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CN101558046A - Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders - Google Patents

Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders Download PDF

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CN101558046A
CN101558046A CNA2007800392665A CN200780039266A CN101558046A CN 101558046 A CN101558046 A CN 101558046A CN A2007800392665 A CNA2007800392665 A CN A2007800392665A CN 200780039266 A CN200780039266 A CN 200780039266A CN 101558046 A CN101558046 A CN 101558046A
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M·R·V·芬利
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AstraZeneca AB
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Abstract

A compound of formula (I) or a pharamaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

Description

The morpholino pyrimidine derivatives that is used for the treatment of proliferative disorders
The present invention relates to morpholino pyrimidine derivatives, their preparation method comprises their pharmaceutical composition and their purposes in treatment, for example treats hyperplasia, and cancer is for example especially treated the disease of mTOR kinases and/or one or more PI3K enzyme mediation.
At present, people recognize that fully the imbalance of oncogene and tumor suppressor gene impels the formation of malignant tumour, for example, and by improving the approach of cell proliferation or raising cell survival.Equally, the signal path of known PI3K/mTOR family mediation has central role in many cell processes (comprising propagation and survival), and the imbalance in path is the origin cause of formation of wide spectrum human cancer and other disease.
The Mammals target of macrolide antibiotic rapamycin (sirolimus (Sirolimus)) is enzyme mTOR.This kind of enzyme belongs to relevant kinases (PIKK) family of phosphatidylinositols (PI) kinases of protein kinase, and it also comprises ATM, ATR, DNA-PK and hSMG-1.Similar with other PIKK family member, mTOR does not have detectable lipid kinase activity, but plays the effect of serine-threonine kinase on the contrary.Many understanding to the mTOR signal are based on the use rapamycin.Rapamycin at first combines with 12 kDa immunophilin FK506-conjugated protein (FKBP 12), and this mixture inhibition mTOR signal (Tee and Blenis, Seminars in Cell andDevelopmental Biology, 2005,16,29-37).MTOR albumen by catalysis kinases zone (FKBP12 (rapamycin)-connection (FRB) zone), the supposition the repressor zone (near the C-end, and have 20 the continuous HEAT of repetition primitives at the most at the N-end) and FRAP-ATM-TRRAP (FAT) and FAT C-stub area composition (Huang and Houghton, Current Opinion in Pharmacology, 2003,3,371-377).
The mTOR kinases is the crucial conditioning agent of cell growth, and show and have the effect of regulating many cell functions, comprise translate, transcribe, mRNA circulation, protein stability, actin cytoskeleton reorganization and autophagy (Jacinto and Hall, Nature Reviews Molecular andCell Biology, 2005,4,117-126).The mTOR kinases will come from the signal of somatomedin (for example Regular Insulin or rhIGF-1) and nutrient substance (for example amino acid and glucose) and integrate, to regulate the cell growth.The mTOR kinases is by the PI3K-Akt path, by growth factor activation.The mTOR kinases function that fullest characterizes in mammalian cell is to regulate to translate, it is by two paths, promptly examine candy body S6K1 activation (with raising carry 5 '-mRNAs in few pyrimidine zone, end (TOP) translates) and the inhibition (translating) of 4E-BP1 with the dependent mRNA of permission CAP-carry out.
Usually, the investigator uses rapamycin and relevant forms of rapamycin analogs (based on them at the specificity of mTOR as target in the born of the same parents) to suppress, and has probed into physiology and the pathological effect of mTOR.Yet, latest data proposes, rapamycin demonstrates variable restraining effect to the mTOR semiotic function, and think, directly suppress mTOR kinases zone and can show the anticancer significantly widely disease activity of anticancer disease activity that obtains than rapamycin (people such as Edinger, Cancer Research, 2003,63,8451-8460).For this reason, can use effectively and the optionally inhibitor of mTOR kinase activity,, and provide the therapeutical agent of usefulness so that understand the mTOR kinase function more completely.
Have considerable evidence to show now, the path upstream of mTOR is the PI3K path for example, is activated (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,489-501 in cancer continually; Bjornsti and Houghton, Nature Reviews Cancer, 2004,4,335-348; People such as Inoki, Nature Genetics, 2005,37,19-24).The component in the PI3K path that for example, suddenlys change in different human tumors comprises the activation sudden change of growth factor receptors and amplification and/or the overexpression of PI3K and Akt.
Explanation on evidence in addition, endothelial cell proliferation may also depend on the mTOR signal.Endothelial cell proliferation be by the vascular endothelial growth factor of PI3K-Akt-mTOR signal path (VEGF) activation stimulated (Dancey, Expert Opinion on Investigational Drugs, 2005,14,313-328).In addition, by influence to the expression of the factor-1 α (HIF-1 α) of hypoxia inducible, think the mTOR kinase signal can partly control VEGF synthetic (people such as Hudson, Molecular and Cellular Biology, 2002,22,7004-7014).Therefore, tumor-blood-vessel growth may depend on the mTOR kinase signal in two ways: the hypoxia inducible of the VEGF by tumour and stroma cell synthetic and the VEGF excitation by endothelium propagation and survival (by the PI3K-Akt-mTOR signal).
These find expression, and the kinase whose pharmacological inhibitor of mTOR should have therapeutic value, can be used for treating various forms of cancers, comprise for example malignant tumour of cancer and sarcoma and leukemia and lymph of noumenal tumour.Especially, the mTOR kinase inhibitor should have therapeutics and be worth, and can be used for treating for example breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer, and cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
Except tumorigenicity, explanation on evidence, the mTOR kinases is played a role in a series of progonoma syndromess.Recent research shows that tumor suppressor protein for example TSC1, TSC2, PTEN and LKB1 can be controlled the mTOR kinase signal consumingly.The forfeiture of these tumor suppressor proteins can cause a large amount of progonoma illnesss, this be because the result that the mTOR kinase signal increases (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005,16,29-37).Setting up the syndromes that molecule gets in touch with the kinase whose dysregulation of mTOR comprises: Peutz-Jeghers syndrome (PJS), the Cowden disease, Bannayan-Riley-Ruvalcaba syndromes (BRRS), the Proteus syndromes, Lhermitte-Duclos disease and tuberous sclerosis (TSC) (people such as Inoki, Nature Genetics, 2005,37,19-24).Patient with these syndromess forms optimum paramnesia tumour specifically in many organs.
Up-to-date research has shown the effect (Easton﹠amp of mTOR kinases in other disease; Houghton, Expert Opinion on Therapeutic Targets, 2004,8,551-564).Show that the propagation of the antigen induction by suppressor T cell, B cell and antibody produce, rapamycin is effective immunosuppressor (Sehgal, Transplantation Proceedings, 2003,35,7S-14S) and thus the mTOR kinase inhibitor also is useful immunosuppressor.The kinase activity that suppresses mTOR also can be effective to prevention of restenosis, in the treatment of vascular system disease, this restenosis is subjected to the normal cell in the vascular system to produce the control (people such as Morice of undesirable propagation in to the response process of introducing support, New England Journal ofMedicine, 2002,346,1773-1780).In addition, forms of rapamycin analogs (everolimus) can reduce the severity of heart allograft vascular lesion and incidence (people such as Eisen, New England Journal of Medicine, 2003,349,847-858).The raising of mTOR kinase activity is relevant with cardiac hypertrophy, and this primary hazard factor as heart failure is important clinically, and is the result (Tee﹠amp of myocardial cell's cell size increase; Blenis, Seminars in Cell and Developmental Biology, 2005,16,29-37).Thus, except cancer, expectation mTOR kinase inhibitor has prevention and treats the value of multiple disease.
Believe that equally many these morpholino pyrimidine derivatives have the activity of inhibition at kinase whose phosphatidylinositols (PI) 3-kinases family.
Phosphatidylinositols (PI) 3-kinases (PI3Ks) is ubiquitous lipid kinase, and it can be as signal converter and protein transportation route in the downstream of cell surface receptor and the intracellular membrane that is constituting.All PI3Ks have an active dual specificity enzyme of lipid kinase, and it can be in the 3-hydroxy position with the phosphoinositide phosphorylation, and the protein kinase activity with less abundant characterization.The lipid products of PI3K-catalyzed reaction (comprises phosphatidylinositols 3,4,5-triguaiacyl phosphate [PI (3,4,5) P 3], phosphatidylinositols 3,4-bisphosphate [PI (3,4) P 2] and phosphatidylinositols 3-Monophosphate [PI (3) P]) in various signal transduction pathways, constitute the second messenger, comprise that on cell proliferation, adhesion, survival, cytoskeleton are reset and current those the indispensable approach of vesica.In all cells, structurally have PI (3) P, and its level can not change significantly along with the excitation of agonist.On the contrary, in most of cell, nominally there is not PI (3,4) P 2And PI (3,4,5) P 3, but they can be assembled under the excitation of agonist apace.
The 3-phosphoinositide second messenger's that PI3K-produces downstream effect is to mediate by the target molecule that comprises 3-phosphoinositide connecting zone (for example pleckstrin homology (PH) zone and definite recently FYVE and phox zone).The albumen target of the better sign of PI3K comprises PDK1 and protein kinase B (PKB).In addition, for example Btk and Itk rely on the PI3K activity to Tyrosylprotein kinase.
According to its physiology substrate specificity, (people such as Vanhaesebroeck, Trends in Biol.Sci., 1997,22,267) can be divided three classes PI3K lipid kinase family.III class PI3K enzyme is separately with the PI phosphorylation.On the contrary, II class PI3K enzyme is with PI and PI4-phosphoric acid ester [PI (4) P] phosphorylation.Although think (4, the 5) P that has only PI 2Be physiological cell matrix, I class PI3K enzyme is PI, PI (4) P and PI 4,5-bisphosphate [PI (4,5) P 2] phosphorylation.PI (4,5) P 2Phosphorylation produce lipid second messenger PI (3,4,5) P 3The farther relevant member of the super family of lipid kinase is an IV class kinases, for example mTOR (discussing above) and DNA-dependant kinase (it is with the serine/threonine residue phosphorylation in the albumen substrate).Most of research and the PI3K lipid kinase of understanding are I class PI3K enzymes.
The heterodimer that I class PI3Ks is made up of p110 catalytic subunit and regulator subunit.Based on adjusting side and regulation mechanism, this family is further divided into Ia class and Ib fermentoid.The Ia fermentoid comprises regulator subunit (the p85 α with five uniquenesses, p55 α, p50 α, p85 β and p55 γ) (the p110 α of catalytic subunit of three uniquenesses of dimerization, p110 β and p110 δ), all catalytic subunits can interact with all regulator subunits, form various heterodimers.In the response that the somatomedin to receptor tyrosine kinase encourages,, usually Ia class PI3Ks is activated by its regulator subunit SH2 zone and activated receptor or for example interaction of the concrete phosphate tyrosine residues of IRS-1 of joint albumen.In all cell types, structurally express p110 α and p110 β, and p110 δ expression more is confined to leukocytes and some epithelial cells.On the contrary, simple classification Ib enzyme comprises the catalytic subunit with the interactional p110 γ of p101 regulator subunit.In addition, as if in the response to g protein coupled receptor system (GPCRs), classification Ib enzyme is activated, and its expression is limited to white corpuscle and myocardial cell.
Have considerable evidence to show now, in multiple human cancer, Ia class PI3K enzyme can help directly or indirectly to cause tumour (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,489-501).For example, in some tumours, the p110 alpha subunit obtains amplification, for example ovarian tumor (people such as Shayesteh, Nature Genetics, 1999,21,99-102) and cervix neoplasms (people such as Ma, Oncogene, 2000,19,2739-2744).In recent years, activation in the catalytic site of p110 α catalytic subunit sudden change is relevant with various other tumours, and for example colorectum is regional and those tumours of breast and lung people such as (, Science, 2004,304,554) Samuels.In cancer for example in ovary and the colorectal carcinoma, also determined the relevant sudden change of tumour in the p85 α regulator subunit (people such as Philp, Cancer Research, 2001,61,7426-7429).Except direct influence, it is believed that, the activation of Ia class PI3Ks helps the tumorigenic situation in the appearance of signal path upstream, for example, via the ligand dependent of receptor tyrosine kinase, GPCR system or integrin or the activation of part dependent/non-dependent (people such as Vara, CancerTreatment Reviews, 2004,30,193-204).The example in this stream signal path comprises the overexpression (people such as Harari of receptor tyrosine kinase erbB2 in causing the various tumours of activatory in path that PI3K mediates, Oncogene, 2000,19,6102-6114) and the overexpression of ras oncogene (people such as Kauffmann-Zeh,, Nature, 1997,385,544-548).In addition, Ia class PI3Ks can help tumorigenicity (movable institute causes by various downstream signals) indirectly.For example, by PI (3,4,5) P that PI3K mediated 3The imbalance that generates, PTEN tumor suppression Phosphoric acid esterase (its catalysis PI (3,4,5) P 3PI (4,5) P is got back in conversion 2) the forfeiture of effect relevant with very large-scale tumour (Simpson and Parsons, Exp.Cell Res., 2001,264,29-41).In addition, it is believed that the increase of the effect of activity that other PI3K mediates will help lend some impetus to various cancers, and for example activation by Akt (Nicholson and Anderson, Cellular Signalling, 2002,14,381-395).
The effect in mediation propagation in tumour cell and survival signal, explanation on evidence, Ia class PI3K enzyme helps tumorigenicity in the relevant stroma cell of tumour.For example, know, to preceding angiogenic factor for example in the response of VEGF, the PI3K signal in the generation angiokinesis of mediation endotheliocyte, play an important role (people such as Abid, Arterioscler.Thromb.Vasc.Biol., 2004,24,294-300).Because I class PI3K enzyme also relate to reactivity and migration (Sawyer, Expert Opinion Investig.Drugs, 2004,13,1-19), invade and metastasis by suppressing tumour cell, the PI3K enzyme inhibitors should provide the treatment benefit.In addition, I class PI3K enzyme in the immunocyte of the pre-neoplastic generation effect that helps inflammatory cell is regulated, play an important role (Coussens and Werb, Nature, 2002,420,860-867).
These find expression, and the pharmacological inhibitor of I class PI3K enzyme has therapeutic value, can be used for treating various diseases, comprises the various forms Cancerous disease, comprise for example malignant tumour of cancer and sarcoma and leukemia and lymph of noumenal tumour.Especially, the inhibitor of I class PI3K enzyme should have therapeutics and be worth, and can be used for treating for example breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer, and cholangiocarcinoma, bone cancer, bladder cancer, head and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
PI3K γ (Ib class PI3K) is by the GPCRs activatory, and this has obtained proof at last in the mouse that lacks enzyme.Thus, in response to various chemotaxis materials (for example IL-8, C5a, fMLP and MIP-1a) excitation, derived from lack PI3K γ-neutrophil and the scavenger cell of animal can not produce PI (3,4,5) P 3, and be intact (people such as Hirsch, Science, 2000,287 (5455), 1049-1053 by protein tyrosine kinase coupled receptor to the signal of Ia class PI3Ks; People such as Li, Science, 2002,287 (5455), 1046-1049; People such as Sasaki, Science, 2002,287 (5455), 1040-1046).In addition, in the cell of no PI3K γ, PI (3,4,5) P 3The phosphorylation of the PKB of mediation is not to originate from these GPCR parts.Combine, the result shows that in the hematopoietic cell of having a rest, PI3K γ is by the unique PI3K heterogeneous of activatory in the GPCRs body at least.When to the neutrophil that derives from mouse marrow with derive from wild-type and PI3K γ -/-When the peritoneal macrophages of mouse carries out in vitro tests, in chemotaxis and adherence test, observe (but not eliminating fully) performance of reduction.Yet this is converted into neutrophil that IL-8 drives and is penetrated into rapid damage in the tissue (people such as Hirsch, Science, 2000,287 (5455), 1049-1053). up-to-date data propose, and PI3K γ is relevant with the path finding process, and it is irrelevant with the generation (being used for reactivity) of mechanical force, because the random migration in the cell that lacks PI3K γ does not weaken (people such as Hannigan, Proc.Nat.Acad.of Sciences of U.S.A., 2002,99 (6), 3603-8).The data of contact PI3K γ and respiratory system disease pathology show, PI3K γ is in the lung infiltration of regulating endotaxin induction and cause having central role aspect the neutrophil activation of acute lung injury (people such as Yum, J.Immunology, 2001,167 (11), 6601-8).Although PI3K γ expresses at the white cell camber, as if its forfeiture does not hinder hematopoiesis, and the mouse that does not have a PI3K γ can grow and reproducible these truely hint that this PI3K heterogeneous can be used as the potential drug targets.Research for the stunning mouse also confirms, PI3K γ be mast cell's activatory necessity toughener (people such as Laffargue, Immunity, 2002,16 (3), 441-451).
