CN102884049A - Heterocyclic amides as ROCK inhibitors - Google Patents

Heterocyclic amides as ROCK inhibitors Download PDF

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CN102884049A
CN102884049A CN2011800119496A CN201180011949A CN102884049A CN 102884049 A CN102884049 A CN 102884049A CN 2011800119496 A CN2011800119496 A CN 2011800119496A CN 201180011949 A CN201180011949 A CN 201180011949A CN 102884049 A CN102884049 A CN 102884049A
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alkyl
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CN102884049B (en
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D·雷森
O·戴非尔特
N·卡瓦尔
P·布罗姆
S·波兰德
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Ph Pharmaceutical Co ltd
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A Makemu Limited-Liability Co
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Abstract

The present invention relates to new kinase inhibitors of formula (I), more specifically ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In particular, the present invention relates to new ROCK inhibitors, compositions, in particular pharmaceuticals, comprising such inhibitors, and to uses of such inhibitors in the treatment and prophylaxis of disease. In addition, the invention relates to methods of treatment and use of said compounds in the manufacture of a medicament for the application to a number of therapeutic indications including sexual dysfunction, inflammatory diseases, ophthalmic diseases and Respiratory diseases.

Description

Heterocycleamide as the ROCK inhibitor
Technical field
The present invention relates to a kind of novel kinase inhibitor, more particularly is the ROCK inhibitor, comprises the composition of this class inhibitor, particularly medicine, and the purposes of this inhibitor aspect treatment and preventing disease.Specifically, the present invention relates to a kind of novel ROCK inhibitor, comprise the composition, particularly medicine of this class inhibitor, and the purposes of this inhibitor aspect treatment and preventing disease.
Background technology
Serine/threonine protein kitase ROCK is comprised of two kinds of isomer ROCK I and ROCKII in human body.ROCK I is encoded at No. 18 karyomit(e)s, and ROCKII(also is referred to as the Rho kinases) then be positioned at karyomit(e) No. 12..Both molecular masses all are about 160kD.Both have 65% homology at (aminoacid sequence), and wherein the homology in kinases district is up to 95%.Although their sequence is very similar, tissue distribution is had nothing in common with each other.The expression of ROCK I highest level can be observed from heart, lung and bone tissue, and ROCKII then mainly expresses at brain.These two kinds of isomer of nearest data presentation have the functional redundancy of part, and ROCK I is involved in immunocompetence more, and ROCKII then is involved in smooth muscle function.This term of ROCK refers to that ROCK I(has another name called ROK-β, p160ROCK or Rho kinase beta) and ROCKII(have another name called ROCK-α or Rho kinases α).
The ROCK activity has been proved to be the homologue by Rho(Ras) gtp binding protein a member---GTPase RhoA affects and strengthens.The RhoA of active form GTP combined interacts with ROCK Rho protein binding domain (RBD) generation that is positioned at from suppressing the C-terminal ring.After combination, the interaction between ROCK negativity regulatory region and the kinases district is destroyed.This process is so that kinases obtains the open conformation that is in active condition fully.This open conformation is also by due to the combination of lipid incitant (for example arachidonic acid) and the PH structural domain of kinases C-terminal structural domain.Another activation mechanism in the apoptosis process has also been described, and relate to through Caspase (caspase)-3 and-2(or granzyme granzyme B) the carboxyl terminal cracking respectively ROCK I and II carried out.
ROCK plays an important role in various cell functions, activation, spinous process retraction, wound healing, cell transformation and the genetic expression of for example migration, hyperplasia, survival and the thrombin induction reaction of the downward modulation of the tissue of smooth muscle contraction, actin cytoskeleton, platelet activation, myosin Phosphoric acid esterase cell adhesion, aortic smooth muscle cell, cardiac myocyte hypertrophy, bronchial smooth muscle contraction, smooth muscle contraction and the restructuring of nonmuscle cells skeleton, capacity regulation and control anion channel.ROCK also plays a role in relating to many signal pathways of autoimmunization and aspect of inflammation.ROCK has been proved to be and has played a role aspect the activation of NF-κ B, and this NF-κ B is a kind of key molecule that causes TNF and other inflammatory cytokines to produce.It was reported, the ROCK inhibitor can resist the generation that lipopolysaccharides (LPS) stimulates TNF-α and the IL-6 factor in the THP-1 scavenger cell.Therefore, the ROCK inhibitor provides useful therapy to treat autoimmune disorder, diseases associated with inflammation and response to oxidative stress.
Generally speaking, ROCK is the major control point of smooth muscle cell function, and is inflammatory process and the fibrosis of many ill organs and the crucial signaling composition of remodeling process of various inflammatory cells.Have obvious sign to show that ROCK has related to the pathogenesis of numerous disease, in the middle of comprised asthma, chronic obstructive pulmonary disease and glaucoma.In addition, ROCK involves various diseases and obstacle, in the middle of comprised eye illness, respiratory tract disease, cardiovascular disorder and vascular disease, diseases associated with inflammation, neural system and central nervous system disease, proliferative disease, kidney disease, sexual dysfunction, disease in the blood system, skeletal diseases, diabetes, benign prostate hyperplasia, graft-rejection, hepatic diseases, systemic lupus erythematous, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease and acquired immune deficiency syndrome (AIDS).
As illustration, ROCK looks like the target spot of a safety with gene knockout model and a large amount of academic research.Study on monitoring after the listing of the data of these knock out mice and fasudil (Fasudil) (the strong ROCK inhibitor of appropriateness that is used for the treatment of the cerebral vasospasm after the subarachnoid hemorrhage) combination has shown that ROCK is a real and significant drug targets.
The ROCK inhibitor can be used as the curative drug that treatment relates to the obstacle of ROCK approach.Therefore, we extremely need to develop a kind of various ROCK inhibitor relevant with the ROCK activation that can be used for treating, and consider that particularly these disease great majority are all treated deficiency at present.Some unrestriced examples are glaucoma, asthma and chronic obstructive pulmonary disease.
Glaucoma, a class may cause visual deterioration and blind disease because of optic nerve injury, causes because intraocular pressure increases.This is the blind common cause of adult, is a kind of chronic disease that needs lifelong control after making a definite diagnosis mostly.Because present treatment can only be controlled and can't radical curing of disease, and further stimulated, the side effect of part and whole body, this disease needs the therapeutics of an improvement.In addition, other favourable influence, namely the anti-inflammatory of ROCK inhibitor and neurotization composition will be paid the utmost attention to.Quote Tonofibrils, Focal adhesions and the MLC phosphorylation that can change the TM human cell of cellular form and minimizing incubation such as the ROCK inhibitor of Y-27632; The human trabecular meshwork shape tissue of their diastole vitro culture, the external human Schlemm pipeline endotheliocyte of diastole can significantly increase the girder outflow with it when the part is applied to animal, cause advantageously reducing intraocular pressure.
Allergic asthma is a kind of because the heredity susceptible person produces the non-habitual immune response to ubiquitous environment albumen, thus the respiratory tract chronic inflammatory diseases that causes.Although the methods for the treatment of of successful is arranged, morbidity can't be effected a radical cure to some extent because of these therapies to be increased; Situation is still being aggravated now, and increasing nonresponder is arranged.Novel, efficient, the steroid-sparing that can do with these all factors of disease are essential.
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD) be one group restricted take chronic non-reversibility respiratory tract, with unusual Inflammatory response, bronchoconstriction and lung tissue reinvent and damage disease as feature.It is one of human main causes of death, and morbidity increases just steadily.Because present therapy is not enough to cure diseases, our exigence is sought new methods for the treatment of.Because glucocorticosteroid only has limited or absolutely void effect, therefore only use till now bronchodilator.Quote the human bronchial prepared product that can diastole separates such as the ROCK inhibitor of Y-27632, the resistance of respiratory tract that suppresses anesthetized animal increases, the diastole effect of the outer and beta-receptor agonist that body is interior of intensive aspect, and after suction, give rapidly bronchiectasis.In addition, the ROCK inhibitor can be blocked H 2O 2The tracheal smooth muscle of inducing shrinks (clinical marker of response to oxidative stress).
Relevant with respiratory inflammation is, the ROCK inhibitor can resist the antiphlogistic drug mediation the enhancing of striding endothelial cell permeability, keep blood vessel endothelium barrier integrity, suppress in the irritated Respiratory Tract of Mice of inflow, the formation that prevents pulmonary edema and neutrophil migration, inhibition of the eosinophilic granulocyte after ovalbumin excites in the body tumour necrosis factor (TNF) that anaphylaxis and blocking-up LPS to methacholine and serotonin induce and discharge.As for respiratory tract fibrosis and reinvent the aspect, the ROCK inhibitor can be blocked the migration that asm cell is induced.ROCK is found in human lung cancer cell line, tracheal smooth muscle cell and the human airway unstriated muscle of calf for the external evidence of Airway Remodeling effect.ROCK generally results from (wherein the excalation of ROCK causes the myocardial fibrosis of decay) in the mouse for evidence in the body of fibrosis effect.Y-27632 decays to ROCK for myocardial infarction and fasudil (fasudil) for the myocardial fibrosis of the congestive heart failure of chronic hypertension rat model and brings other indication for the importance of reinventing.At last, the ROCK inhibitor increases the apoptotic cell loss of smooth muscle cell.
The human sexual response of masculinity and femininity is understood the interaction of Yin Shengli, psychology and Hormone Factors and is produced.One of them something in common of masculinity and femininity human sexual response is that blood vessel function is replied, thereby it can make because of the vascular smooth muscle relaxation that sexual stimulus brings phallic sex organization congested.Therefore, when the unstriated muscle of perineum blood vessel loosened, the blood pressure in penis and the clitoris and volume of blood flow also increased thereupon.The inflow of arterial blood will cause penis or corpora cavernosa clitoridis to enlarge, thereby cause erecing.
Impotence (male erectile dysfunction) generally is defined as and can't reaches and keep the erectile ability of sex expression and sexual intercourse of enough being satisfied with.Impotence may be because psychological disorders, nervous system abnormality or other comprise the physiological barrier of hormonoprivia, 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 is increased to 50 years old and will be increased to approximately 50%, and will be up to 67% during by 70 years old.According to estimates, can be painful because of the impotence problem up to 3,000 ten thousand U.S. male sex.
The women be along with the increase at age also can be faced sexual dysfunction, and with the climacterium outbreak with increase the risk of vascular disease.Therefore, the same with the male sex, women's sexual arousal has at least a part to increase with the volume of blood flow that makes clitoris hyperemia.The volume of blood flow of vagina has also increased the degree of lubrication of vagina.Therefore, Female sexual dysfunction may be owing to can't reaching or keep clitoris hyperemia period in whole sexuality and/or vaginal lubrication causes.
At present, major part is used for the treatment of the signal transduction pathway of the vasodilator energy target minimizing calcium ion of erective dysfunction, and this need to start the contraction movement of vascular smooth muscle.Yet from physiological angle, vasoconstrictive startup is a very acute activity, the time length only from the several seconds by several minutes.Erectile tissue remains on relaxed state by the long-term vasoconstriction of calcium dependent/non-dependent signal transduction pathway.Keeping the vasoconstrictive signal pathway of calcium dependent/non-dependent is the RhoA/Rho kinase pathways.The ROCK inhibitor is also corresponding useful for the treatment erective dysfunction.Therefore, from one side, the present invention comprises a kind of method that is used for the treatment of the sex sexual dysfunction, and it comprises comprising to the individual topical application that these needs are arranged and can weaken in the tested body of organ the compound of the Rho kinase activity of sexual stimulus and the composition of pharmaceutically acceptable carrier.
Several known ROCK inhibitor type are arranged at present.Current emphasis is the application of tumour and cardiovascular disorder.Till now, the outstanding treatment potentiality of ROCK inhibitor are only limited in the limited scope.Its reason is that ROCK is a kind of so effectively and widely biochemical regulator, and the general restraining effect of ROCK can be brought powerful biological effect, but also is considered to be the side effect of most of disease treatments.In fact, the ROCK inhibitor is subject to the obstruction of ROCK keying action when regulating the stage of nourishing of smooth muscle cell contraction with the medical use of stronger anti-inflammatory component treatment disease.The ROCK inhibitor of general administration can bring out blood pressure and obviously descend.Therefore, we have high demand to ROCK inhibitor of different nature.
For by regulating smooth muscle function and/or inflammatory process and/or reinvent the specific aim of launching disease and specifically treat, our high expectations ROCK inhibitor can the target Target organ, enters other organs with the medicine of avoiding large deal.Therefore, local or local medicinal application is desired.Generally, the medicine of topical application is used for the treatment of respiratory tract, eyes, sexual dysfunction and dermatopathy.In addition, local injection/the penetrate into potential medical use that pathological tissues further enlarges the ROCK inhibitor of topical application.If specific condition is met, these topical application can allow the medicine of high density to reach destination organization.In addition, bring the ROCK inhibitor into medical applications that implant and support can further enlarge the topical therapeutic cardiovascular disorder, these diseases are atherosclerosis, coronary heart disease and cardiac failure for example.Although directly by top-priority, the levels of drugs that enters systemic circulation attracts people's attention topical application in medical practice.For example, treat respiratory tract disease by the suction local delivery and will consist of the risk that general exposes, this is because can make high amount of drug enter gi tract and/or whole body by pulmonary absorption.As for the Eye disease treating of local delivery, also the existence because of cornea low-permeability, low fluid displacement, efficient drainage and eyelid blood vessel causes high amount of drug to enter gi tract and/or systemic circulation.Then there is seepage to advance the higher threat of systemic circulation as for percutaneous drug delivery, local injection and Implantable Medical Device.Therefore, except topical application, compound preferably has the other attribute that can avoid serious general to expose.
In case soft medicine is to enter systemic circulation with regard to the bioactive compounds of deactivation.This deactivation can realize in liver, but preferred deactivation should come across in the blood.These compounds will be brought into play local predictive role after in a single day being applied topically to destination organization/organ.When they from this tissue leakage to systemic circulation the time, they are with very rapidly deactivation.Therefore, select soft medicine in destination organization/organ, fully to stablize bringing into play required biological effect, but can in blood, be degraded into rapidly the compound of non-activity on the biology.In addition, it is most preferred that selection can be retained in the soft medicine of its biological targets.This characteristic will limit the number of times of administration every day, and the total loading of high expectations minimizing medicine and meta-bolites, also will improve significantly patient compliance in addition.
Generally speaking, we still have the necessary design and development ROCK inhibitor of continuing at present, to be used for the treatment of far-ranging morbid state.Compound described herein can be used for treating or alleviating the various obstacles relevant with the ROCK activation or the seriousness of illness with pharmaceutically acceptable composition.More particularly, compound of the present invention is preferred for preventing and/or treating disease or the obstacle of at least a ROCK of relating to, for example with the function of smooth muscle cell, inflammation, fibrosis, excessive cell proliferation, vasculogenesis excessively, hyperergy, barrier function obstacle, nerve degeneration pathology and reinvent relevant disease.For example, compound of the present invention can be used for preventing and/or treating following disease and illness:
-ophthalmic diseases or illness: include but not limited to retinopathy, optic neuropathy, glaucoma and retina degenerative disease, such as macular degeneration, retinitis pigmentosa and inflammatory eye illness.
-respiratory tract disease; Include but not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibrous lesions, chronic obstructive pulmonary disease (COPD); Bronchitis and rhinitis and respiratory distress syndrome
-throat, the disease of nose and ear: include but not limited to nasal sinus problem, hearing problem, tonsillitis, toothache, ulcer and rhinitis,
-dermatosis: include but not limited to hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulcer.
-intestinal tract disease: include but not limited to inflammatory bowel (IBD), enteritis, gastro-enteritis, intestinal obstruction, ileitis, ecphyaditis and Crohn's disease.
-cardiovascular and vascular disease: include but are not limited to pulmonary hypertension and lung vasoconstriction.
-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, Crohn's disease and ulcerative colitis.
-nervous system disorders: include but not limited to neuropathic pain.Therefore the compounds of this invention is applicable to prevent nerve degenerative diseases and the stimulating neural regeneration of various nervous system disorderss.
-proliferative disease: such as but not limited to mammary gland, colon, intestines, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate gland or thyroid cancer; Castleman's disease, leukemia, sarcoma, lymphoma; Malignocytoma (malignoma) and melanoma.
-kidney disease: include but not limited to kidney region fibrosis or renal insufficiency
-sexual dysfunction: be intended to comprise because of the defective type vasoactive and reply the masculinity and femininity sexual dysfunction that causes.Soft ROCK inhibitor of the present invention also can be used for treating the sexual dysfunction that is caused by many reasons.For instance, in one embodiment, soft ROCK inhibitor can be used for treating the sexual dysfunction relevant with hypogonadism disease, and more particularly, this hypogonadism disease is relevant with the reduction of androgen levels.In another embodiment, soft ROCK inhibitor can be used for treating the sexual dysfunction relevant with many reasons, and this includes but not limited to bladder disease, hypertension, diabetes or operation on pelvis sequela.In addition, soft ROCK inhibitor can be used for treating the sexual dysfunction by using some drugs to cause, for example is used for the treatment of the medicine of hypertension, depression or anxiety.
-skeletal diseases: include but not limited to osteoporosis and osteoarthritis
-in addition, compound of the present invention can be used for preventing and/or treating for example hyperplasia of prostate, graft-rejection, spasm, chronic obstructive the urinary bladder disease and irritated such disease and illness.
Summary of the invention
We find that surprisingly compound described herein as the inhibitor of ROCK, is soft ROCK inhibitor specifically.Compared to present known Rock inhibitor, for example described in the WO2007/042321, the difference of the compounds of this invention is their very fast compounds (as by PON-1 (PON1) activity) that converts non-activity on the function to.
PON1 is the dependent serum class of a kind of calcium ion A-esterase, and its synthetic reaching in liver is secreted in blood, and is combined with high-density lipoprotein (HDL) (HDLs) exclusivity.In addition, it can cracking comprises the specific subgroup of matrix of organophosphorus, aryl ester, lactone and cyclic carbonate.Therefore, the Y substituting group of selected the compounds of this invention is generally by following listed formula (I) conduct expression, to comprise the substituting group of the group (more specifically saying aryl ester and lactone) that is selected from aryl ester, lactone and cyclic carbonate.
Unless regulation is arranged in the literary composition in addition, asterisk used herein is to represent that described unit price or divalent group are connected to that point that its relevant structure and this group form its a part of structure.
From first aspect, the invention provides a kind of formula (I) compound or its steric isomer, tautomer, racemic modification, metabolite, prodrug or pro-drug, salt, hydrate or solvate,
Figure DEST_PATH_GDA00002198413500061
Wherein
R 1Be selected from the group that comprises hydrogen, alkyl or cycloalkyl; Not
Ar is selected from and comprises following group:
Figure DEST_PATH_GDA00002198413500062
Wherein X is selected from the group that comprises hydrogen or halogen;
Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-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 2-8Thiazolinyl is substituted independently respectively base and replaces; This substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 3Be selected from following group: hydrogen; By O-Het 2Or-S-Het 3The C that replaces 2-8Thiazolinyl; Or by the optional C that replaces of 1,2 or 3 substituting group 1-20Alkyl, this substituting group are independently selected from respectively and comprise aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3-S-C 1-6Alkyl reaches-O-C 1-6The group of alkyl; Wherein said-O-C 1-6Alkyl;-S-C 1-6Alkyl; Or C 3-6Cycloalkenyl group; Be substituted independently respectively base and replace, this substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 4Be selected from following group: by O-Het 2Or-S-Het 3The C that replaces 2-8Thiazolinyl or by the optional C that replaces of 1,2 or 3 substituting group 1-20Alkyl, this substituting group are independently selected from respectively and comprise aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21,-C(=O)-SR 22,-C(=O)-NR 7R 8, Het 1,-O-Het 2,-S-Het 3,-O-C 1-6Alkyl reaches-O-C 1-6The group of alkyl;
Wherein said-O-C 1-6Alkyl;-S-C 1-6Alkyl; Or C 3-6Cycloalkenyl group; Being substituted independently respectively base replaces; This substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group; Or;
R 3And R 4The nitrogen-atoms that links to each other with them forms heterocycle, and it is replaced by a substituting group, and this substituting group is selected from following group :-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3C 1-6Alkyl; C 1-6Alkyl-O-C 1-4Alkyl; Or C 1-6Alkyl-O-C 2-4Thiazolinyl; Each described C wherein 1-6Alkyl; C 1-6Alkyl-O-C 1-4Alkyl; Or C 1-6Alkyl-O-C 2-4Thiazolinyl is replaced by 1,2 or 3 substituting group respectively independently, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group;
R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; 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)-group; At least one R wherein 5Or R 6Be selected from C 1-6Alkyl; 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 1-6Alkyl-C(=O)-or C 2-8Thiazolinyl-C(=O)-separately replaced by 1,2 or 3 substituting group, this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
R 7Or R 8Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; Described C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group;
R 9Or R 10Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; Described C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group;
R 13Or R 14Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-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)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
R 21Be selected from and comprise C 1-20Alkyl; C 1-20Thiazolinyl; C 1-20Alkynyl; The optional C that replaces 3-15Cycloalkyl; The optional aryl that replaces; The optional heterocyclic radical that replaces; The group of the optional heteroaryl that replaces;
Wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, and this substituting group is independently selected from and comprises halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O) 2-, aryl-C(=O) ,-C(=O)-NR 13R 14, C 3-10Cycloalkyl ,-O-C(=O)-C 1-6Alkyl, C 1-6Alkyl-O-, C 1-6Alkyl-S-, aryl, heteroaryl, and the group of heterocyclic radical or be selected from following formula:
Or
R 21Coupled carbonyl oxygen base and " aryl or heteroaryl " are formed on the cyclic ester ring that the cyclic ester ring comprises 4 to 9 carbon atoms together; R 22Can be by 1,2,3 or the optional C that replaces of more substituting group 1-20Alkyl, this substituting group are independently selected from and comprise halogen, hydroxyl, amino, cyano group, and single or two (C 1-4Alkyl) amino group;
Het 1, Het 2Or Het 3Be independently selected from respectively following group;
Figure DEST_PATH_GDA00002198413500082
From another aspect, the invention provides the compounds of this invention, be used for suppressing in external or the body purposes of at least a kinase activity, or comprise the composition of this compound.
From another aspect, the invention provides the compounds of this invention, be used for suppressing the active purposes of at least a ROCK kinases (for example ROCKII and/or ROCKI isomer), or comprise the composition of this compound.
From another aspect, the invention provides the medicine and/or the animal medicinal composition that comprise the compounds of this invention.
From another aspect, the invention provides the compounds of this invention for the mankind or veterinary medicament.
From another aspect, the invention provides the compounds of this invention in the purposes of preparation in the medicine, described medicine is used for the treatment of and/or prevents at least a eye illness that is selected from, respiratory tract disease, cardiovascular disorder and vascular disease, diseases associated with inflammation, the disease of neural system and central nervous system disease and/or obstacle: proliferative disease, kidney disease, sexual dysfunction, hematologic disease, skeletal diseases, diabetes, benign prostate hyperplasia, graft-rejection, hepatic diseases, systemic lupus erythematous, spasm, hypertension, the chronic obstructive bladder disease, premature labor, infect, allergy, obesity, pancreatic disease and acquired immune deficiency syndrome (AIDS).
The detailed description of invention
The present invention is now further described.In the paragraph below, different aspect of the present invention all can be defined in more detail.Unless clear and definite expression, otherwise defined each aspect also may be in conjunction with any other one or more aspects.Specifically, anyly be expressed as preferred or favourable characteristic and also may be expressed as one or more preferred or favourable characteristics in conjunction with any other.
Unless regulation is arranged in the literary composition in addition, asterisk used herein is to represent that described unit price or divalent group are connected to that point that its relevant structure and this group form its a part of structure.
Undefined (racemization) center of asymmetry that may be present in the compounds of this invention will be by drawing the wave key or straight key is made Alternation Display, to manifest the undefined tridimensional character of key.
As referred to above, a first aspect of the present invention provides the compound of formula (I)
Figure DEST_PATH_GDA00002198413500091
Wherein Y, R 1And Ar as defined above, comprises stereoisomer form, solvate, pharmaceutically acceptable addition salt.
When describing compound of the present invention, unless regulation is arranged in the literary composition in addition, used term will be annotated by following definition:
Self or refer to formula C as " alkyl " term of the part of another group xH 2x+1Complete stable hydrocarbon, wherein x is the number more than or equal to 1.In general, alkyl group of the present invention comprises 1 to 20 carbon atom.Alkyl group can be straight or branched, and may be by indicated herein replacement.Added subscript after carbon atom, this subscript refers to the amount of carbon atom that the group of naming may comprise.Therefore, for instance, C 1-4Alkyl refers to have an alkyl to four carbon atom.The example of alkyl group is methyl, ethyl, n-propyl, sec.-propyl, butyl and isomer thereof (as: normal-butyl, isobutyl-and the tertiary butyl); Amyl group and isomer thereof, hexyl and isomer thereof, heptyl and isomer thereof, octyl group and isomer thereof, nonyl and isomer thereof; Decyl and isomer thereof.C 1-C 6Alkyl comprises all straight chains, side chain, or has the group of naphthene base of 1 to 6 carbon atom, has also therefore comprised methyl, ethyl, n-propyl, sec.-propyl, butyl and isomer thereof (as: normal-butyl, isobutyl-and the tertiary butyl); Amyl group and isomer thereof, hexyl and isomer thereof, cyclopentyl, 2-, 3-or 4-methylcyclopentyl, cyclopentyl-methyl and cyclohexyl.
" the optional alkyl that replaces " this term refers at any available tie point by the optional alkyl group (such as 1 to 4 substituting group, such as 1,2,3 or 4 substituting group or 1 to 2 substituting group) that replaces of one or more substituting groups.These substituent non-limitative examples have comprised halogen, hydroxyl, carbonyl, nitro, amino, oximido, imido grpup, azido-, diazanyl, cyano group, aryl, heteroaryl, cycloalkyl, acyl group, alkylamino, alkoxyl group, sulfydryl, alkylthio, carboxylic acid, amido, alkyl ester, carbamate, thio acylamino, urea, sulfonamido and similar.
Except as otherwise noted, otherwise " thiazolinyl " term used herein refers to contain straight chain, ring-type or the branched hydrocarbyl group of at least one carbon-to-carbon double bond.The example of alkenyl has comprised vinyl, E-and Z-type propenyl, pseudoallyl, E-and Z-type butenyl, 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.The optional thiazolinyl that replaces refers to optionally have the thiazolinyl of one or more substituting groups (such as 1,2,3 or 4), described substituting group be selected from above-mentioned to substituted alkyl defined those.
Except as otherwise noted, otherwise " alkynyl " term used herein refers to contain the straight or branched alkyl of at least one carbon-to-carbon triple bond.The example of alkynyl group has comprised ethynyl, E-and Z-type proyl, isopropyl alkynyl, E-and Z-type butynyl, E-and Z-type isobutyl alkynyl, E-and Z-type pentynyl, E-and Z-type hexin base and similar group.The optional alkynyl that replaces refers to optionally have the alkynyl of one or more substituting groups (such as 1,2,3 or 4), described substituting group be selected from above-mentioned to substituted alkyl defined those.
Self or as the part of another group " " term refers to group of naphthene base to cycloalkyl, that is to say, is the unit price that has 1,2 or 3 ring texture, saturated or unsaturated alkyl group.Cycloalkyl comprises all saturated or fractional saturations hydrocarbyl group of (comprising 1 or 2 two key), contains 1 to 3 ring, comprises monocycle, dicyclo, multi-ring alkyl group.Group of naphthene base may comprise 3 or more carbon atom in ring, then generally comprise 3 to 15 atoms according to the present invention.The further ring of polycyclic naphthene base can be by the fusion of one or more volution atom, bridge joint and/or adding.Group of naphthene base also may be considered to be the homocyclic ring subset of hereinafter discussing.The example of group of naphthene base includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and ring decyl, wherein is preferably cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, dicyclo (2.2.1) heptane base." optional replace cycloalkyl " refers to optionally have one or more substituent cycloalkyl (such as 1 to 3 substituting group, such as 1,2,3 or 4 substituting group), described substituting group be selected from above-mentioned to substituted alkyl defined those.When prefix " Asia " and cyclic group use simultaneously, hereinafter be also referred to as cycloalkylidene, this is to mean cyclic group defined herein two singly-bounds are arranged.Cycloalkylidene group of the present invention preferably contains the carbon atom of associated group of naphthene base equal amts.
