CN102884049B - Heterocycleamide as ROCK inhibitor - Google Patents

Abstract

The present invention relates to a kind of novel inhibitors of kinases, be more particularly ROCK inhibitor, comprise the composition of this kind of inhibitor, particularly medicine, and the purposes that this inhibitor is in terms for the treatment of and preventing disease.Specifically, the present invention relates to a kind of novel ROCK inhibitor, comprise the composition of this kind of inhibitor, particularly medicine, and the purposes that this inhibitor is in terms for the treatment of and preventing disease.Additionally, the present invention relates to methods for the treatment of and described compound purposes in preparing medicine, described medicine is applicable to multiple treatment indication, inclusive dysfunction, diseases associated with inflammation, ophthalmology disease and respiratory disease.

Description

Heterocycleamide as ROCK inhibitor

Technical field

The present invention relates to a kind of novel inhibitors of kinases, be more particularly ROCK inhibitor, comprise this kind of inhibitor Composition, particularly medicine, and this inhibitor is treating and preventing the purposes in terms of disease.Specifically, the present invention relates to And a kind of novel ROCK inhibitor, comprise the composition of this kind of inhibitor, particularly medicine, and this inhibitor in treatment and Purposes in terms of prevention disease.

Background technology

Serine/threonine protein kitase ROCK is made up of two kinds of isomers ROCK I and ROCK II in human body.ROCK I is encoded at No. 18 chromosomes, and ROCK II (also referred to as Rho kinases) is then positioned at No. 12 chromosomes.Both molecular masses It is each about 160 kD.Both (amino acid sequences) have the homology of 65%, and wherein the homology in kinases district is up to 95%.To the greatest extent The sequence managing them is much like, but Tissue distribution is had nothing in common with each other.The expression of ROCK I highest level can be from heart, lung and bone Structure observation arrives, and ROCK II then mainly expresses at brain.Nearest data display both isomers have function partly rich Yu Xing, ROCK I is involved in immunocompetence more, and ROCK II is then involved in smooth muscle function.This term of ROCK refers to ROCK I (having another name called ROK-β, p160ROCK or Rho kinase beta) and ROCK II (has another name called ROCK-α or Rho kinases α).

ROCK activity has been demonstrated by a member GTPase RhoA institute of Rho (Ras homologue) gtp binding protein Affect and strengthen.Active form GTP combines the RhoA of state and the ROCK Rho protein binding domain being positioned at from suppression carboxyl terminal ring (RBD) interaction is produced.After bonding, the interaction between ROCK negativity regulatory region and kinases district is destroyed.This mistake Journey makes kinases obtain the open conformation being completely in activated state.This open conformation is also by lipid activity factor (such as peanut Tetraenoic acid) with the combination of the PH domain of kinases carboxy-terminal domains caused by.Also illustrate in apoptosis process another Activation mechanism, and relate to through Caspase (caspase)-3 and-2 (or granzyme granzyme B) respectively to ROCK I and II The c-terminus cracking carried out.

ROCK plays an important role in various cell functions, such as the group of smooth muscle contraction, actin cytoskeleton Knit, platelet activation, the downward of myosin phosphatase cell adherence, the migration of aortic smooth muscle cell, hyperplasia, survival and Thrombin induction reaction, cardiac myocyte hypertrophy, bronchial smooth muscle contraction, smooth muscle contraction and the restructuring of nonmuscle cells skeleton, Capacity the regulation and control activation of anion channel, neural process retraction, wound healing, cell transformation and gene expression.ROCK is also relating to Many signal pathways of autoimmunity and aspect of inflammation play a role.ROCK has been demonstrated in terms of the activation of NF-κ B to play Effect, this NF-κ B is a kind of key molecule causing TNF and other inflammatory cytokines to produce.It was reported, ROCK inhibitor can resist lipopolysaccharides (LPS) stimulates TNF-α and the generation of the IL-6 factor in THP-1 macrophage.Therefore, ROCK Inhibitor provides useful therapy to treat autoimmune disease, diseases associated with inflammation and response to oxidative stress.Generally speaking, ROCK is the major control point of smooth muscle cell function, and is the inflammatory process of various inflammatory cell and many affected organ Fibrillatable and the crucial signaling composition of remodeling process.ROCK relate to the morbidity machine of numerous disease to have obvious sign to show System, in the middle of include asthma, chronic obstructive pulmonary disease and glaucoma.Additionally, ROCK involves various disease and obstacle, central bag Eye illness, breathing problem, angiocardiopathy and vascular diseases, diseases associated with inflammation, nervous system and central nervous system disease are included Disease, proliferative disease, kidney trouble, sex dysfunction, disease in the blood system, skeletal diseases, diabetes, benign prostatic hyperplasis Disease, graft-rejection, liver diseases, systemic loupus erythematosus, spasm, hypertension, chronic obstructive bladder disease, premature labor, Infection, allergy, obesity, pancreatic disease and AIDS.

With gene knockout model and substantial amounts of academic research illustratively, ROCK looks like the target spot of a safety.This The data of a little knock out mice are studied with the post-market surveillance of Fasudil (Fasudil) and (are used for treating cavum subarachnoidale to go out The strong ROCK inhibitor of appropriateness of the cerebral angiospasm after blood) combine, indicating ROCK is a real and significant medicine target Mark.

ROCK inhibitor can be used as treating the curative drug of the obstacle relating to ROCK approach.Therefore, we extremely need Develop a kind of can be used for and treat the various ROCK inhibitor relevant to ROCK activation, be especially considering that these diseases are most at present Number all insufficient therapy.Some unrestriced examples are glaucoma, asthma and chronic obstructive pulmonary disease.

Glaucoma, a class may result in hypopsia and blind disease, is because of intraocular pressure because of optic nerve injury Increase and cause.This is the common cause that adult is blind, is a kind of chronic disease needing after making a definite diagnosis and controlling all the life mostly. Due to current treatment can only control and cannot radical curing of disease, and suffer further to stimulate, side effect locally and systemically, this disease The sick cure needing an improvement.Additionally, other positive influences, namely the anti-inflammatory of ROCK inhibitor becomes with nerve regneration Divide and will be prioritized.Quote the ROCK inhibitor of such as Y-27632 and can change cellular morphology and to reduce the TM mankind of incubation thin The Tonofibrils of born of the same parents, Focal adhesions and MLC phosphorylation；The human trabecular meshwork shape tissue of they diastole in vitro culture, diastole are external Mankind's Schlemm pipeline endothelial cell, can dramatically increase girder with being applied topically to animal and flow out, cause advantageously dropping Low intraocular pressure.

Allergic asthma is a kind of anti-to ubiquitous environment albumen generation non-habitual immunity because of heredity susceptible person Should, thus the respiratory tract chronic inflammatory diseases caused.Although there being the methods for the treatment of of successful, illness rate because of these therapies without Method is effected a radical cure and be increased；Situation is still in aggravation now, and has increasing nonresponder.Can do with all factors of this disease Novel, efficient, steroid-sparing be required.

Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) be one group with slowly Property irreversibility respiratory tract is restricted to react with abnormal inflammatory, the reinventing and damage and be characterized of bronchoconstriction and lung tissue Disease.It is the one of the main reasons of human death, and illness rate the most steadily increases.Owing to current therapy is not enough to cure disease Disease, our exigence seeks new methods for the treatment of.Only there is limited or absolutely void effect due to glucocorticoid, because of This most only uses bronchodilator.The people of the ROCK inhibitor energy diastole separation quoting such as Y-27632 props up gas Pipe prepared product, the resistance of respiratory tract of suppression anesthetized animal increases, and strengthens the diastole effect of the beta-receptor activator of in vitro and in vivo, And give rapid bronchiectasis after inhalation.Additionally, ROCK inhibitor can block H₂O₂The tracheal smooth muscle of induction shrinks (clinical marker of response to oxidative stress).

Relevant to respiratory inflammation, ROCK inhibitor can resist the increasing across endothelial cell permeability of antiphlogistic mediation By force, keep blood vessel endothelium barrier integrity, suppress internal ovalbumin to excite after eosinophil inflow, prevent lung In the formation of oedema and neutrophil migration, suppression allergy Respiratory Tract of Mice anti-to the allergy of methacholine and serotonin TNF (TNF) release of LPS induction and should be blocked.As for respiratory tract fibrillatable and reinvent aspect, ROCK inhibitor The migration of asm cell induction can be blocked.ROCK is found in the mankind's for the external evidence of Airway Remodeling effect Lung cancer cell line, the airway smooth muscle cells of calf and human airway smooth muscle.ROCK is for the internal card of Fibrosis parameters According to typically resulting from (wherein the excalation of ROCK causes the myocardial fibrosis of decay) in mouse.Y-27632 obstructs for cardiac muscle Plug and Fasudil (fasudil) for the congestive heart failure of CH rat model myocardial fibrosis decay For ROCK, other indication is brought for the importance reinvented.Finally, the apoptosis of ROCK inhibitor increase smooth muscle cell is thin Born of the same parents lose.

The human sexual response of masculinity and femininity can produce because of the interaction of physiology, psychology and Hormone Factors.The male sex and One of them of female body reaction is common that blood vessel function response, the vascular smooth muscle pine that it can bring because of sexual stimulus Relax thus make phallic property tissue congested.Therefore, when the smooth muscle of perineum blood vessel loosens, the blood pressure in penis and clitoris It is consequently increased with CBF.The inflow of arterial blood will cause penis or corpora cavernosa clitoridis to expand, thus cause erecing.

Impotence (male erectile dysfunction) is typically defined as being unable to reach and maintaining enough carrying out being satisfied with sex expression and property The erectile ability handed over.Impotence be possibly due to mental handicape, nervous system abnormality or other include the physiological barrier of anhormonia, Or the combination of many reasons causes forming.In the U.S., impotence estimates to have influence on 40 years old male sex of 40%, along with the age increases To improve to about 50% by 50 years old, during by 70 years old, will be up to 67%.According to estimates, up to 30,000,000 American male can be because of impotence problem And it is painful.

Women is along with the increase also meeting at age is in the face of sex dysfunction, and shows effect with climacteric and increase vascular diseases Risk.Therefore, as the male sex, at least part of meeting of sexual arousal of women increases with the CBF making clitoral engorgement.Cloudy The CBF in road too increases the degree of lubrication of vagina.Therefore, Female sexual dysfunction is likely due to when whole sexuality Phase is unable to reach or maintains clitoral engorgement and/or vaginal lubrication to cause.

At present, the vasodilator energy targeting being mostly used in treatment erectile dysfunction reduces the signal transduction of calcium ion Approach, this contraction movement needing to start vascular smooth muscle.But, from the point of view of physiological angle, vasoconstrictive startup is one The most acute activity, the duration is only from several seconds to several minutes.Erectile tissue passes through calcium dependent/non-dependent signal transduction pathway Long-term vessel retraction be maintained at relaxed state.Keeping the vasoconstrictive signal pathway of calcium dependent/non-dependent is RhoA/Rho kinases Approach.ROCK inhibitor is the most useful for treatment erectile dysfunction.Therefore, from the point of view of on the one hand, the present invention comprises one Kind for the method for the treatment of sex sex dysfunction, it includes comprising to individuals in need local application can be at device Official's subject weakens compound and the composition of pharmaceutically acceptable carrier of the Rho kinase activity to sexual stimulus.

There is several known ROCK inhibitor type at present.Current it is important that tumour and the application of angiocardiopathy.Arrive Till Xian, the outstanding treatment potentiality of ROCK inhibitor are only limited in limited scope.Its reason is that ROCK is such a Effectively with biochemical regulator widely, the general inhibitory action of ROCK can be brought powerful biological effect, but be also regarded as The side effect of most of disease treatments.It is true that the ROCK inhibitor medical application of stronger anti-inflammatory component treatment disease is subject to The ROCK key effect obstruction when regulating the stage of nourishing of smooth muscle cell contraction.The ROCK inhibitor of systemic applications can lure Send out blood pressure to be decreased obviously.Therefore, we have high demand to ROCK inhibitor of different nature.

In order to by regulation smooth muscle function and/or inflammatory process and/or reinvent launch disease specific aim specifically treat, Our high expectations ROCK inhibitor energy targeting target organ, to avoid the medicine of big deal to enter other organs.Therefore, local Or the medicinal application of local is desired.Under normal circumstances, the medicine of topical application is used for treating respiratory tract, eyes, property merit Can obstacle and dermatopathy.Additionally, local injection/penetrate into pathological tissues and expand the ROCK inhibitor of topical application further Potential medical application.If specific condition is met, these topical application can allow the medicine of high concentration to reach destination organization. Additionally, ROCK inhibitor is brought implant into and support can expand local further and treat the medical applications of angiocardiopathy, These diseases such as atherosclerotic, coronary heart disease and heart failure.

Although directly topical application is prioritized in medical practice, but enter the levels of drugs of systemic circulation But attract people's attention.Such as, treating breathing problem by suction local delivery will constitute the risk that general exposes, this It is because high amount of drug to be made to enter intestines and stomach and/or whole body by pulmonary absorption.As for the Eye disease treating of local delivery, also because of The existence of cornea hypotonicity, low fluid displacement, efficient drainage and eyelid blood vessel causes high amount of drug to enter intestines and stomach and/or complete Body circulates.The grave danger leaking into systemic circulation is then had as percutaneous drug delivery, local injection and Implantable Medical Device.Cause This, in addition to topical application, compound preferably has the other attribute being avoided that serious systemic exposes.

Soft medicine is once the bioactive compound entering systemic circulation just inactivation.This deactivation can be at liver Middle realization, but preferably deactivation should come across in blood.After these compounds are once applied topically to destination organization/organ The predictive role of local will be played.When they are from this tissue leakage to system is circulated, they will very rapidly go out Live.Therefore, select soft medicine can in destination organization/organ substantially stabilized biological effect needed for playing, but can be at blood Liquid is degraded into rapidly compound inactive on biology.Additionally, it is most preferred that selection can be retained in its biological targets Soft medicine.The number of times that restriction is given daily by this characteristic, and high expectations reduces medicine and the total load of metabolite, this Also patient compliance will be significantly increased outward.

Sum it up, we still have lasting necessary design and exploitation ROCK inhibitor at present, wide for therapeutic domain General morbid state.Compound described herein and pharmaceutically acceptable composition can be used for treatment or alleviate and ROCK activation Relevant various obstacles or the seriousness of illness.More specifically, the compound of the present invention is preferred for prevention and/or treats extremely Few a kind of disease relating to ROCK or obstacle, such as with the function of smooth muscle cell, inflammation, fibrillatable, excessive cell proliferation, Angiogenesis excessively, high response, barrier dysfunction, nerve degeneration pathology and reinvent relevant disease.Such as, the present invention Compound can be used for preventing and/or treating following disease and illness:

-ophthalmology disease or illness: include but not limited to PVR, optic neuropathy, glaucoma and retina regression Property disease, such as macular degeneration, retinal pigment degeneration and inflammatory eye conditions.

-breathing problem；Include but not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrillatable, lung Inflammation, capsule fibrous lesions, chronic obstructive pulmonary disease (COPD)；Bronchitis and rhinitis and Respiratory Distress Syndrome(RDS)

The disease of-throat, nose and ear: include but not limited to sinus problem, hearing problem, tonsillitis, toothache, ulcer and Rhinitis,

-disease of skin: include but not limited to hyperkeratinization, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, Spongiosis and ulcer.

-intestines problem: include but not limited to inflammatory bowel disease (IBD), enteritis, gastroenteritis, intestinal obstruction, ileitis, appendicitis And Crohn disease.

-cardiovascular and vascular diseases: include but are not limited to pulmonary hypertension and Pulmonary Vascular shrinks.

-diseases associated with inflammation: include but are not limited to contact dermatitis, allergic dermatitis, psoriasis, rheumatoid arthritis, Juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis arthropathica, inflammatory bowel disease, Crohn disease and ulcerative colitis.

-the nervous system disease: include but not limited to neuropathic pain.Therefore the compounds of this invention is applicable to prevent various god Nerve degenerative diseases and stimulating neural regeneration through systemic disease.

-proliferative disease: such as but not limited to mammary gland, colon, intestines, skin, head and neck, nerve, uterus, kidney, lung, Liver, ovary, pancreas, prostate or thyroid cancer；Castleman's disease, leukaemia, sarcoma, lymthoma；Malignocytoma And melanoma (malignoma).

-kidney trouble: include but not limited to kidney region fibrosis or renal insufficiency

-sex dysfunction: be intended to the masculinity and femininity sex dysfunction including causing because of deficiency vasoactive response.This The soft ROCK inhibitor of invention can also be used for the sex dysfunction that treatment is caused by many reasons.For example, a reality Executing in scheme, soft ROCK inhibitor can be used for treating the sex dysfunction relevant to hypogonadism disease, more specifically, This hypogonadism disease is relevant with the reduction of androgen levels.In another embodiment, soft ROCK inhibitor can be used In the sex dysfunction that treatment is relevant with many reasons, this includes but not limited to bladder disease, hypertension, diabetes or pelvic cavity hand Art sequelae.Additionally, soft ROCK inhibitor can be used for treating the sex dysfunction by using some drugs to cause, such as, it is used for Treatment hypertension, depression or the medicine of anxiety.

-skeletal diseases: include but not limited to osteoporosis and osteoarthritis

-additionally, the compound of the present invention can be used for prevention and/or treats such as hyperplasia of prostate, graft-rejection, convulsion Contraction, chronic obstructive cystipathy and the such disease of allergy and illness.

Summary of the invention

It has surprisingly been found that compounds described herein is used as the inhibitor of ROCK, the most soft ROCK presses down Preparation.Compared to the Rock inhibitor being currently known, such as described in WO2007/042321, the district of the compounds of this invention It is not that they very fast are converted into the most inactive compound (as by PON-1 (PON1) activity).

PON1 is a kind of calcium ion dependent serum class A-esterase, and it synthesizes in liver and secretes in blood, and Be combined with HDL (HDLs) exclusivity.Additionally, it can crack comprises organophosphor, aryl ester, lactone and ring-type carbon The specific subgroup of matrix of acid esters.Therefore, the Y substituent of selected the compounds of this invention is typically by formula (I) listed below As expression, to include taking of group (more specifically aryl ester and lactone) selected from aryl ester, lactone and cyclic carbonate Dai Ji.

Unless otherwise provided, asterisk used herein is used to indicate that described unit price or divalent group are connected to its phase The structure closed and this group form that point of part thereof of structure.

From the point of view of first aspect, the invention provides a kind of formula (I) compound or its stereoisomer, dynamic isomer, Racemic modification, metabolin, prodrug or pro-drug, salt, hydrate or solvate,

Wherein

R¹Selected from the group comprising hydrogen, alkyl or cycloalkyl；Not

Ar is selected from comprising following group:

Wherein X is selected from the group comprising hydrogen or halogen；

Y is the aryl or heteroaryl being substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹；-C (=O)- SR²²；-C (=O)-NR³R⁴；-NR⁵R⁶；-O-C_1-6Alkyl；-S-C_1-6Alkyl；-O-C_2-8Thiazolinyl；-S-C_2-8Thiazolinyl；-C_1-6Alkyl； Or-C_2-8The group of thiazolinyl；

Wherein said-O-C_1-6Alkyl；-S-C_1-6Alkyl；-O-C_2-8Thiazolinyl；-S-C_2-8Thiazolinyl；-C_1-6Alkyl；Or-C_2-8 Thiazolinyl is separately substituted with a substituent；This substituent is selected from including C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)- NR³R⁴；Het¹；-O-Het²；And-S-Het³Group；

R³Group selected from following: hydrogen；By O-Het²Or-S-Het³Substituted C_2-8Thiazolinyl；Or by 1,2 or 3 substituents Optionally substituted C_1-20Alkyl, this substituent is separately selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)- OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³；-S-C_1-6Alkyl and-O-C_1-6The group of alkyl Not；

Wherein said-O-C_1-6Alkyl；-S-C_1-6Alkyl；Or C_3-6Cycloalkenyl group；Separately it is substituted with a substituent, should Substituent is selected from including C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；Het¹；-O-Het²；And-S-Het³Group Not；

R⁴Group selected from following: by O-Het²Or-S-Het³Substituted C_2-8Thiazolinyl or optional by 1,2 or 3 substituents Substituted C_1-20Alkyl, this substituent is separately selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹、-C (=O)-SR²²,-C (=O)-NR⁷R⁸、Het¹、-O-Het²、-S-Het³、-O-C_1-6Alkyl and-O-C_1-6The group of alkyl；

Wherein said-O-C_1-6Alkyl；-S-C_1-6Alkyl；Or C_3-6Cycloalkenyl group；Separately it is substituted with a substituent；Should Substituent is selected from including C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；Het¹；-O-Het²；And-S-Het³Group Not；Or；

R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is replaced by a substituent, and this substituent is selected from down The group of row；-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；-S-Het³；C_1-6Alkyl； C_1-6Alkyl-O-C_1-4Alkyl；Or C_1-6Alkyl-O-C_2-4Thiazolinyl；The most each described C_1-6Alkyl；C_1-6Alkyl-O-C_1-4Alkane Base；Or C_1-6Alkyl-O-C_2-4Thiazolinyl is separately replaced by 1,2 or 3 substituents, and this substituent is separately selected from bag Containing aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²； And-S-Het³Group:

R⁵Or R⁶Separately selected from comprising hydrogen；C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkyl-S-C_1-6Alkane Base-；C_2-8Thiazolinyl；C_1-6Alkyl-C (=O)-or C_2-8Thiazolinyl-C (=O)-group；At least one of which R⁵Or R⁶Selected from C_1-6Alkane Base；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkyl-S-C_1-6Alkyl-；C_2-8Thiazolinyl；C_1-6Alkyl-C (=O)-or C_2-8Thiazolinyl-C (=O)-, wherein said C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkyl-S-C_1-6Alkyl-；C_2-8Thiazolinyl；C_1-6Alkane Base-C (=O)-or C_2-8Thiazolinyl-C (=O)-each replaced by 1,2 or 3 substituents, this substituent is separately selected from bag Containing aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²；And-S-Het³Group:

R⁷Or R⁸Separately selected from comprising hydrogen；Or C_1-6The group of alkyl；Described C_1-6Alkyl is by 1,2 or 3 substituents Replacing, this substituent is separately selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；And-C (=O)- NH₂Group:

R⁹Or R¹⁰Separately selected from comprising hydrogen；Or C_1-6The group of alkyl；Described C_1-6Alkyl is by 1,2 or 3 replacements Base replaces, and this substituent is separately selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；And-C (=O)- NH₂Group；

R¹³Or R¹⁴Separately selected from comprising hydrogen；C_1-6Alkyl；C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkane Base-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-group, and wherein said C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-； C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-each replaced by 1,2 or 3 substituents, this substituent is independently Ground is selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²；And-S-Het³Group；

R²¹Selected from comprising C_1-20Alkyl；C_1-20Thiazolinyl；C_1-20Alkynyl；Optionally substituted C_3-15Cycloalkyl；Optionally substituted virtue Base；Optionally substituted heterocyclic radical；The group of optionally substituted heteroaryl；

Wherein said C_1-20Alkyl can be optionally substituted by 1,2,3 or more substituents, this substituent independently selected from Comprise halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-C (=O)-NR¹³R¹⁴、 C_3-10Cycloalkyl ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6The group of alkyl-S-, aryl, heteroaryl and heterocyclic radical Or selected from following formula:

Or

R²¹Coupled carbonyloxy group and " aryl or heteroaryl " are formed at cyclic ester ring together and comprise 4 to 9 carbon atoms Cyclic ester ring；

R²²It is can be by 1,2, the 3 or more optionally substituted C of substituent_1-20Alkyl, this substituent is independently selected from comprising Halogen, hydroxyl, amino, cyano group and single or double (C_1-4Alkyl) group of amino；

Het¹、Het²Or Het³Separately selected from following group；

From the point of view of in terms of another, the invention provides the compounds of this invention, for external or internal suppression at least one The purposes of kinase activity, or comprise the composition of this compound.

From the point of view of in terms of another, the invention provides the compounds of this invention, be used for suppressing at least one ROCK kinases (example Such as ROCKII and/or ROCKI isomers) purposes of activity, or comprise the composition of this compound.

From the point of view of in terms of another, the invention provides the medicine and/or animal medicinal composition comprising the compounds of this invention.

From the point of view of in terms of another, present invention provide for the compounds of this invention of the mankind or veterinary medicament.

From the point of view of in terms of another, the invention provides the compounds of this invention purposes in preparing medicine, described medicine For treat and/or prevent at least one be selected from eye illness, breathing problem, angiocardiopathy and vascular diseases, diseases associated with inflammation, Nervous system and the disease of central nervous system disease and/or obstacle: proliferative disease, kidney trouble, sex dysfunction, blood Disease, skeletal diseases, diabetes, benign prostate hyperplasia, graft-rejection, liver diseases, systemic loupus erythematosus, convulsion Contraction, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease and AIDS.

The detailed description of invention

The present invention is now by further description.In following paragraph, the different aspect of the present invention all can be by more detail Definition.Unless clear and definite expression, otherwise be likely to can be in conjunction with any other one or more sides for defined each aspect Face.Specifically, any it be expressed as preferred or favourable characteristic and be likely to be expressed as in conjunction with any other preferred or favourable One or more characteristics.

Unless otherwise provided, asterisk used herein is used to indicate that described unit price or divalent group are connected to its phase The structure closed and this group form that point of part thereof of structure.

Undefined (racemization) center of asymmetry being likely to be present in the compounds of this invention will be by drawing wave key or straight key Make alternately display, to manifest the undefined tridimensional character of key.

As was mentioned above, a first aspect of the present invention provides the compound of formula (I)

Wherein Y, R¹And Ar is as defined above, including stereoisomer form, solvate, pharmaceutically acceptable addition Salt.

When describing the compound of the present invention, unless otherwise provided, otherwise term used will be annotated by following definition Release:

Self or " alkyl " term as a part for another group refer to formula C_xH_2x+1Fully saturated hydrocarbon, wherein x is Number more than or equal to 1.In general, the alkyl group of the present invention comprises 1 to 20 carbon atom.Alkyl group can be straight Chain or side chain, and may be by replacement indicated herein.Adding subscript after carbon atom, this subscript refers to named base The amount of carbon atom that group may comprise.So that it takes up a position, for example, C_1-4Alkyl refers to the alkyl with one to four carbon atom.Alkyl The example of group is methyl, ethyl, n-pro-pyl, isopropyl, butyl and isomers (such as: normal-butyl, isobutyl group and the tert-butyl group) thereof； Amyl group and isomers, hexyl and isomers thereof, heptyl and isomers thereof, octyl group and isomers thereof, nonyl and isomers thereof；The last of the ten Heavenly stems Base and isomers thereof.C₁-C₆Alkyl includes all straight chains, side chain, or has the group of naphthene base of 1 to 6 carbon atom, the most therefore Include methyl, ethyl, n-pro-pyl, isopropyl, butyl and isomers (such as: normal-butyl, isobutyl group and the tert-butyl group) thereof；Amyl group and Its isomers, hexyl and isomers thereof, cyclopenta, 2-, 3-or 4-methylcyclopentyl, cyclopentyl-methyl and cyclohexyl.

" optionally substituted alkyl " this term refers at any available tie point optional by one or more substituents Substituted alkyl group (such as 1 to 4 substituent, such as 1,2,3 or 4 substituents or 1 to 2 substituent).These replace The non-limitative example of base include halogen, hydroxyl, carbonyl, nitro, amino, oximido, imido grpup, azido, diazanyl, cyano group, Aryl, heteroaryl, cycloalkyl, acyl group, alkyl amino, alkoxyl, sulfydryl, alkylthio group, carboxylic acid, acylamino-, Arrcostab, amino first Acid esters, thio acylamino, urea, sulfonamido and similar.