Thus, except tumorigenicity, explanation on evidence, I class PI3K enzyme in other disease, play a role (people such as Wymann, Trends in Pharmacological Science, 2003,24,366-376).In immune cell, Ia class PI3K enzyme and simple Ib fermentoid all have important effect (Koyasu, Nature Immunology, 2003,4,313-319), and they are treatment targets of inflammatory and irritated indication thus.Up-to-date report shows, the mouse that lacks PI3K γ and PI3K δ can grow, but have the inflammatory that weakens and anaphylactic response (people such as Ali, Nature, 2004,431 (7011), 1007-11).By the anti-inflammatory effect or directly influence the myocardial cell, the restraining effect of PI3K also can be used for treating cardiovascular disorder (people such as Prasad, Trends in Cardiovascular Medicine, 2003,13,206-212).Thus, except cancer, the inhibitor of expectation I class PI3K enzyme has prevention and treats the value of multiple disease.
Differentiate some compounds of the kinases (PI3KKs) that inhibition PI3Ks is relevant with phosphatidylinositols (PI) kinases, comprised wortmannin and quercetin derivative L Y294002.These compounds are rationally concrete inhibitor (surpassing other kinases) of PI3Ks and PI3KKs, but they lack usefulness, and show less selectivity in PI3K family.
Correspondingly, desirablely be, effectively mTOR and/or PI3K inhibitor are provided further, be used for the treatment of cancer, inflammatory or obstructive respiratory tract disease, immunity or cardiovascular disorder.
Morpholino pyrimidine derivatives and PI3K inhibitor are known in the art.
International Patent Application WO 2004/048365 discloses the compound that has the PI3K enzyme inhibition activity and can be used for treating cancer.These compounds are pyrimidines that virtue is amino and heteroaryl amino replaces, and with regard to their virtue amino and heteroaryl amino substituting group, it is different from compound of the present invention.These substituting groups are not equivalent to of the present invention-XR 1Substituting group.The active inhibitor of the PI3K that is used for the treatment of cancer is also disclosed in european patent application 1277738, it mentions the bicyclic heteroaryl compounds that the 4-morpholino replaces, for example quinazoline and pyrido [3,2-d] pyrimidine derivatives, with the tricyclic heteroaryl compounds of 4-morpholino replacement, rather than monocyclic pyrimidine derivatives.
On the chemical abstracts database, registered chemical compound lot; 4-morpholine-4-base-6-(phenyl sulfonyl methyl)-2-pyridin-4-yl-pyrimidine and 4-{6-[(benzene sulfonyl for example) methyl]-2-pyridine-2-yl pyrimidines-4-yl } morpholine; but do not show applicability, and do not propose these compounds and have mTOR and/or PI3K and suppress active or useful curative properties.
Unexpectedly, we find that some morpholino pyrimidine derivatives has useful curative properties.Do not wish to be bound by theory, it is believed that, the therepic use of this derivative stems from their inhibition activity at mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib fermentoid).Because the signal path of PI3K/mTOR family mediation has central role in many cell processes (comprising propagation and survival), with because the imbalance in these paths is origin causes of formation of wide spectrum human cancer and other disease, so people expect that this derivative has therepic use.Especially, people expect that this derivative has antiproliferative and/or apoptosis performance, and this is meant that they can be used for treating hyperplasia, for example cancer.Compound of the present invention also can be effective to suppress not have the cell proliferation of control, and the cell proliferation of this no control comes from various non-malignant diseases, for example inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder.
Usually, compound of the present invention has effective inhibition activity at the mTOR kinases, but this compound also can have effective inhibition activity at one or more PI3K enzymes (for example Ia fermentoid and/or Ib fermentoid).
According to one aspect of the present invention, provide the compound of formula (I)
Figure A20078003926600161
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R 9,-OR 9,-SR 9,-SOR 9,-SO 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15With-NR 9SO 2R 10
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-SR 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl,
Medicine as the treatment hyperplasia.
According to another aspect of the present invention, provide the compound of formula (I)
Figure A20078003926600181
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR8;
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R 9,-OR 9,-SR 9,-SOR 9,-SO 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15With-NR 9SO 2R 10
Or X-R 1Be-CR 6R 7OH;
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-SR 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl,
Medicine as the treatment hyperplasia.
According to another aspect of the present invention, provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R 9,-OR 9,-SR 9,-SOR 9,-SO 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15With-NR 9SO 2R 10
Or X-R 1Be-CR 6R 7OH;
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-SR 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl
Medicine as the treatment hyperplasia.
According to another aspect of the present invention, provide the compound of formula (I)
Figure A20078003926600231
Formula (I)
Or the purposes of its pharmacologically acceptable salt in the preparation medicine, this medicine is used for the treatment of hyperplasia; Wherein m is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R 9,-OR 9,-SR 9,-SOR 9,-SO 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15With-NR 9SO 2R 10
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-SR 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
According to another aspect of the present invention, provide the compound of formula (I)
Figure A20078003926600251
Formula (I)
Or the purposes of its pharmacologically acceptable salt in the preparation medicine, this medicine is used for the treatment of hyperplasia; Wherein m is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R 9,-OR 9,-SR 9,-SOR 9,-SO 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15With-NR 9SO 2R 10
Or X-R 1Be-CR 6R 7OH;
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-SR 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
According to another aspect of the present invention, provide the compound of formula (I)
Figure A20078003926600281
Formula (I)
Or the purposes of its pharmacologically acceptable salt in the preparation medicine, this medicine is used for the treatment of hyperplasia; Wherein m is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R 9,-OR 9,-SR 9,-SOR 9,-SO 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15With-NR 9SO 2R 10
Or X-R 1Be-CR 6R 7OH
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-SR 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-R 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
According to further aspect of the present invention, also provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is O, 1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-(O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R 9,-OR 9,-SR 9,-SOR 9,-O 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15And NR 9SO 2R 10
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-R 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
According to further aspect of the present invention, also provide the compound of formula (I)
Figure A20078003926600321
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-(O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R 9,-OR 9,-SR 9,-SOR 9,-O 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15And NR 9SO 2R 10
Or X-R 1Be-CR 6R 7OH;
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-R 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
According to further aspect of the present invention, also provide the compound of formula (I)
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro ,-R 9,-OR 9,-SR 9,-SOR 9,-O 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15And NR 9SO 2R 10
Or X-R 1Be-CR 6R 7OH;
R 2Be to be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16
When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-R 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
Can there be stereoisomeric forms in any ratio in the compound of some formula (I).Be appreciated that all how much and optically active isomer and its mixture of the formula of the present invention includes (I) compound, comprise raceme.Tautomer and its mixture also form one aspect of the present invention.Solvate and its mixture also form one aspect of the present invention.For example, the suitable solvent thing of formula (I) compound is for example hydrate, for example hydrate of semihydrate, monohydrate, two-hydrate or three-hydrate or its other number.
The compound that the present invention relates to formula defined herein (I) with and salt.The salt that is used for pharmaceutical composition is pharmacologically acceptable salt, but other salt can be used for the compound of preparation formula (I) and their pharmacologically acceptable salt.Pharmacologically acceptable salt of the present invention can for example comprise the acid salt of formula defined herein (I) compound, and formula (I) compound is fully alkaline, so that form this salt.This acid salt is including, but not limited to fumarate, mesylate, hydrochloride, hydrobromate, Citrate trianion and maleate and the salt that forms with phosphoric acid and sulfuric acid.In addition, if formula (I) compound is abundant tart, salt is alkali salt, example including, but not limited to: an alkali metal salt is sodium or sylvite for example, alkaline earth salt is calcium or magnesium salts for example, or organic amine salt triethylamine, thanomin, diethanolamine, trolamine, morpholine, N-methyl piperidine, N-ethylpiperidine, dibenzylamine or amino acid lysine salt for example for example.
The compound of formula (I) also can be provided with the form of hydrolyzable ester in the body.The ester that comprises cleavable in the body of formula (I) compound of carboxyl or hydroxyl for example is: cleavable produces the pharmaceutically acceptable ester of parent acid or alcohol in human or animal body.This ester can by for example intravenously give the experimental animal test compound and subsequently the body fluid of check test animal identified.
The suitable pharmaceutically acceptable ester of carboxyl comprises C 1-6The alkoxy methyl ester is methoxymethyl ester for example, C 1-6The alkanoyloxymethyl ester is the oxy acid methyl neopentyl ester for example, phthalidyl ester, C 3-8Cyclo alkoxy carbonyl oxygen base C 1-6Alkyl ester is 1-cyclohexyl-carbonyl oxygen base ethyl ester for example, and 1,3-dioxole-2-ketone group methyl ester is the 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl ester, and C 1-6The alkoxy-carbonyl oxy ethyl ester is 1-methoxycarbonyl oxygen base ethyl ester for example; With can on any carboxyl of The compounds of this invention, form ester.
The suitable pharmaceutically acceptable ester of hydroxyl comprises inorganic ester for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and α-acyloxyalkyl group ether and owing to the related compound that obtains parent hydroxy is decomposed in hydrolysis in the body of ester.The example of α-acyloxyalkyl group ether comprises acetoxyl group methoxy-ether and 2,2-dimethyl propylene acyloxy methoxy-ether.The option that forms the interior hydrolyzable ester of body of hydroxyl comprises C 1-10Alkyloyl, formyl radical for example, ethanoyl, benzoyl, phenylacetyl, the benzoyl of replacement and phenylacetyl; C 1-10Carbalkoxy (obtaining alkyl carbonate), for example ethoxycarbonyl; Two-C 1-4Alkyl-carbamoyl and N-(two-C 1-4The alkylamino ethyl)-N-C 1-4Alkyl-carbamoyl (obtaining carbamate); Two-C 1-4Alkylamino ethanoyl and carboxyl ethanoyl.The example of the ring substituents on phenylacetyl and the benzoyl comprise aminomethyl, C 1-4Alkylamino methyl and two-(C 1-4Alkyl) aminomethyl is with the morpholino or the piperazinyl of 3-that is connected basic shack nitrogen-atoms and benzoyl basic ring by methylene radical or 4-position.Hydrolyzable ester comprises for example R in other useful body AC (O) OC 1-6Alkyl-CO-, wherein R ABe benzyloxy-C for example 1-4Alkyl or phenyl.In this ester, the suitable substituent on the phenyl comprises for example 4-C 1-4Piperazinyl-C 1-4Alkyl, piperazinyl-C 1-4Alkyl and morpholino-C 1-4Alkyl.
Also can be with the compound of prodrug form giving construction (I), it decomposes in human or animal body, obtains the compound of formula (I).The various forms of prodrug is known in this area.For example, this prodrug derivatives referring to:
A) Design of Prodrugs, edited by H.Bundgaard, (Elsevier, 1985) andMethods in Enzymology, Vol.42, p.309-396, people such as edited by K.Widder, (Academic Press, 1985);
b)A Textbook of Drug Design and Development,edited byKrogsgaard-Larsen and H.Bundgaard,Chapter 5“Design and Applicationof Prodrugs”,by H.Bundgaard p.113-191(1991);
c)H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992);
D) people such as H.Bundgaard, Journal of Pharmaceutical Sciences, 77,285 (1988); And
E) people such as N.Kakeya, Chem Pharm Bull, 32,692 (1984).
General terms " C in this specification sheets P-qAlkyl " comprise straight chain and branched-chain alkyl.Yet, speak of single alkyl for example " propyl group " only specifically be used for straight chain pattern (being n-propyl and sec.-propyl), speak of single branched-chain alkyl for example " tertiary butyl " only specifically be used for the side chain pattern.
C P-qPrefix C in alkyl and other term (wherein p and q are integers) P-qShow the carbon atom scope that exists in the group, for example C 1-4Alkyl comprises C 1Alkyl (methyl), C 2Alkyl (ethyl), C 3Alkyl (propyl group of n-propyl and sec.-propyl form) and C 4Alkyl (normal-butyl, sec-butyl, isobutyl-and the tertiary butyl).
Term C P-qAlkoxyl group comprises-O-C P-qAlkyl.
Term C P-qAlkyloyl comprises-C (O) alkyl.
Term halogen comprises fluorine, chlorine, bromine and iodine.
" carbocyclic ring " is monocycle, dicyclo or the three-loop system that comprises saturated, the unsaturated or fractional saturation of 3 to 14 annular atomses, wherein encircles CH 2Group can be replaced by the C=O group." carbocyclic ring " comprises " aryl ", " C P-qCycloalkyl " and " C P-qCycloalkenyl group ".
" aryl " is aromatic series monocycle, dicyclo or trinucleated carbocyclic ring system.
" C P-qCycloalkenyl group " be monocycle, dicyclo or the three ring carbocyclic ring ring systems that comprise the unsaturated or fractional saturation of at least 1 C=C key, wherein encircle CH 2Group can be replaced by the C=O group.
" C P-qCycloalkyl " be saturated monocycle, dicyclo or three ring carbocyclic ring ring systems, wherein encircle CH 2Group can be replaced by the C=O group.
" heterocyclic radical " is monocycle, dicyclo or the three-loop system that comprises saturated, the unsaturated or fractional saturation of 3 to 14 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, this ring can be that carbon or nitrogen connect, and wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH 2Group can be replaced by the C=O group." heterocyclic radical " comprises " heteroaryl ", " the assorted alkyl of ring " and " the assorted thiazolinyl of ring ".
" heteroaryl " is aromatic series monocycle, dicyclo or trinucleated heterocyclic radical, especially has 5 to 1O annular atomses, and wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, and wherein nuclear nitrogen or sulphur can be oxidized.
" the assorted thiazolinyl of ring " is monocycle, dicyclo or the tricyclic heterocyclic basic ring system with unsaturated or fractional saturation of 5 to 10 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, this ring can be that carbon or nitrogen connect, and wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH 2Group can be replaced by the C=O group.
" the assorted alkyl of ring " is saturated monocycle, dicyclo or the tricyclic heterocyclic system with 5 to 10 annular atomses, wherein 1,2,3 or 4 annular atoms is selected from nitrogen, sulphur or oxygen, this ring can be that carbon or nitrogen connect, and wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH 2Group can be replaced by the C=O group.
This specification sheets can use the combination term, comprises the group of an above functional group with description.Unless this paper describes in addition, otherwise can explain this term according to what this area was understood.For example, carbocyclic ring C P-qAlkyl comprises the C that is replaced by carbocyclic ring P-qAlkyl, heterocyclic radical C P-qAlkyl comprises the C that is replaced by heterocyclic radical P-qAlkyl, two (C P-qAlkyl) amino comprises by 2 C P-qThe amino that alkyl (can be identical or different) replaces.
Halo C P-qThe C that alkyl is replaced by 1 or 1 above halogenic substituent (especially 1,2 or 3 halogenic substituent) P-qAlkyl.Equally, other general terms that comprises halogen halo C for example P-qAlkoxyl group can comprise 1 or 1 above halogenic substituent (especially 1,2 or 3 halogenic substituent).
Hydroxyl C P-qThe C that alkyl is replaced by 1 or 1 above hydroxyl substituent (especially 1,2 or 3 hydroxyl substituent) P-qAlkyl.Equally, other general terms that comprises hydroxyl hydroxyl C for example P-qAlkoxyl group can comprise 1 or 1 above hydroxyl substituent (especially 1,2 or 3 hydroxyl substituent).
C P-qAlkoxy C P-qAlkyl is by 1 or 1 above C P-qAlkoxy substituent (1,2 or 3 C especially P-qAlkoxy substituent) C of Qu Daiing P-qAlkyl.Equally, comprise C P-qOther general terms of alkoxyl group is C for example P-qAlkoxy C P-qAlkoxyl group can comprise 1 or 1 above C P-qAlkoxy substituent (1,2 or 3 C especially P-qAlkoxy substituent).
If optional substituting group is selected from " 1 or 2 ", " 1,2 or 3 " or " 1,2,3 or 4 " individual group or substituting group, should be appreciated that, this definition comprises and is selected from all substituting groups that specify group, promptly all substituting groups are identical, or substituting group is selected from two or more groups that specify, and promptly substituting group is inequality.
(ACD/Name version 8.0) names compound of the present invention by means of computer software.
" hyperplasia " comprises for example for example inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder of cancer and non-malignant diseases of malignant diseases.