If defined alkyl group is divalence, namely two singly-bounds are attached to other two groups, and they will be called as " alkylidene group " group.The unrestricted example of alkylidene group has comprised methylene radical, ethylidene, methyl methene, trimethylene, propylidene, tetramethylene, ethyl ethylidene, 1,2-dimethyl ethylidene, pentamethylene and cyclohexyl.Same, if alkenyl group defined above and following defined alkynyl group are divalence, namely there are two singly-bounds to be attached to other two groups, they reach " alkynylene " group with being called as respectively " alkenylene ".Alkylidene group of the present invention preferably contains the carbon atom of associated alkyl group equal amts.If have alkylidene group or cycloalkylidene double-basis, that will be connected to molecular structure by common carbon atom or different carbon atoms, central preferred common carbon atom.For this point is described, name of the present invention has added asterisk, C 3Alkylidene group may be *-CH for example 2CH 2CH 2-*, *-CH(-CH 2CH 3)-* or *-CH 2CH(-CH 3)-.Same, C 3Cycloalkylidene may be
If have the cycloalkylidene group, be preferably C 3-C 6Cycloalkylidene group, more preferably C 3Cycloalkylidene group (being the cyclopropylidene group) wherein can be connected to structure by common carbon atom.Cycloalkylidene and alkylidene group diradical in the compounds of this invention are possible, but preferably can not be substituted.
Self or as the heterocyclic radical of the part of another group " or " heterocycle " term refers to non-aromatic, the fully saturated or undersaturated cyclic group of part (for instance; 3 to 13 yuan of monocycles or 7 to 17 yuan of dicyclos or 10 to 20 yuan of three ring systems; or altogether comprise 3 to 10 annular atomses), wherein at least one carbon atoms ring at least one heteroatoms must be arranged.For comprising heteroatomic each ring in the heterocyclic group, can have 1,2,3 or 4 heteroatoms, be selected from nitrogen-atoms, Sauerstoffatom and/or sulphur atom, wherein nitrogen and sulfur heteroatom are optionally oxidized, and nitrogen heteroatom is optionally quaternized.If valence state allows, heterocyclic group can be connected to any heteroatoms or the carbon atom of ring or loop systems.The ring of many ring heterocycles can be by the fusion of one or more volution atom, bridge joint and/or adding.The optional heterocycle that replaces refers to optionally have one or more substituent heterocycles (such as 1 to 4 substituting group or as 1,2,3 or 4), is selected from those that substituted aryl is defined.
The example of heterocyclic group has comprised piperidines, azetidine, tetrahydroglyoxaline, imidazolidyl isoxazoline-3-yl oxazolidinyl isoxazole alkyl, thiazolidyl, the isothiazole alkyl, piperidyl, succinimide, the 3H-indyl, the isoindoline base, chromenyl, different chromanyl, xanthenyl, the 2H-pyrryl, the 1-pyrrolinyl, the 2-pyrrolinyl, the 3-pyrrolinyl, pyrrolidyl, the 4H-quinolizinyl, the 4aH-carbazyl, 2-oxo piperazinyl, piperazinyl, the homopiperazine base, the 2-pyrazolinyl, the 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, the 4H-pyranyl, 3,4-dihydro-2H-pyranyl, phthalazinyl, the oxa-cyclobutyl, the thia cyclobutyl, the 3-dioxolanyl, 1,3-dioxane base, 2,5-dioxy imidazolidyl (dioximidazolidinyl) 2,2,4-piperidone base, 2-Oxypertine base, 2-oxygen pyrrolidone-base (oxopyrrolodinyl), 2-oxygen azepine
Figure DEST_PATH_GDA00002198413500112
Base, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base, tetrahydro-thienyl, tetrahydric quinoline group, tetrahydro isoquinolyl, thio-morpholinyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, 1, the 3-dioxolanyl, 1,4-oxygen thia cyclohexyl (oxathianyl), 1,4-dithiane base (dithianyl), 1,3,5-trioxane base (trioxanyl), 6H-1,2,5-thiadiazine base, 2H-1,5,2-dithiazine base, 2H-oxocin base (oxocinyl), the 1H-pyrrolidyl, tetrahydrochysene-1,1-dioxo thienyl, N-formyl piperazine base and morpholinyl.
" aryl " term used herein refers to contain monocycle (being phenyl) or a plurality of aromatic nucleus merges (as: naphthalene or anthracene) or covalently bound polynary unsaturated and fragrant hydrocarbyl group, usually contains 6 to 10 atoms; It is fragrant wherein having a ring at least.Aromatic nucleus can optionally comprise one to three other ring (cycloalkyl, heterocyclic radical or heteroaryl) with its fusion.Aryl also is intended to comprise the partial hydrogenation derivative of the carbon-loop system of enumerating herein.The unrestricted example of aryl has comprised phenyl, xenyl, biphenylene, 5-or 6-tetralin base (tetralinyl), 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-base difficult to understand, 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-pentalenyl (pentalenyl), 1,2-, 3-, or 4-fluorenyl, 4-or 5-dihydro indenyl, 5-, 6-, 7-, or 8-tetralyl, 1,2,3, the 4-tetralyl, 1,4-dihydro naphthyl, hexichol [a, d] cycloheptenyl, and 1-, 2-, 3-, 4-, or 5-pyrenyl.
Aromatic ring can optionally be replaced by one or more substituting groups." optional replace aryl " refers to any available tie point is optional has one or more substituent aryl (such as 1 to 5 substituting group, such as 1,2,3 or 4).These substituent unrestricted examples be selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarboxyl, azido-, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxyl group ,-SO 2-NH 2, aryl, heteroaryl, aralkyl, haloalkyl, halogenated alkoxy, carbalkoxy, alkyl amino-carbonyl, heteroarylalkyl, alkyl sulfonamide, heterocyclic radical, alkyl-carbonyl-amino alkyl, aryloxy, alkyl-carbonyl, acyl group, aryl carbonyl, aminocarboxyl, alkyl sulfinic acid ,-SO 2R a, alkylthio, carboxyl and similarly, wherein R aIt is alkyl or cycloalkyl.
If the carbon atom of aromatic yl group is substituted by heteroatoms, consequent ring is called as heteroaryl ring.
Self or refer to as " heteroaryl " term of the part of another group but be not limited only to aromatic nucleus or the loop systems of 5 to 12 carbon atoms, wherein contain 1 to 3 ring and merge or covalent attachment, usually contain 5 to 8 atoms; Wherein have at least one to be fragrant, the one or more carbon atoms in wherein one or more these rings can be replaced by oxygen, nitrogen or sulphur atom, and wherein nitrogen and sulfur heteroatom are optionally oxidized, and nitrogen heteroatom is optionally quaternized.These rings can be fused to aryl, cycloalkyl, heteroaryl or heterocyclic ring.The unrestricted example of these heteroaryls has comprised: pyrryl, furyl, thienyl, pyrazolyl, imidazolyl oxazolinyl isoxazolyl, thiazolyl, isothiazolyl, triazolyl oxadiazolyl, thiadiazolyl group, tetrazyl, the oxa-triazole, the thiatriazole base, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl oxazinyl dioxin base, thiazinyl, triazinyl, imidazoles [2,1-b] [1,3] thiazolyl, thieno-[3,2-b] furyl, thieno-[3,2-b] thienyl, [2,3-d] [1,3] thiazolyl, thieno-[2,3-d] imidazolyl, tetrazolo [1,5-a] pyridyl, indyl, the indolizine base, pseudoindoyl, benzofuryl, benzo is given a tongue-lashing the base of muttering, 1(4H)-benzo gives a tongue-lashing the base of muttering, 1(2H)-benzo gives a tongue-lashing the base of muttering, 3,4-dihydro-1(2H)-benzo is given a tongue-lashing the base of muttering, 3,4-dihydro-1(2H)-benzo is given a tongue-lashing the base of muttering, isobenzofuran-base, benzothienyl, isobenzo-thienyl, indazolyl, benzimidazolyl-, 1, the 3-benzoxazolyl, 1,2-benzoisoxazole base, 2,1-benzoisoxazole base, 1, the 3-benzothiazolyl, 1, the 2-[4-morpholinodithio base, 2,1-benzisothiazole base, the benzotriazole base, 1,2,3-Ben Bing oxadiazole, 2,1,3-Ben Bing oxadiazole, 1,2,3-diazosulfide base, 2,1,3-diazosulfide base, the thiophene pyridyl, purine radicals, imidazo [1,2-a] pyridyl, 6-oxygen-pyridazine-1(6H)-Ji, the 2-oxo pyridine-1(2H)-Ji, 6-oxygen pyridazine-1(6H)-Ji, the 2-oxo pyridine-1(2H)-Ji, 1,3-benzo dioxolyl, quinolyl, isoquinolyl, scold the piperazine base, quinazolyl, quinoxalinyl, the 7-azaindolyl, the 6-azaindolyl, the 5-azaindolyl, the 4-azaindolyl.
" pyrryl " used herein (being also referred to as azoles base azolyl) term has comprised pyrroles-1-base, pyrroles-2-base and pyrroles-3-base." furyl furanyl " used herein (being also referred to as furans furyl) term has comprised furans-2-base and furans-3-base." thienyl thiophenyl " used herein (being also referred to as thiophene thienyl) term has comprised thiophene-2-base and thiene-3-yl-." pyrazolyl " used herein (being also referred to as 1H-pyrazolyl and 1,2-azoles base) term has comprised pyrazol-1-yl, pyrazole-3-yl, pyrazoles-4-base and pyrazoles-5-base." imidazolyl " used herein term has comprised imidazoles-1-base, imidazoles-2-base, imidazol-4 yl and imidazoles-5-base.“ oxazolyl used herein " (being also referred to as 1,3-oxazolyl) term comprises oxazolyl-2-base; Oxazolyl-4-Ji is Ji oxazolyl-5-base.“ isoxazolyl used herein " (being also referred to as 1,2-oxazolyl) term comprises isoxazolyl-3-base; Isoxazolyl-4-base Ji isoxazolyl-5-base." thiazolyl " used herein (being also referred to as the 1,3-thiazoles base) term has comprised thiazolyl-2-base; Thiazolyl-4-base and thiazolyl-5-base (being also referred to as 2-thiazolyl, 4-thiazolyl and 5-thiazolyl)." isothiazolyl " used herein (being also referred to as 1,2-isothiazolyl) term has comprised isothiazolyl-3-base, isothiazolyl-4-base and isothiazolyl-5-base." triazolyl " used herein term has comprised 1H-triazolyl and 4H-1,2,4-triazolyl, " 1H-triazolyl " comprised 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazole-4-yl, 1H-1,2,3-triazole-5-base, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazole-3-base and 1H-1,2,4-triazole-5-base." 4H-1,2,4-triazolyl " comprised 4H-1,2,4-triazole-4-yl and 4H-1,2,4-triazole-3-base.“ oxadiazolyl used herein " term comprised 1,2,3-oxadiazole-4-base, 1,2,3-oxadiazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,5-oxadiazole-3-base and 1,3,4-oxadiazole-2-base." thiadiazolyl group " used herein term has comprised 1,2,3-thiadiazoles-4-base, 1,2,3-thiadiazoles-5-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, 1,2,5-thiadiazoles-3-base (being also referred to as furazan-3-yl) and 1,3,4-thiadiazoles-2-base." tetrazyl " used herein term has comprised 1H-TETRAZOLE-1-base, 1H-TETRAZOLE-5-base, 2H-tetrazolium-2-base, has reached 2H-tetrazolium-5-base." oxa-triazolyl " used herein term has comprised 1,2,3,4-oxa-triazole-5-base and 1,2,3,5-oxa-triazole-4-yl." thiatriazole base " used herein term has comprised 1,2,3,4-thiatriazole-5-base and 1,2,3,5-thiatriazole-4-base." pyridyl pyridinyl " used herein term has comprised (being also referred to as " pyridine pyridyl ") pyridine-2-base, pyridin-3-yl and pyridin-4-yl (being also referred to as 2-pyridyl, 3-pyridyl and 4-pyridyl)." pyrimidyl " used herein term has comprised pyrimidine-2-base, pyrimidine-4-yl, pyrimidine-5-base and pyrimidine-6-base." pyrazinyl " used herein term has comprised pyrazine-2-base and pyrazine-3-base." pyridazinyl (pyridazinyl) " used herein term has comprised oiazines-3-base and oiazines-4-base.“ oxazinyl used herein " (being also referred to as " Isosorbide-5-Nitrae-oxazinyl ") term comprised Isosorbide-5-Nitrae-oxazines-4-base and Isosorbide-5-Nitrae-oxazines-5-base.“ dioxin base used herein " (being also referred to as " Isosorbide-5-Nitrae-dioxin bases ") term comprised Isosorbide-5-Nitrae-dioxin-2-base and Isosorbide-5-Nitrae-dioxin-3-base." thiazinyl " used herein (being also referred to as " Isosorbide-5-Nitrae-thiazinyl ") term has comprised 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 Isosorbide-5-Nitrae-thiazine-6-base." triazinyl " used herein term has comprised 1,3,5-triazines-2-base, 1,2,4-triazine-3-base, 1,2,4-triazine-5-base, 1,2,4-triazine-6-base, 1,2,3-triazine-4-base and 1,2,3-triazine-5-base." imidazo [2,1-b] [1,3] thiazolyl " used herein term has comprised 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." thieno-[3,2-b] furyl " used herein term has comprised thieno-[3,2-b] furans-2-base, thieno-[3,2-b] furans-3-base, thieno-[3,2-b] furans-4-base, has reached thieno-[3,2-b] furans-5-base." thieno-[3,2-b] thienyl " used herein term has comprised 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 has comprised thieno-[2,3-d] [1,3] thiazol-2-yl, thieno-[2,3-d] [1,3] thiazole-5-base and thieno-[2,3-d] [1,3] thiazole-6-base." thieno-[2,3-d] imidazolyl " used herein term has comprised thieno-[2,3-d] imidazoles-2-base, thieno-[2,3-d] imidazol-4 yl and thieno-[2,3-d] imidazoles-5-base." tetrazolo [1,5-a] pyridyl " used herein term has comprised tetrazolo [1,5-a] pyridine-5-base, tetrazolo [1,5-a] pyridine-6-base, tetrazolo [1,5-a] pyridin-7-yl, has reached tetrazolo [1,5-a] pyridine-8-base." indyl " used herein term has comprised indoles-1-base, indoles-2-base, indol-3-yl ,-indoles-4-base, indoles-5-base, indoles-6-base and indoles-7-base.It is used herein that " " term has comprised that indolizine-1-is basic, indolizine-2-is basic, indolizine-3-is basic, indolizine-5-is basic, indolizine-6-is basic, indolizine-7-is basic, it is basic to reach indolizine-8-to the indolizine base." pseudoindoyl " used herein " term has comprised isoindole-1-base, isoindole-2-base, isoindole-3-base, isoindole-4-base, isoindole-5-base, isoindole-6-base and isoindole-7-base." benzofuryl " used herein (being also referred to as benzo [b] furyl) term has comprised cumarone-2-base, cumarone-3-base, cumarone-4-base, cumarone-5-base, cumarone-6-base and cumarone-7-base." isobenzofuran-base " used herein (being also referred to as benzo [c] furyl) term has comprised isobenzofuran-1-base, isobenzofuran-3-base, isobenzofuran-4-base, isobenzofuran-5-base, isobenzofuran-6-base and isobenzofuran-7-base." benzothienyl " used herein (being also referred to as benzo [b] thienyl) term has comprised that 2-benzo [b] thienyl, 3-benzo [b] thienyl, 4-benzo [b] thienyl, 5-benzo [b] thienyl, 6-benzo [b] thienyl reach-7-benzo [b] thienyl (being also referred to as thionaphthene-2-base, thionaphthene-3-base, thionaphthene-4-base, thionaphthene-5-base, thionaphthene-6-base and thionaphthene-7-yl)." isobenzo-thienyl " used herein (being also referred to as benzo [c] thienyl) term has comprised different thionaphthene-1-base, different thionaphthene-3-base, different thionaphthene-4-base, different thionaphthene-5-base, different thionaphthene-6-base and different thionaphthene-7-base." indazolyl " used herein (being also referred to as 1H-indazolyl or 2-azaindolyl) term has comprised that 1H-indazole-1-is basic, 1H-indazole-3-is basic, 1H-indazole-4-is basic, 1H-indazole-5-is basic, 1H-indazole-6-is basic, 1H-indazole-7-is basic, 2H-indazole-2-is basic, 2H-indazole-3-is basic, 2H-indazole-4-is basic, 2H-indazole-5-is basic, 2H-indazole-6-is basic, it is basic to reach 2H-indazole-7-." benzimidazolyl-" used herein term has comprised benzoglyoxaline-1-base, benzimidazolyl-2 radicals-Ji, benzoglyoxaline-4-base, benzoglyoxaline-5-base, benzoglyoxaline-6-base and benzoglyoxaline-7-base." 1,3-benzoxazolyl " used herein term has comprised 1,3-benzoxazole-2-base, 1,3-benzoxazole-4-base, 1,3-benzoxazole-5-base, 1,3-benzoxazole-6-base and 1,3-benzoxazole-7-base." 1,2-benzoisoxazole base " used herein term has comprised 1,2-benzoisoxazole-3-base, 1,2-benzoisoxazole-4-base, 1,2-benzoisoxazole-5-base, 1,2-benzoisoxazole-6-base and 1,2-benzoisoxazole-7-base." 2,1-benzoisoxazole " used herein term has comprised 2,1-benzoisoxazole-3-base, 2,1-benzoisoxazole-4-base, 2,1-benzoisoxazole-5-base, 2,1-benzoisoxazole-6-base and 2,1-benzoisoxazole-7-base." 1,3-benzothiazolyl " used herein term has comprised 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-benzisothiazole base " used herein term has comprised 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-benzisothiazole base " used herein term has comprised 2,1-benzisothiazole-3-base, 2,1-benzisothiazole-4-base, 2,1-benzisothiazole-5-base, 2,1-benzisothiazole-6-base and 2,1-benzisothiazole-7-base." benzotriazole base " used herein term has comprised benzotriazole-1-base, benzotriazole-4-base, benzotriazole-5-base, benzotriazole-6-base and benzotriazole-7-base." 1,2,3-Ben Bing oxadiazolyl " used herein term has comprised 1,2,3-Ben Bing oxadiazole-4-base, 1,2,3-Ben Bing oxadiazole-5-base, 1,2,3-Ben Bing oxadiazole-6-base and 1,2,3-Ben Bing oxadiazole-7-base." 2,1,3-Ben Bing oxadiazolyl " used herein term has comprised 2,1,3-Ben Bing oxadiazole-4-base, 2,1,3-Ben Bing oxadiazole-5-base, 2,1,3-Ben Bing oxadiazole-6-base and 2,1,3-Ben Bing oxadiazole-7-base." 1,2,3-Ben Bing oxadiazolyl " used herein term has comprised 1,2,3-Ben Bing oxadiazole-4-base, 1,2,3-Ben Bing oxadiazole-5-base, 1,2,3-Ben Bing oxadiazole-6-base and 1,2,3-Ben Bing oxadiazole-7-base." 2,1,3-diazosulfide base " used herein term has comprised 2,1,3-diazosulfide-4-base, 2,1,3-diazosulfide-5-base, 2,1,3-diazosulfide-6-base and 2,1,3-diazosulfide-7-base." thienopyridine base " used herein term has comprised thieno-[2,3-b] pyridyl, thieno-[2,3-c] pyridyl, thieno-[3,2-c] pyridyl and thieno-[3,2-b] pyridyl." purine radicals " used herein term has comprised purine-2-base, purine-6-base, purine-7-base and purine-8-base." imidazo [1; 2-a] pyridyl " used herein term has comprised imidazo [1,2-a] pyridine-2-is basic, 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-benzo dioxolyl " used herein term has comprised 1,3-benzo dioxole-4-base, 1,3-benzo dioxole-5-base, 1,3-benzo dioxole-6-base, and 1,3-benzo dioxole-7-base." quinolyl " used herein term has comprised quinoline-2-base, quinoline-3-base, quinolyl-4, quinoline-5-base, quinoline-6-base, quinoline-7-base and quinoline-8-yl." isoquinolyl " used herein term has comprised isoquinolyl-1, isoquinoline 99.9-3-base, isoquinoline 99.9-4-base, isoquinoline 99.9-5-base, isoquinoline 99.9-6-base, isoquinoline 99.9-7-base and isoquinoline 99.9-8-base." scolding the piperazine base " used herein term has comprised scolds piperazine-3-base, scolds piperazine-4-base, scolds piperazine-5-base, scolds piperazine-6-base, scolds piperazine-7-base and scold piperazine-8-base." quinazolyl " used herein term has comprised quinazoline-2-base, quinazoline-4-base, quinazoline-5-base, quinazoline-6-base, quinazoline-7-base and quinazoline-8-base." quinoxalinyl " used herein term has comprised quinoxaline-2-base, quinoxaline-5-base, has reached quinoxalin-6-yl." 7-azaindolyl " used herein term refers to 1H-pyrroles's [2,3-b] pyridyl and comprises 7-azaindole-1-base, 7-azaindole-2-base, 7-azaindole-3-base, 7-azaindole-4-base, 7-azaindole-5-base, 7-azaindole-6-base." 6-azaindolyl " used herein term refers to 1H-pyrroles's [2,3-c] pyridyl and comprises 6-azaindole-1-base, 6-azaindole-2-base, 6-azaindole-3-base, 6-azaindole-4-base, 6-azaindole-5-base, 6-azaindole-7-base." 5-azaindolyl " used herein term refers to 1H-pyrroles's [3,2-c] pyridyl and comprises 5-azaindole-1-base, 5-azaindole-2-base, 5-azaindole-3-base, 5-azaindole-4-base, 5-azaindole-6-base, 5-azaindole-7-base." 4-azaindolyl " used herein term refers to 1H-pyrroles's [3,2-b] pyridyl and comprises 4-azaindole-1-base, 4-azaindole-2-base, 4-azaindole-3-base, 4-azaindole-5-base, 4-azaindole-6-base, 4-azaindole-7-base.
For instance, the unrestricted example of heteroaryl can be 2-or 3-furans, 2-or 3-thienyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 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-triazole-1-,-4-or-5-base, 1,2,4-triazole-1-,-3-,-4-or-5-base, 1H-TETRAZOLE-1-, or-the 5-base, 2H-tetrazolium-2-, or-the 5-base, 1,2,3-oxadiazole-4-or-5-base, 1,2,4-oxadiazole-3-or-5-base, 1,2, the 5-oxadiazolyl, 1,3, the 4-oxadiazolyl, 1,2,3-thiadiazoles-4-or-5-base, 1,2,4-thiadiazoles-3-or-5-base, 1,2,5-thiadiazoles-3-or-4-base, 1,3, the 4-thiadiazolyl group, 1-or 5-tetrazyl, 2-, 3-or 4-pyridine, 3-or 4-pyridazinyl, 2-, 4-, 5-or 6-pyrimidyl, 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-cumarone, 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, 1,4-oxazine-2-or-3-base, 1,4-dioxin-2-or-3-base, 1,4-thiazine-2-or-3-base, 1,2, the 3-triazinyl, 1,2, the 4-triazinyl, 1,3,5-triazine-2-,-4-or-6-base, thieno-[2,3-b] furans-2-,-3-,-4-, or-the 5-base, benzoglyoxaline-1-base,-2-base,-4-base,-5-base,-6-base, or-the 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, 3-, 4-, 5-, 6-or 7-benzisothiazole base, 1,3-benzothiazole-2-base,-4-base,-5-base,-6-base or-the 7-base, 1,3-benzo dioxole-4-base,-5-base,-6-base, or-the 7-base, benzotriazole-1-base,-4-base,-5-base,-6-base or-7-base 1-, the 2-thianthrenyl, 3-, 4-or 5-isobenzofuran-base, 1-, 2-, 3-, 4-or 9-xanthenyl, 1-, 2-, 3-or 4-benzo oxathiin base, 2-, the 3-pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-indolizinyl, 2-, 3-, 4-or 5-pseudoindoyl, 1H-indazole-1-base, the 3-base,-4-base,-5-base,-6-base, or-the 7-base, 2H-indazole-2-base, the 3-base,-4-base,-5-base,-6-base, or-the 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, imidazo [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] pyridine-8-base, 2-, 6-, 7-or 8-purine radicals, 4-, 5-or 6-phthalazinyl, 2-, 3-or 4-naphthyridinyl, 2-, 5-or 6-quinoxalinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, 1-, 2-, 3-or 4-quinolizinyl, 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-isoquinolyl isoquinolinyl(isoquinolyl isoquinolyl)), 3-, 4-, 5-, 6-, 7-or 8-scold the 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-carbolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-phenanthridinyl, 1-, 2-, 3-or 4-acridyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-(1,7) the phenanthrolene base, 1-or 2-phenazinyl, 1-, 2-, 3-, 4-, or lysivane base, 3-or 4-furazan base, 1-, 2-, 3-, 4-, or 10-Fei oxazinyl, or the derivative that replaces in addition.
" optional replace heteroaryl " refers to optionally have one or more substituent heteroaryls (such as 1 to 4 substituting group, such as 1,2,3 or 4), is selected from above-mentioned to the substituted aryl definition those.
" oxo " used herein term refers to group=O.
" alkoxyl group " used herein term refers to formula-OR bGroup, R wherein bIt is alkyl.Alkoxyl group is C preferably 1-C 10Alkoxyl group, C 1-C 6Alkoxyl group or C 1-C 4Alkoxyl group.The unrestricted example of applicable alkoxyl group has comprised methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, amyl group oxygen and hexyloxy.If the Sauerstoffatom of alkoxy base is replaced by sulphur, consequent group is called as thio alkoxy." halogenated alkoxy " is an alkoxy base, and wherein the one or more hydrogen atoms in the alkyl group are replaced by halogen.The unrestricted example of applicable halogenated alkoxy has comprised fluorine methoxyl group, difluoro-methoxy, trifluoromethoxy, 2,2,2-trifluoro ethoxy, 1,1,2,2-tetrafluoro oxyethyl group, 2-fluorine oxyethyl group, 2-chloroethoxy, 2,2-difluoroethoxy, 2,2,2-three chloroethoxies; Trifluoromethoxy, 2-bromine oxethyl, pentafluoroethyl group, 3,3,3-trichlorine propoxy-, 4,4,4-trichlorine butoxy.Used herein " aryloxy " group of term representative-O-aryl, wherein the definition of aryl please see above.
The group of " aryl carbonyl " used herein or " aroyl " term representative-C(O)-aryl, wherein the definition of aryl please see above.Self or refer to have the group that above-mentioned group of naphthene base is connected to the abovementioned alkyl chain as " cycloalkylalkyl " term of the part of another group.The example of this class cycloalkylalkyl has comprised cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl, 1-cyclopentyl ethyl, 1-cyclohexyl ethyl, 2-cyclopentyl ethyl, 2-cyclohexyl ethyl, cyclobutyl propyl ester, cyclopentyl propyl ester, 3-cyclopentyl butyl, cyclohexyl butyl and similar.
Self or refer to have the group that above-mentioned heterocyclic radical group is connected to the abovementioned alkyl chain as " heterocyclic radical-alkyl " term of the part of another group, namely be connected to-R d-R cGroup, wherein R dAlkylidene group or the alkylidene group that replaced by alkyl group, and R cIt is the heterocyclic radical group.
