, propylene-1,3-two bases, methylene radical-1,1-two bases etc.

Term used herein " alkynyl " is meant the alkyl that contains two to ten carbon and at least one carbon-to-carbon three key, and it is selected from optional replacement of substituting group of following groups, and allows the replacement of multiple degree: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Like this " alkynyl " can comprise one or more O, S, S (O), or S (O) ₂Atom.

Term used herein " alkynylene " is meant the straight or branched bivalent hydrocarbon radical that contains two to ten carbon atoms and one or more carbon-to-carbon three key; it is selected from optional replacement of substituting group of following groups; and allow the replacement of multiple degree: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Like this " alkynylene " can comprise one or more O, S, S (O), or S (O) ₂Atom.The example of " alkynylene " used herein includes, but are not limited to acetylene-1,2-two bases, propine-1,3-two bases etc.

" cycloalkyl " used herein is meant the optional alicyclic hydrocarbon radical that has one or more degrees of unsaturation and contain three to 12 carbon atoms; it is selected from optional replacement of substituting group of following groups; and allow the replacement of multiple degree: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl." cycloalkyl " comprise, cyclopropyl for example, and cyclobutyl, cyclopentyl, cyclohexyl, suberyl, or the ring octyl group etc.

Term used herein " cycloalkylidene " is meant and contains three to 12 carbon atoms and optional alicyclic bivalent hydrocarbon radical with non-aromatic of one or more degrees of unsaturation; it is selected from optional replacement of substituting group of following groups; and allow the replacement of multiple degree: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.The example of " cycloalkylidene " used herein includes, but are not limited to encircle the third-1, and 1-two bases encircle the third-1,2-two bases, ring fourth-1,2-two bases, ring penta-1,3-two bases, hexamethylene-1,4-two bases, ring heptan-1,4-two bases, or ring suffering-1,5-two bases etc.

Term used herein " heterocycle " or " heterocyclic radical " are meant optional three to ten binary heterocycles with one or more degrees of unsaturation, and it comprises one or more S of being selected from, SO, SO ₂, the replacement heteroatoms of O or N, and be selected from optional replacement of substituting group of following groups, and allow multiple degree to replace: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl, oxo, hydroxyl; sulfydryl is by the optional amino that replaces of alkyl, carboxyl; by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl, nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Such ring can be chosen wantonly and be fused on one or more other " heterocycles " or the cycloalkyl ring.The example of " heterocycle " includes, but are not limited to tetrahydrofuran (THF), and 1,4-dioxane, 1,3-dioxane, piperidines, Pyrrolidine, morpholine, piperazine etc.

Term used herein " inferior heterocyclic radical " is meant optional three to ten binary heterocyclic radicals with one or more degrees of unsaturation, and it comprises one or more S of being selected from, SO, SO ₂, the heteroatoms of O or N, and be selected from optional replacement of substituting group of following groups, and allow the more that the kind degree replaces: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl, oxo, hydroxyl; sulfydryl is by the optional amino that replaces of alkyl, carboxyl; by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl, nitro; cyano group, halogen, or rudimentary perfluoroalkyl.Such ring can be chosen wantonly and be fused to one or more phenyl ring, or on one or more other " heterocycles " or the cycloalkyl ring.The example of " inferior heterocyclic radical " includes, but are not limited to tetrahydrofuran (THF)-2,5-two bases, morpholine-2,3-two bases, pyrans-2,4-two bases, 1,4-dioxane-2,3-two bases, 1,3-dioxane-2,4-two bases, piperidines-2,4-two bases, piperidines-1,4-two bases, Pyrrolidine-1,3-two bases, morpholine-2,4-two bases, piperazine-1,4-two bases etc.

Term used herein " aryl " is meant phenyl ring or is fused to the phenyl ring system of the optional replacement on the phenyl ring of one or more optional replacements that it is selected from optional replacement of substituting group of following groups, and allows multiple degree to replace: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl, oxygen, hydroxyl; sulfydryl is by the optional amino that replaces of alkyl, carboxyl; tetrazyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; acyl group, aroyl, 4-hetaroylpyrazol; acyloxy; aryl acyloxy, assorted aryl acyloxy, alkoxy carbonyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.The example of aryl includes, but are not limited to phenyl, 2-naphthyl, 1-naphthyl, 1-anthryl etc.

Term used herein " arylidene " is meant the phenyl ring double-basis or is fused to phenyl ring system double-basis on the phenyl ring of one or more optional replacements that it is selected from optional replacement of substituting group of following groups, and allows the replacement of multiple degree: low alkyl group; lower alkoxy, low-grade alkyl sulphur alkyl, low alkyl group sulfinyl; the low alkyl group alkylsulfonyl, oxo, hydroxyl; sulfydryl is by the optional amino that replaces of alkyl, carboxyl; tetrazyl is by the optional formamyl that replaces of alkyl, by the optional amino-sulfonyl that replaces of alkyl; acyl group, aroyl, 4-hetaroylpyrazol; acyloxy; aryl acyloxy, assorted aryl acyloxy, alkoxy carbonyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.The example of " arylidene " includes, but are not limited to benzene-1,4-two bases, naphthalene-1,8-two bases etc.

Term used herein " heteroaryl " is meant and comprises one or more nitrogen, five to seven yuan of aromatic rings of oxygen or sulfur heteroatom or many cyclophanes heterocycle, and N-oxide compound and sulphur monoxide and sulphur dioxide are the fragrant heterocyclic substituted things of permission there; heteroaryl is selected from optional replacement of substituting group of following groups, and allows repeatedly to replace: low alkyl group, lower alkoxy; the low-grade alkyl sulphur alkyl, low alkyl group sulfinyl, low alkyl group alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl, tetrazyl is by the optional formamyl that replaces of alkyl; by the optional amino-sulfonyl that replaces of alkyl; acyl group, aroyl, 4-hetaroylpyrazol; acyloxy; aryl acyloxy, assorted aryl acyloxy, alkoxy carbonyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.For many cyclophanes loop systems, wherein one or more rings can comprise one or more heteroatomss.The example of " heteroaryl " used herein has furans, thiophene, pyrroles, imidazoles, pyrazoles, triazole, tetrazolium, thiazole oxazole ， isoxazole ， oxadiazole, thiadiazoles, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline 99.9, quinazoline, cumarone, thionaphthene, indoles and indazole etc.

Term used herein " heteroarylidene " is meant and comprises one or more nitrogen, five to seven yuan of aromatic ring double-basis of oxygen or sulfur heteroatom or many cyclophanes heterocycle double-basis, and N-oxide compound and sulphur monoxide and sulphur dioxide are the fragrant heterocyclic substituted things of permission there; heteroarylidene is selected from optional replacement of substituting group of following groups, and allows multiple degree to replace: low alkyl group, lower alkoxy; the low-grade alkyl sulphur alkyl, low alkyl group sulfinyl, low alkyl group alkylsulfonyl; oxo, hydroxyl, sulfydryl; by the optional amino that replaces of alkyl; carboxyl, tetrazyl is by the optional formamyl that replaces of alkyl; by the optional amino-sulfonyl that replaces of alkyl; acyl group, aroyl, 4-hetaroylpyrazol; acyloxy; aryl acyloxy, assorted aryl acyloxy, alkoxy carbonyl; alkoxy; the optional siloxy that replaces of alkyl or aryl, alkoxy, the optional silyl that replaces of alkyl or aryl; nitro; cyano group, halogen, or rudimentary perfluoroalkyl.For many cyclophanes loop systems double-basis, wherein one or more rings can comprise one or more heteroatomss.The example of " heteroarylidene " used herein has furans-2,5-two bases, thiophene-2,4-two bases, 1,3,4-oxadiazole-2,5-two bases, 1,3,4-thiadiazoles-2,5-two bases, 1,3-thiazoles-2,4-two bases, 1,3-thiazoles-2,5-two bases, pyridine-2,4-two bases, pyridine-2,3-two bases, pyridine-2,5-two bases, pyrimidine-2,4-two bases, quinoline-2,3-two bases etc.

Term used herein " fused rings alkylaryl " is meant the cycloalkyl that is fused to aryl, two atoms of these two partial commons of cycloalkyl and aryl, and wherein aryl is the position that metalepsy takes place.The example of " fused rings alkylaryl " used herein comprises the 5-indanyl, 5,6,7, and 8-tetrahydrochysene-2-naphthyl,

Deng.

Term used herein " fused rings alkyl arylene " is meant the fused rings alkylaryl, and aryl wherein is a divalence.Example comprises

Deng.

Term used herein " fused-aryl cycloalkyl " is meant the aryl that is fused to cycloalkyl, two atoms of these two partial commons of aryl and cycloalkyl, and wherein cycloalkyl is the position that metalepsy takes place.The example of " fused-aryl cycloalkyl " used herein comprises the 1-indanyl, the 2-indanyl, and 1-(1,2,3, the 4-tetralyl), Deng.

Term used herein " fused-aryl cycloalkylidene " is meant the fused-aryl cycloalkyl, and cycloalkyl wherein is a divalence.Example comprises,

Deng.

Term used herein " annelated heterocycles Ji Fangji " is meant the heterocyclic radical that is fused to aryl, two atoms of these two partial commons of heterocyclic radical and aryl, and wherein aryl is the position that metalepsy takes place.The example of " annelated heterocycles Ji Fangji " used herein comprises 3,4-methylene-dioxy-1-phenyl,

Deng.

Term used herein " annelated heterocycles base arylidene " is meant annelated heterocycles Ji Fangji, and aryl wherein is a divalence.Example comprises,

Deng.

Term used herein " fused-aryl heterocyclic radical " is meant the aryl that is fused to heterocyclic radical, two atoms of these two partial commons of aryl and heterocyclic radical, and wherein heterocyclic radical is the position that metalepsy takes place.The example of " fused-aryl heterocyclic radical " used herein comprises 2-(1,3-benzene dioxy base),

Deng.

Term used herein " the inferior heterocyclic radical of fused-aryl " is meant the fused-aryl heterocyclic radical, and heterocyclic radical wherein is a divalence.Example comprises Deng.

Term used herein " fused rings miscellaneous alkyl aryl " is meant the cycloalkyl that is fused to heteroaryl, two atoms of these two partial commons of cycloalkyl and heteroaryl, and wherein heteroaryl is the position that metalepsy takes place.The example of " fused rings miscellaneous alkyl aryl " used herein comprises 5-azepine-6-indanyl,

Deng.

Term used herein " fused rings alkyl inferior heteroaryl " is meant the fused rings miscellaneous alkyl aryl, and heteroaryl wherein is a divalence.Example comprises

Deng.

Term used herein " condensed heteroaryl cycloalkyl " is meant the heteroaryl that is fused to cycloalkyl, two atoms of these two partial commons of heteroaryl and cycloalkyl, and wherein cycloalkyl is the position that metalepsy takes place.The example of " condensed heteroaryl cycloalkyl " used herein comprises 5-azepine-1-indanyl,

Deng.

Term used herein " condensed heteroaryl cycloalkylidene " is meant the condensed heteroaryl cycloalkyl, and cycloalkyl wherein is a divalence.Example comprises

Deng.

Term used herein " annelated heterocycles base heteroaryl " is meant the heterocyclic radical that is fused to heteroaryl, two atoms of these two partial commons of heterocyclic radical and heteroaryl, and wherein heteroaryl is the position that metalepsy takes place.The example of " annelated heterocycles base heteroaryl " used herein comprises 1,2,3,4-tetrahydrochysene-β-Ka Lin-8-base, and 6,7-dihydro-4H-thieno-[3,2-c] pyridine,

Deng.

Term used herein " annelated heterocycles base inferior heteroaryl " is meant annelated heterocycles base heteroaryl, and heteroaryl wherein is a divalence.Example comprises

Deng.

Term used herein " condensed heteroaryl heterocyclic radical " is meant the heteroaryl that is fused to heterocyclic radical, two atoms of these two partial commons of heteroaryl and heterocyclic radical, and wherein heterocyclic radical is the position that metalepsy takes place.The example of " condensed heteroaryl heterocyclic radical " used herein comprises 5-azepine-2,3-Dihydrobenzofuranes-2-base,

Deng.

Term used herein " the inferior heterocyclic radical of condensed heteroaryl " is meant the condensed heteroaryl heterocyclic radical, and heterocyclic radical wherein is a divalence.Example comprises

Deng.

Term used herein " acid isostere " be meant can be under the physiological pH condition ionization and with the substituting group of net negative charge.The example of this " acid isostere " includes but not limited to heteroaryl, such as but not limited to isoxazol-3-ol-5-base, and 1H-tetrazolium-5-base, or 2H-tetrazolium-5-base.This acid isostere includes but not limited to heterocyclic radical, such as but not limited to imidazolidine-2, and 4-diketone-5-base, imidazolidine-2,4-diketone-1-base, 1,3-thiazoles alkane-2,4-diketone-5-base, or 5-hydroxyl-4H-pyrans-4-ketone-2-base.

Term used herein " directly key " is as the part of varied texture explanation, is meant with (front and back) substituting group at the variable flank that is called as " direct key " directly to be connected.

Term used herein " whole haloalkyl " is meant the straight or branched hydrocarbon that contains 1 to 10 carbon atom, and the position of each metalepsy generation is all replaced by halogen atom there.Whole haloalkyl can be replaced by one or more halogen atoms.The example of " whole haloalkyl " used herein includes, but are not limited to trifluoromethyl and 1,1-two chloro-2,2,2-trifluoroethyl etc.

Term used herein " geminal " is meant two identical or different independent atoms, and chemical group or substituting group link to each other with same atom.A kind of like this " geminal " relation can occur in atomchain or the loop systems.For example, in the 2-methoxypyridine, nitrogen-atoms and methoxyl group are " geminal " relation.

Term used herein " ortho position " is meant two identical or different independent atoms, and chemical group or substituting group link to each other with adjacent atom.Two such " ortho position " atoms, substituting group or chemical group can replace the adjacent atom of successive in atomchain or the loop systems.For example, in catechol, two phenolic hydroxyl groups are considered to " ortho position " relation.

Term used herein " alkoxyl group " is meant radicals R _aO-, wherein R _aIt is alkyl.

Term used herein " alkene oxygen base " is meant radicals R _aO-, wherein R _aIt is thiazolinyl.

Term used herein " alkynyloxy group " is meant radicals R _aO-, wherein R _aIt is alkynyl.

Term used herein " alkyl alkylthio base " is meant radicals R _aS-, wherein R _aIt is alkyl.

Term used herein " thiazolinyl sulfane base " is meant radicals R _aS-, wherein R _aIt is thiazolinyl.

Term used herein " alkynyl sulfane base " is meant radicals R _aS-, wherein R _aIt is alkynyl.

Term used herein " alkyl sulphinyl " is meant radicals R _aS (O)-, R wherein _aIt is alkyl.

Term used herein " thiazolinyl sulfinyl " is meant radicals R _aS (O)-, R wherein _aIt is thiazolinyl.

Term used herein " alkynyl sulfinyl " is meant radicals R _aS (O)-, R wherein _aIt is alkynyl.

Term used herein " alkyl sulphonyl " is meant radicals R _aSO ₂-, R wherein _aIt is alkyl.

Term used herein " thiazolinyl alkylsulfonyl " is meant radicals R _aSO ₂-, R wherein _aIt is thiazolinyl.

Term used herein " alkynyl alkylsulfonyl " is meant radicals R _aSO ₂-, R wherein _aIt is alkynyl.

Term used herein " acyl group " is meant radicals R _aC (O)-, R wherein _aBe alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, or heterocyclic radical.

Term used herein " aroyl " is meant radicals R _aC (O)-, R wherein _aIt is aryl.

Term used herein " 4-hetaroylpyrazol " is meant radicals R _aC (O)-, R wherein _aIt is heteroaryl.

Term used herein " alkoxy carbonyl " is meant radicals R _aOC (O)-, R wherein _aBe alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, or heterocyclic radical.

Term used herein " aryl acyloxy " is meant radicals R _aC (O) O-, wherein R _aIt is aryl.

Term used herein " assorted aryl acyloxy " is meant radicals R _aC (O) O-, wherein R _aIt is heteroaryl.

Term used herein " is chosen wantonly " and is represented that the incident of describing subsequently may take place or not take place, and comprises event and not event.

Term used herein " replacement " is meant that appointed substituting group or a plurality of substituting group replace, and except as otherwise noted, multiple degree replacement is allowed to.

Term used herein " comprises " can refer to one or more arbitrary O, S, SO, SO ₂, N or N-alkyl be at alkyl defined above, thiazolinyl, and any locational embedding of alkynyl or naphthenic substituent replaces, comprises, for example ,-CH ₂-O-CH ₂-,-CH ₂-SO ₂-CH ₂-,-CH ₂-NH-CH ₃Deng.

When term " alkyl " or " aryl " or any one their prefix root appeared in the substituent title (for example, the alkoxy aryl aryloxy), they were understood to include those definition to " alkyl " and " aryl " that above provide.Carbon atom specify number (for example, C ₁-C ₁₀) should refer to alkyl independently, the carbon atom number in alkenyl or alkynyl or the cycloalkyl refers to that perhaps term " alkyl " appears at the carbon atom number of big substituent moieties wherein with its prefix root.

Term used herein " oxo " should refer to substituting group=O.

Term used herein " halogen " should comprise iodine, bromine, chlorine and fluorine.

Term used herein " sulfydryl " should refer to substituting group-SH.

Term used herein " carboxyl " should refer to substituting group-COOH.

Term used herein " cyano group " should refer to substituting group-CN.

Term used herein " sulphonamide " should refer to substituting group-SO ₂NH ₂

Term used herein " carbamyl " should refer to substituting group-C (O) NH ₂

Term used herein " sulfane base " should refer to substituting group-S-.

Term used herein " sulfinyl " should refer to substituting group-S (O)-.

Term used herein " alkylsulfonyl " should refer to substituting group-S (O) ₂-.

The compound of formula (I) can be according to the preparation of following reacting flow chart (define consistent of variable wherein and preamble or define in schema and embodiment).In these reactions, can use equally to one skilled in the art will appreciate that but the more not detailed in this article variable of mentioning.

Schema 1 has been described the preparation method of the compound of formula (2).Ar in this schema ₁And Ar ₃Have and the middle Ar of formula (I) ₁And Ar ₃Same implication.R ₅₁Represent substituting group for example, but be not limited to alkyl, aryl, heteroaryl, alkoxy or halogen.

Schema 1

Two sulphonamide (2) are by preparing handling phenylenediamine (1) under 0 ℃ to 100 ℃ temperature in the presence of alkali such as pyridine or the triethylamine in aprotic solvent such as methylene dichloride or DMF with aryl or heteroaryl SULPHURYL CHLORIDE.