Any part of any R group or this group or substituent suitable meaning comprise:
C 1-4Alkyl: methyl, ethyl, propyl group, butyl, 2-methyl-propyl and uncle's fourth
Base;
C 1-6Alkyl: C 1-4Alkyl, amyl group, 2, the 2-dimethylpropyl, the 3-methyl butyl and
Hexyl;
C 3-6Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
C 3-6Cycloalkyl C 1-4Alkyl: cyclopropyl methyl, cyclopropyl ethyl, cyclobutylmethyl, ring penta
Ylmethyl and cyclohexyl methyl;
Aryl: phenyl and naphthyl;
Aryl C 1-4Alkyl: benzyl, styroyl, naphthyl methyl and naphthyl ethyl;
Carbocyclic ring: aryl, cyclohexenyl and C 3-6Cycloalkyl;
Halogen: fluorine, chlorine, bromine and iodine;
C 1-4Alkoxyl group: methoxyl group, oxyethyl group, propoxy-and isopropoxy;
C 1-6Alkoxyl group: C 1-4Alkoxyl group, pentyloxy, 1-ethyl propoxy-and hexyloxy;
C 1-6Alkyloyl: ethanoyl, propionyl and 2-methylpropionyl;
Heteroaryl: pyridyl, imidazolyl, quinolyl, the cinnolines base, pyrimidyl,
Thienyl, pyrryl, pyrazolyl, thiazolyl, thiazolyl,
Triazolyl , oxazolyl , isoxazolyl, furyl, pyridazinyl,
Pyrazinyl, indyl, benzofuryl, dibenzofuran group
And benzothienyl;
Heteroaryl C 1-4Alkyl: pyrryl methyl, pyrryl ethyl, imidazolyl methyl, imidazoles
The base ethyl, pyrazolyl methyl, pyrazolyl ethyl, furyl first
Base, the furyl ethyl, thienyl methyl, thienyl ethyl,
Pyridylmethyl, pyridyl ethyl, pyrazinyl methyl, pyrazine
The base ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrimidyl third
Base, the pyrimidyl butyl, the imidazolyl propyl group, the imidazolyl butyl,
The quinolyl propyl group, 1,3,4-triazolyl propyl group is with the oxazolyl methyl;
Heterocyclic radical: heteroaryl, pyrrolidyl, isoquinolyl, quinoxalinyl, benzene
Benzothiazolyl, benzoxazolyl, piperidyl, piperazinyl, nitrogen
The heterocycle butane group, morpholinyl, tetrahydro isoquinolyl, tetrahydrochysene quinoline
The quinoline base, indolinyl, dihydro-2H-pyranyl and tetrahydrochysene furan
The base of muttering.
It should be noted that for the given example of the term that uses in the specification sheets be not restrictive.
M, X, 1Y and Y 2, R 1, R 2And R 3Concrete meaning as follows.If suitable, this meaning can be used in combination with any aspect of the present invention or its part and any definition, claim or embodiment defined herein.
m
In one aspect of the invention, m is 0,1,2 or 3.
In yet another aspect, m is 0,1 or 2.
Further, m is 0 or 1.
In yet another aspect, m is 0, like this R 3Do not exist.
In yet another aspect, m is 1, R 3It is methyl.
1 Y and Y 2
In one aspect of the invention, 1Y is N, Y 2Be CR 8
In another aspect of the present invention, 1Y is N, Y 2Be CH.
Of the present invention aspect another, 1Y is CR 8, Y 2Be N.
Further, 1Y is CH or CF, Y 2Be N.
Further, 1Y is CH, Y 2Be N.
X
In one aspect of the invention, X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-NR 4C (O)-,-C (O) NR 4-,-S (O) 2NR 4-and-NR 4S (O) 2-.
In yet another aspect, X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7,-C (O) NR 4-and-NR 4C (O)-.
Further, X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4-and-NR 4C (O)-.
Further, X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-and-S (O) 2CR 6R 7-.
In yet another aspect, X is selected from following connection base :-SCR 6R 7-,-S (O) CR 6R 7-and-S (O) 2CR 6R 7-.
In yet another aspect, X is selected from following connection base :-NR 4CH 2-,-OCH 2-,-OCH (CH 3)-,-OC (CH 3) 2-,-SCH 2-,-SCH (CH 3)-,-C (CH 3) 2-,-S (O) CH 2-,-S (O) CH (CH 3)-,-S (O) C (CH 3) 2-,-S (O) 2CH 2-,-S (O) 2CH (CH 3)-,-S (O) 2C (CH 3) 2-,-C (O) NR 4-and-NR 4C (O)-.
In yet another aspect, X is selected from following connection base :-NR 4CH 2-,-OCH 2-,-SCH 2-,-S (O) CH 2-,-S (O) 2CH 2-,-C (O) NR 4-and-NR 4C (O)-.
In yet another aspect, X is selected from following connection base :-NR 4CH 2-,-OCH 2-,-OCH (CH 3)-,-OC (CH 3) 2-,-SCH 2-,-SCH (CH 3)-,-SC (CH 3) 2-,-S (O) CH 2-,-S (O) CH (CH 3)-,-S (O) C (CH 3) 2-,-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-.
In yet another aspect, X is selected from following connection base :-NR 4CH 2-,-OCH 2-,-SCH 2-,-S (O) CH 2-and-S (O) 2CH 2-.
Further, X is selected from following connection base :-NHCH 2-,-N (CH 3) CH 2-,-OCH 2-,-OCH (CH 3)-,-OC (CH 3) 2-,-SCH 2-,-SCH (CH 3)-,-SC (CH 3) 2-,-S (O) CH 2-,-S (O) CH (CH 3)-,-S (O) C (CH 3) 2-,-S (O) 2CH 2-,-S (O) 2CH (CH 3)-,-S (O) 2C (CH 3) 2-,-C (O) NH-,-C (O) N (CH 3)-,-NHC (O)-and-N (CH 3) C (O)-.
Further, X is selected from following connection base :-NHCH 2-,-N (CH 3) CH 2-,-OCH 2-,-SCH 2-,-S (O) CH 2-,-S (O) 2CH 2-,-C (O) NH-,-C (O) N (CH 3)-,-NHC (O)-and-N (CH 3) C (O)-.
Further, X is selected from following connection base :-NHCH 2-,-N (CH 3) CH 2-,-OCH 2-,-OCH (CH 3)-,-OC (CH 3) 2-,-SCH 2-,-SCH (CH 3)-,-SC (CH 3) 2-,-S (O) CH 2-,-S (O) CH (CH 3)-,-S (O) C (CH 3) 2-,-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-.
Further, X is selected from following connection base :-NHCH 2-,-N (CH 3) CH 2-,-OCH 2-,-SCH 2-and-S (O) 2CH 2-.
In yet another aspect, X is-SCH 2-or-S (O) 2CH 2-.
In yet another aspect, X is-SCH 2-,-SCH (CH 3)-or-SC (CH 3) 2-.
In yet another aspect, X is-S (O) CH 2-,-S (O) CH (CH 3)-or-S (O) C (CH 3) 2-.
In yet another aspect, X is-S (O) 2CH 2-,-S (O) 2CH (CH 3)-or-S (O) 2C (CH 3) 2-.
In yet another aspect, X is-S (O) 2CH 2-.
In yet another aspect, X is-S (O) 2C (CH 3) 2-.
R 1
In one aspect of the invention, R 1Be to be selected from following group: C 1-4Alkyl, C 3-10Cycloalkyl, aryl, C 3-10Cycloalkyl C 1-4Alkyl, aryl C 1-4Alkyl, the assorted alkyl of ring, heteroaryl, the assorted alkyl C of ring 1-4Alkyl, heteroaryl C 1-4Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R 9,-OR 9,-COR 9,-CONR 9R 10,-NR 9R 10With-NR 9COR 10
In yet another aspect, R 1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R 9,-OR 9,-COR 9,-CONR 9R 10,-NR 9R 10With-NR 9COR 10
Further, R 1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH 3,-CONH 2With-CONHCH 3
In yet another aspect, R 1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH 2CH 2OH ,-,-CH 2CH 2NC (O) CH 3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl,, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.
In yet another aspect, R 1It is methyl.
X-R 1
In one embodiment, X-R 1Be-C (CH 3) 2OH or-CH 2OH.
In one embodiment, X-R 1Be-CH 2OH.
R 2
In one aspect of the invention, R 2Be selected from carbocyclic ring or heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In one aspect of the invention, R 2Be selected from carbocyclic ring or heterocyclic radical, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In one aspect of the invention, R 2Be selected from 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In one aspect of the invention, R 2Be selected from 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In one aspect of the invention, R 2Be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In one aspect of the invention, R 2Be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In yet another aspect, R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In yet another aspect, R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
In yet another aspect, R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH by one or more 2,-CONHCH 3With-CON (CH 3) 2
In yet another aspect, R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH by one or more 2,-CONHCH 3With-CON (CH 3) 2
In yet another aspect, R 2By-NR 17SO 2R 18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH 2,-CONHCH 3With-CON (CH 3) 2
In yet another aspect, R 2By-NHSO 2R 18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH 2,-CONHCH 3With-CON (CH 3) 2
In yet another aspect, R 2By-NHSO 2R 18Replace, also choose wantonly by one or more phenyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH 2,-CONHCH 3With-CON (CH 3) 2
In yet another aspect, R 2Be optional quilt-NR 17SO 2R 18The phenyl or the pyridyl that replace.
In yet another aspect, R 2Be optional quilt-NHSO 2R 18The phenyl or the pyridyl that replace.
In yet another aspect, R 2Be
A wherein 1And A 2Be selected from CH or N, condition is at least one A 1Or A 2Be CH.
In yet another aspect, R 2Be
Figure A20078003926600462
A wherein 1And A 2Be selected from CH or N, condition is at least one A 1Or A 2Be CH.
R 4
In one aspect of the invention, R 4Be hydrogen or methyl.
In yet another aspect, R 4Be hydrogen.
R 4 With R 1
In another aspect of the present invention, as X when being following :-NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-NR 4C (O)-,-NR 4C (O) NR 5-or-NR 4S (O) 2-, R 1And R 4The atom that is connected with them forms 5-to 10-unit heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In another aspect of the present invention, as X when being following :-NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-NR 4C (O)-,-NR 4C (O) NR 5-or-NR 4S (O) 2-, R 1And R 4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
R 5
In one aspect of the invention, R 5Be hydrogen or methyl.
In yet another aspect, R 5Be hydrogen.
In yet another aspect, R 5It is methyl.
R 6
In one aspect of the invention, R 6Be hydrogen or methyl.
In yet another aspect, R 6Be hydrogen.
In yet another aspect, R 6It is methyl.
R 7
In one aspect of the invention, R 7Be hydrogen or methyl.
In yet another aspect, R 7Be hydrogen.
In yet another aspect, R 7It is methyl.
R 8
In one aspect of the invention, R 8It is hydrogen or halogen.
In yet another aspect, R 8Be hydrogen or fluorine.
Further, R 8Be hydrogen.
R 9
In one aspect of the invention, R 9Be hydrogen or optional by 1,2 or 3 C that is selected from following substituted radical replacement 1-4Alkyl: halogen, cyano group, nitro, hydroxyl, C 1-4Alkoxyl group, amino, C 1-4Alkylamino and two (C 1-4Alkyl) amino.
In yet another aspect, R 9Be hydrogen or the optional C that is replaced by 1,2 or 3 halogenic substituent 1-4Alkyl.
Further, R 9Be hydrogen, methyl or trifluoromethyl.
R 10
In one aspect of the invention, R 10Be hydrogen.
R 11
In one aspect of the invention, R 11Be hydrogen or be selected from C 1-4The group of the assorted alkyl of alkyl, aryl and ring, this group is optional to be replaced by 1,2 or 3 group that is selected from halogen, hydroxyl and cyano group.
In yet another aspect, R 11Be hydrogen, optional by methyl, phenyl or the pyrrolidyl of hydroxyl or cyano group replacement.
In yet another aspect, R 11Be hydrogen or methyl.
R 12
In one aspect of the invention, R 12Be hydrogen or methyl.
R 17
In one aspect of the invention, R 17Be hydrogen or be selected from following group: C 1-4Alkyl, the assorted alkyl of aryl and ring, this group is optional to be selected from following group replacement by 1,2 or 3: halogen, hydroxyl and cyano group.
In yet another aspect, R 17Be hydrogen, optional by methyl, phenyl or the pyrrolidyl of hydroxyl or cyano group replacement.
In yet another aspect, R 17Be hydrogen or methyl.
In yet another aspect, R 17Be hydrogen.
R 18
In one aspect of the invention, R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In one aspect of the invention, R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, phenyl, naphthyl, pyrryl, imidazolyl , isoxazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, azepine (aza) indyl, indyl, quinolyl, benzimidazolyl-, benzofuryl, dibenzofuran group, benzothienyl, phenyl C 1-6Alkyl, naphthyl C 1-6Alkyl, pyrryl C 1-6Alkyl, imidazolyl C 1-6Alkyl , isoxazolyl C 1-6Alkyl, pyrazolyl C 1-6Alkyl, furyl C 1-6Alkyl, thienyl C 1-6Alkyl, pyridyl C 1-6Alkyl, pyrimidyl C 1-6Alkyl, pyridazinyl C 1-6Alkyl, azaindolyl C 1-6Alkyl, indyl C 1-6Alkyl, quinolyl C 1-6Alkyl, benzimidazolyl-C 1-6Alkyl, benzofuryl C 1-6Alkyl, dibenzofuran group C 1-6Alkyl, benzothienyl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In one aspect of the invention, R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In one aspect of the invention, R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH 2(cyclopropyl) ,-CH 2CH 2NMe 2,-CH (CH 3) CH 2OH ,-C (CH 3) 2CH 2OH ,-CH 2CH 2OH ,-CH 2CH 2CH 2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH 2(imidazoles-2-yl) ,-CH 2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl.
In one aspect of the invention, R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, butyl, cyclopropyl and 4-fluorophenyl.
Hypotype or its pharmacologically acceptable salt of formula (I) compound are provided in one aspect of the invention; M is 0,1 or 2;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-NR 4C (O)-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R 9,-OR 9,-COR 9,-CONR 9R 10,-NR 9R 10With-NR 9COR 10Or X-R 1Be-C (CH 3) 2OH or-CH 2OH;
R 2Be selected from aryl and heteroaryl, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
When existing, each R 3It is methyl;
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or, as X when being following :-NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4C (O)-or-NR 4S (O) 2-, R 1And R 4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino;
With
R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In another aspect of the present invention, provide hypotype or its pharmacologically acceptable salt of formula (I) compound; M is 0,1 or 2;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-NR 4CH 2-,-OCH 2-,-OCH (CH 3)-,-OC (CH 3) 2-,-SCH 2-,-SCH (CH 3)-,-SC (CH 3) 2-,-S (O) CH 2-,-S (O) CH (CH 3)-,-S (O) C (CH 3) 2-,-S (O) 2CH 2-,-S (O) 2CH (CH 3)-,-S (O) 2C (CH 3) 2-,-C (O) NR 4-and-NR 4C (O)-;
R 1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R 9,-OR 9,-COR 9,-CONR 9R 10,-NR 9R 10With-NR 9COR 10
Or X-R 1Be-C (CH 3) 2OH or-CH 2OH;
R 2Be selected from 5 or 6 yuan of aryl and heteroaryl, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
When existing, each R 3It is methyl;
R 4Be hydrogen or C 1-6Alkyl;
Or as X be-NR 4CH 2-or-NR 4C (O)-time, R 1And R 4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino;
R 11And R 12Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino; With
R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In another specific category of formula (I) compound or pharmaceutically acceptable salt thereof;
M is O or 1;
1Y is CH, Y 2Be N;
X is selected from following connection base :-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-;
R 1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH 3,-CONH 2With-CONHCH 3
Or-XR 1Be-C (CH 3) 2OH or-CH 2OH;
R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
When existing, R 3It is methyl;
R 11And R 12Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino; With
R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In the further specific category of formula (I) compound or pharmaceutically acceptable salt thereof;
M is 1;
X is selected from following connection base :-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-;
1Y is CH, Y 2Be N.
R 1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH 3,-CONH 2With-CONHCH 3
R 2By-NHSO 2R 18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH 2,-CONHCH 3With-CON (CH 3) 2
R 3It is methyl; With
R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In the further specific category of formula (I) compound or pharmaceutically acceptable salt thereof;
M is 1;
X is selected from following connection base :-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-;
1Y is CH, Y 2Be N.
R 1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH 2CH 2OH ,-CH 2CH 2NC (O) CH 3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base;
R 2Be
Figure A20078003926600561
Wherein: A 1And A 2Be selected from CH or N, condition is at least one A 1Or A 2Be CH;
R 17Be hydrogen;
R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH 2(cyclopropyl) ,-CH 2CH 2NMe 2,-CH (CH 3) CH 2OH ,-C (CH 3) 2CH 2OH ,-CH 2CH 2OH ,-CH 2CH 2CH 2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH 2(imidazoles-2-yl) ,-CH 2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl;
With, R 3It is methyl.