Self or refer to-CO as " carboxyl " or " hydroxycarbonyl group " term of the part of another group 2The H group.Therefore, carboxyalkyl be have at least one-CO 2The substituent alkyl group of H.
Self or refer to be connected to the carboxylic group of alkyl group as " carbalkoxy " term of the part of another group, namely consist of-C(=O) OR e, R wherein eIt is above-mentioned defined alkyl.
Self or refer to-O-C(=O) R as " alkyl carbonyl oxy " term of the part of another group e, R wherein eIt is above-mentioned defined alkyl.
Self or as " alkyl-carbonyl-amino " formula of referring to of the part of another group be-NH(C=O) R or-(C=O) group of R of NR ', wherein R and R ' are the alkyl of alkyl or replacement respectively independently.
Self or as " thiocarbonyl " of the part of another group refer to-C(=S)-group.
Self or refer to comprise a group that is connected to the Sauerstoffatom of optional straight or branched alkyl group, group of naphthene base, aralkyl or the cycloalkylalkyl group that replaces as " alkoxyl group " of the part of another group.The unrestricted example of applicable alkoxy base has comprised methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, 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 of using alone or in combination refers to the alkyl that has as defined above, and the halogen that wherein one or more hydrogen are defined as above replaces.The unrestricted example of this class haloalkyl has comprised chloromethyl, 1-bromotrifluoromethane, methyl fluoride, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and similar.
" halogenated aryl " term of using alone or in combination refers to wherein one or more hydrogen and is defined the aryl that has above-mentioned definition that halogen as above replaces.
" halogenated alkoxy " term of using alone or in combination refers to formula and is the group of-O-alkyl, and wherein alkyl group is replaced by 1,2 or 3 halogen atom.For instance, " halogenated alkoxy " comprised-OCF 3,-OCHF 2,-OCH 2F ,-O-CF 2-CF 3,-O-CH 2-CF 3,-O-CH 2-CHF 2, and-O-CH 2-CH 2F.
When the present invention uses " replacement " this term, it is to replace in order to show that one or more hydrogen atoms are selected from other group of designated groups in the expression formula, and prerequisite is to specify the normal valence state of atom not surmounted, and this replacement can produce the compound of stable chemical nature, namely is enough to tolerate from reaction mixture be separated to useful purity grade and be mixed with therapeutical agent.
If group can be optionally substituted, this class group may be substituted one or many, preferably can be substituted once, twice or three times.For instance, substituting group can be selected from the group that comprises halogen, hydroxyl, oxo, nitro, amido, carboxyl, amino, cyano group, halogenated alkoxy and haloalkyl.
Used herein refers to the optional alkyl that replaces, the optional aryl that replaces or the optional cycloalkyl that replaces such as " alkyl, aryl or cycloalkyl, each can be optionally substituted " or " alkyl, aryl or cycloalkyl can be optionally substituted " term.
According to described herein, compounds more of the present invention may contain the one or more asymmetric c atoms as asymmetric center, and this may cause different optical siomerism form (as: enantiomer or diastereomer).The present invention includes might configuration these optical siomerism forms and their mixture.
That more summarizes says, from above-mentioned finding, the professional will know and know that compound of the present invention may exist with the form of different isomer and/or tautomer, include but not limited to geometrical isomer, conformer, E/Z type isomer, steric isomer (being enantiomer and diastereomer) and corresponding to the identical substituent isomer of the different positions that encircles in the compounds of this invention.All these possible isomer, tautomer and their mixture will be included in the scope of invention.
Use the term of " compound of the present invention " or the compound that similar terms refers to comprise general formula I and any subgroup thereof whenever in the present invention.This term refers to that also table 1 is to the compound shown in 11, their derivative, N-oxide compound, salt, solvate, hydrate, stereoisomer form, racemic mixture, tautomeric forms, optical isomer, analogue, prodrug, ester and meta-bolites and their quaternised nitrogen analogue.The N-oxide form of described compound is intended to comprise the compound that one or more nitrogen-atoms are oxidized to so-called N-oxide compound.
In this specification sheets and the claims, the singulative of use " a kind of ", " one " and " being somebody's turn to do " also comprise plural indication thing, unless this content clearly illustrates that in addition.For instance, " a compound a compound " refers to one or the compound above.
Employed other terms are all understood by the those skilled in the art in the above and the specification sheets.
In further embodiment, the invention provides the compound of formula (I)
Wherein,
R 1Hydrogen or C 1-4Alkyl; Methyl particularly;
Ar as defined above, and
Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-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 be substituted independently respectively base replaces; This substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 3Be selected from and comprise following group: hydrogen; Can be by the optional C that replaces of 1,2 or 3 substituting group 1-20Alkyl, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6The group of alkyl-S-and C1-6 alkyl-O-; Special R 3Hydrogen;
R 4Be selected from and comprise C 1-20The group of alkyl, this C 1-20Alkyl is replaced by 1,2 or 3 substituting group is optional, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; Special R 4Be selected from and comprise C 1-20The group of alkyl, this C 1-20Alkyl is replaced by 1,2 or 3 substituting group is optional, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2And-S-Het 3Group; Or
R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C (=O)-SR 22-C(=O)-NR 9R 10-O-Het 2And-S-Het 3Group; Special R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group is optional, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group; More special R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group;
R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; 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)-group; At least one R wherein 5Or R 6Be selected from C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-, each described C wherein 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-can be replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group; Special R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-group; At least one R wherein 5Or R 6Be selected from C 1-6Alkyl; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-, each described C wherein 1-6Alkyl; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-Het 1-O-Het 3And-S-Het 3Group; More special R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl-C(=O)-group; At least one R wherein 5Or R 6Be selected from C 1-6Alkyl; Or C 1-6Alkyl-C(=O)-, each described C wherein 1-6Alkyl or C 1-6Alkyl-C(=O)-replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-Het 1-O-Het 2And-S-Het 3Group; More special R 5Or R 6Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; At least one R wherein 5Or R 6Be selected from C 1-6Alkyl; This C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group can be independently selected from respectively and comprise-Het 1-O-Het 2And-S-Het 3Group;
R 7Or R 8Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; They are replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group; Special R 7Or R 8Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; They are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NH 2Group; More special R 7Or R 8Be independently selected from respectively and comprise hydrogen; Or by-C(=O)-OR 21The C that replaces 1-6Alkyl;
R 9Or R 10Be independently selected from respectively and comprise hydrogen or C 1-6The group of alkyl; Described C 1-6Alkyl by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
R 13Or R 14Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-group, each described C wherein 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group; Special R 13And R 14Represented hydrogen;
R 21Be selected from and comprise C 1-20Alkyl; C 1-20Thiazolinyl; The optional C that replaces 3-15Cycloalkyl; The optional heterocyclic radical that replaces; And the group of the optional aryl that replaces;
Wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, and this substituting group is selected from and comprises halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O) 2-, aryl-C(=O) ,-C(=O)-NR 13R 14,-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:
Figure DEST_PATH_GDA00002198413500201
Or
R 21The cyclic ester ring that the carbonyl oxygen base that links to each other with their and phenyl form following formula
Wherein q is from 1 to 6 integer;
R 22C 1-20Alkyl can by 1,2,3 or more halogenic substituent be optional replaces;
Het 1, Het 2Or Het 3Be independently selected from respectively and comprise following group;
Figure DEST_PATH_GDA00002198413500203
The compound that another group attracts people's attention according to the present invention is the compound of formula (I), but following one or more restriction is arranged;
-Ar has represented pyridyl, can be by the optional replacement of halogen; Special Ar has represented the pyridyl that is replaced by fluorine; Ar has represented in embodiment further
Figure DEST_PATH_GDA00002198413500212
Wherein X is hydrogen or halogen; Special X is hydrogen or fluorine; More special X is fluorine;
-R 1Represent hydrogen or C 1-4Alkyl; C especially 1-4Alkyl; Methyl more especially;
-Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-NR 3R 4-NR 5R 6-O-C 1-6Alkyl; Or-C 1-6The group of alkyl;
Wherein said-O-C 1-6Alkyl or-C 1-6Alkyl is substituted independently respectively base and replaces; This substituting group be selected from comprise-C(=O)-NR 3R 4,-O-Het 2And S-Het 3Group; In specific embodiment, described Het 2Or Het 3Be independently selected from respectively and comprise following group
Figure DEST_PATH_GDA00002198413500213
-Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-O-C 1-6Alkyl; Or-C 1-6The group of alkyl;
Wherein said-O-C 1-6Alkyl or-C 1-6Alkyl is substituted independently respectively base and replaces; This substituting group be selected from comprise-C(=O)-OR 21, and Het 1Group; In specific embodiment, described;
R 21Be selected from-C 1-6Alkyl or aryl; More special described R 21Be selected from-C 1-6Alkyl or phenyl; And
Described Het 1Be selected from and comprise following group
-R 3Hydrogen;
-R 4Be substituted base replacement-C 1-6Alkyl, this substituting group is selected from-O-Het 2Or-S-Het 3
-R 4Be substituted base replacement-C 1-6Alkyl, this substituting group be selected from-C(=O)-and OR 21,-C(=O)-SR 22, or Het 1In specific embodiment, described R 21Be substituted base replacement-C 1-6Alkyl, this substituting group be selected from-C(=O)-and OR 21, or Het 1In embodiment further, described R 21Be-C 1-6Alkyl;
-R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-group; At least one R wherein 5Or R 6Be selected from and comprise C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-group; Reach wherein each described C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-be substituted base replaces, and this substituting group be selected from comprise-C(=O)-OR 21, Het 1And-S-Het 3Group; In specific embodiment, described;
R 21Be selected from-C 1-6Alkyl or aryl; More special described R 21A-C 1-6Alkyl; And
Described Het 1Or Het 3Be independently selected from respectively and comprise following group:
Figure 374992DEST_PATH_IMAGE001
-R 21Be selected from-C 1-6Alkyl, aryl or the optional heteroaryl that replaces; More special described R 21Be selected from-C 1-6Alkyl, 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 the oxygen base;
-aryl represents phenyl;
-heteroaryl represents 3,4-dihydro-1(2H)-benzopyranyl, 3, the 4-dihydro-1(2H)-benzopyranyl or indyl; Indyl especially;
-Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-O-C 1-6Alkyl; Or-C 1-6The group of alkyl;
Wherein said-O-C 1-6Alkyl or-C 1-6Alkyl is substituted independently respectively base and replaces; This substituting group be selected from comprise-C(=O)-OR 21, and Het 1Group; In specific embodiment, described;
R 21Be selected from-C 1-6Alkyl or aryl; More special described R 21Be selected from-C 1-6Alkyl or phenyl;
Described Het 1Be selected from and comprise following group
Figure DEST_PATH_GDA00002198413500222
And wherein said-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-O-C 1-6Alkyl; Or-C 1-6Alkyl is between aryl or heteroaryl and molecule remainder junction position and contraposition, as with as shown in following formula IIa-XXIIIa and the IIb-XXIIIb.
In specific embodiment, the invention provides the compound of formula (I), wherein defined Y substituting group namely as substituting group or a substituent part, comprises at least one and is selected from C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3The group of group.In more specific embodiment, the invention provides the compound of formula (I), wherein the substituent further substituting group of Y be positioned at aryl or heteroaryl and molecule remainder junction between position and contraposition, as with shown in following formula IIa-XXIIIa and the IIb-XXIIIb.In more specific embodiment, the invention provides the compound of the formula (I) that any one different embodiments as herein described defines, its collateral condition be when the Y representative be selected from-C(=O)-OR 21Or-C(=O)-SR 22When the aryl that substituting group replaces or heteroaryl, and wherein said R 21Or R 22Represent unsubstituted C 1-20During alkyl, described-C(=O)-OR 21Or-C(=O)-SR 22Be positioned at aryl or heteroaryl and molecule remainder junction between position and contraposition, as with shown in following formula IIa, IIb, IIIa and the IIIb.In further embodiment, the invention provides the compound of formula (I), but following one or more restriction is arranged;
-Y is 2-oxo-2, and 3-dihydro benzo furyl or Y are that phenyl, indyl or thienyl, described Phenylindole base and thienyl are substituted base and replace, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-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 base and replaces, and this substituting group be selected from comprise C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
-R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-group; At least one R wherein 5Or R 6Be selected from and comprise C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-group; Reach wherein each described C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-be substituted base replaces, and this substituting group be selected from comprise-C(=O)-OR 21, Het 1And-S-Het 3Group;
-R 21Be selected from and comprise C 1-20Alkyl; The optional C that replaces 3-10Cycloalkyl; The optional aryl that replaces; And the group of the optional heterocyclic radical that replaces; Wherein said C 1-20Alkyl can be substituted that base is optional to be replaced, and this substituting group is selected from: halogen, cyano group, hydroxyl ,-C(=O)-NR 13R 14,-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:
Special R 21Be selected from and comprise C 1-20Alkyl; The optional C that replaces 3-10Cycloalkyl; The optional aryl that replaces; And the group of the optional heterocyclic radical that replaces; Wherein said C 1-20Alkyl is substituted base and replaces, and this substituting group is selected from: halogen, cyano group, hydroxyl ,-C(=O)-NR 13R 14,-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:
Figure DEST_PATH_GDA00002198413500241
More special R 21Be selected from and comprise C 1-20Alkyl; C 3-10Cycloalkyl; And the group of the optional aryl that replaces; Wherein said C 1-20Alkyl is substituted base and replaces, and this substituting group be selected from comprise halogen ,-O-C(=O)-C 1-6The group of alkyl, or be selected from following formula:
Figure DEST_PATH_GDA00002198413500242
-heterocyclic radical used herein is selected from: piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be [3,2-b] furyl also; Be selected from especially: piperidyl, 1,3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base;
-optional replacement C used herein 3-10Cycloalkyl is selected from the group that comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and ring decyl, wherein be preferably cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and dicyclo (2,2,1) heptane; Wherein said C 3-10Cycloalkyl can by 1,2,3 or more multi-substituent be optional replaces, and is 1,2 or 3 especially; 1 or 2 more especially; 1 more especially; This substituting group is selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
The heterocycle of-optional replacement used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base; Wherein said heterocyclic radical can by 1,2,3 or more multi-substituent replace, be 1 especially; This substituting group be selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarboxyl, azido-, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxyl group ,-SO 2-NH 2, aryl, heteroaryl, aralkyl, haloalkyl, halogenated alkoxy, carbalkoxy, alkyl amino-carbonyl, heteroarylalkyl, alkyl sulfonamide, heterocyclic radical, alkyl-carbonyl-amino alkyl, aryloxy, alkyl-carbonyl, acyl group, aryl carbonyl, aminocarboxyl, alkyl sulfoxide ,-SO 2R a, alkylthio, carboxyl group and similarly, R wherein aIt is alkyl or cycloalkyl; Be preferably selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
-aryl used herein is selected from the group that comprises phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl or 1,2,3,4-tetralyl, and wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group can be selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; Be phenyl or 1,2,3,4-tetralyl especially, wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; More special phenyl can be by the optional replacement of 1,2,3,4 or 5 substituting group; This substituting group can be selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio;
-heteroaryl used herein is selected from and comprises furyl, thienyl, pyrryl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, benzofuryl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3, the 4-dihydro-1(2H)-benzopyranyl, and 2, the group of 3-dihydro-1(4H)-benzopyranyl, wherein said heteroaryl can be by 1,2,3,4 or 5 optional replacements of substituting group, this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; Furyl, thienyl, pyridyl, benzopyranyl, 1(2H especially)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl; Wherein said heteroaryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo or C 1-4Alkyl;
-Y is 2-oxo-2, and 3-dihydro benzo furyl or Y are phenyl, indyl or thienyl, and described Phenylindole base and thienyl are substituted base and replace, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-O-C 1-6Alkyl;-C 1-6Alkyl; Or-C 2-8The group of thiazolinyl; Described-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-O-C 1-6Alkyl;-C 1-6Alkyl; Or-C 2-8Thiazolinyl be attached to the Y position between position or contraposition, with respect to Y with the combination of molecule rest part; And wherein said-O-C 1-6Alkyl or-C 2-8Thiazolinyl is substituted base and replaces, and this substituting group is selected from: C(=O)-and OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3
-collateral condition is when Y is phenyl, indyl or thienyl, described Phenylindole base and thienyl by-C(=O)-OR 21Or-C(=O)-SR 22Replace; And wherein said R 21Or R 22Represent unsubstituted C 1-20During alkyl, described-C(=O)-OR 21Or-C(=O)-SR 22With respect to the combination of described phenyl, indyl or thienyl and molecule other parts be between position or contraposition, as with shown in following formula IIa, IIb, IIIa and the IIIb.
The compound that the present invention attracts people's attention is the compound of formula of the present invention (Ia)
Figure DEST_PATH_GDA00002198413500251
Wherein,
R 1Be selected from and comprise hydrogen, C 1-4Alkyl or C 3-6The group of cycloalkyl;
Ar is selected from and comprises following group:
Figure DEST_PATH_GDA00002198413500261
Wherein X is selected from the group that comprises hydrogen or halogen;
L is direct key, C 1-4Alkyl or-O-C 1-4Alkyl;
T is-O-R 21Or-NR 3R 4
R 3Be selected from following group: hydrogen; C 1-20Alkyl can be replaced by 1,2 or 3 substituting group is optional, this substituting group can be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; Special R 3Hydrogen;
R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; More special R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2And-S-Het 3Group; Or;
R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group; Special R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises Het 1-O-Het 2And-S-Het 3Group;
R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group; Special R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NH 2Group;
R 9Or R 10Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
R 13Or R 14Be independently selected from respectively following group: hydrogen; C 1-6Alkyl; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-, and wherein said C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
R 21Be selected from following group: C 1-20Alkyl; C 1-20Thiazolinyl; C 1-20Alkynyl; The optional C that replaces 3-15Cycloalkyl; The optional heterocyclic radical that replaces; And the optional aryl that replaces;
Wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, and this substituting group is selected from following group: the 2-of halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O), aryl-C(=O) ,-C(=O)-NR 13R 14,-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 following formula:
Figure DEST_PATH_GDA00002198413500271
Or
R 21The cyclic ester that the carbonyl oxygen base that links to each other with their and phenyl form following formula
Figure DEST_PATH_GDA00002198413500272
Wherein q is from 1 to 6 integer;
R 22C 1-20Alkyl can by 1,2,3 or more halogenic substituent be optional replaces;
Het 1, Het 2Or Het 3Be independently selected from respectively and comprise following group;
Figure DEST_PATH_GDA00002198413500273
Figure DEST_PATH_GDA00002198413500281
In further embodiment, the invention provides the compound of formula (Ia), but following one or more restriction is arranged;
-Ar represents pyridyl, can be chosen wantonly replacement by halogen; The pyridyl that special Ar representative can be replaced by fluorine; In embodiment further, the Ar representative
Figure DEST_PATH_GDA00002198413500282
Wherein X is hydrogen or halogen; Special X is hydrogen or fluorine; More special X is hydrogen;
-R 1Represent hydrogen or C 1-4Alkyl; C especially 1-4Alkyl; Methyl more especially;
-R 3Hydrogen;
-R 4Be selected from-O-Het 2, or-S-Het 3Substituting group replaces-C 1-6Alkyl; In specific embodiment, described Het 2Or Het 3Be selected from and comprise following group
Figure DEST_PATH_GDA00002198413500283
-R 4Be selected from-C(=O)-OR 21,-C(=O)-SR 22,-C(=O)-NR 7R 8, or Het 1Substituting group replaces-C 1-6Alkyl; Special-C 1-6Alkyl is selected from-C(=O)-and OR 21Or Het 1Substituting group replace; In specific embodiment, described R 21Be-C 1-6Alkyl and described Het 1Be
Or
-R 3And R 4The nitrogen-atoms that links to each other with them forms heterocycle, and it is by C 1-6Alkyl replaces; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NR 9R 10Group;
-R 21Be selected from and comprise C 1-20Alkyl; The optional C that replaces 3-10Cycloalkyl; The optional aryl that replaces; And the group of the optional heterocyclic radical that replaces; Wherein said C 1-20Alkyl can be substituted that base is optional to be replaced, this substituting group be selected from halogen, cyano group, hydroxyl ,-C(=O)-NR 13R 14,-O-C(=O)-C 1-6Alkyl, C 1-6Alkyl-O-, C 1-6Alkyl-S-, aryl, heterocyclic radical, and C 3-10Cycloalkyl, or following formula:
Special R 21Be selected from and comprise C 1-20Alkyl; The optional C that replaces 3-10Cycloalkyl; The optional aryl that replaces; And the group of the optional heterocyclic radical that replaces; Wherein said C 1-20Alkyl is substituted base and replaces, this substituting group be selected from comprise halogen, cyano group, hydroxyl ,-C(=O)-NR 13R 14,-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:
Figure DEST_PATH_GDA00002198413500292
More special R 21Be selected from and comprise C 1-20Alkyl; The optional C that replaces 3-10Cycloalkyl; The optional aryl that replaces; And the group of the optional heterocyclic radical that replaces; Wherein said C 1-20Alkyl is substituted base and replaces, and described substituting group is selected from: 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 following formula:
Figure DEST_PATH_GDA00002198413500293
More special R 21Be selected from and comprise C 1-20Alkyl; C 3-10Cycloalkyl; And the group of the optional aryl that replaces; Wherein said C 1-20Alkyl is substituted base and replaces, and this substituting group be selected from comprise halogen ,-O-C(=O)-C 1-6The group of alkyl, or following formula:
Figure DEST_PATH_GDA00002198413500294
-heterocyclic radical used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base;
The C of-optional replacement used herein 3-10Cycloalkyl is selected from the group that comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and ring decyl, wherein is preferably cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, reaches dicyclo (2.2.1) heptane base; Wherein said C 3-10Cycloalkyl can by 1,2,3 or more multi-substituent be optional replaces, and is 1,2 or 3 especially; 1 or 2 more especially; 1 more especially; This substituting group is selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
The heterocyclic radical of-optional replacement used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base; Wherein said heterocyclic radical can by 1,2,3 or more multi-substituent be optional replaces, and is 1 especially; This substituting group be selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine (hydrazine), aminocarboxyl, azido-, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxyl group ,-SO 2-NH 2, aryl, heteroaryl, aralkyl, alkylhalide group, halogen alkoxyl group, carbalkoxy, alkyl amino-carbonyl, heteroarylalkyl, alkyl sulfonamide, heterocyclic radical, alkyl-carbonyl-amino alkyl, aryloxy, alkyl-carbonyl, acyl group, aryl carbonyl, aminocarboxyl, alkyl sulfoxide ,-SO 2R a, alkylthio, carboxyl group and similarly, R wherein aIt is alkyl or cycloalkyl; Be preferably selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
-aryl used herein is selected from and comprises phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl, or the group of 1,2,3,4-tetralyl, and wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group, or C 1-4Alkylthio; Phenyl or 1,2,3,4-tetralyl especially; Wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; More special phenyl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio;
-heteroaryl used herein is selected from and comprises furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, benzofuryl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3, the group of 4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl; Wherein said heteroaryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; Furyl, thienyl, pyridyl, benzopyranyl, 1(2H especially)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl; Wherein said heteroaryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo or C 1-4Alkyl;
--L be in benzyl ring between the position or contraposition, this is the combination with respect to described benzyl ring and molecule remainder, suc as formula show among IIa and the IIb-COOR 21Group;
-collateral condition be when L be that direct key and T are-O-R 21, and R wherein 21Unsubstituted C 1-20During alkyl, described L-(C=O)-T be in benzyl ring between position or contraposition, this is the combination with respect to described benzyl ring and molecule remainder, suc as formula show among IIa and the IIb-COOR 21Group;
The compound that the present invention attracts people's attention is the compound of formula of the present invention (Ib)
Figure DEST_PATH_GDA00002198413500311
Wherein,
R 1To select self-contained group hydrogen, C 1-4Alkyl or C 3-6Cycloalkyl;
Ar is selected from and comprises following group:
Figure DEST_PATH_GDA00002198413500312
Wherein X is selected from the group that comprises hydrogen or halogen;
Z is selected to comprise-O-;-NR 5-; And-NR 5-C(=O)-divalent radical;
W represents C 1-6Alkyl, it can be selected from-O-Het 2-S-Het 3Or C(=O)-NR 3R 4Substituting group replace; And R wherein 3, R 4, R 5, Het 2And Het 3Be defined as in any previous embodiments to the compound among formula I or the Ia defined those.
In one of them embodiment of the present invention, formula Ib compound is further characterized in that
-R 3Be selected from following group: hydrogen; C 1-20Alkyl, they can be replaced by 1,2 or 3 substituting group is optional, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; Special R 3Hydrogen;
-R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; More special R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2And-S-Het 3Group; Or;
-R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group; Special R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises Het 1-O-Het 2And-S-Het 3Group;
-R 5Hydrogen;
-R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group; Special R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NH 2Group;
-R 9Or R 10Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
-R 13Or R 14Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-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)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
-R 21Be selected from following group: C 1-20Alkyl; C 1-20Thiazolinyl; C 1-20Alkynyl; The optional C that replaces 3-15Cycloalkyl; The optional heterocyclic radical that replaces; And the optional aryl that replaces;
-wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, and this substituting group is selected from following group: halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O) 2-, aryl-C(=O) ,-C(=O)-NR 13R 14,-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 following formula:
Figure DEST_PATH_GDA00002198413500331
Or
-R 21The cyclic ester that the carbonyl oxygen base that links to each other with their and phenyl form following formula
-wherein q is from 1 to 6 integer;
-R 22C 1-20Alkyl can by 1,2,3 or more halogenic substituent be optional replaces;
Het 1, Het 2Or Het 3Be independently selected from respectively and comprise following group;
Figure DEST_PATH_GDA00002198413500333
In further embodiment, the invention provides the compound of formula (Ib), but following one or more restriction is arranged;
-R 3Hydrogen;
-R 4Be selected from-O-Het 2, or-S-Het 3Substituting group replaces-C 1-6Alkyl; In specific embodiment, described Het 2Or Het 3Be selected from and comprise following group
Figure DEST_PATH_GDA00002198413500341
In preferred embodiments, the invention provides the compound of formula IIa, 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, XIXa, XXa, XXIa, XXIb, XXIIa, XXIIIa or XXIVa.
Figure DEST_PATH_GDA00002198413500351
Figure DEST_PATH_GDA00002198413500361
Figure DEST_PATH_GDA00002198413500371
Wherein,
Q is from 2 to 6 integer;
R 11The C that replaces 1-6Alkyl, or replace-C 2-8Thiazolinyl; Described-C 1-6Alkyl reaches-C 2-8Thiazolinyl is substituted independently respectively base and replaces, this substituting group be selected from comprise C (=O)-OR 21-C (=O)-SR 22-C (=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 12The C that replaces 1-6The C of alkyl, replacement 1-6Alkyl-S-C 1-6Alkyl or replacement-C 2-8Thiazolinyl; Described-C 1-6Alkyl, C 1-6Alkyl-S-C 1-6Alkyl reaches-C 2-8Thiazolinyl is replaced by 1,2 or 3 substituting group respectively independently, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C (=O)-OR 21-C (=O)-SR 22Het 1-O-Het 2And-S-Het 3Group; And
Wherein Ar, R 1, R 21, R 22, R 3, R 4, R 5, R 6, Het 1, Het 2And Het 3Has this paper identical connotation defined previously.Compound of the present invention can prepare according to the reaction scheme that following examples provide, but one of skill in the art can understand these only as demonstration of the present invention, and compound of the present invention can be according to any organic chemistry professional's working standard synthesis technique preparation.In preferred embodiments, compound useful as kinase inhibitors of the present invention is at least one ROCK kinases provides restraining effect more especially, is selected from ROCKI and ROCKII, is soft ROCK inhibitor more especially.