Schema 2 has been described the synthetic method of the compound of formula (4).

Schema 2

Phenylenediamine (1) is placing an order sulfonation to obtain sulphonamide aniline (3) in 0 ℃ to 100 ℃ temperature at aprotic solvent in such as but not limited to methylene dichloride or DMF with aryl or heteroaryl SULPHURYL CHLORIDE in the presence of alkali such as pyridine or the triethylamine.Such sulfonation reaction preferably takes place under the condition of using 0.5 to 1.5 molar equivalent SULPHURYL CHLORIDE.Gained sulphonamide aniline (3) with aryl or heteroaryl SULPHURYL CHLORIDE in the presence of alkali such as pyridine or the triethylamine in aprotic solvent such as methylene dichloride or DMF under 0 ℃ to 100 ℃ temperature further sulfonation so that two sulphonamide (4) to be provided.

Schema 3 has been described the another kind of synthetic method of the compound of formula (4).

Schema 3

Do not replace or be substituted basic R ₅₁The 2-N-methyl-p-nitroaniline (5) that replaces can with aryl or heteroaryl SULPHURYL CHLORIDE in solvent pyridine and optional non-proton solubility promoter such as DMF or second eyeball in the presence of alkali such as pyridine or the triethylamine under 0 ℃ to 100 ℃ temperature sulfonation with acquisition 2-sulfonamido nitro aryl intermediate.The 2-sulfonamido nitro-aromatic of Huo Deing is used such as but not limited to noble metal catalyst such as palladium hydrogenation on carbon like this, perhaps uses SnCl ₂In EtOH, (perhaps use LiAlH ₄) reduction of reductive method, so that 2-sulfonamido aniline (6) to be provided.Obtain (4) with preceding method sulfonation aniline (6).

Schema 4 has been described the preparation method of SULPHURYL CHLORIDE (8).R ₅₂Be such as but not limited to alkyl, aryl, alkoxyl group, or-substituting group of alkylaryl.

Schema 4

SULPHURYL CHLORIDE (8) by aromatic hydrocarbons or assorted aromatic hydrocarbons (7) and chlorsulfonic acid in solvent such as DCM or DCE under 0 ℃ to 100 ℃ temperature prepared in reaction, to obtain required SULPHURYL CHLORIDE (8).

Schema 5 has been described the another kind of synthetic method of SULPHURYL CHLORIDE (8).X is Br or I.M is-MgX or Li.

Schema 5

The aromatic hydrocarbons of halogen substituent or assorted aromatic hydrocarbons (9) in solvent such as ether or THF, ℃ handle to make its metallization with MAGNESIUM METAL down to 100 ℃ in temperature-20, obtain M to be-organometallic reagent (10) of MgX.In addition, with n-Butyl Lithium in rare gas element in solvent such as ether or THF, handle (9) in temperature-78 ℃ down to 0 ℃, obtaining wherein, M is Li (10).In addition, with 2 normal tert-butyl lithium in rare gas element in solvent such as ether or THF, handle (9) in temperature-78 ℃ down to 0 ℃, obtaining wherein, M is Li (10).The assorted aromatic hydrocarbons (10) of metallization aromatic hydrocarbons of Xing Chenging or metallization is handled in ether solvents such as THF with sulfurous gas and is obtained-sulfinate like this, and-sulfinate is handled with N-chlorosuccinimide or sulfuryl chloride subsequently, so that purpose SULPHURYL CHLORIDE (8) to be provided.

The present invention also provides and has synthesized the method that is used as the compound of intermediate in the preparation of the compound of formula (I) in the method for the compound that preparation formula (I) is provided.

Program A

At the aryl sulfonyl chloride (2.2mmol) that in the solution of DCM (4mL) and pyridine (1mL), repeatedly adds 0 ℃ under 0 ℃ to 0 ℃ O-Phenylene Diamine (1mmol) on a small quantity.While stirring reaction mixture is heated to RT gradually then, continue stirs, until determining that through TLC or LC-MS reaction finishes.In some cases, can allow to react the DMAP catalysis of spending the night and carrying out and/or adding catalytic amount for guaranteeing to react to finish.Reaction mixture is used DCM (5mL) dilution then.Organic phase the 10%HCl aqueous solution (5mL), water (5mL) and the water washing of 5mL salt.Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc system wash-out purifying, obtains the two sulphonamide that need through rapid column chromatography (flashcolumn chromatography).

Program B

At the aryl sulfonyl chloride (1.1mmol) that in the solution of DCM (4mL) and pyridine (1mL), repeatedly adds 0 ℃ under 0 ℃ to 0 ℃ O-Phenylene Diamine (1mmol) on a small quantity.While stirring reaction mixture is heated to RT gradually then, continue stirs, until determining that through TLC or LC-MS reaction finishes.Reaction mixture is used DCM (5mL) dilution then.Organic phase water (2 * 5mL) and the water washing of 5mL salt.Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc system wash-out purifying, obtains sulphonamide through rapid column chromatography (flash column chromatography).

As above gained list sulphonamide (1mmol) is dissolved in DCM (2mL) and the pyridine (2mL).Under RT, add aryl sulfonyl chloride (1.1mmol) then, then reaction mixture under RT, stirs spend the night or to reaction through TLC or LC-MS is definite finishes.In some cases, can allow to react the DMAP catalysis of spending the night and carrying out and/or adding catalytic amount for guaranteeing to react to finish.Reaction mixture is used DCM (5mL) dilution then.Organic phase the 10%HCl aqueous solution (5mL), water (5mL) and the water washing of 5mL salt.Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc system wash-out purifying, obtains the two sulphonamide that need through rapid column chromatography (flash column chromatography).

Program C

Under RT, in the stirred solution of pyridine (4mL), add SULPHURYL CHLORIDE (2.2mmol), at 100 ℃ of heating gained reaction mixtures, determine to finish through TLC or LC-MS then until reaction to N-methyl-p-nitroaniline (2mmol).Reaction mixture is with EtOAc (20mL) dilution, and with the 10%HCl aqueous solution (2 * 10mL), water (2 * 10mL) and salt solution (10mL) wash.Product can be without being further purified direct use, perhaps can use after being the eluent purifying with the EtOAc/ hexane on the silica gel column chromatography.

Hydrogenation is finished under 1 normal atmosphere with 10%Pd/C (wetting) in MeOH.In addition, when hydrogenation is inapplicable, finish reduction according to following method: to adding iron powder (20mmol) from the sulphonamide (2mmol) among the above-mentioned AcOH (2mL) with Fe/AcOH.Determine to finish through TLC or LC-MS until reaction at 100 ℃ of reacting by heating mixtures then.Reaction mixture is to RT subsequently, and under brute force stirs with EtOAc (20mL) dilution.With Celite pad filtering suspension liquid, filtrate vacuum concentration is subsequently removed most of acetate then.The gained residue is dissolved in EtOAc (20mL) again, uses the saturated bicarbonate aqueous solution (20mL) successively, water (20mL) and salt solution (20mL) washing.Product is used for further conversion under the situation of not carrying out any purifying.

Term used herein " pharmaceutical composition " is meant a kind of composition, and it can be by for example oral, part, parenteral, suck spraying, or mode such as rectum, to comprise conventional non-toxic carrier, thinner, adjuvant, the unit dose formulations of vehicle etc. gives mammalian hosts.

Term used herein " parenteral " comprises subcutaneous injection, intravenous injection, and intramuscularly, intracisternal injection (intracisternal injection), or pass through infusion techniques.

The pharmaceutical composition that contains compound of the present invention can be to be suitable for form for oral use, tablet for example, lozenge (troches), lozenge (lozenges), water-based or oiliness suspensoid, dispersion powder or granule, emulsion, hard or soft capsule, perhaps syrup or elixir.Composition for oral use can be according to the preparation of any currently known methods, and such composition may contain one or more and be selected from sweeting agent, perfume compound, and the reagent of tinting material and sanitas is to provide the attractive in appearance and good preparation of mouthfeel good opinion on the pharmacopedics.Tablet can comprise activeconstituents and be suitable for making the mixture of the nontoxic pharmaceutical excipient of tablet.These vehicle may be, inert diluent for example, and as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation and disintegrating agent are as W-Gum or Lalgine; Tackiness agent, as starch, gelatin or gum arabic; And lubricant, as Magnesium Stearate, stearic acid or talcum powder.Tablet can be a dressing not, perhaps with the known technology dressing postponing in GI disintegration and absorption, thereby the effect that the longer time continues is provided.For example, can use time-delay material such as glyceryl monostearate or distearin.Tablet can also be with being described in United States Patent (USP) 4,356, and 108,4,166,452 and 4,265,874 technology coatings is to form the osmotic therapeutic tablets of controlled release.

Formulation for oral use also can be a hard gelatin capsule, and activeconstituents wherein and inert solid diluent be lime carbonate for example, and calcium phosphate or kaolin mix, or soft gelatin capsule, activeconstituents wherein and water or oil medium such as peanut oil, whiteruss, or mixed with olive oil.

Aqueous suspension can comprise active compound and be suitable for making the mixture of the vehicle of aqueous suspension.Such vehicle is a suspending agent, Xylo-Mucine for example, methylcellulose gum, HPMC, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic; Dispersion or wetting agent can be natural phospholipids, as Yelkin TTS, or the condensation product of alkylene oxide and lipid acid, as polyoxyethylene stearic acid ester, or the condensation product of oxyethane and long chain aliphatic alcohol, as 17 ethyls-alkene oxygen hexadecanol (Heptadecaethyl-eneoxycetanol), or oxyethane and derive from lipid acid and the condensation product of the part ester of hexitol (partial esters), as octadecanoic acid ester of polyethylene glycol, or oxyethane and derive from lipid acid and the condensation product of the part ester of hexitan (partial esters), as the polyethylene sorbitan mono-oleic acid ester.Aqueous suspension can also comprise one or more tinting materials, and one or more perfume compound, and one or more sweeting agents are as sucrose or asccharin.

The oiliness suspensoid can be suspended in vegetables oil such as peanut oil by making activeconstituents, sweet oil, and sesame oil or Oleum Cocois, perhaps formulated in mineral oil such as the whiteruss.The oiliness suspensoid can comprise thickening material, for example beeswax, paraffinum durum or hexadecanol.Sweeting agent as indicated above and perfume compound can add wherein to provide mouthfeel good oral preparations.These compositions are preserved by adding oxidation inhibitor such as xitix.

Be suitable for providing active compound and dispersion or wetting agent, the mixture of suspending agent and one or more sanitass by adding dispersion powder and the granule that entry prepares aqueous suspension.Suitable dispersion or wetting agent and suspending agent with above mentioned those as an example.Other vehicle is sweeting agent for example, and perfume compound and tinting material can appear in the aqueous suspension equally.

Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be a vegetables oil, for example sweet oil or peanut oil, or mineral oil, for example whiteruss, or its mixture.Examples of suitable emulsifiers can be a natural gum, for example Sudan Gum-arabic (gum acacia) or tragacanth, natural phospholipid, soybean phospholipid for example, Yelkin TTS and available from ester or part ester (partial esters), for example sorbitan mono-oleic acid ester of lipid acid and hexitan, and the condensation product of described part ester and oxyethane, for example polyoxyethylenesorbitan sorbitan monooleate.Emulsion can comprise sweeting agent and perfume compound equally.

Syrup and elixir sweeting agent such as glycerine, propylene glycol, sorbyl alcohol or sucrose preparation.Such formulation also can comprise negative catalyst (demulcent), sanitas and fragrance and tinting material.Pharmaceutical composition can be the form of sterile water for injection or oily suspension.This suspension can be according to currently known methods with above-described suitable dispersion or wetting agent and suspending agent preparation.Aseptic injection preparation can be aseptic injectable solution or the suspension in nontoxic administered parenterally acceptable diluent or solvent, for example solution in 1,3 butylene glycol equally.Operable in acceptable vehicle and solvent is water, Ringer ' s solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil (fixed oils) is used as solvent or suspending medium easily.Be this purpose, the fixed oil of any gentleness with synthetic glycerine monoesters or triglyceride can use.In addition, lipid acid such as oleic acid are found in the purposes in the preparation injection.

Composition can be the form of suppository also, is used for the rectal administration of compound of the present invention.These compositions can prepare by medicine is mixed with the nonirritant excipient that suits, and this vehicle is solid at normal temperatures, but is liquid under rectal temperature, discharges medicine thereby therefore can melt in rectum.Such material comprises, for example theobroma oil and polyoxyethylene glycol.

Use for the part, conceived the ointment that contains compound of the present invention, ointment, gelifying agent, suspendible liquor or the like all is feasible.For the application's purpose, local ointment should comprise mouth wash shua and gargle the larynx agent.

Compound of the present invention can also be with the liposome delivery system, as little individual layer capsule, and the mode administration of big individual layer capsule and multilayer capsule.Liposome can be by multiple phosphatide, and as cholesterol, stearylamide or phosphatidylcholine are formed.

Term used herein " solvate " is the various stoichiometry mixtures by solute (being the compound of formula (I) in the present invention) and solvent composition.The such solvent that is suitable for purpose of the present invention must influence the biological activity of solute hardly.Solvent may be, for example water, ethanol or acetate.

Term used herein " biological hydrolyzable ester (biohydrolyzable ester) " is the ester of medicine (being the compound of formula (I) in the present invention), itself or a) do not influence the biological activity of parent material, but give good body internal characteristic of these materials such as continuous action time, onset time etc., perhaps b) be that lifeless matter is active but be converted into bioactive ingredients easily in subject.Its advantage is that for example, biological hydrolyzable ester is oral from gastrointestinal absorption, and is converted into formula (I) in blood plasma.The example of many such esters is known in the present technique field, and comprises, for example, lower alkyl esters (for example, C1-C4), low-grade acyloxy alkyl ester, lower alkoxy acyloxy alkyl ester, alkoxyl group acyloxyate, alkyl amido alkyl ester and cholinesterase.

Term used herein " biological hydrolyzable acid amides (biohydrolyzable amide) " is the acid amides of medicine (being the compound of general formula (I) in the present invention), itself or a) do not influence the biological activity of parent material, but give good body internal characteristic of these materials such as continuous action time, onset time etc., perhaps b) lifeless matter is active but be converted into bioactive ingredients easily in subject.Biological hydrolyzable acid amides can be oral from gastrointestinal absorption, and be converted into formula (I) in blood plasma.The example of many such acid amides is known in the present technique field, and comprises, for example, and low alkyl group acid amides, alpha-amino acid amides, alkoxy acyl acid amides and alkylamino alkyl oxycarbonyl acid amides.

The prodrug of compound of the present invention is also included within the scope of the present invention.Term used herein " prodrug " comprises biological hydrolyzable acid amides and biological hydrolyzable ester, and comprise that biological hydrolyzable functionality in a) this prodrug is included in the compound in the compound of formula (I), and b) can be at the compound of the bulk drug of particular functional group's bio-oxidation or reduction production (I).The example of these functional groups includes but not limited to 1,4-dihydropyridine, N-alkyl-carbonyl-1,4-dihydropyridine, 1, the tertiary butyl etc.

Term " pharmacologically effective dose " should refer to the tissue that can cause that investigator or clinician seek, the amount of animal or human's biology or the medicine of medical response or medicament.This amount can be the treatment significant quantity.

Term used herein " treatment significant quantity " is meant the medicine of the therapeutic response that can cause the animal or human who is sought or the amount of medicinal ingredients.

Term used herein " treatment " is meant all the various treatments to the suffered specified disease of patient, comprises a kind of or most of of all symptoms that alleviation is caused by disease, thoroughly cures specified disease or prevents the outbreak of this disease.

There is the pharmacy acceptable salt of the compound of the present invention of alkalescence or acidic-group to be also included within the scope of the present invention in the structure.Term " pharmacy acceptable salt " is meant the non-toxic salt of compound of the present invention, and it is usually by free alkali and suitable organic or inorganic acid-respons, and perhaps acid prepares with the organic or inorganic alkali reaction that suits.Representational salt comprises following salt: acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, edetic acid calcium salt, camsilate, carbonate, muriate, Clavulanic Potassium, Citrate trianion, dihydrochloride, the edetic acid ester, ethanedisulphonate, Estolate, ethyl sulfonate, fumarate, gluceptate (gluceptate), gluconate, glutaminate, bismuth glycolyl arsanilate salt, Sucrets salt, Hai Baming (hydrabamine), hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, isethionate, lactic acid salt, lactobiose hydrochlorate, lauroleate, malate, maleate, mandelate, methane sulfonates, MB, methyl nitrate, Methylsulfate, toxilic acid monopotassium salt, mutate, naphthalenesulfonate, nitrate, N-methylglucosamine salt, oxalate, embonate (Embonate), palmitate, pantothenate, phosphoric acid salt/diphosphate, Polygalacturonate, sylvite, salicylate, sodium salt, stearate, subacetate, succinate, tannate, tartrate, teoclate (teoclate), tosylate, three second iodide, leptodactyline and valerates.When having acid substituting group as-COOH, can form ammonium salt, alkylbenzyldimethylasaltsum saltsum, sodium salt, sylvite, calcium salt, barium salts etc. are as dosage form.When having alkali subtituent such as amino, or when alkaline heteroaryl root such as pyridyl, acid-salt comprises example hydrochloric acid salt, hydrobromate, phosphoric acid salt, vitriol, trifluoroacetate, trichloroacetate, acetate, oxalate, maleate, pyruvate salt, malonate, succinate, Citrate trianion, tartrate, fumarate, mandelate, benzoate, cinnamate, methane sulfonates, ethane sulfonate, picrate etc., and comprise and list in Journal ofPharmaceutical Science, 66,2 (1977) relevant acid of pharmacy acceptable salt in p.1-19.

Other non-pharmacy acceptable salt can be used for the preparation of compound of the present invention, and these have formed another aspect of the present invention.

In addition, the compound of some formulas (I) can form solvate with water or ordinary organic solvents.Such solvate is also contained in the scope of the present invention.

Term " analgesia ", " anti-nociception " and " anti-sense of touch pain (allodynia) " is used to describe pain relief, and alleviates pain relevant with neuropathic pain and relevant with the neuropathic pain usually relevant bitterly pain of sense of touch.

The compound of " almost can not pass through blood brain barrier " used herein or " by partially or completely getting rid of outside brain " is that the speed that diffuses through blood brain barrier is lower than the compound in the speed of experimenter's peripheral-system diffusion.

In one embodiment, under the dosage level that can stimulate experimenter's periphery GalR1 acceptor, the compound of " almost can not pass through blood brain barrier " or " by partially or completely getting rid of outside brain " may with about detectability or the level that is lower than detectability appear in experimenter's brain.