In one aspect of the invention, the formula (Ia) or (Ib) hypotype of compound are provided
Figure A20078003926600562
Or its pharmacologically acceptable salt;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-NR 4C (O)-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: C 1-6Alkyl, carbocyclic ring, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R 9,-OR 9,-COR 9,-CONR 9R 10,-NR 9R 10And-NR 9COR 10Or X-R 1Be-C (CH 3) 2OH or-CH 2OH;
R 2Be selected from aryl and heteroaryl, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
R 3It is methyl;
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or, as X when being following :-NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4C (O)-or-NR 4S (O) 2-, R 1And R 4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino;
With
R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In another aspect of the present invention, the formula (Ia) or (Ib) hypotype of compound are provided
Or its pharmacologically acceptable salt;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be N, another is CR 8
X is selected from following connection base :-NR 4CH 2-,-OCH 2-,-OCH (CH 3)-,-OC (CH 3) 2-,-SCH 2-,-SCH (CH 3)-,-SC (CH 3) 2-,-S (O) CH 2-,-S (O) CH (CH 3)-,-S (O) C (CH 3) 2-,-S (O) 2CH 2-,-S (O) 2CH (CH 3)-,-S (O) 2C (CH 3) 2-,-C (O) NR 4-and-NR 4C (O)-;
R 1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R 9,-OR 9,-COR 9,-CONR 9R 10,-NR 9R 10With-NR 9COR 10
Or X-R 1Be-C (CH 3) 2OH or-CH 2OH;
R 2Be selected from 5 or 6 yuan of aryl and heteroaryl, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
R 3It is methyl;
R 4Be hydrogen or C 1-6Alkyl;
Or as X be-NR 4CH 2-or-NR 4C (O)-time, R 1And R 4The atom that is connected with them forms 5-or 6-unit heterocycle, and wherein 1 ring carbon atom is optional is replaced by N or O, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino;
R 11And R 12Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino; With
R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In formula (Ia) or (Ib) in another specific category of compound or pharmaceutically acceptable salt thereof;
1Y is CH, Y 2Be N;
X is selected from following connection base :-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-;
R 1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH 3,-CONH 2With-CONHCH 3
Or-XR 1Be-C (CH 3) 2OH or-CH 2OH;
R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHSO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
R 3It is methyl;
R 11And R 12Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocyclic ring and heterocyclic radical, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino and two (C 1-6Alkyl) amino; With
R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In formula (Ia) or (Ib) in the further specific category of compound or pharmaceutically acceptable salt thereof;
Figure A20078003926600611
X is selected from following connection base :-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-;
1Y is CH, and Y 2Be N.
R 1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH 3,-CONH 2With-CONHCH 3
R 2By-NHSO 2R 18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH 2,-CONHCH 3With-CON (CH 3) 2
R 3It is methyl; With
R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
In formula (Ia) or (Ib) in the further specific category of compound or pharmaceutically acceptable salt thereof;
Figure A20078003926600621
M is 1;
X is selected from following connection base :-S (O) 2CH 2-,-S (O) 2CH (CH 3)-and-S (O) 2C (CH 3) 2-;
1Y is CH, Y 2Be N.
R 1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH 2CH 2OH ,-CH 2CH 2NC (O) CH 3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base,, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base;
R 2Be
Figure A20078003926600631
A wherein 1And A 2Be selected from CH or N, condition is at least one A 1Or A 2Be CH;
R 17Be hydrogen; With
R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH 2(cyclopropyl) ,-CH 2CH 2NMe 2,-CH (CH 3) CH 2OH ,-C (CH 3) 2CH 2OH ,-CH 2CH 2OH ,-CH 2CH 2CH 2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH 2(imidazoles-2-yl) ,-CH 2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl;
With, R 3It is methyl.
Another aspect of the present invention provides each a kind of compound or combination of compounds or its pharmacologically acceptable salt that is selected from embodiment.
The present invention also provides the method for preparation formula (I) compound or pharmaceutically acceptable salt thereof.
The compound of formula (I), wherein X=-S (O) 2CR 6R 7-, can be prepared as follows: at room temperature, in water and ethanol mixed solvent system, (for example) uses
Figure A20078003926600632
With the compound oxidation of formula (I), wherein X=SCR 6R 7-.
Figure A20078003926600641
The compound of formula (I), wherein R 1X=R 1OCR 6R 7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (I) (R wherein 1X=HOCR 6R 7-) with the compound of formula (II) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react.
Figure A20078003926600642
The compound of formula (I), wherein R 1X=R 1R 4NCR 6R 7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (I) (R wherein 1X=HR 4NCR 6R 7-) with the compound of formula (II) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react; Or, at suitable reductive agent NaCNBH for example 3Existence under, the compound of formula (I) (R wherein 1X=HR 4NCR 6R 7-) react with the compound of formula (III).
Figure A20078003926600643
The compound of formula (I), wherein X 1-S (O) 2CR 6R 7-,-SCR 6R 7-,-OCR 6R 7-,-R 4NCR 6R 7-,-S (O) CR 6R 7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (IV) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with the compound of formula V.
Figure A20078003926600651
The compound of formula (I), wherein X 1=-SCR 6R 7-, can be prepared as follows: at suitable solvent for example in the ethanol, the compound of formula (IV) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with thiocarbamide; the compound of production (VI); then; at appropriate base sodium hydroxide and solvent N for example for example; under the existence of dinethylformamide, the compound of formula (VI) and the compound of formula (II) are reacted.
Figure A20078003926600652
The compound of formula (I), wherein X=-R 4NC (O)-, can be prepared as follows: the compound of formula (VII) and formula R 1R 4The amine of NH reacts, and with known method in the document, for example uses for example HATU of coupler, or is converted into chloride of acid before this reaction, and carboxylic acid is suitably activated.
Figure A20078003926600653
The compound of formula (I), wherein X=-S (O) 2CR 6R 7-, can be prepared as follows: appropriate base for example sodium hydride or potassium tert.-butoxide in the presence of, at suitable solvent for example tetrahydrofuran (THF) or N, in the dinethylformamide, the compound of formula (I) (X=-S (O) wherein 2CH 2-) continuously the compound with formula (VIII) react, then with the compound of formula (IX) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) reaction.
Figure A20078003926600661
The compound of formula (I), wherein R 1X=HOCR 6R 7-, can be prepared as follows: in suitable solvent, the suitable organometallic compound of the compound of formula (X) and formula (XI) and formula (XII) for example Grignard reagent reacts.If R 6And R 7Be different, in step subsequently, can use known technology in the document so, for example the compound of formula (X) is converted into the Weinreb acid amides, and with the reaction of the organometallic reagent of formula (XI), then with the organometallic reagent reaction of formula (XII).
Figure A20078003926600662
The compound of formula (I) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XIII) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)) with suitable organometallic reagent (boric acid R for example 2B (OH) 2Or boric acid ester R 2B (OR) 2Or the like) prepare.Perhaps, if R 2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (I) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XIII) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)), by reacting with required amine, alcohol or mercaptan.
Figure A20078003926600663
Should be understood that utilize above-listed or document in for example oxidation of known technology, alkylation, reduction amination or the like, the compound of formula (XIII) can be transformed into the compound of another formula (XIII).
The compound of formula (XIII), wherein X 1=-S (O) 2CR 6R 7-,-SCR 6R 7-,-OCR 6R 7-,-R 4NCR 6R 7-,-S (O) CR 6R 7-, can be prepared as follows: choose wantonly at appropriate base for example tetrahydrofuran (THF) or N of triethylamine and solvent for example, under the existence of dinethylformamide, the compound of formula (XIV) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with the compound of formula V.
Figure A20078003926600671
The compound of formula (XIII), wherein X 1=-SCR 6R 7-, can be prepared as follows: at suitable solvent for example in the ethanol, the compound of formula (XIV) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) react with thiocarbamide; the compound of production (XV); then; at appropriate base sodium hydroxide and solvent N for example for example; under the existence of dinethylformamide, the compound of formula (XV) and the compound of formula (II) are reacted.
Figure A20078003926600672
The compound of formula (XIII), wherein X-R 4NC (O)-, can be prepared as follows: the compound of formula (XVI) and formula R 1R 4The amine of NH reacts, and with known method in the document, for example uses for example HATU of coupler, or is converted into chloride of acid before this reaction, and carboxylic acid is suitably activated.
The compound of formula (XIII), wherein X=-S (O) 2CR 6R 7-, can be prepared as follows: appropriate base for example sodium hydride or potassium tert.-butoxide in the presence of, at suitable solvent for example tetrahydrofuran (THF) or N, in the dinethylformamide, the compound of formula (XIII) (X=-S (O) wherein 2CH 2-) continuously and the compound of formula (VIII) react, then with the compound of formula (IX) (L wherein 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) reaction.
Figure A20078003926600681
The compound of formula (XIII), wherein R 1X=HOCR 6R 7-, can be prepared as follows: in suitable solvent, the suitable organometallic compound of the compound of formula (XVII) and formula (XI) and formula (XII) for example Grignard reagent reacts.If R 6And R 7Be different, in step subsequently, can use known technology in the document so, for example the compound of formula (XVII) is converted into the Weinreb acid amides, and with the reaction of the organometallic reagent of formula (XI), then with the organometallic reagent reaction of formula (XII).
The compound of formula (IV) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XIV) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like), L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like)) with suitable organometallic reagent (boric acid R for example 2B (OH) 2Or boron ester R 2B (OR) 2Or the like) prepare.Perhaps, if R 2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (IV) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XIV) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)), by reacting with required amine, alcohol or mercaptan.
Figure A20078003926600691
The compound of formula (X) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XVII) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like), R is hydrogen or C 1-4Alkyl) with suitable organometallic reagent (boric acid R for example 2B (OH) 2Or boron ester R 2B (OR) 2Or the like) prepare.Perhaps, if R 2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (X) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XVII) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)), by reacting with required amine, alcohol or mercaptan.
Figure A20078003926600692
The compound of formula (XVIII) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XIX) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)) with suitable organometallic reagent (boric acid R for example 2B (OH) 2Or boron ester R 2B (OR) 2Or the like) prepare.Perhaps, if R 2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (XVIII) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XIX) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)), by reacting with required amine, alcohol or mercaptan.
Figure A20078003926600701
The compound of formula (XX) can be prepared as follows: in the presence of suitable metal catalyzer (for example palladium or copper), at suitable solvent for example 1, in the 4-diox, with the compound of formula (XXI) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)) with suitable organometallic reagent (boric acid R for example 2B (OH) 2Or boron ester R 2B (OR) 2Or the like) prepare.Perhaps, if R 2Be connected with pyrimidine ring by nitrogen, oxygen or sulphur atom, formula (XX) compound can be prepared as follows: appropriate base for example salt of wormwood in the presence of, at suitable solvent N for example, in the dinethylformamide, by the compound of formula (XXI) (L wherein 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like)), by reacting with required amine, alcohol or mercaptan.
Figure A20078003926600702
The compound of formula (I), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like); can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of; at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXII) and formula (XXIII) reacts.
Figure A20078003926600703
Should be understood that utilize above-listed or document in for example oxidation of known technology, alkylation, reduction amination or the like, the compound of formula (XXII) can be become the compound of another formula (XXII).
The compound of formula (IV), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like); can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of; at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXIV) and formula (XXIII) reacts.
Figure A20078003926600711
The compound of formula (X), wherein L 1Be that leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like) and R are hydrogen or C 1-4Alkyl can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXV) and formula (XXIII) reacts.
Figure A20078003926600712
The compound of formula (XVIII), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like); can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of; at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXVI) and formula (XXIII) reacts.
Figure A20078003926600713
The compound of formula (XX), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXVII) and formula (XXIII) reacts.
Figure A20078003926600721
The compound of formula (XIII), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXVIII) and formula (XXIII) reacts.
Figure A20078003926600722
Should be understood that utilize above-listed or document in for example oxidation of known technology, alkylation, reduction amination or the like, the compound of formula (XIII) can be transformed into the compound of another formula (XIII).
The compound of formula (XIV), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXIX) and formula (XXIII) reacts.
The compound of formula (XVII), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like) and R be hydrogen or C 1-4Alkyl can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXX) and formula (XXIII) reacts.
Figure A20078003926600732
The compound of formula (XIX), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXXI) and formula (XXIII) reacts.
Figure A20078003926600733
The compound of formula (XXI), wherein L 1Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl or the like), and L 2Be leavings group (for example halogen, tolylsulfonyl, methylsulfonyl ,-SMe ,-S (O) 2Me or the like), can be prepared as follows: choose wantonly appropriate base for example triethylamine in the presence of, at suitable solvent N for example, in the dinethylformamide, the compound of the compound of formula (XXXII) and formula (XXIII) reacts.
Figure A20078003926600741
The compound of formula (I), wherein R 1X=H 2NCH 2-, can be prepared as follows: at suitable solvent for example in the ethanol, with hydrogen and suitable catalyst for example palladium/carbon with the compound reduction of formula (XVIII), for example hydrogenation.
Figure A20078003926600742
The compound of formula (I), wherein R 1X=H 2NC (O)-, can be prepared as follows: at suitable solvent for example in the water-ethanol admixture, with sodium hydroxide for example with the compound hydrolysis of formula (XVIII).
Figure A20078003926600743
The compound of formula (I), wherein R 1X=H 2NCR 6R 7-, can be prepared as follows: react by the compound of formula (XVIII) and organometallic compound (XI) with (XII).
The compound of formula (XIII), wherein R 1X=H 2NCH 2-, can be prepared as follows: at suitable solvent for example in the ethanol, with hydrogen and suitable catalyst for example palladium/carbon with the compound reduction of formula (XIX), for example hydrogenation.
Figure A20078003926600751
The compound of formula (XIII), wherein R 1X=H 2NC (O)-, can be prepared as follows: at suitable solvent for example in the water-ethanol admixture, with sodium hydroxide for example with the compound hydrolysis of formula (XIX).
Figure A20078003926600752
The compound of formula (XIII), wherein R 1X=H 2NCR 6R 7-, can be prepared as follows: the compound of formula (XIX) and organometallic compound (XI) and (XII) react.
Should be understood that R 2Group can (be chosen wantonly and protect with nitrogen with the form of carbocyclic ring or heterocyclic amine at first; this protecting group is including, but not limited to nitro, tert.-butoxy carbamate or the like) introduce in any stage; in the presence of appropriate base; by reacting with SULPHURYL CHLORIDE (or other suitable activation species); or utilizing that known other forms the method for sulphonamide in the document, it can be converted into sulphonamide at synthetic follow-up phase (after the suitable deprotection).
Should be understood that some the various ring substituents in The compounds of this invention, can introduce or produce that immediately, this is included in the method for the present invention aspect before or after said process by the substitution reaction of standard aromatics by conventional modified with functional group.For example, utilize the substitution reaction of standard aromatics or pass through conventional modified with functional group, the compound of formula (I) can change other formula (I) compound into.This reaction and modification comprise: for example, introduce substituting group by means of aromatics substitution reaction, substituent reduction, substituent alkylation and substituent oxidation.The reagent of this method and reaction conditions are well-known at chemical field.The object lesson of aromatics substitution reaction comprises: use concentrated nitric acid to introduce nitro, under the Friedel processing condition, use for example acyl halide and Lewis acid (for example aluminum chloride) introducing acyl group; Under the Friedel processing condition, use haloalkane and Lewis acid (for example aluminum chloride) to introduce alkyl; With the introducing halogen group.The object lesson of modifying comprises: handling (in the presence of hydrochloric acid, heating) by for example catalytic hydrogenation (using nickel catalyzator) or with iron, is amino with nitroreduction; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.
Should also be understood that in some reactions that this paper mentions, may need/wish any sensitive group in the protection compound.The situation that needs or wish to protect and the appropriate method of protection are known to those skilled in the art.Can use GPF (General Protection False base (explanation for example,, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991) according to standard practices referring to T.W.Green.Thus, if reactant comprises group for example amino, carboxyl or hydroxyl, may in some reactions that this paper mentions, protect this group.
The appropriate protection base of amino or alkylamino is an acyl group for example, alkyloyl ethanoyl for example for example, carbalkoxy, for example methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyl, aryl methoxycarbonyl, for example carbobenzoxy-(Cbz), or aroyl, for example benzoyl.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Thus, for example, acyl group is alkyloyl or carbalkoxy or aroyl for example, can be for example by with appropriate base for example alkali metal hydroxide for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps; acyl group is tertbutyloxycarbonyl for example; can for example remove by handling with appropriate acid (for example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid); for aryl methoxycarbonyl carbobenzoxy-(Cbz) for example, can be for example by with catalyzer for example carbon carry palladium hydrogenation or by with Lewis acid for example three (trifluoroacetic acid) boron handle and remove.For the suitable possible protecting group of primary amino is phthaloyl for example, and it can be by with alkylamine dimethylamino propylamine or handle with hydrazine and to remove for example.