The present invention also further provides as defined above use of a compound or has comprised the composition of described compound as the purposes of the mankind or veterinary medicament, be used to the disease that prevents and/or treats at least a ROCK of relating to or obstacle especially, for example with the function of smooth muscle cell, inflammation, fibrosis, excessive cell proliferation, vasculogenesis is excessive, hyperergy, the barrier function obstacle, the nerve degeneration pathology, function, inflammation, fibrosis, excessive cell proliferation, vasculogenesis is excessive, hyperergy, the barrier function obstacle, the nerve degeneration pathology with reinvent relevant disease.
In further embodiment, the composition that the invention provides use of a compound as defined above or comprise described compound is used for the treatment of and/or prevents at least a eye illness that is selected from, respiratory tract disease, throat, nose and ear disease, intestinal tract disease, cardiovascular disorder and vascular disease, diseases associated with inflammation, the disease of neural system and central nervous system disease and/or obstacle: proliferative disease, kidney disease, sexual dysfunction, disease in the blood system, skeletal diseases, diabetes, benign prostate hyperplasia, graft-rejection, hepatic diseases, systemic lupus erythematous, spasm, hypertension, the chronic obstructive bladder disease, premature labor, infect, allergy, obesity, pancreatic disease and acquired immune deficiency syndrome (AIDS).
In preferred embodiments, the composition that the invention provides use of a compound as defined above or comprise described compound is used for the treatment of and/or prevents disease of eye, comprising but be not limited to retinopathy, optic neuropathy, glaucoma and retina degenerative disease, such as macular degeneration, retinitis pigmentosa and inflammatory eye illness, and/or be used for prevention, treat and/or alleviate complication and/or relative symptom.
Special these compounds are selected from and comprise following group;
The Y of formula I compound is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-O-C 1-6Alkyl; Or-C 1-6The group of alkyl; Wherein said-O-C 1-6Alkyl or-C 1-6Alkyl is substituted independently respectively base and replaces; This substituting group be selected from comprise-C(=O)-OR 21, and Het 1Group; And R 4Be selected from-C(=O)-OR 21,-C(=O)-SR 22, or Het 1Substituting group replace-C 1-6Alkyl; And
Formula Ia compound, wherein Ar representative
Figure DEST_PATH_GDA00002198413500381
Wherein X is hydrogen or halogen;
-L is direct key, C 1-4Alkyl or-O-C 1-4Alkyl;
-T is-O-R 21Or-NR 3R 4
-R 1Represent hydrogen or C 1-4Alkyl;
-R 3Hydrogen;
-R 4Be selected from-C(=O)-OR 21,-C(=O)-SR 22,-C(=O)-NR 7R 8, or Het 1Substituting group replace-C 1-6Alkyl; Special-C 1-6Alkyl is selected from-C(=O)-and OR 21Or Het 1Substituting group replace; In specific embodiment, described R 21Be-C 1-6Alkyl; Or
-R 3And R 4The nitrogen-atoms that links to each other with them forms heterocycle, and it is by C 1-6Alkyl replaces; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NR 9R 10Group;
-R 9Or R 10Be independently selected from respectively and comprise hydrogen or C 1-6The group of alkyl; Described C 1-6Alkyl by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
-R 21Be selected from and comprise C 1-20Alkyl; The optional C that replaces 3-10Cycloalkyl; The optional aryl that replaces; And the group of the optional heterocyclic radical that replaces; Wherein said C 1-20Alkyl can be substituted that base is optional to be replaced, and this substituting group is selected from: 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 following formula:
Figure DEST_PATH_GDA00002198413500391
-heterocyclic radical used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base;
-optional replacement C used herein 3-10Cycloalkyl is selected from the group that comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and ring decyl, wherein be preferably cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and dicyclo (2,2,1) heptane; Wherein said C 3-10Cycloalkyl can by 1,2,3 or more multi-substituent be optional replaces, and is 1,2 or 3 especially; 1 or 2 more especially; 1 more especially; This substituting group is selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
The heterocycle of-optional replacement used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base; Wherein said heterocyclic radical can by 1,2,3 or more multi-substituent replace, be 1 especially; This substituting group be selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarboxyl, azido-, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxyl group ,-SO 2-NH 2, aryl, heteroaryl, aralkyl, haloalkyl, halogenated alkoxy, carbalkoxy, alkyl amino-carbonyl, heteroarylalkyl, alkyl sulfonamide, heterocyclic radical, alkyl-carbonyl-amino alkyl, aryloxy, alkyl-carbonyl, acyl group, aryl carbonyl, aminocarboxyl, alkyl sulfoxide ,-SO 2R a, alkylthio, carboxyl group and similarly, R wherein aIt is alkyl or cycloalkyl; Be preferably selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
-aryl used herein is selected from the group that comprises phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl or 1,2,3,4-tetralyl; Wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group can be selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group, or C 1-4Alkylthio; Phenyl or 1,2,3,4-tetralyl especially; Wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; More special phenyl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio;
-heteroaryl used herein is selected from and comprises furyl, thienyl, pyrryl oxazolyl, thiazolyl, imidazolyl, pyrazolyl isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, benzofuryl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3, the 4-dihydro-1(2H)-benzopyranyl, and 2, the group of 3-dihydro-1(4H)-benzopyranyl, wherein said heteroaryl can be by 1,2,3,4 or 5 optional replacements of substituting group, this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; Furyl, thienyl, pyridyl, benzopyranyl, 1(2H especially)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl; Wherein said heteroaryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo or C 1-4Alkyl;
Be particularly useful in and treat and/or prevent disease of eye, comprising but be not limited to retinopathy, optic neuropathy, glaucoma and retina degenerative disease, such as macular degeneration, retinitis pigmentosa and inflammatory eye illness, and/or be used for prevention, treat and/or alleviate complication and/or relative symptom.Therefore, the purpose of this invention is to provide described compound, to be used for the treatment of and/or to prevent disease of eye, comprising but be not limited to retinopathy, optic neuropathy, glaucoma and retina degenerative disease, such as macular degeneration, retinitis pigmentosa and inflammatory eye illness, and/or prevention, treat and/or alleviate complication and/or relative symptom; The treatment glaucoma more especially.Be the method in order to provide to be used for the treatment of and/or to prevent to be selected from the disease of eye of following group in addition, wherein comprised retinopathy, optic neuropathy, glaucoma, inflammatory eye illness, such as the retina degenerative disease of macular degeneration and retinitis pigmentosa; Be preferably glaucoma; Described method comprises the formula I compound of the present invention to patient's administering therapeutic significant quantity that needs are arranged; Compound as defined above especially.
In another preferred embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or prevents the purposes of respiratory tract disease; Comprising but be not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering and become sick, chronic obstructive pulmonary disease (COPD); Bronchitis and rhinitis and respiratory distress syndrome, and/or prevent, treat and/or alleviate complication and/or relative symptom.
Special these compounds are selected from and comprise following group;
Formula I compound, wherein Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-NR 3R 4-NR 5R 6-O-C 1-6Alkyl; Or-C 1-6The group of alkyl; Wherein said-O-C 1-6Alkyl or-C 1-6Alkyl is substituted independently respectively base and replaces; This substituting group be selected from comprise-C(=O)-NR 3R 4,-O-Het 2And S-Het 3Group;
In specific embodiment, described Het 2Or Het 3Be independently selected from respectively and comprise following group:
Figure DEST_PATH_GDA00002198413500411
And
Formula Ia compound, wherein Ar representative
Wherein X is hydrogen or halogen;
-L is direct key, C 1-4Alkyl, or-O-C 1-4Alkyl;
-T is-O-R 21Or-NR 3R 4
-R 1Represent hydrogen or C 1-4Alkyl;
-R 3Hydrogen;
-R 4Be selected from-O-Het 2, or-S-Het 3Substituting group replace-C 1-6Alkyl; In specific embodiment, described Het 2Or Het 3Be selected from and comprise following group
Figure DEST_PATH_GDA00002198413500413
-Het 2Or Het 3Be independently selected from respectively and comprise following group;
Figure DEST_PATH_GDA00002198413500421
And
The compound of formula Ib;
Be particularly useful in and treat and/or prevent respiratory tract disease; Comprising but be not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering and become sick, chronic obstructive pulmonary disease (COPD); Bronchitis and rhinitis and respiratory distress syndrome, and/or prevent, treat and/or alleviate complication and/or relative symptom.. therefore, the purpose of this invention is to provide described compound, to be used for the treatment of and/or to prevent respiratory tract disease; Comprising but be not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering and become sick, chronic obstructive pulmonary disease (COPD); Bronchitis and rhinitis and respiratory distress syndrome, and/or prevent, treat and/or alleviate complication and/or relative symptom.The method in order to provide to be used for the treatment of and/or to prevent respiratory tract disease in addition; Comprising but be not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering and become sick, chronic obstructive pulmonary disease (COPD); Bronchitis and rhinitis and respiratory distress syndrome, described method comprise the formula I compound of the present invention to patient's administering therapeutic significant quantity that needs are arranged; Compound as defined above especially.In further embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or the purposes of preventing cardiovascular disease and vascular disease: include but not limited to that the cerebrovascular shrinks, again perfusion, anoxic peripheral circulation disease, the myocardial hypertrophy Acute Stroke, congestive heart failure, the cardiovascular and cerebrovascular ischemic, heart disease, heart reconstruction, stenocardia, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, pulmonary hypertension, the lung vasoconstriction, atherosclerosis, atherosclerosis, aneurysma, hemorrhage, Raynand's disease, thrombosis (comprising the deep layer thrombosis) and thrombocyte relative disease, and/or prevention, the treatment and/or alleviate complication and/or relative symptom and/or alleviate complication and/or relative symptom.
In further embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or prevents the purposes of throat, nose and ear disease: include but not limited to nasal sinus problem, hearing problem, tonsillitis, toothache, ulcer and rhinitis
In further embodiment, the invention provides compound as defined above or comprise the purposes that the composition of described compound is used for the treatment of and/or prevents dermatosis: include but not limited to hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulcer.
In further embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or the purposes of prevention of intestinal tract disease; Include but not limited to inflammatory bowel (IBD), colitis, gastro-enteritis, intestinal obstruction, ileitis, ecphyaditis and Crohn's disease.
In another embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or the purposes of 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, Crohn's disease and ulcerative colitis, and/or prevention, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.
In another embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the purposes of prevention, treatment and/or management neural system and central nervous system disease: include but not limited to apoplexy, meningitis, convulsions, brain or Spinal injury and inflammatory and such as demyelination, multiple sclerosis and the neuropathic pain of Alzheimer's disease.Compound of the present invention also thereby be applicable to prevent nerve degenerative diseases and the stimulating neural regeneration of various nervous system disorderss and/or prevention, is treated and/or is alleviated complication and/or relative symptom.
In another embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or prevents proliferative disease: such as but not limited to brain (neurospongioma) mammary gland, colon, intestines, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate gland or thyroid cancer; Castleman's disease, leukemia, sarcoma, lymphoma; Malignocytoma (malignoma) and melanoma; And/or prevention, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.
In another embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or prevents the purposes of kidney disease: include but not limited to kidney region fibrosis or renal insufficiency; And/or prevention, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.
In another embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or preventative handicapped purposes: include but not limited to sexual disorder, bladder disease, hypertension, diabetes or operation on pelvis sequela; And/or prophylactic treatment for example is used for the treatment of the medicine of hypertension, depression or anxiety by the sexual dysfunction of using some drugs to cause.
In another embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or the purposes of preclude blood disease: include but not limited to kidney region fibrosis or renal insufficiency; 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 purposes that the composition of described compound is used for the treatment of and/or prevents 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 composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or the purposes of prevent diabetes: include but not limited to hyperglycemia and type 1 diabetes; And/or prevention, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.
In another embodiment, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or prevents the purposes of following disease, such as disease and/or the obstacle of benign prostate hyperplasia, graft-rejection, hepatic diseases, systemic lupus erythematous, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease and acquired immune deficiency syndrome (AIDS), and/or prevent, treat and/or alleviate complication and/or relative symptom.
In preferred embodiments, the composition that the invention provides compound as defined above or comprise described compound is used for the treatment of and/or the purposes of preventing glaucoma, asthma, sexual dysfunction or chronic obstructive pulmonary disease.
The present invention further provides compound as defined above or comprised the composition of described compound, to be used for the treatment of and/or to prevent the purposes of at least a following disease, comprised eye illness, respiratory tract disease, cardiovascular disorder and vascular disease, diseases associated with inflammation, the disease of neural system and central nervous system disease and/or obstacle: proliferative disease, kidney disease, sexual dysfunction, disease in the blood system, skeletal diseases, diabetes, benign prostate hyperplasia, graft-rejection, hepatic diseases, systemic lupus erythematous, spasm, hypertension, the chronic obstructive bladder disease, premature labor, infect, allergy, obesity, pancreatic disease and acquired immune deficiency syndrome (AIDS).
In preferred embodiments, compound as defined above is provided or has comprised the composition of described compound, to be used for the treatment of and/or to prevent disease of eye, comprising but be not limited to retinopathy, optic neuropathy, glaucoma and retina degenerative disease, such as macular degeneration, retinitis pigmentosa and inflammatory eye illness, and/or prevention, treat and/or alleviate complication and/or relative symptom.
In another preferred embodiment, compound as defined above is provided or has comprised the composition of described compound, to be used for the treatment of and/or to prevent respiratory tract disease; Comprising but be not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering and become sick, chronic obstructive pulmonary disease (COPD); Bronchitis and rhinitis and respiratory 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 the composition of described compound, to be used for the treatment of and/or preventing cardiovascular disease and vascular disease: include but not limited to that the cerebrovascular shrinks, again perfusion, anoxic peripheral circulation disease, the myocardial hypertrophy Acute Stroke, congestive heart failure, the cardiovascular and cerebrovascular ischemic, heart disease, heart reconstruction, stenocardia, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, pulmonary hypertension, the lung vasoconstriction, atherosclerosis, atherosclerosis, aneurysma, hemorrhage, Raynand's disease, thrombosis (comprising the deep layer thrombosis) and thrombocyte relative disease, and/or prevention, the treatment and/or alleviate complication and/or relative symptom and/or alleviate complication and/or relative symptom.
In another embodiment, the invention provides compound as defined above or comprise the composition of described compound, to be used for the treatment of 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, Crohn's disease and ulcerative 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 composition of described compound, to be used for the treatment of and/or to prevent neural system and central nervous system disease: include but not limited to apoplexy, meningitis, convulsions, brain or Spinal injury and inflammatory and such as demyelination, multiple sclerosis and the neuropathic pain of Alzheimer's disease.Compound of the present invention also thereby be applicable to prevent nerve degenerative diseases and the stimulating neural regeneration of various nervous system disorderss and/or prevention, is treated and/or is alleviated complication and/or relative symptom.
In another embodiment, the invention provides compound as defined above or comprise the composition of described compound, to be used for the treatment of and/or to prevent proliferative disease: such as but not limited to brain (neurospongioma) mammary gland, colon, intestines, skin, head and neck, nerve, uterus, kidney, lung, liver, ovary, pancreas, prostate gland or thyroid cancer; Castleman's disease, leukemia, sarcoma, lymphoma; Malignocytoma (malignoma) and melanoma; 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 composition of described compound, to be used for the treatment of and/or to prevent kidney disease: include but not limited to kidney region fibrosis or renal insufficiency; And/or prevention, treat and/or alleviate complication and/or relative symptom and/or inflammatory reaction.
In another embodiment, the invention provides as defined above compound or comprise the composition of described compound for the preparation of the purposes of the medicine that treats and/or prevents sexual dysfunction: include but not limited to sexual disorder, bladder disease, hypertension, diabetes or operation on pelvis sequela; And/or prophylactic treatment for example is used for the treatment of the medicine of hypertension, depression or anxiety by the sexual dysfunction of using some drugs to cause.
In another embodiment, the invention provides compound as defined above or comprise the composition of described compound, to be used for the treatment of and/or the preclude blood disease: include but not limited to kidney region fibrosis or renal insufficiency; 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 composition of described compound, to be used for the treatment of and/or to prevent 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 composition of described compound, to be used for the treatment of and/or prevent diabetes: include but not limited to hyperglycemia and type 1 diabetes; 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 composition of described compound, being used for the treatment of and/or preventing disease and/or obstacle such as benign prostate hyperplasia, graft-rejection, hepatic diseases, systemic lupus erythematous, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease and acquired immune deficiency syndrome (AIDS), 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 composition of described compound, to be used for the treatment of and/or preventing glaucoma, asthma, sexual dysfunction or chronic obstructive pulmonary disease.
Methods for the treatment of
The present invention further provides and be used for the treatment of and/or prevent at least a disease of eye illness, respiratory tract disease, cardiovascular disorder and vascular disease, diseases associated with inflammation, neural system and central nervous system disease and/or the method for obstacle of having comprised: proliferative disease; Kidney disease; Sexual dysfunction; Disease in the blood system; Skeletal diseases; Diabetes; Benign prostate hyperplasia; Graft-rejection; Hepatic diseases; Systemic lupus erythematous; Spasm; Hypertension; The chronic obstructive bladder disease; Premature labor; Infect; Allergy; Obesity; Pancreatic disease and acquired immune deficiency syndrome (AIDS); Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.In preferred embodiments, the invention provides the method that treats and/or prevents disease of eye, comprising but be not limited to retinopathy, optic neuropathy, glaucoma and retina degenerative disease, such as macular degeneration, retinitis pigmentosa and inflammatory eye illness; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another preferred embodiment, the invention provides a method that is used for the treatment of and/or prevents respiratory tract disease; Comprising but be not limited to pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering and become sick, chronic obstructive pulmonary disease
(COPD); Bronchitis and rhinitis and respiratory distress syndrome, described method comprise herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents cardiovascular disorder and vascular disease: include but not limited to that the cerebrovascular shrinks, again perfusion, anoxic peripheral circulation disease, the myocardial hypertrophy Acute Stroke, congestive heart failure, the cardiovascular and cerebrovascular ischemic, heart disease, heart reconstruction, stenocardia, coronary vasospasm, cerebral vasospasm, restenosis, hypertension, pulmonary hypertension, the lung vasoconstriction, atherosclerosis, atherosclerosis, aneurysma, hemorrhage, Raynand's disease, thrombosis (comprising the deep layer thrombosis) and thrombocyte relative disease; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents 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, Crohn's disease and ulcerative colitis; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents neural system and central nervous system disease: include but not limited to that apoplexy, meningitis, convulsions, brain or Spinal injury and inflammatory reach demyelination, multiple sclerosis and the neuropathic pain such as Alzheimer's disease.Compound of the present invention also thereby be applicable to prevent nerve degenerative diseases and the stimulating neural regeneration of various nervous system disorderss; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents proliferative disease: such as but not limited to brain (neurospongioma), mammary gland, colon, intestines, skin, head and neck, nerve, ovary, kidney, lung, liver, uterus, pancreas, prostate gland or thyroid cancer; Castleman's disease, leukemia, sarcoma, lymphoma; Malignocytoma (malignoma) and melanoma; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents kidney disease: include but not limited to kidney region fibrosis or renal insufficiency; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.In another embodiment, the invention provides a method that treats and/or prevents sexual dysfunction: include but not limited to sexual disorder, bladder disease, hypertension, diabetes or operation on pelvis sequela; And/or prophylactic treatment for example is used for the treatment of the medicine of hypertension, depression or anxiety by the sexual dysfunction of using some drugs to cause; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents hematologic disease: include but not limited to kidney region fibrosis or renal insufficiency; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents skeletal diseases: include but not limited to osteoporosis and osteoarthritis; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents diabetes: include but not limited to hyperglycemia and type 1 diabetes; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In another embodiment, the invention provides a method that treats and/or prevents such as benign prostate hyperplasia, graft-rejection, hepatic diseases, systemic lupus erythematous, spasm, hypertension, chronic obstructive bladder disease, premature labor, infection, allergy, obesity, pancreatic disease and acquired immune deficiency syndrome (AIDS); Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
In preferred embodiments, the invention provides a method that treats and/or prevents glaucoma, asthma, sexual dysfunction or chronic obstructive pulmonary disease; Described method comprises herein compound or the composition of definition to patient's administering therapeutic significant quantity that these needs are arranged.
The present invention will be particularly preferably in can be with less than 10 μ M in the ROCK inhibition analysis hereinafter described, preferably less than the IC of 1 μ M 50Value suppresses formula I compound or its any subgroup of ROCK.
Described restraining effect may betide in external and/or the body, in the time of in betiding body, preferably carries out in selectivity mode as defined above.
" patient's condition of ROCK mediation " used herein or " disease " refer to known any disease that can play a role or other harmful situations." patient's condition of ROCK mediation " used herein or " disease " also refer to can reach by the ROCK inhibitor disease or the patient's condition of mitigation.Correspondingly, another embodiment of the invention relates to play a role lower treatment or alleviate the seriousness of one or more diseases of ROCK.
Aspect pharmaceutical use, compound of the present invention can be used as free acid or alkali and/or with pharmaceutically acceptable sour addition/or form (as: obtaining by avirulent organic or inorganic acid or alkali), hydrate, solvate and/or the mixture of base addition salt, and/or with prodrug or the pro-drug form of ester class.Except other have indicate, otherwise " solvate " used herein term refers to any array configuration with the compounds of this invention and suitable inorganic solvent (as: hydrate) or organic solvent (such as but not limited to alcohols, ketone, ester class and similarly) formation.The professional will know know this class salt, hydrate, solvate etc. and the preparation; The reference of salt, hydrate, solvate etc. is found in for example US-A-6, and 372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733.
According to pharmaceutically-acceptable salts compound of the present invention, namely present with water, oil soluble or dispersed product form, comprised the quaternary ammonium salt of conventional non-toxic salts or formation, as: from inorganic or organic acid or base.The example that this class adds hydrochlorate has comprised acetic acid, hexanodioic acid, sodium alginate, aspartic acid, phenylformic acid, benzene, sodium pyrosulfate, butyric acid, citric acid, camphor tree, camphor, cyclopentane propionate, glyconic acid, sodium lauryl sulphate, ethyl sulfonic acid, fumaric acid, enanthic acid, glycerine, isourea vitriol, heptan, caproic acid, hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, the 2-hydroxyethylsulfonic acid, milk-product, toxilic acid, sulfonic acid, the 2-naphthene sulfonic acid, Nicotine, oxalate, pamoate, pectin, persulphate, the 3-phenylpropyl alcohol, picrate, trimethylacetic acid, propionic acid, succsinic acid, tartrate, thiocyanate-, tosic acid, undeeanoic acid.Alkali salt comprised ammonium salt, such as the alkaline metal salt of sodium and sylvite, such as the alkaline-earth metal salt of calcium salt and magnesium salts, such as dicyclohexyl amine salt organic base salt, N-methyl D-glucosamine, with such as arginine, the amino acid whose salt of Methionin etc.In addition, contain the basic nitrogen group can carry out with following reagent quaternized, such as elementary alkyl halide, such as muriate, bromide and the iodide of methyl, ethyl, propyl group and butyl; Dialkyl sulfate such as dimethyl, diethyl, dibutyl and diamyl vitriol; Long-chain halogenide is such as decyl, lauryl, tetradecyl and stearic muriate, bromide and iodide; Aralkyl halide is such as benzyl and phenethyl bromide compound etc.Other pharmacy acceptable salts have comprised vitriol and the vitriol of ethanol.
Generally for pharmaceutical applications, compound of the present invention can be made as and comprise at least one the compounds of this invention and at least a pharmaceutically acceptable carrier, thinner or vehicle and/or assistant agent, optionally pharmaceutical preparation or the pharmaceutical composition of one or more other pharmaceutically active compounds.
By the mode of unrestricted example, this class preparation may give with the form that is fit to oral dispenser, the outer dispenser (as by intravenous injection, intramuscular injection or subcutaneous injection or intravenous drip) of intestines, local dispenser (comprising eye), inhalation, skin patch, implant, suppository etc.The pesticide supplying form that this class is suitable-based on administering mode, may be solid, semisolid or liquid form-with and preparation method thereof and for the preparation of the carrier of process, thinner and auxiliary material are all known for the professional; Can be referring to for example US-A-6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733, and such as the such manual of standards of Remington ' s Pharmaceutical Sciences latest edition.
Some of this class preparation is preferred but nonrestrictive example has comprised tablet, pill, powder, lozenge, sachet, flat capsule medicament, elixir, suspension, emulsion, solution, syrup, sprays, ointment, creme, lotion, the soft or hard capsule, suppository, eye drops, the powder of aseptic injection and sterile packed (need rebuild before usually using) is to be used as bolus injection administration and/or successive administration, and can be with the carrier that itself is applicable to these preparations, vehicle and thinner are prepared, for example lactose, glucose, sucrose, sorbyl alcohol, N.F,USP MANNITOL, starch, gum arabic, calcium phosphate, alginates, tragacanth gum, gelatin, Calucium Silicate powder, Microcrystalline Cellulose, polyvinylpyrrolidone, polyoxyethylene glycol, Mierocrystalline cellulose, water (aseptic), methylcellulose gum, methyl-propyl group hydroxybenzoate, talcum powder, Magnesium Stearate, edible oil, vegetables oil and mineral oil or its suitable mixture.Preparation can be chosen wantonly and comprise other drug active substance (may or may not can and compound of the present invention produce synergy) and other materials commonly used such as lubricant, wetting agent, emulsifying agent and suspension agent, dispersion agent, disintegrating agent, weighting agent, filler, preservation agent, sweeting agent, seasonings, flux-regulating agent, releasing agent etc. in pharmaceutical preparation.Said composition also can be made into preparation, providing fast, to continue or to postpone the wherein release of contained active compound, for example uses liposome or based on the hydrophilic macromolecule matrix of natural gel or synthetic polymer.In order to strengthen compound dissolution degree and/or the stability of pharmaceutical composition of the present invention, adopt α, β-and γ-cyclodextrin and derivative thereof will bring benefit.Coupling collar dextrin and derivative thereof come the interesting mode of preparation compound can consult EP-A-721,331.Special, pharmaceutical composition of the present invention has comprised the compounds of this invention and the pharmaceutically acceptable cyclodextrin of significant quantity.
In addition, can improve solubleness and/or the stability of compound such as the cosolvent of alcohols.During waterborne compositions, the salt that adds the compounds of this invention will be more suitable in preparation, and this is because they water-soluble higher.
Be similar to the references such as the known composition of pyridine carboxamide, prescription (and used carrier, vehicle, thinner etc.), drug delivery route and be found in US-A-4,997,834 and EP-A-0370498.
For pain therapy, compound of the present invention can be used by the part.For local dispenser, spraying, ointment or transdermal patch or other compounds that is applicable to external application, transdermal and/or intradermal administration form may be more useful.
For ophthalmic applications, solution, gelifying agent, tablet reach and similarly usually can use normal saline solution, gel or vehicle as main carriers.Ophthalmic preparation preferably can prepare with comfortable pH value with suitable buffering system.
More special, composition can be made the particle for the treatment of significant quantity of the solid dispersion that comprises the compounds of this invention and the pharmaceutical preparation of one or more pharmaceutically acceptable water-soluble polymerss.
" solid dispersion " this term refers to comprise solid-state (rather than liquid state or gaseous state) system that has two compositions at least, and one of them composition can more or less be distributed in other one or more compositions equably.When described composition dispersiveness so that system at chemistry with physical properties is unified or everywhere homogeneous or single-phase composition of being defined by thermodynamics, this class solid dispersion will be called as " sosoloid ".Sosoloid is a kind of preferred physical system, and this is because wherein composition is to the organism of using bioavailable normally.
Form preparation compound with nanoparticle may further bring convenience, described nanoparticle have be adsorbed on its surface, be enough to effective median size is maintained surface-modifying agent less than 1000nM.Suitable surface-modifying agent is preferably selected known organic and inorganic drug vehicle.This class vehicle comprises various polymkeric substance, low-molecular weight oligo thing, natural product and tensio-active agent.Preferred surface-modifying agent comprises nonionic and anion surfactant.