Unless otherwise stated, " thiazolinyl " term used herein refer to the straight chain containing at least one carbon-to-carbon double bond, Ring-type or branched chain hydrocarbyl groups.The example of alkenyl includes vinyl, E-and Z-type acrylic, isopropenyl, E-and Z-type fourth Thiazolinyl, E-and Z-type isobutenyl, E-and Z-type pentenyl, E-and Z-type hexenyl, E, E-, E, Z-, Z, E-, Z, Z-hexadienyl And similar group.Optionally substituted thiazolinyl refers to optionally have the alkene of one or more substituent (such as 1,2,3 or 4) Base, described substituent is selected from above-mentioned to replacing those defined in alkyl.

Unless otherwise stated, " alkynyl " term used herein refers to the straight chain containing at least one carbon-to-carbon triple bond Or branched hydrocarbyl.The example of alkynyl group include acetenyl, E-and Z-type propinyl, isopropynyl, E-and Z-type butynyl, E-and Z-type butynyl, E-and Z-type pentynyl, E-and Z-type hexin base and similar group.Optionally substituted alkynyl refers to selectivity Ground has the alkynyl of one or more substituent (such as 1,2,3 or 4), and described substituent is selected from above-mentioned to replacing defined in alkyl Those.

Self or " cycloalkyl " term as a part for another group refer to group of naphthene base, say, that be to gather around There are the unit price of 1,2 or 3 circuluses, saturated or unsaturated alkyl group.Cycloalkyl includes all of saturated or fractional saturation The hydrocarbyl group of (comprising 1 or 2 double bond), containing 1 to 3 ring, including monocycle, dicyclo, polycyclic alkyl group.Group of naphthene base 3 or more carbon atom may be comprised in ring, the most generally comprise 3 to 15 atoms according to the present invention.Polycyclic naphthene base Further ring can by one or more volution atoms merge, bridge and/or add.Group of naphthene base is likely to be considered It it is the homoatomic ring subset being discussed below.The example of group of naphthene base includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, suberyl, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and ring decyl, the most preferably cyclopropyl, Cyclopenta, cyclohexyl, adamantyl, dicyclo (2.2.1) heptane base." optionally substituted cycloalkyl " refers to optionally have one Individual or the cycloalkyl (such as 1 to 3 substituent, such as 1,2,3 or 4 substituents) of multiple substituent, described substituent is selected from above-mentioned To replacing those defined in alkyl.When prefix " sub-" uses with cyclic group simultaneously, hereinafter also referred to cycloalkylidene, this is meaning Refer to that cyclic group defined herein has two singly-bounds.The cycloalkylene group of the present invention preferably comprises associated cycloalkyl base The carbon atom of group's equal number.

If defined alkyl group is divalence, i.e. two singly-bounds are attached to other two groups, and they will be referred to as " alkylidene " group.The non-limiting examples of alkylidene group include methylene, ethylidene, methyl methene, 1,3-propylidene, Asia Propyl group, tetramethylene, ethylethylene residue, 1,2-dimethylethylene, pentamethylene and cyclohexyl.Same, if being determined above Alkenyl group and the alkynyl group defined below of justice are divalence, i.e. have two singly-bounds to be attached to other two groups, it Will be known respectively as " alkenylene " and " alkynylene " group.

The alkylidene group of the present invention preferably comprises the carbon atom of associated alkyl group equal number.If there is Asia Alkyl or cycloalkylidene double-basis, that will be connected to molecular structure by common carbon atom or different carbon atoms, central excellent Select common carbon atom.In order to this point is described, the name of the present invention adds asterisk, C₃Alkylidene group is probably example Such as *-CH₂CH₂CH₂-*, *-CH (-CH₂CH₃)-* or *-CH₂CH(-CH₃)-*.Same, C₃Cycloalkylidene is probably

If there is cycloalkylene group, preferably C₃-C₆Cycloalkylene group, more preferably C₃Cycloalkylene group is (i.e. sub- Cyclopropyl group), wherein can be connected to structure by common carbon atom.Cycloalkylidene in the compounds of this invention and alkylidene Diradical likely, but preferably can not be replaced.

Self or as the heterocyclic radical "or" heterocycle of a part of another group " term refer to non-aromatic, fully saturated or The undersaturated cyclic group of part (for example, 3 to 13 yuan of monocycles or 7 to 17 yuan of dicyclos or 10 to 20 yuan of three ring system, or altogether Comprise 3 to 10 annular atomses), at least one of which carbon atoms ring must there is at least one hetero atom.For heterocyclic group In comprise heteroatomic each ring, can have 1,2,3 or 4 hetero atoms, selected from nitrogen-atoms, oxygen atom and/or sulphur atom, wherein Nitrogen and sulfur heteroatom are the most oxidized, and nitrogen heteroatom is the most quaternized.If if valence state allows, heterocycle Group can be connected to ring or any hetero atom of loop systems or carbon atom.The ring of polycyclic heterocycle can pass through one or more spiral shells Annular atoms merges, bridges and/or add.Optionally substituted heterocycle refers to optionally have the heterocycle of one or more substituent (such as 1 to 4 substituent or such as 1,2,3 or 4), selected from those defining substituted aryl.

The example of heterocyclic group includes piperidines, azetidine, imidazoline, imidazolidinyl, isoxazolines base, oxazolidine Base, isoxazole alkyl, thiazolidinyl, isothiazole alkyl, piperidyl, succinimide, 3H-indyl, isoindoline base, chromene Base, different Chromanyl, ton base, 2H-pyrrole radicals, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinoline Piperazine base, 4aH-carbazyl, 2-oxopiperazinyl, piperazinyl, homopiperazine base, 2-pyrazolinyl, 3-pyrazolinyl, pyranose, two Hydrogen-2H-pyranose, 4H-pyranose, 3,4-dihydro-2H-pyranose, phthalazinyl, oxetanylmethoxy, thietanyl, 3-dioxy Penta ring group, 1,3-dioxane base, 2,5-dioxoimidazolidin base (dioximidazolidinyl) 2,2,4-piperidone base, 2-Oxypertine base, 2-oxygen pyrrolidone-base (oxopyrrolodinyl), 2-oxygen azepineBase, indolinyl, THP trtrahydropyranyl, Tetrahydrofuran base, tetrahydro-thienyl, tetrahydric quinoline group, tetrahydro isoquinolyl, thio-morpholinyl, thiomorpholino sulfoxide, sulphur generation Morpholinyl sulfone, DOX base, Isosorbide-5-Nitrae-oxygen thia cyclohexyl (oxathianyl), Isosorbide-5-Nitrae-dithiane base (dithianyl), 1,3,5-trioxane base (trioxanyl), 6H-1,2,5-thiadiazine bases, 2H-1,5,2-dithiazine bases, 2H-oxa-ring Sarohornene base (oxocinyl), 1H-pyrrolidinyl, tetrahydrochysene-1,1-dioxythiophene base, N-formyl piperazine base and morpholinyl.

" aryl " term used herein refers to merge (such as: naphthalene containing monocycle (i.e. phenyl) or multiple aromatic rings Or anthracene) or covalently bound polynary unsaturation and the hydrocarbyl group of fragrance, generally containing 6 to 10 atoms；At least one of which Ring is fragrant.Aromatic rings can optionally comprise one to three the other ring merged with it (cycloalkyl, heterocyclic radical or miscellaneous Aryl).Aryl also aims to comprise the part hydrogenated derivatives of carbon-loop system listed herewith.The non-limiting examples of aryl includes Phenyl, xenyl, biphenylene, 5-or 6-tetralin base (tetralinyl), 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-Austria base, 1-or 2-naphthyl, 1-, 2-or 3-indenyl, 1-, 2-or 9-anthryl, 1-2-, 3-, 4-or 5-acenaphthenyl (acenaphtylenyl), 3-, 4-or 5-dihydro-acenaphthylene base (acenaphtenyl), 1-, 2-, 3-, 4-or 10-phenanthryl, 1-or 2-pentalene base (pentalenyl), 1,2-, 3-or 4-fluorenyl, 4-or 5-dihydro indenyl, 5-, 6-, 7-or 8-tetralyl, 1,2,3,4-tetra- Hydrogen naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl, hexichol [a, d] cycloheptenyl and 1-, 2-, 3-, 4-or 5-pyrenyl.

Aromatic ring can optionally be substituted with one or more substituents." optionally substituted aryl " refer to any can Tie point optionally there is the aryl (such as 1 to 5 substituent, such as 1,2,3 or 4) of one or more substituent.These The non-limiting examples of substituent selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, amino carbonyl, azido, cyano group, alkyl, Cycloalkyl, thiazolinyl, alkynyl, cycloalkyl-alkyl, alkyl amino, alkoxyl ,-SO₂-NH₂, aryl, heteroaryl, aralkyl, alkyl halide Base, halogenated alkoxy, alkoxy carbonyl group, alkyl amino-carbonyl, heteroaryl alkyl, alkyl sulfonamide, heterocyclic radical, alkyl-carbonyl-amino Alkyl, aryloxy group, alkyl-carbonyl, acyl group, aryl carbonyl, amino carbonyl, alkyl sulfinic acid ,-SO₂R^a, alkylthio group, carboxyl and class As, wherein R^aIt it is alkyl or cycloalkyl.

If the carbon atom of aromatic yl group is substituted by hetero atom, consequent ring is referred to as heteroaryl ring.

Self or " heteroaryl " term as a part for another group refer to but are not limited only to 5 to 12 carbon atoms Aromatic rings or loop systems, wherein contain 1 to 3 ring and merge or covalent bond, generally containing 5 to 8 atoms；At least a part of which It is fragrant for having one, and the one or more carbon atoms in wherein one or more these rings can be replaced by oxygen, nitrogen or sulphur atom, Wherein nitrogen and sulfur heteroatom are the most oxidized, and nitrogen heteroatom is the most quaternized.These rings can be melted Close aryl, cycloalkyl, heteroaryl or heterocyclic ring.The non-limiting examples of these heteroaryls includes: pyrrole radicals, furyl, Thienyl, pyrazolyl, imidazole radicals, oxazoline base, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, di azoly, thiadiazoles Base, tetrazole radical, oxa-triazole, thiatriazole base, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, piperazine base, two English Base, thiazinyl, triazine radical, imidazoles [2,1-b] [1,3] thiazolyl, thieno [3,2-b] furyl, thieno [3,2-b] thiophene Base, [2,3-d] [1,3] thiazolyl, thieno [2,3-d] imidazole radicals, tetrazolo [1,5-a] pyridine radicals, indyl, indolizine base, Base of muttering given a tongue-lashing by isoindolyl, benzofuranyl, benzo, base of muttering given a tongue-lashing by 1 (4H)-benzo, base of muttering given a tongue-lashing by 1 (2H)-benzo, 3,4-dihydro-1 (2H)-benzo give a tongue-lashing base of muttering, 3,4-dihydro-1 (2H)-benzo gives a tongue-lashing base of muttering, isobenzofuran-base, benzothienyl, different benzothiophene Base, indazolyl, benzimidazolyl, 1,3-benzoxazolyl group, 1,2-benzisoxa oxazolyl, 2,1-benzisoxa oxazolyl, 1,3-benzene Benzothiazolyl, 1,2-[4-morpholinodithio base, 2,1-benzisothia oxazolyl, BTA base, 1,2,3-benzodiazoles, 2,1,3-benzene And diazole, 1,2,3-diazosulfide bases, 2,1,3-diazosulfide base, thiophene pyridine radicals, purine radicals, imidazo [1,2- A] pyridine radicals, 6-oxygen-pyridazine-1 (6H)-base, 2-oxo pyridine-1 (2H)-base, 6-oxygen pyridazine-1 (6H)-base, 2-oxo pyridine- 1 (2H)-base, 1,3-benzodioxole group, quinolyl, isoquinolyl, scold piperazine base, quinazolyl, quinoxalinyl, 7- Azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

" pyrrole radicals " used herein (also referred to as oxazolyl azolyl) term includes pyrroles's-1-base, pyrroles's-2-base and pyrrole Cough up-3-base." furyl furanyl " used herein (also referred to as furans furyl) term include furans-2-base and furans- 3-base." thienyl thiophenyl " used herein (also referred to as thiophene thienyl) term includes thiophene-2-base and thiophene Fen-3-base." pyrazolyl " used herein (also referred to as 1H-pyrazolyl and 1,2-oxazolyl) term includes pyrazol-1-yl, pyrrole Azoles-3-base, pyrazoles-4-base and pyrazoles-5-base." imidazole radicals " used herein term include imidazoles-1-base, imidazoles-2-base, Imidazol-4 yl and imidazoles-5-base." oxazolyl " used herein (also referred to as 1,3-oxazolyl) term includes oxazolyl-2- Base；Oxazolyl-4-base and oxazolyl-5-base." isoxazolyl " used herein (also referred to as 1,2-oxazolyl) term includes Isoxazolyl-3-base；Isoxazolyl-4-base and isoxazolyl-5-base." thiazolyl " used herein (also referred to as 1,3-thiazoles Base) term includes thiazolyl-2-base；Thiazolyl-4-base and thiazolyl-5-base (also referred to as 2-thiazolyl, 4-thiazolyl and 5- Thiazolyl)." isothiazolyl " used herein (also referred to as 1,2-isothiazolyl) term includes isothiazolyl-3-base, different thiophene Oxazolyl-4-base and isothiazolyl-5-base." triazolyl " used herein term includes 1H-triazolyl and 4H-1,2,4-triazoles Base, " 1H-triazolyl " includes 1H-1,2,3-triazol-1-yls, 1H-1,2,3-triazole-4-yls, 1H-1,2,3-triazole-5-bases, 1H-1,2,4-triazol-1-yls, 1H-1,2,4-triazole-3-base and 1H-1,2,4-triazole-5-bases." 4H-1,2,4-triazolyls " wrap Include 4H-1,2,4-triazole-4-yls and 4H-1,2,4-triazole-3-bases." di azoly " used herein term includes 1, and 2, 3-diazole-4-base, 1,2,3-diazole-5-bases, 1,2,4-diazole-3-bases, 1,2,4-diazole-5-bases, 1,2,5- Diazole-3-base and 1,3,4-diazole-2-bases." thiadiazolyl group " used herein term includes 1,2,3-thiadiazoles-4-bases, 1,2,3-thiadiazoles-5-base, 1,2,4-thiadiazoles-3-bases, 1,2,4-thiadiazoles-5-bases, 1,2,5-thiadiazoles-3-bases are (also referred to as For furazan-3-base) and 1,3,4-thiadiazoles-2-bases." tetrazole radical " used herein term includes 1H-TETRAZOLE-1-base, 1H- Tetrazolium-5-base, 2H-tetrazolium-2-base and 2H-tetrazolium-5-base." oxa-triazolyl " used herein term includes 1, and 2,3, 4-oxa-triazole-5-base and 1,2,3,5-oxa-triazole-4-yls." thiatriazole base " used herein term includes 1,2,3,4- Thiatriazole-5-base and 1,2,3,5-thiatriazole-4-bases." pyridine radicals pyridinyl " used herein term includes (also referred to as " pyridine pyridyl ") pyridine-2-base, pyridin-3-yl and pyridin-4-yl (also referred to as 2-pyridine radicals, 3-pyridine radicals and 4-pyridine Base)." pyrimidine radicals " used herein term includes pyrimidine-2-base, pyrimidine-4-yl, pyrimidine-5-base and pyrimidine-6-base.Herein " pyrazinyl " term used includes pyrazine-2-base and pyrazine-3-base." pyridazinyl (pyridazinyl) " used herein art Language includes oiazines-3-base and oiazines-4-base." piperazine base " used herein (also referred to as " Isosorbide-5-Nitrae-piperazine base ") art Language includes Isosorbide-5-Nitrae-piperazine-4-base and Isosorbide-5-Nitrae-piperazine-5-base." two English bases " used herein (also referred to as " Isosorbide-5-Nitrae-two English Base ") term includes Isosorbide-5-Nitrae-two English-2-base and Isosorbide-5-Nitrae-two English-3-base." thiazinyl " used herein (also referred to as " Isosorbide-5-Nitrae- Thiazinyl ") term includes Isosorbide-5-Nitrae-thiazine-2-base, Isosorbide-5-Nitrae-thiazine-3-base, Isosorbide-5-Nitrae-thiazine-4-base, Isosorbide-5-Nitrae-thiazine-5-base and 1, 4-thiazine-6-base." triazine radical " used herein term include 1,3,5-triazines-2-base, 1,2,4-triazine-3-bases, 1,2, 4-triazine-5-base, 1,2,4-triazine-6-bases, 1,2,3-triazine-4-bases and 1,2,3-triazine-5-bases." imidazoles used herein And [2,1-b] [1,3] thiazolyl " term includes imidazo [2,1-b] [1,3] thiazol-2-yl, imidazo [2,1-b] [1,3] Thiazole-3-base, imidazo [2,1-b] [1,3] thiazole-5-base and imidazo [2,1-b] [1,3] thiazole-6-base.Used herein " thieno [3,2-b] furyl " term include thieno [3,2-b] furans-2-base, thieno [3,2-b] furans-3-base, Thieno [3,2-b] furans-4-base and thieno [3,2-b] furans-5-base." thieno [3,2-b] thiophene used herein Base " term include thieno [3,2-b] thiophene-2-base, thieno [3,2-b] thiene-3-yl, thieno [3,2-b] thiophene- 5-base and thieno [3,2-b] thiophene-6-base." thieno [2,3-d] [1,3] thiazolyl " used herein term includes thiophene Fen also [2,3-d] [1,3] thiazol-2-yl, thieno [2,3-d] [1,3] thiazole-5-base and thieno [2,3-d] [1,3] thiophene Azoles-6-base." thieno [2,3-d] imidazole radicals " used herein term includes thieno [2,3-d] imidazoles-2-base, thiophene And [2,3-d] imidazol-4 yl and thieno [2,3-d] imidazoles-5-base." tetrazolo [1,5-a] pyridine radicals " used herein art Language include tetrazolo [1,5-a] pyridine-5-base, tetrazolo [1,5-a] pyridine-6-base, tetrazolo [1,5-a] pyridin-7-yl, And tetrazolo [1,5-a] pyridine-8-base." indyl " used herein term includes indoles-1-base, indoles-2-base, Yin Diindyl-3-base ,-indoles-4-base, indoles-5-base, indoles-6-base and indoles-7-base.It is used herein that " " term includes indolizine base Indolizine-1-base, indolizine-2-base, indolizine-3-base, indolizine-5-base, indolizine-6-base, indolizine-7-base and indolizine-8-base.This Place use " isoindolyl " " term include iso-indoles-1-base, iso-indoles-2-base, iso-indoles-3-base, iso-indoles-4-base, Iso-indoles-5-base, iso-indoles-6-base and iso-indoles-7-base." benzofuranyl " used herein (also referred to as benzo [b] furans Base) term includes benzofuran-2-base, benzofuran-3-base, benzofuran-4-base, benzofuran-5-base, benzo furan Mutter-6-base and benzofuran-7-base." isobenzofuran-base " used herein (also referred to as benzo [c] furyl) term includes Isobenzofuran-1-base, isobenzofuran-3-base, isobenzofuran-4-base, isobenzofuran-5-base, isobenzofuran- 6-base and isobenzofuran-7-base." benzothienyl " used herein (also referred to as benzo [b] thienyl) term includes 2- Benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl And-7-benzo [b] thienyl (also referred to as benzothiophene-2-base, benzothiophene-3-base, benzothiophene-4-base, benzothiophene- 5-base, benzothiophene-6-base and benzothiophene-7-base)." isobenzo-thienyl " used herein (also referred to as benzo [c] thiophene Base) term include different benzothiophene-1-base, different benzothiophene-3-base, different benzothiophene-4-base, different benzothiophene-5-base, Different benzothiophene-6-base and different benzothiophene-7-base." indazolyl " used herein (also referred to as 1H-indazolyl or 2-azepine Yin Diindyl base) term includes 1H-indazole-1-base, 1H-indazole-3-base, 1H-indazole-4-base, 1H-indazole-5-base, 1H-indazole-6- Base, 1H-indazole-7-base, 2H-indazole-2-base, 2H-indazole-3-base, 2H-indazole-4-base, 2H-indazole-5-base, 2H-indazole- 6-base and 2H-indazole-7-base." benzimidazolyl " used herein term include benzimidazole-1-base, benzimidazolyl-2 radicals- Base, benzimidazole-4-base, benzimidazole-5-base, benzimidazole-6-base and benzimidazole-7-base." 1,3-benzene used herein And oxazolyl " term includes 1,3-benzothiazole-2-base, 1,3-benzothiazole-4-base, 1,3-benzothiazole-5-base, 1,3- Benzothiazole-6-base and 1,3-benzothiazole-7-base." 1,2-benzisoxa oxazolyl " used herein term includes 1,2-benzene And isoxazole-3-base, 1,2-benzo isoxazole-4-base, 1,2-benzo isoxazole-5-base, 1,2-benzo isoxazole-6-base and 1, 2-benzo isoxazole-7-base." 2,1-benzo isoxazole " used herein term includes 2,1-benzo isoxazole-3-base, 2, 1-benzo isoxazole-4-base, 2,1-benzo isoxazole-5-base, 2,1-benzo isoxazole-6-base and 2,1-benzo isoxazole-7- Base." 1,3-benzothiazolyl " used herein term includes 1,3-benzothiazole-2-base, 1,3-benzothiazole-4-base, 1, 3-benzothiazole-5-base, 1,3-benzothiazol-6-yl and 1,3-benzothiazole-7-base." 1,2-benzisothia used herein Oxazolyl " term includes 1,2-benzisothiazole-3-base, 1,2-benzisothiazole-4-base, 1,2-benzisothiazole-5-base, 1, 2-benzisothiazole-6-base and 1,2-benzisothiazole-7-base." 2,1-benzisothia oxazolyl " used herein term includes 2,1-benzisothiazole-3-bases, 2,1-benzisothiazole-4-base, 2,1-benzisothiazole-5-base, 2,1-benzisothiazole-6- Base and 2,1-benzisothiazole-7-base." BTA base " used herein term includes BTA-1-base, benzo three Azoles-4-base, BTA-5-base, BTA-6-base and BTA-7-base." 1,2,3-benzo two used herein Oxazolyl " term includes 1,2,3-benzodiazole-4-bases, 1,2,3-benzodiazole-5-bases, 1,2,3-benzodiazoles- 6-base and 1,2,3-benzodiazole-7-bases." 2,1,3-benzodiazole base " used herein term includes 2,1,3-benzene And diazole-4-base, 2,1,3-benzodiazole-5-base, 2,1,3-benzodiazole-6-base and 2,1,3-benzodiazole- 7-base." 1,2,3-benzodiazole base " used herein term includes 1,2,3-benzodiazole-4-bases, 1,2,3-benzos Diazole-5-base, 1,2,3-benzodiazole-6-bases and 1,2,3-benzodiazole-7-bases." 2,1,3-benzene used herein And thiadiazolyl group " term includes 2,1,3-diazosulfide-4-base, 2,1,3-diazosulfide-5-base, 2,1,3-benzo thiophene Diazole-6-base and 2,1,3-diazosulfide-7-base." thienopyridine base " used herein term include thieno [2, 3-b] pyridine radicals, thieno [2,3-c] pyridine radicals, thieno [3,2-c] pyridine radicals and thieno [3,2-b] pyridine radicals.Herein " purine radicals " term used includes purine-2-base, purine-6-base, purine-7-base and purine-8-base.Used herein " imidazo [1,2-a] pyridine radicals " term include imidazo [1,2-a] pyridine-2-base, imidazo [1,2-a] pyridin-3-yl, Imidazo [1,2-a] pyridin-4-yl, imidazo [1,2-a] pyridine-5-base, imidazo [1,2-a] pyridine-6-base and imidazo [1,2-a] pyridin-7-yl." 1,3-benzodioxole group " used herein term includes 1, dioxy between 3-benzo Heterocyclic pentene-4-base, 1,3-benzodioxole-5-base, 1,3-benzodioxole-6-base and 1,3- Benzodioxole-7-base." quinolyl " used herein term include quinoline-2-base, quinoline-3-base, quinoline- 4-base, quinoline-5-base, quinoline-6-base, quinoline-7-base and quinoline-8-yl." isoquinolyl " used herein term includes Isoquinolyl-1, isoquinolin-3-base, isoquinolin-4-base, isoquinolin-5-base, isoquinolin-6-base, isoquinolin-7-base and isoquinoline Quinoline-8-base." scolding piperazine base " used herein term include scold piperazine-3-base, scold piperazine-4-base, scold piperazine-5-base, scold piperazine-6-base, Scold piperazine-7-base and scold piperazine-8-base." quinazolyl " used herein term includes quinazoline-2-base, quinazoline-4-base, quinoline Oxazoline-5-base, quinazoline-6-base, quinazoline-7-base and quinazoline-8-base." quinoxalinyl " used herein term includes Quinoxaline-2-base, quinoxaline-5-base and quinoxalin-6-yl." 7-azaindolyl " used herein term refers to 1H-pyrroles [2,3-b] pyridine radicals and include 7-azaindole-1-base, 7-azaindole-2-base, 7-azaindole-3-base, 7-azepine Yin Diindyl-4-base, 7-azaindole-5-base, 7-azaindole-6-base." 6-azaindolyl " used herein term refers to 1H-pyrrole Cough up [2,3-c] pyridine radicals and include 6-azaindole-1-base, 6-azaindole-2-base, 6-azaindole-3-base, 6-azepine Yin Diindyl-4-base, 6-azaindole-5-base, 6-azaindole-7-base." 5-azaindolyl " used herein term refers to 1H-pyrrole Cough up [3,2-c] pyridine radicals and include 5-azaindole-1-base, 5-azaindole-2-base, 5-azaindole-3-base, 5-azepine Yin Diindyl-4-base, 5-azaindole-6-base, 5-azaindole-7-base." 4-azaindolyl " used herein term refers to 1H-pyrrole Cough up [3,2-b] pyridine radicals and include 4-azaindole-1-base, 4-azaindole-2-base, 4-azaindole-3-base, 4-azepine Yin Diindyl-5-base, 4-azaindole-6-base, 4-azaindole-7-base.