The appropriate protection base of hydroxyl is an acyl group for example, alkyloyl ethanoyl for example for example, and aroyl is benzoyl for example, or arylmethyl benzyl for example.The deprotection condition of above-mentioned protecting group must change with the selection of protecting group.Thus, for example, acyl group is alkyloyl or aroyl for example, can be for example by with appropriate base for example alkali metal hydroxide for example lithium hydroxide or sodium hydroxide hydrolysis are removed.Perhaps, for arylmethyl benzyl for example, can be for example by with catalyzer for example carbon carry palladium hydrogenation and remove.
The appropriate protection base of carboxyl is an esterified group for example; for example methyl or ethyl; its can be for example by with alkali for example sodium hydroxide hydrolysis remove; or the tertiary butyl for example; its can be for example by with acid for example organic acid for example trifluoroacetic acid handle and remove; or benzyl for example, its can be for example by with catalyzer for example carbon carry palladium hydrogenation and remove.
In the traditional method of using chemical field to know synthetic, can be in office what easily step remove protecting group.
Many intermediates defined herein are new, and provide these intermediates as further feature of the present invention.
Biological test
Following test can be used for measuring The compounds of this invention as the mTOR kinase inhibitor, as the PI3 kinase inhibitor, as the activatory vitro inhibition agent of PI3 kinase signal path with as the effect of the vitro inhibition agent of MDA-MB-468 human breast adenocarcinoma cell propagation.
(a) External mTOR kinase assay
This test use the AlphaScreen technology (people such as Gray, Analytical Biochemistry, 2003,313:234-245), the determination test compound suppresses the ability by recombinant chou mTOR phosphorylation.
In the HEK293 cell, the C end disappearance (EMBL accession designation number L34075) that will comprise the mTOR of mTOR amino-acid residue 1362 to 2549 stably is expressed as the fusions of FLAG mark, as people such as Vilella-Bach, at Journal of Biochemistry, 1999,274, as described in the 4266-4272.MTOR (1362-2549) stabilized cell of HEK293 FLAG mark is tied up to Dulbecco modification Eagle ' s growth medium (DMEM; InvitrogenLimited, Paisley, UK Catalogue No.41966-029) in use 5%CO 237 ℃ of conventional down maintenances, merge until reaching 70-90%, growth medium comprises the fetus calf serum (FCS of 10% heat inactivation; Sigma, Poole, Dorset, UK, Catalogue No.F0392), 1%L-glutamine (Gibco, Catalogue No.25030-024) and 2mg/mlGeneticin (G418 vitriol; Invitrogen Limited, UK Catalogue No.10131-027).After in warm-blooded animal HEK293 clone, expressing, use FLAG epi-position mark to come purifying expressed proteins (using the standard purification technology).
In DMSO, test compound is prepared as the 10mM stock solution, and is diluted to as required in the water, obtain a series of final experimental concentration.Each diluted chemical compound thing of equal portions (2 μ l) is put into the hole of the Greiner white polystyrene plates of 384 hole lower volume (LV) (Greiner Bio-one).Biotinylated peptide matrix (the Biotin-Ahx-Lys-Lys-Ala-Asn-Gln-Val-Phe-Leu-Gly-Phe-Thr-T yr-Val-Ala-Pro-Ser-Val-Leu-Glu-Ser-Val-Lys-Glu-NH of mTOR enzyme, 1 μ M with the recombinant chou purifying 2Bachem UK Ltd), ATP (20 μ M) and buffering solution [comprise Tris-HCl pH7.4 damping fluid (50mM), EGTA (0.1mM), bovine serum albumin (0.5mg/mL), DTT (1.25mM) and Manganous chloride tetrahydrate (10mM)] 30 μ l mixtures at room temperature stirred 90 minutes.
Use 5%DMSO to replace test compound, create the control wells that produces peak signal (being equivalent to maximum enzyme activity).Replace test compound by adding EDTA (83mM), create the control wells that produces minimum signal (enzyme that is equivalent to suppress fully).At room temperature, these testing liquids were cultivated 2 hours.
By adding 10 μ l EDTA (50mM), bovine serum albumin (BSA; 0.5mg/mL) and Tris-HCl pH7.4 damping fluid (50mM) (comprise p70 S6 kinases (T389) 1A5 monoclonal antibody (Cell Signalling Technology, Catalogue No.9206B) and the AlphaScreenStreptavidin donor) mixture stop each reaction, add A protein receptor bead (200ng; Perkin Elmer, Catalogue No. is respectively 6760002B and 6760137R), at room temperature, in the dark will test plate and place about 20 hours.Use Packard Envision instrument, read the signal (producing by laser excitation) that obtains at 680nm.
Because the phosphorylation of mTOR mediation, original position has formed the biotinylation peptide of phosphorylation.The biotinylation peptide of the phosphorylation relevant with AlphaScreen Streptavidin donor bead forms mixture with p70S6 kinases (T389) 1A5 monoclonal antibody (it is relevant with Alphascreen albumin A acceptor bead).In case in 680nm laser excitation, the donor bead: acceptor bead mixture just produces the signal that can measure.Correspondingly, the existence of mTOR kinase activity can produce test signal.In the presence of the mTOR kinase inhibitor, strength of signal reduces.
For the test compound that is given, the mTOR enzyme suppresses can be with IC 50Value representation.
(b) External PI3K enzyme test
This test use the AlphaScreen technology (people such as Gray, Analytical Biochemistry, 2003,313:234-245), suppress the ability of the recombinant type I PI3K enzyme phosphorylation of lipid PI (4,5) P2 with the determination test compound.
Use standard molecular biology and PCR clone technology, separate the dna fragmentation of coding people's PI3K catalysis and regulator subunit from the cDNA storehouse.Selected dna fragmentation is used to produce rhabdovirus expression vector.Especially, with the full length DNA subclone of the human PI3K p110 heterogeneous of each p110 α, p110 β and p110 δ type Ia (the EMBLAccession Nos. for p110 α, p110 β and p110 δ is respectively HSU79143, S67334, Y10055) to pDEST10 carrier (Invitrogen Limited, Fountain Drive, Paisley, UK) in.Carrier is the inlet adaptive version that comprises the Fastbac1 of 6-His epi-position mark.With the intercepting form (being equivalent to amino-acid residue 144-1102 (EMBL Accession No.X8336A)) of the human PI3K p110 of Ib class γ heterogeneous and total length mankind's p85 α regulator subunits (EMBL Accession No.HSP13KIN) also subclone in the pFastBac1 carrier that comprises 6-His epi-position mark.With p85 α regulator subunit co expression type i a p110 structure.After use standard baculovirus expression technology is expressed, use the standard purification technology in rhabdovirus system, use His epi-position mark, the expressed proteins purifying.
Use standard molecular biology and PCR clone technology, from cDNA storehouse DNA isolation (it is equivalent to the amino acid 263 to 380 of the general acceptor in human phosphatase inositol (Grp1) PH zone).The dna fragmentation subclone that obtains (is comprised GST epi-position mark (Amersham Pharmacia Biotech, Rainham, Essex to pGEX 4T1 coli expression carrier, UK)) in, as people such as Gray, at Analytical Biochemistry, 2003, described in the 313:234-245.Express the Grp1 PH zone of GST mark, and use the standard technique purifying.
In DMSO, test compound is prepared as the 10mM stock solution, and is diluted to as required in the water, obtain a series of final experimental concentration.Each diluted chemical compound thing of equal portions (2 μ l) is put into white polystyrene plate (the Greiner Bio-one of Greiner 384 hole lower volume (LV), Brunel Way, Stonehouse, Gloucestershire, UK Catalogue No.784075) the hole in.PI3K enzyme (15ng), DiC8-PI (4,5) P2 matrix (40 μ M with each selected recombinant chou purifying; Cell Signals Inc., Kinnear Road, Columbus, USA, CatalogueNo.901), Adenosine Triphosphate (ATP; 4 μ M) and buffering solution [comprise Tris-HCl pH7.6 damping fluid (40mM, 10 μ l), 3-[(3-courage amido propyl) dimethylamino]-1-propanesulfonic acid inner salt (CHAPS; 0.04%) dithiothreitol (DTT) (DTT; 2mM) and magnesium chloride (10mM)] mixture at room temperature stirred 20 minutes.
Use 5%DMSO to replace test compound, create the control wells that produces minimum signal (being equivalent to maximum enzyme activity).Add wortmannin (6uM; Calbiochem/MerckBioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No.681675) replace test compound, establishment can produce the control wells of peak signal (enzyme that is equivalent to suppress fully).At room temperature, also these testing liquids were stirred the companion 20 minutes.
Stop each reaction by the mixture that adds 10 μ l EDTA (100mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl pH7.6 damping fluid (40mM).
Add biotinylated-DiC8-PI (3,4,5) P3 (50nM; Cell Signals Inc., Catalogue No.107), GST-Grp1 PH albumen (2.5nM) and the anti-GST donor of AlphaScreen and the acceptor bead (100ng of recombinant chou purifying; Packard BioscienceLimited, Station Road, Pangbourne, Berkshire, UK, Catalogue No.6760603M), at room temperature, in the dark will test plate and place about 5 to 20 hours.Use Packard AlphaQuest instrument, read the signal (causing by laser excitation) that obtains at 680nm.
Because the phosphorylation of the PI3K of PI (4,5) P2 mediation, original position forms PI (3,4,5) P3.GST-Grp1 PH region protein (it is relevant with the anti-GST donor of AlphaScreen bead) forms mixture with biotinylated PI (3,4,5) P3 (it is relevant with Alphascreen Streptavidn acceptor bead).Enzyme living PI (3,4,5) P3 and biotinylated PI (3,4,5) the P3 competition of hastening parturition combines with the PH region protein.In case in 680nm laser excitation, the donor bead: acceptor bead mixture produces the signal that can measure.Correspondingly, the PI3K enzymic activity forms PI (3,4,5) P3 and competes with biotinylated PI (3,4,5) P3 subsequently, causes signal to reduce.In the presence of the PI3K enzyme inhibitors, strength of signal is recovered.
For the test compound that is given, the PI3K enzyme suppresses with IC 50Value representation.
(c) External phosphate-Ser473 Akt test
This test determination test compound suppresses Serine 473 suppresses phosphorylation in Akt ability, uses Acumen Explorer technology (Acumen Bioscience Limited), plate reader (feature that can be used for rapid determination image that laser scanning produces) to estimate.
In DMEM (FCS and the 1%L-glutamine that comprise 10% heat inactivation), (LGC Promochem, Teddington, Middlesex, UK, Catalogue No.HTB-132) uses 5%CO with MDA-MB-468 human breast gland cell system 2Routine remains on 37 ℃, until the fusion that reaches 70-90%.
For this test, use ' Accutase ' (Innovative Cell Technologies Inc., San Diego, CA, USA; Catalogue No.AT104), uses the normal structure culture method, cell is shifted out from culturing bottle, and be resuspended in the medium, obtain every mL 1.7x10 5Individual cell.Aliquot sample (90 μ l) is seeded into black Packard 96 hole plate (PerkinElmer, Boston, MA, USA; Catalogue No.6005182) in inner 60 holes of each, obtains the density of every hole~15000 cell.Equal portions (90 μ l) substratum medium is placed in the external holes, to prevent fringing effect.With cell 5%CO 237 ℃ of following overnight incubation, make them bonding.
At the 2nd day, handle cell with test compound, and use 5% CO 2Cultivated 2 hours down at 37 ℃.In DMSO, test compound is prepared as the 10mM stock solution, and uses the growth medium serial dilution as required, obtain a series of concentration (its be required final experimental concentration 10 times).Each diluted chemical compound thing of equal portions (10 μ l) is placed on (in triplicate) in the hole, obtains the concentration of ultimate demand.As minimum response contrast, each plate comprises the have 100 μ MLY294002 hole of final concn of (Calbiochem, Beeston, UK, Catalogue No.440202).As the peak response contrast, the hole comprises 1% DMSO and replaces test compound.After the cultivation, handled 1 hour, the inclusion of plate is fixed by at room temperature using 1.6% formalin (Sigma, Poole, Dorset, UK, Catalogue No.F1635).
Use Tecan 96 holes to wash dish device (pumping velocity 10mm/sec), carry out all suction and washing steps subsequently.Remove stationary liquid, with phosphate-buffered saline (PBS; 50 μ l; Gibco, Catalogue No.10010015) inclusion of washing plate.At room temperature, with the cell permeabilization damping fluid (mixture that comprises PBS and 0.5%Tween-20) of equal portions (50 μ l) inclusion of plate was handled 10 minutes.Remove ' saturatingization ' damping fluid, at room temperature, in the mixture of PBS and 0.05%Tween-20, with comprising 5% skim-milk [' Marvel ' (registered trademark); Premier Beverages, Stafford, GB] equal portions (50 μ l) sealing damping fluid handled 1 hour, with nonspecific binding site sealing.Remove ' sealing ' damping fluid, and at room temperature with the anti-phosphate-Akt of rabbit (Ser473) antibody-solutions (every hole 50 μ l; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) (diluting 1: 500 in ' sealing ' damping fluid) with cell cultures 1 hour.Washed cell is three times in the mixture of PBS and 0.05%Tween-20.Subsequently, at room temperature, with the anti-rabbit igg of Alexafluor488 labelled goat (every hole 50 μ l; Molecular Probes Invitrogen Limited, Paisley, UK, Catalogue No.A11008) (being diluted to 1: 500 in ' sealing ' damping fluid) with cell cultures l hour.With the mixture washed cell of PBS and 0.05%Tween-20 3 times.The PBS (50 μ l) of equal portions is joined in each hole, seal plate with black plate sealer, and detection and analysis of fluorescence signal.
The fluorescent agent quantitative response data that each compound obtains are analyzed, and the inhibition kilsyth basalt of Serine 473 that will be in Akt is shown IC 50Value.
(d) External MDA-MB-468 human breast gland cancer proliferation test
This test determination test compound suppresses the ability of cell proliferation, uses the CellomicsArrayscan technology to estimate.According to the conventional MDA-MB-468 human breast gland cell system (LGC Promochem, Catalogue No.HTB-132) that keeps that comes described in this paper biology mensuration (b).
For this proliferation test, to use Accutase that cell is removed from culturing bottle, and be seeded in 60 holes, inside of black Packard 96 hole plates, density is 8000 cells in every hole, in the complete growth medium of 100 μ l.External holes comprises the aseptic PBS of 100 μ l.With cell 5%CO 237 ℃ of following overnight incubation, make them bonding.
At the 2nd day, handle cell with test compound, and use 5%CO 2Cultivated 48 hours down at 37 ℃.In DMSO, test compound is prepared as the 10mM stock solution, and uses the growth medium serial dilution as required, obtain a series of experimental concentration.Each diluted chemical compound thing of equal portions (50 μ l) is placed in the hole, uses 5%CO 2Cultivated 2 days down at 37 ℃.Each plate comprises the control wells of no test compound.
At the 4th day, add the reagent (Sigma, Catalogue No.B9285) (finally diluting 1: 1000) of BrdU mark, 37 ℃ of culturing cells 2 hours.Remove medium,, handled 30 minutes with the mixture (90% ethanol, 5% Glacial acetic acid and 5% water) of 100 μ l ethanol and Glacial acetic acid, the cell fixation in each hole by at room temperature.Wash twice in cell in each hole with PBS (100 μ l).(2M, 100 μ l) join in each hole with aqueous hydrochloric acid.After at room temperature 20 minutes, use twice of PBS washed cell.With hydrogen peroxide (3%, 50 μ l; Sigma CatalogueNo.H1009) joins in each hole.After at room temperature 10 minutes, with PBS washing hole once more.
By at room temperature using mouse anti BrdU antibody (50 μ l; Caltag, Burlingame, CA, US; Catalogue No.MD5200) (in the PBS that comprises 1%BSA and 0.05%Tween-20, is diluted to 1: 40) and cultivates the combination that detected BrdU in 1 hour.Remove unconjugated antibody with the PBS washed twice.Visual for introducing BrdU at room temperature, handled cell 1 hour with PBS (50 μ l) and 0.05% Tween-20 damping fluid (1: 1000 dilution that comprises the anti-mouse IgG of Alexa fluor 488 labelled goat).For nuclear visual, and 1: 1000 dilution of adding Hoechst pigment (stain) (Molecular Probes, CatalogueNo.H3570).Each plate is washed with PBS successively.Subsequently, PBS (100 μ l) is joined in each hole, use the Cellomics matrix-scanning to analyze plate, thereby estimate the number of total cell number and BrdU positive cell.