The interesting mode of another preparation the compounds of this invention has comprised mixes compound in the hydrophilic polymer, then be coated in this mixture on many globules as filming, thereby generation can conveniently prepare and the composition of tool good biological operability, and is applicable to prepare pharmaceutical dosage form for oral use.Be suitable for pearl and can take various forms as the material of core, as long as described material is pharmaceutically acceptable and has suitable size and hardness.The example of this material is polymkeric substance, inorganic substance, organic substance, glucide and its ramification.Said preparation can prepare in a known manner, and this is usually directed to mix at least a compound of the present invention and one or more pharmaceutically acceptable carriers, can mix if necessary other pharmaceutical active compounds under aseptic condition.Reference 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 such as the such manual of standards of Remington ' sPharmaceutical Sciences latest edition.
Pharmaceutical preparation of the present invention is preferably made unit dosage or suitably packaged, for example the upholder of box, bubble-cap, bottle, bottle, sachet, ampoule or any other suitable single dose or multiple doses or container (posting suitable label); Optionally add the one or more brochures that comprise product information and/or operation instruction.In general, this unitary dose will comprise at least a between 1 and 1000mg between and the common the compounds of this invention between 5 to 500mg, such as per unit dosage approximately 10,25,50,100,200,300 or 400mg.
This compound can be by the number of ways dispenser, this has comprised oral cavity, rectum, eye, Transdermal absorption, subcutaneous, intravenous injection, intramuscular injection or nasal cavity, the illness that depends primarily on specific used preparation and need be treated and prevent, and optimal way is generally oral and intravenously administrable.At least a compound of the present invention is usually so that " significant quantity " is used, be that is to say after carrying out suitable dispenser and can bring the formula I-XXIV of desirable treatment or preventive effect or the amount of any its subgroup for the person of being injected.Usually depend on illness and the drug delivery route that need be treated and prevent; this significant quantity usually can between every day patient's per kilogram of body weight 0.01 to 1000mg; more often be between 0.1 to 500mg; for example between 1 to 250mg; such as patient's per kilogram of body weight approximately 5,10,20,50,100,150,200 or 250mg every day, can with single dose every day, every per daily dose be divided into one or many; or continue medication, as: use and instil.The treatment doctor may be according to deciding formulation rate, route of administration and further treatment plan such as age, sex, patient's general status and character and the seriousness of disease/symptom.Reference 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 such as the such manual of standards of Remington ' s Pharmaceutical Sciences latest edition.
According to method of the present invention, described pharmaceutical composition can be respectively in different time dispensers or simultaneously with that separate or single array configuration in therapeutic process.Therefore, the present invention should be understood to contain all these simultaneously or the treatment plan that replaces, and " " this term will correspondingly be made annotation in dispenser (administration).
For oral form, composition of the present invention can be sneaked into suitable additive, for example vehicle, stablizer or inert diluent, and use usual mode to convert suitable pesticide supplying form to, for example tablet, coating tablet, hard capsule, the aqueous solution, alcohol or oily solution.The example of suitable inert carrier is Sudan Gum-arabic, magnesium oxide, magnesiumcarbonate, potassiumphosphate, lactose, glucose or starch, particularly W-Gum.In this case, the preparation of medicine can be dry and moist particle the two.Suitable oiliness vehicle or solvent are vegetables oil or animal oil, such as sunflower seed oil or Oils,glyceridic,cod-liver.The suitable solvent of the aqueous solution or spirituous solution is water, ethanol, sugar soln or their mixture.Polyoxyethylene glycol and polypropylene glycol also are applicable to the further auxiliary agent of other pesticide supplying forms.As the tablet that discharges immediately, these compositions can contain Microcrystalline Cellulose, secondary calcium phosphate, starch, Magnesium Stearate and lactose and/or other vehicle, tackiness agent, weighting agent, disintegrating agent, thinner and lubricant known in the art.
When by nasal aerosol or suction dispenser, these compositions can be according to the technology preparation of the known field of pharmaceutical preparations in field, and can be prepared into salts solution, adopt phenylcarbinol or other suitable sanitass, absorption enhancer with the raising bioavailability, and adopt fluorocarbon known in the art and/or other solubilizing agent or dispersion agent.The compounds of this invention or its pharmaceutically solution, suspension or the emulsion of the physiological tolerance salt in the acceptable solvent have been comprised with the suitable pharmaceutical formulation of aerosol or spray form dispenser, for example ethanol or water, or the mixture of this kind solvent.If needed, said preparation can also comprise other pharmacy auxiliary agents, for example tensio-active agent, emulsifying agent, stablizer and propelling agent in addition.
For subcutaneous injection, compound of the present invention can add usual material if the need arises, therefore for example can add solubilizing agent, emulsifying agent or further auxiliary agent in solution, suspension or the emulsion.Compound of the present invention also can be frozen drying, and the lyophilizate that obtains can be used for producing injection liquid or infusion preparation.For instance, suitable solvent has comprised water, normal saline solution or alcohol, such as ethanol, propyl alcohol, glycerine, and in addition also just like the sugar soln of glucose solution or mannitol solution, the perhaps mixture of above-mentioned all kinds of SOLVENTS.Injection liquid or suspension can be made according to the known technology in field, use suitable nontoxic, the outer acceptable thinner of intestines or solvent, N.F,USP MANNITOL, 1 for example, 3-butyleneglycol, ringer's solution, water or etc. the sodium chloride solution that oozes, the dispersion agent or the moistening and suspension agent that perhaps are fit to, for example aseptic, nonirritant, fixed oil comprise mono-glycerides or triglyceride and the lipid acid of synthetic comprising oleic acid.
When being rectal administration by the suppository mode, these preparations may be made by mixing the compounds of this invention and suitable non-irritating auxiliary material, for example theobroma oil, synthetic glyceryl ester or polyoxyethylene glycol, they are solid state under general temperature, but in rectal cavity, can liquefy and/or dissolving, to discharge medicine.
In preferred embodiments, compound of the present invention and composition are all used by the part, are used for for instance part or absorption and non-adsorption applications.
Said composition has its certain values in veterinary applications, its purpose not only comprises and prevents and/or treats Animal diseases, and grows and/or their weight and/or quantity and/or the quality of the product that obtains with it from animal of meat or other for promotion such as important economically animal such as ox, pig, sheep, chicken, fishes.Therefore, in yet another aspect, the present invention relates to the composition for veterinary purpose, said composition comprises at least a the compounds of this invention and at least a suitable carrier (namely being fit to the carrier that animal is used).The invention still further relates to the compounds of this invention and prepare this based composition.
To be that the present invention is illustrated by following synthetic and biological example now, but this be with the scope that does not limit the present invention in any way.
Embodiment
A. the physico-chemical property of compound
A.1. the purity of compound
Except as otherwise noted, otherwise the purity of compound will confirm by liquid chromatography/mass spectrometry (LC/MS), and will be as follows:
HPLC system: Waters2690 and Waters996 photoelectron diode array detector; Post: C18; Gradient: solvent orange 2 A (H 2O/ formic acid 26.5nM) 0%, to solvent B(CH 3CN/ formic acid 17nM) in 3 minute 80%.Flow: 2.75ml/ minute.
Mass spectrograph: micelle platform LC.Ionization: electron spray(ES) (polarity: negative and positive)
A.2. the separability of configuration:
Adopt the absolute configuration of Cahn-Ingold-Prelog system divides asymmetric center, wherein four of asymmetric carbon groups will be according to one group of sequence rules rank.The visible Cahn of reference; Ingold; Prelog Angew.Chem.Int.Ed.Eng/.1966,5,385-415.
A.3. stereochemistry:
One of skill in the art is known that, specific enantiomer (or diastereomer) can obtain by diverse ways, (as: salt that forms with optical activity acid or alkali can be used for forming diastereo-isomerism salt such as but not limited to chiral separation, they can promote the separation of the compound optically active isomer of formula I or any subgroup), asymmetric synthetic or preparation type chiral chromatography (uses different posts, as from the Chiral Technologies Europe (Illkirch of company, France) Chiralcel OD-H(tris-methyl benzoate, 46x250 or 100x250mm, 5 μ m), Chiralcel DJ(tris-3,5-dimethylphenyl carbamate, 46x250 or 100x250mm, 5 μ m), Chiralpak AD(tris-methyl benzoate, 46x250mm, 10 μ m) and Chiralpak AS (tris-(S)-1-phenyl ethyl carbamate, 46x250mm, 10 μ m)).If talk about easily, steric isomer can be obtained (this compounds comprises amino acid) from the commercial coating of configuration known.
A.4. the title of molecule
MDL ISIS TM/ Draw 2.3 softwares are used to specify the title of molecule.
B. compound is synthetic
B.1. intermediate
Compound of the present invention can be prepared by method well known to those skilled in the art and synthetic and experimental arrangement as follows.For instance, intermediate C can basis, obtains (acid amides that carries out subsequently the Suzuki linked reaction forms) but be not limited only to following general sequence:
PG has represented suitable blocking group, for example T.Greene and P.Wuts, in " Greene ' s Protective Group in OrganicChemistry " (4th edition, John Wiley ﹠amp; Sons Inc) group described in.
Figure DEST_PATH_GDA00002198413500521
(a) ArNH 2, TBTU, HOBt, DIEA, DMF, rt or ArNH 2, DCC, HOBt, DIEA, DMF/DCM,
rt；
(b) Ghosez reagent [Me 2C=C(Cl) NMe 2], THF, rt, then be ArNH 2, Py
(c) ArNH 2, Cul, Cs 2CO 3, DMEDA, dioxolane, 130 ° of C, 16h;
(d) 2MNa 2CO 3(aq), Pd(PPh 3) 4, toluene or DME, ethanol, N 2, MW, 130 ° of C.
The general procedure of preparation acid amides
Option A. at DMF(10ml) in corresponding carboxylic acid solution (1mmol) add DIEA(3mmol, 3 equivalents), TBTU(1.3mmol, 1.3 equivalents) and HOBt(0.3mmol, 0.3 equivalent).At room temperature stirred reaction mixture 5-10 minute, then add corresponding amine (1.1 equivalent).Then stirred reaction mixture 16 to 24 hours uses vinyl acetic monomer (100ml) dilution, uses 0.1MHCl(50ml again) and saturated sodium carbonate (50ml) washing.Organic phase is through MgSO 4Drying is removed solvent again under vacuum.
Another kind of scheme: add gradually the DCC(1 equivalent to the corresponding carboxylic acid solution in DMF/DCM mixture (0.25M) (1 equivalent)), HOBt(1 equivalent) and the DIEA(3 equivalent).Adding corresponding amine (1 equivalent) before, at room temperature stirred solution is 30 minutes.At room temperature stirred reaction mixture is 1 hour to 3 days.Solvent is removed under vacuum.Residue is separated in DCM and water.Come extraction product with DCM.Organic layer is separated, with yellow soda ash (or 1N NaOH), 1N hydrochloric acid and the salt water washing of 2M, through MgSO 4Drying, evaporation.
Another kind of scheme: will be at CH 3CN(4ml) mixture in the corresponding carboxylic acid in (200mg, 1.0 equivalents) and the amine (2.0 equivalent) adds the HOBT(0.4 equivalent) and EDCI(approximately 120mg, 1.5 equivalents).With the temperature stirred reaction mixture of 30 ° of C 16 hours.The LC-MS Faxian shows that reaction finishes.Then solvent is concentrated into drying, obtains crude product, not purifiedly be directly used in next step.Crude product is dissolved in DCM/TFA=7: 1(4ml).With the temperature stirred reaction mixture of 30 ° of C 16 hours.The LC-MS Faxian shows that reaction finishes.Then reaction mixture is concentrated and use preparative high performance liquid chromatography (prepHPLC) carries out purifying with crude product, to obtain final product.
Option b. at anhydrous THF(10ml) in corresponding carboxylic acid solution (5mmol) add Ghosez reagent (10mmol, 2 equivalents).At room temperature stirred reaction mixture is 2.5 hours, then solution is removed under vacuum.Residue is dissolved at anhydrous pyridine and is cooled to 0 ° of C, then adds corresponding amine (5.5mmol, 1.1 equivalents).At room temperature stirred reaction mixture is 1 hour.Steam altogether to remove pyridine by toluene, then residue is dissolved in EtOAc(100ml) and use 1M NaOH(50ml), water (50ml) and salt solution (50ml) washs.Organic phase is through MgSO 4Then drying is removed solvent under vacuum.
Scheme C. carries out degassed processing by pass into nitrogen toward solution to the corresponding carboxylic acid solution (1mmol) in the dioxolane (2ml).Add copper (I) iodide (0.25mmol, 0.25 equivalent), Cs 2CO 3(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).With the temperature of 130 ° of C stirred reaction mixture 24 hours in the bottle of sealing.Use the diatomite filtration reaction mixture, then use EtOAc(200ml) washing diatomite.With 1M sodium bicarbonate (100ml), 0.1MHCl(100ml), water (100ml) and salt solution (100ml) wash filtrate.Organic layer is through MgSO 4Then drying is removed solvent under vacuum.
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 solution (3ml, 6mmol, 4 equivalents) be in MW container (Biotage, 20ml).Tetrakis triphenylphosphine palladium (0) catalyzer (4 % by mole) is front adding, and washes reaction vessel with nitrogen.Before sealing and using MW to carry out irradiation 1-1.5 hour with the temperature of 130 ° of C, again wash reaction vessel with nitrogen.Then allow residue cooling in the reaction mixture, and use the diatomite filtration reaction mixture.With vinyl acetic monomer (200ml) and methyl alcohol (100ml) wash residual thing.Solvent is removed under vacuum, then added among the DCM.Filter, use the DCM washing precipitate, then carry out drying program.This compound can be used with such state or carry out purifying (silica gel, DCM/MeOH gradient) with the flash chromatography method.
Intermediate 1:3-bromo-uncle 4-(1--butoxy carbonyl amino-ethyl)-phenylformic acid
Figure DEST_PATH_GDA00002198413500541
To at EtOH(100 to 200ml) in 4-acetyl-3-bromo-phenylformic acid (40 to 80mmol) solution in add the DIEA(1.6 equivalent) and oxammonium hydrochloride (1.6 equivalent).Under refluxad stirred reaction mixture is 1 hour.Reaction mixture is cooled to room temperature, then under reduced pressure desolventizing.Residue is added into the KHSO of water and 20% 4Solution.Filter, wash throw out with water, then carry out drying program.
To the 3-bromo-4-[1-(hydroxyl imido grpup in acetic acid (30 to 300ml))-ethyl]-add activated zinc (5-10 equivalent) in the solution of phenylformic acid (10 to 50mmol).Stirred reaction mixture 10 minutes or up to 3.5 hours at room temperature.Filter reaction mixture, then use the acetic acid washing precipitate.Under reduced pressure remove the solvent of filtrate.
The 4-(1-amino-ethyl of crude product)-3-bromo-phenylformic acid (15323 to 30727 μ mol) is suspended in THF/1MNa 2CO 3: 1/1(100ml) in the mixture or acetone/1MNa 2CO 3: 1/1(100ml) mixture or acetone/2MNa 2CO 3: 8/2(100ml) mixture and interpolation (Boc) 2The O(1.5 equivalent).At room temperature stirred reaction mixture is 1 to 2 hour.Under reduced pressure remove organic solvent or add ether, the separated or reaction mixture of two layers is filtered, and then under reduced pressure removes organic solvent.With citric acid or 20%KHSO 4Then solution dilution water-based residue extracts with EtOAc.With the organic layer of salt water washing merging, through MgSO 4Drying, then under reduced pressure desolventizing.Whenever necessary, with column chromatography compound is carried out purifying (silica gel, DCM/MeOH gradient).
Intermediate 2:{1-[2-bromo-4-(pyridine-4-meaning-carbamyl)-phenyl]-ethyl }-carboxylamine tert-butyl ester.
Figure DEST_PATH_GDA00002198413500542
To at DMF(10 to 30ml) in 3-bromo-uncle 4-(1--butoxy carbonyl amino-ethyl)-phenylformic acid (7496 to 61011 μ mol) adds the DIEA(2 equivalent), the TBTU(1.3 equivalent) and the HOBt(0.3 equivalent).At room temperature stirred reaction mixture is 5 minutes.Add 4-aminopyridine (1.5 equivalent), then reach at room temperature stirred reaction mixture 2.5 hours to spending the night.If can also observe starting raw material, add more DIEA(0.39 equivalent), the TBTU(0.25 equivalent), the HOBt(0.06 equivalent) and 4-aminopyridine (0.28 equivalent), then stirred reaction mixture 2 hours at room temperature.Use the EtOAc diluted reaction mixture, then use 0.1M HCl, saturated Na 2CO 3Or saturated NaHCO 3Washing.Organic layer is through MgSO 4Drying, then under reduced pressure desolventizing.With the flash chromatography method compound is carried out purifying (silica gel, DCM/MeOH gradient).
Intermediate 3:2 '-(uncle 1--butoxy carbonyl amino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid.
Figure DEST_PATH_GDA00002198413500551
Method 1: at DME/EtOH/ water: 2/1/1(10ml) in the mixture 1-[2-bromo-4-(pyridin-4-yl-carbamyl)-phenyl]-ethyl-add Na in the solution of carboxylamine tert-butyl ester (2 to 3mmol) and 3-carboxyl phenylo boric acid (1.2 equivalent) 2CO 3(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).With the temperature of 135 ° of C reacting by heating mixture 30 minutes in microwave oven.Under reduced pressure desolventizing.Dilute residue with MeOH, then filter with diatomite.With MeOH washing diatomite residue.Then under reduced pressure desolventizing puts into DCM with residue.Filter and use the DCM washing precipitate, then carry out drying program.With half preparation type LC-MS compound is carried out purifying or uses DCM/MeOH(3/2) the dilution residue, then add gac toward reaction mixture.At room temperature stirred the mixture 10 minutes, and then used filtered through silica gel.Use DCM/MeOH(8/2) the wash residual thing, and then wash with MeOH.Then under reduced pressure desolventizing.
Method 2: in toluene/EtOH:5/3(32ml) 1-[2-bromo-4-(pyridin-4-yl-carbamyl)-phenyl]-ethyl-be added in the Na in the water (8ml) in the solution of carboxylamine tert-butyl ester (6912 μ Mol) and 3-carboxyl phenylo boric acid (1.0 equivalent) 2CO 3(3 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.03 equivalent) solution.Under refluxad the reacting by heating mixture is 3 hours.Add more 3-carboxyl phenylo boric acid (0.35 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.015 equivalent), and then reacting by heating mixture 3 hours under refluxad.Reaction mixture is cooled to room temperature, and uses diatomite filtration.With EtOAc and MeOH washing.Then under reduced pressure desolventizing carries out purifying (silica gel, DCM/MeOH gradient) with the flash chromatography method with compound.
Intermediate 4:[2 '-(uncle 1--butoxy carbonyl amino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-yl]-acetic acid
Figure DEST_PATH_GDA00002198413500561
To at DME/EtOH/2NNa 2CO 3: 1/1/1(10ml) in the mixture 1-[2-bromo-4-(pyridine e4-base-carbamyl)-phenyl]-ethyl-add 3-carboxyl aminomethyl phenyl boric acid (1.5 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent) in the solution of carboxylamine tert-butyl ester (1951 μ Mol).With the temperature of 160 ° of C reacting by heating mixture 15 minutes in microwave oven.Reaction mixture is cooled to room temperature, washs with diatomite filtration and with EtOAc and MeOH.Under reduced pressure desolventizing.With column chromatography compound is carried out purifying (silica gel, DCM/MeOH gradient)
Intermediate 5:3-[2 '-(uncle 1--butoxy carbonyl amino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-yl]-propionic acid
Figure DEST_PATH_GDA00002198413500562
To at DME/EtOH/2NNa 2CO 3: 1/1/1(20ml) in the mixture 1-[2-bromo-4-(pyridine e-4-base-carbamyl)-phenyl]-ethyl-add 3-carboxy ethyl phenyl-boron dihydroxide (1.5 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent) in the solution of carboxylamine tert-butyl ester (3122 μ Mol).With the temperature of 160 ° of C reacting by heating mixture 15 minutes in microwave oven.Reaction mixture is cooled to room temperature, washs with diatomite filtration and with EtOAc and MeOH.Under reduced pressure desolventizing.With column chromatography compound is carried out purifying (silica gel, DCM/MeOH gradient).
Intermediate 6:{1-[3 '-hydroxyl-5-(pyridin-4-yl-carbamyl)-xenyl-2-yl]-ethyl }-carboxylamine tert-butyl ester
Figure DEST_PATH_GDA00002198413500571
To at DME/EtOH:1/1(8ml) in the mixture 1-[2-bromo-4-(pyridin-4-yl-carbamyl)-phenyl]-ethyl }-add Na in the solution of carboxylamine tert-butyl ester (2087 μ Mol) and 3-hydroxybenzene boric acid (1.55 equivalent) 2CO 3(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Wash reaction mixture with Ar, and in microwave oven, heated 1.5 hours with the temperature of 130 ° of C.Reaction mixture is cooled to room temperature, uses 1N NaHCO 3Dilution and extract with EtOAc.Use 1N NaHCO 3The extraction organic layer, the aqueous layer that then merges with citric acid and 1N HCl acidifying.Extract aqueous layer with EtOAc, then organic layer is through MgSO 4Drying and under reduced pressure desolventizing.This compound carries out purifying by the EtOAc recrystallization.
Intermediate 7:[2 '-(uncle 1--butoxy carbonyl amino-ethyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-base oxygen base]-acetic acid.
Figure DEST_PATH_GDA00002198413500572
To in toluene/ethanol: 5/3(12ml) in the mixture 1-[2-bromo-4-(pyridin-4-yl-carbamyl)-phenyl]-ethyl-carboxylamine tert-butyl ester (0.48 gram) adds 3-benzene oxygen-jasmal boric acid (2 equivalent) and the Na of (4ml) in water 2CO 3Solution (4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.06 equivalent).Under refluxad the reacting by heating mixture is 2 hours.Reaction mixture is cooled to room temperature and uses diatomite filtration.With EtOAc and EtOH washing washing diatomite residue.Then under reduced pressure desolventizing puts into DCM with residue.Filter and use the DCM washing precipitate, then carry out drying program.With column chromatography compound is carried out purifying (silica gel, DCM/MeOH gradient).
Intermediate 8:{1-[2-bromo-4-(3-fluoro-pyridin-4-yl-carbamyl)-phenyl]-ethyl }-carboxylamine tert-butyl ester.
Figure DEST_PATH_GDA00002198413500581
To at anhydrous THF(20ml) in 3-bromo-uncle 4-(1--butoxy carbonyl amino-ethyl)-add Ghosez reagent (2 equivalent) in the benzoic acid solution (8352 μ mol).At room temperature stirred the mixture 2 hours.Under reduced pressure desolventizing.Residue is dissolved in anhydrous pyridine (20ml), then adds 3-fluoro-pyridin-4-yl amine (1.2 equivalent).At room temperature stirred reaction mixture is 2.5 hours.Under reduced pressure remove pyridine.Residue is dissolved in 1N Na 2CO 3, and extract with EtOAc.Use 1N NaHCO 3, the organic layer that merges of citric acid and water washing.Organic layer is through MgSO 4Drying, then under reduced pressure desolventizing.With column chromatography compound is carried out purifying (silica gel, DCM/MeOH gradient).
Intermediate 9:2 '-(uncle 1--butoxy carbonyl amino-ethyl)-5 '-(3-fluoro-pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid
Figure DEST_PATH_GDA00002198413500582
To at DME/EtOH/water:1/1/1(10ml) in the mixture 1-[2-bromo-4-(3-fluoro-pyridin-4-yl-carbamyl)-phenyl]-ethyl }-add Na in the solution of carboxylamine tert-butyl ester (2841 μ Mol) and 3-carboxyl phenylo boric acid (1.5 equivalent) 2CO 3(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).With 130 ℃ temperature reacting by heating mixture 1.5 hours in microwave oven.Water and citric acid (acid ph value) diluted reaction mixture, and extract with EtOAc.The organic layer that merges is through MgSO 4Drying, under reduced pressure desolventizing.With column chromatography compound is carried out purifying (silica gel, DCM/MeOH gradient).
Intermediate 10:[2 '-(uncle 1--butoxy carbonyl amino-ethyl)-5 '-(3-fluoro-pyridin-4-yl-carbamyl)-xenyl-3-base oxygen base]-acetic acid.
Figure DEST_PATH_GDA00002198413500591
To at DME water: 9/1(15ml) 1-[2-bromo-4-(3-fluoro-pyridin-4-yl-carbamyl)-phenyl]-ethyl }-add K in the solution of carboxylamine tert-butyl ester (3400 to 3650 μ Mol) and 3-benzene oxygen-jasmal boric acid (1 equivalent) 3PO 4(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).With 130 ℃ temperature reacting by heating mixture 30 minutes in microwave oven.Gac is added in the reaction mixture, then uses the diatomite filtration mixture.With EtOAc and water washing residue.Aqueous layer is separated, then extracts with EtOAc.With the organic layer of salt water washing merging, through MgSO 4Under reduced pressure desolventizing after the drying.With column chromatography compound is carried out purifying (silica gel, cyclohexane/acetone gradient).
To at THF(25ml) [2 '-(uncle 1--butoxy carbonyl amino-ethyl)-5 '-(3-fluoro-pyridin-4-yl-carbamyl)-phenyl]-xenyl-3-base oxygen base]-add the Pd/C(0.5 equivalent in the solution of jasmal (2mmol)).Wash reaction mixture with hydrogen, will be at THF(5ml) in cyclohexadiene solution dropwise join in the reaction mixture.Temperature with 55 ° of C under hydrogen environment stirred the mixture 24 hours.Add diatomite, then stirred suspension 20 minutes at room temperature.With suspension filtered, then use THF(50ml) the wash residual thing.Under reduced pressure desolventizing.
Intermediate 11:{1-[3 '-amino-5-(pyridin-4-yl-carbamyl)-xenyl-2-yl]-ethyl }-carboxylamine tert-butyl ester.
Figure DEST_PATH_GDA00002198413500592
To at DME/ ethanol/1N Na 2CO 3: 1/1/1(3ml) 1-[b-bromo-4-(pyridin-4-yl-carbamyl)-phenyl]-ethyl }-add tetrakis triphenylphosphine palladium (Pdtetrakis) (0.05 equivalent) in the solution of carboxylamine tert-butyl ester (1428 μ Mol) and 3-aminophenyl boric acid (2 equivalent).With 150 ℃ temperature reacting by heating mixture 15 minutes in microwave oven.Reaction mixture is cooled to room temperature, dilute with water and extract with EtOAc.With the organic layer of 0.5N HCl washing merging, through MgSO 4Under reduced pressure desolventizing after the drying.
Intermediate 12:{1-[3 '-amino-5-(3-fluoro-pyridin-4-yl-carbamyl)-xenyl-2-yl]-ethyl }-carboxylamine tert-butyl ester
Figure DEST_PATH_GDA00002198413500601
To at DME/ ethanol/1N Na 2CO 3: 1/1/1(10ml) 1-[2-bromo-4-(3-fluoro-pyridin-4-yl-carbamyl)-phenyl]-ethyl }-carboxylamine tert-butyl ester (1094 μ mol) and 3-aminophenyl boric acid (2 equivalent) adding tetrakis triphenylphosphine palladium (Pdtetrakis) (0.05 equivalent).With 130 ℃ temperature reacting by heating mixture 1.5 hours in microwave oven.Reaction mixture is cooled to room temperature, and then water and citric acid dilution extract with EtOAc.The organic layer that water and salt water washing merge.Organic layer is through MgSO 4Drying, then under reduced pressure desolventizing.With column chromatography compound is carried out purifying (silica gel, DCM/MeOH gradient).