For example, the non-limiting examples of heteroaryl can be 2-or 3-furans, 2-or 3-thienyl, 1-, 2-or 3-pyrrole Cough up base, 1-, 2-, 4-or 5-imidazole radicals, 1-, 3-, 4-or 5-pyrazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isothiazolyl, 2-, 4-or 5-thiazolyl, 1,2,3-triazoles-1-,-4-or-5-base, 1,2,4-triazole-1-,- 3-,-4-or-5-base, 1H-TETRAZOLE-1-or-5-base, 2H-tetrazolium-2-or-5-base, 1,2,3-diazole-4-or-5-bases, 1, 2,4-diazole-3-or-5-bases, 1,2,5-di azolies, 1,3,4-di azolies, 1,2,3-thiadiazoles-4-or-5-bases, 1, 2,4-thiadiazoles-3-or-5-bases, 1,2,5-thiadiazoles-3-or-4-bases, 1,3,4-thiadiazolyl groups, 1-or 5-tetrazole radical, 2-, 3- Or 4-pyridine, 3-or 4-pyridazinyl, 2-, 4-, 5-or 6-pyrimidine radicals, 2-, 3-, 4-, 5-6-2H-thiapyran base, 2-, 3-or 4- 4H-thiapyran base, 4-azaindole-1-, 2-, 3-, 5-or 7-base, 5-azaindole-1-or 2-, 3-, 4-, 6-or 7-base, 6- Azaindole-1,2-, 3-, 4-, 5-or 7-base, 7-azaindole-1-, 2-, 3-, 4,5-or 6-base, 2-, 3-, 4-, 5-, 6- Or 7-benzofuran, 1-, 3-, 4-or 5-isobenzofuran, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 1-, 3-, 4-or 5- Isobenzo-thienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 2-or 3-pyrazinyl, Isosorbide-5-Nitrae-piperazine-2-or-3-base, Isosorbide-5-Nitrae- Two English-2-or-3-bases, Isosorbide-5-Nitrae-thiazine-2-or-3-base, 1,2,3-triazine radicals, 1,2,4-triazine radicals, 1,3,5-triazines-2-,- 4-or-6-base, thieno [2,3-b] furans-2-,-3-,-4-or-5-base, benzimidazole-1-base ,-2-base ,-4-base ,-5- Base ,-6-base or-7-base, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 3-, 4-, 5-, 6-or 7-benzisothiazole, 2-, 4-, 5-, 6-or 7-benzoxazolyl group, 3-, 4-, 5-, 6-or 7-benzisothia oxazolyl, 1,3-benzothiazole-2-base ,-4-base ,- 5-base ,-6-base or-7-base, 1,3-benzodioxole-4-base ,-5-base ,-6-base or-7-base, BTA-1- Base ,-4-base ,-5-base ,-6-base or-7-base 1-, 2-thianthrene group, 3-, 4-or 5-isobenzofuran-base, 1-, 2-, 3-, 4-or 9- Ton base, 1-, 2-, 3-or 4-benzo oxathiin base, 2-, 3-pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8- Indolizine base, 2-, 3-, 4-or 5-isoindolyl, 1H-indazole-1-base, 3-base ,-4-base ,-5-base ,-6-base or-7-base, 2H- Indazole-2-base, 3-base ,-4-base ,-5-base ,-6-base or-7-base, imidazo [2,1-b] [1,3] thiazol-2-yl, imidazo [2,1-b] [1,3] thiazole-3-base, imidazo [2,1-b] [1,3] thiazole-5-base or imidazo [2,1-b] [1,3] thiazole-6- Base, imidazo [1,2-a] pyridine-2-base, imidazo [1,2-a] pyridin-3-yl, imidazo [1,2-a] pyridin-4-yl, imidazoles And [1,2-a] pyridine-5-base, imidazo [1,2-a] pyridine-6-base or imidazo [1,2-a] pyridin-7-yl, tetrazolo [1,5- A] pyridine-5-base, tetrazolo [1,5-a] pyridine-6-base, tetrazolo [1,5-a] pyridin-7-yl or tetrazolo [1,5-a] pyrrole Pyridine-8-base, 2-, 6-, 7-or 8-purine radicals, 4-, 5-or 6-phthalazinyl, 2-, 3-or 4-naphthyridines base, 2-, 5-or 6-quinoxalinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, 1-, 2-, 3-or 4-quinolizine base, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl Quinolinyl (quinoline quinolyl), 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinoline Quinoline base isoquinolinyl (isoquinolyl isoquinolyl)), 3-, 4-, 5-, 6-, 7-or 8-scold piperazine base, 2-, 4-, 6-or 7- Pteridyl, 1-, 2-, 3-, 4-or 9-carbazyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-carboline base, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-phenanthridinyl, 1-, 2-, 3-or 4-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-naphthalene are embedding Pyrimidyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-(1,7) phenanthrolene base, 1-or 2-phenazinyl, 1-, 2-, 3-, 4-or lysivane base, 3-or 4-furazanyl, 1-, 2-, 3-, 4-or 10-coffee piperazine base or other substituted derivative Thing.

" optionally substituted heteroaryl " refers to that the heteroaryl optionally having one or more substituent is (as 1 to 4 takes Dai Ji, such as 1,2,3 or 4), selected from those to substituted aryl definition above-mentioned.

" oxo " used herein term refers to group=O.

" alkoxyl " used herein term refers to formula-OR^bGroup, wherein R^bIt it is alkyl.Alkoxyl is preferably C₁-C₁₀Alkoxyl, C₁-C₆Alkoxyl or C₁-C₄Alkoxyl.The non-limiting examples being suitable for alkoxyl includes methoxyl group, ethoxy Base, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, amyl group oxygen and hexyloxy.If alkoxyl The oxygen atom of group is replaced by sulphur, and consequent group is referred to as thio alkoxy." halogenated alkoxy " is an alkoxyl Group, wherein the one or more hydrogen atoms in alkyl group are replaced by halogen rope.It is suitable for the non-limiting examples of halogenated alkoxy Include fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxies, 1,1,2,2-tetrafluoro ethyoxyl, 2-fluorine Ethyoxyl, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-tri-chloroethoxy bases；Trifluoromethoxy, 2-bromine oxethyl, five fluorine Ethyl, 3,3,3-trichlorine propoxyl group, 4,4,4-trichlorine butoxy.

Used herein " " group of term representative-O-aryl, wherein the definition of aryl please see above aryloxy group.

" aryl carbonyl " or " aroyl " term used herein represents the group of-C (O)-aryl, the wherein definition of aryl Please see above.

Self or " cycloalkyl-alkyl " term as a part for another group refer to have above-mentioned group of naphthene base even Receive the group of abovementioned alkyl chain.The example of this kind of cycloalkyl-alkyl includes Cvclopropvlmethvl, cyclobutylmethyl, cyclopenta first Base, cyclohexyl methyl, 1-cyclopentyl ethyl, 1-cyclohexyl-ethyl, 2-cyclopentyl ethyl, 2-cyclohexyl-ethyl, cyclobutyl propyl ester, Cyclopenta propyl ester, 3-cyclopentylbutyl, cyclohexylbutyl and similar.

Self or " heterocyclyl-alkyl " term as a part for another group refer to have above-mentioned heterocyclyl groups even Receive the group of abovementioned alkyl chain, be attached to-R^d-R^cGroup, wherein R^dIt is alkylidene or the alkylene replaced by alkyl group Base, and R^cIt it is heterocyclyl groups.

Self or " carboxyl " or " hydroxycarbonyl group " term as a part for another group refer to-CO₂H group.Therefore, Carboxyalkyl is to have at least one-CO₂The alkyl group of H substituent.

Self or " alkoxy carbonyl group " term as a part for another group refer to be connected to the carboxyl base of alkyl group Group, i.e. constitutes-C (=O) OR^e, wherein R^eIt it is above-mentioned defined alkyl.

Self or " alkyl carbonyl oxy " term as a part for another group refer to-O-C (=O) R^e, wherein R^eOn being State defined alkyl.

Self or " alkyl-carbonyl-amino " formula of referring to as a part for another group are-NH (C=O) R or-NR ' (C =O) group of R, wherein R and R ' is separately alkyl or substituted alkyl.

Self or " thiocarbonyl " as a part for another group refer to-C (=S)-group.

Self or " alkoxyl " as a part for another group refer to that comprising one is connected to optionally substituted straight chain Or the group of the oxygen atom of branched alkyl group, group of naphthene base, aralkyl or cycloalkylalkyl group.It is suitable for alkoxyl base The non-limiting examples of group includes methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, Zhong Ding oxygen Base, tert-butoxy, hexyloxy and similar.

Self or be the upperseat concept of fluorine, chlorine, bromine or iodine as " halogen " or " halogen " term of another group part.

" haloalkyl " term applied alone or in combination refers to have the alkyl being as defined above, wherein one or more The halogen that hydrogen is defined as above is replaced.The non-limiting examples of this kind of haloalkyl includes chloromethyl, 1-bromoethyl, fluorine first Base, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and similar.

" halogenated aryl " term applied alone or in combination refers to wherein one or more hydrogen and is defined halogen as above Institute is substituted has aryl defined above.

" halogenated alkoxy " term applied alone or in combination refers to the group that formula is-O-alkyl, wherein alkyl group Replaced by 1,2 or 3 halogen atoms.For example, " halogenated alkoxy " includes-OCF₃、-OCHF₂、-OCH₂F、-O- CF₂-CF₃、-O-CH₂-CF₃、-O-CH₂-CHF₂, and-O-CH₂-CH₂F。

When the present invention uses " replacement " this term, it is to show one or more hydrogen atom quilts in expression formula Replaced selected from the other group of designated groups, and the normal valency that premise is specified atom is not exceeded, and this replacement can generationization Learn the compound of stable in properties, be i.e. sufficient to resist and be separated to useful purity grade from reactant mixture and be configured to treatment Agent.

If group can be optionally substituted, this kind of group may be replaced one or many, preferably can be replaced one Secondary, twice or thrice.For example, substituent can be selected from comprising halogen rope, hydroxyl, oxo, nitro, acylamino-, carboxyl, ammonia The group of base, cyano group, halogenated alkoxy and haloalkyl.

Used herein such as " alkyl, aryl or cycloalkyl, each be optionally substituted " or " alkyl, aryl or cycloalkanes Base, can be optionally substituted " term refers to optionally substituted alkyl, optionally substituted aryl or optionally substituted cycloalkyl.

According to described herein, some compounds of the present invention may one or more non-right containing as asymmetric center Claiming carbon atom, this may result in different optical isomeric form (such as: enantiomter or diastereoisomer).Bag of the present invention Include likely these optical isomeric form of configuration and their mixture.

More generally, from above-mentioned finding, professional may be with different by the compound being clear from the present invention Presented in isomers and/or dynamic isomer, include but not limited to geometric isomer, rotamer, E/Z type isomery Body, stereoisomer (i.e. enantiomter and diastereoisomer) and corresponding to the diverse location of ring in the compounds of this invention The isomers of identical substituent.All these possible isomers, dynamic isomer and their mixture will be included into invention In the range of.

The term of " compound of the present invention " or similar terms is used to refer to comprise formula I and appoint whenever in the present invention The compound of what subgroup.This term also refers to the compound shown in table 1 to 11, their derivative, N-oxide, salt, molten Agent compound, hydrate, stereoisomer form, racemic mixture, tautomeric forms, optical isomer, analog, front Medicine, ester and metabolite and their quaternized nitrogen analog.The N-oxide form of described compound is intended to comprise one Or multiple nitrogen-atoms is oxidized to the compound of so-called N-oxide.

In this specification and claims, the singulative " a kind of " of use, " one " and " being somebody's turn to do " also include plural number Indication thing, unless this content shows expressly otherwise.For example, " a compound a compound " refers to one or exceedes The compound of one.

The above and other terms used in the description are all understood by those skilled in the art.

In further embodiment, the invention provides the compound of formula (I)

Wherein；

R¹It is hydrogen or C_1-4Alkyl；Particularly methyl；

Ar as defined above, and

Y is the aryl or heteroaryl being substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹；-C (=O)- SR²²；-C (=O)-NR³R⁴；-NR⁵R⁶；-O-C_1-6Alkyl；-C_1-6Alkyl；Or-C_2-8The group of thiazolinyl；

Wherein said-O-C_1-6Alkyl ,-C_1-6Alkyl, or-C_2-8Thiazolinyl；Can separately be substituted with a substituent；Should Substituent is selected from including C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；Het¹；-O-Het²；And-S-Het³Group Not；

R³Selected from comprising following group: hydrogen；Can be by 1,2 or 3 optionally substituted C of substituent_1-20Alkyl, this substituent Separately selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³； C_1-6Alkyl-S-and C_1-6The group of alkyl-O-；R for Te Bie³It is hydrogen；

R⁴Selected from comprising C_1-20The group of alkyl, this C_1-20Alkyl is optionally substituted by 1,2 or 3 substituents, and this substituent divides Not independently selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³；C_1-6 Alkyl-S-and C_1-6The group of alkyl-O-；R for Te Bie⁴Selected from comprising C_1-20The group of alkyl, this C_1-20Alkyl is by 1,2 or 3 Individual substituent is optionally substituted, and this substituent is separately selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)- NR⁷R⁸；Het¹；-O-Het²；And-S-Het³Group；Or

R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is replaced by a substituent, and this substituent is selected from Including-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；-S-Het³；Or C_1-6The group of alkyl Not；Wherein said C_1-6Alkyl is replaced by 1,2 or 3 substituents, this substituent separately selected from comprise-C (=O)- OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；And-S-Het³Group；R for Te Bie³And R⁴With it The nitrogen-atoms that is connected form heterocycle together, it is replaced by a substituent, and this substituent is selected from including-C (=O)-OR²¹；- C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；Or C_1-6The group of alkyl；Wherein said C_1-6Alkyl is by 1,2 or 3 substituents Optionally substituted, this substituent is separately selected from comprising-C (=O)-OR²¹；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；And- S-Het³Group；R for particularly³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is taken by a substituent Generation, and this substituent is selected from including-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；And-S- Het³Group；

R⁵Or R⁶Separately selected from comprising hydrogen；C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkyl-S-C_1-6Alkane Base-；C_2-8Thiazolinyl；C_1-6Alkyl-C (=O)-or C_2-8Thiazolinyl-C (=O)-group；At least one of which R⁵Or R⁶Selected from C_1-6Alkane Base；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-, the most each described C_1-6 Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-can be by 1,2 or 3 replacements Base replaces, and this substituent is separately selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²；And-S- Het³Group；R for Te Bie⁵Or R⁶Separately selected from comprising hydrogen；C_1-6Alkyl；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6 Alkyl-C (=O)-group；At least one of which R⁵Or R⁶Selected from C_1-6Alkyl；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl- C (=O)-, the most each described C_1-6Alkyl；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-by 1,2 or 3 Substituent replaces, and this substituent is separately selected from comprising-C (=O)-OR²¹；-Het¹；-O-Het²；And-S-Het³Group Not；R for particularly⁵Or R⁶Separately selected from comprising hydrogen；C_1-6Alkyl；C_1-6Alkyl-C (=O)-group；At least a part of which One R⁵Or R⁶Selected from C_1-6Alkyl；Or C_1-6Alkyl-C (=O)-, the most each described C_1-6Alkyl or C_1-6Alkyl-C (=O)- Being replaced by 1,2 or 3 substituents, this substituent is separately selected from comprising-C (=O)-OR²¹；-Het¹；-O-Het²；And- S-Het³Group；R for particularly⁵Or R⁶Separately selected from comprising hydrogen；Or C_1-6The group of alkyl；At least one of which R⁵Or R⁶Selected from C_1-6Alkyl；This C_1-6Alkyl is replaced by 1,2 or 3 substituents, this substituent can separately selected from comprising- Het¹；-O-Het²And-S-Het³Group；

R⁷Or R⁸Separately selected from comprising hydrogen；Or C_1-6The group of alkyl；They are replaced by 1,2 or 3 substituents, should Substituent is separately selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；And-C (=O)-NH₂Group Not；R for Te Bie⁷Or R⁸Separately selected from comprising hydrogen；Or C_1-6The group of alkyl；They are taken by 1,2 or 3 substituents In generation, this substituent is separately selected from comprising-C (=O)-OR²¹；And-C (=O)-NH₂Group；R for particularly⁷Or R⁸ Separately selected from comprising hydrogen；Or by-C (=O)-OR²¹Substituted C_1-6Alkyl；

R⁹Or R¹⁰Separately selected from comprising hydrogen or C_1-6The group of alkyl；Described C_1-6Alkyl by 1,2 or 3-C (= O)-OR²¹Substituent is replaced；

R¹³Or R¹⁴Separately selected from comprising hydrogen；C_1-6Alkyl；C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkane Base-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-group, the most each described C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkane Base-；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-replaced by 1,2 or 3 substituents, this substituent is independently Ground is selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²；And-S-Het³Group；R for Te Bie¹³And R¹⁴ Represent hydrogen；

R²¹Selected from comprising C_1-20Alkyl；C_1-20Thiazolinyl；Optionally substituted C_3-15Cycloalkyl；Optionally substituted heterocyclic radical；And appoint Select the group of substituted aryl；

Wherein said C_1-20Alkyl can be optionally substituted by 1,2,3 or more substituents, and this substituent is selected from comprising halogen Rope, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-C (=O)-NR¹³R¹⁴,-O-C (= O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-15The group of cycloalkyl or following formula:

Or

R²¹The cyclic ester ring of following formula is formed together with the carbonyloxy group being connected with them and phenyl

Wherein q is the integer from 1 to 6；

R²²It is C_1-20Alkyl, can be optionally substituted by 1,2,3 or more halogen rope substituents；

Het⁴、Het²Or Het³Separately selected from comprising following group；

The compound attracted people's attention according to another group of the present invention is the compound of formula (I), but has following one or more Limit；

-Ar represents pyridine radicals, can be optionally substituted by halogen；For Te Bie, Ar represents the pyridine radicals replaced by fluorine；? Further in embodiment, Ar represents

-Wherein X is hydrogen or halogen rope；For Te Bie, X is hydrogen or fluorine；For particularly, X is fluorine；

-R¹Represent hydrogen or C_1-4Alkyl；It is C for Te Bie_1-4Alkyl；It it is methyl for particularly；

-Y is the aryl or heteroaryl being substituted with a substituent, and this substituent is selected from including-C (=O)-NR³R⁴；-NR⁵R⁶；- O-C_1-6Alkyl；Or-C_1-6The group of alkyl；

Wherein said-O-C_1-6Alkyl or-C_1-6Alkyl is separately substituted with a substituent；This substituent is selected from bag Include-C (=O)-NR³R⁴、-O-Het²And S-Het³Group；In certain embodiments, described Het²Or Het³The most solely On the spot selected from comprising following group

-Y is the aryl or heteroaryl being substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹；-C (=O)- SR²²；-C (=O)-NR³R⁴；-O-C_1-6Alkyl；Or-C_1-6The group of alkyl；

Wherein said-O-C_1-6Alkyl or-C_1-6Alkyl is separately substituted with a substituent；This substituent is selected from bag Include-C (=O)-OR²¹, and Het¹Group；In certain embodiments, described；

R²¹Selected from-C_1-6Alkyl or aryl；R described for particularly²¹Selected from-C_1-6Alkyl or phenyl；And

Described Het¹Selected from comprising following group

-R³It is hydrogen；

-R⁴It is-the C being substituted with a substituent_1-6Alkyl, this substituent is selected from-O-Het²Or-S-Het³；

-R⁴It is-the C being substituted with a substituent_1-6Alkyl, this substituent is selected from-C (=O)-OR²¹,-C (=O)-SR²², or Het¹；In certain embodiments, described R²¹It is-the C being substituted with a substituent_1-6Alkyl, this substituent selected from-C (=O)- OR²¹, or Het¹；In further embodiment, described R²¹It is-C_1-6Alkyl；

-R⁵Or R⁶Separately selected from comprising hydrogen；C_1-6Alkyl；Or C_1-6Alkyl-S-C_1-6Alkyl-group；The most extremely A few R⁵Or R⁶Selected from comprising C_1-6Alkyl；Or C_1-6Alkyl-S-C_1-6Alkyl-group；And the C described in the most each_1-6Alkane Base；Or C_1-6Alkyl-S-C_1-6Alkyl-be substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹、Het¹And-S- Het³Group；In certain embodiments, described；

R²¹Selected from-C_1-6Alkyl or aryl；R described for particularly²¹It is a-C_1-6Alkyl；And

Described Het¹Or Het³Separately selected from comprising following group:

-R²¹Selected from-C_1-6Alkyl, aryl or optionally substituted heteroaryl；R described for particularly²¹Selected from-C_1-6Alkane Base, 3,4-dihydro-1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl or phenyl, wherein said 3,4- Dihydro-1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl is replaced by epoxide；

-Aryl stands phenyl；

-heteroaryl represents 3,4-dihydro-1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl or indoles Base；It it is indyl for Te Bie；

-Y is the aryl or heteroaryl being substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹；-C (=O)- SR²²；-C (=O)-NR³R⁴；-O-C_1-6Alkyl；Or-C_1-6The group of alkyl；

Wherein said-O-C_1-6Alkyl or-C_1-6Alkyl is separately substituted with a substituent；This substituent is selected from bag Include-C (=O)-OR²¹, and Het¹Group；In certain embodiments, described；

R²¹Selected from-C_1-6Alkyl or aryl；Described R for particularly²¹Selected from-C_1-6Alkyl or phenyl；

Described Het¹Selected from comprising following group

And wherein said-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；-O-C_1-6Alkyl；Or-C_1-6Alkane Base is in aryl or heteroaryl and the meta of molecule remainder junction and contraposition, as with Formula Il a-XXIIIa and IIb- Shown in XXIIIb.

In certain embodiments, the invention provides the compound of formula (I), wherein defined Y substituent, i.e. makees For substituent or a part for substituent, comprise at least one selected from C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²； And-S-Het³The group of group.In embodiment particularly, the invention provides the compound of formula (I), wherein Y takes The base that is further substituted with of Dai Ji is positioned at aryl or heteroaryl and the meta of molecule remainder junction and contraposition, as with following formula Shown in IIa-XXIIIa and IIb-XXIIIb.

In more specific embodiment, the invention provides any one different embodiments as herein described and defined The compound of formula (I), its collateral condition is to be selected from-C (=O)-OR when Y represents²¹；Or-C (=O)-SR²²Substituent replaces Aryl or during heteroaryl, and wherein said R²¹Or R²²Represent unsubstituted C_1-20During alkyl, described-C (=O)- OR²¹；Or-C (=O)-SR²²It is positioned at aryl or heteroaryl and the meta of molecule remainder junction and contraposition, as with following formula Shown in IIa, IIb, IIIa and IIIb.

In further embodiment, the invention provides the compound of formula (I), but have following one or more limit System；

-Y is 2-oxo-2, and 3-dihydro benzo furyl or Y are phenyl, indyl or thienyl, described Phenylindole Base and thienyl are substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)- NR³R⁴；-NR⁵R⁶；-O-C_1-6Alkyl；-C_1-6Alkyl；Or-C_2-8The group of thiazolinyl

Wherein said-O-C_1-6Alkyl or-C_2-8Thiazolinyl is substituted with a substituent, and this substituent selected from include C (=O)- OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；Het¹；-O-het²；And-S-Het³Group；

-R⁵Or R⁶Separately selected from comprising hydrogen；C_1-6Alkyl；Or C_1-6Alkyl-S-C_1-6Alkyl-group；The most extremely A few R⁵Or R⁶Selected from comprising C_1-6Alkyl；Or C_1-6Alkyl-S-C_1-6Alkyl-group；And the C described in the most each_1-6Alkane Base；Or C_1-6Alkyl-S-C_1-6Alkyl-be substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹、Het¹And-S- Het³Group；

-R²¹Selected from comprising C_1-20Alkyl；Optionally substituted C_3-10Cycloalkyl；Optionally substituted aryl；And it is optionally substituted The group of heterocyclic radical；Wherein said C_1-20It is optionally substituted that alkyl can be replaced base, and this substituent is selected from: halogen, cyano group, hydroxyl Base ,-C (=O)-NR¹³R¹⁴,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical, And C_3-10Cycloalkyl or following formula:

R for Te Bie²¹Selected from comprising C_1-20Alkyl；Appoint Select substituted C_3-10Cycloalkyl；Optionally substituted aryl；And the group of optionally substituted heterocyclic radical；Wherein said C_1-20Alkyl Being substituted with a substituent, this substituent is selected from: halogen, cyano group, hydroxyl ,-C (=O)-NR¹³R¹⁴,-O-C (=O)-C_1-6Alkyl, C_1-6 Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-10Cycloalkyl or following formula:

R for particularly²¹Selected from comprising C_1-20Alkyl； C_3-10Cycloalkyl；And the group of optionally substituted aryl；Wherein said C_1-20Alkyl is substituted with a substituent, and the choosing of this substituent From including halogen ,-O-C (=O)-C_1-6The group of alkyl, or selected from following formula:

-heterocyclic radical used herein is selected from: piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-bis- Oxinane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrochysene Furyl and hexahydro furyl also [3,2-b] furyl；It is selected from for Te Bie: piperidyl, 1,3-dioxane base, dihydro Yin Diindyl base, THP trtrahydropyranyl and tetrahydrofuran base；

-optionally substituted C used herein_3-10Cycloalkyl is selected from comprising cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cycloheptyl Base, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and the group of ring decyl, the most preferably cyclopropyl, ring Amyl group, cyclohexyl, adamantyl and dicyclo (2,2,1) heptane；Wherein said C_3-10Cycloalkyl can be by 1,2,3 or more polysubstituted Base is optionally substituted, especially for be 1,2 or 3；It is 1 or 2 for particularly；It is 1 for the most special；This substituent selects From halogen, hydroxyl, oxo, nitro, amino, cyano group, C_1-4Alkyl, C_3-6Cycloalkyl, C_1-4Alkoxyl, or-SO₂-NH₂,

-optionally substituted heterocycle used herein is selected from comprising piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, piperazine Piperazine base, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, tetrahydrochysene The group of pyranose, tetrahydrofuran base and hexahydro furyl also [3,2-b] furyl；For be Te Bie piperidyl, 1,3-dioxa Cyclohexyl, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base；Wherein said heterocyclic radical can be taken by 1,2,3 or more Replace for base, especially for be 1；This substituent is selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, amino carbonyl, nitrine Base, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkyl-alkyl, alkyl amino, alkoxyl ,-SO₂-NH₂, aryl, heteroaryl, Aralkyl, haloalkyl, halogenated alkoxy, alkoxy carbonyl group, alkyl amino-carbonyl, heteroaryl alkyl, alkyl sulfonamide, heterocycle Base, alkylcarbonylaminoalkyl, aryloxy group, alkyl-carbonyl, acyl group, aryl carbonyl, amino carbonyl, alkyl sulfoxide ,-SO₂R^a, alkane Sulfenyl, the group of carboxyl and similar, wherein R^aIt it is alkyl or cycloalkyl；It is preferably selected from halogen, hydroxyl, oxo, nitro, ammonia Base, cyano group, C_1-4Alkyl, C_3-6Cycloalkyl, C_1-4Alkoxyl, or-SO₂-NH₂,

-aryl used herein is selected from comprising phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl or 1, the group of 2,3,4-tetralyls Not, wherein said aryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen, nitro, C_1-4Alkane Base, C_1-4Alkoxyl or C_1-4Alkylthio group；Being phenyl or 1 for Te Bie, 2,3,4-tetralyls, wherein said aryl can quilt 1,2,3,4 or 5 substituents are optionally substituted, and this substituent is selected from halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkoxyl or C_1-4 Alkylthio group；For particularly, phenyl can be optionally substituted by 1,2,3,4 or 5 substituents；This substituent be selected from halogen, nitro, C_1-4Alkyl, C_1-4Alkoxyl or C_1-4Alkylthio group；

-heteroaryl used herein is selected from comprising furyl, thienyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrrole Oxazolyl, isoxazolyl, isothiazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, benzofuranyl, benzo Pyranose, 1 (4H)-benzopyranyl, 1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl and 2,3-bis- The group of hydrogen-1 (4H)-benzopyranyl, wherein said heteroaryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this takes Dai Ji is selected from halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkoxyl or C_1-4Alkylthio group；For be Te Bie furyl, thienyl, Pyridine radicals, benzopyranyl, 1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl and 2,3-dihydro-1 (4H)-benzopyranyl；Wherein said heteroaryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen Element, oxo or C_1-4Alkyl；

-Y is 2-oxo-2, and 3-dihydro benzo furyl or Y are phenyl, indyl or thienyl, described Phenylindole Base and thienyl are substituted with a substituent, and this substituent is selected from including-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)- NR³R⁴；-NR⁵R⁶；-O-C_1-6Alkyl；-C_1-6Alkyl；Or-C_2-8The group of thiazolinyl；Described-C (=O)-OR²¹；-C (=O)- SR²²；-C (=O)-NR³R⁴；-NR⁵R⁶；-O-C_1-6Alkyl；-C_1-6Alkyl；Or-C_2-8Thiazolinyl is attached to the meta of Y location or right Position, for Y is combined with molecule remainder；And wherein said-O-C_1-6Alkyl or-C_2-8Thiazolinyl is replaced base and takes Generation, and this substituent is selected from: C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；het¹；-O-Het²；And-S-Het³；

-collateral condition is when Y is phenyl, indyl or thienyl, described Phenylindole base and thienyl by-C (= O)-OR²¹；Or-C (=O)-SR²²Replace；And wherein said R²¹Or R²²Represent unsubstituted C_1-20During alkyl, described-C (=O)-OR²¹；Or-C (=O)-SR²²For the combination with molecule other parts of described phenyl, indyl or thienyl It is in meta or para position, as with shown in Formula Il a, IIb, IIIa and IIIb.