In another embodiment, under the dosage level of observing experimenter's analgesic effect, the compound of " almost can not pass through blood brain barrier " or " by partially or completely getting rid of outside brain " may with about detectability or the level that is lower than detectability appear in experimenter's brain.

Term used herein " experimenter " comprises mammalian subject, such as but not limited to the people, and dog, cat, ox, horse and other agriculture domestic animal.In one embodiment, the experimenter comprises the experimenter who suffers from one or more above-mentioned diseases or morbid state, perhaps has the experimenter of the risk of catching one or more above-mentioned diseases or morbid state.

GalR1 agonist used herein comprises such compound: 1) it can and suppress that Fu Sikelin (forskolin) inductive cAMP generates in the Bowes cell of expressing human GalR1 acceptor with the GalR1 receptors bind; And 2) it does not suppress not express that Fu Sikelin (forskolin) inductive cAMP generates in the cell strain of GalR1 acceptor.In one embodiment, the GalR1 agonist is to compare the compound that shows stronger effect in functional test with no part.

In another embodiment, the invention provides pharmaceutical composition, it comprises the compound of formula (I):

Ar ₂-SO ₂NH-Ar ₁--NHSO ₂-Ar ₃(I)，

Wherein,

Ar ₁, Ar ₂And Ar ₃With defined above consistent, and the compound of formula (I) is the GalR1 agonist.

In another embodiment, the invention provides pharmaceutical composition, it comprises the compound of formula (I) and pharmaceutically suitable carrier, vehicle, thinner or its mixture.

In another embodiment, the present invention also provides the pharmaceutical composition of the compound that comprises formula (I), and the compound of its Chinese style (I) is the GalR1 agonist, and the compound of formula (I) exists with the amount that enough increases the GalR1 receptor active.In another embodiment, in another embodiment, pharmaceutical composition comprises the compound of formula (I), and the compound of its Chinese style (I) is the GalR1 agonist, and the compound of formula (I) exists enough to stimulate the amount of GalR1.

In another embodiment, the invention provides the pharmaceutical composition of the compound of the formula (I) that comprises effective therapeutic dose, wherein said effective therapeutic dose comprises the amount of compound that can activate the formula (I) of experimenter GalR1 acceptor to small part, perhaps can be improved to less a kind of amount of compound of formula (I) of disease of GalR1 mediation to small part.

Can comprise epileptic seizures by disease or the dysfunction that the GalR1 agonist improves, neuroendocrine imbalance, gastrointestinal dysfunction, the muscle skeleton illness, psychotic behavior such as schizophrenia, migraine, the morphine tolerance, drug habit is opiate addiction especially, and pain is neuropathic pain especially, inflammatory pain, chronic pain, somnopathy, feed/body weight obstacle such as bulimia, bulimia nervosa and anorexia nervosa, metabolic exhaustion is disorderly as emaciation, the europathology disorder, diabetes, hyperlipemia (dyslipidimia), hypertension, amnesia, dysthymia disorders, anxiety disorder, hematencephalon, diarrhoea, and one or more cancers are such as but not limited to squamous cell carcinoma.Therefore, these treatment of diseases can be given the influence of GalR1 agonist.Conceived within the scope of the present invention, the compound of formula (I) and the pharmaceutical composition that comprises the compound of formula (I) can be used for the treatment of with galanin and GalR1 receptors bind (or galanin shortage) is irrelevant but the dysfunction symptom may be by the dysfunction of GalR1 agonist mediation.

In another embodiment, pharmaceutical composition is an oral dosage form.In another embodiment, pharmaceutical composition is the injected dose unit form.

On the other hand, the invention provides the pharmaceutical composition of the compound that comprises formula (I) and one or more other therapeutical agents.In another embodiment, pharmaceutical composition further comprises and is selected from one or more following therapeutical agents: biological response modifier, pain killer, NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), improve state of an illness antirheumatic (DMARDs), glucocorticosteroid, sulfonylurea, biguanides, acarbose, agent for peroxisome proliferator activated receptor (PPAR) agonist, DPP-IV inhibitor, GK activator, Regular Insulin, insulin-mimickers, insulin secretagogue, euglycemic agent, glucagon-like-peptide-1 (GLP-1), glucagon-like-peptide-1 (GLP-1) stand-in, anticholinesterase, tranquilizer (antipsychotics), antidepressive, anticonvulsive agent, HMG-CoA reductase inhibitor, QUESTRAN and Bei Te class (fibrates).In another embodiment, pharmaceutical composition further comprises one or more therapeutical agents such as carcinostatic agent: such as but not limited to endoxan, and nitrosourea, carboplatin, cis-platinum, procarbazine, bleomycin, daunomycin, Zorubicin, methotrexate, cytosine arabinoside, Ro 2-9757, vinealeucoblastine(VLB), vincristine(VCR), Etoposide, taxol, tamoxifen, Sostatin LAR, finasteride, flutamide (flutamide), Interferon, rabbit, interleukin-and anti-tumour antibody and anti-angiogenic compounds and albumen.

In another embodiment, the invention provides a kind of method, comprising: give the pharmaceutical composition that the experimenter comprises the compound of formula (I), the compound of formula wherein (I) is the GalR1 agonist.

In another embodiment, the invention provides a kind of method, comprise: pharmaceutical composition is suffered from by activating the experimenter of the dysfunction that the GalR1 acceptor improves, and pharmaceutical composition wherein comprises the compound of the formula (I) that is enough to increase the active amount of experimenter GalR1.The disease or the dysfunction of available GalR1 agonist treatment comprise epileptic seizures, neuroendocrine imbalance, gastrointestinal dysfunction, the muscle skeleton illness, psychotic behavior such as schizophrenia, migraine, the morphine tolerance, drug habit is opiate addiction especially, and pain is neuropathic pain especially, inflammatory pain, chronic pain, somnopathy, feed/body weight obstacle such as bulimia, bulimia nervosa and anorexia nervosa, metabolic exhaustion is disorderly as emaciation, the europathology disorder, diabetes, hyperlipemia (dyslipidimia), hypertension, amnesia, dysthymia disorders, anxiety disorder, hematencephalon, diarrhoea, and one or more cancers are such as but not limited to squamous cell carcinoma.

For example, comprise that the compound of the present invention of GalR1 agonist and pharmaceutical composition can be used for treating neuropathic pain.In addition, under the dosage that can observe analgesic effect, compound of the present invention can combine with at least a periphery GalR1, but almost can not pass through blood brain barrier.The GalR1 agonist is partially or completely got rid of the risk or the severity that can reduce one or more maincenter mediation side effects relevant with giving experimenter GalR1 agonist outside brain

The pharmaceutical composition of having conceived the compound that can prepare formula (I) within the scope of the invention and having comprised the compound of formula (I) can be used for the treatment of with galanin and GalR1 receptors bind (or galanin shortage) is irrelevant but the dysfunction symptom may be by the dysfunction of GalR1 agonist mediation.

Compound of the present invention can be to approximate or to be lower than the dosage level administration that 1000mg/kg is treated experimenter's body weight.In another embodiment, compound of the present invention is to approximate or to be lower than the dosage level administration of 100mg/kg.In another embodiment, compound of the present invention is to approximate or to be lower than the dosage level administration of 10mg/kg body weight/day.In another embodiment, compound of the present invention is to approximate or to be higher than the dosage level administration of 0.01mg/kg body weight/day.In another embodiment, compound of the present invention is to approximate or to be higher than the dosage level administration of 0.5mg/kg body weight/day.

Can be combined to form the amount of activeconstituents of single dose according to being changed with solid support material by the variation of treatment host and specific administration mode.For example, the preparation that is used for the human oral administration may comprise the compound of 1mg to 2g formula (I) and account for an amount of solid support material of total composition about 5% to 95%.Dosage unit form generally includes about 5mg to the activeconstituents between about 500mg.Dosage comes individuation by the clinician according to the specific clinical state of an illness of being treated the experimenter.Therefore, the given dose level of any particular patient depends on multiple factor, comprises the activity of used specific compound, the age, body weight, general health state (general health), sex, diet, administration time, route of administration, excretion rate, the severity of the drug combination and the specified disease of receiving treatment is self-evident.

In another embodiment, the pharmaceutical composition that comprises the compound of formula (I) can be united with one or more therapeutical agents and given the experimenter, and this therapeutical agent is selected from following therapeutical agent: biological response modifier, pain killer, NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is improved state of an illness antirheumatic (DMARDs), glucocorticosteroid, sulfonylurea, biguanides, acarbose, agent for peroxisome proliferator activated receptor (PPAR) agonist, the DPP-IV inhibitor, the GK activator, Regular Insulin, insulin-mimickers, insulin secretagogue, euglycemic agent, glucagon-like-peptide-1 (GLP-1), glucagon-like-peptide-1 (GLP-1) stand-in, anticholinesterase, tranquilizer, antidepressive, anticonvulsive agent, HMG-CoA reductase inhibitor, QUESTRAN and Bei Te class (fibrates).In another embodiment, the pharmaceutical composition that comprises the compound of formula (I) can be united with one or more therapeutical agents and given the experimenter, and this therapeutical agent is selected from following therapeutical agent: carcinostatic agent is such as but not limited to endoxan, nitrosourea, carboplatin, cis-platinum, procarbazine, bleomycin, daunomycin, Zorubicin, methotrexate, cytosine arabinoside, Ro 2-9757, vinealeucoblastine(VLB), vincristine(VCR), Etoposide, taxol, tamoxifen, Sostatin LAR, finasteride, flutamide, Interferon, rabbit, interleukin-and anti-tumour antibody and anti-angiogenic compounds and albumen.

Neuropathic pain can be improved by GalR1 agonist and experimenter's periphery GalR1 receptors bind, improves at least in part.If the GalR1 agonist is partially or completely stoped by blood brain barrier, cause that the risk of maincenter mediation central nervous system (CNS) side effect will reduce or avoid.In one embodiment, the invention provides the method for the treatment experimenter neuropathic pain that can avoid or reduce experimenter's maincenter mediation side effect risk.This method can almost can not be implemented by the GalR1 agonist of blood brain barrier with any.Because the periphery GalR1 acceptor in the neuropathic pain may be relevant with the sense of touch pain, the invention provides the method that GalR1 agonist treatment that a kind of new passing through give the formula (I) that the experimenter almost can not be by blood brain barrier need be alleviated the experimenter of sense of touch pain.The method of this treatment sense of touch pain can alleviate or eliminate the risk of one or more maincenter mediations CNS side effect.

In another embodiment, the invention provides a kind of method, comprise the experimenter GalR1 agonist of suffering from neuropathic pain, wherein the amount of GalR1 agonist can stimulate experimenter's periphery GalR1 acceptor, and the GalR1 agonist is partially or completely got rid of outside brain.In another embodiment of this method, the GalR1 agonist comprises the compound of formula (I).

In another embodiment, the invention provides a kind of method, comprise that the experimenter who suffers from sense of touch pain can stimulate the GalR1 agonist of periphery GalR1 acceptor with the amount that causes experimenter's analgesic effect, and GalR1 agonist wherein almost can not pass through blood brain barrier under the dosage of observing experimenter's analgesic effect.In another embodiment of this method, the GalR1 agonist comprises the compound of formula (I).

In another embodiment, the invention provides a kind of method, comprise the experimenter GalR1 agonist of suffering from neuropathic pain and at dorsal root ganglion (DRG) horizontal adjustment experimenter periphery GalR1 acceptor, wherein the GalR1 agonist almost can not pass through blood brain barrier under the dosage of observing experimenter's analgesic effect.In another embodiment of this method, the GalR1 agonist comprises the compound of formula (I).

In another embodiment, the invention provides a kind of methods of treatment, comprise the compound of experimenter's formula (I) of suffering from cancer.In another embodiment of this methods of treatment, cancer is a squamous cell carcinoma.In another embodiment of this methods of treatment, the compound of formula (I) is with the amount administration of effective inhibition experimenter cancer cell multiplication.In another embodiment of this methods of treatment, the compound of formula (I) is with the amount administration of effective inhibition or deactivation experimenter cancer cells MAPK path.

Embodiment

The LC-MS The data is moved 4 Waters 1525 binary HPLC pumps, and the MUX in parallel of Mux-UV 2488 hyperchannel ultraviolet-visible(light)detectors (at 215nM and 254nM place record) and Leap Technologies HTS PAL automatic sampler is housed ^TMSystem, (4.6 * 50mm) obtain through gradient elution with Waters Xterra MS C18 post.Three minutes gradient from 25%B (97.5% acetonitrile, 2.5% water, 0.05%TFA) and 75%A (97.5% water, 2.5% acetonitrile 0.05%TFA) move to 100%B.This system links to each other with the Waters Micromass ZQ mass spectrograph that adopts electron spray ionisation.All MS data all obtain with positive ion mode except as otherwise noted. ¹H NMR data obtain with Varian 400MHz spectrograph.

The abbreviation of using among the embodiment is as follows:

The APCI=atmospheric pressure chemical ionization

The BOC=tertbutyloxycarbonyl

BOP=(1-benzotriazole base oxygen base) tris (dimethylamino) Phosphonium hexafluorophosphate

D=days

The DIAD=diisopropyl azo-2-carboxylic acid

The DCC=dicyclohexylcarbodiimide

The DCM=methylene dichloride

The DIC=DIC

The DIEA=diisopropylethylamine

DMA=N, the N-N,N-DIMETHYLACETAMIDE

The DMAP=dimethyl aminopyridine

DME=1, the 2-glycol dimethyl ether

DMF=N, dinethylformamide

DMPU=1,3-dimethyl propenylidene urea

The DMSO=dimethyl sulfoxide (DMSO)

EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride

The EDTA=ethylenediamine tetraacetic acid (EDTA)

The ELISA=Enzyme Linked Immunoadsorbent Assay

The ESI=electron spray ionisation

The ether=diethyl ether

The EtOAc=ethyl acetate

The FBS=foetal calf serum

The g=gram

H, hr=hour

HBTU=O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea (uronium) hexafluorophosphate

The HMPA=hexamethyl phosphoric triamide

The HOBt=1-hydroxybenzotriazole

The Hz=hertz

I.v.=is intravenous

The kD=kilodalton

The L=liter

The LAH=lithium aluminium hydride

The LDA=LDA

The LPS=lipopolysaccharides

The M=mol

The m/z=mass-to-charge ratio

The mbar=millibar

MeOH=methyl alcohol

The mg=milligram

Min=minute

The mL=milliliter

The mM=mmole/liter

The mmol=mmole

The mol=mole

The mp=fusing point

The MS=mass spectrum

N=is normal

The NMM=N-methylmorpholine, the 4-methylmorpholine

The NMR=NMR (Nuclear Magnetic Resonance) spectrum

The p.o.=oral administration

The PBS=phosphate buffered saline(PBS)

The PMA=phorbol myristate acetate

Ppm=1,000,000/portion

Psi=pound/square inch

The Rf=TLC Rf value

Rt, the RT=room temperature

S.c.=is subcutaneous

SPA=gets close to flicker detection method (scintillation proximity assay)

The TEA=triethylamine

The TFA=trifluoroacetic acid

The THF=tetrahydrofuran (THF)

The THP=THP trtrahydropyranyl

The TLC=tlc

TMSBr=bromo trimethyl silane, the trimethyl silyl bromine

The Tr=retention time

Embodiment A

N-(2-aminophenyl)-2-methoxyl group-5-trifyl benzsulfamide

Adding benzene-1 to 2-methoxyl group-5-trifyl-1-benzene sulfonyl chloride (5g) in the solution of anhydrous methylene chloride (10mL) under 0 ℃, 2-diamines (5g) adds anhydrous pyridine (10mL) then.Gained scarlet reaction mixture is stirring at room 4 hours then.Reaction mixture dilutes with methylene dichloride (250mL).Content washs with saturated sodium-chloride water solution (50mL) and saturated aqueous sodium carbonate (50mL).Organic phase dried over sodium sulfate, and vacuum concentration.The gained residue with DCM/EtOAc (7: 1 to 4: 1) wash-out purifying, obtains N-(2-aminophenyl)-2-methoxyl group-5-trifyl benzsulfamide (6g) through flash column chromatography.LC：Tr?0.95min，MS：411(M+1) ⁺， ¹H?NMR(CDCl ₃，400MHz)：δ4.18(bs，2H)，4.21(s，3H)，6.43(m，2H)，6.57(bs，1H)，6.75(dd，1H)，7.02(t，1H)，7.35(d，1H)，8.22(dd，1H)，8.40(d，1H)ppm。

Embodiment B

2-methoxyl group-5-nitrobenzene sulfonyl chloride

Under 0 ℃ to 4-Nitroanisole (3.1g; 20mmol) 1, add the 2mL chlorsulfonic acid in the solution of 2-ethylene dichloride (20mL).The gained reaction mixture is heated to room temperature gradually, reflux 2h then, and all at that time methyl-phenoxides all have been consumed and have finished.Then reaction mixture is cooled to room temperature, and dilutes with chloroform (30mL).Then content is transferred to separating funnel, water (50mL) washing separates each layer.Water layer is then with chloroform (30mL) extraction.The organic layer that merges washs with salt solution (50mL), anhydrous sodium sulfate drying.Solvent removed in vacuo, the gained residue is the eluent purifying with the silica gel flash column chromatography with ethyl acetate/hexane (1: 5 to 1: 1 gradient), obtains being Vandyke brown solid 2-methoxyl group-5-nitrobenzene sulfonyl chloride. ¹H?NMR(CDCl ₃，400MHz)：δ4.21(s，3H)，7.28(d，1H)，8.59(dd，1H)，8.88(d，1H)ppm。

Embodiment 1

In the solution of DCM (25mL) and pyridine (5mL), repeatedly add benzo [b] thiophene-2-SULPHURYL CHLORIDE (5.5mmol) on a small quantity to 0 ℃ O-Phenylene Diamine (5mmol).Reaction mixture is heated to RT then gradually and continues stirring until reaction to be determined to finish through TLC or LC-MS.Reaction mixture is used DCM (25mL) dilution then.Organic phase water (2 * 25mL) and salt solution 25mL washing.Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 1.2g benzo [b] thiophene-2-sulfonic acid (2-amino-phenyl)-acid amides through flash column chromatography.Tr?0.94min，MS：305.7(M+1) ⁺， ¹H?NMR(DMSO-d ₆，400MHz)：δ6.40(t，1H)，6.60(d，1H)，6.78(d，1H)，6.89(t，1H)，7.45(t，1H)，7.50(t，1H)，7.80(s，1H)，7.90(d，1H)，8.80(d，1H)ppm。

As above single sulphonamide (2mmol) of obtaining of method is dissolved in DCM (4mL) and the pyridine (4mL).At room temperature add 2-chloro-5-(trifluoromethyl) benzene sulfonyl chloride (2.2mmol) then, follow the reaction mixture stirred overnight at room temperature, or determine to finish through TLC or LC-MS until reaction.Reaction mixture is used DCM (10mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 710mg benzo [b] thiophene-2-sulfonic acid [2-(2-chloro-5-trifluoromethyl phenylsulfonamido) phenyl]-acid amides through flash column chromatography.Tr?1.2min，MS：547.6(M+1) ⁺， ¹H?NMR(DMSO-d ₆，400MHz)：δ7.0-7.2(m，4H)，7.48(dd，1H)，7.53(dd，1H)，7.90(d，1H)，7.92(d，1H)，7.98(d，1H)，8.02-8.06(m，3H)，9.74(bs，1H)，9.88(bs，1H)ppm。

Embodiment 2

In the solution of 4-anisole mercaptan (10mmol) in anhydrous THF (50mL), repeatedly adding uncle's fourth oxygen potassium (t-BuOK, 12mmol) solid under 0 ℃ on a small quantity.Reaction mixture stirs 30min under 0C, dropwise add 2-N-PROPYLE BROMIDE (1.6g) subsequently.Follow reaction mixture stirring at room 1h, and heat 1h down at 60 ℃.After being cooled to room temperature, reactant dilutes with ethyl acetate (250mL).Organic phase elder generation water (50mL) is used saturated sodium-chloride water solution (100mL) washing then.Organic layer is dry on anhydrous sodium sulphate, and vacuum concentration.Rough 1-sec.-propyl sulfane base-4-anisole (10mmol) is directly used in further conversion without any purifying.