Intermediate uncle 13:4-[2-(1--butoxy carbonyl amino-ethyl)-5-(pyridin-4-yl-carbamyl)-phenyl]-1H-pyrroles-2-carboxylic acid
Figure DEST_PATH_GDA00002198413500602
To at DME/EtOH:1/1(0.8ml) in 1-[2-bromo-4-(pyridin-4-yl-carbamyl)-phenyl]-ethyl }-add Na in the solution of carboxylamine tert-butyl ester (809 μ Mol) and 1H-pyrroles-2-carboxylate methyl ester boric acid (1.15 equivalent) 2CO 3(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Wash reaction mixture with Ar, and in microwave oven, heated 35 minutes with the temperature of 130 ° of C.Reaction mixture is cooled to room temperature, dilute with water and extract with EtOAc.Under reduced pressure remove the solvent of organic layer.
To at THF(1.6ml) and MeOH(1.6ml) in uncle 4-[2-(1--butoxy carbonyl amino-ethyl)-5-(pyridin-4-yl-carbamyl)-phenyl]-add 1N LiOH solution (1.6ml) in the solution of 1H-pyrroles-2-carboxylate methyl ester (661 μ Mol).With the temperature stirred reaction mixture of 40 ° of C 1.5 hours.Use saturated NaHCO 3Then diluted reaction mixture extracts with EtOAc.With 20% citric acid solution acidifying aqueous layer, and then once extract with EtOAc.The organic layer that merges is through MgSO 4Drying, under reduced pressure desolventizing.
Intermediate uncle 14:4-[2-(1--butoxy carbonyl amino-ethyl)-5-(pyridin-4-yl-carbamyl)-phenyl]-the 1H-Indoline-2-carboxylic acid
Figure DEST_PATH_GDA00002198413500611
To at DME/EtOH:1/1(8ml) in 1-[2-bromo-4-(pyridin-4-yl-carbamyl)-phenyl]-ethyl }-add Na in the solution of carboxylamine tert-butyl ester (952 μ Mol) and 4-bromo-1H-indole-2-carboxylic methyl ester boric acid (1.55 equivalent) 2CO 3(4 equivalent) and tetrakis triphenylphosphine palladium (Pd tetrakis) (0.05 equivalent).Wash reaction mixture with Ar, and in microwave oven, heated 35 minutes with the temperature of 130 ° of C.Reaction mixture is cooled to room temperature, and then dilute with water filters.Residue is carried out drying treatment.
To at THF(2.4ml) and MeOH(2.4ml) in the 4-[2-(1-amino-ethyl)-5-(pyridin-4-yl-carbamyl)-phenyl]-add 1N LiOH solution (2.4ml) in 1H-indole-2-carboxylic methyl ester's (600 μ Mol) the solution.Temperature with 40 ° of C stirred the mixture 6 hours.With 1N LiOH diluted reaction mixture, then extract with EtOAc.With 20% citric acid solution acidifying aqueous layer, and then once extract with EtOAc.The organic layer that merges is through MgSO 4Drying, under reduced pressure desolventizing.
Intermediate 15:3-bromo-uncle 4-(-butoxy carbonyl amino-methyl)-phenylformic acid
Figure DEST_PATH_GDA00002198413500612
To at the MeOH(3 liter) 3-bromo-4-tolyl acid suspension (300g, 1.39mol) in add H 2SO 4(6ml).Temperature stirred reaction mixture with 60 ° of C is extremely overnight.Reactant is cooled to room temperature and evaporation, then residue is dissolved in the EtOAc(2 liter).Use saturated NaHCO 3(1 liter) washing EtOAc solution is through MgSO 4Be concentrated into drying after the drying, to obtain corresponding methyl esters, be faint yellow oily thing (303 grams, 95% productive rate).
Will be at anhydrous CCl 4The solution of the previous methyl esters in (1.5 liters) (303 grams, 0.98mol, 1.0 equivalents) is added into anhydrous CCl 4NBS(183.9 gram in (1.5 liters), 1.03mol, 1.05 equivalents) and AIBN(8 gram, 0.049mol, 0.05 equivalent) in the solution, temperature is room temperature.With reaction mixture refluxed 16 hours, be cooled to room temperature and evaporation, then residue is dissolved in the DCM(2.5 liter).Use saturated NaHCO 3(0.6 liter), and H 2O(1 rises * 3) washing DCM solution.Organic layer is through MgSO 4Dry and be concentrated into drying, to obtain the not purified crude product 3-bromo-4-brooethyl-methyl benzoate that is directly used in next step.
With Boc 2NH(175 gram, 0.925mol, 1.0 equivalents) be added into the liter at DMF(3) in t-BuOK(124,5 grams, 1.11mol1.02 equivalent) in the solution, then at room temperature stirred gained solution 1 hour.At room temperature crude product 3-bromo-4-brooethyl-methyl benzoate is added into above-mentioned reaction soln, and stirs and spend the night.Then desolventizing under vacuum condition is dissolved in DCM(500ml with residue).Water (3x500ml) washing DCM solution is through MgSO 4Dry and be concentrated.Use PE: EA=20: 1 carries out purifying with column chromatography with crude product on silica gel, with the tert-Butyl dicarbonate that draws yellow solid-4-amino methyl-3-bromo-methyl benzoate (290 grams, 70% productive rate).
In the temperature of 0 ° of C at the DCM(2.9 liter) in the solution of benzylamine (290 grams, 0.652mol, 1.0 equivalents) of previous tert-Butyl dicarbonate protection in drip TFA(92.8 gram, 0.813mol, 1.25 equivalents), then at room temperature stirred the gained mixture 4 hours.Add 0.5M NaHCO 3To mixture, so that the pH value is transferred to 8.Water (3*500ml) washing reaction mixture is through MgSO 4Concentrated with Rotary Evaporators after dry, with 3-bromo-uncle 4-(that obtains yellow oily-butoxy carbonyl amino-methyl)-methyl benzoate (210 grams, 93.5% productive rate).
Be added on H 2The O(1.26 liter) the NaOH(48.8 gram in, 1.22mol, 2.0 equivalents) at the MeOH(1.26 liter) in 3-bromo-uncle 4-(-butoxy carbonyl amino-methyl)-methyl benzoate (210 grams, 0.61mol, 1.0 equivalents) solution in.With the temperature stirred reaction mixture of 50 ° of C 2 hours.Reactant is cooled to room temperature, and is concentrated to the amount of half.Add 1M HCl solution, residue is acidified to pH value 5.The solid that produces is collected and is dry, with the title intermediate (200 grams, 99.4% productive rate) that draws white solid.
Intermediate 16:[2-bromo-4-(pyridin-4-yl-carbamyl)-benzyl]-carboxylamine tert-butyl ester.
Figure DEST_PATH_GDA00002198413500621
To at the DMA(1 liter) in intermediate 15(100 gram, 0.303mol, 1.0 equivalents) and the solution of 4-aminopyridine (28.5 grams, 0.303mol, 1.0 equivalents) in add Et 3N(30.6 gram, 0.303mol, 1.0 equivalents), DMAP(3.7 gram, 0.030mol, 0.1 equivalent) and HATU(115.2 gram, 0.303mol, 1.0 equivalents).With the temperature stirring reaction solution of 30 ° of C 16 hours.Evaporating solvent under vacuum condition is by adding DCM(600ml) and H 2O(600ml) cured residue is to draw title compound (86.1 grams, 70% productive rate).
Intermediate 17:[2-bromo-4-(3-fluoro-pyridin-4-yl-carbamyl)-benzyl]-carboxylamine tert-butyl ester.
Figure DEST_PATH_GDA00002198413500631
Prepare intermediate 17 according to intermediate 16 described methods.
Intermediate 18:2 '-(uncle-butoxy carbonyl amino-methyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid.
Figure DEST_PATH_GDA00002198413500632
To at DMF(350ml) and H 2O(87.5ml) the intermediate 16(35 gram in, 0.086mol, 1.0 equivalents) and the solution of 3-carboxyl phenylo boric acid (14.27 gram, 0.086,1.0 equivalents) in add Na 2CO 3(18.2 grams, 0.172mol, 2.0 equivalents).Then at N 2Add Pd(dppf under the environment) Cl 2(3.15 grams, 0.0043mol, 0.05 equivalent) is to solution.Stir the solution 16 hours of gained with the temperature of 100 ° of C.Evaporating solvent under vacuum condition, then use DCM:MeOH=10: 1 carries out purifying with column chromatography with residue on silica gel, with the title compound (27 grams, 70% productive rate) that draws brown solid.
Intermediate uncle 19:2'-(-butoxy carbonyl amino-methyl)-5 '-(3-fluoro-pyridin-4-yl-carbamyl)-xenyl-3-carboxylic acid.
Figure DEST_PATH_GDA00002198413500633
Prepare intermediate 19 according to intermediate 18 described methods, from intermediate 17.
Prepare in a similar fashion following intermediate:
Figure DEST_PATH_GDA00002198413500641
Figure DEST_PATH_GDA00002198413500651
Intermediate 27[2 '-(uncle-butoxy carbonyl amino-methyl)-5 '-(pyridin-4-yl-carbamyl)-xenyl-3-base oxygen base]-acetic acid.
Figure DEST_PATH_GDA00002198413500652
To at DMF(300ml) and H 2O(75ml) the common intermediate in (30 grams, 0.074mol, 1.0 equivalents) and [3-(4,4,5,5-tetramethyl--[1,3,2] dioxane pentaborane-2-yl)-benzene oxygen]-ethyl acetate (23 gram, 0.074,1.0 equivalents) adds Na2CO3(15.6 gram, 0.147mol, 2.0 equivalents).Then at N 2Add Pd(dppf under the environment) Cl 2(2.7 grams, 0.0037mol, 0.05 equivalent) is to solution.Stir the solution 16 hours of gained with the temperature of 100 ° of C.With solvent evaporation, then residue is dissolved in MeOH 200ml, and is added into the 1M LiOH of 148ml, stir the solution 16 hours of gained with the temperature of 30 ° of C, check with LC-MS.With solvent evaporation to 1/3, then with 20% aqueous hydrochloric acid the pH value is adjusted to 5, with solvent evaporation, then use DCM:MeOH=10: 1 carries out purifying with column chromatography with residue on silica gel, with the title compound (23.8 grams, two steps become 67.4%) that draws white solid.
Intermediate 28[2 '-(uncle-butoxy carbonyl amino-methyl)-5 '-(3-fluoro-pyridin-4-yl-carbamyl)-xenyl-3-base oxygen base]-acetic acid.
Figure DEST_PATH_GDA00002198413500661
Prepare intermediate 28 according to intermediate 27 described methods, from intermediate 17.
If compound of the present invention contains ester group, just that can prepare according to following overall plan is described:
Figure DEST_PATH_GDA00002198413500662
(e) R ' OH, TBTU, HOBt, DIEA, DMF, rt or R ' OH, DCC, DMAP, DCM, rt;
(f) Ghosez reagent [Me 2C=C(Cl) NMe 2], THF or DCM, rt, then be R ' OH.
Scheme E. is at DMF(1ml) in corresponding carboxylic acid suspension (0.25mmol) in add DIEA(0.75mmol, 3 equivalents), TBTU(0.325mmol, 1.3 equivalents), HOBt(0.075mmol, 0.3 equivalent), then stirred reaction mixture 5 minutes at room temperature then adds corresponding alcohol (1.1-5 equivalent).At room temperature stirred reaction mixture 1-16 hour, then use vinyl acetic monomer (100ml) dilution, use again saturated aqueous sodium carbonate (50ml), 0.1MHCl(50ml), water (50ml) and salt solution (50ml) washing.Organic phase is through MgSO 4After the drying, transfer to vacuum chamber concentrated, with the required ester of output.
Another kind of scheme.
The acids of general type can be in the situation that DMAP exists the mediation by the DCC effect to convert corresponding ester to the Steglich method.This chemistry is method well known to those skilled in the art, and can be according to document precedent (B.Neises and W.Steglich. " Esterification of carboxylic acids with dicyclohexyl carbodiimide/4-dimethylaminopyridine "; Coll.Vol.7:93) carry out.
Scheme F. is at the THF that is cooled to 0 ° of C temperature or DCM(1ml) in the solution of corresponding carboxylic acid (0.25mmol) in add Ghosez reagent (2-trimethylammonium-1-propenyl amine, CAS number are 26189-59-3,0.5mmol, 2 equivalents for 1-chloro-N, N).When being heated to room temperature stirred reaction mixture 1-3 hour, then add corresponding alcohol (1.2 equivalent).At room temperature stirred reaction mixture is 1 hour.Solution for vacuum is evaporated.Dilute residue and use saturated NaHCO with EtOAc 3Washing.Organic layer is through MgSO 4Drying, then under reduced pressure desolventizing.
Acids is converted into the overall plan of thioesters
Figure DEST_PATH_GDA00002198413500671
(g) R ' SH, DCC, DMAP, DCM or DMF, room temperature
To DCM or the DMF(10ml at 0 ° of C) in corresponding carboxylic acid solution (1mmol) in add DCC(1.1mmol, 1.1 equivalents) and DMAP(0.1mmol, 0.1 equivalent), then add corresponding mercaptan (2-4 equivalent).Remove cooling bath, then at room temperature stirred reaction mixture 1-16 hour.Use DCM(100ml) diluted reaction mixture, use again saturated aqueous sodium carbonate (50ml), 0.1M HCl(50ml), the washing of water (50ml) and salt solution (50ml).Organic phase is through MgSO 4After the drying, transfer to vacuum chamber concentrated, with the required thioesters of output.
Another kind of scheme: at CH 3CN(4ml) add the HOBT(0.4 equivalent in the corresponding carboxylic acid in (200mg, 1.0 equivalents) and sulfur alcohol (2.0 equivalent) mixture) and EDCI(approximately 120mg, 1.5 equivalents).With the temperature stirred reaction mixture of 30 ° of C 16 hours.The LC-MS Faxian shows that reaction finishes.Then solvent is concentrated into drying, purifying obtains crude product, not purifiedly is directly used in next step.
Crude product is dissolved in DCM/TFA=7: 1(4ml).With the temperature stirred reaction mixture of 30 ° of C 16 hours.The LC-MS Faxian shows that reaction finishes.Then use preparative high performance liquid chromatography (prepHPLC) to carry out purifying as crude product concentrated the reaching of reaction mixture, to obtain final product.
Assorted alkyl is converted into the overall plan of lactone derivatives
The alcohols of general type or mercaptan can be converted to corresponding assorted alkyl according to overall plan (X=O or S) and link lactone.
Figure DEST_PATH_GDA00002198413500672
(h) DIEA, DMF, room temperature
To at DMF(10ml) in corresponding thiol solution (1mmol) in add DIEA(2mmol, 2 equivalents), then add corresponding bromo lactone (1.1mmol, 1.1 equivalents).At room temperature stirred reaction mixture is 1 hour, then uses vinyl acetic monomer (100ml) dilution, use 0.1M HCl(50ml), water (50ml) and salt solution (50ml) washs.Organic phase is through MgSO 4After the drying, vacuum concentration is with the required lactone of output.
Intermediate 29:3-(2-amino-ethyl sulfenyl)-dihydro-furan-2-ketone
Figure DEST_PATH_GDA00002198413500673
With 3-bromo-dihydro-furan-2-ketone (2.49 gram, 15.1mmol) and 2-(tertbutyloxycarbonyl-amino) sulfur alcohol (2.9 grams, 16.5mmol) is dissolved in the CH of 40ml 3CN.Then with K 2CO 3(4.14 grams, 30mmol) adds in the solution.Stirred 16 hours with 80 ℃ temperature.Solvent evaporation to dry, then is purified to residue with column chromatography (PE/EtOAc=4/1) intermediate 29 of the tertbutyloxycarbonyl protection of 3.8 grams, is colorless oil.
(3.7 restrain previous compound, 14.16mmol) are dissolved in the EtOAc of 10ml.Add the 4N HCl/EtOAc of 40ml to solution.Stirred 2 hours with 25 ℃ temperature.Filter white solid, then with the PE washing, to obtain the intermediate 29 of 2 grams.
Intermediate 30:3-(3-amino-propyl group sulfenyl)-dihydro-furan-2-ketone.
Figure DEST_PATH_GDA00002198413500681
3-amino-propane-1-alcohol (40 grams, 0.533mol) is dissolved among 1 liter the THF.Then in the temperature of 25 ° of C with the Boc among the 450ml THF 2O(127.26 gram, 0.586mol) be added drop-wise in the solution.Stirred 12 hours with 25 ℃ temperature.The water of 500ml is added in the solution, then uses EtOAc(200ml*3) extraction, and use MgSO 4Carry out drying program.Filter and be evaporated to drying, to draw corresponding tertbutyloxycarbonyl (BOC) the protection compound of 60 gram colorless oil.
3-amino-the propane of tertbutyloxycarbonyl protection-1-alcohol (30 grams, 0.171mol) is dissolved among the anhydrous THF of 600ml.With TEA(48ml, 0.345mol) be added in the solution.Then at N 2Temperature with 0 ° of C under the environment is slowly added MsCl(26.67ml) to solution.Stirred 2 hours with 25 ℃ temperature.Wash mixture with water, then carry out drying program with MgSO4.Filter and be evaporated to drying, to draw the Ms-protection product of 40 grams.
With above compound (40 grams, 0.158mol) and CH 3COSK(54.1 gram, 0.474mol) be mixed among 2.7 liters the EtOH.At N 2Temperature with 90 ℃ under the environment stirred 16 hours.With solvent evaporation to dry, then with the thioacetic acid S-(3-t-butoxycarbonyl amino-propyl group of column chromatography (PE/EA=10/1) with purifying mixture to 15 gram) ester is as orange solids.With Na(708mg, 30.8mmol) be added into the anhydrous methanol of 100ml and stir until sodium Metal 99.5 disappears.Above compound (6 grams, 25.8mmol) is added in the solution.At room temperature stirred the mixture 2 hours.TLC demonstration reaction is finished.Will be at 100mlCH 2Cl 2In the solution of 3-bromo-dihydro-furan-2-ketone (5.46 grams, 33.3mmol) add in the mixture, then add the DMF of 100ml.Temperature with 60 ° of C stirred the gained mixture 6 hours.TLC demonstration reaction is finished.Reaction mixture is dispensed to the EA of 800ml and the water of 400ml, then uses EA(800mlx2) aqueous layer extracted.The organic layer that merges is dry, filtration and concentrated to obtain crude product, then are purified to the tertbutyloxycarbonyl protection compound of 3.5 grams with column chromatography (PE/EA=4/1), be colorless oil.
(3.5 grams 12.71mmol) are dissolved among the EtOAc of 10ml tertbutyloxycarbonyl protection derivative.Then the 4NHCl/EtOAc with 40ml is added in the solution.With the temperature stirred reaction mixture of 25 ° of C 2 hours.Filter white solid, then with the PE washing, to obtain the title compound of 2.5 grams.
Intermediate 30:4-(2-amino-ethyl)-[1,3] dioxolan-2-one.
Figure DEST_PATH_GDA00002198413500691
In the autoclave of 100ml, quick NH with 60ml 3In CH 3Saturated solution among the OH is added into 4-bromo-1-butylene (3ml).Then the temperature with 90 ° of C stirred the mixture 16 hours in autoclave.After the reaction, surplus solution is removed under vacuum.Reclaim the hydrobromate (12 grams, 95%) of fourth-3-alkenyl amine, be yellow power supply.
At N 2Under the environment at CH 2Cl 2Be added on the K of (80ml) in the water in the preceding compound suspension in (1 liter) (12 grams, 0.08mol) 2CO 3(33 grams, 0.24mol) solution.Biphase mixture is cooled to 0 ° of C, then dropwise adds Cbz-Cl(22 gram, 0.128mol).After 15 minutes stirring, at room temperature stirred reaction mixture is 14 hours.After reaction is finished, add CH 2Cl 2Reach water in mixture, organic layer is through anhydrous Na 2SO 4After the drying, concentrated and carry out purifying with silica gel column chromatography (oil/vinyl acetic monomer=3: 1) under vacuum condition, to obtain corresponding carbobenzoxy-(Cbz) (Cbz) protection compound (12.2 grams, 75%) as colorless oil.
At N 2Under the environment with room temperature at acetone/H 2O(60ml/50ml) above-claimed cpd (12.2 grams 59.5mmol) add NMO(7.3 gram, 62.5mmol in the stirred solution) and OsO 4(303mg, 1.2mmol).Adding OsO 4After, the color of reaction solution becomes black.Then at room temperature stirred the mixture 10 hours.TLC(CH 2Cl 2/ MeOH=10: 1) show completely consumed of starting raw material.Mixture vacuum-evaporation.Add adding water to residue, then use ethyl acetate extraction.Organic layer is through anhydrous Na 2SO 4After the drying,, concentrated and with silica gel column chromatography (CH under vacuum condition 2Cl 2/ MeOH=10: 1) carry out purifying, to obtain corresponding glycol (12 grams, 85%) as light white solid.
At N 2Under the environment with the temperature of-20～-30 ° of C at CH 2Cl 2Add triethylamine (15.2g, 151mmol) in glycol (200ml) (9 grams, the 37.66mmol) solution.After the several minutes, drip triphosgene (5.5 grams, 18.83mmol) to mixture with such temperature, then the temperature with-20～-30 ° of C stirs half an hour.Then at room temperature stirred the mixture 15 hours.TLC(CH 2Cl 2/ MeOH=10: 1) show that starting raw material almost completely consumes.Add adding water to mixture, then use ethyl acetate extraction.Organic layer is through anhydrous Na 2SO 4Drying, concentrated and with silica gel column chromatography (CH under vacuum condition 2Cl 2/ MeOH=10: 1) carry out purifying, to obtain relative cyclisation dioxolane (6.5 grams, 55%), be light white solid.
At N 2Under the environment at CH 3Add fast dry Pd/C(550mg, 10% in the solution of the above compound OH(100ml) (5.5 grams, 20.5mmol)).Then at H 2Extremely overnight with the stirring at room mixture under the environment.TLC(CH 2Cl 2/ MeOH=10: 1) show that starting raw material almost completely consumes.Use the Celite pad filtering mixt.The solution for vacuum evaporation is then with silica gel (CH 2Cl 2/ MeOH=10: 1) carry out purifying, to obtain title intermediate (2.0 grams, 77%), be white solid.
Intermediate 31:3-(2-hydroxyl-ethyl sulfenyl)-dihydro-furan-2-ketone
To at THF(4ml) in 2-sulfydryl-ethanol (2560 μ Mol) solution in add the DIEA(1.1 equivalent) and 3-bromo-dihydro-furan-2-ketone (1 equivalent).At room temperature stirred reaction mixture is 4 hours.Filtering precipitate, and under reduced pressure desolventizing.
Intermediate 32:3-(3-hydroxyl-propyl sulfenyl)-dihydro-furan-2-ketone
To at DMF(2ml) in 3-sulfydryl-propane-1-alcohol (1685 μ mol) solution in add the DIEA(1.5 equivalent) and 3-bromo-dihydro-furan-2-ketone (1 equivalent).At room temperature stirred reaction mixture is 4 hours.Filtering precipitate, and under reduced pressure desolventizing.
Intermediate 33:3-brooethyl-oxa-ring fourth-2-ketone
Figure DEST_PATH_GDA00002198413500702
With the temperature of 0 ° of C to the Br in ether (150ml) 2Dropwise add saturated NaHCO in the solution (4.86 grams, 0.0303mol) 33-butenoic acid (110ml) (2.6 grams, 0.0302mol).Stirred the mixture after the interpolation 1 hour.TLC(PE: EA=4: 1) the demonstration reaction is finished.Add saturated solution (20ml).Use EtOAc(100mlx3) the extractive reaction thing.With the organic layer of salt water washing merging, through Na 2SO 4After the drying, filter and vacuum concentration, and carry out purifying with column chromatography (sherwood oil/vinyl acetic monomer=20: 1), to obtain title compound (1.73 grams, 35%), be white oily.
Intermediate 34:3-(piperidin-4-ylmethyl sulfenyl)-dihydro-furan-2-ketone
Prepare intermediate 34 according to intermediate 30 described methods, from 4-hydroxymethyl-piperidines-1-carboxylic acid tert-butyl ester.
Intermediate 35:3-(2-hydroxyl-oxyethyl group)-dihydro-furan-2-ketone
Progressively add the M-chloroperoxybenzoic acids of 90 grams to 50 gram 2,3-dihydro-furans in 700ml methyl alcohol and 300ml chloroform, stirred 15 minutes with the temperature of 0 ° of C, and then with the temperature stirred reaction mixture of 25 ° of C 15 hours.Filter the mixture of gained, concentrated filtrate under reduced pressure then is dissolved in residue the chloroform of 500ml again, and with the saturated NaHCO of 200ml 3And the salt water washing of 200ml, organic layer is through Na 2SO 4Refilter after the drying.Concentrated filtrate under reduced pressure is with the 2-methoxyl group-tetrahydrochysene of output 30 grams-furan-3-ol.
In the solution of the 2-methoxyl group-tetrahydrochysene in 200ml DMF-furan-3-ol, progressively add sodium hydride, and stirred 2 hours with the temperature of 0 ° of C, then add 2-benzyloxy-ethanol with dropping funnel, for the time one hour.Stir the mixture 15 hours of gained with the temperature of 25 ° of C, then pour in the water of 400ml, add again the EtOAC(1 liter) and separate.Use saturated NaHCO 3(500ml) the washing organic layer is dry through Na2SO4, filters and concentrates.Then with column chromatography (PE: EA=5: 1) with the residue purifying, to obtain the 3-(2-benzyloxy-oxyethyl group of 10 grams)-2-methoxyl group-tetrahydrochysene-furans (oil).
Add the concentrated H of 30ml in the preceding compound solution in the 40% MeCN aqueous solution of 300ml 2SO4, then the temperature with 35 ° of C stirred the mixture 4 hours.Use NaHCO 3In and the mixture of gained, then under reduced pressure concentrated, add again EtOAC(300ml) and separate.With salt solution (100ml) washing organic layer, after the MgSO4 drying, filter and concentrate, then with column chromatography (PE: EA=1: 1) with the residue purifying, to obtain the 3-(2-benzyloxy-oxyethyl groups of 4.8 grams)-tetrahydrochysene-furans-2-alcohol (oil).
Add the Ac of 17ml in the above-claimed cpd solution in the DMSO of 25ml 2O, then the temperature with 25 ° of C stirred 15 hours, then poured in the water of 100ml, added EtOAC(200ml again) and separate.Use saturated NaHCO 3(50ml) and salt solution (50ml) washing organic layer, after the MgSO4 drying, filter and concentrated.With column chromatography (PE: EA=5: 1) with the residue purifying, to obtain the 3-(2-benzyloxy-oxyethyl group of 2.5 grams)-dihydro-furan-2-ketone (oil).
At 1 normal atmosphere H 2In stir the mixture 5 hours of palladium on the charcoal of 0.5 gram in above compound and the 100ml methyl alcohol with the temperature of 25 ° of C, the mixture of gained is filtered, concentrated its filtrate under reduced pressure is to draw the intermediate 35(oil of 1.35 grams).
Intermediate 36:3-hydroxymethyl-dihydro-thiophene-2-ketone
Sulfo-butyrolactone in the anhydrous tetrahydro furan (200ml) (10 grams, 97.9mmol) is dropwise added in the stirred solution of lithium di-isopropyl ammonia [the n-butyllithium (47.0ml, 117.5mmol) of 2.5M in Diisopropylamine (15. grams, 117.5mmol) and the normal hexane, temperature is-78 ° of C].Stir gained solution 10 minutes, and added simultaneously the formaldehyde (50 gram) [by Paraformaldehyde 96 being heated to 150 ° of C, to form formaldehyde] that carries in the nitrogen gas stream.Reaction is allowed to proceed 2.5 hours with the temperature of-78 ° of C.Remove formaldehyde stream, then reaction is allowed to proceed 30 minutes.Then while stirring the vinyl acetic monomer of 300ml is poured in the reaction mixture, added with the temperature of-78 ° of C then that (～300ml) 1MHCl quencher is warming to room temperature when filtering by bed of diatomaceous earth.Ethyl acetate extraction filtrate with 100ml surpasses 5 times, then the organic layer that merges is carried out drying (Na 2SO 4), be concentrated into oily.With chromatography (PE/EA=9/1) purifying oily matter, to obtain the title compound of 1.70 grams, be colorless oil.
