CN101146795A - Pyrazole derivatives for the inhibition of CDK and GSK - Google Patents

Pyrazole derivatives for the inhibition of CDK and GSK Download PDF

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CN101146795A
CN101146795A CNA2006800092384A CN200680009238A CN101146795A CN 101146795 A CN101146795 A CN 101146795A CN A2006800092384 A CNA2006800092384 A CN A2006800092384A CN 200680009238 A CN200680009238 A CN 200680009238A CN 101146795 A CN101146795 A CN 101146795A
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P·G·怀亚特
V·贝尔迪尼
A·L·吉尔
G·特里瓦撒
A·J·伍德黑德
E·F·纳瓦罗
M·A·奥布赖恩
T·R·菲利普斯
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Astex Therapeutics Ltd
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Abstract

The invention provides compounds of the formula (I), or salts, tautomers, N-oxides or solvates thereof wherein: R1 is selected from: (a) 2,6-dichlorophenyl; (b) 2,6-difluorophenyl; (c) a 2,3,6-trisubstituted phenyl group wherein the substituents for the phenyl group are selected from fluorine, chlorine, methyl and methoxy; (d) a group R0; (e) a group R a; (f) a group Rlb; (g) a group Rlc; (h) a group Rld; and 0) 2,6-difluorophenylamino ; wherein R )0, r R> llaa, T Rj I1bD, T R) I1cC, r R> Iida, r R 2zaa, r R>22bD and RJ are as defined in the claims. The compounds have activity as inhibitors of cdk kinase (such as cdkl or cdk2) and glycogen synthase kinase-3 activity.

Description

Be used to suppress the pyrazole derivatives of CDK and GSK
The present invention relates to suppress or regulate the cell cycle protein dependent kinase (CDK) and the pyrazole compound of glycogen synthase kinase (GSK) kinase activity, described compound in treatment or prevent by described kinase mediated morbid state or the purposes in the illness and have kinase inhibition or regulate active new compound.The pharmaceutical composition that contains described compound and new chemical intermediate also are provided.
Background of invention
The protein kinase of being responsible for the intracellular multiple signal conductive process of control has constituted relevant big enzyme family on the structure.(Hardie, G. and Hanks, S. (1995) The Protein KinaseFacts Book.I and II.Academic Press, San Diego, CA).Kinases can be according to the substrate (for example, protein-tyrosine, protein-serine/threonine, lipid etc.) of its phosphorylation and is divided into different families.Common sequence die body (for example, Hanks, S.K., Hunter, T., FASEB J., 9:576-596 (1995) have been identified corresponding to each kinases family; People such as Knighton, Science, 253:407-414 (1991); People such as Hiles, Cell, 70:419-429 (1992); People such as Kunz, Cell, 73:585-596 (1993); People such as Garcia-Bustos, EMBO J., 13:2352-2361 (1994)).
Protein kinase can characterize according to its regulation mechanism.These mechanism comprise, for example, and self phosphorylation, by other kinase whose commentaries on classics phosphorylation, protein-protein interaction, protein-lipid interaction and protein-polynucleotide interaction.A kind of protein kinase may be subjected to the adjusting of mechanism more than one.
Kinases is regulated many different cell processes by phosphate group being added into target protein, includes but not limited to propagation, differentiation, apoptosis, mobility, transcribes, translates and other signalling process.These phosphorylation events play a part to regulate or regulate and control the molecule ON/OFF switch of target protein biological function.Target protein responds that various extracellulars signal (hormone, neurotransmitter, growth and differentiation factor etc.), cell cycle events, environment or nutrition are coerced etc. and phosphorylation takes place.The effect of suitable protein kinase in signal path be activate or deactivation (directly or indirectly) for example metabolic enzyme, regulate albumen, acceptor, cytoskeletal protein, ionic channel or pump or transcription factor.The not controlled signal that is caused by the control defective of protein phosphorylation effect has related to numerous disease, comprises for example disease and the illness of inflammation, cancer, transformation reactions/asthma, immune disease and illness, central nervous system, and vasculogenesis.
Cell cycle protein dependent kinase
When eukaryotic cell splitted process can broadly be divided into a series of successive that is called G1, S, G2 and M mutually.Verified, by the cell cycle not simultaneously the correct process key of phase depend on the protein families that is called as cell cycle protein dependent kinase (cdks) and be called regulation and control on not on the same group its homologous protein partner's the room and time of cyclin.Cdks is the homology serine-threonine kinase protein of cdc2 (being also referred to as cdk1), and it can utilize ATP as substrate in the phosphorylation of the not homopolypeptide of sequence dependent background.Cyclin is one, and this homologous region is called as " cyclin box " to comprise about 100 protein familieses that amino acid whose homologous region is a feature, and it is used for combination of homospecificity cdk partner protein matter and definition selectivity.
Various cdks and cyclin cause the circulation of a series of cdk/ cyclin mixtures to form in the adjusting of expression level, degradation rate and the activation levels of whole cell cycle, and wherein cdks is the enzymatic activation.The formation of these mixtures is gone down to posterity via the check point control of discontinuous cell cycle, and fissional process can be continued.Can not satisfy necessary biological chemistry standard in given cell cycle check point, promptly can't form essential cdk/ cyclin mixture, can cause the cell cycle to be ended and/or apoptosis.Unusual cell proliferation as shown in the cancer, often is attributable to the disappearance of correct cell cycle control.Therefore suppressing the cdk enzymic activity provides a kind of cell of abnormal division that makes to stop division and/or killed method.The diversity of cdks and cdk mixture and they provide the potential treatment target of the wide spectrum of selecting based on defined biological chemistry theory the decisive role of mediated cell in the cycle.
From the process of G1 phase to S phase of cell cycle mainly by cdk2, cdk3, cdk4 and cdk6 by regulating with D and combining of E type cyclin member.As if D type cyclin helps not go down to posterity by the G1 restriction point, and cdk2/ cyclin E mixture is the key of changing to the S phase from G1.Need to be considered to cdk2/ cyclin A mixture by S phase and the process that enters G2 subsequently.Mitotic division and trigger its G2 to the conversion of M phase, both all are subjected to the adjusting of cdk1 and A and type B cell cyclin mixture.
In the G1 phase, retinocytoma albumen (Rb) and relevant bag shape albumen (pocket protein) is p130 for example, is the substrate of cdk (2,4 and 6)/cyclin mixture.Process by G1 since Rb and p130 by cdk (4/6) thereby/the excessive phosphorylation inactivation of cyclin-D mixture and partly promoting.The excessive phosphorylation of Rb and p130 causes for example release of E2F of transcription factor, and therefore causes by G1 and the necessary gene of process that enters the S phase, for example expression of gene of cyclin E.The expression of cyclin E promotes the formation of cdk2/ cyclin E mixture, and its further phosphorylation by Rb is amplified or kept the E2F level.Cdk2/ cyclin E mixture is the required protein of other dna replication dna of phosphorylation also, NPAT for example, and it relates to the histone biosynthesizing.The process of G1 and the conversion of G1/S also are subjected to being included in the adjusting of the Myc approach of the mitotic division primary stimuli in the cdk2/ cyclin E approach.Cdk2 also is related via the dna damage response pathway that p53 regulates and p53 mediates of p21 level.P21 is the protein inhibitor of cdk2/ cyclin E, therefore can block or postpone the G1/S conversion.Therefore cdk2/ cyclin E mixture can be represented to stimulate the point that is integrated to a certain extent from the biological chemistry of Rb, Myc and p53 approach.Therefore Cdk2 and/or cdk2/ cyclin E mixture have been represented and have been ended in the cell of abnormal division or the restorative good treatment target spot of controlling the cell cycle.
The corner cut look also unclear really in the cell cycle for cdk3.Also do not have homologous cyclin partner to be identified so far, but the negative adjusting form of the dominance of cdk3 postpones G1 phase cell, hint that therefore cdk3 has the effect of regulating the G1/S conversion.
Though most cdks participates in regulation of Cell Cycle, evidence suggests that some cdk family member has participated in other Biochemical processes.With cdk5 is example, and it is that the correct growth of neurone is necessary, and has participated in for example phosphorylation of Tau, NUDE-1, synapsin1, DARPP32 and Munc18/Syntaxin1A mixture of several neuronic protein.Neuronic cdk5 is usually by activating with the p35/p39 combination of proteins.Yet the Cdk5 activity can be by in conjunction with p25 (the brachymemma type of a kind of p35) adjusting of making a return journey.P35 is to the conversion of p25 and cdk5 is active subsequently goes to regulate and can be brought out by local asphyxia, excitotoxicity and beta amyloid peptide.Thereby p25 involved for example pathogenesis of alzheimer's disease of neurodegenerative disease, therefore as having caused people's interest at these treatment of diseases target spots.
Cdk7 is that a kind of cdc2CAK of having is active and in conjunction with the nucleoprotein of cyclin H.Cdk7 has been accredited as the composition of TFII H transcription complex, and it has C-end structure territory (CTD) activity of rna plymerase ii.This HIV-1 transcriptional regulatory with the bio-chemical pathway that is mediated by Tat is relevant.Cdk8 is in conjunction with cyclin C and participate in the phosphorylation of the CTD of rna plymerase ii.Similarly, cdk9/ cyclin-T1 mixture (P-TEFb mixture) participates in the control of rna plymerase ii to extending.The HIV-1 genome also needs PTEF-b by viral trans-acting factor Tat via the interactive transcription activating of itself and cyclin T1.Therefore cdk7, cdk8, cdk9 and P-TEFb mixture are the potential target spots of antiviral therapy.
On molecular level, the mediation of cdk/ cyclin complex activity needs the phosphorylation or the dephosphorylation incident of a series of pungencys and inhibition.The Cdk phosphorylation is finished by one group of cdk activated protein kinase (CAK) and/or such as the kinases of wee1, Myt1 and Mik1.Dephosphorylation is by phosphoesterase cdc25 (a﹠amp for example; C), pp2a or KAP finish.
The activity of Cdk/ cyclin mixture can further be regulated by the endogenous cell protein inhibitor of two families: Kip/Cip family or INK family.INK protein-specific ground is in conjunction with cdk4 and cdk6.P16 Ink4(being also referred to as MTS1) is the potential tumor suppressor gene, and it is undergone mutation in a large amount of primary carcinoma or lacks.Kip/Cip family comprises such as p21 Cip1, waf1, p27 Kip1And p57 Kip2In protein.As discussed previously, p21 is induced by p53 and can deactivation cdk2/ cyclin (E/A) and cdk4/ cyclin (D1/D2/D3) mixture.Having observed atypical low-level p27 in mammary cancer, colorectal carcinoma and prostate cancer expresses.On the contrary, the cross expression of cyclin E in solid tumor shows relevant with patient's prognosis mala.The mistake expression of cyclin D1 is relevant with esophagus cancer, mammary cancer, squamous cell carcinoma and nonsmall-cell lung cancer.
Summarize Cdks and related protein thereof above and in proliferative cell, coordinated and driven the key role of cell cycle.Some wherein biochemical route of playing a crucial role of cdks have also been described.Therefore, a kind of therapeutics that adopts target one class cdks or specific cdks of exploitation monotherapy for the treatment of hyperplasia such as cancer may be in demand.It is also conceivable that the cdk inhibitor is used for the treatment of other illness for example virus infection, autoimmune disease and neurodegenerative disease.When with existing or new therapeutical agent combined therapy, the treatment of target cdk also can provide clinical benefit in the treatment of aforementioned diseases.The anticancer therapy that with cdk is target spot may have the advantage that is better than multiple existing antineoplastic agent because they not with the dna direct effect, therefore reduced the danger of secondary tumor development.
Glycogen synthase kinase
Glycogen synthase kinase-3 (GSK3) is a kind of serine-threonine kinase, and there is (GSK3 α ﹠amp in the isotype with two kinds of wide expression in the mankind; β GSK3 β).GSK3 participates in fetal development, protein synthesis, cell proliferation, cytodifferentiation, microtubule kinetics, cell mobility and apoptosis.Thereby GSK3 relates to the process of morbid state, for example diabetes, cancer, alzheimer's disease, apoplexy, epilepsy, motor neurone disease and/or injury of head.(CDK) is closely related for phylogenetic GSK3 and cell cycle protein dependent kinase.
The peptide substrates consensus sequence of being discerned by GSK3 is (Ser/Thr)-X-X-X-(pSer/pThr), and wherein X is arbitrary amino acid (in (n+1), (n+2), (n+3) position), and pSer and pThr are respectively phosphorylation Serine and phosphorylation Threonine (n+4).GSK3 is at (n) position first Serine of phosphorylation or Threonine.Phosphoric acid-the Serine of (n+4) position or phosphoric acid-Threonine are that startup GSK3 is necessary to obtain maximum substrate conversion.GSK3 α is at Ser21, or GSK3 β causes the restraining effect of GSK3 in the phosphorylation of Ser9.The N-terminal that the GSK3 phosphorylation has been drawn in sudden change and peptide competition research is by suppressing the machine-processed model that can compete with the peptide substrates (S/TXXXpS/pT) of phosphorylation automatically.Also there are data proposition GSK3 α and GSK β to regulate subtly by the phosphorylation of tyrosine 279 and 216 respectively.These residues cause the reduction of kinase activity in the body to the sudden change of Phe.The x-ray crystal structure of GSK3 β helps to disclose all aspects that GSK3 activates and regulates.
The GSK3 structure Mammals insulin replies approach a part and can phosphorylation and therefore deactivation glycogen synthetase.Thus, active and the synthetic possible means that have been regarded as resisting II type or non insulin dependent diabetes (NIDDM) of incremental adjustments glycogen thus of incremental adjustments glycogen synthetase by suppressing GSK3, this illness are that a kind of wherein body tissue becomes and insulin stimulating had the illness of tolerance.Cell in liver, fat or the muscle tissue triggers the Regular Insulin that replying of Regular Insulin is incorporated into the extracellular insulin receptor.It causes proteinic phosphorylation of IRS (IRS) and raising to cytolemma subsequently.The proteinic further phosphorylation of IRS has started the gathering of phosphatidylinositol 3-kinase (PI3K) to cytolemma, and it can discharge second messenger's phosphatidylinositols 3,4, the 5-triphosphoric acid.It promotes 3-lipositol dependence protein matter kinases 1 (PDK1) and the common location of protein kinase B (PKB or Akt) on film, and PDK1 activates PKB there.PKB can come phosphorylation and suppress GSK3 α and/or GSK β whereby by the phosphorylation of Ser9 or ser21 respectively.The inhibition of GSK3 then triggers the active rise of glycogen synthetase.Therefore the therapeutical agent that can suppress GSK3 can bring out and be similar to observed those cell responses in insulin stimulating.Substrate was eukaryotic cell protein synthesis initiation factor 2B (eIF2B) in another of GSK3 was individual.EIF2B passes through phosphorylation and inactivation, therefore can the biosynthesizing of arrestin matter.Therefore, the inhibition of GSK3, for example by " Mammals rapamycin target protein " inactivation (mTOR), but the biosynthesizing of upregulated protein matter.At last, there are some to pass through mitogen-activated protein kinase (MAPK) path, make GSK3 by kinases mitogen-activated protein kinase activated protein kinase 1 (MAPKAP-K1 or RSK) phosphorylation and regulate the active evidence of GSK3 for example.These data promptings GSK3 activity can be subjected to the regulation and control that cell fission, Regular Insulin and amino acid stimulate.
Known GSK3 β also is a kind of important component in the vertebrates Wnt signal pathway.Verified this bio-chemical pathway is very important and can regulate cell proliferation in the healthy tissues for normal embryo development.GSK3 is to be suppressed for replying of Wnt stimulation.This can cause GSK3 the substrate for example gene product and the white dephosphorylation of beta-catenin of Axin, adenomatous polyposis coli (APC).The unusual adjusting of Wnt approach is relevant with many cancers.Sudden change during APC and/or beta-catenin are white is common in colorectal carcinoma and other the tumour.Beta-catenin has also demonstrated the importance in cell attachment in vain.Therefore GSK3 also can regulate the cell attachment process to a certain extent.Except the biochemical route of having described, also there be the phosphorylation of GSK3 by cyclin D1 to participate in fissional adjusting, participate in for example data of the phosphorylation of c-Jun, CCAAT/ enhancer binding protein α (C/EBP α), c-Myc and/or other substrate such as nuclear factor of activated T cells (NFATc), heat shock factor-1 (HSF-1) and c-AMP response element binding protein (CREB) of transcription factor.GSK3 also demonstrates in regulating apoptosis and works, though specificity in a organized way.GSK3 may be closely related with the medical conditions that the neuronal cell apoptosis wherein can take place via the effect of short apoptosis mechanism in regulating apoptosis.These examples of disorders are injury of head, apoplexy, epilepsy, alzheimer's disease and motor neurone disease, stein-leventhal syndrome, the sex change of cortex basal nuclei and Pick's disease.At the external excessively phosphorylation canalicular apparatus associated protein Tau of GSK3 that confirmed.The excessive phosphorylation of Tau has been destroyed it and has been combined with the normal of microtubule, and can cause the formation of Tau microfilament in the cell.It is believed that constantly accumulating of these microfilaments can finally cause neuron dysfunction and sex change.Therefore can provide the method for a kind of restriction and/or prevention neurodegeneration effect by suppressing phosphorylation that GSK3 suppresses Tau.