In the solution of DCM (20ml), adding 32% peroxide acetate aqueous solution (7mL) to above-mentioned rough 1-sec.-propyl sulfane base-4-anisole (calculated value ca.10mmol) under 0 ℃.Reaction mixture stirring at room 2h uses ethyl acetate (150mL) dilution subsequently then.Organic phase water (50mL) and 1% potassium hydroxide aqueous solution (75mL) washing.Organic layer is dry on anhydrous sodium carbonate then, and vacuum concentration, obtains the rough light yellow oil 1-methoxyl group-4-of 2g (propane-2-alkylsulfonyl)-benzene. ¹H?NMR(CDCl ₃，400MHz)：δ1.28(d，6H)，3.16(m，1H)，3.89(s，3H)，7.02(d，2H)，7.80(d，2H)ppm。

In the solution of anhydrous methylene chloride (20mL), dropwise adding chlorsulfonic acid (1mL) to rough 1-methoxyl group-4-(propane-2-alkylsulfonyl)-benzene (8mmol) under 0 ℃.Reaction mixture is heated to room temperature, then adds PCl ₅(0.5g).Gained reaction mixture refluxed 1h.After being cooled to room temperature, reaction mixture is poured onto while vigorous stirring in the frozen water (50mL).Water layer is used EtOAc (2 * 75mL) extractions then.(2 * 50mL) wash the organic extract liquid that merges, dry on anhydrous sodium sulphate, and vacuum concentration with saturated sodium-chloride water solution.Residue with hexane/EtOAc (3: 1) wash-out purifying, obtains 1.25g 2-methoxyl group-5-(propane-2-alkylsulfonyl) benzene sulfonyl chloride through flash column chromatography. ¹H?NMR(CDCl ₃，400MHz)：δ1.31(d，1H)，3.23(m，1H)，4.18(s，3H)，7.30(d，1H)，8.18(dd，1H).8.46(d，H)ppm。

At room temperature in the solution of DCM (2mL) and pyridine (2mL), add 2-methoxyl group-5-(propane-2-alkylsulfonyl) benzene sulfonyl chloride (1.1mmol), reaction mixture stirred overnight at room temperature then to benzo [b] thiophene-2-sulfonic acid (2-aminophenyl)-acid amides (1mmol) (according to the method preparation of embodiment 1).Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue through flash column chromatography with DCM/EtOAc wash-out purifying, obtain 460mg benzo [b] thiophene-2-sulfonic acid 2-[2-methoxyl group-5-(propane-2 alkylsulfonyl) phenylsulfonamido] phenyl-acid amides.Tr?1.09min；MS：581.4(M+1) ⁺. ¹H?NMR(DMSO-d ₆，400MHz)：δ0.97(d，6H)，3.58(m，1H)，4.02(s，3H)，6.84(dd，1H)，7.96(td，1H)，7.10(td，1H)，7.23(dd，1H)，7.44-7.54(m，3H)，7.86(d，1H)，7.90(s，1H)，7.96(d，1H)，8.03(dd，2H)，9.22(bs，1H)，9.79(s，1H)ppm。

Embodiment 3

At room temperature in the solution of DCM (2mL) and pyridine (2mL), add methyl-3-(chlorosulfonyl)-4-methoxybenzoic acid (1.1mmol), reaction mixture stirred overnight at room temperature then to benzo [b] thiophene-2-sulfonic acid (2-aminophenyl)-acid amides (1mmol).Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 350mg 3-[2-(benzo [b] thiophene-2-sulfuryl amino) phenyl sulfamoyl base through flash column chromatography]-the 4-methoxyl methyl benzoate.Tr?1.10min，MS：533.7(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ3.84(s，3H)，4.18(s，3H)，7.0-7.2(m，5H)，7.4-7.6(m，3H)，7.66(s，1H)，7.80(d，1H)，7.83(d，1H)，8.22(dd，1H)，8.34(d，1H)ppm。

Embodiment 4

At room temperature to 3-[2-(benzo [b] thiophene-2-sulfuryl amino)-phenyl sulfamoyl base]-4-methoxyl group-methyl benzoate (5mmol is according to the method acquisition of embodiment 3) adding 4M NaOH aqueous solution (5mL) in the solution of THF (10mL) and methyl alcohol (10mL).The reaction mixture stirred overnight at room temperature is to reacting completely.Vacuum concentration reaction mixture then, and be acidified to the pH value with 10% aqueous hydrochloric acid and be about 3.The white depositions that forms is filtered, and with the ether washing, drying obtains 2.5g 3-[2-(benzo [b] thiophene-2-sulfuryl amino)-phenyl sulfamoyl base]-the 4-methoxybenzoic acid.MS：519.8(M+1) ⁺. ¹H?NMR(DMSO-d ₆，400MHz)：δ4.05(s，3H)，6.89(d，1H)，6.99(dd，1H)，7.11(dd，1H)，7.25(d，1H)，7.38(d，1H)，7.48(dd，1H)，7.53(dd，1H)，7.91(s，1H)，7.98(d，1H)，8.65(d，1H)，8.13(dd，1H)，8.16(dd，1H)ppm。

Embodiment 5

At room temperature to N-(2-aminophenyl)-2-methoxyl group-5-trifyl benzsulfamide (2mmol; method preparation according to embodiment A) in the solution of DCM (4mL) and pyridine (4mL), adds 3-nitrobenzene sulfonyl chloride (2.2mmol), stirring at room reaction mixture then.Use DCM (20mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (20mL), water (20mL) and salt solution (20mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 1.04g 2-methoxyl group-N-[2-(3-nitrobenzene sulfonyl ammonia base) phenyl through flash column chromatography]-5-trifyl benzsulfamide.LC：Tr1.17min，MS：596.6(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.27(s，3H)，6.76(d，1H)，6.78(bs，1H)，7.05(m，1H)，7.16(m，2H)，7.34(d，1H)，7.68(bs，1H)，7.72(t，1H)，8.01(dd，1H)，8.20(dd，1H)，8.25(d，1H)，8.46(dd，1H)，8.55(d，1H)ppm。

Add iron powder (300mg) to the two sulphonamide (1mmol) that obtain according to the method described above in the solution of AcOH (5mL), the gained reaction mixture is at 100 ℃ of heating 30min.Reaction mixture filters through short Celite pad, with methyl alcohol (50mL) and methylene dichloride (25mL) washing and filtering pad.The filtrate vacuum concentration.The gained residue is dissolved among the EtOAc (50mL), with the 1%KOH aqueous solution (25mL) washing.Organic layer is dry on anhydrous sodium sulphate, and solvent removed in vacuo obtains the rough N-[2-of 155mg (3-amino-phenylsulfonamido)-phenyl to doing]-2-methoxyl group-5-trifyl-benzsulfamide.LC：Tr?1.09min；MS：566.4(M+1) ⁺。

In the solution of AcOH (2mL), add NH to the amino intermediate (0.5mmol) that obtains according to the method described above ₄OAc (10mmol), 37% formalin (2mL) and 40% glyoxal water solution (1mL).Reaction mixture is at 100 ℃ of heating 1.5h.After being cooled to room temperature, reaction mixture dilutes with ethyl acetate (50mL).Organic phase water (25mL) and the 1%KOH aqueous solution (25mL) washing.Organic phase is dry on sodium sulfate, and vacuum concentration.Residue with ethyl acetate/methanol (100: 2 to 100: 10) wash-out purifying, obtains 155mgN-[2-(3-imidazoles-1-base-phenylsulfonamido) phenyl after flash column chromatography elder generation is with EtOAc]-2-methoxyl group-5-three fluorine-based-benzsulfamides.LC：Tr?0.90min；MS：617.7(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.15(s，3H)，6.75(d，1H)，7.01(bs，1H)，7.05(t，1H)，7.17(t，1H)，7.30(m?5H)，7.53(m，3H)，7.73(d，2H)，8.04(dd，1H)，8.25(d，1H)ppm。

Embodiment 6

At room temperature to N-(2-amino-phenyl)-2-methoxyl group-5-three fluorine-based benzsulfamide (1mmol, method preparation according to embodiment 3) in the solution of DCM (2mL) and pyridine (2mL), adds 4-nitrobenzene sulfonyl chloride (1.1mmol), reaction mixture stirred overnight at room temperature then.Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 446mg 2-methoxyl group-N-[2-(4-nitrobenzene sulfonyl ammonia base) phenyl through flash column chromatography]-5-three fluorine-based benzsulfamides.LC：Tr?1.15min，MS：596.8(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.27(s，3H)，6.79(d，1H)，6.83(bs，1H)，7.07(m，1H)，7.17(m，2H)，7.34(d，1H)，7.59(bs，1H)，7.90(d，2H)，8.20(t，1H)，8.25(d，1H)，8.30(d，2H)ppm。

To 2-methoxyl group-N-[2-(4-nitrobenzene sulfonyl ammonia base) phenyl]-5-three fluorine-based benzsulfamides (1mmol) add iron powder (300mg) in the solution of AcOH (5mL), and the gained reaction mixture is at 100 ℃ of heating 30min.Reaction mixture filters through short Celite pad, with methyl alcohol (50mL) and methylene dichloride (25mL) washing and filtering pad.The filtrate vacuum concentration.The gained residue is dissolved among the EtOAc (50mL), with the 1%KOH aqueous solution (25mL) washing.Organic layer is dry on anhydrous sodium sulphate, and solvent removed in vacuo obtains the rough N-[2-of 486mg (4-amino phenyl sulfonyl amido)-phenyl to doing]-2-methoxyl group-5-three fluorine-based-benzsulfamides.LC：Tr?1.09min；MS：566.7(M+1) ⁺。

In the solution of AcOH (2mL), add NH to the amino intermediate (0.5mmol) that obtains according to the method described above ₄OAc (10mmol), 37% formalin (2mL) and 40% glyoxal water solution (1mL).Reaction mixture is at 100 ℃ of heating 1.5h.After being cooled to room temperature, reaction mixture dilutes with ethyl acetate (50mL).Organic phase water (25mL) and the 1%KOH aqueous solution (25mL) washing.Organic phase is dry on sodium sulfate, and vacuum concentration.Residue with ethyl acetate/methanol (100: 2 to 100: 10) wash-out purifying, obtains 200mgN-[2-(4-imidazoles-1-base-phenylsulfonamido) phenyl after flash column chromatography elder generation is with EtOAc]-2-methoxyl group-5-three fluorine-based-benzsulfamides.LC：Tr?0.90min；MS：617.6(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.16(s，3H)，6.81(d，1H)，7.05(m，2H)，7.14(m，2H)，7.24(m，3H)，7.43(d，2H)，7.55(bs，1H)，7.75(d，2H)，7.83(s，1H)，8.06(dd，1H)，8.25(d，1H)ppm。

Embodiment 7

At room temperature to N-(2-aminophenyl)-2-methoxyl group-5-three fluorine-based benzsulfamide (0.5mmol, method preparation according to embodiment A) in the solution of DCM (1mL) and pyridine (1mL), adds 5-chloro-3-methyl benzo [b] thiophene-2-SULPHURYL CHLORIDE (0.55mmol), reaction mixture stirred overnight at room temperature then.Use DCM (5mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 202mg 5-chloro-3-methyl benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-5-three fluorine-based-phenylsulfonamido) phenyl]-acid amides through flash column chromatography.LC：Tr?1.32min，MS：655.4(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ2.14(s，3H)，4.29(s，3H)，6.33(bs，1H)，6.54(d，1H)，6.98(t，1H)，7.24(t，1H)，7.35(d，1H)，7.45(dd，1H)，7.49(dd，1H)，7.70(d，1H)，7.75(d，1H)，8.14(bs，1H)，8.17(dd，1H)，8.31(d，1H)ppm。

Embodiment 8

In the solution of DCM (25mL) and pyridine (5mL), repeatedly add 5-bromo-2-anisole SULPHURYL CHLORIDE (5.5mmol) to 0 ℃ O-Phenylene Diamine (5mmol) on a small quantity.Reaction mixture is heated to RT then gradually and continues to stir until reaction to be determined to finish through TLC or LC-MS.Reaction mixture is used DCM (25mL) dilution then.Organic phase water (2 * 25mL) and salt solution 25mL washing.Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 1.07g N-(2-aminophenyl)-5-bromo-2-methoxybenzenesulphoismide through flash column chromatography. ¹H?NMR(CDCl ₃，400MHz)：δ4.08(s，3H)，4.22(bs，2H)，6.52(m，2H)，6.75(m，2H)，7.01(d，1H)，7.03(m，1H)，7.65(dd，1H)，7.88(d，1H)ppm。

As above single sulphonamide (1mmol) of method acquisition is dissolved in DCM (2mL) and the pyridine (2mL).At room temperature add benzo [b] thiophene-2-SULPHURYL CHLORIDE (1.1mmol) then, then the reaction mixture stirred overnight at room temperature.Reaction mixture is used DCM (10mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 390mg benzo [b] thiophene-2-sulfonic acid [2-(5-bromo-2-anisole sulfonamido) phenyl]-acid amides through flash column chromatography.LC：Tr?1.19min，MS：553.5(M+) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.11(s，3H)，7.00(d，1H)，7.1-7.2(m，5H)，7.47(m，2H)，7.62(d，1H)，7.64(d，1H)，7.68(s，1H)，7.78(d，1H)，7.84(dd，2H)ppm。

Embodiment 9

At room temperature to N-(2-aminophenyl)-5-bromo-2-methoxybenzenesulphoismide (0.5mmol; Method preparation according to embodiment 7) in the solution of DCM (1mL) and pyridine (1mL), adds 4,5-dichloro-thiophene-2-SULPHURYL CHLORIDE (0.55mmol), then reaction mixture stirred overnight at room temperature.Reaction mixture is used DCM (5mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 214mg 4,5-dichloro-thiophene-2-sulfonic acid [2-(5-bromo-2-anisole sulfonamido)-phenyl]-acid amides through flash column chromatography.LC：Tr?1.30min，MS：572.8(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.12(s，3H)，7.00(d，1H)，7.10(d，1H)，7.12(dd，1H)，7.22(dd，1H)，7.23-7.32(m，3H)，7.66(dd，1H)，7.70(d，1H)ppm。

Embodiment 10

At room temperature to N-(2-aminophenyl)-5-bromo-2-methoxybenzenesulphoismide (0.5mmol; Method preparation according to embodiment 7) in the solution of DCM (1mL) and pyridine (1mL), adds 5-isoxazole-3-base-thiophene-2-SULPHURYL CHLORIDE (0.55mmol), then reaction mixture stirred overnight at room temperature.Reaction mixture is used DCM (5mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 140mg5-isoxazole-3-base-thiophene-2-sulfonic acid [2-(5-bromo-2-methoxyl group-phenylsulfonamido) phenyl]-acid amides through flash column chromatography.LC：Tr?1.15min，MS：572.0(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.10(s，3H)，6.51(s，1H)，6.99(d，1H)，7.04(d，1H)，7.11(dd，1H)，7.18(dd，12H)，7.25(dd，1H)，7.40(d，1H)，7.46(d，1H)，7.54(dd，1H)，7.64(dd，1H)，7.75(dd，1H)，8.31(s，1H)ppm。

Embodiment 11

In the solution of DCM (20mL) and pyridine (4mL), repeatedly add 4-chlorobenzene sulfonyl chloride (4.4mmol) to 0 ℃ O-Phenylene Diamine (4mmol) on a small quantity.Reaction mixture is heated to RT then gradually and continues to stir until reaction to be determined to finish through TLC or LC-MS.Reaction mixture is used DCM (20mL) dilution then.Organic phase water (2 * 20mL) and salt solution 20mL washing.Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 960mg N-(2-aminophenyl)-4-chlorobenzene sulfonamide through flash column chromatography.LC：Tr?0.92min，MS：284.0(M+1) ⁺。

As above single sulphonamide (1mmol) of method acquisition is dissolved in DCM (2mL) and the pyridine (2mL).At room temperature add 2-methoxyl group-5-nitrobenzene sulfonyl chloride (1.1mmol is according to the method preparation of Embodiment B) then, then the reaction mixture stirred overnight at room temperature.Reaction mixture is used DCM (10mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 325mg N-[2-(4-chloro-phenylsulfonamido) phenyl through flash column chromatography]-2-methoxyl group-5-nitrobenzene sulfonamide.LC：Tr?1.2min，MS：498.1(M+1) ⁺。

Embodiment 12

(2.5M is at the solution of hexane dropwise to add n-Butyl Lithium to-40 ℃ cumarones (10mmol) in the solution of anhydrous THF (15mL); 4.4mL; 11mmol).Reaction mixture stirs 30-40min at-40 ℃.In reaction mixture, feed the about 5-10min of sulfur dioxide gas, keep needle point during feeding just above reaction mixture.Formed white depositions.Subsequently reaction mixture is returned to RT, and continue to stir 1h, mixture dilutes with hexane (20mL) then, is produced as the cumarone-2--sulfinic acid lithium salts of white depositions.Solid filtering and vacuum-drying obtain this salt.