Intermediate 37:3-hydroxymethyl-dihydro-furan-2-ketone
Figure DEST_PATH_GDA00002198413500721
To the NaH(9.77 gram in 250ml THF, 244mmol, 60%) stirred suspension in drip gamma-butyrolactones (20 grams, 232mmol) and the methyl-formiate (14 grams, 232mmol) of 20 grams.Temperature with 25 ° of C stirred the gained mixture 20 hours.Filter solid materials, then with the hexane washing, later with its suspension anhydrous methanol (800ml).Drip HCl-MeOH(4M) solution, then stirred the mixture 1 hour.Through after the careful neutralization of NaOH, filtering mixt, then concentrated filtrate carefully.Add entry, treatment soln as usual then is to draw the ester crude products of 23 grams.Vacuum distillation method (100-120 ℃, 20mmHg) draw the 14 2-methoxyl group-tetrahydrochysene that restrains-furans-3-carboxylate methyl esters, be colorless oil.
Temperature (125mmol) LiAlH that 2-methoxyl group-tetrahydrochysene-the middle interpolation 4.75 of furans-3-carboxylate methyl ester solution (10 grams, 62.5mmol) restrains in the anhydrous THF of 60ml with 25 ° of C 4Mixture cools off after being refluxed 4 hours.The H that adds successively 4.75ml 2The NaOH(10% of O and 4.75ml) aqueous solution is in reaction mixture.Filter the mixture of gained, concentrated filtrate then is to obtain (2-methoxyl group-tetrahydrochysene-furans-3-yl)-methyl alcohol (7 restrain).
In the above-claimed cpd solution in 300ml DMF (7 grams, 53mmol), add NaH(3.2 gram, 80mmol, 60%) and BnBr(12.4ml, 106mmol).Stir the mixture 2 hours of gained with the temperature of 25 ° of C, then pour in 1 liter the water.Reach and use subsequently EtOAc(500ml*3) the extraction mixture.Through MgSO 4The dry organic layer that merges, subsequent filtration and concentrated.With column chromatography (PE: EA=2: 1) with the residue purifying, to draw 3-benzyloxymethyl-2-methoxyl group-tetrahydrochysene-furans (10 gram).To at DCM(180ml) in preceding compound solution (10 grams, 45mmol) in add BF 3.Et 2O(3.4ml) and m-CPBA(9.86g, 48.75mmol, 85%).Temperature with 25 ° of C stirs the gained mixture overnight.Use EtOAc(500ml) diluted reaction mixture, then use 10%Na 2S 2O 3, saturated NaHCO 3And salt water washing.Organic layer is through MgSO 4Then drying is filtered and is concentrated., restrain with the intermediate 37(6.7 that draws benzyl protection the residue purifying with column chromatography).
To at EtOH(200ml) in the solution (6.7 grams, 32.5mmol) of preceding compound in add the 10%Pd/C of 1 gram, and with the temperature of 25 ° of C and 1 normal atmosphere hydrogenation 10 hours.Filtering mixt, then concentrated to obtain title compound (3.9 gram).
Intermediate 38:5-(2-hydroxyl-ethyl)-3H-furans-2-ketone.
Figure DEST_PATH_GDA00002198413500722
Under inert gas environment, with the temperature of 0 ° of C, at THF(150ml) in furans cooling solution (3.40 grams, 50.0mmol) in add 2.5M solution, 55.0mmol in n-BuLi(22ml, the normal hexane).Solution is warming to room temperature, then stirred 3 hours.Then drip TMSCl(5.34 gram, 50mmol with the temperature of 0 ° of C), and restir solution 3 hours at room temperature.Next, solution is cooled to 0 ° of C, then adds for the second time 2.5M solution, 55.0mmol in n-BuLi(22ml, the normal hexane).After at room temperature stirring 3 hours, with acetone/dry-ice condenser oxyethane (2.42 gram, 55.0mmol) is condensed into solution, then restir 12 hours at room temperature.Use NH 4Cl aqueous solution quencher mixture is then with the EtOAc extraction, through Na 2SO 4The dry required product (5 grams, 27.1mmol, 54% two step) of organic layer to obtain the yellow liquid state that merges.
To at CH 2Cl 2Above-claimed cpd (30ml) (3 gram, 16.45mmol) and NaOAc(1.64 gram, 20mmol) drip at CH in the solution 2Cl 2CH (90ml) 3CO 3H(16g, 40% is in H 2Among the O) solution.At room temperature stirred reaction mixture spends the night.Use Na 2SO 3Saturated NaHCO is used in the quencher reaction 3And salt water washing.Under reduced pressure concentrate organic layer.With column chromatography (PE: EA=1: 2) with the residue purifying of gained, with the required product that draws 0.5 gram yellow liquid state (0.5 gram, productive rate: 24%).
Intermediate 39:(2-oxo-tetrahydrochysene-furans-3-base sulfenyl)-acetic acid.
Figure DEST_PATH_GDA00002198413500731
At room temperature potassium ethyl xanthonate (58.0 grams, 364mmol) is suspended in the anhydrous propanone of 200ml.Drip while stirring chloroacetic acid tert-butyl ester (50 grams, 332mmol).After 18 hours by removing by filter Repone K, then with solvent evaporation.Residue is added in the ether, use 5%NaHCO 3, water and salt water washing, through MgSO 4Filter after dry and evaporation, to stay the O-ethyl S-(tertbutyloxycarbonyl of 80 grams) the methyl dithiocarbonates, be thick oily matter.At room temperature use thanomin (323mmol) to stir this oily matter 2 hours.Reaction mixture is added in the ethyl acetate, use again 1.2N HC1, water and salt water washing, through MgSO 4Filter after dry and evaporation.With residue vacuum distilling, to draw 30 sulfydryl that restrains-acetic acid uncle-butyl esters, be clarification oily matter.
To at 300ml CH 3Add K in the 3-bromo-dihydro-furan among the CN-2-ketone solution (16 grams, 97.6mmol) 2CO 3(20 grams, 146mmol then add sulfydryl-acetic acid tert-butyl ester (14.5 grams, 98mmol).With reaction mixture refluxed 2 hours, then cooling.Filtering mixt, then concentrated filtrate.Residue is dissolved in again the EtOAc of 300ml, then uses 1N HCl(100ml*2) washing gained solution.Organic layer is through MaSO 4After the drying, filter and concentrate to obtain tert-butyl ester title compound (23 gram).The esters of 16 grams are dissolved in the HCl-MeOH(4M of 250ml), and stirred 4 hours with the temperature of 25 ° of C.With the temperature that is lower than 45 ° of C concentrated reaction mixture in a vacuum.With column chromatography (EtOAc) with the residue purifying, with obtain 7 the gram title compounds.
B.1. compound of the present invention
In the 1st to 19 following table, listed typical compound of the present invention, present with tabulated form.The title of compound, compound number and the structural information of random appointment have been listed in these tables.
Table 1 has shown the compound result (Cpd represents the numbering of compound) of formula IIa or IIb
Figure DEST_PATH_GDA00002198413500741
Table 1
Figure DEST_PATH_GDA00002198413500742
Figure DEST_PATH_GDA00002198413500751
Figure DEST_PATH_GDA00002198413500761
Figure DEST_PATH_GDA00002198413500771
Figure DEST_PATH_GDA00002198413500791
Figure DEST_PATH_GDA00002198413500801
Figure DEST_PATH_GDA00002198413500811
Figure DEST_PATH_GDA00002198413500821
Table 2 has shown the compound result of formula III a or IIIb
Figure DEST_PATH_GDA00002198413500832
Table 2
Figure DEST_PATH_GDA00002198413500841
Table 3 has shown the compound result of formula IVa or IVb
Figure DEST_PATH_GDA00002198413500842
Table 3
Figure DEST_PATH_GDA00002198413500851
Figure DEST_PATH_GDA00002198413500861
Figure DEST_PATH_GDA00002198413500871
Table 4 has shown the compound result of formula Va and Vb
Figure DEST_PATH_GDA00002198413500881
Table 4
Figure DEST_PATH_GDA00002198413500882
Figure DEST_PATH_GDA00002198413500891
Table 5 has shown the compound result of formula VIa and VIb
Figure DEST_PATH_GDA00002198413500892
Table 5
Figure DEST_PATH_GDA00002198413500893
Table 6 has shown the compound result of formula VIIa and VIIb
Figure DEST_PATH_GDA00002198413500901
Table 6
Figure DEST_PATH_GDA00002198413500902
Table 7 has shown the compound result of formula VIIIa and VIIIb.
Figure DEST_PATH_GDA00002198413500911
Table 7
Figure DEST_PATH_GDA00002198413500912
Table 8 has shown the compound result of formula IXa and IXb.
Figure DEST_PATH_GDA00002198413500913
Table 8
Figure DEST_PATH_GDA00002198413500921
Table 9 has shown the compound result of formula Xa and Xb.
Figure DEST_PATH_GDA00002198413500922
Table 9
Figure DEST_PATH_GDA00002198413500931
Table 10 has shown the compound result of formula XIII.
Table 10
Figure DEST_PATH_GDA00002198413500941
Table 11 has shown the compound result of formula XIV, XV, XVI and XVII.
Table 11
Figure DEST_PATH_GDA00002198413500943
Table 12 has shown the compound result of formula XVIIIa.
Figure DEST_PATH_GDA00002198413500951
Table 12
Figure DEST_PATH_GDA00002198413500952
Table 13 has shown the compound result of formula XIXa.
Figure DEST_PATH_GDA00002198413500953
Table 13
Figure DEST_PATH_GDA00002198413500954
Table 14 has shown the compound result of formula XXa.
Figure DEST_PATH_GDA00002198413500961
Table 14
Figure DEST_PATH_GDA00002198413500962
Table 15 has shown the compound result of formula XXIa.
Figure DEST_PATH_GDA00002198413500963
Table 15
Figure DEST_PATH_GDA00002198413500964
Table 16 has shown the compound result of formula XXIIa.
Figure DEST_PATH_GDA00002198413500965
Table 16
Figure DEST_PATH_GDA00002198413500971
Table 17 has shown the compound result of formula XXIIIa.
Figure DEST_PATH_GDA00002198413500972
Table 17
Figure DEST_PATH_GDA00002198413500973
Table 18 has shown the compound result of formula XXIVa.
Table 18
Figure DEST_PATH_GDA00002198413500982
Other compound (table 19):
Table 19
Figure DEST_PATH_GDA00002198413500983
Figure DEST_PATH_GDA00002198413501001
Figure DEST_PATH_GDA00002198413501011
Figure DEST_PATH_GDA00002198413501021
Figure DEST_PATH_GDA00002198413501031
Figure DEST_PATH_GDA00002198413501041
Figure DEST_PATH_GDA00002198413501051
Figure DEST_PATH_GDA00002198413501061
C. the interior experiment of external and body
C.1.ROCK inhibiting screening active ingredients
C.1.1. kinase inhibition
Method 1-Proqinase arranges
33The analysis of P radio isotope protein kinase is used to determine the IC that suppresses ROCKII 50
To comprise 60mM HEPES-NaOH(pH value 7.5), 3mM MgCl 2, 3mM MnCl 2, 3 μ M sodium-sodium orthovanadates, 1.2mM DTT, 1 μ M ATP, 50 μ g/mlPEG 20.000, 1%(v/v) the about 3x10 of DMSO, 1 μ M ATP( 5Cpm 33The protein kinase (0.5nM-2,5ng/ hole) of P-γ-ATP), substrate (S6 peptide-2000ng/ hole) and restructuring is put into vibrator and is mixed, then with the temperature incubation of 30 ° of C 80 minutes.By adding the 2%H of 50 μ l 3PO 4And the vibrator mixing, with stopped reaction.Behind twice of the 0.9%NaCl solution washing of 200 μ l, calculate dry plate.
Method 2:
Use is from the commercially available ROCK IMAP test kit (production code member R8093) of Molecular Devices company, and the scheme that substantially provides according to manufacturers is carried out the inhibition experiment with fluorescence polarization (FP) method.Used S6 ribosomal protein source property substrate is (Fl)-AKRRRLSSLRA, equally from Molecular Devices company (production code member R7184).The enzyme mixture of ROCK α/ROCKII is from Upstate Biotechnology company (production code member 14-451).
In brief, all compounds are placed into 384 orifice plates and screen to measure the enzyme inhibition, and used concentration adopts incremental 3(or 2 between 100 μ M to 0.3nM) times dilution method.Y compound (Y-27632 is commercially available by Tocris company) is used as with reference to (0.4 μ M).
In order to carry out experiment, the 1 μ l compound solution (each concentration) that will test in DMSO has been put into 10mM Tris-HCl, 10mM MgCl 2, 0.1%BSA, 0.05%NaN 3, the pH value is in 7,2 the 2 μ l enzyme solution.The ultimate density of enzyme is 2.6nM.
At room temperature incubation is after 30 minutes, adds the ATP of 2 μ l and protein substrate at 10mM Tris-HCl, 10mM MgCl 2, 0.1%BSA, 0.05%NaN 3, the pH value is the mixture in 7.2 the solution.The final concentration of ATP is 10 μ M, and the ultimate density of protein substrate then is 0.2 μ M.
At room temperature incubation added the IMAP binding soln (IMAP binding buffer liquid A(1x) of 12 μ l and the mixture of IMAP binding reagents (from ROCK IMAP test kit) after 60 minutes).
Mixture (the cumulative volume: 17 μ l) 60 minutes of at room temperature incubation acquisition like this, use automatic flat-plate reader (Perkin Elmer, Envision 2100-0010HTS type) to measure fluorescence polarization degree, wherein the FP wave filter uses FITC FP 480 exciter filters and FITC FP P-pol 535 and FITC FP S-pol 535 spectral filter (Perkin-Elmer) of giving out light.Use the XL-Fit algorithm that the result is fitted to a curve, and then calculate the IC of each matched curve with the XL-Fit algorithm 50Value.
The IC of reference compound 50Value (Y compound Y-27632) is 0.4 μ M.
Obtained IC 50Value (according to the scheme of afore mentioned rules) is expressed as follows: " +++" represents IC 50Be lower than 0.1 μ M, " ++ " represents IC 50Between 0.1 to 1 μ M; "+" expression IC 50Between 1 to 10 μ M, " " then represents also not determine.
#Cpds Method 1 Method 2 #Cpds Method 1 Method 2 #Cpds Method 1 Method 2
1 +++ 76 ++ 151
2 + 77 +++ 152
3 78 +++ 153
4 +++ 79 +++ 154 +++
5 ++ +++ 80 ++ 155 +++
6 81 +++ 156
7 ++ 82 +++ 157
8 +++ +++ 83 ++ 158
#Cpds Method 1 Method 2 #Cpds Method 1 Method 2 #Cpds Method 1 Method 2
9 +++ 84 ++ 159
10 ++ 85 ++ 160
11 +++ +++ 86 +++ 161
12 ++ +++ 87 ++ 162
13 +++ +++ 88 +++ ++ 163
14 ++ 89 ++ 164
15 ++ 90 +++ ++ 165
16 ++ 91 ++ 166 ++ ++
17 ++ 92 ++ 167 ++ +++
18 ++ 93 +++ 168 ++ ++
19 ++ 94 ++ 169 +++
20 + 95 ++ 170 ++ +++
21 + 96 +++ 171 ++
22 + 97 +++ 172 ++ ++
23 + 98 173 ++
24 + 99 174 ++
25 ++ 100 175 +++
26 ++ 101 +++ 176 +++
27 +++ 102 +++ 177 ++
28 ++ ++ 103 178 ++
29 104 179 ++
30 105 +++ 180 ++
31 ++ 106 +++ 181 +
32 ++ 107 182 ++
33 +++ 108 183 ++
34 +++ 109 184 ++
35 ++ 110 185 ++
[0659]
#Cpds Method 1 Method 2 #Cpds Method 1 Method 2 #Cpds Method 1 Method 2
36 +++ 111 186
37 ++ +++ 112 +++ 187 ++
38 ++ 113 ++ 188 +
39 ++ 114 189 ++
40 +++ 115 190 ++
41 ++ 116 191 ++
42 ++ 117 192 +
43 ++ 118 193 ++
44 +++ +++ 119 194 +
45 +++ +++ 120 195 +
46 ++ +++ 121 196
47 ++ +++ 122 + 197
48 ++ 123 198
49 124 + 199
50 125 200
51 126 201
52 127 + 202
53 ++ 128 203
54 129 204
55 +++ 130 +++ 205
56 ++ 131 ++ ++ 206
57 132 207
58 +++ +++ 133 208
59 +++ 134 ++ +++ 209
60 ++ +++ 135 210
61 ++ 136 ++ 211
62 +++ 137 ++ 212
[0660]
#Cpds Method 1 Method 2 #Cpds Method 1 Method 2 #Cpds Method 1 Method 2
63 ++ 138 213
64 +++ 139 214
65 +++ +++ 140 215
66 141 ++ 216
67 +++ 142 ++ 217
68 +++ 143 ++ 218
69 +++ 144 219
70 +++ +++ 145 220
71 ++ ++ 146 221
72 +++ 147 +++ 222
73 +++ 148 223
74 ++ 149 224
75 +++ 150
C.1.2. use the PBMC of LPS-stimulation in the situation that there is and do not exist the cell detection of blood plasma ROCK activity
PBMC in order to ensure LPS stimulates, and in conjunction with albumen (LBP) enrichment medium, this will promote to transmit LPS to CD14 acceptor and strengthen the immune response that LPS induces with LPS.The secreted cytokine that goes out of active PBMC has comprised the TNF(tumour necrosis factor), this can detect by colorimetric ELISA method and draw.In the situation that there is active compound, it is suppressed that the release of TNF tumour necrosis factor relies on mode with concentration.Next, in the situation that existing, blood plasma use identical setting to carry out check analysis.
For instance, compound 46 has been showed IC 50That 120nM(detects without blood plasma), and have (IC in the situation of blood plasma 5010 μ M) then be inactive.
C.1.3. the unstriated muscle that uses the organ bath of guinea pig trachea to calculate the soft ROCK inhibitor of external generation loosens activity
Prepare the tracheal ring of cavy, then use the bronchoconstriction agent carbachol incubation of fixed concentration.Later, add the soft ROCK inhibitor that concentration increases gradually, and be the measurement of concetration tracheae shrinkage character of each compound.IC is measured in this research equipment 50, this power of inducing with it is equivalent to be subjected to 50% compound concentration of the viewed power of vehicle treatment tracheae as expression.
In addition, also use the reservation of above-described guinea pig trachea organ bath assessment objective.In brief, by the maximum stretching reaction that the ROCK inhibitor is induced, tracheal ring is washed thoroughly.Later add again carbachol, and then measure shrinkage character, whether prolong after flushing with the inhibition activity of determining the ROCK inhibitor.Prolongation after the flushing suppress activity also mean compound in vivo lung can prolong delay.
For instance, compound 46 has been showed IC 50Be 500nM.
C.2. pharmacological property
C.2.1. the stability test in the mankind and/or the rat plasma
Concentration incubation compound in rat (mouse or rabbit) or human plasma with 1 μ M.Put at a fixed time sample drawn, then behind protein precipitation, determine residual compound with LC-MS/MS.Transformation period with minute as the expression.
Figure DEST_PATH_GDA00002198413501111
C.2.2. to the drug metabolism Enzymic stability of lung S9
Use contains lung S9(from the smoker) and 1 μ M solution of the reaction mixture incubation ROCK inhibitor of NADPH, UDPGA, PAPS and GSH cofactor.0,15,30 and 60 minute collection sample behind incubation.In the situation that there is not the cofactor yet parallel running of experiment of ROCK inhibitor and S9 part incubation negative control sample.By using LC-MS/MS to analyze, measure the metabolic half life (with minute as representing) of the remaining ROCK compound per-cent of each time point, ROCK compound and the metabolic half life of control compound.
#Cpd T1/2 people's lung S9
46 53
47 >60
65 >60
C.2.3. the stability analysis in the rabbit aqueous humor
Concentration (AH) incubation compound in the rabbit aqueous humor with 1 μ M.Put at a fixed time sample drawn, then behind protein precipitation, determine residual compound with LC-MS/MS.
#Cpd T1/2 rabbit AH
46 >60
[0678]
#Cpd T1/2 rabbit AH
169 >60
C.2.4. reaction kinetics is in conjunction with sign
This detects to report that the displacement binding technology is the basis.It relates to uses the specific probe of establishing as the ATP-binding site of ROCK.When being incorporated into reactive site, probe can produce a signal.In the situation that there is ROCK ATP competitive inhibitor, the position of probe can be departed from enzyme and moved, and signal is also upset.The displacement of monitoring probe within for some time, and definite Kon and Koff constant.The mechanism of action of inhibitor is determined in use by Enzymology method based on the OMNIA technology of fluorescence.
C.2.5. the anti-inflammatory activity of soft ROCK inhibitor in chmice acute LPS lung attack model that generates
, using and attacking mouse in the LPS tracheae after half an hour by the nasal cavity administered compound.After 24 hours, mouse is condemned to death, and then collects bronchoalveolar lavage fluid (BALF) and total cellular score, and the per-cent of definite neutrophilic granulocyte.Anti-inflammatory activity represents with the reduction of the reduction of BALF total cellular score and the neutrophilic granulocyte number compared with non-treatment control group.
C.2.6. the intraocular pressure of normotensive rat or rabbit (IOP) reduces
Use the Tonolab tonometer to measure the IOP of normal arterial pressure rat.Because intraocular pressure scope (average approximately 10) between 8-12mmHg, therefore usually can observe the highest range of decrease of 3mmHg.Timolol (beta-blocker), clonidine (alpha-receptor agonist) and brimonidine (α 2-receptor stimulant) lower 2-3mmHg with IOP.The intraocular pressure scope of normal arterial pressure rabbit (average approximately 18) between 15-20mmHg, the highest 3-4mmHg of decreasing by that obtains.

Claims (31)

1. formula (I) compound or its steric isomer, tautomer, racemic modification, metabolite, prodrug or pro-drug, salt, hydrate or solvate,
Figure FDA00002089896600011
Wherein
R 1Be selected from the group that comprises hydrogen, alkyl or cycloalkyl;
Ar is selected from following group:
Figure FDA00002089896600012
Wherein X is selected from the group that comprises hydrogen or halogen;
Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-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 2-8Thiazolinyl is substituted independently respectively base and replaces; This substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 3Be selected from following group: hydrogen; By O-Het 2Or-S-Het 3The C that replaces 2-8Thiazolinyl; Or by the optional C that replaces of 1,2 or 3 substituting group 1-20Alkyl, this substituting group are independently selected from respectively and comprise aryl, heteroaryl, C 36Cycloalkenyl group ,-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 16Alkyl-S-and C 16The group of alkyl-O-;
Wherein said-O-C 1-6Alkyl;-S-C 1-6Alkyl; Or C 3-6Cycloalkenyl group; Be substituted independently respectively base and replace, this substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 4Be selected from following group: by O-Het 2Or-S-Het 3The C that replaces 2-8Thiazolinyl or by the optional C that replaces of 1,2 or 3 substituting group 1-20Alkyl, this substituting group are independently selected from respectively and comprise aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21,-C(=O)-SR 22,-C(=O)-NR 7R 8, Het 1,-O-Het 2,-S-Het 3,-O-C 1-6Alkyl reaches-O-C 16The group of alkyl;
Wherein said-O-C 1-6Alkyl;-S-C 1-6Alkyl; Or C 3-6Cycloalkenyl group; Being substituted independently respectively base replaces; This substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group; Or;
R 3And R 4The nitrogen-atoms that links to each other with them forms heterocycle, and it is replaced by a substituting group, and this substituting group is selected from following group :-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3C 1-6Alkyl; C 1-6Alkyl-O-C 1-4Alkyl; Or C 1-6Alkyl-O-C 2-4Thiazolinyl; Each described C wherein 1-6Alkyl; C 1-6Alkyl-O-C 1-4Alkyl; Or C 1- 6Alkyl-O-C 2-4Thiazolinyl is replaced by 1,2 or 3 substituting group respectively independently, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group;
R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; 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)-group; At least one R wherein 5Or R 6Be selected from C 1-6Alkyl; 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 1-6Alkyl-C(=O)-or C 2-8Thiazolinyl-C(=O)-separately replaced by 1,2 or 3 substituting group, this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
R 7Or R 8Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; Described C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group;
R 7Or R 10Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; Described C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group;
R 13Or R 14Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-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)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
R 21Be selected from and comprise C 1-20Alkyl; C 1-20Thiazolinyl; C 1-20Alkynyl; The optional C that replaces 3-15Cycloalkyl; The optional aryl that replaces; The optional heterocyclic radical that replaces; The group of the optional heteroaryl that replaces;
Wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, this substituting group be independently selected from comprise the 2-of halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O), aryl-C(=O) ,-C(=O)-NR 13R 14,-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 be selected from following formula:
Figure FDA00002089896600031
Or
R 21Coupled carbonyl oxygen base and " aryl or heteroaryl " are formed on the cyclic ester ring that the cyclic ester ring comprises 4 to 9 carbon atoms together;
R 22Can be by 1,2,3 or the optional C that replaces of more substituting group 1-20Alkyl, this substituting group are independently selected from and comprise halogen, hydroxyl, amino, cyano group, and single or two (C 1-4Alkyl) amino group;
Het 1, Het 2Or Het 3Be independently selected from respectively following group;
Figure FDA00002089896600032
2. according to claim 1 compound, wherein;
R 1Hydrogen or C 1-4Alkyl;
Ar is selected from following group:
Figure FDA00002089896600033
Wherein X is selected from the group that comprises hydrogen or fluorine;
Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-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 is substituted base and replaces, and this substituting group be selected from comprise C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 3Be selected from and comprise hydrogen; C 1-20The group of alkyl, described C 1-20Alkyl can be replaced by 1,2,3 substituting group is optional, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3, C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; Special R 3Hydrogen;
R 4Be selected from and comprise C 1-20The group of alkyl, described C 1-20Alkyl is replaced by 1,2,3 substituting group, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; Or;
R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group;
R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; Or C 1-6Alkyl-C(=O)-group; At least one R wherein 5Or R 6Be selected from C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-, and wherein said C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
R 7Or R 8Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; Described C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group;
R 9Or R 10Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl; Described C 1-6Alkyl by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
R 13Or R 14Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; And C 1- 6Alkyl-C(=O)-group; Special R 11And R 12Hydrogen;
R 21Be selected from and comprise C 1-20Alkyl; C 1-20Thiazolinyl; C 1-20Alkynyl; C 3-15Cycloalkyl; The optional heterocyclic radical that replaces; And the group of the optional aryl that replaces;
Wherein said C 1-20Alkyl can be replaced by 1,2 or 3 or more substituting group are optional, and this substituting group is selected from and comprises halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O) 2-, aryl-C(=O) ,-C(=O)-NR 13R 14,-O-C(=O)-C 1-6Alkyl, C 1-6Alkyl-O-, C 1-6The group of alkyl-S-, aryl, heteroaryl, heterocyclic radical or be selected from following formula:
Or
R 21The cyclic ester that the carbonyl oxygen base that links to each other with their and phenyl form following formula
Wherein q is from 1 to 6 integer;
R 22Can be by 1,2,3 or the optional C that replaces of more halogenic substituent 1-20Alkyl;
Het 1, Het 2Or Het 3Be independently selected from respectively following group;
Figure FDA00002089896600052
3. according to claim 1 and 2 compound, wherein;
-Ar represents pyridyl, can be chosen wantonly replacement by halogen; The pyridyl that special Ar representative is replaced by fluorine; In embodiment further, the Ar representative
-
Figure FDA00002089896600053
Wherein X is hydrogen or halogen;
-R 1Represent hydrogen or C 1-4Alkyl;
-Y is substituted aryl or the heteroaryl that base replaces, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 21
-C(=O)-NR 3R 4-NR 5R 6-O-C 1-6Alkyl; Or-C 1-6The group of alkyl;
Wherein said-O-C 1-6Alkyl or-C 1-6Alkyl can be substituted independently respectively base and replace; This substituting group be selected from comprise-C(=O)-OR 21, Het 1And S-Het 3Group;
-R 3Hydrogen;
-R 4Be-C 1-6Alkyl, can be selected from-C(=O)-OR 21Or Het 1Substituting group replace;
-R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-group; At least one R wherein 5Or R 6Be selected from and comprise C 1-6Alkyl; Or C 1-6Alkyl-S-C 1-6Alkyl-group; And wherein said C 1-6Alkyl; Or
C 1-6Alkyl-S-C 1-6Alkyl-be substituted separately base replaces, and this substituting group be selected from comprise-C(=O)-OR 21, Het 1And-S-Het 3Group;
-R 21Be selected from-C 1-6Alkyl, aryl or the optional heteroaryl that replaces;
-aryl represents phenyl; And
-heteroaryl represents thienyl, 3, the 4-dihydro-1(2H)-and benzopyranyl, 3, the 4-dihydro-1(2H)-benzopyranyl or indyl.