Diffuse type large B cell lymphoid tumor (DLBCL)
The process of cell cycle is to regulate and control by cyclin, cell cycle protein dependent kinase (CDK) with as the combined action of the proteic CDK supressor of cell cycle negative regulation (CDKi).P27KIP1 is CDKi crucial in the cell cycle regulating, and its degraded is that the conversion of G1/S is necessary.Although in the lymphocyte of propagation, lack the expression of p27KIP1, reported that some aggressive B cell lymphomas demonstrate unusual p27KIP1 dyeing.In the lymphoma of this type, found the high expression level that p27KIP1 is unusual.In single argument and multivariate analysis, the clinical correlation analysis of these discoveries shows that the expression of high-caliber p27KIP1 is bad prognostic indicator in this type tumour.These results show has unusual p27KIP1 to express in the diffuse type large B cell lymphoid tumor (DLBCL), have bad Clinical symptoms, prompting is by causing this unusual p27KIPl protein to lose function with the proteic interaction of other cell cycle regulatory factors.(Br.J.Cancer.1999Jul; 80 (9): 1427-34.p27KIPl is unconventionality expression and relevant with bad clinical effectiveness in the diffuse type large B cell lymphoid tumor.Saez A，Sanchez E，Sanchez-Beato M，Cruz MA，ChaconI，Munoz E，Camacho FI，Martinez-Montero JC，Mollejo M，Garcia JF，Piris MA.Department of Pathology，Virgen de la Salud Hospital，Toledo，Spain.)
Chronic lymphocytic leukemia
B cell chronic lymphocytic leukemia (CLL) is the modal leukemia in the western hemisphere, and has every year 10,000 new cases to be diagnosed (Parker SL approximately, Tong T, Bolden S, Wingo PA:Cancer statistics, 1997.Ca.Cancer.J.Clin.47:5, (1997)).With respect to the leukemia of other form, total prognosis bona of CLL is even the patient in late period also has the survival median in 3 years.
Compare with the treatment based on alkylating agent of previous use, add fludarabine and can cause the response fully (27% pair 3%) of higher rate and the survival time that gets nowhere (33 pairs 17 months) as the initial treatment of CLL patient with sympotoms.Though the response fully that reaches after treatment clinically is an initial step of improving the CLL survival rate, most of patients does not reach alleviation fully or fludarabine is not reacted.Moreover, the CLL patient of useful fludarabine treatment all recur at last, thereby make it can only be used as simple releiving property medicament (Rai KR, Peterson B, Elias L, Shepherd L, Hines J, NelsonD, Cheson B, Kolitz J, Schiffer CA:A randomized comparison offludarabine and chlorambucil for patients with previously untreatedchronic lymphocytic leukemia.A CALGB SWOG, CTG/NCI-C and ECOGInter-Group Study.Blood88:141a, 1996 (summary 552, suppl1).Therefore, if want to realize the further improvement of this disease treatment, must identify cytotoxicity with additional fludarabine and the new medicament of removing the chemical sproof new role mechanism of bringing out by inherent CLL r factor.
About CLL patient's relatively poor and bad survival rate to therapeutic response study to such an extent that the normative forecast factor the most widely is unusual p53 function, it is a feature with point mutation or karyomit(e) 17p13 disappearance.Really, in fact there is not reaction in those have CLL patient's the case series of multiple single institution of unusual p53 function, to be proved to be to the treatment of alkylating agent or purine analogue.A kind of introducing of having the ability to overcome the drug-fast therapeutical agent relevant with the p53 sudden change of CLL may be for becoming the important advance of this disease treatment.
The inhibitor good fortune of cell cycle protein dependent kinase draws benefit (flavopiridol) and CYC202 at the external apoptosis that brings out from the malignant cell of B cell chronic lymphocytic leukemia (B-CLL).
Good fortune draws the benefit administration to cause the dependent decomposition of caspase-to active stimulation of caspase3 and p27 (kip1), and p27 is the negative regulatory factor of a kind of cell cycle, and it is crossed in B-CLL and expresses.(Blood.1998 Nov 15；92(10)：3804-16Flavopiridol induces apoptosis inchronic lymphocytic leukemia cells via activation of caspase-3 withoutevidence of bcl-2 modulation or dependence on functional p53.Byrd JC，Shinn C，Waselenko JK，Fuchs EJ，Lehman TA，Nguyen PL，Flinn IW，Diehl LF，Sausville E，Grever MR)。
Prior art
WO02/34721 from Du Pont discloses a kind of indeno as cell cycle protein dependent kinase inhibitor [1,2-c] pyrazoles-4-ketone.
From the WO01/81348 of Bristol Myers Squibb described 5-sulphur-, sulfinyl-and sulfonyl pyrazole also [3,4-b]-pyridine as the purposes of cell cycle protein dependent kinase inhibitor.
WO00/62778 from Bristol Myers Squibb discloses a kind of protein tyrosine kinase inhibitor equally.
From the WO01/72745A1 of Cyclacel described 4-heteroaryl-pyrimidine and preparation thereof that 2-replaces, the pharmaceutical composition that comprises them and its as the purposes of cell cycle protein dependent kinase (CDK) inhibitor with and in the treatment proliferative disease purposes in cancer, leukemia, the psoriasis etc. for example.
WO99/21845 from Agouron has described a kind of cell cycle protein dependent kinase (CDK) that is used to suppress, for example the 4-aminothiazole derivs of CDK1, CDK2, CDK4 and CDK6.This invention also relates to the treatment of the pharmaceutical composition that comprises this compound or preventive use and these compounds for treating malignant diseases by giving significant quantity and the method for other disease.
WO01/53274 from Agouron discloses a kind of compound as the CDK kinase inhibitor, and it can comprise and is connected to the phenyl ring that is replaced by acid amides that contains the N heterocyclic group.
WO01/98290 (Pharmacia ﹠amp; Upjohn) a kind of 3-aminocarboxyl-2-amide group-thiophene derivant as kinases inhibitor is disclosed.
Disclose from the WO01/53268 of Agouron and WO01/02369 that for example the compound of cell proliferation is regulated or suppressed to cell cycle protein dependent kinase or Tyrosylprotein kinase by the arrestin kinases.The compound of Agouron has directly or is connected to via CH=CH or CH=N group the aryl or the heteroaryl ring of the 3-position of indazole ring.
WO00/39108 and WO02/00651 (both all belong to Du Pont medicine) have described heterogeneous ring compound, and it is a trypsin-like serine protease, especially the inhibitor of Xa factor and zymoplasm.It is said that this compound can be used as anti-coagulant or is used to prevent thromboembolism.
US2002/0091116 (people such as Zhu), WO01/19798 and WO01/64642 disclose not on the same group the heterogeneous ring compound as the Xa factor inhibitor separately.Disclose and exemplified the pyrazolecarboxamide compounds that some 1-replace.
US6,127,382, WO01/70668, WO00/68191, WO97/48672, WO97/19052 and WO97/19062 (all belonging to Allergan) disclose separately be used for the treatment of the various hyperproliferation diseases that comprise cancer have an active compound of retinoids.
WO02/070510 (Bayer) has described a kind of amino-dicarboxylic acid compound that is used for the treatment of cardiovascular disorder.Though mentioned pyrazoles prevailingly, in this part file, do not had the specific embodiment of pyrazoles.
WO97/03071 (Knoll AG) discloses a kind of heterocyclic radical-carboxamides derivatives that is used for the treatment of central nervous system disorders.Mentioned the example of pyrazoles prevailingly, but do not had to disclose or exemplify concrete pyrazole compound as heterocyclic radical.
WO97/40017 (Novo Nordisk) has described the compound as the conditioning agent of Protein-tyrosine-phosphatase.
WO03/020217 (Univ.Connecticut) discloses a kind of cannabin(e) (cannabinoid) receptor modulators pyrazoles 3-acid amides that is used for the treatment of nervous disorders.Wherein having described (the 15th page) this compound can be used in the cancer chemotherapy, but and does not know that as carcinostatic agent whether effectively or its whether administration for other purpose this compound.
WO01/58869 (Bristol Myers Squibb) discloses the cannabinoid receptor conditioning agent that can be used for treating multiple disease.The main application of being predicted is for the treatment respiratory disease, although mentioned the treatment of cancer.
WO01/02385 (Aventis Crop Science) discloses 1-(the quinolyl-4)-1H-pyrazole derivatives as mycocide.The unsubstituted pyrazoles as the 1-of synthetic intermediate is wherein disclosed.
WO2004/039795 (Fujisawa) discloses the acid amides as the pyrazole group that comprises the 1-replacement of inhibitors of apolipoprotein b secretion.It is said that this compound can be used for treating illnesss such as hyperlipidemia.
WO2004/000318 (Cellular Genomics) discloses the monocycle class as the various amino-replacement of kinase modulator.No pyrazoles exemplify compound.
Summary of the invention
The invention provides and have that cell cycle protein dependent kinase suppresses or it is active to regulate and glycogen synthase kinase-3 (GSK3) suppresses or regulate active compound, and estimate that it can be used for preventing or treating by kinase mediated morbid state or illness.
Therefore, for example, estimate that compound of the present invention will can be used for alleviating or reducing the incidence of cancer.
First aspect the invention provides the compound of formula (I):
Figure A20068000923800241
Wherein:
R 1Be selected from:
(a) 2, the 6-dichlorophenyl;
(b) 2, the 6-difluorophenyl;
(c) 2,3, the 6-trisubstd phenyl, wherein the substituting group of this phenyl is selected from fluorine, chlorine, methyl and methoxyl group;
(d) radicals R 0,
(e) radicals R 1a
(f) radicals R 1b
(g) radicals R 1c
(h) radicals R 1dWith
(j) 2,6-difluorophenyl amino;
R 0Be carbocyclic ring or heterocyclic group with 3-12 ring members; Or the C that is randomly replaced by one or more substituting groups 1-8Alkyl, described substituting group is selected from fluorine, hydroxyl, cyano group; C 1-4-oxyl, amino, list-or two-C 1-4Alkyl amino and carbocyclic ring or heterocyclic group with 3-12 ring members, and wherein 1 or 2 carbon atom of alkyl can randomly be selected from O, S, NH, SO, SO 2Atom or group replace;
R 1aBe selected from cyclopropyl-cyano group-methyl; Furyl; The benzoisoxazole base; The methyl-isoxazole base; The mono-substituted phenyl of 2-and 2, the dibasic phenyl of 6-, wherein the substituting group on the phenyl moiety is selected from methoxyl group, oxyethyl group, fluorine, chlorine and difluoro-methoxy; Condition is R 1aNot 2,6-difluorophenyl or 2,6-dichlorophenyl;
R 1bBe selected from tetrahydrofuran base; And list-replacement and dibasic phenyl, wherein the substituting group on the phenyl moiety is selected from fluorine; Chlorine; Methoxyl group; Oxyethyl group and methyl sulphonyl;
R 1cBe selected from; The benzoisoxazole base; Contain one or two and be selected from the heteroatomic quinary heteroaryl ring of O and N and contain six of one or two nitrogen heteroatom ring members-first heteroaryl ring, heteroaryl ring is randomly replaced by methyl, fluorine, chlorine or trifluoromethyl in each case; With the phenyl that is selected from the substituting group replacement of bromine, chlorine, fluorine, methyl, trifluoromethyl, oxyethyl group, methoxyl group, methoxy ethoxy, methoxymethyl, dimethylaminomethyl and difluoro-methoxy by, two or three; Condition is R 1aNot 2, the 6-difluorophenyl;
R 1dBe radicals R 1e-(CH 2) nCH (CN)-, wherein n is 0-2 and R 1eBe carbocyclic ring or heterocyclic group with 3-12 ring members;
R 2aAnd R 2bRespectively do for oneself hydrogen or methyl;
And wherein:
If R A. 1Be (a) 2,6-dichlorophenyl and R 2aAnd R 2bBe all hydrogen; R then 3Can be selected from:
(i) group
Figure A20068000923800251
R wherein 9Be selected from C (O) NR 5R 6C (O)-R 10With 2-pyrimidyl, wherein R 10Be the C that is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group and methoxyl group 1-4Alkyl; And R 11, R wherein 11Be the C that is replaced by one or more substituting groups that are selected from fluorine, chlorine and cyano group 1-4Alkyl;
(ii) group
Figure A20068000923800252
R wherein 12Be C 2-4Alkyl;
(iii) group
Figure A20068000923800253
R wherein 13Be selected from methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl and 1-pyrrolidyl;
The (iv) substituted 3-pyridyl or the 4-pyridyl of following formula
Figure A20068000923800261
Radicals R wherein 14Position or contraposition and be selected from methyl, methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl, 1-pyrrolidyl, 4-piperidyl oxygen base, 1-C between with the valence link of asterisk mark 1-4Alkoxy carbonyl-piperidin-4-yl oxygen base, 2-hydroxyl-oxethyl and 2-methoxy ethoxy; With
(v) be selected from 2-pyrazinyl, 5-pyrimidyl, cyclohexyl, 1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base (4-cyclohexanone ethylene ketal), 4-methyl sulphonyl amino-cyclohexyl, tetrahydric thiapyran-4-group, 1,1-dioxo-tetrahydric thiapyran-4-group, tetrahydropyran-4-base, 4,4-difluoro cyclohexyl and 3, the group of 5-dimethyl isoxazole-4-base; With
If R B. 1Be (b) 2,6-difluorophenyl and R 2aAnd R 2bBe all hydrogen; R then 3Can be selected from:
(vi) 1-methyl-piperidines-3-base; 4-(2-dimethylamino ethoxy)-cyclohexyl; With the 4-piperidyl that N-replaces, wherein the N-substituting group is selected from cyano methyl and cyano ethyl; With
(vii) group
R wherein 13As hereinbefore defined; With
If R C. 1Be (c) 2,3, the 6-trisubstd phenyl, wherein the substituting group of this phenyl is selected from fluorine, chlorine, methyl and methoxyl group; And R 2aAnd R 2bBe all hydrogen; R then 3Can be selected from group defined herein (ii), (xi), (xii) and (xiii); With
(viii) 4-piperidyl and 1-methyl-4-piperidyl;
(ix) tetrahydropyran-4-base; With
(x) group:
Figure A20068000923800263
R wherein 4Be C 1-4Alkyl;
If R D. 1Be (d) radicals R 0, R wherein 0Be carbocyclic ring or heterocyclic group with 3-12 ring members; Or the C that is randomly replaced by one or more substituting groups 1-8Alkyl, described substituting group is selected from fluorine, hydroxyl, cyano group; C 1-4-oxyl, amino, list-or two C 1-4Alkyl amino and have the carbocyclic ring or the heterocyclic group of 3-12 ring members, and wherein 1 or 2 carbon atom of alkyl can randomly be selected from O, S, NH, SO, SO 2Atom or group replace; R then 3Can be selected from:
(xi) group:
Figure A20068000923800271
R wherein 7For:
● except C 1-4Unsubstituted alkyl outside the alkyl;
● have one or more substituent substituted C 1-4Alkyl, described substituting group is selected from fluorine, chlorine, hydroxyl, methyl sulphonyl, cyano group, methoxyl group, NR 5R 6With contain 4-7 unit saturated carbon ring or the heterocycle that is selected from the heteroatomic ring member of O, N and S to too many by two;
● group NR 5R 6, R wherein 5And R 6Be selected from hydrogen and C 1-4Alkyl, C 1-2Alkoxyl group and C 1-2Alkoxy-C 1-4Alkyl, condition are R 5And R 6In to be no more than one be C 1-2Alkoxyl group, or NR 5R 6Formation contains one or two five or the hexa-atomic saturated heterocyclic that are selected from the heteroatomic ring member of O, N and S, and this heterocycle is randomly by one or more methyl substituted;
● contain one or two and be selected from the heteroatomic ring member of N, S and O and randomly by methyl, methoxyl group, fluorine, chlorine or group NR 5R 6Five or the six membered heteroaryl that replace;
● randomly by methyl, methoxyl group, fluorine, chlorine, cyano group or group NR 5R 6The phenyl that replaces;
● C 3-6Cycloalkyl; With
● contain one or two five or hexa-atomic saturated heterocyclic that is selected from the heteroatomic ring member of O, N and S, this heterocycle is randomly by one or more methyl substituted; With
(xii) group:
Figure A20068000923800272
R wherein 12aFor by one or more fluorine, chlorine, C of being selected from 3-6Cycloalkyl, oxa--C 4-6Cycloalkyl, cyano group, methoxyl group and NR 5R 6The C that replaces of substituting group 1-4Alkyl, condition are when there being group NR 5R 6The time, R 12Sauerstoffatom that is connected and group NR 5R 6Between have at least two carbon atoms; If with E. R 1Be (e) radicals R 1aAnd R 2aAnd R 2bBe all hydrogen, then R 3Can be (xiii) group
Figure A20068000923800281
With
If R F. 1Be (f) radicals R 1bAnd R 2aAnd R 2bBe all hydrogen, then R 3Can be (xiv) methyl; With
If R G. 1Be (g) radicals R 1cAnd R 2aAnd R 2bBe all hydrogen, then R 3Can be (xv) group
With:
If R H. 1Be (h) radicals R 1d, R then 3Be group-Y-R 3a, wherein Y is that valence link or length are the alkylidene chain and the R of 1,2 or 3 carbon atom 3aBe selected from hydrogen and carbocyclic ring and heterocyclic group with 3-12 ring members;
If R J. 1Be (j) 2,6-difluorophenyl amino, and R 2aAnd R 2bBe all hydrogen; R then 3Can be methyl; With
If R K. 1Be 2,6-dichlorophenyl and (k) R 2aBe methyl and R 2bBe hydrogen, perhaps (I) R 2aBe hydrogen and R 2bBe methyl; R then 3Can be 4-piperidines group;
Or its salt, tautomer, solvate and N-oxide compound.