The fluorescent agent quantitative response data that each compound obtains are analyzed, and with the inhibition degree of MDA-MB-468 cell growth with IC 50Value representation.
Although the pharmacology performance of formula (I) compound resemble expectation change with structural modification, people believe usually formula (I) activity that compound had can one or more above-mentioned tests (a) in (d), under following concentration or dosage, obtain the proof :-
Test (a) :-for chemical compound lot, for the kinase whose IC of mTOR 50Value especially less than 5 μ M, for embodiment 4, is measured IC less than 10 μ M under three situations 50Value, value is 3.32,2.49 and 2.25 μ M;
Test (b) :-for the IC of the human PI3K of p110 γ Ib class 50Value is less than 10 μ M; IC for the human PI3K of p110 α type i a 50Value is less than 10 μ M; For embodiment 4, under three situations, measure IC 50Value, value>134,54,>698 μ M, show that this compound may be a mTOR inhibitor optionally;
Test (c) :-for chemical compound lot, for the IC of the Serine among the Akt 473 50Value especially less than 35 μ M, for embodiment 4, is measured IC less than 100 μ M under three situations 50The value, value be 11.29,24.05 and>31.88 μ M;
Test (d) :-IC 50Value is less than 20 μ M;
Compound of the present invention is favourable, because they have pharmacological activity.Especially, The compounds of this invention is regulated (especially suppressing) mTOR kinases and/or phosphatidylinositol-3-kinase (PI3K) enzyme, for example Ia class PI3K enzyme (for example PI3K α, PI3K β and PI3K δ) and Ib class PI3K enzyme (PI3K γ).More particularly, compound adjusting of the present invention (especially suppressing) mTOR kinases.More particularly, one or more PI3K enzyme of compound adjusting of the present invention (especially suppressing).The rejection that can use test method that this paper lists and the test method in the experimental section to come proof formula (I) compound.Correspondingly, formula (I) compound can be used for handling the condition/disease of (treatment or prevention) people and inhuman animal, and this condition/disease is by mTOR kinases and/or the mediation of one or more PI3K enzymes, and is especially kinase mediated by mTOR.
The present invention also provides pharmaceutical composition, and it comprises combining of formula defined herein (I) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable diluent or carrier.
Composition of the present invention can also be the form that is suitable for an orally using (tablet for example, lozenge, hard or soft capsule, moisture or oily suspensions, emulsion, dispersible powder or particle, slurries or elixir), local type of service (emulsifiable paste for example, ointment, gelifying agent or moisture or oily solution or suspension), inhalation form (for example finely divided powder or liquid aerosol), be blown into form of medication (for example finely divided powder) or administered parenterally form (intravenously for example, subcutaneous, the aseptic aqueous solution of intraperitoneal or intramuscularly or oily solution, or be used for the suppository of rectal administration).
Can utilize conventional pharmaceutical vehicle well known in the art, obtain composition of the present invention by ordinary method.Thus, the composition for oral design can comprise for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.
Can need to change with the amount of active ingredients that produces single formulation with one or more mixed with excipients, this depends on the host and the concrete mode of administration of being treated.For example, it (more suitably is 1 to 250mg that the preparation that designs for human oral for example comprises the promoting agent of 1mg to 1g usually, for example 1 to 100mg), promoting agent and suitable and make things convenient for the vehicle of quantity to be mixed, vehicle can be total composition weight about 5 to about 98% between change.
According to character and severity, animal or patient's age and the sex and the route of administration of morbid state,, be used for the treatment of or prevent the amount nature difference of the formula I compound of purpose according to well-known medical principle.
In the process of formula (I) compound that uses treatment or prevention purpose, give per daily dose usually, scope is for example to accept 1mg/kg to 100mg/kg body weight, if necessary, with the separate dosage forms administration.Usually, when using parenteral route, give low dosage.Thus, for example, for intravenous administration, normally used dosage range is 1mg/kg to a 25mg/kg body weight for example.Equally, for inhalation, the dosage range of use is 1mg/kg to a 25mg/kg body weight for example.Typically, unit dosage comprises about 10mg to 0.5g compound of the present invention.
As this paper stated, known mTOR kinases and PI3K enzyme had effect in tumorigenicity and many other diseases.We have found that the compound of formula (I) has the effective antitumour activity, think that this anti-tumor activity obtains by suppressing mTOR kinases and/or one or more PI3K enzymes.
Correspondingly, compound of the present invention is valuable anti-tumor agents.Especially, compound of the present invention suppress and/or treatment entity and/or liquid tumor disease in as antiproliferative, apoptosis and/or anti-to invade medicament be valuable.Especially, expect that compound of the present invention can be effective to prevent or treats suppressing for example those tumours of Ia class PI3K enzyme and Ib class PI3K enzyme sensitivity of mTOR and/or one or more PI3K enzymes.Further, expect compound of the present invention can be effective to prevent treat separately or part by mTOR and/or one or more PI3K enzymes those tumours of Ia class PI3K enzyme and the mediation of Ib class PI3K enzyme for example.Thus, this compound can produce mTOR enzyme inhibition effect in the warm-blooded animal of this treatment of needs.Some compound can produce the PI3K enzyme and suppress effect in the warm-blooded animal of this treatment of needs.
As this paper statement, the inhibitor of mTOR kinases and/or one or more PI3K enzymes has therapeutic value, is used for the treatment of hyperplasia, for example cancer and sarcoma and leukemia and lymph malignant tumour of cancer, especially noumenal tumour for example is in particular for treating for example breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer, cholangiocarcinoma, the bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae, and leukemia [comprising acute lymph leukemia (ALL) and chronic myelogenic leukemia (CML)], multiple myeloma and lymphoma.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used as medicine among the people warm-blooded animal.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce anti-proliferative effect among the people warm-blooded animal.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce the apoptosis effect among the people warm-blooded animal.
According to further feature of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein warm-blooded animal for example among the people as anti-ly invading medicament, be used to suppress and/or treat for example purposes of cancer of hyperplasia.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce the purposes of anti-proliferative effect among the people warm-blooded animal.
According to the further feature of this aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein purposes in the preparation medicine is provided, this medicine be used for warm-blooded animal for example the people produce anti-proliferative effect.
According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example to be used to produce the purposes of apoptosis effect among the people warm-blooded animal.
According to the further feature of this aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein purposes in the preparation medicine is provided, this medicine be used for warm-blooded animal for example the people produce the apoptosis effect.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is for example invaded medicament as resisting among the people warm-blooded animal, is used for for example cancer of inhibition and/or treatment hyperplasia.
According to the further feature of this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs for example produces the method for anti-proliferative effect among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
Further feature according to this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs for example produces anti-method of invading effect by inhibition and/or treatment noumenal tumour disease among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
According to further aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine for example is used for prevention or treats for example cancer of hyperplasia among the people warm-blooded animal.
Further feature according to this aspect of the present invention, the warm-blooded animal that provides in this treatment of needs is prevention or treatment hyperplasia method for cancer for example among the people for example, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
According to further aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, be used for prevention or treatment to suppressing the responsive tumour of mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib class PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability.
Further feature according to this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is used for prevention or treats suppressing the responsive tumour of mTOR kinases and/or one or more PI3K enzyme (for example Ia fermentoid and/or Ib class PI3K enzyme), and mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability.
Further feature according to this aspect of the present invention, provide prevention or treatment to suppressing the method for the responsive tumour of mTOR kinases and/or one or more PI3K enzymes (for example Ia fermentoid and/or Ib class PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.
According to further aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, be used to provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect).
Further feature according to this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, and this medicine is used to provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect).
According to further aspect of the present invention, a kind of method is provided, be used to provide mTOR kinase inhibition effect and/or PI3K enzyme to suppress effect (for example Ia class PI3K enzyme or Ib class PI3K enzyme suppress effect), this method comprises the formula I compound or pharmaceutically acceptable salt thereof defined herein that gives significant quantity.
According to further feature of the present invention, provide the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in treatment cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder defined herein.
According to further feature of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein in the treatment noumenal tumour purposes in cancer and sarcoma and leukemia and the lymph malignant tumour for example.
According to further feature of the present invention, provide the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in treatment breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer defined herein.
According to further feature of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, has been used for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is used for the treatment of cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, this medicine is used for the treatment of noumenal tumour for example cancer and sarcoma and leukemia and lymph malignant tumour.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, and this medicine is used for the treatment of breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer.
According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine defined herein is provided, and this medicine is used for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is for example treated the method for cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is the treatment noumenal tumour method of cancer and sarcoma and leukemia and lymph malignant tumour for example among the people for example, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is for example treated the method for breast cancer, colorectal carcinoma, lung cancer (comprising small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma) and prostate cancer among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
According to further feature of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs is for example treated cholangiocarcinoma, bone cancer, bladder cancer, brain and neck cancer, kidney, liver cancer, gastrointestinal tissue's cancer, esophagus cancer, ovarian cancer, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphadenomatous method among the people, and this method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.
As this paper stated, after the compound of giving construction (I),, can partly bring into play the interior effect of body of formula (I) compound by one or more metabolite that within human or animal body, forms.
The invention further relates to combined therapy, wherein simultaneously or sequentially the compound or pharmaceutically acceptable salt thereof of giving construction (I) or, comprise the pharmaceutical composition or the preparation of formula (I) compound, or give with combination preparation form with employed other treatment of control tumor disease.
Especially, treatment defined herein can be used as monotherapy, or except compound of the present invention, can also comprise routine operation or radiotherapy or chemotherapy.Correspondingly, compound of the present invention can also be used in combination with the existing therapeutical agent of treatment cancer.
The suitable medicament that uses in the combination comprises:
(i) antiproliferative/antitumour drug and its combination, for example for example alkylating agent that uses of medical science oncology (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Metabolic antagonist (antifolate for example, for example 5 FU 5 fluorouracil and Tegafur of fluorine pyrimidine for example, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); Antitumor antibiotics (anthracycline antibiotics for example, Dx for example, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, actinomycin and mithramycin); Antimitotic agent (vinca alkaloids for example, vincristin for example, vincaleucoblastine, desacetyl vinblastine amide and Vinorelbine and Japanese yew class medicine, for example pure and mild taxotere of Pacific yew (taxotere)); With local isomerase inhibitors (epipodophyllotoxin for example, for example Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);
(ii) cytostatic agent, estrogen antagonist (Tamoxifen for example for example, Toremifene Citrate, Reynolds former times phenol, droloxifene and iodoxyfene), estrogen receptor is born conditioning agent (for example fulvestrant), androgen antagonist (for example bicalutamide, flutamide, Nilutamide and acetate Sai Pulong), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogen (for example megestrol), aromatase inhibitor is (for example as Anastrozole, letrozole, vorozole and Exemestane) and the inhibitor of 5 finasteride for example;
(iii) anti-intrusion medicament (for example c-Src kinases man group inhibitor, for example 4-(6-chloro-2,3-methylene dioxo group aniline base)-7-[2-(4-methylpiperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-aminomethyl phenyl)-2-{6-[4-(2-hydroxyethyl) piperazine-1-yl]-2-methylpyrimidine-4-base is amino thiazole-5-carboxylic acid amides (Dasatinib, BMS-354825; J.Med.Chem., 2004,47,6658-6661) and the inhibitors of metalloproteinase inhibitor of Marimastat (marimastat) and upar function for example);
The (iv) inhibitor of somatomedin function: for example, this inhibitor comprises growth factor antibodies and growth factor receptor antibody (for example, anti-erbB 2 antibody Herceptin [Herceptin] and anti-erbB1 antibody Cetuximab [C225]); This inhibitor also comprises for example tyrosine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example for example for example, ZD1839), N-(3-ethynyl phenyl)-6, (the dust Lip river is for the Buddhist nun for 7-two (2-methoxy ethoxy) quinazoline-4-amine, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitor, lapatinibditosylate for example), the inhibitor of pHGF family, the inhibitor of PDGF family, imatinib for example, (for example Ras/Raf signal suppressing agent of the inhibitor of serine/threonine kinase, for example farnesyl transferase inhibitor, for example Xarelto (BAY 43-9006)) and the inhibitor by MEK and/or the kinase whose cell signal of Akt;
(v) anti-angiogenic formation medicament, those medicaments that for example suppress the vascular endothelial growth factor effect, [for example anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF (Avastin) and vegf receptor tyrosine kinase inhibitor, for example 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline (ZD6474; Embodiment 2 among the WO 01/32651), 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline (AZD2171; Embodiment 240 among the WO 00/47212), Wa Talani (vatalanib) (PTK787; WO 98/35985) and SU11248 (Sutent (Sunitinib); WO 01/60814) and the compound by other mechanism work (for example linomide, the inhibitor and the angiostatin of beta 2 integrin alpha v β 3 functions)];
(vi) blood vessel injury agent, for example Combretastatin A-4 4 and the compound that is disclosed among International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and the WO 02/08213;
(vii) antisense therapy, for example at above-listed target those, for example ISIS 2503, a kind of anti-ras antisense agents;
(viii) gene therapy method, comprise the method for replacing for example unusual p53 of aberrant gene or unusual BRCA1 or BRCA2, GDEPT (the direct enzyme precursor pharmacotherapy of gene) method, for example use those methods of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, with the method for increase patient for chemotherapy or radiocurable tolerance, for example multi-drug resistant gene therapy; With
(ix) immunotherapy method, comprise method in the immunogenic external and body that improves the patient tumors cell, for example for example interleukin 2, interleukin 4 or rHuGM-CSF carry out transfection with cytokine, reduce the method for T cell anergy, the immunocyte of use transfection is the method for the dendritic cell of cytokine transfection for example, use cytokine transfection tumor cell line method and use anti-spy to answer the method for antibody.
With reference now to following illustrative embodiment, further explains the present invention.
Except as otherwise noted, starting raw material is commercially available.All solvents and commercial reagent are the laboratory grades, and can be used as it is.
In an embodiment, record on Bruker DPX 300 (300MHz), Bruker DRX 400 (400MHz) instrument or Bruker DRX 500 (500MHz) instrument 1H NMR spectrum.Chloroform-d (δ H7.27ppm), methyl-sulphoxide-d 6H2.50ppm) or acetone-d 6H2.05ppm) central peak as interior mark.Use following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; The m multiplet; Br, broad peak.
(0.04-0.063mm Merck) carries out column chromatography to use silica gel.Usually, KromasilKR-100-5-C18 reversed-phase column (250x20mm, Akzo Nobel) is used to prepare HPLC, with the mixture of acetonitrile and water [comprising 0.1% trifluoroacetic acid (TFA)] as elutriant, flow velocity 10mL/min.
Following method is used for the analysis of liquid chromatography (LC)/mass spectrum (MS):
HPLC:Agilent 1100 or Waters Alliance HT (2790﹠amp; 2795)
Mass spectrograph: Waters ZQ ESCi
The HPLC post
The standard HPLC post that uses is Phemonenex Gemini C185 μ m, 50x2mm.
Acid HPLC method
The mobile phase of using is: mobile phase A: water
Mobile phase B: acetonitrile
Moving phase C:1% formic acid, each method back is quick balance in 50: 50 water: MeCN (v/v), uses the 5mL flow velocity, 0.45min.
Four kinds of general HPLC methods are suitable:
5 minutes monitoring acid methods
Time/minute Mobile phase A: Mobile phase B: Moving phase C: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
4 0 95 5 6 1.1
4.5 0 95 5 6 1.1
Early stage the wash-out compound acid method in early stage
Time/minute Mobile phase A: Mobile phase B: Moving phase C: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
4 57.5 37.5 5 6 1.1
4.5 57.5 37.5 5 6 1.1
Mid-term the wash-out compound acid method in mid-term
Time/minute Mobile phase A: Mobile phase B: Moving phase C: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
0.01 67.5 27.5 5 6 1.1
4.5 27.5 67.5 5 6 1.1
The later stage acid method of later stage wash-out compound
Time/minute Mobile phase A: Mobile phase B: Moving phase C: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
0.01 27.5 67.5 5 6 1.1
4.5 5 95 5 6 1.1
Alkali formula HPLC method
In some cases, need for compound ionsization or chromatographic separation, standard acid method may be not suitable for.In the case, four kinds of corresponding alkali formula HPLC methods are suitable.
The mobile phase of using is: mobile phase A: water
Mobile phase B: acetonitrile
Moving phase D:0.1% 880 ammonia/acetonitrile
Each method back is quick balance, uses the 5mL flow velocity, 0.45min.