The solid suspension of Huo Deing is in DCM (50mL) according to the method described above, and handles with N-chloro-succinimide (11mmol) at 0 ℃.Gained suspension returns to room temperature then, and vigorous stirring is spent the night simultaneously.Filter the Vandyke brown reaction mixture, and wash with DCM.The filtrate vacuum concentration, the gained residue is made the eluent purifying through silica gel column chromatography with the EtOAc/ hexane, and obtaining 1.19g is light brown solid cumarone-2-SULPHURYL CHLORIDE.

At room temperature to N-(2-aminophenyl)-4-chlorobenzene sulfonamide (0.5mmol, according to the preparation of the method for embodiment 11) in the solution of DCM (1mL) and pyridine (1mL), add the cumarone-2-SULPHURYL CHLORIDE (0.55mmol) of preparation according to the method described above, then the reaction mixture stirred overnight at room temperature or to reaction through TLC or LC-MS is definite finishes.Reaction mixture is used DCM (5mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 92mg cumarone-2-sulfonic acid [2-(4-chlorobenzene sulfonamido) phenyl]-acid amides through flash column chromatography.LC：Tr?1.13min，MS：464.0(M+1) ⁺。

Embodiment 13

At room temperature to N-(2-aminophenyl)-4-chlorobenzene sulfonamide (0.5mmol, according to the preparation of the method for embodiment 11) in the solution of DCM (1mL) and pyridine (1mL), add benzo [b] thiophene-2-SULPHURYL CHLORIDE (0.55mmol) of preparation according to the method described above, then the reaction mixture stirred overnight at room temperature or to reaction through TLC or LC-MS is definite finishes.Reaction mixture is used DCM (5mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 180mg benzo [b] thiophene-2-sulfonic acid [2-(4-chlorobenzene sulfonamido) phenyl]-acid amides through flash column chromatography.LC：Tr?1.23min，MS：479.8(M+1) ⁺。

Embodiment 14

In the solution of DCM (20ml), adding 32% peroxide acetate aqueous solution (7mL) to 1-methoxyl group-4-methyl sulphur alkylbenzene (10mmol) under 0 ℃.Reaction mixture stirring at room 2h uses ethyl acetate (100mL) dilution subsequently then.Organic phase water (50mL) and 1% potassium hydroxide aqueous solution (75mL) washing.Organic layer is dry on anhydrous sodium carbonate then, and vacuum concentration, and obtaining 1.5g is the rough 1-methylsulfonyl-4-anisole of pale solid.

In the solution of anhydrous methylene chloride (20mL), dropwise adding chlorsulfonic acid (1mL) to rough 1-methylsulfonyl-4-anisole (8mmol) under 0 ℃.Reaction mixture is heated to room temperature, then adds PCl ₅(0.5g).Gained reaction mixture refluxed 1h.After being cooled to room temperature, reaction mixture is poured onto in the frozen water (50mL) of stirring.Water layer is used EtOAc (2 * 40mL) extractions then.(2 * 40mL) wash the organic extract liquid that merges, dry on anhydrous sodium sulphate, and vacuum concentration with saturated sodium-chloride water solution.Residue with hexane/EtOAc (3: 1) wash-out purifying, obtains 1.6g 5-methylsulfonyl-2-anisole SULPHURYL CHLORIDE through flash column chromatography.

At room temperature to N-(2-aminophenyl)-4-chlorobenzene sulfonamide (0.5mmol; method preparation according to embodiment 11) in the solution of DCM (1mL) and pyridine (1mL), adds 5-methylsulfonyl-2-anisole SULPHURYL CHLORIDE (0.55mmol), the reaction mixture stirred overnight at room temperature then of preparation according to the method described above.Use DCM (5mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 160mg N-[2-(4-chlorobenzene sulfonamido) phenyl through flash column chromatography]-5-methylsulfonyl-2-methoxybenzenesulphoismide.LC：Tr?1.05min，MS：531.9(M+1) ⁺。

Embodiment 15

At room temperature to benzo [b] thiophene-2-sulfonic acid (2-aminophenyl)-acid amides (1mmol, method preparation according to embodiment 1) in the solution of DCM (2mL) and pyridine (2mL), adds 4-methoxyl group-2-nitrobenzene sulfonyl chloride (1.1mmol), reaction mixture stirred overnight at room temperature then.Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 348mg benzo [b] thiophene-2-sulfonic acid [2-(4-methoxyl group-2-nitro-phenylsulfonamido) phenyl]-acid amides through flash column chromatography.LC：Tr1.09min；MS：520.7(M+1) ⁺。

Embodiment 16

At room temperature to benzo [b] thiophene-2-sulfonic acid (2-amino-phenyl)-acid amides (1mmol; method preparation according to embodiment 1) in the solution of DCM (2mL) and pyridine (2mL), adds 5-methylsulfonyl-2-anisole SULPHURYL CHLORIDE (1.1mmol), reaction mixture stirred overnight at room temperature then.Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 330mg benzo [b] thiophene-2-sulfonic acid [2-(4-methylsulfonyl-2-methoxyl group-phenylsulfonamido) phenyl]-acid amides through flash column chromatography.LC：Tr?1.06min；MS：553.8(M+1) ⁺。

Embodiment 17

At room temperature to benzo [b] thiophene-2-sulfonic acid (2-aminophenyl)-acid amides (1mmol, method preparation according to embodiment 1) in the solution of DCM (2mL) and pyridine (2mL), adds 2-methoxyl group-5-Methyl benzenesulfonyl chlorine (1.1mmol), reaction mixture stirred overnight at room temperature then.Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 390mg benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-5-Methyl benzenesulfonyl amino) phenyl]-acid amides through flash column chromatography.LC：Tr?1.25min；MS：489.1(M+1) ⁺。

Embodiment 18

In the solution of dioxane (5mL), once add solid sodium methylate (2mmol) to benzo [b] thiophene-2-sulfonic acid [2-(2-chloro-5-trifluoromethyl phenylsulfonamido) phenyl]-acid amides (0.5mmol), the gained reaction mixture then reflux 4h (calculated value, ca.).After reaction was finished, reaction mixture was cooled to RT, and vacuum concentration.The gained residue redissolves in EtOAc (10mL), and water (10mL) and salt solution (10mL) washing.Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 204mg benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-5-trifluoromethyl-sulfuryl amino) phenyl]-acid amides through flash column chromatography.LC：Tr?1.20min；MS：544.1(M+1) ⁺。

Embodiment 19

In the solution of dry DCM (20mL), add triethylamine (4mL) to 2-(4-anisole alkylsulfonyl) ethanol (20mmol).Reaction mixture is cooled to 0 ℃, subsequently methylsulfonyl chloride (3mL) dropwise.Reaction mixture is stirring at room 12h then, uses DCM (150mL) dilution afterwards.Organic phase is with the 10%HCl aqueous solution (50mL) washing, and is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with hexane/EtOAc (3: 1 to 1: 1) wash-out purifying, obtains 5-ethene alkylsulfonyl-2-anisole (3g) through flash column chromatography.

In the solution of anhydrous methylene chloride (30mL), dropwise adding chlorsulfonic acid (3mL) to the 5-ethene alkylsulfonyl-2-anisole (3g) that obtains according to the method described above under 0 ℃.Reaction mixture is heated to room temperature, then divides three times and adds PCl ₅(3g).Gained reaction mixture refluxed 2h.After being cooled to room temperature, reaction mixture is poured onto in the frozen water (100mL), stirs simultaneously.(2 * 150mL) extract content with EtOAc.(2 * 100mL) wash the organic phase that merges, dry on anhydrous sodium sulphate, and vacuum concentration with saturated sodium-chloride water solution.The gained residue with ethyl acetate/hexane (1: 4 to 1: 1) wash-out purifying, obtains 5-ethene alkylsulfonyl-2-anisole SULPHURYL CHLORIDE (3g) through column chromatography.

At room temperature to benzo [b] thiophene-2-sulfonic acid (2-aminophenyl)-acid amides (10mmol; method preparation according to embodiment 1) in the solution of DCM (20mL) and pyridine (20mL), adds 5-ethene alkylsulfonyl-2-anisole SULPHURYL CHLORIDE (11mmol), reaction mixture stirred overnight at room temperature then.Use DCM (100mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (100mL), water (100mL) and salt solution (100mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains benzo [b] thiophene-2-sulfonic acid [2-(5-ethene alkylsulfonyl-2-anisole sulfonamido) phenyl] acid amides (2.8g) through flash column chromatography.LC：Tr?1.15min；MS：565.9(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.17(s，3H)，6.03(d，1H)，6.42(d，1H)，6.56(dd，1H)，6.81(dd，1H)，6.97(t，1H)，7.13(t，1H)，7.18(d，1H)，7.32(d，1H)，7.42-7.52(m，2H)，7.62(s，1H)，7.80(d，1H)，7.83(d，1H)，8.04(dd，1H)，8.19(d，1H)ppm。

Benzo [b] thiophene-2-sulfonic acid [2-(5-ethene alkylsulfonyl-2-methoxyl group-phenylsulfonamido)-phenyl]-acid amides (0.5mmol) to preparation according to the method described above adds Me in the solution of anhydrous THF (10mL) ₂NH-THF solution (2.5mL; 2M Me ₂NH is at the solution of THF).Gained reaction mixture stirring at room 30min.After the solvent removed in vacuo; the gained residue with DCM/ methyl alcohol (100: 2 to 100: 10) wash-out purifying, obtains 290mg benzo [b] thiophene-2-sulfonic acid { 2-[5-(2-dimethylamino ethylsulfonyl)-2-anisole sulfonamido] phenyl }-acid amides after flash column chromatography is earlier with EtOAc.LC：Tr?0.99min；MS：610.7(M+1) ⁺。

Embodiment 20

In the solution of dry DMF (3mL), add 2H-tetrazolium (25mg) to benzo [b] thiophene-2-sulfonic acid [2-(5-ethene alkylsulfonyl-2-anisole sulfonamido) phenyl]-acid amides (0.2mmol is according to the method preparation of embodiment 19).The gained reaction mixture stirred 2 hours in 110 ℃ in sealed tube.With DCM (20mL) diluted reaction mixture, and wash with saturated nacl aqueous solution (25mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/ methyl alcohol/AcOH (100: 2: 1 to 100: 10: 2) wash-out purifying, obtains two separable positional isomerss (regio-isomer) after flash column chromatography elder generation is with EtOAc.Polarity is less is benzo [b] thiophene-2-sulfonic acid { 2-[2-methoxyl group-5-(2-tetrazolium-2-base-second sulphonyl)-phenylsulfonamido]-phenyl }-acid amides (51mg).LC：Tr?1.08min；MS：635.6(M+1) ⁺。

Embodiment 21

In the solution of anhydrous THF (2mL), add the 0.2mL tetramethyleneimine to benzo [b] thiophene-2-sulfonic acid [2-(5-ethene alkylsulfonyl-2-anisole sulfonamido) phenyl]-acid amides (0.2mmol is according to the method preparation of embodiment 19).Gained reaction mixture stirring at room 1h.With DCM (10mL) diluted reaction mixture, and wash with saturated sodium-chloride water solution (25mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/ methyl alcohol/AcOH (100: 2: 1 to 100: 10: 2) wash-out purifying, obtains 121mg benzo [b] thiophene-2-sulfonic acid { 2-[2-methoxyl group-5-(2-tetramethyleneimine-1-base-ethylsulfonyl)-phenylsulfonamido] phenyl } acid amides after flash column chromatography is earlier with EtOAc.LC：Tr?0.94min；MS：636.8(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ1.68(m，4H)，2.38(m，4H)，2.78(t，2H)，3.28(t，2H)，4.20(s，3H)，6.76(d，1H)，6.96(d，1H)，7.14(t，1H)，7.21(d，1H)，7.36(d，1H)，7.41(t，1H)，7.49(t，1H)，7.60(s，1H)，7.79(d，1H)，7.83(d，1H)，8.07(d，1H)，8.26(d，1H)ppm。

Embodiment 22

In the solution of dry THF (2mL), add 0.2mL 1-methylpiperazine to benzo [b] thiophene-2-sulfonic acid [2-(5-ethene alkylsulfonyl-2-anisole sulfonamido) phenyl] acid amides (0.2mmol is according to the method preparation of embodiment 19).Gained reaction mixture stirring at room 1h.With DCM (10mL) diluted reaction mixture, and wash with saturated sodium-chloride water solution (25mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/ methyl alcohol/AcOH (100: 2: 1 to 100: 10: 2) wash-out purifying, obtains 118mg benzo [b] thiophene-2-sulfonic acid { 2-[2-methoxyl group-5-(2-tetramethyleneimine-1-base-ethylsulfonyl)-phenylsulfonamido] phenyl } acid amides after flash column chromatography is earlier with EtOAc.LC：Tr?0.84min；MS：666.0(M+1) ⁺。

Embodiment 23

Under 0 ℃ to 4 '-methoxyl group-2,2,2-trifluoroacetyl benzene (5mmol) adds the 0.5mL chlorsulfonic acid 1 in the solution of 2-ethylene dichloride (10mL).The gained reaction mixture is heated to room temperature gradually, then reflux 4h.Then reaction mixture is cooled to room temperature, with chloroform (30mL) dilution.Content is transferred in the separating funnel subsequently, and water (50mL) washing separates each layer.Water layer is then with chloroform (30mL) extraction.The organic phase that merges is with salt solution (50mL) washing, and is dry on anhydrous sodium sulphate.Solvent removed in vacuo, the gained residue is the eluent purifying through the silica gel flash column chromatography with ethyl acetate/hexane (1: 10 to 1: 2 gradient), obtains 440mg 5-(1,1-two chloro-2,2,2-trifluoroethyl)-2-anisole SULPHURYL CHLORIDE. ¹H?NMR(CDCl ₃，400MHz)：δ4.14(s，3H)，7.14(d，1H)，8.14(dd，1H)，8.44(d，1H)ppm。

At room temperature to benzo [b] thiophene-2-sulfonic acid (2-aminophenyl)-acid amides (1mmol, method preparation according to embodiment 1) in the solution of DCM (2mL) and pyridine (2mL), adds 5-(1,1-two chloro-2,2, the 2-trifluoroethyl)-2-anisole SULPHURYL CHLORIDE (1.1mmol), reaction mixture stirred overnight at room temperature then.Use DCM (20mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (20mL), water (20mL) and salt solution (20mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 374mg benzo [b] thiophene-2-sulfonic acid [2-(5-(1,1-two chloro-2,2,2-trifluoroethyl)-2-methoxyl group-phenylsulfonamido)-phenyl]-acid amides through flash column chromatography.LC：Tr?1.40min；MS：625.8(M+1)。

Embodiment 24

At room temperature to N-(2-amino-phenyl)-4-chlorobenzene sulfonamide (1.0mmol, method preparation according to embodiment 11) in the solution of DCM (2mL) and pyridine (2mL), adds 2-chloro-5-(trifluoromethyl) benzene sulfonyl chloride (1.1mmol), reaction mixture stirred overnight at room temperature then.Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 419mg 2-chloro-N-[2-(4-chloro-phenylsulfonamido) phenyl through flash column chromatography]-5-trifluoromethyl benzsulfamide.LC：Tr?1.25min；MS：525.9(M+1)。

To 2-chloro-N-[2-(4-chloro-phenylsulfonamido) phenyl]-5-trifluoromethyl benzsulfamide (0.5mmol) once adds solid sodium methylate (2mmol) in the solution of dioxane (5mL), the gained reaction mixture then reflux 4h (calculated value, ca.).After reaction was finished, reaction mixture was cooled to RT, and vacuum concentration.The gained residue redissolves in EtOAc (10mL), and water (10mL) and salt solution (10mL) washing.Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 160mgN-[2-(4-chlorobenzene sulfonamido) phenyl through flash column chromatography]-2-methoxyl group-5-trifluoromethyl benzsulfamide.LC：Tr1.22min；MS：521.8(M+1) ⁺。

Embodiment 25

At room temperature to benzo [b] thiophene-2-sulfonic acid (2-amino-phenyl)-acid amides (1mmol, according to the preparation of the method for embodiment 1) in the solution of DCM (2mL) and pyridine (2mL), add 2-methoxyl group-4-nitrobenzene sulfonyl chloride (1.1mmol), then the reaction mixture stirred overnight at room temperature or to reaction through TLC or LC-MS is definite finishes.Use DCM (20mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (20mL), water (20mL) and salt solution (20mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, generates 353mg benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-4-nitrobenzene sulfonyl ammonia base) phenyl]-acid amides through flash column chromatography.LC：Tr?1.21min；MS：520.7.7(M+1) ⁺. ¹H?NMR(CDCl ₃，400MHz)：δ4.24(s，3H)，6.72(bs，1H)，6.88(d，1H)，7.03(t，1H)，7.16(t，1H)，7.30(d，1H)，7.52(t，1H)，7.51(t，1H)，7.64(s，1H)，7.67-7.88(m，5H)，7.92(s，1H)ppm。

In the solution of ethyl acetate (5mL) and methyl alcohol (5mL), add the palladium that is positioned on the gac (10%, wet about 20mg) to above-mentioned benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-4-nitrobenzene sulfonyl ammonia base) phenyl] acid amides (0.5mmol).Reaction mixture vacuum outgas 5min stirs 20min down at hydrogen atmosphere (1atm).With short Celite pad filter reaction mixture, filter pad washs with methyl alcohol (20mL) and methylene dichloride (20mL).The organic phase vacuum concentration that merges obtains the amino intermediate of 238mg.LC：Tr?1.13min，MS：490.9(M+1) ⁺. ¹H?NMR(DMSO-d ₆，400MHz)：δ3.82(s，3H)，6.03(dd，1H)，6.06(bs，2H)，6.21(d，1H)，6.90(m，2H)，7.05(td，1H)，7.20(dd，1H)，7.46(td，1H)，7.52(td，1H)，7.88(s，1H)，7.97(dd，1H)，8.06(dd，1H)，8.66(bs，1H)，9.78(bs，1H)ppm。

In the solution of AcOH (2mL), add NH to the amino intermediate (0.3mmol) that obtains according to the method described above ₄OAc (10mmol), 37% formalin (2mL) and 40% glyoxal water solution (1mL).Reaction mixture is at 100 ℃ of heating 1.5h.After being cooled to room temperature, reaction mixture dilutes with ethyl acetate (50mL).Organic phase water (25mL) and the 1%KOH aqueous solution (25mL) washing.Organic phase is dry on sodium sulfate, and vacuum concentration.The gained residue with DCM/ methyl alcohol (100: 2 to 100: 10) wash-out purifying, obtains 98mg benzo [b] thiophene-2-sulfonic acid [2-(4-imidazoles-1-base-2-anisole sulfonamido) phenyl]-acid amides after flash column chromatography is earlier with hexane/EtOAc (1: 1).LC：Tr?0.87min；MS：541.6(M+1) ⁺. ¹H?NMR(DMSO-d ₆，400MHz)：δ4.06(s，3H)，6.80(dd，1H)，6.95(td，1H)，7.06(m，2H)，7.13(s，1H)，7.23(dd，1H)，7.29(d，1H)，7.52-7.42(m，3H)，7.67(d，1H)，7.88(s，1H)，7.90(s，1H)，7.94(d，1H)，8.02(d，1H)，8.46(s，1H)，9.06(bs，1H)ppm。