The present invention especially also provides:
Be used to prevent or treat by the formula defined herein (I) of cell cycle protein dependent kinase or glycogen synthase kinase-3 disease states mediated or illness or the compound of its any subgroup or embodiment.
Prevention or treatment be by the method for cell cycle protein dependent kinase or glycogen synthase kinase-3 disease states mediated or illness, and this method comprises the compound of its individuality of needs being used formula defined herein (I) or its any subgroup or embodiment.
Alleviate or reduce the method by the incidence of cell cycle protein dependent kinase or glycogen synthase kinase-3 disease states mediated or illness, this method comprises the compound of its individuality of needs being used formula defined herein (I) or its any subgroup or embodiment.
Treatment comprises abnormal cell growth or the disease that caused by abnormal cell growth or the method for illness in Mammals, and this method comprises administration is suppressed the formula defined herein (I) of abnormal cell growth significant quantity or the compound of its any subgroup or embodiment.
Alleviate or reduce the method for the incidence of the disease that comprises abnormal cell growth or caused by abnormal cell growth or illness in Mammals, this method comprises administration is suppressed the formula defined herein (I) of abnormal cell growth significant quantity or the compound of its any subgroup or embodiment.
Treatment comprises abnormal cell growth or the disease that caused by abnormal cell growth or the method for illness in Mammals, and this method comprises administration is suppressed cdk kinases (as ckd1 or ckd2) or the formula defined herein (I) of the active significant quantity of glycogen synthase kinase-3 or the compound of its any subgroup or embodiment.
Alleviate or reduce the method for the incidence of the disease that comprises abnormal cell growth or caused by abnormal cell growth or illness in Mammals, this method comprises administration is suppressed cdk kinases (as ckd1 or ckd2) or the formula defined herein (I) of the active significant quantity of glycogen synthase kinase-3 or the compound of its any subgroup or embodiment.
The method that suppresses cell cycle protein dependent kinase or glycogen synthase kinase-3, this method comprise makes kinases contact with kinase whose formula (I) defined herein of inhibition or the compound of its any subgroup or embodiment.
Regulate the method for cell processes (for example cell fission), this method realizes by the activity that the compound with formula defined herein (I) or its any subgroup or embodiment suppresses cell cycle protein dependent kinase or glycogen synthase kinase-3.
Be used to prevent or treat the formula defined herein (I) of morbid state as herein described or the compound of its any subgroup or embodiment.
The purposes of the compound of formula defined herein (I) or its any subgroup or embodiment in the preparation medicine, wherein said medicine is used for one or more purposes defined herein.
Comprise formula defined herein (I) or the compound of its any subgroup or embodiment and the pharmaceutical composition of pharmaceutically acceptable carrier.
Comprise formula defined herein (I) or the compound of its any subgroup or embodiment and the pharmaceutical composition of pharmaceutically acceptable carrier, it is to be suitable for Orally administered form.
Be used for the pharmaceutical composition used with the aqueous solution form, described pharmaceutical composition is included in solubleness in the water greater than 25mg/ml, usually greater than 50mg/ml and be preferably greater than the formula defined herein (I) of salt form of 100mg/ml or the compound of its any subgroup or embodiment.
Be used in formula defined herein (I) in the medicine or the compound of its any subgroup or embodiment.
Diagnosis and treatment be by the method for cell cycle protein dependent kinase disease states mediated or illness, and this method comprises that whether (i) screening patient is disease or the illness that use is had the treatment sensitivity that the active compound of anti-cell cyclin-dependent kinase carries out to determine that this patient is suffering from the disease that maybe may suffer from or illness; (ii), use the compound of formula defined herein (I) or its any subgroup or embodiment then to the patient therefore showing that disease of patient or illness are under the situation of susceptibility.
The purposes of the compound of formula defined herein (I) or its any subgroup or embodiment in the preparation medicine, described medicine is used for screened and be determined and suffer from disease or illness or have the disease suffered from or the patient of the danger of illness treatment or preventing disease state or illness, and described disease or illness have the treatment sensitivity that the active compound of anti-cell cyclin-dependent kinase carries out to use.
Be used for suppressing the formula defined herein (I) of tumor growth or the compound of its any subgroup or embodiment Mammals.
Be used for suppressing the formula defined herein (I) of growth of tumour cell (for example Mammals) or the compound of its any subgroup or embodiment.
The method that suppresses tumor growth in Mammals (for example people), this method comprise to Mammals (for example people) uses the formula defined herein (I) of inhibition tumor growth significant quantity or the compound of its any subgroup or embodiment.
The method that suppresses tumour cell (tumour cell that for example is present in Mammals such as philtrum) growth, this method comprise makes tumour cell contact with formula defined herein (I) that suppresses the growth of tumour cell significant quantity or the compound of its any subgroup or embodiment.
Be used for above-mentioned any purposes and method and as the described compound defined herein of this paper other parts.
General preferred meaning and definition
In this part, with the same in all other parts of the application, unless context has explanation in addition, otherwise to all subgroups that comprise formula defined herein (I) of mentioning of formula (I) compound, and term ' subgroup ' comprises all preferred meaning, embodiment, embodiment and particular compound defined herein.
In addition; formula (I) compound and mentioning of its subgroup are comprised its ionic species, salt, solvate, isomer, tautomer, N-oxide compound, ester, prodrug, isotropic substance and protected form; as following discussion: preferably its salt or tautomer or isomer or N-oxide compound or solvate, and more preferably its salt or tautomer or N-oxide compound or solvate.
Unless context has explanation in addition, otherwise general preferred meaning hereinafter and definition will be applicable to R 1To R 14In each and their various subgroups, Asia-definition, example and embodiment.
Unless context has requirement in addition, otherwise any herein to any compound subgroup in the formula that also will be referred to (I) of the mentioning scope of formula (I) and its any preferred meaning and example.
Unless context has explanation in addition, otherwise mentioning of " carbocyclic ring " used herein and " heterocycle " group both comprised the aromatics ring system, comprise non-aromatics ring system again.Therefore, for example, term " carbocyclic ring and heterocyclic group " comprises aromatics, non-aromatics, undersaturated, fractional saturation in its scope and complete saturated carbocyclic ring and heterocycle ring system.Generally speaking, this class group can be monocyclic or bicyclic, can contain for example 3-12 ring members, more generally is 5-10 ring members.The example of monocyclic groups be contain 3,4,5,6,7 and 8 ring memberses, be the group of 3-7, preferred 5 or 6 ring memberses more generally.The example of bicyclic groups be contain 8,9,10,11 and 12 ring memberses, be those of 9 or 10 ring memberses more generally.
Carbocyclic ring or heterocyclic group can be have 5-12 ring members, be the aryl or the heteroaryl of 5-10 ring members more generally.Term used herein " aryl " refers to the carbon ring group with aromatic character, the heterocyclic group that term " heteroaryl " is used to represent to have aromatic character in this article.Term " aryl " and " heteroaryl " comprise that wherein one or more rings are many rings (for example two rings) ring systems of non-aromatics, and condition is that at least one ring is an aromatics.In this class polycyclic system, group can connect by aromatic ring or by non-aromatic ring.Aryl or heteroaryl can be monocycle or bicyclic groups, can be unsubstituted or are replaced by one or more substituting groups, for example by one or more radicals R defined herein 15Replace.
Term " non-aromatic group " comprises the unsaturated ring system that does not have aromatic character, fractional saturation and complete saturated carbocyclic ring and heterocycle ring system.Term " undersaturated " and " fractional saturation " refer to that ring structure wherein contains the atom of a shared above valence link, promptly ring contains for example ring of C=C, C ≡ C or N=C key of at least one Multiple Bonds.Term " fully saturated " and " saturated " refer to the ring that does not wherein have Multiple Bonds between the annular atoms.Saturated carbon ring group comprises hereinafter defined cycloalkyl.The carbon ring group of fractional saturation comprises hereinafter defined cycloalkenyl group, for example cyclopentenyl, cycloheptenyl and cyclooctene base.Other example of cycloalkenyl group has cyclohexenyl.
The example of heteroaryl have contain 5-12 ring members, be the monocycle and the bicyclic groups of 5-10 ring members more generally.Heteroaryl can be for example five yuan or single six-membered rings or by condensed five and six-ring or two condensed six-rings or two ring structures that formed by two condensed five-rings as an other example.Each ring can contain about at the most 4 heteroatomss, and described heteroatoms is selected from nitrogen, sulphur and oxygen usually.Usually heteroaryl ring contains 4 heteroatomss at the most, more generally contains 3 heteroatomss at the most, more generally contains 2 at the most, 1 heteroatoms for example.In one embodiment, heteroaryl ring contains at least one theheterocyclic nitrogen atom.The heteroaryl ring nitrogen may be alkaline, and as under the situation of imidazoles or pyridine, perhaps right and wrong alkalescence basically is as under the situation of indoles or pyrroles's nitrogen.Generally speaking, comprise that the basic nitrogen atom number that exists in the heteroaryl of any amino substituting group of ring is less than 5.
The example of quinary heteroaryl includes but not limited to pyrroles, furans, thiophene, imidazoles, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazoles, triazole and tetrazol group.
The example of six membered heteroaryl includes but not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
Bicyclic heteroaryl can be for example to be selected from following group:
A) with 5-that contains 1,2 or 3 ring hetero atom or 6-unit ring condensed phenyl ring;
B) with 5-that contains 1,2 or 3 ring hetero atom or 6-unit ring condensed pyridine ring;
C) with 5-that contains 1 or 2 ring hetero atom or 6-unit ring condensed pyrimidine ring;
D) with 5-that contains 1,2 or 3 ring hetero atom or 6-unit ring condensed pyrrole ring;
E) with 5-that contains 1 or 2 ring hetero atom or 6-unit ring condensed pyrazoles ring;
F) with 5-that contains 1 or 2 ring hetero atom or 6-unit ring condensed pyrazine ring;
G) with 5-that contains 1 or 2 ring hetero atom or 6-unit ring condensed imidazole ring;
H) condense De oxazole ring with 5-that contains 1 or 2 ring hetero atom or 6-unit ring;
I) with 5-that contains 1 or 2 ring hetero atom or 6-unit ring condensed isoxazole ring;
J) with 5-that contains 1 or 2 ring hetero atom or 6-unit ring condensed thiazole ring;
K) with 5-that contains 1 or 2 ring hetero atom or 6-unit ring condensed isothiazole ring;
1) with 5-that contains 1,2 or 3 ring hetero atom or 6-unit ring condensed thiphene ring;
M) with 5-that contains 1,2 or 3 ring hetero atom or 6-unit ring condensed furan nucleus;
N) with 5-that contains 1,2 or 3 ring hetero atom or 6-unit ring condensed cyclohexyl ring; With
O) with 5-that contains 1,2 or 3 ring hetero atom or 6-unit ring condensed cyclopentyl ring.
A subgroup of bicyclic heteroaryl is formed to (o) by above (a) to (e) with (g).
The object lesson that contains with the pentacyclic bicyclic heteroaryl of another five-ring condensed includes but not limited to Imidazothiazole (for example imidazo [2,1-b] thiazole) and imidazo imidazoles (for example imidazo [1,2-a] imidazoles).
The object lesson that contains with the bicyclic heteroaryl of five-ring condensed six-ring includes but not limited to cumarone, thionaphthene, benzoglyoxaline benzoxazole, the Yi benzoxazole, benzoisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indoles, isoindole, indolizine, indoline, xylylenimine, purine (VITAMIN B4 for example, guanine), indazole, (for example pyrazolo [1 for pyrazolopyrimidine, 5-a] pyrimidine), triazolo pyrimidine (for example [1,2,4] triazolo [1,5-a] pyrimidine), benzo dioxole and Pyrazolopyridine (for example pyrazolo [1,5-a] pyridine) group.
The object lesson that contains the bicyclic heteroaryl of two condensed six-rings includes but not limited to quinoline, isoquinoline 99.9, chroman, benzo dihydro thiapyran (thiochroman), chromene, heterochromatic alkene, chroman, heterochromatic full, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnolines, phthalazines, naphthyridines and pteridine group.
A subgroup of heteroaryl comprises pyridyl, pyrryl, furyl, thienyl, imidazolyl oxazolyl oxadiazole base oxatriazole base isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, triazinyl, triazolyl, tetrazyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, chromanyl, benzo dihydro thiapyran base, benzimidazolyl-benzoxazolyl, benzoisoxazole, benzothiazolyl and benzisothiazole, isobenzofuran-base, indyl, pseudoindoyl, the indolizine base, indolinyl, dihydro-iso indolyl, purine radicals (VITAMIN B4 for example, guanine), indazolyl, the benzo dioxolyl, chromenyl, heterochromatic thiazolinyl, different chromanyl, the benzodioxan base, quinolizinyl benzoxazinyl, the benzodiazine base, the pyridopyridine base, quinoxalinyl, quinazolyl, the cinnolines base, phthalazinyl, naphthyridinyl and pteridyl.
Contain the polyaromatic of aromatic ring and non-aromatic ring and the example of heteroaryl and comprise naphthane, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzo thiophene (dihydrobenzthiene), Dihydrobenzofuranes, 2,3-dihydro-benzo [1,4] dioxines, benzo [1,3] dioxole, 4,5,6,7-tetrahydrochysene benzfuran, indoline and indane group.
The example of isocyclic aryl comprises phenyl, naphthyl, indenyl and tetralyl.
The example of non-aromatic heterocyclic group comprises unsubstituted or substituted (by one or more radicals R 15Replace) have 3-12 ring members, normally 4-12 ring members, be the heterocyclic group of 5-10 ring members more generally.This class group can for example be monocyclic or bicyclic, and has 1-5 heteroatomic ring member (more generally being 1,2,3 or 4 heteroatomic ring member) usually, and described heteroatoms is selected from nitrogen, oxygen and sulphur usually.
When having sulphur, under the situation that the atom that adjoins and group allow, its can with-S-,-S (O)-or-S (O) 2-form exist.
Heterocyclic group for example can contain cyclic ether part (for example at tetrahydrofuran (THF) with in the diox), cyclic thioether part (for example in tetramethylene sulfide and dithiane), cyclic amine part (for example in tetramethyleneimine), cyclic amide part (for example in pyrrolidone), cyclic thioamide, ring-type thioester, cyclic ester part (for example in butyrolactone), cyclic sulfones (for example in tetramethylene sulfone and cyclobufene sultone (sulpholene)), cyclic sulphoxide, ring-type sulphonamide and its combination (for example morpholine and parathiazan and S-oxide compound and S, S-dioxide).Other example of heterocyclic group is those (for example in imidazolidin-2-ones) that contain ring-type urea part.
In a subgroup of heterocyclic radical, heterocyclic radical contains cyclic ether part (for example at tetrahydrofuran (THF) with in the diox), cyclic thioether part (for example in tetramethylene sulfide and dithiane), cyclic amine part (for example in tetramethyleneimine), cyclic sulfones (for example in tetramethylene sulfone and cyclobufene sultone), cyclic sulphoxide, ring-type sulphonamide and its combination (for example parathiazan).
The example of monocycle non-aromatic heterocyclic group comprises 5-, 6-and 7-unit monocyclic heterocycles group.Object lesson comprises morpholine, piperidines (piperidino for example, the 2-piperidyl, 3-piperidyl and 4-piperidyl), tetramethyleneimine (1-pyrrolidyl for example, 2-pyrrolidyl and 3-pyrrolidyl), pyrrolidone, pyrans (2H-pyrans or 4H-pyrans), dihydro-thiophene, dihydropyrane, dihydrofuran, thiazoline, tetrahydrofuran (THF), tetramethylene sulfide diox, tetrahydropyrans (for example 4-THP trtrahydropyranyl), tetrahydroglyoxaline, imidazolidone oxazoline, thiazoline, the 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazine such as N methyl piperazine.Other example comprises parathiazan and S-oxide compound and S, S-dioxide (particularly parathiazan).Example in addition also comprises azetidine, piperidone, piperazine ketone and N-Alkylpiperidine such as N-methyl piperidine.
A preferred subgroup of non-aromatic heterocycle is by saturated group such as azetidine, tetramethyleneimine, piperidines, morpholine, parathiazan, parathiazan S, and S-dioxide, piperazine, N-alkylpiperazine and N-Alkylpiperidine are formed.