The compound that the present invention attracts people's attention is the compound of formula (Ia)

Wherein；

R¹Selected from comprising hydrogen, C_1-4Alkyl or C_3-6The group of cycloalkyl；

Ar is selected from comprising following group:

Wherein X is selected from the group comprising hydrogen or halogen；

L is direct key, C_1-4Alkyl or-O-C_1-4Alkyl；

T is-O-R²¹Or-NR³R⁴；

R³Group selected from following: hydrogen；C_1-20Alkyl, can be optionally substituted by 1,2 or 3 substituents, and this substituent can be distinguished Independently selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³；C_1-6Alkane Base-S-and C_1-6The group of alkyl-O-；R for Te Bie³It is hydrogen；

R⁴Selected from comprising C_1-20The group of alkyl, they are replaced by 1,2 or 3 substituents, and this substituent separately selects Self-contained-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³；C_1-6Alkyl-S-and C_1-6The group of alkyl-O-；R for particularly⁴Selected from comprising C_1-20The group of alkyl, they are replaced by 1,2 or 3 substituents, This substituent is separately selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²； And-S-Het³Group；Or；

R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is replaced by a substituent, and this substituent is selected from Including-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；-S-Het³；Or C_1-6The group of alkyl Not；Wherein said C_1-6Alkyl is replaced by 1,2 or 3 substituents, this substituent separately selected from comprise-C (=O)- OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；And-S-Het³Group；R for Te Bie³And R⁴With it The nitrogen-atoms that is connected form heterocycle together, it is replaced by a substituent, and this substituent is selected from including-C (=O)-OR²¹；- C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；Or C_1-6The group of alkyl；Wherein said C_1-6Alkyl is by 1,2 or 3 replacements Base replaces, and this substituent is separately selected from comprising Het¹；-O-Het²；And-S-Het³Group；

R⁷Or R⁸Separately selected from following group: hydrogen；Or C_1-6Alkyl, they are replaced by 1,2 or 3 substituents, This substituent is separately selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；And-C (=O)-NH₂Group Not；R for Te Bie⁷Or R⁸Separately selected from following group: hydrogen；Or C_1-6Alkyl, they are taken by 1,2 or 3 substituents In generation, this substituent is separately selected from comprising-C (=O)-OR²¹；And-C (=O)-NH₂Group；

R⁹Or R¹⁰Separately selected from following group: hydrogen；Or C_1-6Alkyl, they are by 1,2 or 3-C (=O)-OR²¹ Substituent replaces；

R¹³Or R¹⁴Separately selected from following group: hydrogen；C_1-6Alkyl；C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkane Base-；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-, and wherein said C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkane Base-；C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-each replaced by 1,2 or 3 substituents, this substituent is respectively Independently selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²；And-S-Het³Group；

R²¹Group selected from following: C_1-20Alkyl；C_1-20Thiazolinyl；C_1-20Alkynyl；Optionally substituted C_3-15Cycloalkyl；Optionally Substituted heterocyclic radical；And optionally substituted aryl；

Wherein said C_1-20Alkyl can be optionally substituted by 1,2,3 or more substituents, and this substituent is selected from following Group: halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-C (=O)-NR¹³R¹⁴、- O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-15Cycloalkyl or be selected from down Formula:

Or

R²¹The cyclic ester of following formula is formed together with the carbonyloxy group being connected with them and phenyl

Wherein q is the integer from 1 to 6；

R²²It is C_1-20Alkyl, can be optionally substituted by 1,2,3 or more halogenic substituents；

Het¹、Het²Or Het³Separately selected from comprising following group；

In further embodiment, the invention provides the compound of formula (Ia), but have following one or more Limit；

-Ar represent pyridine radicals, can be optionally substituted by halogen；For Te Bie, Ar represents the pyridine radicals that can be replaced by fluorine；More In further embodiment, Ar represents

-Wherein X is hydrogen or halogen；For Te Bie, X is hydrogen or fluorine；For particularly, X is hydrogen；

-R¹Represent hydrogen or C_1-4Alkyl；It is C for Te Bie_1-4Alkyl；It it is methyl for particularly；

-R³It is hydrogen；

-R⁴It is to be selected from-O-Het², or-S-Het³Substituted-the C of substituent_1-6Alkyl；In certain embodiments, institute The Het stated²Or Het³Selected from comprising following group

-R⁴It is to be selected from-C (=O)-OR²¹,-C (=O)-SR²²,-C (=O)-NR⁷R⁸, or Het¹Substituent is substituted- C_1-6Alkyl；-C for Te Bie_1-6Alkyl is selected from-C (=O)-OR²¹Or Het¹Substituent replace；In specific embodiment In, described R²¹It is-C_1-6Alkyl and described Het¹It is

Or

-R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is by C_1-6Alkyl replaces；Wherein said C_1-6Alkyl Being replaced by 1,2 or 3 substituents, this substituent is separately selected from comprising-C (=O)-OR²¹；And-C (=O)-NR⁹R¹⁰'s Group；

-R²¹Selected from comprising C_1-20Alkyl；Optionally substituted C_3-10Cycloalkyl；Optionally substituted aryl；And it is optionally substituted The group of heterocyclic radical；Wherein said C_1-20It is optionally substituted that alkyl can be replaced base, and this substituent is selected from halogen, cyano group, hydroxyl Base ,-C (=O)-NR¹³R¹⁴,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heterocyclic radical and C_3-10Ring Alkyl, or following formula:

R for Te Bie²¹Selected from comprising C_1-20Alkyl；Appoint Select substituted C_3-10Cycloalkyl；Optionally substituted aryl；And the group of optionally substituted heterocyclic radical；Wherein said C_1-20Alkyl Being substituted with a substituent, this substituent is selected from comprising halogen, cyano group, hydroxyl ,-C (=O)-NR¹³R¹⁴,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heterocyclic radical and C_3-10The group of cycloalkyl, or following formula:

R for particularly²¹Selected from comprising C_1-20Alkyl； Optionally substituted C_3-10Cycloalkyl；Optionally substituted aryl；And the group of optionally substituted heterocyclic radical；Wherein said C_1-20Alkane Base is substituted with a substituent, and described substituent is selected from: halogen, cyano group, hydroxyl ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6 Alkyl-S-, aryl, heterocyclic radical and C_3-10Cycloalkyl, or following formula:

R for the most special²¹Selected from comprising C_1-20Alkane Base；C_3-10Cycloalkyl；And the group of optionally substituted aryl；Wherein said C_1-20Alkyl is substituted with a substituent, and this substituent Selected from including halogen ,-O-C (=O)-C_1-6The group of alkyl, or following formula:

-heterocyclic radical used herein selected from comprise piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, piperazinyl, 1, 3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, The group of tetrahydrofuran base and hexahydro furyl also [3,2-b] furyl；For be Te Bie piperidyl, 1,3-dioxane Base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base；

-optionally substituted C used herein_3-10Cycloalkyl is selected from comprising cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring Heptyl, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and the group of ring decyl, the most preferably cyclopropyl, Cyclopenta, cyclohexyl, adamantyl and dicyclo (2.2.1) heptane base；Wherein said C_3-10Cycloalkyl can by 1,2,3 or more Multi-substituent is optionally substituted, especially for be 1,2 or 3；It is 1 or 2 for particularly；It is 1 for the most special；This takes Dai Ji is selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C_1-4Alkyl, C_3-6Cycloalkyl, C_1-4Alkoxyl, or-SO₂-NH₂,

-optionally substituted heterocyclic radical used herein selected from comprise piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, Piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, four The group of hydrogen pyranose, tetrahydrofuran base and hexahydro furyl also [3,2-b] furyl；For be Te Bie piperidyl, 1,3-dioxy Azacyclohexane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base；Wherein said heterocyclic radical can be by 1,2,3 or more Substituent is optionally substituted, especially for be 1；This substituent is selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine (hydrazine), ammonia Base carbonyl, azido, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkyl-alkyl, alkyl amino, alkoxyl ,-SO₂-NH₂、 Aryl, heteroaryl, aralkyl, alkylhalide group, alkyl groups in the halogenalkoxy, alkoxy carbonyl group, alkyl amino-carbonyl, heteroaryl alkyl, alkyl sulfonyl Amine, heterocyclic radical, alkylcarbonylaminoalkyl, aryloxy group, alkyl-carbonyl, acyl group, aryl carbonyl, amino carbonyl, alkyl sulfoxide ,- SO₂R^a, alkylthio group, the group of carboxyl and similar, wherein R^aIt it is alkyl or cycloalkyl；It is preferably selected from halogen, hydroxyl, oxo, nitre Base, amino, cyano group, C_1-4Alkyl, C_3-6Cycloalkyl, C_1-4Alkoxyl, or-SO₂-NH₂,

-aryl used herein is selected from comprising phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl, or 1, the group of 2,3,4-tetralyls Not, wherein said aryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen, nitro, C_1-4Alkane Base, C_1-4Alkoxyl, or C_1-4Alkylthio group；It is phenyl or 1 for Te Bie, 2,3,4-tetralyls；Wherein said aryl can quilt 1,2,3,4 or 5 substituents are optionally substituted, and this substituent is selected from halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkoxyl or C_1-4 Alkylthio group；For particularly, phenyl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen, nitro, C_1-4 Alkyl, C_1-4Alkoxyl or C_1-4Alkylthio group；

-heteroaryl used herein is selected from comprising furyl, thienyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrrole Oxazolyl, isoxazolyl, isothiazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, benzofuranyl, benzo Pyranose, 1 (4H)-benzopyranyl, 1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl and 2,3-bis- The group of hydrogen-1 (4H)-benzopyranyl；Wherein said heteroaryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this takes Dai Ji is selected from halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkoxyl or C_1-4Alkylthio group；For be Te Bie furyl, thienyl, Pyridine radicals, benzopyranyl, 1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl and 2,3-dihydro-1 (4H)-benzopyranyl；Wherein said heteroaryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen Element, oxo or C_1-4Alkyl；

--L is in the meta or para position of benzyl ring, and this is to come relative to the combination of described benzyl ring with molecule remainder Say, such as-the COOR shown in Formula II a and IIb²¹Group；

-collateral condition is to be direct key and T is-O-R as L²¹, and wherein R²¹It is unsubstituted C_1-20During alkyl, described L-(C=O)-T be in the meta or para position of benzyl ring, this is to come relative to the combination of described benzyl ring with molecule remainder Say, such as-the COOR shown in Formula II a and IIb²¹Group；

The compound that the present invention attracts people's attention is the compound of formula (Ib)

Wherein；

R¹It is to select self-contained group hydrogen, C_1-4Alkyl or C_3-6Cycloalkyl；

Ar is selected from comprising following group:

Wherein X is selected from the group comprising hydrogen or halogen；

Z is selected from comprising-O-；-NR⁵-；And-NR⁵-C (=O)-bilvalent radical；

W represents C_1-6Alkyl, it can be selected from-O-Het²；-S-Het³；Or C (=O)-NR³R⁴Substituent replace；And

Wherein R³、R⁴、R⁵、Het²And Het³Be defined as in any foregoing embodiments to the compound in Formulas I or Ia Defined those.

In one of them embodiment of the present invention, Formulas I b compound is further characterized by

-R³Group selected from following: hydrogen: C_1-20Alkyl, they can be optionally substituted by 1,2 or 3 substituents, this substituent Separately selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³； C_1-6Alkyl-S-and C_1-6The group of alkyl-O-；R for Te Bie³It is hydrogen；

-R⁴Selected from comprising C_1-20The group of alkyl, they are replaced by 1,2 or 3 substituents, and this substituent is separately Selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³；C_1-6Alkyl-S- And C_1-6The group of alkyl-O-；R for particularly⁴Selected from comprising C_1-20The group of alkyl, they are taken by 1,2 or 3 substituents In generation, this substituent is separately selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O- Het²；And-S-Het³Group；Or；

-R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is replaced by a substituent, and the choosing of this substituent From including-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；-S-Het³；Or C_1-6Alkyl Group；Wherein said C_1-6Alkyl is replaced by 1,2 or 3 substituents, this substituent separately selected from comprise-C (=O)- OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；-O-Het²；And-S-Het³Group；R for Te Bie³And R⁴With it The nitrogen-atoms that is connected form heterocycle together, it is replaced by a substituent, and this substituent is selected from including-C (=O)-OR²¹；- C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；Or C_1-6The group of alkyl；Wherein said C_1-6Alkyl is by 1,2 or 3 replacements Base replaces, and this substituent is separately selected from comprising Het¹；-O-Het²；And-S-Het³Group；

-R⁵It is hydrogen；

-R⁷Or R⁸Separately selected from following group: hydrogen；Or C_1-6Alkyl, they are replaced by 1,2 or 3 substituents, This substituent is separately selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；And-C (=O)-NH₂Group Not；R for Te Bie⁷Or R⁸Separately selected from following group: hydrogen；Or C_1-6Alkyl, they are taken by 1,2 or 3 substituents In generation, this substituent is separately selected from comprising-C (=O)-OR²¹；And-C (=O)-NH₂Group；

-R⁹Or R¹⁰Separately selected from following group: hydrogen；Or C_1-6Alkyl, they by 1,2 or 3-C (=O)- OR²¹Substituent is replaced；

-R¹³Or R¹⁴Separately selected from comprising hydrogen；C_1-6Alkyl；C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-；C_1-6Alkane Base-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-group；And wherein said C_1-6Alkyl；C_1-6Alkyl-O-C_1-6Alkyl-； C_1-6Alkyl-S-C_1-6Alkyl-；Or C_1-6Alkyl-C (=O)-each replaced by 1,2 or 3 substituents, this substituent is independently Ground is selected from comprising-C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²；And-S-Het³Group；

-R²¹Group selected from following: C_1-20Alkyl；C_1-20Thiazolinyl；C_1-20Alkynyl；Optionally substituted C_3-15Cycloalkyl；Optionally Substituted heterocyclic radical；And optionally substituted aryl；

-wherein said C_1-20Alkyl can be optionally substituted by 1,2,3 or more substituents, and this substituent is selected from following Group: halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-C (=O)-NR¹³R¹⁴、- O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-15Cycloalkyl or be selected from down Formula:

-Or

-R²¹The cyclic ester of following formula is formed together with the carbonyloxy group being connected with them and phenyl

-

-wherein q be the integer from 1 to 6；

-R²²It is C_1-20Alkyl, can be optionally substituted by 1,2,3 or more halogenic substituents；

Het¹、Het²Or Het³Separately selected from comprising following group；

In further embodiment, the invention provides the compound of formula (Ib), but have following one or more Limit；

-R³It is hydrogen；

-R⁴It is to be selected from-O-Het², or-S-Het³Substituted-the C of substituent_1-6Alkyl；In certain embodiments, institute The Het stated²Or Het³Selected from comprising following group

In preferred embodiments, the invention provides Formula II a, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa、IIb、IIIb、IVb、Vb、VIb、VIIb、VIIIb、IXb、Xb、XI、XII、XIII、XIV、XV、XVI、XVII、XVIIIa、 The compound of XIXa, XXa, XXIa, XXIb, XXIIa, XXIIIa or XXIVa.

Wherein；

Q is the integer from 2 to 6；

R¹¹It is substituted C_1-6Alkyl, or substituted-C_2-8Thiazolinyl；Described-C_1-6Alkyl and-C_2-8Thiazolinyl is separately Being substituted with a substituent, this substituent is selected from including C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；Het¹；-O- Het²；And-S-Het³Group；

R¹²It is substituted C_1-6Alkyl, substituted C_1-6Alkyl-S-C_1-6Alkyl or substituted-C_2-8Thiazolinyl；Described-C_1-6 Alkyl, C_1-6Alkyl-S-C_1-6Alkyl and-C_2-8Thiazolinyl is separately replaced by 1,2 or 3 substituents, and this substituent is the most solely On the spot selected from comprising aryl, heteroaryl, C_3-6Cycloalkenyl group ,-C (=O)-OR²¹；-C (=O)-SR²²；Het¹；-O-Het²；And-S- Het³Group；And

Wherein Ar, R¹、R²¹、R²²、R³、R⁴、R⁵、R⁶、Het¹、Het²And Het³There is previously herein defined identical culvert Justice.

The compound of the present invention can be prepared according to the reaction scheme that following example are provided, but the professional people of this area Member would appreciate that these are all only used as the demonstration of the present invention, and the compound of the present invention can be according to any organic chemistry professional Working standard synthesis technique prepare.

In preferred embodiments, the compound of the present invention can be used as inhibitors of kinases, particularly for be to be at least One ROCK kinases provides inhibitory action, selected from ROCKI and ROCKII, particularly for be soft ROCK inhibitor.

The present invention still further provides use of a compound as defined above or the composition work comprising described compound For the mankind or the purposes of veterinary medicament, especially for be for preventing and/or treat at least one disease relating to ROCK or barrier Hinder, such as with the function of smooth muscle cell, inflammation, fibrillatable, excessive cell proliferation, Angiogenesis excessively, high response, screen Barrier dysfunction, nerve degeneration pathology, function, inflammation, fibrillatable, excessive cell proliferation, Angiogenesis reaction excessive, high Property, barrier dysfunction, nerve degeneration pathology and reinvent relevant disease.

In further embodiment, the invention provides use of a compound as defined above or comprise described chemical combination The composition of thing is used for treating and/or prevent at least one to be selected from eye illness, breathing problem, throat, nose and ear disease, intestines Tract disease, angiocardiopathy and the disease of vascular diseases, diseases associated with inflammation, nervous system and central nervous system disease and/or Obstacle: proliferative disease, kidney trouble, sex dysfunction, disease in the blood system, skeletal diseases, diabetes, benign prostate increase Raw disease, graft-rejection, liver diseases, systemic loupus erythematosus, spasm, hypertension, chronic obstructive bladder disease, early Product, infection, allergy, obesity, pancreatic disease and AIDS.

In preferred embodiments, the invention provides use of a compound as defined above or comprise described compound Composition be used for treating and/or preventing disease of eye, including but not limited to PVR, optic neuropathy, green light Eye and retina DD, such as macular degeneration, retinal pigment degeneration and inflammatory eye conditions, and/or be used for preventing, treatment And/or alleviate complication and/or relative symptom.

For Te Bie, these compounds are selected from comprising following group；

The Y of compound of formula I is the aryl or heteroaryl being substituted with a substituent, this substituent selected from include-C (=O)- OR²¹；-C (=O)-SR²²；-C (=O)-NR³R⁴；-O-C_1-6Alkyl；Or-C_1-6The group of alkyl；Wherein said-O-C_1-6Alkane Base or-C_1-6Alkyl is separately substituted with a substituent；This substituent is selected from including-C (=O)-OR²¹, and Het¹Group； And R⁴It is to be selected from-C (=O)-OR²¹,-C (=O)-SR²², or Het¹Substituted-the C of substituent_1-6Alkyl；And

Formulas I a compound, wherein Ar represents

Wherein X is hydrogen or halogen；

-L is direct key, C_1-4Alkyl or-O-C_1-4Alkyl；

-T is-O-R²¹Or-NR³R⁴

-R¹Represent hydrogen or C_1-4Alkyl；

-R³It is hydrogen；

-R⁴It is to be selected from-C (=O)-OR²¹,-C (=O)-SR²²,-C (=O)-NR⁷R⁸, or Het¹Substituent substituted- C_1-6Alkyl；-C for Te Bie_1-6Alkyl is selected from-C (=O)-OR²¹Or Het¹Substituent replace；In specific embodiment In, described R²¹It is-C_1-6Alkyl；Or

-R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is by C_1-6Alkyl replaces；Wherein said C_1-6Alkyl Being replaced by 1,2 or 3 substituents, this substituent is separately selected from comprising-C (=O)-OR²¹；And-C (=O)-NR⁹R¹⁰'s Group；

-R⁹Or R¹⁰Separately selected from comprising hydrogen or C_1-6The group of alkyl；Described C_1-6Alkyl by 1,2 or 3-C (= O)-OR²¹Substituent is replaced；

-R²¹Selected from comprising C_1-20Alkyl；Optionally substituted C_3-10Cycloalkyl；Optionally substituted aryl；And it is optionally substituted The group of heterocyclic radical；Wherein said C_1-20It is optionally substituted that alkyl can be replaced base, and this substituent is selected from: halogen, cyano group, hydroxyl Base ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heterocyclic radical and C_3-10Cycloalkyl, or following formula:

-heterocyclic radical used herein selected from comprise piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, piperazinyl, 1, 3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, The group of tetrahydrofuran base and hexahydro furyl also [3,2-b] furyl；For be Te Bie piperidyl, 1,3-dioxane Base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base；

-optionally substituted C used herein_3-10Cycloalkyl is selected from comprising cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cycloheptyl Base, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and the group of ring decyl, the most preferably cyclopropyl, ring Amyl group, cyclohexyl, adamantyl and dicyclo (2,2,1) heptane；Wherein said C_3-10Cycloalkyl can be by 1,2,3 or more polysubstituted Base is optionally substituted, especially for be 1,2 or 3；It is 1 or 2 for particularly；It is 1 for the most special；This substituent selects From halogen, hydroxyl, oxo, nitro, amino, cyano group, C_1-4Alkyl, C_3-6Cycloalkyl, C_1-4Alkoxyl, or-SO₂-NH₂,

-optionally substituted heterocycle used herein is selected from comprising piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, piperazine Piperazine base, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, tetrahydrochysene The group of pyranose, tetrahydrofuran base and hexahydro furyl also [3,2-b] furyl；For be Te Bie piperidyl, 1,3-dioxa Cyclohexyl, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base；Wherein said heterocyclic radical can be taken by 1,2,3 or more Replace for base, especially for be 1: this substituent is selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, amino carbonyl, nitrine Base, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkyl-alkyl, alkyl amino, alkoxyl ,-SO₂-NH₂, aryl, heteroaryl, Aralkyl, haloalkyl, halogenated alkoxy, alkoxy carbonyl group, alkyl amino-carbonyl, heteroaryl alkyl, alkyl sulfonamide, heterocycle Base, alkylcarbonylaminoalkyl, aryloxy group, alkyl-carbonyl, acyl group, aryl carbonyl, amino carbonyl, alkyl sulfoxide ,-SO₂R^a, alkane Sulfenyl, the group of carboxyl and similar, wherein R^aIt it is alkyl or cycloalkyl；It is preferably selected from halogen, hydroxyl, oxo, nitro, ammonia Base, cyano group, C_1-4Alkyl, C_3-6Cycloalkyl, C_1-4Alkoxyl, or-SO₂-NH₂,

-aryl used herein is selected from comprising phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl or 1, the group of 2,3,4-tetralyls Not；Wherein said aryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen, nitro, C_1-4Alkane Base, C_1-4Alkoxyl, or C_1-4Alkylthio group；It is phenyl or 1 for Te Bie, 2,3,4-tetralyls；Wherein said aryl can quilt 1,2,3,4 or 5 substituents are optionally substituted, and this substituent is selected from halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkoxyl or C_1-4 Alkylthio group；For particularly, phenyl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen, nitro, C_1-4 Alkyl, C_1-4Alkoxyl or C_1-4Alkylthio group；

-heteroaryl used herein is selected from comprising furyl, thienyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrrole Oxazolyl, isoxazolyl, isothiazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical, benzofuranyl, benzo Pyranose, 1 (4H)-benzopyranyl, 1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl and 2,3-bis- The group of hydrogen-1 (4H)-benzopyranyl, wherein said heteroaryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this takes Dai Ji is selected from halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkoxyl or C_1-4Alkylthio group；For be Te Bie furyl, thienyl, Pyridine radicals, benzopyranyl, 1 (2H)-benzopyranyl, 3,4-dihydro-1 (2H)-benzopyranyl and 2,3-dihydro-1 (4H)-benzopyranyl；Wherein said heteroaryl can be optionally substituted by 1,2,3,4 or 5 substituents, and this substituent is selected from halogen Element, oxo or C_1-4Alkyl；

It is particularly useful in treatment and/or prevention disease of eye, including but not limited to PVR, optic neuropathy Become, glaucoma and retina DD, such as macular degeneration, retinal pigment degeneration and inflammatory eye conditions, and/or for pre- Anti-, treat and/or alleviate complication and/or relative symptom.Therefore, it is an object of the invention to provide described chemical combination Thing, for treatment and/or prevention disease of eye, including but not limited to PVR, optic neuropathy, glaucoma and Retina DD, such as macular degeneration, retinal pigment degeneration and inflammatory eye conditions, and/or prevention, treat and/or alleviate Complication and/or relative symptom；It it is treatment glaucoma for particularly.In addition one it is to provide for for treating And/or prevention is selected from the method for disease of eye of following group, wherein contain PVR, optic neuropathy, glaucoma, The retina DD of inflammatory eye conditions, such as macular degeneration and retinal pigment degeneration；It is preferably glaucoma；Described method Including the formula I to patient therapeuticallv's effective dose in need；It is chemical combination as defined above for Te Bie Thing.

In another preferred embodiment, the invention provides compound as defined above or comprise described compound Composition for treating and/or prevent the purposes of breathing problem；Including but not limited to pulmonary fibrosis, pulmonary emphysema, slow Property bronchitis, asthma, fibrillatable, pneumonia, capsule fibroid become sick, chronic obstructive pulmonary disease (COPD)；Bronchitis and nose Inflammation and Respiratory Distress Syndrome(RDS), and/or prevent, treat and/or alleviate complication and/or relative symptom.

For Te Bie, these compounds are selected from comprising following group；

Compound of formula I, wherein Y is the aryl or heteroaryl being substituted with a substituent, this substituent selected from include-C (= O)-NR³R⁴；-NR⁵R⁶；-O-C_1-6Alkyl；Or-C_1-6The group of alkyl；Wherein said-O-C_1-6Alkyl or-C_1-6Alkyl is respectively It is substituted with a substituent independently；This substituent is selected from including-C (=O)-NR³R⁴、-O-Het²And S-Het³Group；Specific Embodiment in, described Het²Or Het³Separately selected from comprising following group；

And

Formulas I a compound, wherein Ar represents

Wherein X is hydrogen or halogen；

-L is direct key, C_1-4Alkyl, or-O-C_1-4Alkyl；

-T is-O-R²¹Or-NR³R⁴；

-R¹Represent hydrogen or C_1-4Alkyl；

-R³It is hydrogen；

-R⁴It is to be selected from-O-Het², or-S-Het³Substituted-the C of substituent_1-6Alkyl；In certain embodiments, Described Het²Or Het³Selected from comprising following group

-Het²Or Het³Separately selected from comprising following group；

And

The compound of Formulas I b；

It is particularly useful in treatment and/or prevention breathing problem；Including but not limited to pulmonary fibrosis, pulmonary emphysema, slow Property bronchitis, asthma, fibrillatable, pneumonia, capsule fibroid become sick, COPD (COPD)；Bronchitis and Rhinitis and Respiratory Distress Syndrome(RDS), and/or prevent, treat and/or alleviate complication and/or relative symptom.Therefore, originally The purpose of invention is to provide described compound, for treatment and/or prevention breathing problem；Including but not limited to lung Fibrillatable, pulmonary emphysema, chronic bronchitis, asthma, fibrillatable, pneumonia, capsule fibroid become sick, chronic obstructive pulmonary disease (COPD)；Bronchitis and rhinitis and Respiratory Distress Syndrome(RDS), and/or prevention, treat and/or alleviate complication and/or and its Relevant symptom.In addition one it is to provide for for the method treated and/or prevent breathing problem；Including but do not limit Sick, chronic obstructive pulmonary disease is become in pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrillatable, pneumonia, capsule fibroid (COPD)；Bronchitis and rhinitis and Respiratory Distress Syndrome(RDS), described method includes patient therapeuticallv in need effective The formula I of amount；It it is compound as defined above for Te Bie.

In further embodiment, the invention provides compound as defined above or comprise described compound Composition is for treating and/or prevent the purposes of angiocardiopathy and vascular diseases: includes but not limited to cerebral vasoconstriction, fill Note, anoxic peripheral circulation disease, myocardial hypertrophy Acute Stroke, congestive heart failure, cardiovascular and cerebrovascular ischemic, heart disease, the heart Dirty reinvent, angina pectoris, coronarospasm, cerebral angiospasm, ISR, hypertension, pulmonary hypertension, Pulmonary Vascular shrink, dynamic Pulse atherosclerosis, atherosclerotic, aneurysm, hemorrhage, Raynand's disease, thrombosis (including deep layer thrombosis) and blood are little Plate relevant disease, and/or prevention, treat and/or alleviate complication and/or relative symptom and/or alleviate complication and/ Or relative symptom.