4. according to claim 1 to 3 each compounds, wherein;
Y substituting group in its definition comprises at least one and is selected from C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3The substituting group of group.
5. according to claim 1 to 4 each compounds, collateral condition be when the Y representative be selected from-C(=O)-OR 21Or-C(=O)-SR 22The aryl that replaces of substituting group or during heteroaryl, and wherein said R 21Or R 22Represent unsubstituted C 1- 20During alkyl, described-C(=O)-OR 21Or-C(=O)-SR 22With respect to the combination of described aryl or heteroaryl and molecule rest part be between position or contraposition.
6. according to claim 1 to 4 each compounds, wherein;
Y is 2-oxo-2, and 3-dihydro benzo furyl or Y are phenyl or thienyl, and described phenyl and thienyl are substituted base and replace, this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4-NR 5R 6-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 is substituted independently respectively base and replaces; This substituting group is selected from and comprises C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 3Hydrogen;
R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 16Alkyl-S-and C 1-6The group of alkyl-O-; Or;
R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1Or C 1-6The group of alkyl; Institute wherein
The C that states 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises Het 1-O-Het 2And-S-Het 3Group;
R 5Or R 6Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; Or C 1-6Alkyl-C(=O)-group; At least one R wherein 5Or
R 6Be selected from C 1-6Alkyl; Or C 1-6Alkyl-C(=O)-, and wherein said C 1-6Alkyl; Or C 1-6Alkyl-C(=O)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-Het 1-O-Het 2And-S-Het 3Group;
R 7Or R 8Be independently selected from respectively and comprise hydrogen; Or C 1-6The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NH 2Group;
R 21Be selected from and comprise C 1-20Alkyl; C 3-10Cycloalkyl; And the group of the optional aryl that replaces;
Wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, and this substituting group is selected from and comprises halogen, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O) 2-, aryl-C(=O) ,-O-C(=O)-C 1-6Alkyl, C 1-6The group of alkyl-O-, aryl, heteroaryl, heterocyclic radical or be selected from following formula:
Figure FDA00002089896600071
Or
R 21The carbonyl oxygen base that links to each other with their and phenyl form and comprise following cyclic ester
Figure FDA00002089896600072
Wherein q is from 1 to 6 integer;
R 22C 1-20Alkyl can by 1,2,3 or more halogenic substituent be optional replaces;
Het 1, Het 2Or Het 3Be independently selected from respectively the group of following formula;
Heterocyclic radical used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base;
Aryl used herein is selected from the group that comprises phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl or 1,2,3,4-tetralyl; Wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group; Described substituting group is selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group, or C 1-4Alkylthio; And
Heteroaryl used herein is selected from following group: furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, benzofuryl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl; Wherein said heteroaryl can be by the optional replacement of 1,2,3,4 or 5 substituting group; Described substituting group is selected from halogen, carbonyl, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio.
7. the compounds of this invention of formula Ia representative or its steric isomer, tautomer, racemic modification, metabolite, prodrug or dive base, salt, hydrate or solvate
Figure FDA00002089896600082
Wherein,
R 1Be selected from and comprise hydrogen, C 1-4Alkyl or C 3-6The group of cycloalkyl;
Ar is selected from following group:
Figure FDA00002089896600091
Wherein X is selected from the group that comprises hydrogen or halogen;
L is direct key, C 1-4Alkyl or-O-C 1-4Alkyl;
T is-O-R 21Or-NR 3R 4
R 3Be selected from following group: hydrogen; C 1-20Alkyl can be replaced by 1,2 or 3 substituting group is optional, this substituting group can be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; Special R 3Hydrogen;
R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; More special R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2And-S-Het 3Group; Or;
R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group; Special R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises Het 1-O-Het 2And-S-Het 3Group;
R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group; Special R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NH 2Group;
R 9Or R 10Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
R 13Or R 14Be independently selected from respectively following group: hydrogen; C 1-6Alkyl; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-, and wherein said C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-S-C 1-6Alkyl-; Or C 1-6Alkyl-C(=O)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
R 21Be selected from following group: C 1-20Alkyl; C 1-20Thiazolinyl; C 1-20Alkynyl; The optional C that replaces 3-15Cycloalkyl; The optional heterocyclic radical that replaces; And the optional aryl that replaces;
Wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, and this substituting group is selected from following group:
Halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O) 2-, aryl-C(=O) ,-C(=O)-NR 13R 14,-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 following formula:
Figure FDA00002089896600101
Or
R 21The cyclic ester that the carbonyl oxygen base that links to each other with their and phenyl form following formula
Figure FDA00002089896600102
Wherein q is from 1 to 6 integer;
R 22C 1-20Alkyl can by 1,2,3 or more halogenic substituent be optional replaces;
Het 1, Het 2Or Het 3Be independently selected from respectively following group;
Figure FDA00002089896600103
Figure FDA00002089896600111
8. according to the compound of formula Ia, wherein Ar represents
Wherein X is hydrogen or halogen;
-L is direct key, C 1-4Alkyl, or-O-C 1-4Alkyl;
-T is-O-R 21Or-NR 3R 4
-R 1Represent hydrogen or C 1-4Alkyl;
-R 3Hydrogen;
-R 4Be selected from-O-Het 2, or-S-Het 3Substituting group replace-C 1-6Alkyl; In specific embodiment, described Het 2Or Het 3Be selected from following group
Figure FDA00002089896600113
-Het 2Or Het 3Be independently selected from respectively following group;
Figure FDA00002089896600121
9. according to the compound of formula Ia, wherein Ar represents
Figure FDA00002089896600122
Wherein X is hydrogen or halogen;
-L is direct key, C 1-4Alkyl, or-O-C 1-4Alkyl;
-T is-O-R 21Or-NR 3R 4
-R 1Represent hydrogen or C 1-4Alkyl;
-R 3Hydrogen;
-R 4Be selected from-C(=O)-OR 21,-C(=O)-SR 22,-C(=O)-NR 7R 8, or Het 1Substituting group replace-C 1-6Alkyl; Special-C 1-6Alkyl is selected from-C(=O)-and OR 21Or Het 1Substituting group replace; In specific embodiment, described R 21Be-C 1-6Alkyl; Or
-R 3And R 4The nitrogen-atoms that links to each other with them forms heterocycle, and it is by C 1-6Alkyl replaces; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NR 9R 10Group;
-R 9Or R 10Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
-R 21Be selected from following group: C 1-20Alkyl; The optional C that replaces 3-10Cycloalkyl; The optional aryl that replaces; And the optional heterocyclic radical that replaces; Wherein said C 1-20Alkyl can be substituted that base is optional to be replaced, and this substituting group 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 be selected from following formula:
Figure FDA00002089896600131
-heterocyclic radical used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base;
The C of-optional replacement used herein 3-10Cycloalkyl is selected from the group that comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, adamantyl, dicyclo (2.2.1) heptane base and ring decyl, wherein is preferably cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, reaches dicyclo (2.2.1) heptane base; Wherein said C 3-10Cycloalkyl can by 1,2,3 or more multi-substituent be optional replaces, and is 1,2 or 3 especially; 1 or 2 more especially; 1 more especially; This substituting group is selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 3-6Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
The heterocyclic radical of-optional replacement used herein is selected from and comprises piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, piperazinyl, 1,3-dioxane base, 3-dioxolanyl, tetrahydric quinoline group, tetrahydro isoquinolyl, indolinyl, THP trtrahydropyranyl, tetrahydrofuran base and hexahydro furyl be the group of [3,2-b] furyl also; Piperidyl, 1 especially, 3-dioxane base, indolinyl, THP trtrahydropyranyl and tetrahydrofuran base; Wherein said heterocyclic radical can by 1,2,3 or more multi-substituent be optional replaces, and is 1 especially; This substituting group be selected from halogen, hydroxyl, oxo, nitro, amino, hydrazine, aminocarboxyl, azido-, cyano group, alkyl, cycloalkyl, thiazolinyl, alkynyl, cycloalkylalkyl, alkylamino, alkoxyl group ,-SO 2-NH 2, aryl, heteroaryl, aralkyl, alkylhalide group, halogen alkoxyl group, carbalkoxy, alkyl amino-carbonyl, heteroarylalkyl, alkyl sulfonamide, heterocyclic radical, alkyl-carbonyl-amino alkyl, aryloxy, alkyl-carbonyl, acyl group, aryl carbonyl, aminocarboxyl, alkyl sulfoxide ,-SO 2R a, alkylthio, carboxyl group and similarly, R wherein aIt is alkyl or cycloalkyl; Preferably be selected from halogen, hydroxyl, oxo, nitro, amino, cyano group, C 1-4Alkyl, C 36Cycloalkyl, C 1-4Alkoxyl group, or-SO 2-NH 2,
-aryl used herein is selected from and comprises phenyl, naphthyl, Isosorbide-5-Nitrae-dihydro naphthyl, or the group of 1,2,3,4-tetralyl, and wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, nitro, C 14Alkyl, C 1-4Alkoxyl group, or C 1-4Alkylthio; Phenyl or 1,2,3,4-tetralyl especially; Wherein said aryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; More special phenyl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio;
-heteroaryl used herein is selected from and comprises furyl, thienyl, pyrryl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, benzofuryl, benzopyranyl, 1(4H)-benzopyranyl, 1(2H)-benzopyranyl, 3, the group of 4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl; Wherein said heteroaryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo, nitro, C 1-4Alkyl, C 1-4Alkoxyl group or C 1-4Alkylthio; Furyl, thienyl, pyridyl, benzopyranyl, 1(2H especially)-benzopyranyl, 3,4-dihydro-1(2H)-benzopyranyl, and 2,3-dihydro-1(4H)-benzopyranyl; Wherein said heteroaryl can be by the optional replacement of 1,2,3,4 or 5 substituting group, and this substituting group is selected from halogen, oxo or C 1-4Alkyl.
10. according to claim 7 to 9 each compounds, collateral condition be when L be that direct key and T are-O-R 21, and R wherein 21Unsubstituted C 1-20During alkyl, described L-(C=O)-T is with respect to combination position or contraposition place bonding between phenyl ring of described benzyl ring and molecule rest part.
11. the compounds of this invention or its steric isomer, tautomer, racemic modification, metabolite, prodrug or pro-drug, salt, hydrate or the solvate of formula Ib representative
Figure FDA00002089896600141
Wherein,
-R 1Be selected from and comprise hydrogen, C 1-4Alkyl or C 3-6The group of cycloalkyl;
-Ar is selected from following group:
Figure FDA00002089896600142
-wherein X is selected from the group that comprises hydrogen or halogen;
-Z is selected from the divalent radical that comprises following group :-O-;-NR 5-; And-NR 5-C(=O)-;
-W represents C 1-6Alkyl is selected from-O-Het 2-S-Het 3Or C(=O)-NR 3R 4Substituting group replace;
-R 3Be selected from following group: hydrogen; C 1-20Alkyl, they can be replaced by 1,2 or 3 substituting group is optional, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; Special R 3Hydrogen;
-R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2-S-Het 3C 1-6Alkyl-S-and C 1-6The group of alkyl-O-; More special R 4Be selected from and comprise C 1-20The group of alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 7R 8Het 1-O-Het 2And-S-Het 3Group; Or;
-R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2-S-Het 3Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1-O-Het 2And-S-Het 3Group; Special R 3And R 4The nitrogen-atoms that links to each other with their forms heterocycle, and it is replaced by a substituting group, and this substituting group be selected from comprise-C(=O)-OR 21-C(=O)-SR 22-C(=O)-NR 9R 10Het 1Or C 1-6The group of alkyl; Wherein said C 1-6Alkyl is replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises Het 1-O-Het 2And-S-Het 3Group;
-R 5Hydrogen;
-R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C(=O)-OR 21And-C(=O)-NH 2Group; Special R 7Or R 8Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they are replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21And-C(=O)-NH 2Group;
-R 9Or R 10Be independently selected from respectively following group: hydrogen; Or C 1-6Alkyl, they by 1,2 or 3-C(=O)-OR 21Substituting group replaces;
-R 13Or R 14Be independently selected from respectively and comprise hydrogen; C 1-6Alkyl; C 1-6Alkyl; C 1-6Alkyl-O-C 1-6Alkyl-; C 1-6Alkyl-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)-is separately replaced by 1,2 or 3 substituting group, this substituting group be independently selected from respectively comprise-C(=O)-OR 21-C(=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
-R 21Be selected from following group: C 1-20Alkyl; C 1-20Thiazolinyl; C 1-20Alkynyl; The optional C that replaces 3-15Cycloalkyl; The optional heterocyclic radical that replaces; And the optional aryl that replaces;
-wherein said C 1-20Alkyl can by 1,2,3 or more substituting group be optional replaces, and this substituting group is selected from following group: halogen, cyano group, hydroxyl, aryl-O-, aryl-S-, aryl-S(=O) 2-, aryl-C(=O) ,-C(=O)-NR 13R 14,-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 following formula:
Or
-R 21The cyclic ester that the carbonyl oxygen base that links to each other with their and phenyl form following formula
Figure FDA00002089896600162
-wherein q is from 1 to 6 integer;
-R 22C 1-20Alkyl can by 1,2,3 or more halogenic substituent be optional replaces;
-Het 1, Het 2Or Het 3Be independently selected from respectively following group;
Figure FDA00002089896600163
12. compound according to claim 11, wherein
-Z is selected to comprise-O-;-NR 5-; And-NR 5-C(=O)-the divalent radical of group;
-W represents C 1-6Alkyl is selected from-O-Het 2-S-Het 3Or C(=O)-NR 3R 4Substituting group replace;
-Ar representative
-
Figure FDA00002089896600171
Wherein X is hydrogen or halogen;
-R 1Represent hydrogen or C 1-4Alkyl;
-R 3Hydrogen;
-R 4Be-C 1-6Alkyl is selected from-O-Het 2, or-S-Het 3Substituting group replace; In specific embodiment, described
Het 2Or Het 3Be selected from and comprise following group
Figure FDA00002089896600172
13. according to claim 1 to 5 each defined compounds and have the compound of the compound representative of one of following structural: IIa, 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, XIXa, XXa, XXIa, XXIb, XXIIa, XXIIIa or XXIVa;
Figure FDA00002089896600173
Figure FDA00002089896600181
Figure FDA00002089896600191
Figure FDA00002089896600201
Wherein,
Q is from 2 to 6 integer;
R 11The C that replaces 1-6Alkyl, or replace-C 2-8Thiazolinyl; Described-C 1-6Alkyl reaches-C 2-8Thiazolinyl is substituted independently respectively base and replaces, this substituting group be selected from comprise C (=O)-OR 21-C (=O)-SR 22-C (=O)-NR 3R 4Het 1-O-Het 2And-S-Het 3Group;
R 12The C that replaces 1-6The C of alkyl, replacement 1-6Alkyl-S-C 1-6Alkyl or replacement-C 2-8Thiazolinyl; Described-C 1-6Alkyl, C 1-6Alkyl-S-C 1-6Alkyl reaches-C 2-8Thiazolinyl is replaced by 1,2 or 3 substituting group respectively independently, and this substituting group is independently selected from respectively and comprises aryl, heteroaryl, C 3-6Cycloalkenyl group ,-C (=O)-OR 21-C (=O)-SR 22Het 1-O-Het 2And-S-Het 3Group;
And
Wherein Ar, R 1, R 21, R 22, R 3, R 4, R 5, R 6, Het 1, Het 2And Het 3Has defined identical connotation in the claim 1 to 5.
14. according to claim 1 to 13 each compounds, as the mankind or veterinary medicament.
15. comprise according to claim 1 to 13 each the compositions of described compound, be applicable to as the mankind or veterinary medicament.
16. to 13 each compound or the purposes that are used for suppressing kinase whose activity of composition according to claim 15, be the ROCK kinases especially according to claim 1.
17. be used for preventing and/or treating the disease of at least a ROCK of relating to or the purposes of obstacle to 13 each compound or compositions according to claim 15 according to claim 1, for example: with the function of smooth muscle cell, inflammation, fibrosis, excessive cell proliferation, vasculogenesis excessively, hyperergy, barrier function obstacle, nerve degeneration pathology and reinvent relevant disease.
18. according to claim 1 to 13 each compound or the purposes of composition according to claim 15, be used for the treatment of and/or prevent at least a disease or the obstacle that is selected from following group: eye illness, respiratory tract disease, throat, nose and ear disease, intestinal tract disease, dermatosis, cardiovascular disorder and vascular disease, diseases associated with inflammation, nervous system disorders, proliferative disease, kidney disease, sexual dysfunction, skeletal diseases, benign prostate hyperplasia, graft-rejection, spasm, hypertension, chronic obstructive bladder disease and allergy.
19. according to claim 1 to 13 each compound or the purposes of composition according to claim 15, be used for the treatment of and/or prevent to be selected from the disease of eye of following group: retinopathy, optic neuropathy, glaucoma, inflammatory eye illness and such as the retina degenerative disease of macular degeneration and retinitis pigmentosa; Be preferably glaucoma.
20. according to claim 1 to 13 each compound or the purposes of composition according to claim 15, be used for the treatment of and/or prevent to be selected from the respiratory tract disease of following group: pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering become disease, chronic obstructive pulmonary disease (COPD), bronchitis, rhinitis and respiratory distress syndrome, are preferably asthma or chronic obstructive pulmonary disease (COPD).
21. according to claim 1 to 13 each compound or the purposes of composition according to claim 15, be used for the treatment of and/or prevent to be selected from throat, nose and the ear disease of following group: nasal sinus problem, hearing problem, tonsillitis, toothache, ulcer and rhinitis.
22. according to claim 1 to 13 each compound or the purposes of composition according to claim 15, be used for the treatment of and/or prevent to be selected from the dermatosis of following group: hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis and ulcer.
23. according to claim 1 to 13 each compound or the purposes of composition according to claim 15, be used for the treatment of and/or prevent to be selected from the intestinal tract disease of following group: inflammatory bowel (IBD), colitis, gastro-enteritis, intestinal obstruction, ileitis, ecphyaditis and Crohn's disease.
24. according to claim 1 to 13 each compound or the purposes of composition according to claim 15, be used for the treatment of and/or prevent to be selected from the sexual dysfunction of following group: erective dysfunction, hypogonadism disease, bladder disease, hypertension, pulmonary hypertension or operation on pelvis; And/or be used for the treatment of the sexual dysfunction relevant with the treatment of using some drugs, for example be used for the treatment of the medicine of hypertension, depression or anxiety.
25. be used for the treatment of and/or prevent at least a eye illness, respiratory tract disease, throat, nose and ear disease, intestinal tract disease, the dermatosis of being selected from, cardiovascular disorder and vascular disease, diseases associated with inflammation, neural system and central nervous system disease, proliferative disease, kidney disease, sexual dysfunction, skeletal diseases, benign prostate hyperplasia, graft-rejection, spasm, hypertension, chronic obstructive the urinary bladder disease and irritated disease or the method for obstacle; Described method comprises the defined compound of claim 1 to 13 of patient's administering therapeutic significant quantity that needs are arranged or the defined composition of claim 15.
26. be used for the treatment of and/or prevent to be selected from retinopathy, optic neuropathy, glaucoma, inflammatory eye illness, such as the method for the disease of eye of the retina degenerative disease of macular degeneration and retinitis pigmentosa; Be preferably glaucoma; Described method comprises the defined compound of claim 1 to 10 to patient's administering therapeutic significant quantity that needs are arranged; Claim 7 or 9 defined compounds or the defined composition of claim 15 especially.
27. be used for the treatment of and/or prevent to be selected from pulmonary fibrosis, pulmonary emphysema, chronic bronchitis, asthma, fibrosis, pneumonia, capsule fibering and become sick, chronic obstructive pulmonary disease (COPD); The method of the respiratory tract disease of bronchitis and rhinitis and respiratory distress syndrome; Be preferably asthma or chronic obstructive pulmonary disease (COPD); Described method comprises the claim 1 to 8 of patient's administering therapeutic significant quantity that needs are arranged or 11 to 12 each defined compounds; Claim 8,11 and 12 defined compounds or the defined composition of claim 15 especially.
28. be used for the treatment of and/or prevent to be selected from the method for throat, nose and the ear disease of nasal sinus problem, hearing problem, tonsillitis, toothache, ulcer and rhinitis; Described method comprises the defined compound of claim 1 to 13 of patient's administering therapeutic significant quantity that needs are arranged or the defined composition of claim 15.
29. be used for the treatment of and/or prevent to be selected from the method for the dermatosis of hyperkeratosis, parakeratosis, hypergranulosis, acanthosis, dyskeratosis, spongiosis disease and ulcer; Described method comprises the defined compound of claim 1 to 13 of patient's administering therapeutic significant quantity that needs are arranged or the defined composition of claim 15.
30. be used for the treatment of and/or prevent to be selected from the method for the intestinal tract disease of inflammatory bowel (IBD), colitis, gastro-enteritis, intestinal obstruction, ileitis, ecphyaditis and Crohn's disease; Described method comprises the defined compound of claim 1 to 13 of patient's administering therapeutic significant quantity that needs are arranged or the defined composition of claim 15.
31. be used for the treatment of and/or prevent to be selected from the method for the sexual dysfunction of erective dysfunction, hypogonadism disease, bladder disease, hypertension, diabetes or operation on pelvis; And/or be used for the treatment of the sexual dysfunction relevant with the treatment of using some drugs, for example be used for the treatment of the medicine of hypertension, depression or anxiety; Described method comprises the defined compound of claim 1 to 13 of patient's administering therapeutic significant quantity that needs are arranged or the defined composition of claim 15.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN107935987A (en) * 2017-12-31 2018-04-20 佛山市赛维斯医药科技有限公司 ROCK inhibitor, preparation method and its usage containing methyl naphthalene and thiophene-carboxamides structure
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CN108047195A (en) * 2017-12-31 2018-05-18 佛山市赛维斯医药科技有限公司 A kind of amides compound of cyano-thiophene containing propylene glycol and application thereof
CN108047193A (en) * 2017-12-31 2018-05-18 佛山市赛维斯医药科技有限公司 Alcoxyl thiophene-carboxamides class ROCK inhibitor, preparation method and its usage
CN108047194A (en) * 2017-12-31 2018-05-18 佛山市赛维斯医药科技有限公司 Containing methyl naphthalene and propylene glycol thiophene-carboxamides class compound, preparation method and its usage
CN108101885A (en) * 2017-12-31 2018-06-01 佛山市赛维斯医药科技有限公司 Containing isopropylamine and nitrothiophene amides structural compounds, preparation method and the usage
CN108129452A (en) * 2017-12-31 2018-06-08 佛山市赛维斯医药科技有限公司 One kind contains isopropyl naphthalene and propylene glycol nitrothiophene amides compound and application thereof
CN108191821A (en) * 2017-12-31 2018-06-22 佛山市赛维斯医药科技有限公司 A kind of ROCK inhibitor and purposes containing methyl naphthalene and cyano-thiophene amide class formation
CN108191820A (en) * 2017-12-31 2018-06-22 佛山市赛维斯医药科技有限公司 A kind of compound containing isopropylamine and thiophene-carboxamides class formation
WO2023236924A1 (en) * 2022-06-09 2023-12-14 朗捷睿(苏州)生物科技有限公司 Biphenyl compound, pharmaceutical composition, method for preparing same, and use thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103874683A (en) * 2011-08-31 2014-06-18 阿玛克姆股份有限公司 Novel rock kinase inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007133622A2 (en) * 2006-05-12 2007-11-22 Vertex Pharmaceuticals Incorporated Selective inhibitors of rock protein kinase and uses thereof
CN101248046A (en) * 2005-07-11 2008-08-20 德福根有限公司 Amide derivatives as kinase inhibitors
CN101287707A (en) * 2005-10-13 2008-10-15 德福根有限公司 Kinase inhibitors
WO2009027392A1 (en) * 2007-08-27 2009-03-05 Abbott Gmbh & Co. Kg 4-(4-pyridinyl)-benzamides and their use as rock activity modulators
WO2010032875A2 (en) * 2008-09-18 2010-03-25 Astellas Pharma Inc. Heterocyclic carboxamide compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009500437A (en) * 2005-07-11 2009-01-08 デブジェン エヌブイ Amide derivatives as kinase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101248046A (en) * 2005-07-11 2008-08-20 德福根有限公司 Amide derivatives as kinase inhibitors
CN101287707A (en) * 2005-10-13 2008-10-15 德福根有限公司 Kinase inhibitors
WO2007133622A2 (en) * 2006-05-12 2007-11-22 Vertex Pharmaceuticals Incorporated Selective inhibitors of rock protein kinase and uses thereof
WO2009027392A1 (en) * 2007-08-27 2009-03-05 Abbott Gmbh & Co. Kg 4-(4-pyridinyl)-benzamides and their use as rock activity modulators
WO2010032875A2 (en) * 2008-09-18 2010-03-25 Astellas Pharma Inc. Heterocyclic carboxamide compounds

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN107935987A (en) * 2017-12-31 2018-04-20 佛山市赛维斯医药科技有限公司 ROCK inhibitor, preparation method and its usage containing methyl naphthalene and thiophene-carboxamides structure
CN107935986A (en) * 2017-12-31 2018-04-20 佛山市赛维斯医药科技有限公司 Isopropylamine and halogenated thiophene amide-type structural compounds, preparation method and the usage
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CN108047193A (en) * 2017-12-31 2018-05-18 佛山市赛维斯医药科技有限公司 Alcoxyl thiophene-carboxamides class ROCK inhibitor, preparation method and its usage
CN108047194A (en) * 2017-12-31 2018-05-18 佛山市赛维斯医药科技有限公司 Containing methyl naphthalene and propylene glycol thiophene-carboxamides class compound, preparation method and its usage
CN108101885A (en) * 2017-12-31 2018-06-01 佛山市赛维斯医药科技有限公司 Containing isopropylamine and nitrothiophene amides structural compounds, preparation method and the usage
CN108129452A (en) * 2017-12-31 2018-06-08 佛山市赛维斯医药科技有限公司 One kind contains isopropyl naphthalene and propylene glycol nitrothiophene amides compound and application thereof
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WO2023236924A1 (en) * 2022-06-09 2023-12-14 朗捷睿(苏州)生物科技有限公司 Biphenyl compound, pharmaceutical composition, method for preparing same, and use thereof

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