Another subgroup of non-aromatic heterocycle is by tetramethyleneimine, piperidines, morpholine, parathiazan, parathiazan S, and S-dioxide, piperazine and N-alkylpiperazine such as N methyl piperazine are formed.
A concrete subgroup of heterocyclic radical is made up of tetramethyleneimine, piperidines, morpholine and N-alkylpiperazine (for example N methyl piperazine) and optional parathiazan.
The example of non-aromatics carbon ring group comprises cycloalkyl such as cyclohexyl and cyclopentyl, cycloalkenyl group such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctene base and cyclohexadienyl, cyclooctatetraene, naphthane methyne and naphthalane base.
Preferred non-aromatics carbon ring group is a monocycle, most preferably is saturated monocycle.
Typical example has three, four, five and hexa-atomic saturated carbon ring, for example randomly substituted cyclopentyl and cyclohexyl ring.
A subgroup of non-aromatics carbon ring group comprises unsubstituted or substituted (by one or more radicals R 15Replace) monocyclic groups, particularly saturated monocyclic groups, for example cycloalkyl.The example of this class cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl; More generally be cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.
Other example of non-aromatics cyclic group comprises bridged-ring system such as bicyclic alkane and azabicyclic alkane, but this class bridged-ring system generally is less preferred." bridged-ring system " means the wherein ring system of two shared two above atoms of ring, referring to for example Advanced Organic Chemistry, and Jerry March, the 4th edition, Wiley Interscience, 131-133 page or leaf, 1992.The example of bridging ring system comprises two ring [2.2.1] heptane, aza-bicyclo [2.2.1] heptane, two ring [2.2.2] octanes, aza-bicyclo [2.2.2] octane, two ring [3.2.1] octane and aza-bicyclo [3.2.1] octanes.An object lesson of bridging ring system is 1-aza-bicyclo [2.2.2] octane-3-base.
Mention at this paper under the situation of carbocyclic ring and heterocyclic group that unless context has explanation in addition, otherwise carbocyclic ring or heterocycle may be unsubstituted or by one or more substituting group radicals R 15Replace described radicals R 15Be selected from halogen, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, amino, list-or two-C 1-4Alkyl amino, carbocyclic ring and heterocyclic group with 3-12 ring members; Radicals R a-R b, R wherein aBe valence link, O, CO, X 1C (X 2), C (X 2) X 1, X 1C (X 2) X 1, S, SO, SO 2, NR c, SO 2NR cOr NR cSO 2R bBe selected from hydrogen, have carbocyclic ring and the heterocyclic group and the C of 3-12 ring members 1-8Alkyl, described C 1-8Alkyl is randomly by one or more hydroxyl, oxo base, halogen, cyano group, nitro, carboxyl, amino, list-or two-C that are selected from 1-4The substituting group of alkyl amino, the carbocyclic ring with 3-12 ring members and heterocyclic group replaces, and C wherein 1-8One or more carbon atoms of alkyl can be randomly by O, S, SO, SO 2, NR c, X 1C (X 2), C (X 2) X 1Or X 1C (X 2) X 1Replace;
R cBe selected from hydrogen and C 1-4Alkyl; And
X 1Be O, S or NR c, X 2Be=O ,=S or=NR c
In the substituting group radicals R 15Contain or comprise under the situation of carbocyclic ring or heterocyclic group, described carbocyclic ring or heterocyclic group can be unsubstituted or can be own by one or more other substituting group radicals R 15Replace.In a subgroup of formula (I) compound, the substituting group radicals R that this class is other 15Can comprise carbocyclic ring or heterocyclic group, itself further is not substituted usually.In another subgroup of formula (I) compound, described other substituting group does not comprise carbocyclic ring or heterocyclic group, but is selected from above at R 15Definition in the group listed.
Can select substituent R 15Be no more than 20 non-hydrogen atoms so that they contain, for example be no more than 15 non-hydrogen atoms, for example be no more than 12 or 11 or 10 or 9 or 8 or 7 or 6 or 5 non-hydrogen atoms.
Have at carbocyclic ring and heterocyclic group and a pair ofly to be positioned at identical or to adjoin under the substituent situation on the annular atoms, thereby two substituting groups can connect and form cyclic group.Therefore, two radicals R of adjoining 15Can form 5-unit's heteroaryl ring or 5-or 6-non-aromatic carbocyclic of unit or heterocycle with carbon atom or heteroatoms that they connected, wherein said heteroaryl and heterocyclic radical contain 3 heteroatomic ring members that are selected from N, O and S at the most.For example, be positioned at ring adjoin on the carbon atom a pair of substituting group that adjoins can via one or more heteroatomss be connected with substituted alkylidene group randomly with form the condensed oxa--, two oxa-s-, azepine-, diaza or oxa--azepine-cycloalkyl.
The substituent example that this class connects comprises:
Figure A20068000923800371
The example of halogenic substituent comprises fluorine, chlorine, bromine and iodine.Preferred especially fluorine and chlorine.
Above and in the definition of hereinafter used formula (I) compound, term " alkyl " is a generic term, it comprise have full carbon skeleton and the aliphatics of forming by carbon and hydrogen atom, alicyclic and aromatic group, other has except the situation of explanation.
In some cases, as defined herein, atom or atomic group that one or more carbon atoms of formation carbon skeleton can be prescribed replace.
The example of alkyl comprises alkyl, cycloalkyl, cycloalkenyl group, isocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenyl alkyl and carbocyclic ring aralkyl, arylalkenyl and sweet-smelling alkynyl.This class group can be unsubstituted or be replaced by one or more substituting groups as defined herein having under the situation of explanation.Unless context has explanation in addition, otherwise hereinafter the example and the preferred meaning of statement are applicable to each hydrocarbyl substituent mentioned or the substituting group that contains alkyl in the substituent various definition of formula (I) compound.
Prefix " C used herein X-y" (wherein x and y are integer) refer to the carbonatoms in the given group.Therefore, C 1-4Alkyl contains 1-4 carbon atom, C 3-6Cycloalkyl contains 3-6 carbon atom etc.
Preferred non-aromatic hydrocarbyl is saturated group such as alkyl and cycloalkyl.
For example, generally speaking, unless context has explanation in addition, otherwise alkyl can have 8 carbon atoms at the most.In having the alkyl subgroup of 1-8 carbon atom, object lesson has C 1-6Alkyl is as C 1-4Alkyl (C for example 1-3Alkyl or C 1-2Alkyl or C 2-3Alkyl or C 2-4Alkyl), the object lesson of any each numerical value or be selected from C 1, C 2, C 3, C 4, C 5, C 6, C 7And C 8The combination of the numerical value of alkyl.
Straight chained alkyl both contained in term " alkyl ", contains branched-chain alkyl again.The example of alkyl comprise methyl, ethyl, propyl group, sec.-propyl, just-butyl, isobutyl-, tert-butyl, just-amyl group, 2-amyl group, 3-amyl group, 2-methyl butyl, 3-methyl butyl and just-hexyl and isomer thereof.In having the alkyl subgroup of 1-8 carbon atom, object lesson is C 1-6Alkyl is as C 1-4Alkyl (C for example 1-3Alkyl or C 1-2Alkyl or C 2-3Alkyl or C 2-4Alkyl).
The example of cycloalkyl has derived from those of cyclopropane, tetramethylene, pentamethylene, hexanaphthene and suberane.In the cycloalkyl subgroup, cycloalkyl has 3-8 carbon atom, and object lesson has C 3-6Cycloalkyl.
The example of alkenyl includes but not limited to vinyl (vinyl), 1-propenyl, 2-propenyl (allyl group), pseudoallyl, butenyl, fourth-1,4-dialkylene, pentenyl and hexenyl.In the alkenyl subgroup, alkenyl has 2-8 carbon atom, and object lesson has C 2-6Alkenyl is as C 2-4Alkenyl.
The example of cycloalkenyl group includes but not limited to cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclopentadienyl and cyclohexenyl.In the cycloalkenyl group subgroup, cycloalkenyl group has 3-8 carbon atom, and object lesson has C 3-6Cycloalkenyl group.
The example of alkynyl includes but not limited to ethynyl and 2-propynyl (propargyl).In having the alkynyl subgroup of 2-8 carbon atom, object lesson has C 2-6Alkynyl is as C 2-4Alkynyl.
The example of isocyclic aryl comprises substituted and unsubstituted phenyl.
The example of cycloalkylalkyl, cycloalkenyl alkyl, carbocyclic ring aralkyl, arylalkenyl and sweet-smelling alkynyl comprises styroyl, benzyl, styryl, phenylacetylene base, cyclohexyl methyl, cyclopentyl-methyl, cyclobutylmethyl, cyclopropyl methyl and cyclopentenyl methyl.
When existing and under the situation of explanation, alkyl can randomly be replaced by one or more substituting groups, and described substituting group is selected from: hydroxyl, oxo base, alkoxyl group, carboxyl, halogen, cyano group, nitro, amino, list-or two-C 1-4Alkyl amino and monocycle or bicyclic carbocyclic ring and heterocyclic group with 3-12 (3-10 usually, more generally 5-10 is individual) ring members.Preferred substituted comprises halogen such as fluorine.Therefore, for example, substituted alkyl can be partially fluorinated or fluoridized group, as difluoromethyl or trifluoromethyl.In one embodiment, preferred substituted comprise have 3-7 ring members, more generally be the monocyclic carbocyclic ring and the heterocyclic group of 3,4,5 or 6 ring memberses.
Under the situation of explanation, one or more carbon atoms of alkyl can be randomly by O, S, SO, SO 2, NR c, X 1C (X 2), C (X 2) X 1Or X 1C (X 2) X 1(or its subgroup) replaces, wherein X 1And X 2As hereinbefore defined, condition is a carbon atom that keeps alkyl at least.For example, 1,2,3 or 4 carbon atom of alkyl can be replaced by one of listed atom or group, and replacement atom or group can be identical or different.Generally speaking, the quantity of linearity in the quantity of superseded linearity or skeleton carbon atom and the group that replaces them or skeletal atom is consistent.Wherein one or more carbon atoms of alkyl are comprised ether and thioether (C is replaced by O or S), acid amides, ester, thioamides and thioester by the example of defined replacement atom or the displaced group of group above (C-C are by X 1C (X 2) or C (X 2) X 1Replacement), (C is by SO or SO for sulfone and sulfoxide 2Replacement), (C is by NR for amine cReplace).Other example comprises urea, carbonic ether and carbamate, and (C-C-C is by X 1C (X 2) X 1Replace).
Have at amino under the situation of two hydrocarbyl substituents, they can and randomly be connected to form 4-7 ring members, be the ring structure of 5-6 ring members more generally with another heteroatoms such as nitrogen, sulphur or oxygen with nitrogen-atoms that they connected.
Term used herein " azepine-cycloalkyl " refers to one of them carbocyclic ring member by the displaced cycloalkyl of nitrogen-atoms.Therefore, the example of azepine-cycloalkyl comprises piperidines and tetramethyleneimine.Term used herein " oxa--cycloalkyl " refers to one of them carbocyclic ring member by the displaced cycloalkyl of Sauerstoffatom.Therefore, the example of oxa--cycloalkyl comprises tetrahydrofuran (THF) and tetrahydropyrans.Similarly, term " diaza-cycloalkyl ", " two oxa-s-cycloalkyl " and " azepine-oxa--cycloalkyl " refer to wherein two carbocyclic ring members respectively by two nitrogen-atoms or by two Sauerstoffatoms or by a nitrogen-atoms and the displaced cycloalkyl of Sauerstoffatom.Therefore, at oxa--C 4-6In the cycloalkyl, there are 3-5 carbocyclic ring member and oxygen ring members.For example, oxa--cyclohexyl is a THP trtrahydropyranyl.
No matter be about be present on carbocyclic ring or the heterocyclic moiety substituting group or about being present in other locational other substituting group of formula (I) compound, definition " R used herein a-R b" especially comprise such compound, wherein R aBe selected from valence link, O, CO, OC (O), SC (O), NR cC (O), OC (S), SC (S), NR cC (S), OC (NR c), SC (NR c), NR cC (NR c), C (O) O, C (O) S, C (O) NR c, C (S) O, C (S) S, C (S) NR c, C (NR c) O, C (NR c) S, C (NR c) NR c, OC (O) O, SC (O) O, NR cC (O) O, OC (S) O, SC (S) O, NR cC (S) O, OC (NR c) O, SC (NR c) O, NR cC (NR c) O, OC (O) S, SC (O) S, NR cC (O) S, OC (S) S, SC (S) S, NR cC (S) S, OC (NR c) S, SC (NR c) S, NR cC (NR c) S, OC (O) NR c, SC (O) NR c, NR cC (O) NR c, OC (S) NR c, SC (S) NR c, NR cC (S) NR c, OC (NR c) NR c, SC (NR c) NR c, NR cC (NR cNR c, S, SO, SO 2, NR c, SO 2NR cAnd NR cSO 2, R wherein cAs hereinbefore defined.
Part R bCan be that hydrogen or its can be carbocyclic ring and heterocyclic group and the optional such substituted C as hereinbefore defined that is selected from and has 3-12 (normally 3-10, be 5-10 more generally) ring members 1-8Alkyl.The example of alkyl, carbocyclic ring and heterocyclic group is as indicated above.
If R aBe O and R bBe C 1-8Alkyl, R aAnd R bForm-oxyl together.Preferred-oxyl comprises saturated-oxyl such as alkoxyl group (C for example 1-6Alkoxyl group more generally is C 1-4Alkoxyl group such as oxyethyl group and methoxyl group, particularly methoxyl group), cycloalkyloxy (C for example 3-6Cycloalkyloxy is as ring propoxy-, cyclobutoxy group, cyclopentyloxy and cyclohexyloxy) and cycloalkyl alkoxy (C for example 3-6Cycloalkyl-C 1-2Alkoxyl group such as cyclo propyl methoxy).
-oxyl can be replaced by various substituting groups defined herein.For example, alkoxyl group can be by halogen (for example in difluoro-methoxy and trifluoromethoxy), hydroxyl (for example in hydroxyl-oxethyl), C 1-2Alkoxyl group (for example in methoxy ethoxy), hydroxyl-C 1-2Alkyl (in the '-hydroxyethoxy base oxethyl) or cyclic group (for example cycloalkyl or above defined non-aromatic heterocyclic group) replace.Having the non-aromatic heterocyclic group is that wherein heterocyclic group is saturated cyclic amine such as morpholine, piperidines, tetramethyleneimine, piperazine, C as the example of substituent alkoxyl group 1-4-alkyl-piperazine, C 3-7-cycloalkyl-piperazine, tetrahydropyrans or tetrahydrofuran (THF) and alkoxyl group are C 1-4Alkoxyl group, be C more generally 1-3Those of alkoxyl group such as methoxyl group, oxyethyl group or just-propoxy-.
Derivative that alkoxyl group can be replaced by monocyclic groups such as tetramethyleneimine, piperidines, morpholine and piperazine and N-thereof such as N-benzyl, N-C 1-4Acyl group and N-C 1-4The alkoxy carbonyl derivative replaces.Object lesson comprises pyrrolidino (pyrrolidino) oxyethyl group, piperidino-(1-position only) (piperidino) oxyethyl group and Piperazino (piperazino) oxyethyl group.
If R aBe valence link and R bBe C 1-8Alkyl, alkyl R a-R bExample as hereinbefore defined.Alkyl can be saturated group such as cycloalkyl and alkyl, and the object lesson of this class group comprises methyl, ethyl and cyclopropyl.Alkyl (for example alkyl) can be replaced by various groups defined herein and atom.The example of substituted alkyl comprises the alkyl that is replaced by one or more following groups: halogen atom such as fluorine and chlorine (object lesson comprises bromotrifluoromethane, chloroethyl and trifluoromethyl) or hydroxyl (for example hydroxymethyl and hydroxyethyl), C 1-8Acyloxy (for example acetoxy-methyl and benzyloxymethyl), amino and single-and two-alkylamino (for example amino-ethyl, methylamino ethyl, dimethylaminomethyl, dimethyl aminoethyl and tert-butyl amino methyl), alkoxyl group (C for example 1-2Alkoxyl group such as methoxyl group-in methoxy ethyl) and cyclic group cycloalkyl, aryl, heteroaryl and non-aromatic heterocycle as hereinbefore defined).
The object lesson of the alkyl that is replaced by cyclic group is that wherein cyclic group is saturated cyclic amine such as morpholine, piperidines, tetramethyleneimine, piperazine, C 1-4-alkyl-piperazine, C 3-7-cycloalkyl-piperazine, tetrahydropyrans or tetrahydrofuran (THF) and alkyl are C 1-4Alkyl, be C more generally 1-3Those of alkyl such as methyl, ethyl or just-propyl group.The object lesson of the alkyl that is replaced by cyclic group comprises that pyrrolidino methyl, pyrrolidino propyl group, morpholino methyl, morpholino ethyl, morpholino propyl group, piperidino methyl, Piperazino methyl and its N-defined herein replace form.
Object lesson by the alkyl of aryl and heteroaryl replacement comprises benzyl and pyridylmethyl.