In further embodiment, the invention provides compound as defined above or comprise described compound Composition is for treating and/or prevent throat, nose and the purposes of ear disease: include but not limited to that sinus problem, hearing are asked Topic, tonsillitis, toothache, ulcer and rhinitis,

In further embodiment, the invention provides compound as defined above or comprise described compound Composition is for treating and/or prevent the purposes of disease of skin: include but not limited to that hyperkeratinization, parakeratosis, stratum granulosum increase Thickness, acanthosis, dyskeratosis, spongiosis and ulcer.

In further embodiment, the invention provides compound as defined above or comprise described compound Composition is for treatment and/or the purposes of prevention of intestinal tract disease；Include but not limited to IBD (JBD), colitis, stomach and intestine Inflammation, intestinal obstruction, ileitis, appendicitis and Crohn disease.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing is for treatment and/or the purposes of preventing inflammatory disease: include but are not limited to contact dermatitis, allergic dermatitis, ox-hide Tinea, rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis arthropathica, inflammatory bowel disease, Crow grace Sick and ulcerative colitis, and/or prevention, treat and/or alleviate complication and/or relative symptom and/or inflammation is anti- Should.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing is for preventing, treat and/or manage the purposes of nervous system and central nervous system disease: include but not limited to apoplexy, brain Film is scorching, faint from fear, brain or spinal cord injury and inflammatory and the demyelinating disease of such as Alzheimer's disease, multiple sclerosis and god Through property pain.The compound of the present invention also thus is applicable to prevent nerve degenerative diseases and the stimulation of various the nervous system disease Nerve regneration, and/or prevent, treat and/or alleviate complication and/or relative symptom.

In another embodiment, the invention provides compound as defined above or comprise the group of described compound Compound is used for treating and/or preventing proliferative disease: such as but not limited to brain (glioma) mammary gland, colon, intestines, skin, Head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate or thyroid cancer；Castleman's disease, white blood Disease, sarcoma, lymthoma；Malignocytoma (malignoma) and melanoma；And/or prevent, treat and/or alleviate complication And/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing is for treating and/or prevent the purposes of kidney trouble: include but not limited to kidney region fibrosis or renal insufficiency；And/or Prevent, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing is for treatment and/or preventative handicapped purposes: include but not limited to sexual disorder, bladder disease, hypertension, sugar Urine disease or operation on pelvis sequelae；And/or prophylactic treatment is by the sex dysfunction using some drugs to cause, such as, it is used for treating The medicine of hypertension, depression or anxiety.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing is for treating and/or prevent the purposes of hematologic disease: include but not limited to kidney region fibrosis or renal insufficiency；And/or Prevent, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing is for treating and/or prevent the purposes of skeletal diseases: include but not limited to osteoporosis and osteoarthritis；And/or prevention, Treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing is for treating and/or prevent the purposes of diabetes: include but not limited to hyperglycaemia and type 1 diabetes；And/or prevention, treatment And/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing for treating and/or prevent the purposes of following disease, such as benign prostate hyperplasia, graft-rejection, liver diseases, Systemic loupus erythematosus, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreas disease Sick and the disease of AIDS and/or obstacle, and/or prevention, treat and/or alleviate complication and/or relative symptom.

In preferred embodiments, the invention provides compound as defined above or comprise the group of described compound Compound is for treatment and/or the purposes of preventing glaucoma, asthma, sex dysfunction or chronic obstructive pulmonary disease.

Invention further provides compound as defined above or comprise the composition of described compound, for controlling Treat and/or prevent the purposes of at least one following disease, include eye illness, breathing problem, angiocardiopathy and vascular diseases, The disease of diseases associated with inflammation, nervous system and central nervous system disease and/or obstacle: proliferative disease, kidney trouble, property merit Can obstacle, disease in the blood system, skeletal diseases, diabetes, benign prostate hyperplasia, graft-rejection, liver diseases, be System property lupus erythematosus, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease And AIDS.

In preferred embodiments, it is provided that as defined above compound or comprise the composition of described compound, For treatment and/or prevention disease of eye, including but not limited to PVR, optic neuropathy, glaucoma with regard Nethike embrane DD, such as macular degeneration, retinal pigment degeneration and inflammatory eye conditions, and/or prevention, treat and/or alleviate also Send out disease and/or relative symptom.

In another preferred embodiment, it is provided that as defined above compound or comprise the combination of described compound Thing, for treatment and/or prevention breathing problem；Including but not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchial Inflammation, asthma, fibrillatable, pneumonia, capsule fibroid become sick, COPD (COPD)；Bronchitis and rhinitis and exhale Inhale Distress syndrome, and/or prevent, treat and/or alleviate complication and/or relative symptom.

In further embodiment, the invention provides compound as defined above or comprise described compound Composition, for treatment and/or prevention angiocardiopathy and vascular diseases: include but not limited to cerebral vasoconstriction, Reperfu-sion, Anoxic peripheral circulation disease, myocardial hypertrophy Acute Stroke, congestive heart failure, cardiovascular and cerebrovascular ischemic, heart disease, heart weight Mould, angina pectoris, coronarospasm, cerebral angiospasm, ISR, hypertension, pulmonary hypertension, Pulmonary Vascular shrink, artery congee Sample hardening, atherosclerotic, aneurysm, hemorrhage, Raynand's disease, thrombosis (including deep layer thrombosis) and blood platelet phase Related disorders, and/or prevention, treat and/or alleviate complication and/or relative symptom and/or alleviate complication and/or with Its relevant symptom.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing, for treatment and/or preventing inflammatory disease: include but are not limited to contact dermatitis, allergic dermatitis, psoriasis, Rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriasis arthropathica, inflammatory bowel disease, Crohn disease and Stain ulcer colitis, and/or prevent, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing, for treating and/or prevent nervous system and central nervous system disease: include but not limited to apoplexy, meningitis, shy Faint, brain or spinal cord injury and inflammatory and the demyelinating disease of such as Alzheimer's disease, multiple sclerosis and nerve pain Bitterly.The compound of the present invention also thus be applicable to prevent the nerve degenerative diseases of various the nervous system disease and stimulate nerve again Raw, and/or prevent, treat and/or alleviate complication and/or relative symptom.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing, for treatment and/or prevention proliferative disease: such as but not limited to brain (glioma) mammary gland, colon, intestines, skin, Head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate or thyroid cancer；Castleman's disease, white blood Disease, sarcoma, lymthoma: malignocytoma (malignoma) and melanoma；And/or prevent, treat and/or alleviate complication And/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the group of described compound Compound, for treatment and/or prevention kidney trouble: include but not limited to kidney region fibrosis or renal insufficiency；And/or it is pre- Prevent, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the group of described compound Compound is for preparing treatment and/or the purposes of preventative handicapped medicine: include but not limited to sexual disorder, bladder disease Disease, hypertension, diabetes or operation on pelvis sequelae；And/or prophylactic treatment is by the sex dysfunction using some drugs to cause, Such as treating the medicine of hypertension, depression or anxiety.

In another embodiment, the invention provides compound as defined above or comprise the combination of described compound Thing, for treatment and/or prevention hematologic disease: include but not limited to kidney region fibrosis or renal insufficiency；And/or it is pre- Prevent, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the group of described compound Compound, for treatment and/or prevention skeletal diseases: include but not limited to osteoporosis and osteoarthritis；And/or prevention, Treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the group of described compound Compound, for treatment and/or prevention diabetes: include but not limited to hyperglycaemia and type 1 diabetes；And/or prevention, treatment And/or alleviate complication and/or relative symptom and/or inflammatory reaction.

In another embodiment, the invention provides compound as defined above or comprise the group of described compound Compound, for treating and/or prevent such as benign prostate hyperplasia, graft-rejection, liver diseases, systematicness erythema Lupus, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease and AIDS Disease and/or obstacle, and/or prevention, treat and/or alleviate complication and/or relative symptom.

In preferred embodiments, the invention provides compound as defined above or comprise the group of described compound Compound, for treatment and/or preventing glaucoma, asthma, sex dysfunction or chronic obstructive pulmonary disease.

Methods for the treatment of

The invention further provides for treatment and/or prevent at least one to include eye illness, breathing problem, painstaking effort Pipe disease and the disease of vascular diseases, diseases associated with inflammation, nervous system and central nervous system disease and/or the method for obstacle: Proliferative disease；Kidney trouble；Sex dysfunction；Disease in the blood system；Skeletal diseases；Diabetes；Benign prostate hyperplasia； Graft-rejection；Liver diseases；Systemic loupus erythematosus；Spasm；Hypertension；Chronic obstructive bladder disease；Premature labor: sense Dye；Allergy；Obesity；Pancreatic disease and AIDS；Described method includes patient in need's administering therapeutic effective dose Defined herein compound or composition.

In preferred embodiments, the invention provides treatment and/or prevention disease of eye method, including but It is not limited to PVR, optic neuropathy, glaucoma and retina DD, such as macular degeneration, retinal pigment change Property and inflammatory eye conditions；Described method includes the defined herein compound to patient in need's administering therapeutic effective dose or group Compound.

In another preferred embodiment, the present invention provides one for the side treating and/or preventing breathing problem Method；Become including but not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrillatable, pneumonia, capsule fibroid Sick, COPD (COPD)；Bronchitis and rhinitis and Respiratory Distress Syndrome(RDS), described method includes there being this to need The defined herein compound of the patient therapeuticallv's effective dose wanted or composition.

In another embodiment, the invention provides a treatment and/or prevention angiocardiopathy and vascular diseases Method: include but not limited to cerebral vasoconstriction, Reperfu-sion, anoxic peripheral circulation disease, myocardial hypertrophy Acute Stroke, congested Heart failure, cardiovascular and cerebrovascular ischemic, heart disease, heart reconstruction, angina pectoris, coronarospasm, cerebral angiospasm, the narrowest Narrow, hypertension, pulmonary hypertension, Pulmonary Vascular contraction, atherosclerotic, atherosclerotic, aneurysm, hemorrhage, Lei Nuoshi Disease, thrombosis (including deep layer thrombosis) and blood platelet relevant disease；Described method includes executing patient in need With defined herein compound or the composition of therapeutically effective amount.

In another embodiment, the invention provides one treatment and/or the method for preventing inflammatory disease: include but It is not limited only to contact dermatitis, allergic dermatitis, psoriasis, rheumatoid arthritis, juvenile rheumatoid arthritis, rigid spine Inflammation, psoriasis arthropathica, inflammatory bowel disease, Crohn disease and ulcerative colitis；Described method includes the trouble having these needs The defined herein compound of person's administering therapeutic effective dose or composition.

In another embodiment, the invention provides a treatment and/or prevention nervous system and central nervous system The method of disease: include but not limited to apoplexy, meningitis, convulsions, brain or spinal cord injury and inflammatory and such as Alzheimers The demyelinating disease of disease, multiple sclerosis and neuropathic pain.The compound of the present invention also thus is applicable to prevent various god Nerve degenerative diseases and stimulating neural regeneration through systemic disease；Described method includes patient in need's administering therapeutic The defined herein compound of effective dose or composition.

In another embodiment, the invention provides one treatment and/or prevention proliferative disease method: such as but It is not limited to brain (glioma), mammary gland, colon, intestines, skin, head and neck, nerve, ovary, kidney, lung, liver, uterus, pancreas Gland, prostate or thyroid cancer；Castleman's disease, leukaemia, sarcoma, lymthoma；Malignocytoma (malignoma) and Melanoma；Described method includes the defined herein compound to patient in need's administering therapeutic effective dose or combination Thing.

In another embodiment, the invention provides one treatment and/or prevention kidney trouble method: include but not It is limited to kidney region fibrosis or renal insufficiency；Described method includes to patient in need's administering therapeutic effective dose herein The compound of definition or composition.

In another embodiment, the invention provides one treatment and/or preventative handicapped method: include but It is not limited to sexual disorder, bladder disease, hypertension, diabetes or operation on pelvis sequelae；And/or prophylactic treatment is by using certain A little drug-induced sex dysfunctions, such as treating the medicine of hypertension, depression or anxiety；Described method includes there being this The defined herein compound of the patient therapeuticallv's effective dose needed or composition.

In another embodiment, the invention provides one treatment and/or prevention hematologic disease method: include but not It is limited to kidney region fibrosis or renal insufficiency；Described method includes to patient in need's administering therapeutic effective dose herein The compound of definition or composition.

In another embodiment, the invention provides one treatment and/or prevention skeletal diseases method: include but not It is limited to osteoporosis and osteoarthritis；It is defined herein that described method includes patient in need's administering therapeutic effective dose Compound or composition.

In another embodiment, the invention provides a treatment and/or the method for prevention diabetes: include but do not limit In hyperglycaemia and type 1 diabetes；Described method includes the defined herein change to patient in need's administering therapeutic effective dose Compound or composition.

In another embodiment, the invention provides a treatment and/or prevent such as benign prostate hyperplasia, shifting Plant rejection, liver diseases, systemic loupus erythematosus, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, The method of allergy, obesity, pancreatic disease and AIDS；Described method includes patient in need's administering therapeutic effective The defined herein compound of amount or composition.

In preferred embodiments, the invention provides a treatment and/or preventing glaucoma, asthma, property function barrier Hinder or the method for chronic obstructive pulmonary disease；It is defined herein that described method includes patient in need's administering therapeutic effective dose Compound or composition.

In the ROCK inhibition analysis that the present invention will particularly preferably be described below can with less than 10 μMs, preferably smaller than 1 μM IC₅₀The compound of formula I of value suppression ROCK or its any subgroup.

Described inhibitory action is it may happen that in external and/or internal, when betiding internal, preferably to be as defined above Selective mode carry out.

The patient's condition of mediation " ROCK " used herein or " disease ", any disease referring to be known to play a role or other Harmful situation." patient's condition of ROCK mediation " used herein or " disease " also refer to reach to alleviate by ROCK inhibitor make Disease or the patient's condition.Correspondingly, another embodiment of the invention relates to ROCK and plays a role lower treatment or alleviate Individual or the seriousness of more disease.

In terms of medicinal usage, the compound of the present invention can be used as free acid or alkali and/or with pharmaceutically acceptable acid The form of addition/or base addition salts (such as: obtained by avirulent organic or inorganic acid or alkali), hydrate, solvate and/ Or compound, and/or with the prodrug of esters or pro-drug form.Outside indicating, " solvate " the most used herein art Language refer to any the compounds of this invention and suitable inorganic solvent (such as: hydrate) or organic solvent (such as but not limited to alcohols, Ketone, esters and similar) combining form of formation.Professional will be clear from this kind of salt, hydrate, solvate etc. and It is prepared；The reference of salt, hydrate, solvate etc. is found in such as US-A-6,372,778, US-A-6,369,086, US- A-6,369,087 and US-A-6,372,733.

Pharmaceutically-acceptable salts compound according to the present invention, i.e. presents with water, oil-soluble or dispersible products form, Include the quaternary ammonium salt of conventional non-toxic salts or formation, such as: from inorganic or organic acid or base.This kind of example adding hydrochlorate Include acetic acid, adipic acid, sodium alginate, asparatate, benzoic acid, benzene, niter cake, butyric acid, citric acid, camphor tree, camphor tree Brain, cyclopentane propionate, gluconic acid, lauryl sodium sulfate, ethyl sulfonic acid, fumaric acid, enanthic acid, glycerine, isourea sulfate, heptan, Caproic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, 2-isethionic acid, dairy products, maleic acid, sulfonic acid, 2-naphthalene sulfonic acids, nicotine, oxalic acid Salt, pamoate, pectin, persulfate, 3-phenylpropyl alcohol, picrate, pivalic acid, propionic acid, butanedioic acid, tartaric acid, rhodanate, right Toluenesulfonic acid, undecanoic acid.Alkali salt includes the alkaline earth of the alkaline metal salt of ammonium salt, such as sodium and sylvite, such as calcium salt and magnesium salts Organic base salt, N-methyl-D-glucarnine and such as arginine, the lysine etc. of metallic salt, such as dicyclohexyl amine salt Deng amino acid whose salt.Carry out quaternized additionally, the group Han basic nitrogen may be used to lower reagent, such as elementary alkyl halide, such as first The chloride of base, ethyl, propyl group and butyl, bromide and iodide；Dialkyl sulfate such as dimethyl, diethyl, dibutyl With diamyl sulfate；Long chain halide, such as decyl, lauryl, myristyl and stearyl chlorides, bromide and iodide； Aralkyl halide, such as benzyl and phenylethyl bromide etc..Other pharmaceutically acceptable salts include the sulfate of ethanol And sulfate.

For pharmaceutical applications, the compound of the present invention can be made as comprising at least one the compounds of this invention And at least one pharmaceutically acceptable carrier, diluent or excipient and/or assistant agent, other pharmacy the most one or more The pharmaceutical preparation of reactive compound or pharmaceutical composition.

By the way of non-limiting examples, this kind of preparation may be with applicable oral administration, parenteral dispenser (as passed through vein Injection, intramuscular injection or hypodermic injection or drip-feed), local drug delivery (including eye), inhalation, skin patch, implantation The form of thing, suppository etc. gives.This kind of suitable pesticide supplying form-based on administering mode, it may be possible to solid, semisolid or liquid Form-with and preparation method thereof and for the carrier of preparation process, diluent and auxiliary material, the most known to professional；Can join See such as US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, and such as Remington ' s Pharmaceutical such the manual of standards of Sciences latest edition.

Some preferred but nonrestrictive example of this kind of preparation includes tablet, pill, powder, lozenge, sachet, sachet Medicament, elixir, suspension, emulsion, solution, syrup, spray, ointment, creme, lotion, soft or hard capsule, suppository, eye drops, nothing The powder of bacterium injection and aseptic packaging (needing to rebuild before generally using) for use as bolus administration and/or continuously to Medicine, it is possible to prepare with itself being applicable to the carrier of these preparations, excipient and diluent, such as lactose, glucose, sugarcane Sugar, sorbierite, mannitol, starch, Arabic gum, calcium phosphate, alginate, bassora gum, gelatin, calcium silicates, microcrystalline cellulose Element, polyvinylpyrrolidone, polyethylene glycol, cellulose, water (aseptic), methylcellulose, methyI-oropvD hydroxybenzoate, talcum Powder, magnesium stearate, edible oil, vegetable oil and mineral oil or its suitable mixture.Preparation can optionally comprise other drug and live Property material (or may may produce synergy with the compound of the present invention) and in pharmaceutical preparation conventional other Material such as lubricant, wetting agent, emulsifying agent and suspending agent, dispersant, disintegrant, filler, filler, antistaling agent, sweetener, tune Taste agent, flux-regulating agent, releasing agent etc..Said composition can also be made into preparation, to provide quickly, continue or postpone wherein institute Release containing reactive compound, such as, use liposome or hydrophilic macromolecule base based on natural gel or synthetic polymer Matter.In order to strengthen compound solubility and/or the stability of pharmaceutical composition of the present invention, use α, β-and gamma-cyclodextrin and Derivative will bring benefit.Coupling collar dextrin and derivative thereof carry out the interesting mode of preparation compound and see EP-A-721,331.For Te Bie, the pharmaceutical composition of the present invention contains the compounds of this invention of effective dose and pharmaceutically may be used The cyclodextrin accepted.

Additionally, the cosolvent of such as alcohols can improve solubility and/or the stability of compound.Preparing waterborne compositions Time, the salt adding the compounds of this invention will be more suitable, this is because their water solubility is higher.

It is similar to composition known to pyridine carboxamide, formula (and carrier used, excipient, diluent etc.), dispenser Approach etc. are with reference to being found in US-A-4,997,834 and EP-A-0370498.

For pain therapy, the compound of the present invention can locally be used.For local drug delivery, spraying, ointment or transdermal Patch or other compounds being applicable to external application, transdermal and/or intradermal administration form may be more useful.

For ophthalmic applications, solution, gel, tablet and similar would generally use normal saline solution, gel or tax Shape agent is as main carriers.Ophthalmic preparation is it is desirable that prepare with comfortable pH value by suitable buffer system.

For particularly, composition can make the therapeutically effective amount of the solid dispersions comprising the compounds of this invention Grain and the pharmaceutical preparation of one or more pharmaceutically acceptable water-soluble polymers.

Solid-state that " solid dispersions " this term refers to comprise at least two compositions (rather than liquid or gaseous state) system, One of them composition can more or less be evenly dispersed in other one or more compositions.When described composition dispersiveness make be System is unified or homogeneous or single-phase be made up of thermodynamically define everywhere in chemical and physical features, and this kind of solid dispersions will It is referred to as " solid solution ".Solid solution is a kind of preferably physical system, this is because wherein the composition organism to being used is led to It it is often bioavailable.

May bring convenience further with the form preparation compound of nano particle, described nanoparticle has absorption and exists Its surface, be enough to effective average grain diameter is maintained the surface modifier less than 1000nM.Suitably surface modifier is preferred Select known organic and inorganic drug excipient.This kind of excipient includes various polymer, low-molecular weight oligo thing, natural product Thing and surfactant.Preferably surface modifier includes nonionic and anion surfactant.

The interesting mode of another preparation the compounds of this invention includes and compound is mixed hydrophilic polymer In thing, then this mixture is coated on many globules as film, thus produces that can conveniently prepare and have good biological can With the composition of property, and it is applicable to prepare pharmaceutical dosage form for oral use.Being suitable for pearl can be in many as the material of core The form of kind, as long as described material is pharmaceutically acceptable and has suitable size and hardness.The example of this material is poly- Compound, inorganic substances, organic substance, glucide and its ramification.

Said preparation can be prepared in a known manner, this compound being usually directed to mix at least one present invention and one or many Plant pharmaceutically acceptable carrier, can aseptically mix other pharmaceutical active compounds if necessary.Reference Document is found in US-A-6, and 372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, and all Such as Remington ' the s Pharmaceutical such manual of standards of Sciences latest edition.

The pharmaceutical preparation of the present invention is preferably made unit dosage forms or the most packaged, such as box, bubble-cap, bottle, bottle, perfume (or spice) Bag, ampoule or any other suitable single dose or the holder of multiple dose or container (posting suitable label)；Optionally add The upper one or more pamphlets comprising product information and/or operation instruction.In general, this UD will comprise at least one The compounds of this invention between kind between 1 and 1000mg and generally between 5 to 500mg, as per unit dosage about 10,25, 50,100,200,300 or 400mg.

This compound can pass through number of ways dispenser, this include oral cavity, rectum, eye, Transdermal absorption, subcutaneous, vein Injection, intramuscular injection or nasal cavity, depend primarily on specific preparation used and the illness that need to be treated and prevent, and preferred embodiment Usually it is administered orally and intravenously administrable.At least one compound of the present invention is generally so that " effective dose " is used, say, that closing Preferably treatment or the amount of its subgroup of the Formulas I-XXIV of preventive effect or any can be brought for the person of being injected after suitable dispenser.Generally Depending on illness and the drug delivery route that need to be treated and prevent, this effective dose would generally be between per kg patient body weight 0.01 every day To 1000mg, more be often between 0.1 to 500mg, such as between 1 to 250mg, as per kg patient body weight's every day about 5, 10,20,50,100,150,200 or 250mg, it is possible to single dose every day, daily dosage is divided into one or many, or continues It is administered, such as: use and instil.Treatment doctor may be according to such as age, sex, the general status of patient and disease/symptom Character and seriousness determine formulation rate, method of administration and further therapeutic scheme.Bibliography is found in US-A-6,372, 778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, and such as Remington ' s The such manual of standards of Pharmaceutical Sciences latest edition.

According to the method for the present invention, described pharmaceutical composition can be the most respectively in different time dispensers Or simultaneously with separate or single combining form.Therefore, the present invention should be understood to contain all these either simultaneously or alternately Therapeutic scheme, and " " this term will correspondingly be made annotation in dispenser (administration).

For oral form, the composition of the present invention can be mixed into suitable additive, such as excipient, stabilizer or lazy Property diluent, and use usual mode to be converted into suitable pesticide supplying form, such as tablet, coating tablet, hard capsule, water-soluble Liquid, alcohol or oily solution.The example of suitable inert carrier be gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, Glucose or starch, particularly cornstarch.In this case, the preparation of medicine can be to be dried and moist particle two Person.Suitably oiliness excipient or solvent are vegetable oil or animal oil, such as sunflower oil or cod-liver oil.The aqueous solution or alcoholic solution Suitable solvent be water, ethanol, sugar juice or their mixture.Polyethylene glycol and polypropylene glycol are also applied for other dispenser shapes The further auxiliary agent of formula.As the tablet discharged immediately, these compositions can contain microcrystalline cellulose, calcium monohydrogen phosphate, starch, Magnesium stearate and lactose and/or other excipient, adhesive, filler, disintegrant, diluent and lubrication known in the art Agent.

When by nasal aerosol or suction dispenser, these compositions can be according to pharmaceutical preparation known to field Prepared by the technology in field, it is possible to be prepared as salting liquid, uses phenmethylol or other suitable preservatives, sorbefacient to carry High bioavilability, and use fluorocarbon known in the art and/or other solubilizer or dispersant.With aerosol or spray The suitable pharmaceutical formulation of mist agent form dispenser include the compounds of this invention or its pharmaceutically the physiology in acceptable solvent resistance to By solution, suspension or the emulsion of salt, such as ethanol or water, or the mixture of this kind solvent.If needed, said preparation is another Other pharmaceutical auxiliaries, such as surfactant, emulsifying agent, stabilizer and propellant can also be comprised outward.

For hypodermic injection, the compound of the present invention can add usual material if the need arises, the most molten Liquid, suspension or emulsion can add solubilizer, emulsifying agent or further auxiliary agent.The compound of the present invention also can be frozen dry Dry, and acquired lyophilizate can be used for producing parenteral solution or infusion preparation.For example, suitable solvent includes Water, normal saline solution or alcohol, such as ethanol, propyl alcohol, glycerine, also the most molten just like the sugar of glucose solution or mannitol solution Liquid, or the mixture of above-mentioned various solvent.Parenteral solution or suspension can be made according to technology known to field, use Acceptable diluent the most nontoxic, parenteral or solvent, such as mannitol, 1,3-BDO, ringer's solution, water or isotonic Sodium chloride solution, or the dispersant that is suitable for or moistening and suspending agent, the most aseptic, nonirritant, fixed oil, including people The monoglyceride of work synthesis or diglyceride and aliphatic acid, including oleic acid.

When being rectally by suppository routes, these preparations may be by mixing the compounds of this invention and the most non- Excitant auxiliary material is made, such as cocoa butter, Prof. Du Yucang glyceride or polyethylene glycol, they at general temperature in solid-like State, but can liquefy and/or dissolve in rectal cavity, to discharge medicine.

In preferred embodiments, the compound of the present invention and composition are all locally used, for example for office Portion or absorption and non-adsorbed apply.

Said composition has its certain values in veterinary applications, and its purpose not only includes prevention and/or treatment Animal diseases, And be the most important animal such as ox, pig, sheep, chicken, fish etc. promote growth and/or their weight and/or meat or its The quantity of the product that it obtains with animal and/or quality.Therefore, in yet another aspect from the point of view of, the present invention relates to for beast The composition on medical way, said composition comprises at least one the compounds of this invention and at least one suitable carrier (is i.e. suitable for dynamic The carrier that thing uses).The invention further relates to use the compounds of this invention to prepare this based composition.

To be that the present invention is illustrated by following Prof. Du Yucang and biological example now, but this will never in any form Limit the scope of the present invention.

Embodiment

A. the physicochemical property of compound

A.1. the purity of compound

Unless otherwise stated, the purity of compound will be confirmed by liquid chromatography/mass spectrometry (LC/MS), as follows:

HPLC system: Waters2690 and Waters996 photoelectron diode array detector；Post: C18；Gradient: solvent A(H₂O/ formic acid 26.5nM) 0%, to solvent B (CH₃CN/ formic acid 17nM) in 3 minutes 80%.Flow: 2.75ml/ minute.