Embodiment 26

Under 0 ℃ to 0 ℃ benzene-1,2-diamines (1mmol) in the solution of DCM (4mL) and pyridine (1mL) on a small quantity repeatedly (the reinforced time is 10-15min) add benzo [b] thiophene-2-SULPHURYL CHLORIDE (2.2mmol).Reaction mixture is heated to RT then gradually and continues to stir 6h.Use DCM (10mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with EtOAc/DCM (1% to 3%) wash-out purifying, obtains 425mg N-[2-(thionaphthene-2-alkylsulfonyl) amino after flash column chromatography elder generation is with DCM] phenyl-thionaphthene-2-sulphonamide.LC：Tr?1.18min；MS：501.7(M+1) ⁺. ¹H?NMR(DMSO-d ₆，400MHz)：δ7.14(A2B2，4H)，7.48(dd，2H)，7.54(dd，2H)，7.95(s，2H)，7.97(d，2H)，8.03(d，2H)ppm。

Embodiment 27

To 0 ℃ benzene-1,2-diamines (0.5mmol) repeatedly adds cumarone-2-SULPHURYL CHLORIDE (1.1mmol on a small quantity in 10-15min in the solution of DCM (2mL) and pyridine (0.5mL) under 0 ℃; Method preparation according to embodiment 12).Reaction mixture is heated to RT then gradually and continues to stir 6h.Use DCM (5mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue with EtOAc/DCM (1% to 3%) wash-out purifying, obtains 117mg N-{2-[(1-cumarone-2-base alkylsulfonyl after flash column chromatography elder generation is with DCM) amino] phenyl }-1-cumarone-2-sulphonamide.Tr?1.18min；MS：469.7(M+1) ⁺。

Embodiment 28

In the solution of DCM (20mL) and pyridine (4mL), repeatedly add 3 to 0 ℃ O-Phenylene Diamine (4mmol) on a small quantity, 4-two chloro phenylsulfonyl chloride (4.4mmol).Reaction mixture is heated to RT then gradually and continues stirring until reaction to be determined to finish through TLC or LC-MS.Reaction mixture is used DCM (20mL) dilution then.Organic phase water (2 * 20mL) and salt solution 20mL washing.Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 760mg N-(2-amino-phenyl)-3,4-two chloro-benzsulfamides through flash column chromatography.LC：Tr?0.98min，MS：317.0(M+1) ⁺；H?NMR(CDCl ₃，400MHz)：δ4.95(bs，2H)，6.45(t，1H)，6.11(d，1H)，6.72(d，1H)，6.92(t，1H)，7.59(dd，1H)，7.80(d，3H)ppm。

Single sulphonamide (1mmol) of Huo Deing is dissolved in DCM (2mL) and the pyridine (2mL) according to the method described above.At room temperature add 5-fluoro-2-methoxyl group-benzene sulfonyl chloride (1.1mmol), then the reaction mixture stirred overnight at room temperature.Reaction mixture is used DCM (10mL) dilution then.Organic phase is washed with 10% aqueous hydrochloric acid (10mL), water (10mL) and salt solution (10mL).Organic phase anhydrous sodium sulfate drying, and vacuum concentration.The gained residue with DCM/EtOAc wash-out purifying, obtains 302mg N-[2-(3,4-dichlorobenzene sulfonamido)-phenyl through flash column chromatography]-5-fluoro-2-methoxybenzenesulphoismide.LC：Tr?1.19min；MS：505.5(M+1) ⁺； ¹H?NMR(DMSO-d ₆，400MHz)：δ3.92(s，3H)，6.85(dd，1H)，7.02(m，1H)，7.08(m，2H)，7.28(dd，1H)，7.40(dd，1H)，7.50(m，1H)，7.56(dd，1H)，7.80(d，1H)，7.82(s，1H)，9.11(bs，1H)，9.56(bs，1H)ppm。

Embodiment 29

To pyridine-4-boric acid (3mmol), 4-bromo-2-N-methyl-p-nitroaniline (2mmol) and Pd (PPh ₃) ₄(20mg) mixture at DME (10mL) adds 2M Na ₂CO ₃The aqueous solution.Suspension is then at refluxed under nitrogen 36h.After being cooled to room temperature, reaction mixture dilutes with ethyl acetate (150mL).Organic phase is with salt solution (50mL) washing, and is dry on sodium sulfate, and vacuum concentration.The gained residue with ethyl acetate/methanol (10: 1) wash-out purifying, obtains 516mg 2-nitro-4-pyridin-4-yl aniline after column chromatography is earlier with hexane/ethyl acetate (1: 1).LC：Tr?0.44min，MS：216.1(M+1) ⁺. ¹H?NMR(DMSO-d ₆，400MHz)：δ7.13(d，1H)，7.60(d，2H)，7.69(bs，2H)，7.88(dd，1H)，8.37(d，1H)，8.55(d，2H)ppm。

In the solution of pyridine (3mL), add 4-chloro-benzene sulfonyl chloride (1.2mmol) to 2-nitro-4-pyridin-4-yl aniline (1mmol), gained mixture stirring at room 24h.With ethyl acetate (20mL) diluted reaction mixture.Content is with salt solution (25mL) washing, and is dry on sodium sulfate, and vacuum concentration.The gained residue is used the eluent ethyl acetate purifying after column chromatography is earlier with hexane/ethyl acetate (1: 1), obtain 156mg 4-chloro-N-(2-nitro-4-pyridin-4-yl phenyl) benzsulfamide.

To 4-chloro-N-(2-nitro-4-pyridin-4-yl phenyl) benzsulfamide (0.2mmol) in the solution of ethyl acetate (10mL), add gac (10%, wet, the 10mg) palladium on.Reaction mixture vacuum outgas 5min stirs 20min down at hydrogen (1atm).With short Celite pad filter reaction mixture, filter pad washs with methyl alcohol (10mL) and ethyl acetate (15mL).The organic phase vacuum concentration that merges obtains 58mg N-(2-amino-4-pyridin-4-yl phenyl)-4-chlorobenzene sulfonamide.

In the solution of pyridine (0.5mL), add 5-bromo-2-methoxyl group-benzene sulfonyl chloride (0.12mmol) to N-(2-amino-4-pyridin-4-yl phenyl)-4-chlorobenzene sulfonamide (0.1mmol).Reaction mixture stirring at room 2h uses ethyl acetate (10mL) dilution then.Content is with salt solution (10mL) washing, and is dry on sodium sulfate, and vacuum concentration.The gained residue is used the eluent ethyl acetate purifying after column chromatography is earlier with hexane/ethyl acetate (1: 1), obtain 49mg 5-bromo-N-[2-(4-chlorobenzene sulfonamido)-5-pyridin-4-yl phenyl]-the 2-methoxybenzenesulphoismide.LC：Tr?0.94min，MS：610.8(M+1) ⁺。

Embodiment 30

In the solution of pyridine (3mL), add 5-bromo-2-anisole SULPHURYL CHLORIDE (1.2mmol) to 4-fluoro-2-N-methyl-p-nitroaniline (1mmol), gained mixture stirring at room 24h.With ethyl acetate (20mL) diluted reaction mixture.Content is with the 10%HCl aqueous solution (20mL) and salt solution (20mL) washing, and is dry on sodium sulfate, and vacuum concentration.The gained residue with hexane/ethyl acetate wash-out purifying, obtains 223mg 5-bromo-N-(4-fluoro-2-nitrophenyl)-2-methoxybenzenesulphoismide through column chromatography.

Above-mentioned nitro intermediate (0.5mmol) is dissolved among the EtOH (10mL), and (2.5mmol) handles with tin chloride (II).Reaction mixture reflux 12h.Content is cooled to RT, handles pH value to reaction mixture between 8-9 with the 1M NaOH aqueous solution, causes throw out to form.Filtering precipitate washs with methyl alcohol (10mL) and DCM (10mL) then.The filtrate vacuum concentration that merges, the gained residue is eluent wash-out purifying through column chromatography with the DCM/ ethyl acetate, obtains 115mg 5-bromo-N-(4-fluoro-2-aminophenyl)-2-methoxybenzenesulphoismide.

In the solution of pyridine (0.5mL) and DCM (2mL), add 4-chlorobenzene sulfonyl chloride (0.12mmol) to 5-bromo-N-(4-fluoro-2-aminophenyl)-2-methoxybenzenesulphoismide (0.1mmol).Reaction mixture stirring at room 4h uses ethyl acetate (10mL) dilution then.Content is with the 10%HCl aqueous solution (10mL) and salt solution (10mL) washing, and is dry on sodium sulfate, and vacuum concentration.The gained residue is used the eluent ethyl acetate purifying after column chromatography is earlier with hexane/ethyl acetate (1: 1), obtain 43mg 5-bromo-N-[2-(4-chlorobenzene sulfonamido)-4-fluorophenyl]-the 2-methoxybenzenesulphoismide.LC：Tr?1.10min，MS：551.8(M+1) ⁺。

Embodiment 31

To 0 ℃ 4-fluorobenzene-1,2-diamines (1mmol) repeatedly adds thionaphthene-2-SULPHURYL CHLORIDE (2.2mmol) on a small quantity in the solution of DCM (2mL) and pyridine (2mL).The stirring at room reaction mixture is determined to finish through TLC or LC-MS until reaction then.Use DCM (15mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (5mL), water (5mL) and salt solution (5mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue is through flash column chromatography DCM/EtOAc wash-out purifying, and obtaining 192mg is solid N, N '-(4-fluoro-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide).

¹H?NMR(DMSO-d ₆；300MHz)δ6.8-6.9(m，1H)，7.0-7.2(m，2H)，7.4-7.6(m，4H)，7.83(s，1H)，7.9-8.0(m，4H)，8.04(s，1H)，9.7-10.1(br?s，2H)ppm。

Embodiment 32

To 4-cyano group benzene-1,2-diamines (1mmol) repeatedly adds thionaphthene-2-SULPHURYL CHLORIDE (2.2mmol) on a small quantity in the solution of pyridine (4mL).In 80 ℃ of reacting by heating mixtures and stirring, determine to finish through TLC or LC-MS then until reaction.Use ethyl acetate (20mL) diluted reaction mixture subsequently.Organic phase is washed with 10% aqueous hydrochloric acid (15mL), water (15mL) and salt solution (5mL).Organic phase is dry on anhydrous sodium sulphate, and vacuum concentration.The gained residue is through flash column chromatography DCM/EtOAc wash-out purifying, and obtaining 184mg is solid N, N '-(4-cyano group-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide).

¹H?NMR(CDCl ₃；300MHz)δ7.31(s，1H)；7.4-7.6(m，6H)，7.65(s，1H)，7.7-7.9(m，5H)ppm。

Embodiment 33

N, N '-(4-chloro-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide) (310mg) according to the method for embodiment 31 with 4-chlorobenzene-1,2-diamines and thionaphthene-2-SULPHURYL CHLORIDE is essential starting raw material preparation.

¹H?NMR(DMSO-d ₆；300MHz)δ7.18(s，2H)，7.22(s，1H)，7.4-7.6(m，4H)，7.9-8.1(m，6H)，9.8-10.1(br?s，2H)ppm。

Embodiment 34

N, N '-(4-bromo-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide) (255mg) according to the method for embodiment 31 with 4-bromobenzene-1,2-diamines and thionaphthene-2-SULPHURYL CHLORIDE is essential starting raw material preparation.

¹H?NMR(DMSO-d ₆；300MHz)δ7.06(d，1H)，7.2-7.4(m，2H)，7.4-7.7(m，4H)，7.9-8.1(m，6H)，9.8-10.2(br?s，2H)ppm。

Embodiment 35

N, N '-(4-methoxyl group-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide) (472mg) according to the method for embodiment 31 with 4-anisole-1,2-diamines and thionaphthene-2-SULPHURYL CHLORIDE is essential starting raw material preparation.

¹H?NMR(DMSO-d ₆；300MHz)δ3.58(s，3H)，6.62(dd，1H)，6.81(d，1H)，6.88(d，1H)，7.4-7.6(m，4H)，7.83(s，1H)，7.9-8.2(m，5H)，9.65(br?s，2H)ppm。

Embodiment 36

At room temperature to 3-[2-(benzo [b] thiophene-2-sulfonamido)-phenyl sulfamoyl base]-4-methoxybenzoic acid (1mmol; see embodiment 4) in the solution of dry DMF (4mL), add DIEA (1.5mmol) and HBTU (1.2mmol), mixture stirs 30min.At room temperature add TERTIARY BUTYL AMINE (1.2mmol) subsequently while stirring, and continue to stir 60min again.Reaction mixture water (20mL) dilution, the throw out of formation filters and washes with water.Obtain white solid (488mg), this solid is not purified to be directly used in further conversion.

¹H?NMR(DMSO-d ₆；300MHz)δ1.36(s，9H)，4.05(s，3H)，6.90(d，1H)，6.98(t，1H)，7.12(t，1H)，7.23(d，1H)，7.30(d，1H)，7.4-7.6(m，2H)，7.85-8.05(m，3H)，8.05-8.15(m，3H)，9.10(s，1H)，9.82(s，1H)ppm。

The amide product that obtains from above (0.5mmol) is suspended in the dry-out benzene (10mL), handles with Phosphorus Oxychloride (1mL).After the reaction mixture refluxed 3h, reaction is finished.The POCl that solvent removed in vacuo is excessive ₃, gained residue Virahol recrystallization obtains the benzo that 125mg is a faint yellow solid [b] thiophene-2-sulfonic acid [2-(5-cyano group-2-anisole sulfonamido)-phenyl]-acid amides.

¹H?NMR(DMSO-d ₆；300MHz)δ4.05(s，3H)，6.90(d，1H)，7.02(t，1H)，7.14(t，1H)，7.25(d，1H)，7.4-7.6(m，3H)，7.91(s，1H)，7.95-8.05(m，2H)，8.06-8.14(m，2H)，9.18(br?s，1H)，9.82(br?s，1H)ppm。

Embodiment 37

At room temperature to 3-[2-(benzo [b] thiophene-2-sulfonamido)-phenyl sulfamoyl base]-4-methoxybenzoic acid (1mmol; see embodiment 4) in the solution of dry DMF (4mL), add DIEA (4.5mmol) and HBTU (1.2mmol), mixture stirs 30min.At room temperature add N-hydroxyl acetamidine (2.0mmol) subsequently while stirring, and continue to stir 60min again.(2 * 20mL) washings are in anhydrous Na with ethyl acetate (30mL) dilution, water for reaction mixture ₂SO ₄Last dry.Solvent removed in vacuo, obtain into white solid 385g oxamate (oxamate ester) (488mg), this solid is directly used in further conversion without any purifying.

The oxamate (0.35mmol) that obtains according to the method described above is suspended in the dimethylbenzene (6mL), with powdery 4

Molecular sieve (1g) is handled.After the reaction mixture reflux 6h, reaction is finished.Content filters then, and solvent removed in vacuo obtains the benzo that 29mg is a pale solid [b] thiophene-2-sulfonic acid { 2-[2-methoxyl group-5-(3-methyl-[1,2,4] uh diazole-5-yl) phenylsulfonamido] phenyl }-acid amides.

¹H?NMR(DMSO-d ₆；300MHz)δ2.38(s，3H)，4.05(s，3H)，6.90(d，1H)，6.98(t，1H)，7.12(t，1H)，7.23(d，1H)，7.30(d，1H)，7.4-7.6(m，2H)，7.85-8.05(m，3H)，8.05-8.15(m，3H)，9.10(s，1H)，9.82(s，1H)ppm。

Embodiment 38

(1.5g, 11.8mmol) (3.9ml 47.2mmol) adds concentrated hydrochloric acid (3.9mL) in the solution of ethanol (10mL), gained solution is at 50 ℃ of heating 6h with 37% formalin to 2 thiophene ethyl amine.All volatile matter are removed in decompression.Residue places the dioxane (13mL) and the 2N NaOH aqueous solution (12.8mL), is cooled to 0 ℃.(2.24g 10.28mmol) handles reaction mixture, and stirring at room 10 with two dimethyl dicarbonate butyl esters.Use ethyl acetate (25mL) diluted reaction mixture then, water layer extracts with ethyl acetate (10mL).The organic phase water that merges, the salt water washing is at Na ₂SO ₄Last dry.Removal of solvent under reduced pressure, product with 3%EtOAc/ hexane wash-out purifying, obtains 1.7g 6,7-dihydro-4H-thieno-[3,2-c] pyridine-5-carboxylic acid tertiary butyl ester through silica gel column chromatography.

2-chlorosulfonyl-6; 7-dihydro-4H-thieno-[3; 2-c] method described according to embodiment 12 of pyridine-5-carboxylic acid tertiary butyl ester (0.25g); with n-Butyl Lithium and N-chloro-succinimide from 6; 7-dihydro-4H-thieno-[3; 2-c] pyridine-5-carboxylic acid tertiary butyl ester (1.6g, 6.69mmol) preparation.

2-[2-(benzo [b] thiophene-2-sulfuryl amino)-phenyl sulfamoyl base]-6; 7-dihydro-4H-thieno-[3; 2-c] pyridine-5-carboxylic acid tertiary butyl ester (280mg) is according to the program among the embodiment 2; with 2-chlorosulfonyl-6,7-dihydro-4H-thieno-[3,2-c] pyridine-5-carboxylic acid tertiary butyl ester (0.049g; 0.148mmol) and benzo [b] thiophene-2-sulfonic acid (2-amino-phenyl)-acid amides (0.045g; 0.148mmol, according to the method preparation of embodiment 1), prepare in DCM with pyridine.

¹HNMR(400MHz，CDCl ₃)δ1.48(s，9H)，2.76-2.85(m，2H)，3.65-3.75(m，2H)，4.39(s，2H)，7.06-7.24(m，5H)，7.36-7.52(m，4H)，7.71(s，1H)，7.78-7.86(m，2H)ppm。

Embodiment 39

N, N '-(4,5-two chloro-1, the 2-phenylene) two (1-thionaphthenes-2-sulphonamide) (120mg) with 4,5-two chloro-benzene-1,2-diamines (0.06g, 0.33mmol) and benzo [b] thiophene-2-SULPHURYL CHLORIDE (0.157g 0.67mmol), prepares according to the program among the embodiment 32.