If R aBe SO 2NR c, R bCan be for example hydrogen or randomly substituted C 1-8Alkyl or carbocyclic ring or heterocyclic group.R wherein aBe SO 2NR cR a-R bExample comprise amino-sulfonyl, C 1-4Alkyl amino sulfonyl and two-C 1-4Alkyl amino sulfonyl and by cyclic amino such as piperidines, morpholine, tetramethyleneimine, the sulphonamide that forms of the substituted piperazine of N-such as N methyl piperazine randomly.
R wherein aBe SO 2Radicals R a-R bExample comprise alkyl sulphonyl, heteroarylsulfonyl and aryl sulfonyl, particularly monocyclic aryl and heteroarylsulfonyl.Object lesson comprises methyl sulphonyl, phenyl sulfonyl and tosyl group.
If R aBe NR c, R bCan be for example hydrogen or randomly substituted C 1-8Alkyl or carbocyclic ring or heterocyclic group.R wherein aBe NR cR a-R bExample comprise amino, C 1-4Alkylamino (for example methylamino, ethylamino, propyl group amino, sec.-propyl amino, tert-butyl amino), two-C 1-4Alkylamino (for example dimethylamino and diethylamino) and cycloalkyl amino (for example cyclopropyl amino, cyclopentyl amino and cyclohexyl amino).
R 1To R 15Specific embodiments and preferred meaning
In one embodiment, R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen and R 3Be (i) group:
Figure A20068000923800411
R wherein 9Be selected from C (O) NR 5R 6C (O)-R 10With the 2-pyrimidyl, wherein R10Be the C that is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group and methoxyl group 1-4Alkyl; And R 11, R wherein 11Be the C that is replaced by one or more substituting groups that are selected from fluorine, chlorine and cyano group 1-4Alkyl.
In the compound subgroup in this embodiment, R 9Be selected from C (O) NR 5R 6C (O)-R 10, R wherein 10Be the C that is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group and methoxyl group 1-4Alkyl; And R 11, R wherein 11Be the C that is replaced by one or more substituting groups that are selected from fluorine, chlorine and cyano group 1-4Alkyl.
In this embodiment, if R 9Be C (O) NR 5R 6, group NR 5R 6For example can be dimethylamino and cyclic amine for example morpholine, piperidines, piperazine, N methyl piperazine, tetramethyleneimine and thiazolidine.Concrete heterocycle comprises morpholinyl, 4-methylpiperazine base and tetramethyleneimine.
If R 9Be C (O)-R 10, R 10Object lesson comprise methyl, trifluoromethyl and methoxymethyl.
If R 9Be radicals R 11, R 11Example comprises ethyl such as cyano methyl, 2-cyano ethyl and the 2-fluoro ethyl that substituted methyl and 2-replace.
In another embodiment of the invention, R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen and R 3Be (ii) group:
Figure A20068000923800421
R wherein 12Be C 2-4Alkyl.
C 2-4Described in the preferred meaning and definitional part that alkyl can be general as mentioned.Therefore, it can be C 2-C 3Group or C 2, C 3Or C 4Alkyl.Concrete C 2-4Alkyl have ethyl, different-propyl group, just-butyl, different-butyl and tert-butyl; More particularly group is different-propyl group and different-butyl.
In another embodiment, R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen and R 3Be (iii) group:
Figure A20068000923800422
R wherein 13Be selected from methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl and 1-pyrrolidyl.
Concrete radicals R 13Comprise 4-morpholino and 1-methyl-4-piperazinyl.
In another embodiment, R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen and R 3Be the (iv) substituted 3-pyridyl or the 4-pyridyl of following formula
Figure A20068000923800431
Radicals R wherein 14Position or contraposition and be selected from methyl, methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl, 1-pyrrolidyl, 4-piperidyl oxygen base, 1-C between with the valence link of asterisk mark 1-4Alkoxy carbonyl-piperidin-4-yl oxygen base, 2-hydroxyl-oxethyl and 2-methoxy ethoxy.
More specifically, R 14Be selected from methyl, methyl sulphonyl, 4-morpholino, 1-methyl-4-piperazinyl, 4-piperidyl oxygen base, 1-C 1-4Alkoxy carbonyl-piperidin-4-yl oxygen base, 2-hydroxyl-oxethyl and 2-methoxy ethoxy.
In another embodiment, R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen and R 3For (v) being selected from 2-pyrazinyl, 5-pyrimidyl, cyclohexyl, 1; 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base (4-cyclohexanone ethylene ketal), 4-methyl sulphonyl amino-cyclohexyl, tetrahydric thiapyran-4-group, 1; 1-dioxo-tetrahydric thiapyran-4-group, tetrahydropyran-4-base, 4; 4-difluoro cyclohexyl and 3, the group of 5-dimethyl isoxazole-4-base.
In this embodiment, R 3Can be selected from 2-pyrazinyl, 5-pyrimidyl, cyclohexyl, l; 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base (4-cyclohexanone ethylene ketal), 4-methyl sulphonyl amino-cyclohexyl, tetrahydric thiapyran-4-group, 1; 1-dioxo-tetrahydric thiapyran-4-group and 3,5-dimethyl isoxazole-4-base.
In another embodiment, R 1Be (b) 2,6-difluorophenyl, R 2aAnd R 2bBe all hydrogen and R 3Be selected from:
(vi) 1-methyl-piperidines-3-base; 4-(2-dimethylamino ethoxy)-cyclohexyl; With the substituted 4-piperidyl of N-, wherein the N-substituting group is selected from cyano methyl and cyano ethyl; With
(vii) group:
Figure A20068000923800432
R wherein 13Be the substituted 4-piperidyl of N-, wherein the N-substituting group is C 1-4Alkoxy carbonyl, C 1-4C in the alkoxy carbonyl 1-4Alkoxyl group part can be selected from methoxyl group, oxyethyl group, propoxy-, different-propoxy-, butoxy, different-butoxy and uncle-butoxy.A concrete C 1-4Alkoxy carbonyl is different-propoxycarbonyl.
In a compound subgroup, R 1Be 2,6-difluorophenyl, R 2aAnd R 2bBe all hydrogen and R 3Be selected from 1-methyl-piperidines-3-base; 4-(2-dimethylamino ethoxy)-cyclohexyl; With the substituted 4-piperidyl of N-, wherein the N-substituting group is selected from cyano methyl and cyano ethyl.
In another compound subgroup, R 1Be 2,6-difluorophenyl, R 2aAnd R 2bBe all hydrogen and R 3Be group:
Figure A20068000923800441
R wherein 13Be selected from 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl and 1-pyrrolidyl.
Concrete radicals R 13Comprise 4-morpholino and 1-methyl-4-piperazinyl.
In another embodiment, R 1Be (c) 2,3, the 6-trisubstd phenyl, wherein the substituting group of this phenyl is selected from fluorine, chlorine, methyl and methoxyl group; R 2aAnd R 2bBe all hydrogen; And R 3Be selected from (viii) 4-piperidyl and 1-methyl-4-piperidyl, (ix) tetrahydropyran-4-base, defined herein group (ii), (xi), (xii) and (xiii); And be selected from addition:
(x) group
Figure A20068000923800442
R wherein 4Be C 1-4Alkyl.
In this embodiment, R 3Can be selected from (x) 4-piperidyl and 1-methyl-4-piperidyl and group defined herein (ii), (x), (xi), (xii) and (xiii).
Common 2,3, the 6-trisubstd phenyl has fluorine, chlorine, methyl or methoxy in the 2-position.2,3, the 6-trisubstd phenyl preferably has at least two substituting groups that are selected from fluorine and chlorine and exists.When having methoxyl group, methoxyl group is preferably placed at the 2-position or the 6-position of phenyl, more preferably is positioned at the 2-position.
2,3, the object lesson of 6-trisubstd phenyl has 2,3,6-trichlorophenyl, 2,3,6-trifluorophenyl, 2,3-two fluoro-6-chloro-phenyl-s, 2,3-two fluoro-6-p-methoxy-phenyls, 2,3-two fluoro-6-aminomethyl phenyls, 3-chloro-2,6-difluorophenyl, 3-methyl-2,6-difluorophenyl, 2-chloro-3,6-difluorophenyl, 2-fluoro-3-methyl-6-chloro-phenyl-, 2-chloro-3-methyl-6-fluorophenyl, 2-chloro-3-methoxyl group-6-fluorophenyl and 2-methoxyl group-3-fluoro-6-chloro-phenyl-.
More specific example has 2,3-two fluoro-6-p-methoxy-phenyls, 3-chloro-2,6-difluorophenyl and 2-chloro-3,6-difluorophenyl.
R therein 1For defined herein 2,3, in the compound subgroup of 6-trisubstd phenyl, R 3Be 4-piperidyl or 1-methyl-4-piperidyl.
R therein 1For defined herein 2,3, in another compound subgroup of 6-trisubstd phenyl, R 3Be group:
Figure A20068000923800451
R wherein 4Be C defined herein 1-4Alkyl.
C 1-4The example of alkyl comprise methyl, ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-and tert-butyl.A special C 1-4Alkyl is a methyl.
R therein 1For defined herein 2,3, in another compound subgroup of 6-trisubstd phenyl, R 3Be group:
Figure A20068000923800452
R wherein 12Be C defined herein 2-4Alkyl.C 2-4Alkyl can be for example ethyl, just-propyl group, sec.-propyl, just-butyl, isobutyl-or tert-butyl.Concrete C 2-4Alkyl comprises ethyl, sec.-propyl and tert-butyl, more specifically C 1-4Alkyl R 12Be ethyl and sec.-propyl.
R therein 1For defined herein 2,3, in another compound subgroup of 6-trisubstd phenyl, R 3Be group:
Figure A20068000923800453
R wherein 7As defined herein.
In a compound subgroup, R 7Be C 1-4Unsubstituted alkyl outside the alkyl.The example of this class alkyl comprises cyclopropyl and cyclopropyl methyl.
In another compound subgroup, R 7For having one or more fluorine, chlorine, hydroxyl, methyl sulphonyl, cyano group, methoxyl group, NR of being selected from 5R 6With contain 4-7 unit saturated carbon ring or the substituent substituted C of heterocyclic that is selected from the heteroatomic ring member of O, N and S to too many by two 1-4Alkyl.In this subgroup, concrete example comprises the C that has one or more substituting groups (for example one, two or three substituting group) 1-4Alkyl, particularly substituted methyl and ethyl.More specifically, C 1-4Alkyl can be selected from trifluoromethyl, 2,2,2-trifluoroethyl, 2-methoxy ethyl, 2-cyano ethyl, chloromethyl, 2-hydroxyethyl, tetrahydropyran-4-base methyl and formula-CH 2-CH 2-NR 5R 6Group.Group-CH 2-CH 2-NR 5R 6Object lesson comprise 2-(4-morpholinyl) ethyl, 2-(1-methyl-4-piperazinyl) ethyl, 2-(1-pyrrolidyl) ethyl, 2-(3-thiazolidyl) ethyl, 2-dimethyl aminoethyl, 2-(N-methyl-N-methoxyl group amino) ethyl and 2-(N-methoxyl group amino) ethyl.
In another compound subgroup, R 7Be group NR 5R 6, R wherein 5And R 6Be selected from hydrogen and C 1-4Alkyl, C 1-2Alkoxyl group and C 1-2Alkoxy-C 1-4Alkyl, condition are R 5And R 6In to be no more than one be C 1-2Alkoxyl group, or NR 5R 6Formation contains one or two five or the hexa-atomic saturated heterocyclic that are selected from the heteroatomic ring member of O, N and S, and this heterocycle is randomly by one or more methyl substituted.Concrete non-annularity group NR 5R 6Comprise amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxyl group amino and N-methyl-N-methoxyl group amino; A preferred group is a dimethylamino.Concrete cyclic group NR 5R 6Comprise morpholine, piperidines, piperazine, N methyl piperazine, tetramethyleneimine and thiazolidine.
In another compound subgroup, R 7Be selected from the heteroatomic ring member of N, S and O and randomly by methyl, methoxyl group, fluorine, chlorine or group NR for containing one or two 5R 6Five or the six membered heteroaryl that replace.Five and the example of six membered heteroaryl comprise imidazoles, pyrazoles and pyridyl, substituent object lesson comprises methyl and NR 5R 6
In another compound subgroup, R 7For randomly by methyl, methoxyl group, fluorine, chlorine, cyano group or group NR 5R 6The phenyl that replaces, the object lesson of this class group comprises 4-fluorophenyl, 4-p-methoxy-phenyl and 4-cyano-phenyl.
In another compound subgroup, R 7Be C 3-6Cycloalkyl; The example of cycloalkyl has cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Specific example has cyclopropyl and cyclohexyl.
In another compound subgroup, R 7For containing one or two five or hexa-atomic saturated heterocyclic that is selected from the heteroatomic ring member of O, N and S, this heterocycle is randomly by one or more methyl substituted.Five or hexa-atomic saturated rings can be selected from for example morpholine, piperidines, piperazine, N methyl piperazine, tetramethyleneimine and thiazolidine, a specific example is a morpholine.
R therein 1For defined herein 2,3, in another compound subgroup of 6-trisubstd phenyl, R 3Be (xii) group:
Figure A20068000923800471
R wherein 12aAs defined herein.
In a compound subgroup, R 12aFor by one or more fluorine, chlorine, C of being selected from 3-6Cycloalkyl, oxa--C 4-6The C that the substituting group of cycloalkyl, cyano group and methoxyl group replaces 1-4Alkyl.
In another compound subgroup, R 12aFor by one or more fluorine, C of being selected from 3-6Alkyl, oxa--C 4-6The C that the substituting group of cycloalkyl, cyano group and methoxyl group replaces 1-4Alkyl.
The example of substituted alkyl has substituted methyl and substituted ethyl (for example 1-ethyl and 2-ethyl, preferably 2-ethyl).
Work as R 12aDuring for substituted methyl, object lesson comprises methoxymethyl, cyclopropyl methyl and tetrahydropyrans ylmethyl.A preferred radicals R 12aBe substituted methyl, particularly methoxymethyl.
Work as R 12aDuring for substituted ethyl, object lesson comprises 2-dimethyl aminoethyl, 2-methoxy ethyl and 2-(4-morpholino) ethyl.
In another embodiment, R 1Be (e) radicals R 1a, R 2aAnd R 2bBe all hydrogen, and R 3Be (xiii) group
Figure A20068000923800472
In this embodiment, R 1aBe selected from cyclopropyl-cyano group-methyl; Furyl; The benzoisoxazole base; The methyl-isoxazole base; The mono-substituted phenyl of 2-and 2, the dibasic phenyl of 6-, wherein the substituting group on the phenyl moiety is selected from methoxyl group, oxyethyl group, fluorine, chlorine and difluoro-methoxy; Condition is R1aNot 2,6-difluorophenyl or 2,6-difluorophenyl.
In a compound subgroup, R 1aBe selected from furyl; The benzoisoxazole base; The methyl-isoxazole base; The mono-substituted phenyl of 2-and 2, the dibasic phenyl of 6-, wherein the substituting group on the phenyl moiety is selected from methoxyl group, oxyethyl group, fluorine, chlorine and difluoro-methoxy; Condition is R 1aNot 2,6-difluorophenyl or 2,6-dichlorophenyl.
In another compound subgroup, R 1aBe selected from the mono-substituted phenyl of 2-and 2, the dibasic phenyl of 6-, wherein the substituting group on the phenyl moiety is selected from methoxyl group, oxyethyl group, fluorine, chlorine and difluoro-methoxy; Condition is R 1aNot 2,6-difluorophenyl or 2,6-dichlorophenyl.In this subgroup, the object lesson of the phenyl of list-replacement and two-replacement comprises 2-fluoro-6-p-methoxy-phenyl, 2-fluoro-6-chloro-phenyl-, 2-difluoro-methoxy phenyl and 2-chloro-6-p-methoxy-phenyl.
In another compound subgroup, R 1aBe selected from furyl; Benzoisoxazole base and methyl-isoxazole base.
In another compound subgroup, R 1aBe cyclopropyl-cyano group-methyl.
In another embodiment, R 1Be (f) radicals R 1b, R 2aAnd R 2bBe all hydrogen, and R 3Be (xiv) methyl.
In another embodiment, R 1Be (g) radicals R 1c, R 2aAnd R 2bBe all hydrogen, and R 3Be (xv) group
In this embodiment, R 1cBe selected from; The benzoisoxazole base; Contain one or two and be selected from the heteroatomic quinary heteroaryl ring of O and N and contain six of one or two nitrogen heteroatom ring members-first heteroaryl ring, heteroaryl ring is randomly replaced by methyl, fluorine, chlorine or trifluoromethyl in each case; With the phenyl that is selected from the substituting group replacement of bromine, chlorine, fluorine, methyl, trifluoromethyl, oxyethyl group, methoxyl group, methoxy ethoxy, methoxymethyl, dimethylaminomethyl and difluoro-methoxy by, two or three; Condition is R 1aNot 2, the 6-difluorophenyl;
In a compound subgroup, R 1cBe selected from the benzoisoxazole base; Contain one or two heteroatomic quinary heteroaryl ring that is selected from O and N, this heteroaryl ring is randomly replaced by methyl, fluorine, chlorine or trifluoromethyl; With the phenyl that is selected from the substituting group replacement of bromine, chlorine, fluorine, methyl, trifluoromethyl, oxyethyl group, methoxyl group, methoxy ethoxy and difluoro-methoxy by, two or three; Condition is R 1aNot 2, the 6-difluorophenyl.