Mass spectrograph: micelle platform LC.Ionization: electron spray (polarity: negative and positive)

A.2. the separability of configuration:

Cahn-Ingold-Prelog system is used to divide the absolute configuration of asymmetric center, wherein four of asymmetric carbon Group will be according to one group of sequence rules ranking.Cahn seen from bibliography；Ingold；Prelog Angew.Chem.Int.Ed.Engl.1966、5、385-415。

A.3. spatial chemistry:

One of skill in the art is it is known that specific enantiomter (or diastereoisomer) can be by difference Method obtain, such as but not limited to chiral resolution (such as: with optical activity acid or alkali formed salt can be used for formed diastereomeric Isomery salt, they can promote the separation of the compound light active isomer of Formulas I or any subgroup), asymmetric synthesis or Preparative chiral chromatography (use different posts, as from Chiral Technologies Europe company (Illkirch, France) Chiralcel OD-H (tris-methyl benzoate, 46 × 250 or 100 × 250mm, 5 μm), Chiralcel DJ (tris-dimethylphenylcarbamate, 46 × 250 or 100 × 250mm, 5 μm), Chiralpak AD (tris-benzoic acid Methyl esters, 46 × 250mm, 10 μm) and Chiralpak AS (tris-(S)-1-phenyl ethyl carbamate, 46 × 250mm, 10 μm)).If convenient, stereoisomer can (this compounds includes amino from the commercial paints acquirement of configuration known Acid).

A.4. the title of molecule

MDL ISIS^TM/ Draw 2.3 software is used for specifying the title of molecule.

B. the synthesis of compound

B.1. intermediate

The compound of the present invention can be by method well known to those skilled in the art and synthesis as follows and experimental arrangement Prepare.

For example, intermediate C can basis, but be not limited only to following general sequence and obtain and (carry out subsequently The acid amides of Suzuki coupling reaction is formed):

PG represents suitable blocking group, such as T.Greene and P.Wuts, in " Greene ' s Protective The Group in Organic Chemistry " group described in (4th edition, John Wiley&Sons Inc).

(a)ArNH₂, TBTU, HOBt, DIEA, DMF, rt or ArNH₂, DCC, HOBt, DIEA, DMF/DCM, rt:

(b) Ghosez reagent [Me₂C=C (Cl) NMe₂], THF, rt, be followed by ArNH₂、Py

(c)ArNH₂、Cul、Cs₂CO₃, DMEDA, dioxolanes, 130 DEG C, 16h:

(d)2MNa₂CO₃(aq)、Pd(PPh₃)₄, toluene or DME, ethanol, N₂、MW、130℃.

Prepare the general procedure of acid amides

Option A. add DIEA (3mmol, 3 equivalents), TBTU to the corresponding carboxylic acid solution (1mmol) in DMF (10ml) (1.3mmol, 1.3 equivalents) and HOBt (0.3mmol, 0.3 equivalent).It is stirred at room temperature reactant mixture 5-10 minute, then Add corresponding amine (1.1 equivalent).Stirring reactant mixture 16 to 24 hours, then dilutes with ethyl acetate (100ml), then uses 0.1MHCl (50ml) and saturated sodium carbonate (50ml) washing.Organic phase is through MgSO₄It is dried, then solvent is removed under vacuo.

Another kind of scheme: be gradually added into DCC to the corresponding carboxylic acid solution (1 equivalent) in DMF/DCM mixture (0.25M) (1 equivalent), HOBt (1 equivalent) and DIEA (3 equivalent).Before adding corresponding amine (1 equivalent), it is stirred at room temperature solution 30 Minute.It is stirred at room temperature reactant mixture 1 hour to 3 days.Solvent is removed under vacuo.By residue in DCM and water Separate.Extraction product is carried out with DCM.Organic layer is separated, and washes with the sodium carbonate (or 1N NaOH) of 2M, 1N hydrochloric acid and salt Wash, through MgSO₄It is dried, evaporation.

Another kind of scheme: will be at CH₃In corresponding carboxylic acid (200mg, 1.0 equivalents) in CN (4ml) and amine (2.0 equivalent) Mixture adds HOBT (0.4 equivalent) and EDCI (about 120mg, 1.5 equivalents).Reactant mixture 16 is stirred little with the temperature of 30 DEG C Time.LC-MS Faxian shows that reaction completes.Then by solvent concentration to being dried, obtain crude product, the most purified be directly used in next Step.Crude product is dissolved in DCM/TFA=7: 1 (4ml).Reactant mixture is stirred 16 hours with the temperature of 30 DEG C.LC-MS method Display reaction completes.Then reactant mixture concentrate and use preparative high performance liquid chromatography (prepHPLC) by crude product It is purified, to obtain end product.

Option b. in anhydrous THF (10ml) corresponding carboxylic acid solution (5mmol) add Ghosez reagent (10mmol, 2 Equivalent).Under stopping up temperature, stir reactant mixture 2.5 hours, then solution is removed under vacuo.Residue is dissolved in nothing Water pyrido is cooled to 0 DEG C, then adds corresponding amine (5.5mmol, 1.1 equivalents).It is stirred at room temperature reactant mixture 1 little Time.Being steamed altogether by toluene and remove pyridine, then residue is dissolved in EtOAc (100ml) and with 1M NaOH (50ml), water (50ml) and salt solution (50ml) washing.Organic phase is through MgSO₄It is dried, then solvent is removed under vacuo.

Corresponding carboxylic acid solution (1mmol) in dioxolanes (2ml) is taken off by scheme C. by being passed through nitrogen toward solution Gas disposal.Add copper (I) iodide (0.25mmol, 0.25 equivalent), Cs₂CO₃(2.5mmol, 2.5 equivalents), corresponding amine (1.2mmol, 1.2 equivalents) and N, N '-dimethyl-ethane-1,2-diamines (0.5mmol, 0.5 equivalent).Exist with the temperature of 130 DEG C The bottle closed stirs reactant mixture 24 hours.Filter reactant mixture with diatomite, then wash with EtOAc (200ml) Wash diatomite.Filtrate is washed with 1M sodium acid carbonate (100ml), 0.1MHCl (100ml), water (100ml) and salt solution (100ml).Have Machine layer is through MgSO₄It is dried, then solvent is removed under vacuo.

The general procedure of scheme D.Suzuki reaction

Add suitable boric acid (3mmol, 2 equivalents), corresponding bromination benzene (1.5mmol, 1 equivalent), toluene or DME (3ml), ethanol (3ml) and 2M sodium carbonate liquor (3ml, 6mmol, 4 equivalents) are in MW container (Biotage, 20ml).Adding Tetrakis triphenylphosphine palladium (0) catalyst (4 moles of %) is front, rinses reaction vessel with nitrogen.Seal and use MW with 130 DEG C carrying out Temperature carried out irradiation before 1-1.5 hour, again rinse reaction vessel with nitrogen.Then allow the residue in reactant mixture cold But, and with diatomite reactant mixture is filtered.With ethyl acetate (200ml) and methyl alcohol (100ml) wash residual thing.Solvent is existed Remove under vacuum, be subsequently adding in DCM.Filter, use DCM washing precipitate, be then dried program.This compound can be with this The state of sample is used or is purified (silica gel, DCM/MeOH gradient) with flash-chromatography.

The bromo-4-of intermediate 1:3-(1-t-butoxy carbonylamino-ethyl)-benzoic acid

DIEA is added in 4-acetyl-3-bromo-benzoic acid (40 to the 80mmol) solution in EtOH (100 to 200ml) (1.6 equivalent) and hydroxylamine hydrochloride (1.6 equivalent).Under reflux conditions stirring reactant mixture 1 hour.Reactant mixture is cooled down To room temperature, the most under reduced pressure remove solvent.Residue is added into the KHSO of water and 20%₄Solution.Filtering, it is heavy to wash with water Shallow lake thing, is then dried program.

To the bromo-4-of the 3-in acetic acid (30 to 300ml) [1-(hydroxyl imido grpup)-ethyl]-benzoic acid (10 to 50mmol) Solution in add activated zinc (5-10 equivalent).It is stirred at room temperature reactant mixture 10 minutes or up to 3.5 hours.Filter anti- Answer mixture, then use acetic acid washing precipitate.Under reduced pressure remove the solvent of filtrate.

4-(1-amino-ethyl) the bromo-benzoic acid of-3-(15323 to 30727 μm ol) of crude product is suspended in THF/ 1MNa₂CO₃: in 1/1 (100ml) mixture or acetone/1MNa₂CO₃: 1/1 (100ml) mixture or acetone/2MNa₂CO₃: 8/2 (100ml) mixture and interpolation (Boc)₂O (1.5 equivalent).It is stirred at room temperature reactant mixture 1 to 2 hour.Under reduced pressure remove Removing organic solvent or add ether, two layers are separated or reactant mixture is filtered, and the most under reduced pressure remove organic solvent. With citric acid or 20%KHSO₄Solution dilutes aqueous residue, then extracts with EtOAc.The organic layer merged with salt solution washing, Through MgSO₄It is dried, the most under reduced pressure removes solvent.Whenever necessary, with column chromatography compound is purified (silica gel, DCM/MeOH gradient).

Intermediate 2:{1-[the bromo-4-of 2-(pyridin-4-yl-carbamyl)-phenyl]-ethyl }-carbamic acid tert-butyl Ester.

To the bromo-4-of the 3-in DMF (10 to 30ml) (1-t-butoxy carbonylamino-ethyl)-benzoic acid (7496 to 61011 μm ol) add DIEA (2 equivalent), TBTU (1.3 equivalent) and HOBt (0.3 equivalent).It is stirred at room temperature reactant mixture 5 minutes.Then and be stirred at room temperature reactant mixture 2.5 hours to overnight 4-aminopyridine (1.5 equivalent) is added,.If Also it is observed that initiation material, add more DIEA (0.39 equivalent), TBTU (0.25 equivalent), HOBt (0.06 equivalent) and 4- Aminopyridine (0.28 equivalent), is then stirred at room temperature reactant mixture 2 hours.Use EtOAc diluted reaction mixture, then With 0.1M HCl, saturated Na₂CO₃Or saturated NaHCO₃Washing.Organic layer is through MgSO₄It is dried, the most under reduced pressure removes solvent. With flash-chromatography, compound is purified (silica gel, DCM/MeOH gradient).

Intermediate 3:2 '-(1-t-butoxy carbonylamino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl- 3-carboxylic acid.

Method 1: at DME/EtOH/ water: { 1-[the bromo-4-of the 2-(pyridin-4-yl-ammonia first in 2/1/1 (10ml) mixture Acyl group)-phenyl]-ethyl-carbamic acid tert-butyl ester (2 to 3mmol) and 3-Carboxybenzeneboronic acid (1.2 equivalent) solution in Add Na₂CO₃(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).With the temperature of 135 DEG C at micro-wave oven In add thermal reaction mixture 30 minutes.Under reduced pressure remove solvent.Dilute residue with MeOH, then carried out with diatomite Filter.Diatomite residue is washed with MeOH.Under reduced pressure remove solvent, then residue is put into DCM.Filter and wash with DCM Wash sediment, be then dried program.With semi-preparative LC-MS, compound is purified or dilute with DCM/MeOH (3/2) Release residue, then add activated carbon toward reactant mixture.It is stirred at room temperature mixture 10 minutes, then filters with silica gel. With DCM/MeOH (8/2) wash residual thing, wash with MeOH the most again.The most under reduced pressure remove solvent.

Method 2: to { 1-[the bromo-4-of 2-(pyridin-4-yl-carbamyl)-benzene in toluene/EtOH:5/3 (32ml) Base]-ethyl-carbamic acid tert-butyl ester (6912 μMs of ol) and 3-Carboxybenzeneboronic acid (1.0 equivalent) solution in be added in water (8ml) Na in₂CO₃(3 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.03 equivalent) solution.Under reflux conditions Add thermal reaction mixture 3 hours.Add more 3-Carboxybenzeneboronic acid (0.35 equivalent) and tetrakis triphenylphosphine palladium (Pd Tetrakis) (0.015 equivalent), the most under reflux conditions adds thermal reaction mixture 3 hours.Reactant mixture is cooled down To room temperature, and filter with diatomite.Wash with EtOAc and MeOH.Under reduced pressure remove solvent, then with flash-chromatography generalization Compound is purified (silica gel, DCM/MeOH gradient).

Intermediate 4:[2 '-(1-t-butoxy carbonylamino-ethyl)-5 '-(pyridine 4-base-carbamyl)-xenyl- 3-yl]-acetic acid

To at DME/EtOH/2NNa₂CO₃: { 1-[the bromo-4-of 2-(the pyridine e4-base-ammonia first in 1/1/1 (10ml) mixture Acyl group)-phenyl]-ethyl-carbamic acid tert-butyl ester (1951 μMs of ol) solution in add 3-carboxymethyl group phenylboric acid (1.5 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Heat in micro-wave oven with the temperature of 160 DEG C Reactant mixture 15 minutes.Go cold for reactant mixture to room temperature, filter with diatomite and wash with EtOAc and MeOH.Subtracting Pressure removes solvent.With column chromatography, compound is purified (silica gel, DCM/MeOH gradient)

Intermediate 5:3-[2 '-(1-t-butoxy carbonylamino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-biphenyl Base 3-yl]-propionic acid

To at DME/EtOH/2NNa₂CO₃: { 1-[the bromo-4-of 2-(the pyridine e-4-base-ammonia first in 1/1/1 (20ml) mixture Acyl group)-phenyl]-ethyl-carbamic acid tert-butyl ester (3122 μMs of ol) solution in add 3-carboxy ethyl phenylboric acid (1.5 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Heat in micro-wave oven with the temperature of 160 DEG C Reactant mixture 15 minutes.Reactant mixture is cooled to room temperature, filters with diatomite and wash with EtOAc and MeOH.Subtracting Pressure removes solvent.With column chromatography, compound is purified (silica gel, DCM/MeOH gradient).

Intermediate 6:{1-[3 '-hydroxyl-5-(pyridin-4-yl-carbamyl)-xenyl-2-base]-ethyl }-amino first Acid tert-butyl ester

To in DME/EtOH:1/1 (8ml) mixture 1-[the bromo-4-of 2-(pyridin-4-yl-carbamyl)-phenyl]- Ethyl }-carbamic acid tert-butyl ester (2087 μMs of ol) and 3-hydroxy benzenes boric acid (1.55 equivalent) solution in add Na₂CO₃(4 Equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Reactant mixture is rinsed with Ar, and with the temperature of 130 DEG C Degree heats 1.5 hours in micro-wave oven.Reactant mixture is cooled to room temperature, uses 1N NaHCO₃Dilute and extract with EtOAc. Use 1N NaHCO₃Extraction organic layer, the aqueous layer then merged with citric acid and 1N HCl acidifying.Aqueous layer is extracted with EtOAc, Then organic layer is through MgSO₄It is dried and under reduced pressure removes solvent.This compound is purified by EtOAc recrystallization.

Intermediate 7:[2 '-(1-t-butoxy carbonylamino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-biphenyl Base-3-base epoxide]-acetic acid.

To in toluene/ethanol: { 1-[the bromo-4-of 2-(pyridin-4-yl-carbamyl)-benzene in 5/3 (12ml) mixture Base]-ethyl }-carbamic acid tert-butyl ester (0.48 gram) adds 3-benzene oxygen-benzyl acetate boric acid (2 equivalent) and in water (4ml) Na₂CO₃Solution (4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.06 equivalent).Under reflux conditions add Thermal reaction mixture 2 hours.Reactant mixture is cooled to room temperature and filters with diatomite.With EtOAc and EtOH washing washing Diatomite residue.Under reduced pressure remove solvent, then residue is put in DCM.Filter and use DCM washing precipitate, so After carry out drying program.With column chromatography, compound is purified (silica gel, DCM/MeOH gradient).

Intermediate 8:{1-[the bromo-4-of 2-(the fluoro-pyridin-4-yl-carbamyl of 3-)-phenyl]-ethyl }-carbamic acid tert- Butyl ester.

To the bromo-4-of 3-(1-t-butoxy carbonylamino-ethyl)-benzoic acid solution in anhydrous THF (20ml) (8352 μm ol) adds Ghosez reagent (2 equivalent).It is stirred at room temperature mixture 2 hours.Under reduced pressure remove solvent.Will Residue is dissolved in anhydrous pyridine (20ml), is subsequently adding 3-fluoro-pyridin-4-yl amine (1.2 equivalent).It is stirred at room temperature reaction Mixture 2.5 hours.Under reduced pressure remove pyridine.Residue is dissolved in 1N Na₂CO₃, and extract with EtOAc.Use 1N NaHCO₃, citric acid and water washing merge organic layer.Organic layer is through MgSO₄It is dried, the most under reduced pressure removes solvent.With post Compound is purified (silica gel, DCM/MeOH gradient) by chromatography.

Intermediate 9:2 '-(1-t-butoxy carbonylamino-ethyl)-5 '-(the fluoro-pyridin-4-yl-carbamyl of 3-)-connection Phenyl-3-carboxylic acid

To { 1-[the bromo-4-of the 2-(fluoro-pyridin-4-yl-ammonia of 3-in DME/EtOH/water:1/1/1 (10ml) mixture Formoxyl)-phenyl]-ethyl }-carbamic acid tert-butyl ester (2841 μMs of ol) and the solution of 3-Carboxybenzeneboronic acid (1.5 equivalent) Middle addition Na₂CO₃(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).With the temperature of 130 DEG C at microwave Stove adds thermal reaction mixture 1.5 hours.With water and citric acid (acid ph value) diluted reaction mixture, and extract with EtOAc. The organic layer merged is through MgSO₄It is dried, under reduced pressure removes solvent.With column chromatography, compound is purified (silica gel, DCM/ MeOH gradient).

Intermediate 10:[2 '-(1-t-butoxy carbonylamino-ethyl)-5 '-(the fluoro-pyridin-4-yl-carbamyl of 3-)- Xenyl-3-base epoxide]-acetic acid.

To at DME water: { 1-[the bromo-4-of 2-(the fluoro-pyridin-4-yl-carbamyl of 3-)-the phenyl]-second of 9/1 (15ml) Base }-carbamic acid tert-butyl ester (3400 to 3650 μMs of ol) and 3-benzene oxygen-benzyl acetate boric acid (1 equivalent) solution in add K₃PO₄(0.05 works as (4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) tetrakis triphenylphosphine palladium (Pd tetrakis) Amount).In micro-wave oven, thermal reaction mixture is added 30 minutes with the temperature of 130 DEG C.Activated carbon is added in reactant mixture, so Use diatomite filtering mixt afterwards.Residue is washed with EtOAc and water.Aqueous layer is separated, and then extracts with EtOAc.Use salt The organic layer that water washing merges, through MgSO₄Under reduced pressure remove solvent after drying.With column chromatography, compound is purified (silica gel, cyclohexane/acetone gradient).

To [2 '-(1-t-butoxy carbonylamino-ethyl)-5 '-(the fluoro-pyridin-4-yl of the 3--ammonia first at THF (25ml) Acyl group)-phenyl]-xenyl-3-base epoxide] and-benzyl acetate (2mmol) solution in add Pd/C (0.5 equivalent).Rush with hydrogen Wash reactant mixture, the cyclohexadiene solution in THF (5ml) is added dropwise in reactant mixture.Under hydrogen environment Mixture is stirred 24 hours with the temperature of 55 DEG C.Add diatomite, be then stirred at room temperature suspension 20 minutes.By suspension Filter, then with THF (50ml) wash residual thing.Under reduced pressure remove solvent.

Intermediate 11:{1-[3 '-amino-5-(pyridin-4-yl-carbamyl)-xenyl-2-base]-ethyl }-amino first Acid tert-butyl ester.

To at DME/ ethanol/1N Na₂CO₃: in 1/1/1 (3ml) 1-[the bromo-4-of b-(pyridin-4-yl-carbamyl)- Phenyl]-ethyl-carbamic acid tert-butyl ester (1428 μMs of ol) and 3-aminophenyl boronic acid (2 equivalent) solution in add four (triphenylphosphine) palladium (Pd tetrakis) (0.05 equivalent).In micro-wave oven, thermal reaction mixture 15 points is added with the temperature of 150 DEG C Clock.Reactant mixture is cooled to room temperature, dilute with water and extracting with EtOAc.The organic layer merged with 0.5N HCl washing, warp MgSO₄Under reduced pressure remove solvent after drying.

Intermediate 12:{1-[3 '-amino-5-(the fluoro-pyridin-4-yl-carbamyl of 3-)-xenyl-2-base]-ethyl }- Carbamic acid tert-butyl ester

To at DME/ ethanol/1N Na₂CO₃: { 1-[the bromo-4-of 2-(the fluoro-pyridin-4-yl of the 3--ammonia first in 1/1/1 (10ml) Acyl group)-phenyl]-ethyl }-carbamic acid tert-butyl ester (1094 μm ol) and 3-aminophenyl boronic acid (2 equivalent) add four (three Phenylphosphine) palladium (Pd tetrakis) (0.05 equivalent).In micro-wave oven, thermal reaction mixture 1.5 is added little with the temperature of 130 DEG C Time.Reactant mixture is cooled to room temperature, dilutes with water and citric acid, then extract with EtOAc.Wash with water and salt solution and merge Organic layer.Organic layer is through MgSO₄It is dried, the most under reduced pressure removes solvent.With column chromatography, compound is purified (silicon Glue, DCM/MeOH gradient).

Intermediate 13:4-[2-(1-t-butoxy carbonylamino-ethyl)-5-(pyridin-4-yl-carbamyl)-benzene Base]-1H-pyrroles's-2-carboxylic acid

To { 1-[the bromo-4-of 2-(pyridin-4-yl-carbamyl)-the phenyl]-second in DME/EtOH:1/1 (0.8ml) Base }-carbamic acid tert-butyl ester (809 μMs of ol) and 1H-pyrroles's-2-carboxylate methyl ester boric acid (1.15 equivalent) solution in add Na₂CO₃(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Reactant mixture is rinsed with Ar, and with The temperature of 130 DEG C heats 35 minutes in micro-wave oven.Reactant mixture is cooled to room temperature, dilute with water and extracting with EtOAc. Under reduced pressure remove the solvent of organic layer.

To 4-[2-(the 1-t-butoxy carbonylamino-ethyl)-5-(pyrrole in THF (1.6ml) and MeOH (1.6ml) Pyridine-4-base-carbamyl)-phenyl]-1H-pyrroles's-2-carboxylate methyl ester (661 μMs of ol) solution in add 1N LiOH solution (1.6ml).Reactant mixture is stirred 1.5 hours with the temperature of 40 DEG C.Use saturated NaHCO₃Diluted reaction mixture, then uses EtOAc extracts.With 20% citric acid solution acidified aqueous layer, extract with EtOAc the most again.The organic layer warp merged MgSO₄It is dried, under reduced pressure removes solvent.

Intermediate 14:4-[2-(1-t-butoxy carbonylamino-ethyl)-5-(pyridin-4-yl-carbamyl)-benzene Base]-1H-indole-2-carboxylic acid

To { 1-[the bromo-4-of 2-(pyridin-4-yl-carbamyl)-the phenyl]-ethyl } in DME/EtOH:1/1 (8ml)- The solution of carbamic acid tert-butyl ester (952 μMs of ol) and 4-bromo-1H-indole-2-carboxylic methyl ester's boric acid (1.55 equivalent) adds Na₂CO₃(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Reactant mixture is rinsed with Ar, and with The temperature of 130 DEG C heats 35 minutes in micro-wave oven.Reactant mixture is cooled to room temperature, and then dilute with water filters.To residual Thing is stayed to be dried process.

To 4-[2-(the 1-amino-ethyl)-5-(pyridin-4-yl-carbamyl in THF (2.4ml) and MeOH (2.4ml) Base)-phenyl]-1H-indole-2-carboxylic methyl ester (600 μMs of ol) solution in add 1N LiOH solution (2.4ml).With 40 DEG C Temperature stirring mixture 6 hours.With 1N LiOH diluted reaction mixture, then extract with EtOAc.Use 20% citric acid solution Acidified aqueous layer, extracts with EtOAc the most again.The organic layer merged is through MgSO₄It is dried, under reduced pressure removes solvent.

The bromo-4-of intermediate 15:3-(t-butoxy carbonylamino-methyl)-benzoic acid

To adding H in the 3-bromo-4-methyl benzoic acid suspension (300g, 1.39mol) of MeOH (3 liters)₂SO₄(6ml)。 Reactant mixture is stirred to overnight with the temperature of 60 DEG C.Reactant is cooled to room temperature and evaporation, then residue is dissolved in EtOAc (2 liters).Use saturated NaHCO₃(1 liter) washing EtOAc solution, through MgSO₄It is concentrated to dryness after drying, to obtain corresponding first Ester, for pale yellow oil (303 grams, 95% productivity).

Will be at anhydrous CCl₄The solution of the previous methyl esters in (1.5 liters) (303 grams, 0.98mol, 1.0 equivalents) adds to nothing Water CCl₄NBS in (1.5 liters) (183.9 grams, 1.03mol, 1.05 equivalents) and AlBN (8 grams, 0.049mol, 0.05 equivalent) is molten In liquid, temperature is room temperature.Reactant mixture is refluxed 16 hours, is cooled to room temperature and evaporation, then residue is dissolved in DCM (2.5 liters).Use saturated NaHCO₃(0.6 liter) and H₂O (1 liter * 3) washs DCM solution.Organic layer is through MgSO₄It is dried and is concentrated into It is dried, to obtain the most purified crude product 3-bromo-4-bromomethyl-methyl benzoate being directly used in next step.

By Boc₂NH (175 grams, 0.925mol, 1.0 equivalents) add in DMF (3 liters) t-BuOK (124,5 grams, 1.11mol1.02 equivalent) in solution, then it is stirred at room temperature gained solution 1 hour.At room temperature by bromo-for crude product 3-4-bromine Methyl-benzoic acid methyl esters adds to above-mentioned reaction solution, and is stirred overnight.Remove solvent under vacuum, then will residual Thing is dissolved in DCM (500ml).DCM solution is washed, through MgSO with water (3 × 500ml)₄It is dried and is concentrated.Use PE: EA= Crude product is purified on silica gel by 20: 1 with column chromatography, to draw the di-tert-butyl dicarbonate-4-amino of yellow solid The bromo-methyl benzoate of methyl-3-(290 grams, 70% productivity).

The temperature of 0 DEG C in DCM (2.9 liters) previous di-tert-butyl dicarbonate protect benzylamine (290 grams, 0.652mol, 1.0 equivalents) solution in drip TFA (92.8 grams, 0.813mol, 1.25 equivalents), be then stirred at room temperature institute Obtain mixture 4 hours.Add 0.5M NaHCO₃To mixture, so that pH value is adjusted to 8.Mix with water (3*500ml) washing reaction Compound, through MgSO₄Concentrate with Rotary Evaporators after drying, with obtain the bromo-4-of the 3-of yellow oily (t-butoxy carbonylamino- Methyl)-methyl benzoate (210 grams, 93.5% productivity).

It is added on H₂NaOH in O (1.26 liters) (48.8 grams, 1.22mol, 2.0 equivalents) is in MeOH (1.26 liters) In the bromo-4-of 3-(t-butoxy carbonylamino-methyl)-methyl benzoate (210 grams, 0.61mol, 1.0 equivalents) solution.With 50 DEG C temperature stirring reactant mixture 2 hours.Reactant is cooled to room temperature, and is concentrated to the amount of half.Add 1M HCl molten Liquid, to be acidified to pH value 5 by residue.Produced solid is collected and is dried, to draw in the middle of the title of white solid Body (200 grams, 99.4% productivity).

Intermediate 16:[2-bromine 4-(pyridin-4-yl-carbamyl)-benzyl]-carbamic acid tert-butyl ester.