Minute (minute) monitoring alkali formula method
Time/minute Mobile phase A: Mobile phase B: Moving phase D: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
4 0 95 5 6 1.1
4.5 0 95 5 6 1.1
Early stage the wash-out compound alkali formula method in early stage
Time/minute Mobile phase A: Mobile phase B: Moving phase D: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
4 57.5 37.5 5 6 1.1
4.5 57.5 37.5 5 6 1.1
Mid-term the wash-out compound alkali formula method in mid-term
Time/minute Mobile phase A: Mobile phase B: Moving phase D: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
0.01 67.5 27.5 5 6 1.1
4.5 27.5 67.5 5 6 1.1
The later stage alkali formula method of later stage wash-out compound
Time/minute Mobile phase A: Mobile phase B: Moving phase C: Rational curve Flow velocity/ml/min
0.00 95 0 5 1 1.1
0.01 27.5 67.5 5 6 1.1
4.5 5 95 5 6 1.1
Following method is used for the analysis of liquid chromatography (LC)/mass spectrum (MS):
Instrument: Agilent 1100; Post: Waters ' Symmetry ' 2.1x 30mm; Use the mass spectroscopy (APCI) of chemical ioni zation; Flow velocity: 0.7 ml/min; Absorbing wavelength: 254nm; Solvent orange 2 A: water+0.1% TFA; Solvent B: acetonitrile+0.1% TFA; Solvent gradient: 15-95% solvent B, 2.7 minutes, 95% solvent B then, 0.3 minute.
Following method is used for LC and analyzes:
Method A: instrument: Agilent 1100; Post: Kromasil C18 reverse phase silica gel, 100x3mm, 5 μ m particle diameters; Solvent orange 2 A: 0.1%TFA/ water, solvent B:0.08%TFA/ acetonitrile; Flow velocity: 1 ml/min; Solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280nm.Usually, the retention time of record product.
Method B: instrument: Agilent 1100; Post: Waters ' Xterra ' C8 reverse phase silica gel, 100x3mm, 5 μ m particle diameters; Solvent orange 2 A: 0.015M ammonia/water, solvent B: acetonitrile; Flow velocity: 1 ml/min; Solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280rm.Usually, the retention time of record product.
This paper or the following abbreviation of use in following illustrative embodiment:
The HPLC high performance liquid chromatography
HBTU O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate;
HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate;
The HOBT I-hydroxybenzotriazole;
HOAT 1-hydroxyl-7-azepine benzotriazole;
NMP N-methylpyrrolidin-2-ketone;
The DMSO methyl-sulphoxide;
DMF N, dinethylformamide;
The DMA N,N-dimethylacetamide;
The THF tetrahydrofuran (THF);
DME 1, the 2-glycol dimethyl ether;
The DCCI dicyclohexylcarbodiimide;
MeOH methyl alcohol;
The MeCN acetonitrile;
The DCM methylene dichloride;
DIPEA N, the N-diisopropylethylamine;
DBU 1,8-diazabicyclo [5.4.0] 11-7-alkene;
RT room temperature (about 17 to 25 ℃);
The tR retention time;
M/z mass ratio.
Chemical name utilizes software to produce, and this software uses Lexichem Toolkit (v.1.40) (being obtained from OpenEye Scientific Software (www.eyesopen.com)), meets the name of IUPAC with generation.
Embodiment 1:
N-[2-(methylol)-4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] first Sulphonamide
Figure A20078003926600951
With N-[4-bromo-2-(methylol) phenyl] mixture of Toluidrin (250mg), potassium acetate (263mg) and two (valeryls), two boron (273mg) is 1, and the degassing is 5 minutes in the 4-diox (10mL).Add 1,1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (44mg), reaction is heated to 80 ℃, kept 3 hours.Add 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (261mg), ethanol (0.75mL), 2M sodium carbonate solution (2.7mL) and extra 1; 1 '-two (diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (54mg) continues other 3 hours of heating.With refrigerative reaction mixture vacuum concentration, be dissolved in the methyl alcohol, and be loaded on the SCX-2 post.Use the methanol wash post, remove compound with 7N ammonia/methyl alcohol.Vacuum concentrated solution utilizes silica gel chromatography to resistates, with 0-5% methyl alcohol/DCM wash-out.The solid that obtains is ground with diethyl ether, obtain desired material, white solid (62mg).
The NMR spectrum: 1H NMR (DMSO-d 6) δ 307 (3H, s), 3.22 (3H, s), 3.74 (8H, s), 4.53 (2H, s), 4.69 (2H, s), 5.44 (1H, s), 6.89 (1H, s), 7.45 (1H, d), 8.23-8.26 (1H, m), 8.43 (1H, s), 9.10 (1H, s)
Mass spectrum:M+H +457.
The average IC of test (a) 50Be worth 5 μ M.
N-[4-bromo-2-(methylol) phenyl] preparation of Toluidrin is described below:
N-[4-bromo-2-(methylol) phenyl] Toluidrin
Figure A20078003926600952
5-bromo-2-methanesulfonamido-methyl benzoate (1.34g) is dissolved among the THF (30mL), and is cooled to 0 ℃.With 15 minutes lithium aluminum hydride (8.7mL, 1M THF solution) is joined in the solution at leisure.Make reaction be warming up to room temperature, stirred 2 hours, water cancellation is then filtered.Vacuum concentrated solution utilizes silica gel chromatography to resistates, with 2.5% methyl alcohol/DCM wash-out, obtains desired material, white solid (333mg).
The NMR spectrum: 1H NMR (DMSO-d 6) δ 3.01 (3H, s), 4.61 (2H, s), 5.40 (1H, s), 7.26 (1H, d), 7.45-7.48 (1H, m), 7.62 (1H, d), 9.05-9.05 (1H, m)
Mass spectrum:M-H +280.
5-bromo-2-methanesulfonamido-methyl benzoate
Figure A20078003926600961
At 0 ℃, sodium borohydride (659mg) is joined in the methyl alcohol (40mL) and water (4mL) stirred solution of 2-(two (methyl sulphonyl) amino)-5-bromo-methyl benzoate (168g) in the share mode.Make reaction be warming up to room temperature, stirred 2 hours.At 0 ℃ of sodium borohydride that adds other share, stirred 18 hours.Add entry (10mL) and yellow soda ash (2M) (5mL), react with quencher.The vacuum-drying reaction distributes between ethyl acetate (50mL) and water (50mL).Use the dried over mgso organism, vacuum filtration obtains desired material, white solid (1.34g) to doing.
The NMR spectrum: 1H NMR (DMSO-d 6) δ 3.14 (3H, d), 3.89 (3H, s), 7.52-7.57 (1H, m), 7.78-7.81 (1H, m), 7.99 (1H, d)
Mass spectrum:M-H +306.
2-(two (methyl sulphonyl) amino)-5-bromo-methyl benzoate
Figure A20078003926600962
Methyl-2-amino-5-bromo-benzoate (1g) is dissolved in THF (20mL) and the triethylamine (3.6mL).In ice bath, mixture is cooled to 0 ℃, adds methylsulfonyl chloride (1mL) at leisure.0 ℃ of stirring reaction 15 minutes, at room temperature stirred then 19 hours.Water (10mL) cancellation reaction, vacuum concentration.Between ethyl acetate (50mL) and water (50mL), distribute reactant, dry (MgSO 4) organism, filtering, vacuum concentration obtains desired material (1.68g) white solid.
The NMR spectrum: 1H NMR (DMSO-d 6) δ 3.52 (6H, s), 3.87 (3H, s), 7.58 (1H, d), 7.94-7.97 (1H, m), 8.10 (1H, d)
Mass spectrum:M+H +386.
The preparation of 2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine is described below.
2-chloro-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine
With 2, DCM (230mL) suspension of 4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidines (10.56g) carries out magnetic and stirs (in nitrogen atmosphere), and is cooled to-5 ℃.Add triethylamine (6.78mL), then dropwise add DCM (30mL) solution of morpholine (3.85mL), keep temperature of reaction to be lower than-5 ℃.At room temperature stirring reaction is 1 hour, the organic mixture of water (300mL) washing then.Dry (MgSO4) organic phase is filtered, and is evaporated to brown solid, and it is utilized silica gel chromatography, with 50% ethyl acetate/DCM wash-out, obtains desired material (6.81g) white solid.
The NMR spectrum: 1H NMR (DMSO-d 6) δ 3.12 (3H, s), 3.63 (4H, s), 3.68-3.70 (4H, m), 4.45 (2H, s), 6.96 (1H, s)
Mass spectrum:MH+292.
2,4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine
Figure A20078003926600972
With 6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2,4-diketone (12.72g) is suspended in the phosphorus oxychloride (125mL), and reflux is 14 hours in nitrogen atmosphere.With the solution cooling, and vacuum concentration.Frozen water (250mL) is joined in the resistates at leisure, use DCM (3x200mL) to extract product then.The vacuum concentration organism obtains desired material, brown solid (10.56g).
The NMR spectrum: 1H NMR (DMSO-d 6) δ 3.14 (3H, s), 4.79 (2H, s), 7.88 (1H, s)
Mass spectrum:(M-H)-239.
6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2, the 4-diketone
6-(chloromethyl) uridylic (10.00g) is dissolved among the DMF (300mL), adds methyl-sulfinic acid (methanesulphinic) sodium salt (7.64g).To be reflected at 125 ℃ of heating 1 hour.The cooling reaction is filtered, and vacuum concentrated filtrate obtains desired material, yellow solid (12.72g).
The NMR spectrum: 1H NMR (DMSO-d 6) δ 3.10 (3H, s), 4.27 (2H, s), 5.63 (1H, s), 10.94 (1H, s), 11.16 (1H, s).
Embodiment 2:
N-[[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methyl] Toluidrin
Figure A20078003926600982
With [4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methylamine (72mg) is suspended among the DCM (4mL), and handles with triethylamine (0.056mL).Dropwise add methylsulfonyl chloride (0.024mL) then, and stirring reaction spends the night under RT.Add entry (2mL) and come the quencher reaction, separate each layer.Extract water layer with DCM (2x2mL), the dry organism that merges filters, and is evaporated to green oil, and it is prepared purifying in the HPLC system in the alkali formula.The fraction that will comprise product is loaded into methyl alcohol in advance on the SCX post of wash-out, uses methanol wash, uses 7N ammonia/methanol-eluted fractions then.The needed fraction of vacuum-evaporation obtains desired material, white solid (20mg).
The LCMS spectrum:MH+441.58, retention time 1.41 methods: monitoring acid system
The NMR spectrum: 1H NMR (300.132MHz, DMSO-d 6) δ 2.89 (s, 3H), 3.20 (s, 3H), 3.71 (s, 8H), 4.25 (d, 2H), 4.51 (s, 2H), 6.91 (s, 1H), 7.45 (m, 2H), 7.62 (m, 1H), 8.34 (m, 2H).
The average IC of test (a) 50Be worth 6.8 μ M.
Starting raw material [4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methylamine is prepared as follows.
[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] methylamine
Figure A20078003926600991
With 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (228mg), [4-(aminomethyl) phenyl] boric acid (310mg), thiophene-2-carboxylic acid copper (I) (373mg) and Pd (PPh 3) 4(35mg) join in the microwave container, add 1 then, 4-diox (5mL).Tightness system is in microwave reactor, 130 ℃ of heating 1 hour.Further add Pd (PPh 3) 4(10mg), and reaction is heated to 130 ℃, kept 20 minutes.Mixture is changed in the SCX post of using methanol-eluted fractions in advance.Use washed with methanol SCX post then, then use 7N ammonia/methanol-eluted fractions desired material.The evaporation fraction obtains needed compound, emulsifiable paste shape solid (129mg).
The LCMS spectrum:MH+363.55, retention time 0.83 method: monitoring acid system
2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine
Figure A20078003926601001
With 2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine-4-alcohol (15g, 63.97mmol) about 1 hour of reflux in the inferior phosphorus of oxychlorination (100ml).The inferior phosphorus of evaporation oxychlorination is used in the sodium hydroxide solution and resistates, and is extracted in the ethyl acetate.Then with sal epsom with the mixture drying that obtains, filter, evaporate to dryness obtains the crude product chloro-product.Then it is dissolved among the DCM, add morpholine (319mmol, 28ml), stirring reaction at room temperature.In case finish, collect the precipitation that obtains, white solid.Concentrated filtrate obtains more solids, obtains merging productive rate 13.7g.
The NMR spectrum: 1H NMR (300.132MHz, DMSO) δ 2.45 (s, 3H), 3.49-3.74 (m, 8H), 4.37 (s, 2H), 6.66 (s, 1H) ppm..
The LCMS spectrum:MH+304.50, retention time 1.49min, method: monitoring alkaline process.
2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine-4-alcohol
Figure A20078003926601002
(19.07g 100mmol) is suspended in the acetonitrile (400mL) with 6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol.In this stirred suspension, add the methyl-sulfinic acid sodium salt (12.255g, 120mmol) and DMF (100mL).Reaction is heated to 100 ℃ then, obtains the suspension of black, monitor with LCMS.In case finish, remove and desolvate, and products obtained therefrom is joined 1: among 1MeOH: the DCM (200ml), with acetate (10ml) acidifying.The precipitation that collection obtains, water (200ml) and MeOH (100ml) washing, vacuum-drying is spent the night, and obtains title compound, white solid 16.45g.
The NMR spectrum: 1H NMR (300.132MHz, DMSO) δ 2.50 (s, 3H), 3.12 (s, 3H), 4.39 (s, 2H), 6.25 (s, 1H), 13.09 (s, 1H) ppm..
The LCMS spectrum:MH+235.2, retention time 0.5 minute, method: 5 minutes early stages alkali formula method.
6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol
Figure A20078003926601011
With S-methyl-2-sulfo-pseudo-urea sulfuric ester (20g, 71.85mmol), 4-chloracetyl vinyl acetic monomer (10.755mL, 79.04mmol) and yellow soda ash (13.925g 107.78mmol) in water-soluble (100mL), and at room temperature stirs and spends the night.With TLC monitoring reaction, in case finish, collect reaction precipitation, use in the 6N hydrochloric acid and supernatant liquor, obtain more reaction precipitations, equally with its collection.Water (x3) washing accumulative precipitation obtains the off-white color solid then.60 ℃ with its vacuum-drying 48 hours, obtain needed compound, light yellow/white solid 43.2g.
The NMR spectrum: 1H NMR (300.132MHz, CDCl 3) δ 2.59 (s, 3H), 4.35 (s, 2H), 6.41 (s, 1H), 12.70 (s, 1H) ppm
Mass spectrum:M +190
Embodiment 3:
N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] cyclopropyl-sulfonylamide
Figure A20078003926601012
To 4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] add ring third SULPHURYL CHLORIDE (53mg) in pyridine (4mL) solution of aniline (52mg), and stirring reaction spends the night under RT.In reaction mixture, add PS-Tutofusin tris resin (200mg) then, shook mixture 2 hours, filter then, use methanol wash.With the organism evaporate to dryness that merges, then be dissolved among the DMSO (1mL), with preparation HPLC purifying, use Phenomenex ' Gemini ' preparation reversed-phase column (5 microns silica gel, 21.2mm diameter, 100mm length), the polarity mixture decrescence that makes water and acetonitrile (comprising 2% formic acid) obtains title compound (33mg) as elutriant.
The LCMS spectrum:M+H +453.45; Retention time 2.59 methods: monitoring acid system
The average IC of test (a) 50Be worth 0.88 μ M.
Use suitable SULPHURYL CHLORIDE, prepare following compounds with similar fashion.
Figure A20078003926601021
Embodiment 3a: the average IC of test (a) 50Be worth 1.4 μ M.
Embodiment 3b: the average IC of test (a) 50Be worth 4 μ M.
Embodiment 3c: the average IC of test (a) 50Be worth 6 μ M.
Embodiment 3d: the average IC of test (a) 50Be worth 7.1 μ M.
4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] preparation of aniline is described below:
4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] aniline
Figure A20078003926601031
With 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (1.00g, 3.3mmol), 4-aminophenyl boric acid (904mg, 6.60mmol), thiophene-2-carboxylic acid copper (I) (1.64g, 8.58mmol), Pd (PPh 3) 4(153mg, 0.04 equivalent 0.13mmol) joins in the microwave container, and adds 1,4-diox (20mL).Use N 2With the system degassing, sealing and in microwave reactor, 130 ℃ of heating 1 hour.In case cooling is poured reactant in the water into, to filter and collect the precipitation that obtains, vacuum-drying obtains title compound, off-white color solid (988mg).
The LCMS spectrum:MH+349.41, retention time 1.43, method: monitoring acid system
The NMR spectrum: 1H NMR (300.132MHz, DMSO-d 6) δ 3.20 (3H, s), 3.61-3.83 (8H, m), 4.43 (2H, s), 5.57 (1H, s), 6.60 (2H, d), 6.70 (1H, s), 8.04 (2H, d)
Embodiment 4:
N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] Toluidrin
Figure A20078003926601032
To 4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] add in pyridine (3mL) solution of aniline (53mg, 0.15mmol)) methylsulfonyl chloride (21mg, 0.18mmol), and under RT stirring reaction 2 hours.(10mL) joins in the mixture with water, filters collecting precipitation.With this solid of preparation HPLC purifying, obtain desired material, white solid (29mg).