In another subgroup, R 1cBe selected from the benzoisoxazole base and contain one or two heteroatomic quinary heteroaryl ring that is selected from O and N, wherein heteroaryl ring is randomly replaced by methyl, fluorine, chlorine or trifluoromethyl.The example of quinary heteroaryl ring comprises isoxazole, furyl and pyrazoles ring, and these rings can have one or more for example substituting groups of methyl, chlorine and trifluoromethyl that are selected from.
In another subgroup, R 1cBe the phenyl that is selected from the substituting group replacement of bromine, chlorine, fluorine, methyl, trifluoromethyl, oxyethyl group, methoxyl group, methoxy ethoxy, methoxymethyl, dimethylaminomethyl and difluoro-methoxy by, two or three; Condition is R 1aNot 2, the 6-difluorophenyl.In this subgroup, R 1cCan be for example by one, two or three phenyl that is selected from the substituting group replacement of bromine, chlorine, fluorine, methyl, trifluoromethyl, oxyethyl group, methoxyl group, methoxy ethoxy and difluoro-methoxy; Condition is R 1aNot 2, the 6-difluorophenyl.The example of substituted phenyl comprises that 2-is mono-substituted, 3-is mono-substituted, 4-is mono-substituted, 2,3-is dibasic, 2,4-is dibasic, 2,5-is dibasic or 2,6-is dibasic, 2,3,5-is trisubstituted, 2,4,5-is trisubstituted and 2,3, the 6-trisubstd phenyl; More specifically be 2-mono-substituted, 2,3-is dibasic, 2,6-is dibasic and 2,3, the 6-trisubstd phenyl.Substituted phenyl groups example comprises the 2-ethoxyl phenenyl, the 2-Trifluoromethoxyphen-l, 2-fluoro-6-trifluoromethyl, 2, the 6-dichlorophenyl, 2-chloro-6-aminomethyl phenyl, 2-fluoro-6-ethoxyl phenenyl, 2, the 6-3,5-dimethylphenyl, 2-methoxyl group-3-fluorophenyl, 2-fluoro-6-p-methoxy-phenyl, 2-fluoro-3-aminomethyl phenyl, 2-chloro-6-bromophenyl, 2,3, the 6-trifluorophenyl, 2-chloro-3, the 6-difluorophenyl, 2-chloro-3-methyl-6-fluorophenyl, 2-fluoro-3-methyl-6-chloro-phenyl-, 2,3-two fluoro-6-p-methoxy-phenyls, 2,6-two fluoro-3-chloro-phenyl-s, 2-methoxyl group-3, the 6-dichlorophenyl, 2-methoxyl group-6-aminomethyl phenyl, 2,6-two fluoro-3-aminomethyl phenyls and 2-chloro-3-methoxyl group-6-fluorophenyl.Other example comprises 2-chloro-6-dimethylaminomethyl phenyl and 2-chloro-6-methoxymethyl phenyl.In this compound subgroup, in a specific group, substituted phenyl is 2, the 6-dichlorophenyl, and in another specific group, substituted phenyl is not 2,6-dichlorophenyl and/or be not 2,3,6-trisubstd phenyl.
In another embodiment, R 1Be (j) 2,6-difluorophenyl amino, R 2aAnd R 2bBe all hydrogen; And R 3Be methyl.
In another embodiment, R 1Be 2,6-dichlorophenyl, R 3Be 4-piperidines group, and (k) R 2aBe methyl and R 2bBe hydrogen, perhaps (I) R 2aBe hydrogen and R 2bBe methyl.
In another embodiment of the invention, R 1Be (d) radicals R 0, R wherein 0Be carbocyclic ring or heterocyclic group with 3-12 ring members; Or randomly by one or more fluorine, hydroxyl, cyano group, C of being selected from 1-4-oxyl, amino, list-or two-C 1-4The C that alkyl substituting group amino and carbocyclic ring with 3-12 ring members or heterocyclic group replaces 1-8Alkyl, and wherein 1 or 2 carbon atom of alkyl can randomly be selected from O, S, NH, SO, SO 2Atom or group replace; And R 3Be selected from:
(xi) group:
With
(xii) group
Figure A20068000923800502
R wherein 7And R 12aAs defined herein.
In the compound group in this embodiment, R 3Be group:
Figure A20068000923800503
R wherein 7With and example and preferred meaning as defined herein.
Therefore, for example, in a compound subgroup, R 7Be C 1-4Unsubstituted alkyl outside the alkyl.The example of this class alkyl comprises cyclopropyl and cyclopropyl methyl.
In another compound subgroup, R 7For having one or more fluorine, chlorine, hydroxyl, methyl sulphonyl, cyano group, methoxyl group, NR of being selected from 5R 6With contain 4-7 unit saturated carbon ring or the substituent substituted C of heterocyclic that is selected from the heteroatomic ring member of O, N and S to too many by two 1-4Alkyl.In this subgroup, concrete example comprises the C that has one or more substituting groups (for example one, two or three substituting group) 1-4Alkyl, particularly substituted methyl and ethyl.More specifically, C 1-4Alkyl can be selected from trifluoromethyl, 2,2,2-trifluoroethyl, 2-methoxy ethyl, 2-cyano ethyl, chloromethyl, 2-hydroxyethyl, tetrahydropyran-4-base methyl and formula-CH 2-CH 2-NR 5R 6Group.Group-CH 2-CH 2-NR 5R 6Object lesson comprise 2-(4-morpholinyl) ethyl, 2-(1-methyl-4-piperazinyl) ethyl, 2-(1-pyrrolidyl) ethyl, 2-(3-thiazolidyl) ethyl, 2-dimethyl aminoethyl, 2-(N-methyl-N-methoxyl group amino) ethyl and 2-(N-methoxyl group amino) ethyl.
In another compound subgroup, R 7Be group NR 5R 6, R wherein 5And R 6Be selected from hydrogen and C 1-4Alkyl, C 1-2Alkoxyl group and C 1-2Alkoxy-C 1-4Alkyl, condition are R 5And R 6In to be no more than one be C 1-2Alkoxyl group, or NR 5R 6Formation contains one or two five or the hexa-atomic saturated heterocyclic that are selected from the heteroatomic ring member of O, N and S, and this heterocycle is randomly by one or more methyl substituted.Concrete non-annularity group NR 5R 6Comprise amino, methylamino, ethylamino, dimethylamino, diethylamino, methoxyl group amino and N-methyl-N-methoxy amino; A preferred group is a dimethylamino.Concrete cyclic group NR 5R 6Comprise morpholine, piperidines, piperazine, N methyl piperazine, tetramethyleneimine and thiazolidine.
In another compound subgroup, R 7Be selected from the heteroatomic ring member of N, S and O and randomly by methyl, methoxyl group, fluorine, chlorine or group NR for containing one or two 5R 6Five or the six membered heteroaryl that replace.Five and the example of six membered heteroaryl comprise imidazoles, pyrazoles and pyridyl, substituent object lesson comprises methyl and NR 5R 6
In another compound subgroup, R 7Be randomly by methyl, methoxyl group, fluorine, chlorine, cyano group or group NR 5R 6The phenyl that replaces, the object lesson of this class group comprises 4-fluorophenyl, 4-p-methoxy-phenyl and 4-cyano-phenyl.
In another compound subgroup, R 7Be C 3-6Cycloalkyl; The example of cycloalkyl has cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Specific example has cyclopropyl and cyclohexyl.
In another compound subgroup, R 7For containing one or two five or hexa-atomic saturated heterocyclic that is selected from the heteroatomic ring member of O, N and S, this heterocycle is randomly by one or two methyl substituted.Five or hexa-atomic saturated rings can be selected from for example morpholine, piperidines, piperazine, N methyl piperazine, tetramethyleneimine and thiazolidine, a specific example is a morpholine.
R therein 1Be R 0Another compound group in, R 3Be group:
Figure A20068000923800511
R wherein 12aWith and preferred meaning and example as defined herein.
In a compound subgroup, R 12aFor by one or more fluorine, chlorine, C of being selected from 3-6Cycloalkyl, oxa--C 4-6The C that the substituting group of cycloalkyl, cyano group and methoxyl group replaces 1-4Alkyl.
In another compound subgroup, R 12aFor by one or more fluorine, C of being selected from 3-6Alkyl, oxa--C 4-6The C that the substituting group of cycloalkyl, cyano group and methoxyl group replaces 1-4Alkyl.
The example of substituted alkyl has substituted methyl and substituted ethyl (for example 1-ethyl and 2-ethyl, preferably 2-ethyl).
Work as R 12aDuring for substituted methyl, object lesson comprises methoxymethyl, cyclopropyl methyl and tetrahydropyrans ylmethyl.A preferred radicals R 12aBe substituted methyl, particularly methoxymethyl.
Work as R 12aDuring for substituted ethyl, object lesson comprises 2-dimethyl aminoethyl, 2-methoxy ethyl and 2-(4-morpholino) ethyl.
R therein 1Be R 0Previous embodiments, example, group and subgroup in, have the carbocyclic ring or the heterocyclic group R of 3-12 ring members 0Randomly substituted C 1-8The example of alkyl is as mentioned described in the general preferred meaning and definitional part.
More specifically, in one embodiment, R 0Be aryl or heteroaryl.
Work as R 0During for heteroaryl, concrete heteroaryl comprise the bicyclic heteroaryl that contains at the most three heteroatomic ring members that are selected from O, S and N and contain at the most 2 be selected from the heteroatomic ring member of O, S and N and wherein two rings be the bicyclic heteroaryl of aromatic ring.
The example of this class group comprises furyl (for example 2-furyl or 3-furyl), indyl (3-indyl for example, the 6-indyl), 2,3-dihydro-benzo [1,4] dioxine bases (for example 2,3-dihydro-benzo [1,4] dioxine-5-yl), pyrazolyl (for example pyrazoles-5-yl), pyrazolo [1,5-a] pyridyl (for example pyrazolo [1,5-a] pyridin-3-yl) oxazolyl (for example) isoxazolyl (for example isoxazole-4-base), pyridyl (2-pyridyl for example, the 3-pyridyl, the 4-pyridyl), quinolyl (for example 2-quinolyl), pyrryl (for example 3-pyrryl), imidazolyl and thienyl (2-thienyl for example, the 3-thienyl).
Heteroaryl R 0A subgroup form by furyl (for example 2-furyl or 3-furyl), indyl, oxazolyl, isoxazolyl, pyridyl, quinolyl, pyrryl, imidazolyl and thienyl.
Heteroaryl R 0A preferred subgroup comprise 2-furyl, 3-furyl, pyrryl, imidazolyl and thienyl.
Preferred aryl groups R 0It is phenyl.
Radicals R 0Can be unsubstituted or substituted carbocyclic ring or heterocyclic group, wherein one or more substituting groups can be selected from above defined radicals R 15In one embodiment, R 0On the optional free halogen of substituting group, hydroxyl, trifluoromethyl, cyano group, nitro, carboxyl, radicals R a-R bThe radicals R of forming 15a, R wherein aBe valence link, O, CO, X 3C (X 4), C (X 4) X 3, X 3C (X 4) X 3, S, SO or SO 2, and R bBe selected from hydrogen and randomly be selected from hydroxyl, oxo base, halogen, cyano group, nitro, carboxyl and have the non-aromatic carbocyclic of monocycle of 3-6 ring members or C that the substituting group of heterocyclic group replaces by one or more 1-8Alkyl; C wherein 1-8One or more carbon atoms of alkyl can be randomly by O, S, SO, SO 2, X 3C (X 4), C (X 4) X 3Or X 3C (X 4) X 3Replace; X 3Be O or S; X 4For=O or=S.
If carbocyclic ring and heterocyclic group have a pair of substituting group on identical or the annular atoms that adjoins, thereby these two substituting groups can form a cyclic group by bonding.Therefore, two radicals R of adjoining 15Can form 5-unit's heteroaryl ring or 5-or 6-non-aromatic carbocyclic of unit or heterocycle with carbon atom or heteroatoms that they connected, wherein said heteroaryl and heterocyclic radical contain 3 heteroatomic ring members that are selected from N, O and S at the most.Two radicals R of adjoining particularly 15Can form with carbon atom that they connected or heteroatoms and to contain 3 at the most, 2 6-unit non-aromatic heterocyclics that are selected from the heteroatomic ring member of N, O and S particularly.More specifically, two radicals R of adjoining 15Can form and contain 2 6-unit non-aromatic heterocyclics that are selected from the heteroatomic ring member of N or O, as diox, for example [1,4 diox].In one embodiment, R 1Be carbon ring group, phenyl for example, it has a pair of substituting group bonding and forms cyclic group on the annular atoms that adjoins, for example form 2,3-dihydro-benzo [14] dioxines.
More specifically, R 0On substituting group can be selected from halogen, hydroxyl, trifluoromethyl, radicals R a-R b, R wherein aBe valence link or O, R bThe C that is selected from hydrogen and is randomly replaced by one or more substituting groups 1-4Alkyl, described substituting group is selected from hydroxyl, halogen (preferred fluorine) and 5 and 6 yuan of saturated carbon rings and heterocyclic group (for example containing the heteroatomic group that is selected from O, S and N to too many by two, as unsubstituted piperidines, pyrrolidino, morpholino, Piperazino and N methyl piperazine subbase).
Radicals R 0Can be replaced by more than one substituting group.Therefore, for example, can there be 1 or 2 or 3 or 4 substituting group.R therein 0In the embodiment for six-ring (for example carbocyclic ring such as benzyl ring), can have one, two or three substituting group, and these substituting groups can be positioned at 2-, 3-, 4-or the 6-position of this ring.
In a preferred compound group, R 0Be substituted phenyl.For example, substituted phenyl R 0Can be that 2-is mono-substituted, 3-is mono-substituted, 2,6-is dibasic, 2,3-is dibasic, 2,4-is dibasic, 2,5-is dibasic, 2,3,6-is trisubstituted or 2,4,6-is trisubstituted.
More specifically, in a concrete compound group, phenyl R 0Can replace or be replaced by two at 2-and 6-position at 2-position coverlet, substituting group be selected from fluorine, chlorine and R a-R b, R wherein aBe O, R bBe C 1-4Alkyl (for example methyl or ethyl).In a preferred embodiment, phenyl is 2,6-is dibasic, wherein substituting group is selected from for example fluorine, chlorine, methyl, ethyl, trifluoromethyl, difluoro-methoxy and methoxyl group, the object lesson of the substituted phenyl of this class comprises 2-fluoro-6-trifluoromethyl, 2,6-dichlorophenyl, 2,6-difluorophenyl, 2-chloro-6-aminomethyl phenyl, 2-fluoro-6-ethoxyl phenenyl, 2,6-3,5-dimethylphenyl, 2-methoxyl group-3-fluorophenyl, 2-fluoro-6-p-methoxy-phenyl, 2-fluoro-3-aminomethyl phenyl and 2-chloro-6-bromophenyl.One particularly preferred 2, and the dibasic group of 6-is 2, the 6-dichlorophenyl.
In another concrete compound group, phenyl R 0Can be replaced by three at 2-, 3-and 6-position.
Common 2,3,6-trisubstd phenyl R 0Have fluorine, chlorine, methyl or methoxy in the 2-position.2,3, the 6-trisubstd phenyl preferably has at least two substituting groups that are selected from fluorine and chlorine and exists.If there is methoxyl group, methoxyl group is preferably placed at the 2-position or the 6-position of phenyl, more preferably is positioned at the 2-position.
2,3,6-trisubstd phenyl R 0Object lesson have 2,3,6-trichlorophenyl, 2,3,6-trifluorophenyl, 2,3-two fluoro-6-chloro-phenyl-s, 2,3-two fluoro-6-p-methoxy-phenyls, 2,3-two fluoro-6-aminomethyl phenyls, 3-chloro-2,6-difluorophenyl, 3-methyl-2,6-difluorophenyl, 2-chloro-3,6-difluorophenyl, 2-fluoro-3-methyl-6-chloro-phenyl-, 2-chloro-3-methyl-6-fluorophenyl, 2-chloro-3-methoxyl group-6-fluorophenyl and 2-methoxyl group-3-fluoro-6-chloro-phenyl-.
More specific example is 2,3-two fluoro-6-p-methoxy-phenyls, 3-chloro-2,6-difluorophenyl and 2-chloro-3,6-difluorophenyl.
Non-aromatics radicals R 0Object lesson comprise unsubstituted or be substituted (by one or more radicals R 15Replacement) monocyclic cycloalkyl.The example of this class cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl; More generally comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.
Non-aromatics radicals R 0Other example comprise unsubstituted or be substituted (by one or more radicals R 15Replace) have 3-12 ring members, common 4-12 ring members, a heterocyclic group of 5-10 ring members more generally.This class group can be for example monocyclic or bicyclic, and has 1-5 heteroatomic ring member (more generally 1,2,3 or 4 heteroatomic ring member) usually, and described heteroatomic ring member is selected from nitrogen, oxygen and sulphur usually.