To the intermediate 15 (100 grams, 0.303mol, 1.0 equivalents) in DMA (1 liter) and 4-aminopyridine (28.5 grams, 0.303mol, 1.0 equivalents) solution in add Et₃N (30.6 grams, 0.303mol, 1.0 equivalents), DMAP (3.7 grams, 0.030mol, 0.1 equivalent) and HATU (115.2 grams, 0.303mol, 1.0 equivalents).Reaction solution 16 is stirred with the temperature of 30 DEG C Hour.Evaporate solvent under vacuum, by adding DCM (600ml) and H₂O (600ml) cured residue, to draw title Compound (86.1 grams, 70% productivity).

The bromo-4-of intermediate 17:[2-(the fluoro-pyridin-4-yl-carbamyl of 3-)-benzyl]-carbamic acid tert-butyl ester.

Intermediate 17 is prepared according to the method described by intermediate 16.

Intermediate 18:2 '-(t-butoxy carbonylamino-methyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl- 3-carboxylic acid.

To at DMF (350ml) and H₂Intermediate in O (87.5ml) 16 (35 grams, 0.086mol, 1.0 equivalents) and 3-carboxylic The solution of base phenyl boric acid (14.27 grams, 0.086,1.0 equivalents) adds Na₂CO₃(18.2 grams, 0.172mol, 2.0 equivalents).So After at N₂Pd (dppf) Cl is added under environment₂(3.15 grams, 0.0043mol, 0.05 equivalent) are in solution.Stir with the temperature of 100 DEG C Mix the solution 16 hours of gained.Evaporate solvent under vacuum, then use DCM: MeOH=10: 1 on silica gel with post layer Residue is purified by analysis method, to draw the title compound (27 grams, 70% productivity) of brown solid.

Intermediate 19:2 '-(t-butoxy carbonylamino-methyl)-5 '-(the fluoro-pyridin-4-yl-carbamyl of 3-)-connection Phenyl-3-carboxylic acid.

Intermediate 19 is prepared, from the beginning of intermediate 17 according to the method described by intermediate 18.

Prepare following intermediate in a similar fashion:

Intermediate 27 [2 '-(t-butoxy carbonylamino-methyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl- 3-base epoxide]-acetic acid.

To at DMF (300ml) and H₂Common intermediate in O (75ml) (30 grams, 0.074mol, 1.0 equivalents) and [3- (4,4,5,5-tetramethyls-[1,3,2] dioxane defends borine-2-base)-benzene oxygen]-ethyl acetate (23 grams, 0.074,1.0 work as Amount) add Na2CO3 (15.6 grams, 0.147mol, 2.0 equivalents).Then at N₂Pd (dppf) Cl is added under environment₂(2.7 grams, 0.0037mol, 0.05 equivalent) in solution.The solution 16 hours of gained is stirred with the temperature of 100 DEG C.Solvent is evaporated, then Residue is dissolved in MeOH 200ml, and adds the 1M LiOH to 148ml, stir the solution 16 of gained with the temperature of 30 DEG C Hour, check with LC-MS.Solvent is evaporated to 1/3, then with 20% aqueous hydrochloric acid solution, pH value is adjusted to 5, solvent is steamed Send out, then use on silica gel with column chromatography residue be purified at DCM: MeOH=10: 1, to draw white solid Title compound (23.8 grams, two steps become 674%).

Intermediate 28 [2 '-(t-butoxy carbonylamino-methyl)-5 '-(the fluoro-pyridin-4-yl-carbamyl of 3-)-connection Phenyl-3-base epoxide]-acetic acid.

Intermediate 28 is prepared, from the beginning of intermediate 17 according to the method described by intermediate 27.

If the compound of the present invention contains ester group, that just can be according to preparing described by following overall plan:

(e) R ' OH, TBTU, HOBt, DIEA, DMF, rt or R ' OH, DCC, DMAP, DCM, rt；

(f) Ghosez reagent [Me₂C=C (Cl) NMe₂], THF or DCM, rt, be followed by R ' OH.

Scheme E. adds DIEA in the corresponding carboxylic acid suspension (0.25mmol) in DMF (1ml) and (0.75mmol, 3 works as Amount), TBTU (0.325mmol, 1.3 equivalents), HOBt (0.075mmol, 0.3 equivalent), then be stirred at room temperature reaction mixing Thing 5 minutes, then adds corresponding alcohol (1.1-5 equivalent).It is stirred at room temperature reactant mixture 1-16 hour, then uses acetic acid Ethyl ester (100ml) dilutes, then with saturated aqueous sodium carbonate (50ml), 0.1MHCl (50ml), water (50ml) and salt solution (50ml) Washing.Organic phase is through MgSO₄After drying, transfer to vacuum chamber and concentrate, the ester needed for output.

Another kind of scheme.

The mediation that the acids of general type can be acted on by DCC in the presence of DMAP turns with Steglich method Change corresponding ester into.This chemistry is method well known to those skilled in the art, and can be according to literature precedents (B.Neises and W.Steglich.”Esterification of carboxylic acids with dicyclohexyl carbodiimide/4-dimethylaminopyridine”；Coll.Vol.7:93) carry out.

The solution of scheme F. corresponding carboxylic acid (0.25mmol) in being cooled to THF or DCM of 0 DEG C of temperature (1ml) adds Add Ghosez reagent (the chloro-N of 1-, N, 2-trimethyl-1-acrylic amine, No. CAS be 26189-59-3,0.5mmol, 2 equivalents).? Stir reactant mixture 1-3 hour while being heated to room temperature, then add corresponding alcohol (1.2 equivalent).It is stirred at room temperature Reactant mixture 1 hour.Solution for vacuum is evaporated.Dilute residue with EtOAc and use saturated NaHCO₃Washing.Organic layer warp MgSO₄It is dried, the most under reduced pressure removes solvent.

Acids is converted into the overall plan of thioesters

(g) R ' SH, DCC, DMAP, DCM or DMF, room temperature

Add DCC in the corresponding carboxylic acid solution (1mmol) in DCM or DMF (10ml) of 0 DEG C (1.1mmol, 1.1 to work as Amount) and DMAP (0.1mmol, 0.1 equivalent), then add corresponding mercaptan (2-4 equivalent).Remove cooling bath, then in room temperature Lower stirring reactant mixture 1-16 hour.With DCM (100ml) diluted reaction mixture, then use saturated aqueous sodium carbonate (50ml), 0.1M HCl (50ml), water (50ml) and salt solution (50ml) washing.Organic phase is through MgSO₄After drying, vacuum is transferred to Room concentrates, the thioesters needed for output.

Another kind of scheme: at CH₃Corresponding carboxylic acid (200mg, 1.0 equivalents) in CN (4ml) and ethyl mercaptan (2.0 equivalent) Mixture adds HOBT (0.4 equivalent) and EDCl (about 120mg, 1.5 equivalents).Reactant mixture 16 is stirred with the temperature of 30 DEG C Hour.LC-MS Faxian shows that reaction completes.Then by solvent concentration to being dried, purify and obtain crude product, the most purified direct use In next step.

Crude product is dissolved in DCM/TFA=7: 1 (4ml).Reactant mixture is stirred 16 hours with the temperature of 30 DEG C. LC-MS Faxian shows that reaction completes.Then reactant mixture concentrated and use preparative high performance liquid chromatography (prepHPLC) It is purified for crude product, to obtain end product.

Miscellaneous alkyl is converted the overall plan to lactone derivatives

In the alcohols of general type or mercaptan can link to corresponding miscellaneous alkyl according to overall plan (X=O or S) conversion Ester.

(h) DIEA, DMF, room temperature

In the corresponding thiol solution (1mmol) in DMF (10ml), add DIEA (2mmol, 2 equivalents), be subsequently added into Corresponding bromo lactone (1.1mmol, 1.1 equivalents).It is stirred at room temperature reactant mixture 1 hour, then uses ethyl acetate (100ml) dilution, washs with 0.1M HCl (50ml), water (50ml) and salt solution (50ml).Organic phase is through MgSO₄After drying, very Empty concentration, the lactone needed for output.

Intermediate 29:3-(2-amino-ethyl sulfenyl)-dihydro-furan-2-ketone

By 3-bromo-dihydro-furan-2-ketone (2.49 grams, 15.1mmol) and 2-(t-butoxycarbonyl-amino) ethyl mercaptan (2.9 Gram, 16.5mmol) be dissolved in the CH of 40ml₃CN.Then by K₂CO₃(4.14 grams, 30mmol) adds in solution.With the temperature of 80 DEG C Degree stirring 16 hours.It is evaporated to be dried by solvent, then with column chromatography (PE/EtOAc=4/1), residue is purified to 3.8 Gram tertbutyloxycarbonyl protection intermediate 29, for colorless oil.

Previous compound (3.7 grams, 14.16mmol) is dissolved in the EtOAc of 10ml.Add the 4N HCl/ of 40ml EtOAc is in solution.Stir 2 hours with the temperature of 25 DEG C.Filter white solid, then wash, to obtain the centre of 2 grams with PE Body 29.

Intermediate 30:3-(3-amino-propyl sulfenyl)-dihydro-furan-2-ketone.

3-amino-propan-1-alcohol (40 grams, 0.533mol) is dissolved in the THF of 1 liter.Then the temperature at 25 DEG C is incited somebody to action Boc in 450ml THF₂O (127.26 grams, 0.586mol) is added drop-wise in solution.Stir 12 hours with the temperature of 25 DEG C.Will The water of 500ml adds in solution, then extracts with EtOAc (200ml*3), and uses MgSO₄It is dried program.Filter also It is evaporated to be dried, to show that the corresponding tertbutyloxycarbonyl (BOC) of 60 grams of colorless oil protects compound.

3-amino-propan-1-the alcohol (30 grams, 0.171mol) that tertbutyloxycarbonyl is protected is dissolved in the anhydrous THF of 600ml In.TEA (48ml, 0.345mol) is added to solution.Then at N₂It is slowly added MsCl with the temperature of 0 DEG C under environment (26.67ml) in solution.Stir 2 hours with the temperature of 25 DEG C.Wash mixture with water, be then dried journey with MgSO4 Sequence.Filter and be evaporated to be dried, to show that the Ms-of 40 grams protects product.

By above compound (40 grams, 0.158mol) and CH₃COSK (54.1 grams, 0.474mol) is mixed into 2.7 liters In EtOH.At N₂Under environment, the temperature with 90 DEG C stirs 16 hours.It is evaporated to be dried by solvent, then with column chromatography (PE/EA =10/1) using thioacetic acid S-(3-t-butoxycarbonyl amino-propyl group) ester of purifying mixture to 15 gram as orange solids.Will Na (708mg, 30.8mmol) add to 100ml absolute methanol and stir until metallic sodium disappearance.By above compound (6 grams, 25.8mmol) add in solution.It is stirred at room temperature mixture 2 hours.TLC display reaction completes.Will be 100mlCH₂Cl₂In the solution of 3-bromo-dihydro-furan-2-ketone (5.46 grams, 33.3mmol) add in mixture, then add Enter the DMF of 100ml.Gained mixture is stirred 6 hours with the temperature of 60 DEG C.TLC display reaction completes.Reactant mixture is divided It is assigned to the water of EA and 400ml of 800ml, then by EA (800ml × 2) aqueous layer extracted.The organic layer of merging is dried, filter and Concentrate, to obtain crude product, be then purified to the tertbutyloxycarbonyl protection chemical combination of 3.5 grams with column chromatography (PE/EA=4/1) Thing, for colorless oil.

Tertbutyloxycarbonyl protection derivative (3.5 grams, 12.71mmol) is dissolved in the EtOAc of 10ml.Then by 40ml 4NHCl/EtOAc add in solution.Reactant mixture is stirred 2 hours with the temperature of 25 DEG C.Filter white solid, then use PE washs, to obtain the title compound of 2.5 grams.

Intermediate 30:4-(2-amino-ethyl)-[1,3] dioxolan-2-one.

In the autoclave of 100ml, quickly by the NH of 60ml₃In CH₃Saturated solution in OH adds to 4-bromo-1-butylene (3ml).Then in autoclave, mixture is stirred 16 hours with the temperature of 90 DEG C.After reaction, surplus solution is gone under vacuo Remove.Reclaim the hydrobromate (12 grams, 95%) of butyl-3-alkenyl amine, for yellow power supply.

At N₂To at CH under environment₂Cl₂Preceding compound suspension (12 grams, 0.08mol) in (1 liter) is added on water In the K of (80ml)₂CO₃(33 grams, 0.24mol) solution.Biphase mixture is cooled to 0 DEG C, is then added dropwise over Cbz-Cl (22 Gram, 0.128mol).After the stirring of 15 minutes, it is stirred at room temperature reactant mixture 14 hours.After completion of the reaction, add Add CH₂Cl₂And water is in mixture, organic layer is through anhydrous Na₂SO₄After drying, under vacuum concentrate and with silica gel column chromatography (oil/ethyl acetate=3: 1) are purified, to obtain corresponding benzyloxycarbonyl group (Cbz) protection compound (12.2 grams, 75%) For colorless oil.

At N₂With room temperature at acetone/H under environment₂The above-claimed cpd (12.2 grams, 59.5mmol) of O (60ml/50ml) stirs Mix and solution adds NMO (7.3 grams, 62.5mmol) and OsO₄(303mg、1.2mmol).Adding OsO₄After, the color of reactant liquor Become black.Then mixture it is stirred at room temperature 10 hours.TLC(CH₂Cl₂/ MeOH=10: 1) display initiation material is the most complete Consume.Mixture is evaporated in vacuo.Add and add water to residue, be then extracted with ethyl acetate.Organic layer is through anhydrous Na₂SO₄It is dried After, under vacuum concentrate and with silica gel column chromatography (CH₂Cl₂/ MeOH=10: 1) it is purified, to obtain corresponding glycol (12 grams, 85%) are as light white solid.

At N₂Under environment with-20～the temperature of-30 DEG C at CH₂Cl₂(200ml) glycol (9 grams, 37.66mmol) solution Middle interpolation triethylamine (15.2g, 151mmol).After a few minutes, with such temperature dropping triphosgene (5.5 grams, 18.83mmol) in mixture, then with-20～the temperature stirring half an hour of-30 DEG C.Then mixture it is stirred at room temperature 15 hours.TLC(CH₂Cl₂/ MeOH=10: 1) display initiation material consumes the most completely.Add and add water to mixture, then use Ethyl acetate extracts.Organic layer is through anhydrous Na₂SO₄It is dried, concentrates under vacuum and with silica gel column chromatography (CH₂Cl₂/ MeOH= 10: 1) it is purified, to obtain relative cyclisation dioxolane (6.5 grams, 55%), for light white solid.

At N₂To at CH under environment₃The solution (5.5 grams, 20.5mmol) of the above compound in OH (100ml) quickly adds Add dry Pd/C (550mg, 10%).Then at H₂Mixture is stirred at room temperature to overnight under environment.TLC(CH₂Cl₂/ MeOH= 10: 1) display initiation material consumes the most completely.Use Celite pad filtering mixt.Solution for vacuum is evaporated, then with silica gel (CH₂Cl₂/ MeOH=10: 1) it is purified, to obtain title intermediate (2.0 grams, 77%), for white solid.

Intermediate 31:3-(2-hydroxy-ethyl sulfenyl)-dihydro-furan-2-ketone

DIEA (1.1 equivalent) and 3-bromo-two is added in 2-mercapto-ethanol (the 2560 μMs of ol) solution in THF (4ml) Hydrogen-furans-2-ketone (1 equivalent).It is stirred at room temperature reactant mixture 4 hours.Filtering precipitate, and under reduced pressure remove molten Agent.

Intermediate 32:3-(3-hydroxyl-propyl sulfenyl)-dihydro-furan-2-ketone

DIEA (1.5 equivalent) and 3-is added in 3-mercapto-propane-1-alcohol (the 1685 μm ol) solution in DMF (2ml) Bromo-dihydro-furan-2-ketone (1 equivalent).It is stirred at room temperature reactant mixture 4 hours.Filtering precipitate, and under reduced pressure remove Remove solvent.

Intermediate 33:3-bromomethyl-oxa-ring butyl-2-ketone

With the temperature of 0 DEG C to the Br in ether (150ml)₂Solution (4.86 grams, 0.0303mol) is added dropwise over saturated NaHCO₃(110ml) 3-butenoic acid (2.6 grams, 0.0302mol) in.Mixture is stirred 1 hour after interpolation.TLC (PE: EA=4 : 1) show that reaction completes.Add saturated solution (20ml).With EtOAc (100ml × 3) extractive reaction thing.Close with salt solution washing And organic layer, through Na₂SO₄After drying, filter and be concentrated in vacuo, and enter with column chromatography (petroleum ether/ethyl acetate=20: 1) Row purifies, to obtain title compound (1.73 grams, 35%), for white oil.

Intermediate 34:3-(piperidin-4-ylmethyl sulfenyl)-dihydro-furan-2-ketone

Intermediate 34 is prepared, from 4-Hydroxymethyl-piperidine-1-carboxylic acid tert-butyl according to the method described by intermediate 30 Ester starts.

Intermediate 35:3-(2-Hydroxy-ethoxy)-dihydro-furan-2-ketone

To 50 gram 2 in 700ml methyl alcohol and 300ml chloroform, 3-dihydro-furan progressively adds the M-chlorine peroxide benzene of 90 grams Formic acid, stirs 15 minutes with the temperature of 0 DEG C, stirs reactant mixture 15 hours with the temperature of 25 DEG C the most again.Filter gained Mixture, the most under reduced pressure concentrated filtrate, then residue is dissolved in the chloroform of 500ml, and with the saturated NaHCO of 200ml₃ And the salt solution washing of 200ml, organic layer is through Na₂SO4 refilters after drying.Under reduced pressure concentrated filtrate, with the 2-of output 30 grams Methoxy-tetrahydro-furan-3-alcohol.

Sodium hydride is progressively added in the solution of the 2-methoxy-tetrahydro-furan-3-alcohol in 200ml DMF, and with 0 DEG C temperature stir 2 hours, then with dropping funel add 2-benzyloxy-ethanol, for time one hour.Stir with the temperature of 25 DEG C The mixture of gained 15 hours, is subsequently poured in the water of 400ml, then adds EtOAC (1 liter) and separate.With saturated NaHCO₃(500ml) washing organic layer, is dried through Na2SO4, filters and concentrate.Then will with column chromatography (PE: EA=5: 1) Residue purifies, to obtain 3-(2-benzyloxy-ethyoxyl)-2-methoxy-tetrahydro-furan (oily) of 10 grams.

The concentration H of 30ml is added in the preceding compound solution in the 40% MeCN aqueous solution of 300ml₂SO4, so After stir mixture 4 hours with the temperature of 35 DEG C.Use NaHCO₃Neutralize the mixture of gained, the most under reduced pressure concentrate, then add Add EtOAC (300ml) and separate.Wash organic layer with salt solution (100ml), filter after drying through MgSO4 and concentrate, then With column chromatography (PE: EA=1: 1), residue is purified, to obtain 3-(2-benzyloxy-ethyoxyl)-tetrahydrochysene-furan of 4.8 grams Mutter-2-alcohol (oily).

The Ac of 17ml is added in the above-claimed cpd solution in the DMSO of 25ml₂O, then stirs with the temperature of 25 DEG C 15 hours, it is subsequently poured in the water of 100ml, then adds EtOAC (200ml) and separate.Use saturated NaHCO₃(50ml) and Salt solution (50ml) washing organic layer, filters after drying through MgSO4 and concentrates.With column chromatography (PE: EA=5: 1), residue is pure Change, to obtain 3-(2-benzyloxy-ethyoxyl)-dihydro-furan-2-ketone (oily) of 2.5 grams.

At 1 atmospheric pressure H₂In stir in above compound and 100ml methyl alcohol the mixed of palladium on the charcoal of 0.5 gram with the temperature of 25 DEG C Compound 5 hours, the mixture of gained is filtered, and under reduced pressure concentrates its filtrate, to draw the intermediate 35 (oily) of 1.35 grams.

Intermediate 36:3-hydroxymethyl-Dihydro-thiophene-2-ketone

Thiobutryolacatone (10 grams, 97.9mmol) in anhydrous tetrahydro furan (200ml) is added dropwise over lithium diisopropyl Ammonia [the n-butyl lithium (47.0ml, 117.5mmol) of 2.5M, temperature in diisopropylamine (15. grams, 117.5mmol) and n-hexane For-78 DEG C] agitating solution in.Stirring gained solution 10 minutes, adds the formaldehyde (50 grams) carried in nitrogen stream simultaneously and [passes through Paraformaldehyde is heated to 150 DEG C, to form formaldehyde].Reaction is allowed to proceed 2.5 hours with the temperature of-78 DEG C.Remove Formaldehyde stream, then reaction is allowed to continue and carries out 30 minutes.The most while stirring the ethyl acetate of 300ml is poured into reaction mixing In thing, then add (～300ml) 1MHCl quencher with the temperature of-78 DEG C, be warming to room temperature when being filtered by bed of diatomaceous earth. With the ethyl acetate extraction filtrate of 100ml more than 5 times, then the organic layer of merging is dried (Na₂SO₄), it is concentrated into oil Shape.With chromatography (PE/EA=9/1) purified oil, to obtain the title compound of 1.70 grams, for colorless oil.

Intermediate 37:3-hydroxymethyl-dihydro-furan-2-ketone

Drip in the stirred suspension of the NaH (9.77 grams, 244mmol, 60%) in 250ml THF 20 grams γ- Butyrolactone (20 grams, 232mmol) and methyl formate (14 grams, 232mmol).Gained mixture 20 is stirred little with the temperature of 25 DEG C Time.Filter solid material, then wash, later by its suspension absolute methanol (800ml) with hexane.Dropping HCl-MeOH (4M) is molten Liquid, then stirring mixture 1 hour.After the carefully neutralization of NaOH, filtering mixt, the most carefully concentrated filtrate.Add Enter water, process solution the most as usual, to draw the ester crude product of 23 grams.Vacuum distillation method (100-120 DEG C, 20mmHg) draw the 2-methoxy-tetrahydro-furan-3-carboxylate methyl ester of 14 grams, for colorless oil.

With the temperature of 25 DEG C 2-methoxy-tetrahydro-furan-3-carboxylate methyl ester solution in the anhydrous THF of 60ml (10 grams, (125mmol) LiAiH of 4.75 grams is added in 62.5mmol)₄.Mixture cools down after being refluxed 4 hours.It is sequentially added into 4.75ml H₂NaOH (10%) aqueous solution of O and 4.75ml is in reactant mixture.The mixture of filtration gained, then concentrated filtrate, To obtain (2-methoxy-tetrahydro-furan-3-base)-methyl alcohol (7 grams).

Add in the above-claimed cpd solution (7 grams, 53mmol) in 300ml DMF NaH (3.2 grams, 80mmol, 60%) and BnBr (12.4ml, 106mmol).Stir the mixture 2 hours of gained with the temperature of 25 DEG C, be subsequently poured into the water of 1 liter In.And extract mixture with EtOAc (500ml*3) subsequently.Through MgSO₄It is dried the organic layer merged, filters subsequently and concentrate. With column chromatography (PE: EA=2: 1), residue is purified, to draw 3-benzyloxymethyl-2-methoxy-tetrahydro-furan (10 Gram).

BF is added in the preceding compound solution (10 grams, 45mmol) in DCM (180ml)₃.Et₂O (3.4ml) and m- CPBA (9.86g, 48.75mmol, 85%).Gained mixture is stirred overnight with the temperature of 25 DEG C.Dilute with EtOAc (500ml) Reactant mixture, then uses 10%Na₂S₂O₃, saturated NaHCO₃And salt solution washing.Organic layer is through MgSO₄Be dried, then filter and Concentrate.With column chromatography, residue is purified, to draw the intermediate 37 (6.7 grams) of benzyl protection.

The 10%Pd/ of 1 gram is added in the solution (6.7 grams, 32.5mmol) of the preceding compound in EtOH (200ml) C, and hydrogenate 10 hours with the temperature of 25 DEG C and 1 atmospheric pressure.Filtering mixt, then concentrates to obtain title compound (3.9 Gram).

Intermediate 38:5-(2-hydroxy-ethyl)-3H-furans-2-ketone.

In an inert atmosphere, with the temperature of 0 DEG C, to the furans in THF (150ml) cool down solution (3.40 grams, N-BuLi (the 2.5M solution in 22ml, n-hexane, 55.0mmol) is added in 50.0mmol).Solution is warming to room temperature, then Stir 3 hours.Then drip TMSCl (5.34 grams, 50mmol) with the temperature of 0 DEG C, and be at room temperature stirred for solution 3 hours. It follows that solution to be cooled to 0 DEG C, then second time add n-BuLi (2.5M solution in 22ml, n-hexane, 55.0mmol).After being stirred at room temperature 3 hours, by acetone/dry-ice condenser, oxirane (2.42 grams, 55.0mmol) is coagulated It is polymerized to solution, is the most at room temperature stirred for 12 hours.Use NH₄Cl aqueous solution quencher mixture, then extracts with EtOAc, warp Na₂SO₄It is dried the organic layer merged to obtain the required product (5 grams, 27.1mmol, 54% two step) of yellow liquid state.

To at CH₂Cl₂(30ml) above-claimed cpd (3 grams, 16.45mmol) and NaOAc (1.64 grams, 20mmol) in are molten Liquid drips at CH₂Cl₂(90ml) CH in₃CO₃H (16g, 40% in H₂In O) solution.It is stirred at room temperature reactant mixture mistake Night.Use Na₂SO₃Quencher is reacted, and uses saturated NaHCO₃And salt solution washing.Under reduced pressure concentration of organic layers.With column chromatography (PE: EA =1: 2) residue of gained is purified, to draw the required product (05 gram, productivity: 24%) of 0.5 gram of yellow liquid state.

Intermediate 39:(2-oXo-tetrahydro-furan-3-base sulfenyl)-acetic acid.

At room temperature ehtyl potassium xanthate (58.0 grams, 364mmol) is suspended in the anhydrous propanone of 200ml.Limit is stirred Limit dropping chloroacetic acid tert-butyl ester (50 grams, 332mmol).Potassium chloride is filtered to remove after 18 hours, then solvent is evaporated.Will Residue adds in ether, uses 5%NaHCO₃, water and salt solution washing, through MgSO₄Dried filtration and evaporation, to leave the O-of 80 grams Ethyl S-(tertbutyloxycarbonyl) methyl dithiocarbonates, for thick grease.At room temperature should with monoethanolamine (323mmol) stirring Grease 2 hours.Reactant mixture is added in ethyl acetate, then washs with 1.2N HC1, water and salt solution, through MgSO₄It is dried Rear filtration and evaporation.By residue vacuum distillation, to draw the mercapto-acetic acid tert-butyl ester of 30 grams, for clear oil thing.

To at 300ml CH₃3-bromo-dihydro-furan-2-ketone solution (16 grams, 97.6mmol) in CN adds K₂CO₃ (20 grams, 146mmol then add mercapto-acetic acid tert-butyl ester (14.5 grams, 98mmol).Reactant mixture is refluxed 2 little Time, then cool down.Filtering mixt, then concentrated filtrate.Residue is redissolved in the EtOAc of 300ml, then uses 1N HCl (100ml*2) washs gained solution.Organic layer is through MaSO₄After drying, filter and concentrate to obtain tert-butyl ester title compound Thing (23 grams).The ester of 16 grams is dissolved in the HCl-MeOH (4M) of 250ml, and stirs 4 hours with the temperature of 25 DEG C.With less than 45 DEG C temperature concentrated reaction mixture in a vacuum.With column chromatography (EtOAc), residue is purified, to obtain the title of 7 grams Compound.

B.1. the compound of the present invention

In the 1st to 19 following table, list the typical compound of the present invention, present in a tabular form.In these tables The title listing compound, the compound number being randomly assigned and structural information.