The LCMS spectrum:M+H +427.4; Retention time 1.38, method: monitoring acid system
The NMR spectrum: 1H NMR (300.132MHz, DMSO-d 6) δ 3.08 (3H, s), 3.22 (3H, s), 3.75 (8H, s), 4.57 (2H, s), 6.93 (1H, s), 7.33 (2H, d), 8.30 (2H, d), 10.12 (1H, s)
The average IC of test (a) 50Be worth 2.6 μ M.
Embodiment 5:
N-[[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] first Base] Toluidrin
Figure A20078003926601041
With triethylamine (0.038mL, 0.27mmol) join [4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] (100mg is in DCM 0.27mmol) (5mL) solution for methylamine.Add methylsulfonyl chloride (0.021mL, 0.27mmol), and stirring reaction 2 hours at room temperature.Water (5mL) washing organism, dry (MgSO 4), vacuum concentration.Purifying crude product on silica gel with 0-5% methyl alcohol/DCM wash-out, obtains desired material, white solid (90mg).
The LCMS spectrum:M+H +455; Retention time 1.61, method: monitoring alkaline process
The NMR spectrum: 1H NMR (400.132MHz, CDCl 3) δ 1.36 (d, 3H), 2.89 (s, 3H), 3.08 (s, 3H), 3.35 (m, 1H), 3.60 (t, 1H), 3.79 (m, 2H), 4.05 (d, 1H), 4.18 (d, 1H), 4.27 (s, 2H), 4.39 (d, 2H), 4.49 (s, 1H), 4.80 (s, 1H), 6.52 (s, 1H), 7.43 (d, 2H), 8.36 (d, 2H).
The average IC of test (a) 50Be worth 4.5 μ M.
[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] preparation of methylamine is described below.
[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] methylamine
Figure A20078003926601051
With 2-chloro-4-[(3S)-3-methylmorpholine-4-yl]-(1.0g 3.27mmol) is dissolved in 7: 3: 2 DME of 18%DMF: water: in the mixture solution of ethanol (9mL) to 6-(sulfonyloxy methyl ylmethyl) pyrimidine.Then with 4-aminomethyl phenyl borate hydrochlorate (0.92g, 4.91mmol), (115mg 0.16mmol) joins in the solution two (triphenylphosphine) palladium catalysts of 2M sodium carbonate solution (3mL) and dichloro, in nitrogen atmosphere, refluxes 16 hours at 90 ℃.Make reaction be cooled to room temperature, between ethyl acetate and water, distribute then.Use the dried over mgso organism, filter, be concentrated into dried.Crude product oil is utilized silica gel chromatography,, obtain desired material, emulsifiable paste shape solid (400mg) with 0-5% methyl alcohol/DCM wash-out.
The LCMS spectrum:M-H-375; Retention time 1.58, method: monitoring alkaline process
NMR Spectrum: 1H NMR(400.132MHz,CDCl 3)δ1.36(d,3H),3.08(s,3H),3.34(m,1H),3.60(m,1H),3.75(m,1H),3.83(d,1H),3.94(s,2H),4.05(m,1H),4.18(m,1H),4.26(s,2H),4.49(m,1H),6.50(s,1H),7.40(d,2H),8.33(d,2H)。
2-chloro-4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine
Figure A20078003926601052
With 2, (30g 0.13mol) is dissolved in the methylene dichloride 4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine, in-5 ℃ of stirrings (in nitrogen atmosphere).(17.4mL 0.13mol), obtains clarifying brown solution to add triethylamine.(3S)-3-methylmorpholine is dissolved in the methylene dichloride, dropwise adds, keep reaction to be lower than-5 ℃.Remove cooling bath then, stirred the mixture 1 hour.Reflux reaction mixture 2 hours washes reaction mixture then with water, drying, evaporation then.With preparation HPLC purifying crude product, obtain desired material, solid (19.3g).
The NMR spectrum: 1H NMR (400.13MHz, DMSO-d 6) δ 1.21-1.23 (m, 3H), 3.11 (s, 3H), 3.19-3.26 (m, 1H), 3.42-3.49 (m, 1H), 3.58-3.62 (1H, m), 3.73 (d, 1H), 3.92-3.96 (m, 2H), 4.27-4.31 (m, 1H), 4.45 (s, 2H), 6.92 (s, 1H)
The LCMS spectrum:MH+306, retention time 1.42 minutes, method: 5 minutes acid methods
Before described 2, the preparation of 4-two chloro-6-(sulfonyloxy methyl ylmethyl) pyrimidine.
Embodiment 6:
N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] first Sulphonamide
Figure A20078003926601061
With 2-chloro-4-[(3S)-3-methylmorpholine-4-yl]-(150mg 0.49mmol) is dissolved in 7: 3: 2 DME of 18%DMF: water: in the mixture solution of ethanol (1.5mL) to 6-(sulfonyloxy methyl ylmethyl) pyrimidine.(18mg 0.02mmol) joins in the solution, in nitrogen atmosphere, refluxes 16 hours at 90 ℃ with two (triphenylphosphine) palladium catalysts of 4-aminomethyl phenyl borate hydrochlorate (0.74mmol), 2M sodium carbonate solution (0.5mL) and dichloro then.Make reaction be cooled to room temperature, between ethyl acetate and water, distribute then.Use the dried over mgso organism, filter, be concentrated into dried.The crude product solid is dissolved among the DCM, removes by filter insoluble impurities, with preparation HPLC purifying filtrate, obtain needed compound, white solid (87mg) then.
The NMR spectrum: 1H NMR (400.13MHz, DMSO-d 6) δ 1.24 (3H, d), 293 (3H, s), 3.21 (3H, s), 3.24 (1H, m), 3.50 (1H, m), 3.65 (1H, m), 3.78 (1H, d), 3.98 (1H, m), 4.16 (1H, d), 4.43 (1H, s), 4.48 (2H, s), 6.76 (1H, s), 7.17 (2H, d), 8.21 (2H, d)
The LCMS spectrum:M+H +441; Retention time 1.45, method: monitoring acid system
The average IC of test (a) 50Be worth 1 μ M.

Claims (33)

1. the compound of formula (I):
Figure A2007800392660002C1
Formula (I)
Or its pharmacologically acceptable salt; Wherein
M is 0,1,2,3 or 4;
1Y and Y 2Be N or CR independently 8, condition is, 1Y and Y 2One of be that N and another are CR 8
X is selected from following connection base :-CR 4=CR 5-,-CR 4=CR 5CR 6R 7-,-CR 6R 7CR 5=CR 4-,-C ≡ C-,-C ≡ CCR 6R 7-,-CR 6R 7C ≡ C-,-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-NR 4S (O) 2CR 6R 7-,-S (O) 2NR 4CR 6R 7-,-C (O) NR 4-,-NR 4C (O)-,-NR 4C (O) NR 5-,-S (O) 2NR 4-and-NR 4S (O) 2-;
R 1Be to be selected from following group: hydrogen, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, carbocylic radical, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, R 9,-OR 9,-SR 9,-SOR 9,-SO 2R 9,-COR 9,-CO 2R 9,-CONR 9R 10,-NR 9R 10,-NR 9COR 10,-NR 9CO 2R 10,-NR 9CONR 10R 15,-NR 9COCONR 10R 15With-NR 9SO 2R 10
R 2Be to be selected from following group: C 1-6Alkyl, carbocylic radical and heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-SR 11,-SOR 11,-SO 2R 11,-COR 11,-CO 2R 11,-CONR 11R 12,-NR 11R 12,-NR 11COR 12With-NR 11COCONR 12R 16When existing, each R 3Be independently selected from halogen, cyano group, nitro ,-R 13,-OR 13,-SR 13,-SOR 13,-SO 2R 13,-COR 13,-CO 2R 13,-CONR 13R 14,-NR 13R 14,-NR 13COR 14,-NR 13CO 2R 14With-NR 13SO 2R 14
R 4And R 5Be hydrogen or C independently 1-6Alkyl;
Or R 1And R 4The atom that is connected with them forms 5-to 10-unit's carbocyclic ring or heterocycle, and wherein 1,2 or 3 ring carbon atom is optional is replaced by N, O or S, and this ring is chosen wantonly by one or more and is selected from following substituted radical replacement: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 6And R 7Be independently selected from hydrogen, halogen, cyano group, nitro and C 1-6Alkyl;
R 8Be selected from hydrogen, halogen, cyano group and C 1-6Alkyl;
R 9And R 10Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocylic radical, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 11, R 12And R 17Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocylic radical, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl;
R 13, R 14, R 15, R 16And R 18Be hydrogen independently or be selected from following group: C 1-6Alkyl, carbocylic radical, carbocyclic ring C 1-6Alkyl, heterocyclic radical and heterocyclic radical C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
2. according to the compound or pharmaceutically acceptable salt thereof of claim 1, the compound of its Chinese style (I) is formula (Ia) or compound (Ib)
Figure A2007800392660004C1
Or its pharmacologically acceptable salt, wherein R 1, R 2, R 3, X, Y 1And Y 2As definition to the desired formula of claim 1 (I) compound.
3. according to the compound or pharmaceutically acceptable salt thereof of claim 1 or 2, R wherein 3It is methyl.
4. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 3, Y wherein 1Be CR 8, and Y 2Be N.
5. according to the compound or pharmaceutically acceptable salt thereof of claim 4, Y wherein 1Be CH, and Y 2Be N.
6. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 5, wherein X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4CR 6R 7-,-NR 4C (O) NR 5CR 6R 7-,-S (O) 2NR 4CR 6R 7,-C (O) NR 4-and-NR 4C (O)-.
7. according to the compound or pharmaceutically acceptable salt thereof of claim 6, wherein X is selected from following connection base :-NR 4CR 6R 7-,-OCR 6R 7-,-SCR 6R 7-,-S (O) CR 6R 7-,-S (O) 2CR 6R 7-,-C (O) NR 4-and-NR 4C (O)-.
8. according to the compound or pharmaceutically acceptable salt thereof of claim 7, wherein X is selected from following connection base :-NR 4CH 2-,-OCH 2-,-OCH (CH 3)-,-OC (CH 3) 2-,-SCH 2-,-SCH (CH 3)-,-SC (CH 3) 2-,-S (O) CH 2-,-S (O) CH (CH 3)-,-S (O) C (CH 3) 2-,-S (O) 2CH 2-,-S (O) 2CH (CH 3)-,-S (O) 2C (CH 3) 2-,-C (O) NR 4-and-NR 4C (O)-.
9. according to the compound or pharmaceutically acceptable salt thereof of claim 8, wherein X is-S (O) 2CH 2-,-S (O) 2CH (CH 3)-or-S (O) 2C (CH 3) 2-.
10. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 9, R wherein 1Be to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolidyl methyl, pyrrolidyl ethyl, pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, the pyrazolyl methyl, pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optional by 1,2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R 9,-OR 9,-COR 9,-CONR 9R 10,-NR 9R 10With-NR 9COR 10
11. according to the compound or pharmaceutically acceptable salt thereof of claim 10, wherein R 1Be to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group is optional to be selected from following substituted radical replacement by 1 or 2: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH 3,-CONH 2With-CONHCH 3
12. according to the compound or pharmaceutically acceptable salt thereof of claim 11, wherein R 1Be to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH 2CH 2OH ,-CH 2CH 2NC (O) CH 3, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base,, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.
13. according to the compound or pharmaceutically acceptable salt thereof of claim 12, wherein R 1It is methyl.
14. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 13, wherein R 2Be selected from: 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
15. according to the compound or pharmaceutically acceptable salt thereof of claim 14, wherein R 2Be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
16. according to the compound or pharmaceutically acceptable salt thereof of claim 15, wherein R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: halogen, cyano group, nitro ,-R by one or more 11,-OR 11,-COR 11,-CONR 11R 12,-NR 11R 12With-NR 11COR 12
17. according to the compound or pharmaceutically acceptable salt thereof of claim 16, wherein R 2Be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, thiazolyl, this group quilt-NR 17SO 2R 18Replace, and optionally be independently selected from following substituted radical and replace: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH by one or more 2,-CONHCH 3With-CON (CH 3) 2
18. according to the compound or pharmaceutically acceptable salt thereof of claim 17, wherein R 2By-NR 17SO 2R 18Replace, also choose wantonly by one or more phenyl or pyridyl that are independently selected from following substituted radical replacement: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH 2,-CONHCH 3With-CON (CH 3) 2
19. according to the compound or pharmaceutically acceptable salt thereof of claim 18, wherein R 2Be
Figure A2007800392660006C1
A wherein 1And A 2Be selected from CH or N, condition is at least one A 1Or A 2Be CH.
20. according to each compound or pharmaceutically acceptable salt thereof of claim 14 to 19, wherein R 17Be hydrogen.
21. according to each compound or pharmaceutically acceptable salt thereof of claim 1 to 20, wherein R 18Be hydrogen or be selected from following group: C 1-6Alkyl, C 3-6Cycloalkyl, aryl, heteroaryl, aryl C 1-6Alkyl and heteroaryl C 1-6Alkyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
22. according to the compound or pharmaceutically acceptable salt thereof of claim 21, wherein R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl , isoxazolyl, pyrazolyl, pyridyl and pyrimidyl, this group is optional to be selected from following substituted radical and to replace by one or more: halogen, cyano group, nitro, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, halogen C 1-6Alkyl, halogen C 1-6Alkoxyl group, hydroxyl C 1-6Alkyl, hydroxyl C 1-6Alkoxyl group, C 1-6Alkoxy C 1-6Alkyl, C 1-6Alkoxy C 1-6Alkoxyl group, amino, C 1-6Alkylamino, two (C 1-6Alkyl) amino, amino C 1-6Alkyl, (C 1-6Alkyl) amino C 1-6Alkyl, two (C 1-6Alkyl) amino C 1-6Alkyl, cyano group C 1-6Alkyl, C 1-6Alkyl sulphonyl, C 1-6Alkyl sulfonyl amino, C 1-6Alkyl sulphonyl (C 1-6Alkyl) amino, sulfamyl, C 1-6Alkylsulfamoyl group, two (C 1-6Alkyl) sulfamyl, C 1-6Alkanoylamino, C 1-6Alkyloyl (C 1-6Alkyl) amino, formamyl, C 1-6Alkyl-carbamoyl and two (C 1-6Alkyl) formamyl.
23. according to the compound or pharmaceutically acceptable salt thereof of claim 22, wherein R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH 2(cyclopropyl) ,-CH 2CH 2NMe 2,-CH (CH 3) CH 2OH ,-C (CH 3) 2CH 2OH ,-CH 2CH 2OH ,-CH 2CH 2CH 2OH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH 2(imidazoles-2-yl) ,-CH 2(imidazo-3-yl) , isoxazolyl-3-base, 6-oxo-1H-pyridine (pryrdin)-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl, 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl.
24. according to the compound or pharmaceutically acceptable salt thereof of claim 23, wherein R 18Be hydrogen or be selected from following group: methyl, ethyl, propyl group, butyl, cyclopropyl and 4-fluorophenyl.
25., be selected from each embodiment or its pharmacologically acceptable salt according to the compound or pharmaceutically acceptable salt thereof of claim 1.
26. each formula (I) compound or pharmaceutically acceptable salt thereof according to claim 1 to 25 is used as medicine in the treatment of hyperplasia.
27. the purposes of the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof in the preparation medicine, this medicine is used for the treatment of hyperplasia.
28. the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof for example produces the purposes of anti-proliferative effect among the people warm-blooded animal.
29. the purposes of the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof in medication preparation, this medicine for example is used to produce anti-proliferative effect among the people warm-blooded animal.
30. for example produce the method for anti-proliferative effect among the people the warm-blooded animal of this kind of needs treatment, this method comprises each defined formula (I) compound or pharmaceutically acceptable salt thereof of the claim 1 to 25 that gives described animal effective dose.
31. for example treat the method for cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder among the people the warm-blooded animal of this kind of needs treatment, this method comprises each defined formula (I) compound or pharmaceutically acceptable salt thereof of the claim 1 to 25 that gives significant quantity.
32. a pharmaceutical composition, each defined formula (I) compound or pharmaceutically acceptable salt thereof that it comprises claim 1 to 25 combines with pharmaceutically acceptable diluent or carrier.
33. the defined formula of each of claim 1 to 25 (I) compound or pharmaceutically acceptable salt thereof is as medicine.
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