When having sulphur, under the situation that the atom that adjoins and group allow, its can with-S-,-S (O)-or-S (O) 2-form exist.
Heterocyclic group for example can contain cyclic ether part (for example at tetrahydrofuran (THF) with in the diox), cyclic thioether part (for example in tetramethylene sulfide and dithiane), cyclic amine part (for example in tetramethyleneimine), cyclic amide (for example in pyrrolidone), cyclic ester (for example in butyrolactone), cyclic thioamide and thioester, cyclic sulfones (for example in tetramethylene sulfone and cyclobufene sultone), cyclic sulphoxide, ring-type sulphonamide and its combination (for example morpholine and parathiazan and S-oxide compound and S, S-dioxide).
At heterocyclic group R 0A subgroup in, heterocyclic group contains cyclic ether part (for example at tetrahydrofuran (THF) with in the diox), cyclic thioether part (for example in tetramethylene sulfide and dithiane), cyclic amine part (for example in tetramethyleneimine), cyclic sulfones (for example in tetramethylene sulfone and cyclobufene sultone), cyclic sulphoxide, ring-type sulphonamide and its combination (for example parathiazan).
Monocycle non-aromatic heterocyclic group R 0Example comprise 5-, 6-and 7-unit monocyclic heterocycles group are as morpholine, piperidines (piperidino for example, the 2-piperidyl, 3-piperidyl and 4-piperidyl), tetramethyleneimine (1-pyrrolidyl for example, 2-pyrrolidyl and 3-pyrrolidyl), pyrrolidone, pyrans (2H-pyrans or 4H-pyrans), dihydro-thiophene, dihydropyrane, dihydrofuran, thiazoline, tetrahydrofuran (THF), tetramethylene sulfide diox, tetrahydropyrans (for example 4-THP trtrahydropyranyl), tetrahydroglyoxaline, imidazolidone oxazoline, thiazoline, the 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazine such as N methyl piperazine.Other example comprises parathiazan and S-oxide compound and S, S-dioxide (particularly parathiazan).Example in addition also comprises N-Alkylpiperidine such as N-methyl piperidine.
Non-aromatic heterocyclic group R 0A subgroup comprise unsubstituted or be substituted (by one or more radicals R 15Replacement) 5-, 6-and 7-unit's monocyclic heterocycles group such as morpholine, piperidines (for example piperidino, 2-piperidyl, 3-piperidyl and 4-piperidyl), tetramethyleneimine (for example 1-pyrrolidyl, 2-pyrrolidyl and 3-pyrrolidyl), pyrrolidone, piperazine and N-alkylpiperazine such as N methyl piperazine, one of them specific subgroup is made up of tetramethyleneimine, piperidines, morpholine, parathiazan and N methyl piperazine.
Generally speaking, preferred non-aromatic heterocyclic group comprises tetramethyleneimine, piperidines, morpholine, parathiazan, parathiazan S, S-dioxide, piperazine, N-alkylpiperazine and N-Alkylpiperidine.
Another specific heterocyclic group subgroup is made up of tetramethyleneimine, piperidines, morpholine and N-alkylpiperazine and optional N methyl piperazine and parathiazan.
Work as R 0Be the C that is replaced by carbocyclic ring or heterocyclic group 1-8During alkyl, carbocyclic ring and heterocyclic group can be aromatics or non-aromatics and can be selected from the example of this class group mentioned above.The C that substituted alkyl is normally saturated 1-4Alkyl such as alkyl, preferred CH 2Or CH 2CH 2Group.If substituted alkyl is C 2-4Alkyl, in the carbon atom one can be replaced by alkylsulfonyl with its hydrogen atom that is connected, for example at SO 2CH 2In the part.
When with C 1-8Carbocyclic ring that alkyl connects or heterocyclic group be aromatics the time, the example of this class group comprise monocyclic aryl and contain at the most four heteroatomic ring members' that are selected from O, S and N bicyclic heteroaryl and contain at the most 2 be selected from the heteroatomic ring member of O, S and N and wherein two rings be the bicyclic heteroaryl of aromatic ring.
The example of this class group is above having description in " general preferred meaning and definition " part.
The object lesson of this class group comprises furyl (for example 2-furyl or 3-furyl), indyl, oxazolyl, isoxazolyl, pyridyl, quinolyl, pyrryl, imidazolyl and thienyl.As C 1-8The substituent aryl of alkyl and the object lesson of heteroaryl comprise phenyl, imidazolyl, tetrazyl, triazolyl, indyl, 2-furyl, 3-furyl, pyrryl and thienyl.This class group can be by one or more substituent R defined herein 15Or R 15aReplace.
Work as R 0Be the C that is replaced by non-aromatic carbocyclic or heterocyclic group 1-8During alkyl, non-aromatics or heterocyclic group can be the groups that is selected from above-mentioned this class group tabulation.For example, non-aromatic group can be to have 4-7 ring members, a for example 5-7 ring members and contain 0-3,0,1 or 2 monocyclic groups that is selected from the heteroatomic ring member of O, S and N more generally usually.When cyclic group was carbon ring group, it can also be selected from the monocyclic groups with 3 ring memberses.Object lesson comprises monocyclic cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl and 5-, 6-and 7-unit's monocyclic heterocycles group such as morpholine, piperidines (for example piperidino, 2-piperidyl, 3-piperidyl and 4-piperidyl), tetramethyleneimine (for example 1-pyrrolidyl, 2-pyrrolidyl and 3-pyrrolidyl), pyrrolidone, piperazine and N-alkylpiperazine such as N methyl piperazine.Generally speaking, preferred non-aromatic heterocyclic group comprises tetramethyleneimine, piperidines, morpholine, parathiazan and N methyl piperazine.
Work as R 0Be substituted C randomly 1-8During alkyl, alkyl can be as hereinbefore defined, and preferred length is no more than four carbon atom, and more generally length is no more than three carbon atoms, and for example length is one or two carbon atom.
In one embodiment, alkyl is saturated and can is acyclic or cyclic, and is for example acyclic.An acyclic saturated hydrocarbyl (being alkyl) can be the straight or branched alkyl.
Straight chained alkyl R 0Example comprise methyl, ethyl, propyl group and butyl.
Branched-chain alkyl R 0Example comprise sec.-propyl, isobutyl-, tert-butyl and 2,2-dimethyl propyl.
In one embodiment, alkyl is to have 1-6 carbon atom, more generally 1-4 carbon atom, a for example 1-3 carbon atom, the saturated group of the straight chain of 1,2 or 3 carbon atom for example.When alkyl when being substituted, the object lesson of this class group is methyl and the ethyl that is substituted (for example being replaced by carbocyclic ring or heterocyclic group).
C 1-8Alkyl R 0Can be randomly by one or more halogen (for example fluorine), hydroxyl, C of being selected from 1-4-oxyl, amino, list-or two-C 1-4The amino substituting group with carbocyclic ring with 3-12 ring members or heterocyclic group of alkyl replaces, and wherein 1 or 2 carbon atom of alkyl can randomly be selected from O, S, NH, SO, SO 2Atom or group replace.The concrete substituting group of alkyl comprises hydroxyl, chlorine, fluorine (for example in trifluoromethyl), methoxyl group, oxyethyl group, amino, methylamino and dimethylamino, and preferred substituted is hydroxyl and fluorine.
Concrete radicals R 0-CO is the group of listing in following table 1.
In table 1, the tie point of the nitrogen-atoms of group and pyrazoles-4-amino is used from the extended terminal singly-bound of carbonyl and is represented.Therefore, for example, the group B in the table is a trifluoroacetyl group, and the group D in the table is a phenyl acetyl, and the group I in the table is 3-(4-chloro-phenyl-) propionyl.
Figure A20068000923800581
Figure A20068000923800591
Figure A20068000923800601
Figure A20068000923800611
Figure A20068000923800631
Figure A20068000923800641
Preferred radicals R 0-CO comprises the group A to BS in the above table 1.
Preferred radicals R 0-CO-is AJ, AX, BQ, BS and BAI.
A particularly preferred radicals R 0The subgroup of-CO-is made up of AJ, BQ and BS.
Another particularly preferred radicals R 0The subgroup of-CO-is made up of AJ and BQ.
Another preferred group group comprises BBD, BBI and BBJ.
In embodiment of the present invention (H), R 1Be (h) radicals R 1d, R 3Be group-Y-R 3a, wherein Y is that valence link or length are the alkylidene chain of 1,2 or 3 carbon atom, R 3aBe selected from hydrogen and carbocyclic ring and heterocyclic group with 3-12 ring members.
Term " alkylidene group " has its common implication, refers to divalence saturated acyclic hydrocarbon chain.Hydrocarbon chain can be side chain or straight chain.
At alkylidene chain is under the situation of side chain, and it can have one or more methyl chains.The example of alkylidene group comprises-CH 2-,-CH 2-CH 2-,-CH 2-CH 2-CH 2-, CH (CH 3)-,-C (CH 3) 2-,-CH 2-CH (CH 3)-,-CH 2-C (CH 3) 2-and-CH (CH 3)-CH (CH 3)-.
In one embodiment, Y is a valence link.
In another embodiment, Y is an alkylidene chain.
When Y was alkylidene chain, preferably it was a straight chain, more especially contained 1 or 2 carbon atom, preferably contained 1 carbon atom.Therefore, preferred group Y is-CH 2-and-CH 2-CH 2-, most preferred group is (CH 2)-.
At Y is under the situation of side chain, and preferably it has and is no more than two methyl chains.For example, it can have single methyl chains.In one embodiment, Y be group-CH (Me)-.
In a compound subgroup, Y is valence link, CH 2, CH 2CH 2Or CH 2CH (CH 3).
Radicals R 3aBe selected from hydrogen and carbocyclic ring and heterocyclic group with 3-12 ring members.
In a compound subgroup, Y is valence link and R 3aBe hydrogen.
In another compound subgroup, Y is defined alkylidene chain above, and R 3aBe hydrogen.
In another compound subgroup, Y is valence link or alkylidene chain (group-(CH for example 2)-), R 3aBe carbocyclic ring or heterocyclic group.
In another compound subgroup, Y is a valence link, and R 3aBe carbocyclic ring or heterocyclic group.
In another compound subgroup, Y is alkylidene chain (group-(CH for example 2)-), R 3aBe carbocyclic ring or heterocyclic group.
Carbocyclic ring and heterocyclic group R 3aCan be aryl, heteroaryl, non-aromatic carbocyclyl groups or non-aromatic heterocycle, the example of this class group is as mentioned described in general preferred meaning and the definitional part and as mentioned below.
Preferred aryl groups R 3aIt is unsubstituted and substituted phenyl.
Heteroaryl R 3aExample comprise and contain the bicyclic heteroaryl that three at the most (more preferably to too many by twos) are selected from the heteroatomic ring member of O, S and N.Preferred heteroaryl comprises the five-ring that contains one or two heteroatomic ring member and contains the six-ring of single heteroatomic ring member, nitrogen.The object lesson of heteroaryl comprises unsubstituted or substituted pyridyl, imidazoles, pyrazoles, thiazole, isothiazole, isoxazole, oxazole, furyl and thienyl group.
Concrete heteroaryl has unsubstituted and substituted pyridyl, for example 2-pyridyl, 3-pyridyl and 4-pyridyl, especially 3-and 4-pyridyl.If pyridyl is substituted, they can have one or more substituting groups, are no more than two usually, substituting group the most normally, and described substituting group for example is selected from C 1-4Alkyl (for example methyl), halogen (for example fluorine or chlorine, preferably chlorine) and C 1-4Alkoxyl group (for example methoxyl group).Substituting group on the pyridyl can also be selected from amino, list-C 1-4Alkylamino and two-C 1-4Alkylamino, particularly amino.
In one embodiment, if R 3aBe aryl (for example phenyl) or heteroaryl, the substituting group on carbocyclic ring or the heterocyclic group can be selected from radicals R 10a, it is made up of following group: halogen, hydroxyl, trifluoromethyl, cyano group, have monocycle carbocyclic ring and the heterocyclic group and the radicals R of 3-7 (common 5 or 6) ring members a-R b, R wherein aBe valence link, O, CO, X 1C (X 2), C (X 2) X 1, X 1C (X 2) X 1, S, SO, SO 2, NR c, SO 2NR cOr NR cSO 2And R bThe C that is selected from hydrogen, has the carbocyclic ring of 3-7 ring members or heterocyclic group and randomly replaced by one or more substituting groups 1-8Alkyl, described substituting group are selected from hydroxyl, oxo base, halogen, cyano group, nitro, carboxyl, amino, list-or two-C 1-4Alkyl amino, carbocyclic ring or heterocyclic group, and C wherein with 3-7 ring members 1-8One or more carbon atoms of alkyl can be randomly by O, S, SO, SO 2, NR c, X1 C(X 2), C (X 2) X 1Or X 1C (X 2) X 1Replace; R c, X 1And X 2As hereinbefore defined.
Non-aromatics radicals R 3aExample comprise randomly and being substituted (by R 10Or R 10aReplacement) cycloalkyl, oxa--cycloalkyl, azepine-cycloalkyl, diaza-cycloalkyl, two oxa-s-cycloalkyl and azepine-oxa--cycloalkyl.Other example comprises C 7-10Aza-bicyclo alkyl such as 1-aza-bicyclo [2.2.2] octane-3-base.
The object lesson of this class group comprises unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrans, morpholine, tetrahydrofuran (THF), piperidines and pyrrolidino group.
Non-aromatics radicals R 3aA subgroup form by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyrans, tetrahydrofuran (THF), piperidines and pyrrolidino group.
Preferred non-aromatics radicals R 3aComprise unsubstituted or substituted cyclopentyl, cyclohexyl, tetrahydropyrans, tetrahydrofuran (THF), piperidines and pyrrolidino group.
Non-aromatic group can be unsubstituted or by one or more above defined radicals R 15Or R 15aReplace.
R 3aConcrete substituting group (for example (1) works as R 3aWhen being aryl or heteroaryl or (2) work as R 3aWhen being non-aromatic group) be selected from radicals R 15a, it is made up of following group: halogen; Hydroxyl; Have 3-6 ring members and contain 2 monocycle carbocyclic ring and heterocyclic groups that are selected from the heteroatomic ring member of O, N and S at the most; And radicals R a-R b, R wherein aBe valence link, O, CO, CO 2, SO 2, NH, SO 2NH or NHSO 2R bBe selected from hydrogen, have 3-6 ring members and contain 2 heteroatomic carbocyclic ring or heterocyclic groups that are selected from O, N and S at the most; The C that is replaced by one or more substituting groups randomly 1-6Alkyl, described substituting group are selected from hydroxyl, oxo base, halogen, carboxyl, amino, list-or two-C 1-4Alkyl amino, have 3-6 ring members and contain 2 carbocyclic ring or heterocyclic groups that are selected from the heteroatomic ring member of O, N and S at the most; And C wherein 1-6One or two carbon atom of alkyl can be randomly by O, S, SO, SO 2Or NH replaces.
In one embodiment, R 3On preferred R 10a(for example (1) works as R to substituting group 3When being aryl or heteroaryl or (2) work as R 3When being non-aromatic group) comprise halogen; Radicals R a-R b, R wherein aBe valence link, O, CO, C (X 2) X 1, R bThe C that is selected from hydrogen, has the heterocyclic group of 3-7 ring members and randomly replaced by one or more substituting groups 1-4Alkyl, described substituting group are selected from hydroxyl, carboxyl, amino, list-or two-C 1-4Alkyl amino and heterocyclic group with 3-7 ring members.
R 3aOn particularly preferred substituent R 15a(for example (1) works as R 3aWhen being aryl or heteroaryl or (2) work as R 3aWhen being non-aromatic group) comprise halogen, especially fluorine, C 1-3Alkoxyl group such as methoxyl group and randomly by fluorine, hydroxyl (for example hydroxymethyl), C 1-2The C that alkoxyl group or 5-or 6-unit's saturated heterocyclic such as piperidino-(1-position only), morpholino, Piperazino and N methyl piperazine subbase replace 1-3Alkyl.