Table 1 shows the compound results numbering of compound (Cpd represent) of Formula II a or IIb

Table 1

Table 2 shows the compound results of formula III a or IIIb

Table 2

Table 3 shows the compound results of formula IV a or IVb

Table 3

Table 4 shows the compound results of Formula V a and Vb

Table 4

Table 5 shows the compound results of Formula IV a and VIb

Table 5

Table 6 shows the compound results of Formula VII a and VIIb

Table 6

Table 7 shows the compound results of Formula VIII a and VIIIb.

Table 7

Table 8 shows the compound results of Formula IX a and IXb.

Table 8

Table 9 shows the compound results of Formula X a and Xb.

Table 9

Table 10 shows the compound results of Formula X III.

Table 10

Table 11 shows the compound results of Formula X IV, XV, XVI and XVII.

Table 11

Table 12 shows the compound results of Formula X VIIIa.

Table 12

Table 13 shows the compound results of Formula X IXa.

Table 13

Table 14 shows the compound results of Formula X Xa.

Table 14

Table 15 shows the compound results of Formula X XIa.

Table 15

Table 16 shows the compound results of Formula X XIIa.

Table 16

Table 17 shows the compound results of Formula X XIIIa.

Table 17

Table 18 shows the compound results of Formula X XIVa.

Table 18

Other compound (table 19):

Table 19

The most external and experiment in vivo

C.The screening active ingredients of 1.ROCK inhibitory action

C.1.1. kinase inhibition

Method 1-Proqinase is arranged

³³P radio isotope Protein Kinase Assays is used to determine the IC of suppression ROCKII₅₀。

60mM HEPES-NaOH (pH value 7.5), 3mM MgCl will be comprised₂, 3mM MnCl₂, 3 μMs of sodium-sodium orthovanadates, 1.2mM DTT、1μM ATP、50μg/mlPEG_20.000, 1% (v/v) DMSO, 1 μM of ATP (about 3 × 10⁵cpm³³P-γ-ATP)、 The protein kinase (0.5nM-2,5ng/ hole) of substrate (S6 peptide-2000ng/ hole) and restructuring puts into oscillator mixing, then with 30 DEG C Incubation at temperature 80 minutes.By adding the 2%H of 50 μ l₃PO₄And oscillator mixing, to stop reaction.With 200 μ l 0.9% After NaCl solution washes twice, calculate dry plate.

Method 2:

Use the ROCK IMAP kit (production code member R8093) from Molecular Devices companies market, and The scheme provided essentially according to manufacturer performs Inhibition test with fluorescence polarization (FP) method.At the bottom of S6 ribosomal protein source property used Thing is (FI)-AKRRRLSSLRA, also from Molecular Devices company (production code member R7184).ROCKα/ The enzymatic mixture of ROCKII is from Upstate Biotechnology company (production code member 14-451).

In brief, all compounds are placed into 384 orifice plates and carry out screening to measure enzyme level, and concentration used is between 100 μ Between M to 0.3nM, use incremental 3 (or 2) times dilution method.Y compound (Y-27632 is by Tocris companies market) quilt It is used as with reference to (0.4 μM).

In order to perform experiment, the 1 μ l compound solution (each concentration) will tested in DMSO is placed with 10mM Tris-HCl、10mM MgCl₂, 0.1%BSA, 0.05%NaN₃, pH value be 7,22 μ l enzyme solutions in.The ultimate density of enzyme is 2.6nM。

At room temperature incubation is after 30 minutes, adds the ATP of 2 μ l with protein substrate at 10mM Tris-HCl, 10mM MgCl₂, 0.1%BSA, 0.05%NaN₃, pH value be the mixture in the solution of 7.2.Final concentration of 10 μMs of ATP, and albumen The ultimate density of substrate is then 0.2 μM.

At room temperature incubation is after 60 minutes, add 12 μ l IMAP binding soln (IMAP combine buffer A (1 ×) and The mixture of IMAP binding reagents (from ROCK IMAP kit)).

The mixture (cumulative volume: 17 μ l) that at room temperature incubation so obtains 60 minutes, uses automatic flat-plate reader (Perkin Elmer, Envision 2100-0010 HTS type) measures fluorescence polarization degree, and wherein FP wave filter uses FITC FP 480 exciter filters and FITC FP P-poI 535 and FITC FP S-pol 535 give out light optical filter (Perkin-Elmer). Use XL-Fit algorithm that result fits to a curve, the most again calculate the IC of each matched curve with XL-Fit algorithm₅₀ Value.

The IC of reference compound₅₀Value (Y compound Y-27632) is 0.4 μM.

Acquired IC₅₀Value (according to the scheme of above-mentioned regulation) is expressed as follows: " +++ " represents IC₅₀Less than 0.1 μM, " ++ " Represent IC₅₀Between 0.1 to 1 μM；"+", represents IC₅₀Between 1 to 10 μM, " " then represents and has not determined.

C.1.2. PBMC cell detection of ROCK activity in the case of there is and do not exist blood plasma that LPS-stimulates is used

PBMC in order to ensure LPS stimulates, with LPS associated proteins (LBP) rich medium, this can faciliated diffusion LPS extremely CD14 acceptor and the immune response of reinforcement LPS induction.The cell factor gone out secreted by activity PBMC includes TNF (neoplasm necrosis The factor), this can be drawn by the detection of colorimetric ELISA method.In the case of having reactive compound, TNF TNF Discharge and be suppressed with concentrationdependent manner.It follows that use identical setting to carry out check analysis in the presence of blood plasma.

For example, compound 46 illustrates IC₅₀It is 120nM (detecting without blood plasma), and (IC in the case of there is blood plasma₅₀ ＞ 10 μMs) it is then inactive.

C.1.3. the smooth muscle using the soft ROCK inhibitor of the organ bath external generation of calculating of GPT loosens work Property

Prepare the annulus trachealis of cavy, then with the bronchoconstriction agent carbachol incubation of fixed concentration.Later, add dense The soft ROCK inhibitor that degree is gradually increased, and be the measurement of concetration airway constriction characteristic of each compound.This research equipment obtains To measure IC₅₀, this power induced with it is equivalent to the compound concentration of 50% by the excipient treatment viewed power of tracheae As expression.

Additionally, also use the reservation of GPT organ bath described above assessment target.In brief, pressed down by ROCK The maximum stretching reaction that preparation is induced, annulus trachealis is rinsed thoroughly.Add carbachol the most again, measure receipts the most again Contracting characteristic, to determine the most whether the inhibitory activity of ROCK inhibitor extends.Prolongation inhibitory activity after flushing is also meaned Compound lung in vivo and can extend delay.

For example, compound 46 illustrates IC₅₀For 500nM.

C.2. pharmacological property

C.2.1. the stability test in the mankind and/or rat plasma

With the concentration of 1 μM incubation compound in rat (mouse or rabbit) or human plasma.Put extraction at a fixed time Sample, then determines the compound of residual after protein precipitation with LC-MS/MS.Half-life is using minute as representing.

C.2.2. the stability to the drug metabolic enzyme of lung S9

Use containing lung S9 (from smoker) and the reactant mixture of NADPH, UDPGA, PAPS and GSH confactor 1 μM of solution of incubation ROCK inhibitor.0,15,30 and 60 minutes collection samples after incubation.There is no the feelings of confactor With ROCK inhibitor and the experiment also parallel running of S9 part incubation negative control sample under condition.By using LC-MS/MS to divide Analysis, measure the remaining ROCK compound percentage of each time point, ROCK compound metabolic half life (using minute as table Show) and the metabolic half life of control compound.

#Cpd	T1/2 people lung S9
		46	53
47	＞ 60
		65	＞ 60

C.2.3. the stability analysis in rabbit aqueous humor

With the concentration of 1 μM (AH) incubation compound in rabbit aqueous humor.Put sample drawn at a fixed time, then at egg Determine the compound of residual with LC-MS/MS after white matter precipitation.

#Cpd	T1/2 rabbit AH
		46	＞ 60
169	＞ 60

C.2.4. kinetics combines and characterizes

This detection is based on report displacement binding technology.It relates to use specifically for the ATP-binding site of ROCK If probe.A signal can be produced when probe is incorporated into active site.There is being ROCK ATP competitive inhibitor In the case of, the position of probe can be deviateed enzyme and be moved, and signal is also disturbed.The displacement of monitoring probe within a period of time, and Determine Kon and Koff constant.OMNIA technology based on fluorescence is used to be determined the mechanism of action of inhibitor by Enzymology method.

C.2.5. the soft ROCK inhibitor generated anti-inflammatory activity in chmice acute LPS lung challenge model

In by nasal cavity after administered compound half an hour, attack mouse with LPS tracheal strips.After 24 hours, mouse quilt Put to death, then collect BAL fluid (BALF) and TCS, and determine the percentage of neutrophil cell.Anti-inflammatory Activity represents with the reduction of the reduction of BALF TCS and the Neutrophil numbers compared with non-treatment control group.

The intraocular pressure (IOP) of the most normotensive rat or rabbit reduces

Tonolab tonometer is used to measure the IOP of normal blood pressure rats.Owing to intraocular pressure scope is between 8-12mmHg (the most about 10), therefore it is generally observed that the highest range of decrease of 3mmHg.Timolol (beta-blocker), clonidine (α-be subject to Body activator) and Brimonidine (α 2-receptor stimulating agent) IOP is lowered 2-3mmHg.The intraocular pressure scope of normal arterial pressure rabbit between Between 15-20mmHg (the most about 18), obtain the highest decreases by 3-4mmHg.

Claims (29)

1. Formula II a, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VIIa, VIIb, VIIIa, VIIIb, IXa, IXb, Xa, Xb, The compound or its salt of XVIIIa, XIXa, XXa, XXIa, XXIb, or XXIIa,

Wherein

R¹¹It is substituted C_1-6Alkyl, described-C_1-6Alkyl is substituted with a substituent independently, and this substituent is selected from including Het¹、- O-Het², and-S-Het³Group；

R¹²It is substituted C_1-6Alkyl or substituted C_1-6Alkyl-S-C_1-6Alkyl；Described-C_1-6Alkyl and C_1-6Alkyl-S-C_1-6Alkane Base is separately replaced by 1,2 or 3 substituents, and this substituent is separately selected from comprising-C (=O)-OR²¹,-C (= O)-SR²²、Het¹、-O-Het², and-S-Het³Group；And

R¹Selected from comprising hydrogen or C_1-4The group of alkyl；

Ar is selected from following group:

Wherein X is hydrogen or halogen；

R³For hydrogen；

R⁴For by 1,2 or 3 optionally substituted C of substituent_1-20Alkyl, this substituent separately selected from comprise-C (=O)- OR²¹,-C (=O)-SR²²,-C (=O)-NR⁷R⁸、Het¹、-O-Het²、-S-Het³、-O-C_1-6Alkyl and-S-C_1-6The group of alkyl Not；

R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is replaced by a substituent, and this substituent is selected from following Group :-C (=O)-OR²¹,-C (=O)-SR²²,-C (=O)-NR⁹R¹⁰、Het¹、-O-Het²、-S-Het³、C_1-6Alkyl, C_1-6Alkane Base-O-C_1-4Alkyl or C_1-6Alkyl-O-C_2-4Thiazolinyl；

R⁷Or R⁸Separately selected from comprising hydrogen or C_1-6The group of alkyl；Described C_1-6Alkyl is replaced by 1,2 or 3 substituents, This substituent is separately selected from comprising-C (=O)-OR²¹, and-C (=O)-NH₂Group；

R⁹Or R¹⁰Separately selected from comprising hydrogen or C_1-6The group of alkyl；Described C_1-6Alkyl is taken by 1,2 or 3 substituents In generation, this substituent is separately selected from comprising-C (=O)-OR²¹, and-C (=O)-NH₂Group；

R²¹Selected from comprising C_1-20Alkyl, C_2-20Thiazolinyl, C_2-20Alkynyl, C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted Heterocyclic radical, the group of optionally substituted heteroaryl；

Wherein said C_1-20Alkyl can be optionally substituted by 1-4 substituent, this substituent independently selected from comprise halogen, cyano group, Hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-15The group of cycloalkyl or selected from following formula:

Or

R²¹Coupled carbonyloxy group and " aryl or heteroaryl " are formed in cyclic ester ring the ring comprising 4 to 9 carbon atoms together Ester；

R²²It is can be by 1-4 the optionally substituted C of substituent_1-20Alkyl, this substituent is independently selected from comprising halogen, hydroxyl, ammonia Base, cyano group and single or double (C_1-4Alkyl) group of amino；

Het¹、Het²Or Het³Separately selected from following group；

Wherein when occurring every time,

Aryl contains 6-10 atom, the optionally substituted base of described aryl be 1-4 selected from following substituent: halogen, nitro, C_1-4Alkyl, C_1-4Alkoxyl and C_1-4Alkylthio group；

Heteroaryl is the aromatic rings system of 5 to 12 carbon atoms, and wherein 1 to 4 ring carbon atom is by oxygen, nitrogen or sulphur atom generation Replacing, the optionally substituted base of described heteroaryl is that 1-4 is individual selected from following substituent: halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkane Epoxide and C_1-4Alkylthio group；

Heterocyclic radical comprises 3 to 1O annular atoms, and wherein 1 to 4 annular atoms is selected from oxygen, nitrogen or sulphur atom, appointing of described heterocyclic radical Selecting substituent is that 1-4 is individual selected from following substituent: halogen, hydroxyl, oxo, nitro, amino, cyano group, C_1-4Alkyl, C_3-6Cycloalkanes Base, C_1-4Alkoxyl, C_1-4Alkylthio group and-SO₂-NH₂。

Compound the most according to claim 1, wherein:

R¹It is hydrogen or C_1-4Alkyl；

Ar is selected from following group:

Wherein X is selected from the group comprising hydrogen or fluorine；

R³For hydrogen；

R⁴Selected from comprising C_1-20The group of alkyl, described C_1-20Alkyl is replaced by 1,2,3 substituents, and this substituent is each independent Ground is selected from comprising-C (=O)-OR²¹,-C (=O)-SR²²,-C (=O)-NR⁷R⁸、Het¹、-O-Het²、-S-Het³、C_1-6Alkyl- S-and C_1-6The group of alkyl-O-；Or

R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is replaced by a substituent, and this substituent is selected from bag Include-C (=O)-OR²¹,-C (=O)-SR²²,-C (=O)-NR⁹R¹⁰、Het¹、-O-Het²、-S-Het³, or C_1-6The group of alkyl； Wherein said C_1-6Alkyl is replaced by 1,2 or 3 substituents, and this substituent is separately selected from comprising-C (=O)-OR²¹、- C (=O)-SR²²,-C (=O)-NR⁹R¹⁰、Het¹、-O-Het², and-S-Het³Group；

R⁷Or R⁸Separately selected from comprising hydrogen or C_1-6The group of alkyl；Described C_1-6Alkyl is replaced by 1,2 or 3 substituents, This substituent is separately selected from comprising-C (=O)-OR²¹, and-C (=O)-NH₂Group；

R⁹Or R¹⁰Separately selected from comprising hydrogen or C_1-6The group of alkyl；Described C_1-6Alkyl by 1,2 or 3-C (=O)- OR²¹Substituent replaces；

R²¹Selected from comprising C_1-20Alkyl, C_2-20Thiazolinyl, C_2-20Alkynyl, C_3-15Cycloalkyl, optionally substituted heterocyclic radical and optionally take The group of the aryl in generation；

Wherein said C_1-20Alkyl can be optionally substituted by 1-4 substituent, this substituent selected from comprise halogen, cyano group, hydroxyl, Aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkane Base-S-, aryl, heteroaryl, the group of heterocyclic radical or selected from following formula:

Or

R²¹Coupled carbonyloxy group and phenyl form the cyclic ester of following formula together

Wherein q is the integer from 1 to 6；

R²²It is can be by 1-4 the optionally substituted C of halogenic substituent_1-20Alkyl；

Het¹、Het²Or Het³Separately selected from following group；

Wherein when occurring every time,

Aryl contains 6-10 atom, the optionally substituted base of described aryl be 1-4 selected from following substituent: halogen, nitro, C_1-4Alkyl, C_1-4Alkoxyl and C_1-4Alkylthio group；

Heterocyclic radical comprises 3 to 10 annular atomses, and wherein 1 to 4 annular atoms is selected from oxygen, nitrogen or sulphur atom, appointing of described heterocyclic radical Selecting substituent is that 1-4 is individual selected from following substituent: halogen, hydroxyl, oxo, nitro, amino, cyano group, C_1-4Alkyl, C_3-6Cycloalkanes Base, C_1-4Alkoxyl, C_1-4Alkylthio group and-SO₂-NH₂。

Compound the most according to claim 1, wherein:

-Ar represents pyridine radicals, and it can be optionally substituted by halogen；

-R¹Represent hydrogen or C_1-4Alkyl；

-R³It is hydrogen；

-R⁴It is-C_1-6Alkyl, it can be selected from-C (=O)-OR²¹Or Het¹Substituent replace；

-R²¹Selected from-C_1-6Alkyl, optionally substituted aryl or optionally substituted heteroaryl；Wherein

-Aryl stands phenyl, the optionally substituted base of described aryl is that 1-4 is individual selected from following substituent: halogen, nitro, C_1-4Alkane Base, C_1-4Alkoxyl and C_1-4Alkylthio group；And

-heteroaryl represent thienyl, 3,4-dihydro-1 (2H)-benzopyranyl or indyl, described heteroaryl optionally substituted Base is that 1-4 is individual selected from following substituent: halogen, oxo, nitro, C_1-4Alkyl, C_1-4Alkoxyl and C_1-4Alkylthio group.

Compound the most according to claim 1, wherein:

R³It is hydrogen；

R⁴Selected from comprising C_1-20The group of alkyl, they are replaced by 1,2 or 3 substituents, and this substituent is separately selected from bag Containing-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁷R⁸；Het¹；-O-Het²；-S-Het³；C_1-6Alkyl-S-and C_1-6Alkane The group of base-O-；Or

R³And R⁴Forming heterocycle together with the nitrogen-atoms being connected with them, it is replaced by a substituent, and this substituent is selected from bag Include-C (=O)-OR²¹；-C (=O)-SR²²；-C (=O)-NR⁹R¹⁰；Het¹；Or C_1-6The group of alkyl；Wherein said C_1-6Alkane Base is replaced by 1,2 or 3 substituents, and this substituent is separately selected from comprising Het¹；-O-Het²；And-S-Het³Group；

R⁷Or R⁸Separately selected from comprising hydrogen or C_1-6The group of alkyl, described C_1-6Alkyl is replaced by 1,2 or 3 substituents, This substituent is separately selected from comprising-C (=O)-OR²¹, and-C (=O)-NH₂Group；

R²¹Selected from comprising C_1-20Alkyl, C_3-10Cycloalkyl and the group of optionally substituted aryl；

Wherein said C_1-20Alkyl can be optionally substituted by 1-4 substituent, this substituent selected from comprise halogen, hydroxyl, aryl- O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, aryl, heteroaryl Base, the group of heterocyclic radical or selected from following formula:

Or

R²¹Coupled carbonyloxy group and phenyl are formed together and comprise following cyclic ester

Wherein q is the integer from 1 to 6；

R²²It is C_1-20Alkyl, can be optionally substituted by 1-4 halogenic substituent；

Het¹、Het²Or Het³Separately selected from the group of following formula；

Aryl used herein is selected from comprising phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl or 1, the group of 2,3,4-tetralyls；

The optionally substituted base of wherein said aryl is that 1-4 is individual selected from following substituent: halogen, nitro, C_1-4Alkyl, C_1-4Alkane Epoxide or C_1-4Alkylthio group.

Compound the most according to claim 1, wherein

R¹It is hydrogen or C_1-4Alkyl；

Ar is

X is hydrogen or halogen；

R³It is hydrogen；

R⁴It is C_1-6Alkyl, it is selected from following substituent and replaces :-C (=O)-OR²¹、Het¹、-O-Het², or-S-Het³。

6. the compound of claim 1, it is Formula II a, IIb, VIIa, VIIb, XVIIIa, XXIa, or the chemical combination that XXIIa represents Thing or its salt, wherein:

R¹For hydrogen or C_1-4Alkyl；

Ar is selected from following group:

Wherein X is selected from the group comprising hydrogen or halogen；

R²¹Group selected from following: C_1-20Alkyl, C_2-20Thiazolinyl, C_2-20Alkynyl, C_3-15Cycloalkyl, optionally substituted heterocyclic radical and Optionally substituted aryl；

Wherein said C_1-20Alkyl can be optionally substituted by 1-4 substituent, and this substituent is selected from following group: halogen, cyanogen Base, hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl- O-、C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-15Cycloalkyl or selected from following formula:

Or

R²¹Coupled carbonyloxy group and phenyl form the cyclic ester of following formula together

Wherein q is the integer from 1 to 6；

Het¹、Het²Or Het³Separately selected from following group；

Compound the most according to claim 6, wherein Ar represents

Wherein X is hydrogen or halogen；

-R¹It is hydrogen or C_1-4Alkyl.

Compound the most according to claim 6, wherein Ar represents

Wherein X is hydrogen or halogen；

-R¹Represent hydrogen or C_1-4Alkyl；

-R²¹Group selected from following: C_1-20Alkyl；C_3-10Cycloalkyl；Optionally substituted aryl；And optionally substituted heterocyclic radical；Its Described in C_1-20It is optionally substituted that alkyl can be replaced base, and this substituent is selected from following group: halogen, cyano group, hydroxyl ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heterocyclic radical and C_3-10Cycloalkyl or selected from following formula:

Compound the most according to claim 6, wherein Ar represents

Wherein X is hydrogen or halogen；

R¹It is hydrogen or C_1-4Alkyl；

R²¹Group selected from following: C_1-20Alkyl, C_2-20Thiazolinyl, C_2-20Alkynyl, C_3-15Cycloalkyl and optionally substituted aryl, appoint Select substituted heterocyclic radical, optionally substituted heteroaryl；

-wherein said C_1-20Alkyl can be optionally substituted by 1 or 2 substituent, and this substituent is independently selected from following group: halogen Element, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-O-C (=O)-C_1-6Alkyl, C_1-6 Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-15Cycloalkyl or selected from following formula

Compound the most according to claim 1, its compound represented for Formula II a, wherein

Ar is selected from following group:

Wherein

X is hydrogen or halogen；

R¹For hydrogen or C_1-4Alkyl；

R²¹Selected from comprising C_1-20Alkyl, C_2-20Thiazolinyl, C_2-20Alkynyl, C_3-15Cycloalkyl, optionally substituted aryl, optionally substituted Heterocyclic radical, the group of optionally substituted heteroaryl；

Wherein said C_1-20Alkyl can be optionally substituted by 1-4 substituent, this substituent independently selected from comprise halogen, cyano group, Hydroxyl, aryl-O-, aryl-S-, aryl-S (=O)₂-, aryl-C (=O) ,-O-C (=O)-C_1-6Alkyl, C_1-6Alkyl-O-, C_1-6Alkyl-S-, aryl, heteroaryl, heterocyclic radical and C_3-15The group of cycloalkyl or selected from following formula:

Or

R²¹Coupled carbonyloxy group and " aryl or heteroaryl " are formed in cyclic ester ring the ring comprising 4 to 9 carbon atoms together Ester.

11. be selected from following compounds Isosorbide-5-Nitrae, 7,10,14,15,17,31,38,39,41,42,46,47,174,175,183,184, The compound or its salt of 185,188,205,206,207 and 223:

Compound 1:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylate methyl ester；

Compound 4:2 '-(1-amino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylate methyl ester；

Compound 7:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid, ethyl ester；

Compound 10:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-propyl carboxylate；

Compound 14:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-butyl carboxylate；

Compound 15:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid pentyl ester；

Compound 17:2 '-amino methyl-5 '-own ester of (pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid；

Compound 31:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid ring butyl ester；

Compound 38:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid ring penta methyl esters；

Compound 39:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid's methyl esters；

Compound 41:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid 2-methoxy-ethyl ester；

Compound 42:2 '-amino methyl-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid 2-methoxyl group-propyl ester；

Compound 46:2 '-(1-amino-ethyl)-5 '-(the fluoro-pyridin-4-yl-carbamyl of 3-)-xenyl-3-carboxylic acid tetrahydrochysene- Furans-2-ylmethyl ester；

Compound 47:2 '-(1-amino-ethyl)-5 '-(the fluoro-pyridin-4-yl-carbamyl of 3-)-xenyl-3-carboxylic acid tetrahydrochysene- Pyrans-2-ylmethyl ester；

Compound 174:

Compound 175:

Compound 183:

Compound 184:

Compound 185:

Compound 188:

Compound 205:

Compound 206:

Compound 207:

Compound 223:

12. 1 kinds, for preventing and/or treat at least one disease relating to ROCK or the pharmaceutical composition of obstacle, comprise basis The described compound of any one of claim 1 to 11.

13. according to the compound of any one of claim 1 to 11 in preparation in the medicine suppressing the kinase whose activity of ROCK Purposes.

14. are used for preventing and/or treat at least one according to the compound of any one of claim 1 to 11 in preparation relates to ROCK Disease or obstacle medicine in purposes, described disease or obstacle be selected from: inflammation, fibrillatable, excessive cell proliferation, blood vessel Generate excessive, high response, barrier dysfunction, nerve degeneration pathology.

15. to be used for treating and/or prevent at least one to be selected from according to the compound of any one of claim 1 to 11 in preparation following Purposes in the disease of group or the medicine of obstacle: eye illness, breathing problem, ear disease, intestines problem, disease of skin, blood Pipe disease, diseases associated with inflammation, the nervous system disease, proliferative disease, kidney trouble, sex dysfunction, skeletal diseases, optimum before Row gland hyperplasia disease, graft-rejection, spasm, chronic obstructive bladder disease and allergy.

16. purposes according to claim 15, wherein said disease or obstacle are hypertension.

17. purposes according to claim 15, wherein said disease or obstacle are angiocardiopathy.

18. are selected from the eye of following group in preparation for treatment and/or prevention according to the compound of any one of claim 1 to 11 Purposes in the medicine of eyeball disease: PVR, optic neuropathy, glaucoma and inflammatory eye conditions.

19. purposes according to claim 18, wherein said disease of eye is selected from macular degeneration and retinal pigment degeneration Retina DD.

20. are selected from the exhaling of following group in preparation for treatment and/or prevention according to the compound of any one of claim 1 to 11 Inhale the purposes in the medicine of tract disease: pulmonary emphysema, asthma, fibrillatable, pneumonia, capsule fibroid become sick, COPD Disease, bronchitis, rhinitis and Respiratory Distress Syndrome(RDS).

21. purposes according to claim 20, wherein said breathing problem is chronic bronchitis or pulmonary fibrosis.

22. are selected from the larynx of following group in preparation for treatment and/or prevention according to the compound of any one of claim 1 to 11 Purposes in the medicine of throat, nose and ear disease: sinus problem, hearing problem, tonsillitis, ulcer and rhinitis.

23. are preparing the use for treating and/or in the medicine of prevention toothache according to the compound of any one of claim 1 to 11 On the way.

24. are selected from the skin of following group in preparation for treatment and/or prevention according to the compound of any one of claim 1 to 11 Purposes in the medicine of skin disease: hyperkeratinization, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, stratum spinosum epidermidis Oedema and ulcer.

25. are selected from the intestines of following group in preparation for treatment and/or prevention according to the compound of any one of claim 1 to 11 Purposes in the medicine of tract disease: IBD and intestinal obstruction.

26. are selected from the disease of following group in preparation for treatment and/or prevention according to the compound of any one of claim 1 to 11 The sick purposes in medicine: colitis, ileitis, appendicitis.

27. according to the compound of any one of claim 1 to 11 in preparation for treating and/or preventing in the medicine of Crohn disease Purposes.

28. according to the compound of any one of claim 1 to 11 in preparation for treating and/or preventing in the medicine of gastroenteritis Purposes.

29. are selected from the property of following group in preparation for treatment and/or prevention according to the compound of any one of claim 1 to 11 Purposes in handicapped medicine: erectile dysfunction, hypogonadism disease, bladder disease, hypertension, pulmonary artery height Pressure or operation on pelvis；And/or treat relevant property merit for treatment and the medicine using treatment hypertension, depression or anxiety Can obstacle.