¹HNMR(400MHz，DMSO-d ₆)δ7.34(s，2H)，7.41-7.57(m，4H)，7.93-8.20(m，6H)，9.60-10.50(br?s，2H)ppm。

Embodiment 40

N, N '-(4-Trifluoromethyl-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide) are (100mg) with 4-trifluoromethyl-benzene-1,2-diamines (0.06g, 0.33mmol) and benzo [b] thiophene-2-SULPHURYL CHLORIDE (0.157g 0.67mmol), prepares according to the program among the embodiment 32.

¹HNMR(400MHz，DMSO-d ₆)δ7.48(s，1H)，7.42-7.55(m，6H)，7.89-8.08(m，6H)，9.90-10.40(m，2H)ppm。

Embodiment 41

N, N '-(4-chloro-5-fluoro-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide) are (0.108g) with 4-chloro-5-fluoro-benzene-1,2-diamines (0.054g, 0.33mmol) and benzo [b] thiophene-2-SULPHURYL CHLORIDE (0.157g 0.67mmol), prepares according to the program among the embodiment 32.

¹HNMR(400MHz，DMSO-d ₆)δ7.15-7.26(dd，2H)，7.42-7.56(m，4H)，7.90-8.09(m，6H)，9.60-10.30(br?s，2H)ppm。

Embodiment 42

N, N '-(4,5-fluoro-1, the 2-phenylene) two (1-thionaphthenes-2-sulphonamide) (0.095g) with 4,5-two fluoro-benzene-1,2-diamines (0.048g, 0.33mmol) and benzo [b] thiophene-2-SULPHURYL CHLORIDE (0.157g 0.67mmol), prepares according to the program among the embodiment 32.

¹HNMR(400MHz，DMSO-d ₆)δ7.16(t，2H)，7.44-7.56(m，4H)，7.93-8.30(m，6H)，9.80-10.02(br?s，2H)ppm。

Biological analysis

The GalR1 binding analysis is analyzed

[ ¹²⁵I] galanin displacement binding analysis analyze in the research compound to the affinity of GalR1.Bowes melanoma cell film is used for the GalR1 binding analysis.Compound dilutes with 40%DMSO/ water.Used final test concentration is in 0.1nM to 10 μ M scope, and the DMSO ultimate density is 4%.Final binding analysis condition is 25mM Tris-HCL, contains 10mM MgCl ₂PH 7.4 damping fluids, 1-10 μ g film, 300pM[ ¹²⁵I] (SA=2200 Ci/mmoL, (Perkin Elmer, parts number NEX333) and final DMSO concentration are 4% compound (the final analysis volume is 100 μ L) to galanin.Positive control hole (C+) does not have compound, and negative control hole (C-) does not have compound but cold excessive galanin (1 μ M) is arranged.60-90min is at room temperature carried out in reaction.Contain in conjunction with [ ¹²⁵I] membrane filtration of galanin part goes up the back in Unifilter-96 GF/C screen plate (PerkinElmer, parts number 6005177) and separates with cell harvestor.Screen plate washs 5 times with cold pH7.5, the 25mM Tris-HCL that contains 0.05% bovine serum albumin (BSA).After the filtration, add 50 μ L Microscint PS (Packard, parts number 6013631), screen plate seals with TopSeal-A adhesive seal pad (Packard, parts number 6005185).With TopCount device (Packard) metering and Unifilter-96 GF/C plate bonded ¹²⁵The I isotropic substance.

Data analysis

Raw data transforms

[ ¹²⁵I] galanin is in conjunction with suppressing percentage ratio according to equation [100 * 1-{ (sample _Cpm-C- _Cpm)/(C+ _Cpm-C- _Cpm)] calculate.Generate [ ¹²⁵I] galanin is in conjunction with suppressing the experimental data of percentage ratio (Y) with compound concentration (X) ratio.

Fitting of a curve

With sigmoidal type dose response parameter fitting experimental data, calculate IC ₅₀Value, variable slope non-linear regression (GraphPAD Prizm, San Diego, the California) cf. equation Y=valley+(peak value-valley)/(1+10^ ((LogEC50-X) * HillSlope)), wherein X is the logarithm of concentration, and Y is a reacting value, and Y begins to become peak value with the sigmoid type from valley.This be identical " four parameter l ogistic equations ".

The compound of the formula in the table 1 (I) demonstrates IC in above-mentioned binding analysis ₅₀Less than or be about 10 μ M.

Functional experiment based on cell

CAMP measures the exciting functionally active of compound at the Bowes cell in Fu Sikelin (forskolin) stimulated cells by measuring.CAMP cAMP detection kit quantitative assay.The Bowes cell contains Earle ' s salt what be supplemented with 10% foetal calf serum, cultivates among the minimum level dulbecco minimum essential medium Dulbecco eagle of L-glutaminate and sodium bicarbonate.Cell is by containing 95%O ₂And 5%CO ₂37 ℃ of incubators of humidification in 15mL PBS (no Ca ²⁺And Mg ²⁺) culturing cell individual layer 20min gathers in the crops.Pat culturing bottle, disperse cell, cell suspending liquid is with the centrifugal 5min of the rotating speed of 600 * g (4 ℃).Cell is counted with blood-counter system, and is 1 * 10 with stimulating mixture (stimulation mix) (containing anti-cAMP antibody and isobutyl methylxanthine) to be diluted to final cell density ^-6To 5 * 10 ^-6Individual cell/mL.General 10,000 to 50,000 cells in every hole that use are analyzed.Compound is diluted to final analysis concentration in 0.1nM to 10 μ M scope with 1%DMSO/PBS, gets 5 μ L and places Costar black 384 orifice plates.Fu Sikelin dilutes with 1%DMSO/PBS.Galanin dilutes with the PBS that contains adequate proteins enzyme inhibitors mixture (CompleteMini, no EDTA, Roche Diagnostics).Cell (10uL) is cultivated 15min in advance with compound, adds Fu Sikelin (5 to 20uM) then and galanin (0.1 to 10nM) to final analysis volume is 20uL.Containing 95%O ₂And 5%CO ₂37 ℃ of incubators of humidification in behind the culturing cell 30min, add Alexa Fluor 594-cAMP and detect mix reagent (20uL), plate is cultivated 1hr in the room temperature jolting.Read the plate instrument with Envision (Perkin Elmer) fluorescence and measure fluorescence polarization degree (is unit representation with mP).Amount with the standard curve determination cAMP of cAMP (1-100nM).

The compound of the formula in the table 1 (I) demonstrates EC in above-mentioned functional experiment based on cell ₅₀Less than or be about 10 μ M and be confirmed to be the GalR1 agonist.

Behavior evaluation

Animal

Male Sprague Dawley rat (100-150g, neural ligation) is available from Charles River (Portage, the state of Michigan).Before the operation, the animal group support also remains under the environment of adjusted temperature (illumination between 7:00 a.m. to 8:00 p.m.).In operation two weeks of back, when the weight of animals is between 250-350g, begin experiment.Rat allows ad libitum access and drinking-water.

For estimating neuropathic pain, adopt von Frey silk that sciatic nerve is estimated bitterly by the mechanicalness sense of touch that is subjected to the training pawl of ligation animal.Such as previously described (Chaplan etc., Quantitative assessment of tactile allodynia in the rat paw.J NeurosciMeth, 1994; 53:55-62), postoperative two weeks, make rat adapt to the experimental box of making by resin glass, this experimental box is equipped with the silk screen bottom surface to allow the surface, bottom (planter) near the animal rear solid end.(Up-Down) method about the employing Dixons, definition sense of touch are the threshold value of withdrawing less than 4g bitterly, the baseline values of record sense of touch pain.Give test compounds then, measure the threshold value of withdrawing after this.

When the compound of the embodiment 1-30 in the table 1 during with about 15 to 100mg/kg dosed administration, withdraw threshold value and the blank solvent of the impaired animal of sciatic nerve are handled the threshold value of withdrawing of the impaired animal of sciatic nerve and are compared and increased.

Though invention has been described and explanation according to certain embodiments of the present invention, it should be appreciated by those skilled in the art that under the condition that does not exceed the connotation and extension of the present invention and can carry out multiple change to the present invention, revises or substitute.For example, the effective dose outside the dosage described herein is enforceable, because be there are differences by the mammiferous reactivity of treatment.Similarly, the specific pharmacological reaction of observing can according to and depend on selected particular active compounds or do not have pharmaceutical carrier, and the variation of employed formulation and administering mode and changing, and according to object of the present invention with implement these results' of design expection variation and difference.

Reference

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Claims

1. the compound of formula (I):

Ar ₂-SO ₂NH-Ar ₁-NHSO ₂-Ar ₃(I)

Wherein,

Ar ₁Comprise the optional arylidene that replaces 1-4 time, heteroarylidene, fused rings alkyl arylene, annelated heterocycles base arylidene, fused rings alkyl heteroarylidene, or annelated heterocycles base heteroarylidene.Ar wherein ₁Substituting group can comprise:

A) hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-whole haloalkyl;

F)-alkyl;

G)-aryl;

H)-heteroaryl;

I)-cycloalkyl;

J)-the L-aryl;

K)-L-arylidene-aryl;

L)-L-arylidene-alkyl;

M)-the Q-alkyl;

N)-the Q-aryl;

O)-Q-alkylidene group-aryl;

P)-Q-arylidene-alkyl;

Q)-L-Q-alkylidene group-aryl;

R)-arylidene-Q-alkyl;

S)-the L-Q-alkyl;

T)-the L-Q-aryl;

U)-the L-Q-heteroaryl;

V)-the L-Q-cycloalkyl;

W)-L-Q-arylidene-alkyl;

X)-D ₄-alkylidene group-NR ₁R ₂

y)-D ₄-NR ₁R ₂；

Z)-D ₄-alkyl; Or

aa)-D ₄-H；

Wherein,

R ₄And R _{4 '}Comprise independently-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl, or-alkylidene group-aryl;

R ₁And R ₂Comprise hydrogen independently, alkyl, or aryl, wherein R ₁And R ₂Can combine and form and R ₁And R ₂Institute's azine atomic linkage have formula-(CH ₂) _o-Z ₄-(CH ₂) _P-ring;

Wherein

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₄Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂N (H)-,-OC (O)-,-N (R ₃₁)-,-N (C (O) R ₃₁)-,-N (C (O) NHR ₃₁)-,-N (C (O) NR ₃₁R ₃₂)-,-N (S (O) ₂NHR ₃₁)-,-N (SO ₂R ₃₁)-, or-N (C (O) OR ₃₁)-;

Wherein

L comprises direct key ,-alkylidene group, and-alkenylene, or-alkynylene; And

Q comprises direct key ,-CH ₂-,-O-, or-S-;

Ar ₂And Ar ₃Comprise aryl independently, heteroaryl, fused rings alkylaryl, fused rings miscellaneous alkyl aryl, annelated heterocycles Ji Fangji, or annelated heterocycles base heteroaryl, wherein Ar ₂And Ar ₃In contain one of at least and-NHSO ₂-the tie point ortho position or the Sauerstoffatom or the sulphur atom of geminal, and Ar ₂And Ar ₃Can be substituted the optional replacement of base 1 to 5 time, this substituting group comprises:

A) hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-alkyl;

F)-aryl;

G)-cycloalkyl;

H)-heterocyclic radical;

I)-alkylidene group-cycloalkyl;

J)-whole haloalkyl;

K) heteroaryl;

L)-alkylidene group-aryl;

m)-D ₁-H；

n)-D ₁-R ₃；

O)-D ₁-alkyl;

P)-D ₁-aryl;

Q)-D ₁-whole haloalkyl;

R)-D ₁-alkylidene group-R ₃

S)-D ₁-alkylidene group-aryl;

T)-D ₁-alkylidene group-D ₂-R ₃

U)-D ₁-cycloalkyl;

V)-D ₁-heterocyclic radical;

W)-D ₁-aryl;

X)-D ₁-heteroaryl;

Y)-D ₁-arylidene-D ₂-R ₃

Z)-D ₁-heteroarylidene-D ₂-R ₃

Aa)-D ₁-alkylidene group-heteroaryl;

Bb)-D ₁-alkylidenyl-heterocyclic base;

Cc)-D ₁-alkylidene group-aryl;

Dd)-D ₁-alkylidene group-arylidene-D ₂-R ₃

Ee)-D ₁-alkylidene group-heteroarylidene-D ₂-R ₃

Ff)-D ₁-alkylidene group-NR ₅R ₆

Gg)-D ₁-arylidene-NR ₅R ₆Or

Hh)-acid isostere;

Wherein,

R ₇And R ₈Comprise independently-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl ,-alkylidene group-aryl, or-alkylidene group-arylidene-alkyl;

R ₅And R ₆Comprise hydrogen independently, alkyl, or aryl, wherein R ₅And R ₆Can combine and form and R ₅And R ₆Institute's azine atomic linkage have formula-(CH ₂) _o-Z1-(CH ₂) _P-ring,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₄Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂N (H)-,-OC (O)-,-N (R ₉)-,-N (C (O) R ₉)-,-N (C (O) NHR ₉)-,-N (C (O) NR ₉R ₁₀)-,-N (S (O) ₂NHR ₉)-,-N (SO ₂R ₉)-, or-N (C (O) OR ₉)-;

Wherein,

R ₁₁And R ₁₂Comprise independently :-hydrogen ,-alkyl, or-aryl;

And wherein,

Ar ₂, Ar ₃In alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, alkylidene group, cycloalkylidene, inferior heterocyclic radical, arylidene and heteroaryl, and R ₁To R ₃₂Can be substituted the optional replacement of base 1 to 4 time, this substituting group comprises:

A)-hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-whole haloalkyl;

F)-the A-whole haloalkyl;

g)-A-R ₄₀；

H)-the A-alkyl;

I)-the A-aryl;

J)-A-alkylidene group-aryl;

K)-A-alkylidene group-NR ₄₁R ₄₂Or

L)-A-alkylidene group-E-R ₄₃

Wherein,

R wherein ₄₄And R ₄₅Comprise independently :-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl ,-alkylidene group-aryl, or-alkylidene group-arylidene-alkyl;

R ₄₀And R ₄₃Comprise independently :-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl ,-alkylidene group-aryl, or-alkylidene group-arylidene-alkyl; And

R ₄₁And R ₄₂Comprise hydrogen independently, aryl, or alkyl, wherein R ₄₁And R ₄₂Can combine and form and R ₄₁And R ₄₂Institute's azine atomic linkage have formula-(CH ₂) _o-Z ₄-(CH ₂) _P-ring,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Wherein,

Or its pharmacy acceptable salt or prodrug, and the compound of formula wherein (I) is the Ga1R1 agonist.

2. the compound of the formula of claim 1 (I), Ar wherein ₁Substituting group-NHSO ₂-Ar ₂With-NHSO ₂-Ar ₃Be positioned at Ar ₁On the adjacent atom of ring.

3. the compound of the formula of claim 1 (I), Ar wherein ₁Be

Wherein J and K comprise independently:

A) hydrogen;

B)-halogen;

C)-cyano group;

D)-nitro;

E)-whole haloalkyl;

F)-alkyl;

G)-aryl;

H)-heteroaryl;

I)-cycloalkyl;

J)-the L-aryl;

K)-L-arylidene-aryl;

L)-L-arylidene-alkyl;

M)-the Q-alkyl;

N)-the Q-aryl;

O)-Q-alkylidene group-aryl;

P)-Q-arylidene-alkyl;

Q)-L-Q-alkylidene group-aryl;

R)-arylidene-Q-alkyl;

S)-the L-Q-alkyl;

T)-the L-Q-aryl;

U)-the L-Q-heteroaryl;

V)-the L-Q-cycloalkyl;

W)-L-Q-arylidene-alkyl;

X)-D ₄-alkylidene group-NR ₁R ₂

y)-D ₄-NR ₁R ₂；

Z)-D ₄-alkyl; Or

aa)-D ₄-H；

Wherein,

D ₄Comprise direct key ,-CH ₂-,-O-,-N (R ₄)-,-C (O)-,-CON (R ₄)-,-N (R ₄) C (O)-,-N (R ₄) CON (R _{4 '})-,-N (R ₄) C (O) O-,-OC (O) N (R ₄)-,-N (R ₄) SO ₂-,-SO ₂N (R ₄)-,-C (O)-O-,-O-C (O)-,-S-,-S (O)-,-S (O) ₂-,-N (R ₄) SO ₂N (R _{4 '})-, or-N=N-; Wherein, R ₄And R _{4 '}Comprise independently-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl, or-alkylidene group-aryl;

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Wherein,

L comprises direct key ,-alkylidene group, and-alkenylene, or-alkynylene; And

Q comprises direct key ,-CH ₂-,-O-, or-S-.

4. the compound of the formula of claim 3 (I), J wherein and K comprise hydrogen, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, cyano group, carboxyl, amide group ,-D independently ₄-alkyl ,-D ₄-alkylidene group-NR ₁R ₂,-D ₄-NR ₁R ₂,-D ₄-alkyl;-D ₄-H, D wherein ₄Comprise-C (O)-,-CON (R ₄)-,-SO ₂N (R ₄)-,-C (O)-O-, R wherein ₄Comprise-hydrogen ,-alkyl ,-aryl ,-arylidene-alkyl, or-alkylidene group-aryl;

Wherein,

R ₁And R ₂Comprise hydrogen independently, alkyl, or aryl, R wherein ₁And R ₂Can combine and form and R ₁And R ₂Institute's azine atomic linkage have formula-(CH ₂) _o-Z ₄-(CH ₂) _P-ring;

Wherein

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Wherein

R ₃₁And R ₃₂Comprise independently-hydrogen ,-alkyl ,-aryl, or-alkylidene group-aryl; One of at least be group outside the hydrogen among J and the K wherein.

5. the compound of the formula of claim 3 (I), Ar wherein ₂And Ar ₃It is unsubstituted benzothienyl.

6. the compound of the formula of claim 1 (I), Ar wherein ₁Comprise unsubstituted phenylene.

7. the compound of the formula of claim 1 (I), Ar wherein ₁Comprise unsubstituted phenylene, and-NHSO ₂-Ar ₂With-NHSO ₂-Ar ₃Substituting group is positioned at Ar ₁On the adjacent carbons of ring.

8. the compound of the formula of claim 1 (I), Ar wherein ₁And Ar ₃Be different.

9. the compound of the formula of claim 1 (I), Ar wherein ₁And Ar ₃Comprise aryl independently, heteroaryl, or annelated heterocycles base heteroaryl.

10. the compound of the formula of claim 1 (I), Ar wherein ₂And Ar ₃Comprise optional the replacement or unsubstituted phenyl independently, benzothienyl, benzofuryl, or 4,5,6, the 7-tetramethylene sulfide is [3,2-c] pyridyl also.

11. the compound of the formula of claim 1 (I), Ar wherein ₂And Ar ₃Comprise being optionally substituted 1 to 5 time aryl heteroaryl, fused rings alkylaryl, fused rings miscellaneous alkyl aryl, annelated heterocycles Ji Fangji, or annelated heterocycles base heteroaryl, wherein Ar independently ₂And Ar ₃In comprise one of at least

Wherein,

R ₁₄Comprise:

A)-halogen;

B)-cyano group;

C)-nitro;

D)-whole haloalkyl;

e)-D ₁-R ₁₇；

F)-D ₁-alkyl;

G)-D ₁-alkylidene group-R ₁₇

H)-D ₁-alkylidene group-D ₂-R ₁₇

I)-D ₁-aryl;

J)-D ₁-heteroaryl;

K)-D ₁-arylidene-D ₂-R ₁₇

L)-D ₁-heteroarylidene-D ₂-R ₁₇

M)-D ₁-alkylidene group-heteroaryl;

N)-D ₁-alkylidenyl-heterocyclic base;

O)-D ₁-alkylidene group-aryl;

P)-D ₁-alkylidene group-arylidene-D ₂-R ₁₇

Q)-D ₁-alkylidene group-heteroarylidene-D ₂-R ₁₇

R)-D ₁-alkylidene group-NR ₁₈R ₁₉

S)-D ₁-arylidene-NR ₁₈R ₁₉Or

T)-acid isostere;

Wherein,

R ₁₈And R ₁₉Comprise hydrogen independently, aryl, or alkyl, R wherein ₁₈And R ₁₉Can combine and form and R ₁₈And R ₁₉Institute's azine atomic linkage have formula-(CH ₂) _o-Z ₂-(CH ₂) _P-ring,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Wherein,

R ₂₂And R ₂₃Comprise independently :-hydrogen ,-alkyl, or-aryl;

R ₁₅And R ₁₆Comprise independently:

A)-hydrogen

B)-halogen;

C)-cyano group;

D)-alkyl;

E)-aryl;

F)-alkylidene group-aryl;

g)-D ₃-H；

H)-D ₃-alkyl;

I)-D ₃-aryl;

J)-D ₃-alkylidene aryl;

K)-the Y-alkyl;

L)-the Y-aryl;

M)-Y-alkylidene group-aryl;

N)-Y-alkylidene group-NR ₂₄R ₂₅Or

O)-Y-alkylidene group-W-R ₂₆

Wherein,

D ₃Comprise-O--C (O)-O-,-C (O)-NH-,-SO ₂-,-SO ₂-NH-, or-C (O)-;

Y and W comprise-CH independently ₂-,-O-,-N (H) ,-S-, SO ₂-,-CON (H)-,-NHC (O)-,-NHCON (H)-,-NHSO ₂-,-SO ₂N (H)-,-C (O)-O-,-NHSO ₂NH-, or-O-CO-,

R ₂₄And R ₂₅Comprise hydrogen independently, aryl, or alkyl, R wherein ₂₄And R ₂₅Can combine and form and R ₂₄And R ₂₅Institute's azine atomic linkage have formula-(CH ₂) _o-Z ₃-(CH ₂) _P-ring,

Wherein,

O and p be independently 1,2,3 or 4 and o and p sum be less than or equal to 6,

Z ₃Comprise direct key ,-CH ₂-,-C (O)-,-O-,-N (H)-,-S-,-S (O)-,-S (O) ₂-,-CON (H)-,-NHC (O)-,-NHC (O) N (H)-,-NH (SO ₂)-,-S (O) ₂N (H)-,-(O) CO-,-NHS (O) ₂NH-,-OC (O)-,-N (R ₂₉)-,-N (C (O) R ₂₉)-,-N (C (O) NHR ₂₉)-,-N (C (O) NR ₂₉R ₃₀)-,-N (S (O) ₂NHR ₂₉)-,-N (SO ₂R ₂₉)-, or-N (C (O) OR ₂₉)-;

Wherein,

R ₂₉And R ₃₀Comprise hydrogen independently, aryl, alkyl, or-alkylaryl;

R ₂₆Comprise hydrogen, alkyl, aryl, and alkylidene group-aryl;

X comprises sulphur or oxygen; And

M and n are 0,1 or 2 independently.

12. the compound of the formula of claim 11 (I), Ar wherein ₂Comprise

Wherein,

R ₁₄Comprise:

A)-D ₁-perhalogeno-C ₂-C ₆Alkyl;

B)-D ₁-alkylidene group-heteroaryl;

C)-D ₁-alkylidenyl-heterocyclic base;

D)-D ₁-alkylidene group-NR ₁₈R ₁₉Or

E)-acid isostere;

13. the compound of the formula of claim 11 (I), Ar wherein ₂Comprise group

And Ar ₃Comprise

14. the compound of the formula of claim 11 (I), Ar wherein ₂Comprise group

And Ar ₃The phenyl that comprises substituted 11 to 5 time, Ar wherein ₂And Ar ₃Be different.

15. the compound of the formula of claim 11 (I), Ar wherein ₃Comprise the phenyl that is replaced by at least one halogen group.

16. the compound of the formula of claim 11 (I), Ar wherein ₂Comprise group

And Ar3 comprises and is optionally substituted 1 to 5 time phenyl, benzothienyl, or benzofuryl,

Ar2 wherein is identical or different with Ar3.

17. the compound of the formula of claim 11 (I), Ar wherein ₂Comprise unsubstituted benzothienyl.

18. compound; it is selected from following compounds: benzo [b] thiophene-2-sulfonic acid [2-(2-chloro-5-trifluoromethyl phenylsulfonamido) phenyl] acid amides; benzo [b] thiophene-2-sulfonic acid 2-[2-methoxyl group-5-(propane-2-alkylsulfonyl) phenylsulfonamido] and phenyl } acid amides; 3-[2-(benzo [b] thiophene-2-sulfonamido)-phenyl sulfamoyl base]-4-methoxyl group-methyl benzoate; 3-[2-(benzo [b] thiophene-2-sulfonamido)-phenyl sulfamoyl base]-4-methoxyl group-phenylformic acid; N-[2-(3-imidazoles-1-base-phenylsulfonamido)-phenyl]-2-methoxyl group-5-trifyl-benzsulfamide; N-[2-(4-imidazoles-1-base-phenylsulfonamido)-phenyl]-2-methoxyl group-5-trifyl-benzsulfamide; 5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-5-trifyl-phenylsulfonamido)-phenyl]-acid amides; benzo [b] thiophene-2-sulfonic acid [2-(5-bromo-2-methoxyl group-phenylsulfonamido)-phenyl]-acid amides; 4; 5-dichloro-thiophene-2-sulfonic acid [2-(5-bromo-2-methoxyl group-phenylsulfonamido)-phenyl]-acid amides; 5-isoxazole-3-base-thiophene-2-sulfonic acid [2-(5-bromo-2-methoxyl group-phenylsulfonamido)-phenyl]-acid amides; N-[2-(4-chloro-phenylsulfonamido) phenyl]-2-methoxyl group-5-nitrobenzene sulfonamide; cumarone-2-sulfonic acid [2-(4-chloro-phenylsulfonamido) phenyl] acid amides; benzo [b] thiophene-2-sulfonic acid [2-(4-chloro-phenylsulfonamido) phenyl] acid amides; N-[2-(4-chlorobenzene sulfonamido) phenyl]-5-methylsulfonyl-2-methoxybenzenesulphoismide; benzo [b] thiophene-2-sulfonic acid [2-(4-methoxyl group-2-nitro-phenylsulfonamido) phenyl] acid amides; benzo [b] thiophene-2-sulfonic acid [2-(4-methylsulfonyl-2-methoxyl group-phenylsulfonamido)-phenyl] acid amides; benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-5-Methyl benzenesulfonyl amino) phenyl] acid amides; benzo [b] thiophene-2-sulfonic acid [2-(2-methoxyl group-5-trifluoromethyl phenylsulfonamido) phenyl] acid amides; benzo [b] thiophene-2-sulfonic acid 2-[5-(2-dimethylamino ethylsulfonyl)-2-methoxyl group-phenylsulfonamido] and phenyl } acid amides; benzo [b] thiophene-2-sulfonic acid 2-[2-methoxyl group-5-(2-tetrazolium-2-base-ethylsulfonyl)-phenylsulfonamido]-phenyl }-acid amides; benzo [b] thiophene-2-sulfonic acid 2-[2-methoxyl group-5-(2-tetramethyleneimine-1-base-ethylsulfonyl)-phenylsulfonamido]-phenyl }-acid amides; benzo [b] thiophene-2-sulfonic acid 2-[2-methoxyl group-5-(2-tetramethyleneimine-1-base-ethylsulfonyl)-phenylsulfonamido]-phenyl }-acid amides; [(5-(1 for 2-for benzo [b] thiophene-2-sulfonic acid; 1-two chloro-2; 2; the 2-trifluoroethyl)-and 2-methoxyl group-phenylsulfonamido) phenyl] acid amides; N-[2-(4-chlorobenzene sulfonamido) phenyl]-2-methoxyl group-5-trifluoromethyl benzsulfamide, benzo [b] thiophene-2-sulfonic acid [2-(4-imidazoles-1-base-2-anisole sulfonamido) phenyl] acid amides, N-[2-(thionaphthene-2-alkylsulfonyl) amino] phenyl thionaphthene-2-sulphonamide; N-[2-(thionaphthene-2-alkylsulfonyl) amino] phenyl thionaphthene-2-sulphonamide; N-[2-(3,4-dichlorobenzene sulfonamido) phenyl]-5-fluoro-2-methoxybenzenesulphoismide, 5-bromo-N-[2-(4-chlorobenzene sulfonamido)-5-pyridin-4-yl phenyl]-the 2-methoxybenzenesulphoismide; 5-bromo-N-[2-(4-chlorobenzene sulfonamido)-4-fluorophenyl]-the 2-methoxybenzenesulphoismide; N, N '-(4-fluoro-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide); N; N '-(4-cyano group-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide), 2-[2-(benzo [b] thiophene-2-sulfonamido)-phenyl sulfamoyl base]-6; 7-dihydro-4H-thieno-[3; 2-c] pyridine-5-carboxylic acid tert-butyl ester, N, N '-(4; 5-two chloro-1; the 2-phenylene) two (1-thionaphthenes-2-sulphonamide), N, N '-(4-Trifluoromethyl-1; the 2-phenylene) two (1-thionaphthene-2-sulphonamide); N, N '-(4-chloro-5-fluoro-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide); N; N '-(4,5-fluoro-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide); benzo [b] thiophene-2-sulfonic acid [2-(5-cyano group-2-methoxyl group-phenylsulfonamido)-phenyl]-acid amides; benzo [b] thiophene-2-sulfonic acid 2-[2-methoxyl group-5-(the 3-methyl-[1,2,4] oxadiazole-5-yls)-phenylsulfonamido]-phenyl }-acid amides; N; N '-(4-chloro-1,2-phenylene) two (1-thionaphthenes-2-sulphonamide), N; N '-(4-bromo-1; the 2-phenylene) two (1-thionaphthenes-2-sulphonamide), N, N '-(4-methoxyl group-1; the 2-phenylene) two (1-thionaphthenes-2-sulphonamide), and pharmacy acceptable salt.

19. a pharmaceutical composition, it comprises the compound of the described formula of claim 1 (I).

20. the pharmaceutical composition of claim 19, it further comprises pharmaceutically suitable carrier, vehicle, thinner or its mixture.

21. the pharmaceutical composition of claim 19, the compound of formula wherein (I) exists with the amount that is enough to improve the GalR1 receptor active.

22. the pharmaceutical composition of claim 19, the compound of formula wherein (I) is to be enough to the stimulating amount of experimenter GalR1 to exist.

23. the pharmaceutical composition of claim 19, it comprises the compound of the formula (I) of effective therapeutic dose, and wherein said effective therapeutic dose comprises the amount of compound that can activate the formula (I) of experimenter GalR1 acceptor to small part.

24. the pharmaceutical composition of claim 19, it comprises the compound of the formula (I) of effective therapeutic dose, and wherein said effective therapeutic dose comprises the amount that can alleviate the compound of the disease mediated formula of at least a GalR1 (I) to small part.

25. the pharmaceutical composition of claim 24, at least a GalR1 wherein is disease mediated to comprise epileptic seizures, neuroendocrine imbalance, gastrointestinal dysfunction, muscle skeleton illness, psychotic behavior such as schizophrenia, migraine, the morphine tolerance, drug habit is opiate addiction especially, pain is neuropathic pain especially, inflammatory pain, chronic pain, somnopathy, feed/body weight obstacle such as bulimia, nervosa bulimia and anorexia nervosa, metabolic exhaustion is disorderly as emaciation, the europathology disorder, diabetes, hyperlipemia, hypertension, amnesia, dysthymia disorders, anxiety disorder, hematencephalon, or diarrhoea.

26. the pharmaceutical composition of claim 24, the disease mediated cancer that comprises of at least a GalR1 wherein.

27. the pharmaceutical composition of claim 19, it is an oral dosage unit form.

28. the pharmaceutical composition of claim 19, it is the parenteral dosage units form.

29. the pharmaceutical composition of claim 19, it further comprises one or more other therapeutical agents.

30. the pharmaceutical composition of claim 29, it comprises that further one or more are selected from following therapeutical agent: biological response modifier, pain killer, NSAIDs, DMARDs, glucocorticosteroid, sulfonylurea, biguanides, acarbose, the PPAR agonist, DPP-IV inhibitor, GK activator, Regular Insulin, insulin-mimickers, insulin secretagogue, euglycemic agent, GLP-1, the GLP-1 stand-in, anticholinesterase, tranquilizer, antidepressive, anticonvulsive agent, HMG-CoA reductase inhibitor, QUESTRAN and Bei Te class.

31. the pharmaceutical composition of claim 29, it comprises that further one or more are selected from the therapeutical agent of carcinostatic agent.

32. method, it comprises: the pharmaceutical composition that gives the compound of the formula (I) that the experimenter comprises claim 1, wherein under the dosage of observing experimenter's analgesic effect, the compound of this formula (I) can combine with at least a periphery GalR1, but almost can not pass through blood brain barrier.

33. the method for claim 32, the compound of formula wherein (I) is to approximate or to be lower than the dosage level administration of 1000mg/kg experimenter's body weight.

34. the method for claim 32, its further comprise give the experimenter one or more be selected from following therapeutical agent: biological response modifier, pain killer, NSAIDs, DMARDs, glucocorticosteroid, sulfonylurea, biguanides, acarbose, the PPAR agonist, DPP-IV inhibitor, GK activator, Regular Insulin, insulin-mimickers, insulin secretagogue, euglycemic agent, GLP-1, the GLP-1 stand-in, anticholinesterase, tranquilizer, antidepressive, anticonvulsive agent, HMG-CoA reductase inhibitor, QUESTRAN and Bei Te class.

35. the method for claim 32, its further comprise give the experimenter one or more be selected from the therapeutical agent of carcinostatic agent.

36. a method, it comprises: pharmaceutical composition is suffered from by activating the experimenter of the illness that the GalR1 acceptor alleviates, and pharmaceutical composition wherein comprises the compound of formula (I) of the claim 1 of the amount that is enough to improve experimenter GalR1 receptor active.

37. the method for claim 36, illness wherein comprises epileptic seizures, the neuroendocrine imbalance, gastrointestinal dysfunction, muscle skeleton illness, psychotic behavior such as schizophrenia, migraine, the morphine tolerance, drug habit is opiate addiction especially, pain is neuropathic pain especially, inflammatory pain, chronic pain, somnopathy, feed/body weight obstacle such as bulimia, nervosa bulimia and anorexia nervosa, metabolic exhaustion is disorderly as emaciation, the europathology disorder, diabetes, hyperlipemia, hypertension, amnesia, dysthymia disorders, anxiety disorder, hematencephalon, or diarrhoea.

38. the method for claim 36, the compound of formula wherein (I) is to approximate or to be lower than the dosage level administration of 1000mg/kg experimenter's body weight.

39. the method for claim 36, its further comprise give the experimenter one or more be selected from following therapeutical agent: biological response modifier, pain killer, NSAIDs, DMARDs, glucocorticosteroid, sulfonylurea, biguanides, acarbose, the PPAR agonist, DPP-IV inhibitor, GK activator, Regular Insulin, insulin-mimickers, insulin secretagogue, euglycemic agent, GLP-1, the GLP-1 stand-in, anticholinesterase, tranquilizer, antidepressive, anticonvulsive agent, HMG-CoA reductase inhibitor, QUESTRAN and Bei Te class.

40. the method for claim 36, its further comprise give the experimenter one or more be selected from the therapeutical agent of carcinostatic agent.

41. a method, it comprises: the experimenter who suffers from neuropathic pain can stimulate the GalR1 agonist of the amount of periphery GalR1 acceptor, and GalR1 agonist is wherein partially or completely got rid of outside brain.

42. the method for claim 41, GalR1 agonist wherein comprise the compound of the formula (I) of claim 1.

43. method, it comprises: the experimenter who suffers from sense of touch pain can stimulate the GalR1 agonist of periphery GalR1 acceptor with the amount that causes experimenter's analgesic effect, and GalR1 agonist wherein can not pass through blood brain barrier basically under the dosage of observing experimenter's analgesic effect.

44. the method for claim 43, GalR1 agonist wherein comprise the compound of the formula (I) of claim 1.

45. method, it comprises: suffer from the experimenter GalR1 agonist of neuropathic pain and save experimenter's periphery GalR1 acceptor at dorsal root ganglion (DRG) horizontal down-regulation, GalR1 agonist wherein can not pass through blood brain barrier basically under the dosage of observing experimenter's analgesic effect.

46. the method for claim 45, GalR1 agonist wherein comprise the compound of the formula (I) of claim 1.

47. a methods of treatment, it comprises the compound of the formula (I) of experimenter's claim 1 of suffering from cancer.

48. the methods of treatment of claim 47, cancer wherein is a squamous cell carcinoma.

49. the methods of treatment of claim 47, the compound of formula wherein (I) is with the amount administration of effective inhibition experimenter cancer cell multiplication.

50. the methods of treatment of claim 47, the compound of formula wherein (I) is with the amount administration of effective inhibition or deactivation experimenter cancer cells MAPK path.