In another embodiment, R 3aThe substituting group of (no matter being aromatics or non-aromatics) is selected from:
Halogen (for example fluorine and chlorine)
The C that is replaced by one or more substituting groups randomly 1-4Alkoxyl group (for example methoxyl group and oxyethyl group), described substituting group is selected from halogen, hydroxyl, C 1-2Alkoxyl group and contain 1 or 2 heteroatomic five or hexa-atomic saturated heterocyclic that is selected from O, N and S, this heterocycle is randomly further by one or more C 1-4Group (for example methyl) replaces, and wherein when having S, S can be with S, SO or SO 2Form exist;
The C that is replaced by one or more substituting groups randomly 1-4Alkyl, described substituting group is selected from halogen, hydroxyl, C 1-4Alkoxyl group, amino, C 1-4Alkyl sulfonyl-amino, 3-6 unit cycloalkyl (for example cyclopropyl), phenyl (randomly being replaced by one or more halogen, methyl, methoxyl group and amino substituting groups of being selected from) and contain 1 or 2 heteroatomic five and hexa-atomic saturated heterocyclic that is selected from O, N and S, this heterocycle is randomly further by one or more C 1-4Group (for example methyl) replaces, and wherein when having S, S can be with S, SO or SO 2Form exist;
Hydroxyl;
Amino, list-C 1-4Alkylamino, two-C 1-4Alkylamino, benzyloxycarbonyl amino and C 1-4Alkoxycarbonyl amino;
Carboxyl and C 1-4Alkoxy carbonyl;
C 1-4Alkyl amino sulfonyl and C 1-4Alkyl sulfonyl-amino;
C 1-4Alkyl sulphonyl;
Group O-Het sOr NH-Het s, Het wherein sBe to contain 1 or 2 heteroatomic five or hexa-atomic saturated heterocyclic that is selected from O, N and S, this heterocycle is randomly further by one or more C 1-4Group (for example methyl) replaces, and wherein when having S, S can be with S, SO or SO 2Form exist;
Contain 1 or 2 heteroatomic five or hexa-atomic saturated heterocyclic that is selected from O, N and S, this heterocycle is randomly further by one or more C 1-4Group (for example methyl) replaces, and wherein when having S, S can be with S, SO or SO 2Form exist;
The oxo base; With
The hexa-atomic aryl and the heteroaryl rings that contain at the most 2 azo-cycle members and randomly replaced by one or more substituting groups that are selected from halogen, methyl and methoxyl group.
In a preferred compound subgroup, R 3aBe carbocyclic ring or heterocyclic group R 3b, it is selected from phenyl; C 3-6Cycloalkyl; Contain at the most 2 and be selected from N, O, S and SO 2Heteroatomic ring member's the saturated non-aromatic heterocyclic of five and hexavalent; The six membered heteroaryl ring that contains 1,2 or 3 azo-cycle member; With contain 3 quinary heteroaryl rings that are selected from the heteroatomic ring member of N, O and S at the most;
Wherein each carbocyclic ring or heterocyclic group R 3bRandomly by 4 at the most, preferably 3, more preferably 2 (for example 1) substituting groups replacements at the most at the most, described substituting group is selected from amino; Hydroxyl; The oxo base; Fluorine; Chlorine; C 1-4Alkyl-(O) q-, wherein q is 0 or 1, and C 1-4Moieties is randomly by fluorine, hydroxyl or C 1-2Alkoxyl group replaces; List-C 1-4Alkylamino; Two-C 1-4Alkylamino; C 1-4Alkoxy carbonyl; Carboxyl; Radicals R e-R 16, R wherein eBe valence link or C 1-3Alkylidene chain, R 16Be selected from C 1-4Alkyl sulphonyl; C 1-4Alkyl amino sulfonyl; C 1-4Alkyl sulfonyl-amino-; Amino; List-C 1-4Alkylamino; Two-C 1-4Alkylamino; C 1-7--oxyl carbonylamino; Contain 3 azo-cycle members' hexa-atomic aromatic group at the most; C 3-6Cycloalkyl; Contain 1 or 2 and be selected from N, O, S and SO 2Heteroatomic ring member's five or hexa-atomic saturated non-aromatic heterocyclic, when the radicals R of saturated non-aromatic group during randomly by one or more methyl substituted 16And work as aromatic group randomly by one or more fluorine, chlorine, hydroxyl, C of being selected from 1-2Alkoxyl group and C 1-2Radicals R when the group of alkyl replaces 16
In another embodiment, R 3aBe selected from:
Randomly by 1-4 (for example 1-2, for example 1) substituent R 15Or R 15aThe monocyclic aryl that replaces;
Randomly by 1-4 (for example 1-2, for example 1) substituent R 15Or R 15aThe C that replaces 3-C 7Cycloalkyl;
Contain 1 and be selected from the ring hetero atom of O, N and S and randomly by the oxo base and/or by 1-4 (for example 1-2, for example 1) substituent R 10Or R 10aThe saturated five-membered ring that replaces;
Contain 1 or 2 and be selected from the ring hetero atom of O, N and S and randomly by the oxo base and/or by 1-4 (for example 1-2, for example 1) substituent R 10Or R 10aThe saturated hexa-member heterocycle that replaces;
Contain 1 or 2 and be selected from the ring hetero atom of O, N and S and randomly by 1-4 (for example 1-2, for example 1) substituent R 15Or R 15aThe quinary heteroaryl ring that replaces;
Contain 1 or 2 azo-cycle member (preferred 1 azo-cycle member) and randomly by 1-4 (for example 1-2, for example 1) substituent R 15Or R 15aThe six membered heteroaryl ring that replaces;
Have 7-9 ring members separately and randomly by 1-4 (for example 1-2, for example 1) substituent R 15Or R 15aList-azabicyclic the alkyl and the diazabicylo alkyl that replace.
Group Y-R 3aCan be formula (i) defined herein, (ii), (iii), (iv), (v), (vi), (vii), (x), (xi), (xii), (xiii), (xiv) and any one radicals R (xv) 3
In addition, group Y-R 3aAlso can be selected from:
Group (xvi):
Figure A20068000923800691
R wherein 4Be C 1-4Alkyl; With
Group (xvii):
Figure A20068000923800701
R wherein 7aBe selected from:
Except C 1-4Unsubstituted C outside the alkyl 1-4Alkyl;
The C that is replaced by one or more substituting groups 1-4Alkyl, described substituting group is selected from C 3-6Cycloalkyl, fluorine, chlorine, methyl sulphonyl, acetoxyl group, cyano group, methoxyl group; With group NR 5R 6With
Group-(CH 2) nR 8, wherein n is 0 or 1, R 8Be selected from C 3-6Cycloalkyl; Oxa--C 4-6Cycloalkyl; Randomly by one or more phenyl that are selected from the substituting groups replacement of fluorine, chlorine, methoxyl group, cyano group, methyl and trifluoromethyl; The aza-bicyclo alkyl; With contain one or two and be selected from the heteroatomic ring member of O, N and S and randomly by methyl, methoxyl group, fluorine, chlorine or group NR 5R 6The 5-unit heteroaryl that replaces.
In group (xvii), R 4Be C 1-4Alkyl.
C 1-4Alkyl can be as mentioned described in the general preferred meaning and definitional part.Therefore, it can be C 1, C 2, C 3Or C 4Alkyl.Concrete C 1-4Alkyl have methyl, ethyl, different-propyl group, just-butyl, different-butyl and tert-butyl.
A concrete group is a methyl.
The radicals R that another is concrete 4Be ethyl and sec.-propyl.
In group (xvii), work as R 7aBe C 1-4Unsubstituted C outside the alkyl 1-4During alkyl, concrete alkyl is unsubstituted C 2-4Alkenyl such as vinyl and 2-propenyl.A preferred radicals R 7aIt is vinyl.
Substituted C 1-4The C that the example of alkyl is replaced by one or more substituting groups 1-4Alkyl, described substituting group is selected from C 3-6Cycloalkyl, fluorine, chlorine, methyl sulphonyl, acetoxyl group, cyano group, methoxyl group; With group NR 5R 6C 1-4Alkyl can be the ethyl of for example substituted methyl, 1-replacement and the ethyl that 2-replaces.Preferred radicals R 7aComprise the ethyl that 2-replaces, the ethyl that replaces of 2-for example, wherein the 2-substituting group is single substituting group such as methoxyl group.
As substituted C 1-4Alkyl is by NR 5R 6During replacement, NR 5R 6Example comprise dimethylamino and be selected from the heterocycle of morpholine, piperidines, piperazine, N methyl piperazine, tetramethyleneimine and thiazolidine.Concrete heterocycle comprises morpholinyl, 4-methylpiperazine base and tetramethyleneimine.
Work as R 7aBe that wherein n is group-(CH of 0 or 1 2) n-R 8The time, R 8Can be C 3-6Cycloalkyl such as cyclopropyl, cyclopentyl or oxa--C 4-6Cycloalkyl such as tetrahydrofuran base and THP trtrahydropyranyl.In a compound subgroup, n is 0, and in another compound subgroup, n is 1.
Perhaps, work as R 7aBe that wherein n is group-(CH of 0 or 1 2) n-R 8The time, R 8Can be the phenyl that is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, methoxyl group, cyano group, methyl and trifluoromethyl.In a compound subgroup, n is 0, and randomly substituted phenyl directly is connected with the Sauerstoffatom of carbamate.In another compound subgroup, n is 1, and therefore randomly substituted phenyl forms the part of benzyl.R wherein 8Be phenyl groups-(CH 2) n-R 8Object lesson unsubstituted phenyl, 4-fluorophenyl and benzyl are arranged.
In another kind of alternative plan, work as R 7aBe that wherein n is group-(CH of 0 or 1 2) n-R 8The time, R 8Can be and contain one or two and be selected from the heteroatomic ring member of O, N and S and randomly by methyl, methoxyl group, fluorine, chlorine or group NR 5R 6The 5-unit heteroaryl that replaces.The example of heteroaryl is as mentioned described in the general preferred meaning and definitional part.A concrete heteroaryl is a thiazolyl group, and 5-thiazolyl group more especially is preferably when n is 1.
Group Y-R 3aObject lesson in table 2, list.In table 2, the tie point of the nitrogen-atoms of group and pyrazole-3-carboxamide group is used from the extended terminal singly-bound of this group and is represented.Therefore, for example, the group CA in the table is the 4-fluorophenyl, and the group CB in the table is the 4-methoxy-benzyl, and the group CC in the table is 4-(4-methylpiperazine subbase)-phenyl methyl.
Figure A20068000923800721
Figure A20068000923800731
Figure A20068000923800741
Figure A20068000923800751
Figure A20068000923800761
Figure A20068000923800771
Figure A20068000923800781
Figure A20068000923800791
Figure A20068000923800801
Preferred group that is selected from table 2 comprises group CA to CV.
A preferred group subgroup in the table 2 is made up of group CL, CM, ES, ET, FC, FG and FH.
Another the preferred group subgroup that is selected from table 2 comprises group CL, CM and ES, most preferably CL and CM.
Another preferred group is EP.
In embodiment (H), a subgroup of formula (I) compound can be used formula (IV) expression:
Figure A20068000923800802
Or its salt or tautomer or N-oxide compound or solvate;
R wherein 1dAnd R 2As defined herein;
Can there be second optional valence link being numbered between 1 and 2 the carbon atom;
One among U and the T is selected from CH 2, CHR 20, CR 18R 20, NR 21, N (O) R 22, O and S (O) tAmong U and the T another is selected from NR 21, O, CH 2, CHR 18, C (R 18) 2And C=O;
R is 0,1,2,3 or 4; T is 0,1 or 2;
R 18Be selected from hydrogen, halogen (particularly fluorine), C 1-3Alkyl (for example methyl) and C 1-3Alkoxyl group (for example methoxyl group);
R 20Be selected from hydrogen, NHR 21, NOH, NOR 21And R a-R b
R 21Be selected from hydrogen and R d-R b
R dBe selected from valence link, CO, C (X 2) X 1, SO 2And SO 2NR c
R a, R bAnd R cAs hereinbefore defined; With
R 22Be selected from randomly by hydroxyl, C 1-2The C that alkoxyl group, halogen or monocycle 5-or 6-unit's carbocyclic ring or heterocyclic group replace 1-4Saturated hydrocarbyl, condition are that U and T can not be O simultaneously.
In formula (IV), r can be 0,1,2,3 or 4.In one embodiment, r is 0.In another embodiment, r is 2, and r is 4 in another embodiment.
In formula (IV), preferred compound subgroup is wherein only to have single bonded compound group being numbered between 1 and 2 the carbon atom.
Yet, in another compound subgroup, have two keys between 1 and 2 the carbon atom being numbered.
Another compound subgroup is to be substituted by feature together with two on 2-carbon (when being numbered when having singly-bound between 1 and 2 the carbon atom) and/or 6-carbon.Preferably replace and comprise difluoro and dimethyl together with two.
Another compound subgroup be numbered on 3 the carbon atom, promptly exist on the α position at group T alkoxyl group for example methoxyl group be feature.
In formula (IV), comprise such compound, wherein R for example 3aBe selected from any one in the following ring system:
Figure A20068000923800821
Preferred ring system comprises G1 and G3.
A preferred compound subgroup in the formula (IV) can be used formula (IVa) expression:
Figure A20068000923800822
Or its salt or tautomer or N-oxide compound or solvate;
R wherein 1dAnd R 2As hereinbefore defined;
One among U and the T is selected from CH 2, CHR 20, CR 18R 20, NR 21, N (O) R 22, O and S (O) tAmong U and the T another is selected from CH 2, CHR 18, C (R 18) 2And C=O; R is 0,1 or 2; T is 0,1 or 2;
R 18Be selected from hydrogen and C 1-3Alkyl;
R 20Be selected from hydrogen and R a-R b
R 21Be selected from hydrogen and R d-R b
R dBe selected from valence link, CO, C (X 2) X 1, SO 2And SO 2NR c
R a, R bAnd R cAs hereinbefore defined; With
R 22Be selected from randomly by hydroxyl, C 1-2The C that alkoxyl group, halogen or monocycle 5-or 6-unit's carbocyclic ring or heterocyclic group replace 1-4Saturated hydrocarbyl.
In formula (IVa), T is preferably selected from CH 2, CHR 20, CR 18R 20, NR 21, N (O) R 22, O and S (O) tU is preferably selected from CH 2, CHR 18, C (R 18) 2And C=O.
In substituent R 18And R 21Definition in, R bBe preferably selected from hydrogen; Monocycle carbocyclic ring and heterocyclic group with 3-7 ring members; And C 1-4Alkyl (more preferably acyclic saturated C 1-4Group), it is randomly by one or more hydroxyl, oxo base, halogen, amino, list-or two-C that are selected from 1-4Alkyl is amino and have the substituting group replacement of the monocycle carbocyclic ring and the heterocyclic group of 3-7 ring members (more preferably 3-6 ring members), and C wherein 1-4One or more carbon atoms of alkyl can be randomly by O, S, SO, SO 2, NR c, X 1C (X 2), C (X 2) X 1Replace; R cBe selected from hydrogen and C 1-4Alkyl; With
X 1Be O, S or NR c, X 2For=O ,=S or=NR c
R 18Being preferably selected from hydrogen and methyl, most preferably is hydrogen.
R 20Be preferably selected from hydrogen; Hydroxyl; Halogen; Cyano group; Amino; List-C 1-4Saturated hydrocarbyl amino; Two-C 1-4Saturated hydrocarbyl amino; Monocycle 5-or 6-unit's carbocyclic ring and heterocyclic group; Randomly by hydroxyl, C 1-2The C that alkoxyl group, halogen or monocycle 5-or 6-unit's carbocyclic ring or heterocyclic group replace 1-4Saturated hydrocarbyl.
R 20Object lesson hydrogen, hydroxyl, amino, C are arranged 1-2Alkylamino (for example methylamino), C 1-4Alkyl (for example methyl, ethyl, propyl group and butyl), C 1-2Alkoxyl group (for example methoxyl group), C 1-2Alkyl sulfonyl amino (for example methanesulfonamido), hydroxyl-C 1-2Alkyl (for example hydroxymethyl), C 1-2-alkoxy-C 1-2Alkyl (for example methoxymethyl and methoxy ethyl), carboxyl, C 1-4Alkoxy carbonyl (for example ethoxy carbonyl) and amino-C 1-2-alkyl (for example amino methyl).
R 21Object lesson hydrogen is arranged; Randomly by fluorine or five or the C that replaces of hexa-atomic saturated heterocyclic group 1-4Alkyl (for example be selected from (i) methyl, ethyl, just-propyl group, different-propyl group, butyl, 2,2,2-trifluoroethyl and tetrahydrofuran (THF) ylmethyl; And/or (ii) 2-fluoro ethyl and 2, the group of 2-two fluoro ethyls); The cyclopropyl methyl; Substituted or unsubstituted pyridyl-C 1-2Alkyl (for example 2-pyridylmethyl); Substituted or unsubstituted phenyl-C 1-2Alkyl (for example benzyl); C 1-4Alkoxy carbonyl (for example ethoxy carbonyl and uncle-butoxy carbonyl); Substituted and unsubstituted phenyl-C 1-2Alkoxy carbonyl (for example benzyloxycarbonyl); Substituted and unsubstituted 5-and 6-unit's heteroaryl such as pyridyl (for example 2-pyridyl and 6-chloro-2-pyridyl) and pyrimidyl (for example 2-pyrimidyl); C 1-2-alkoxy-C 1-2Alkyl (for example methoxymethyl and methoxy ethyl); C 1-4Alkyl sulphonyl (for example methylsulfonyl).
In each example and preferred meaning of above embodiment (H), R 1dBe radicals R 1e-(CH 2) nCH (CN)-, wherein n is 0,1 or 2, R 1eBe carbocyclic ring or heterocyclic group with 3-12 ring members.
Carbocyclic ring and heterocyclic group can as preferred meaning and definitional part described in.
Preferred n is 0.
Concrete carbocyclic ring and heterocyclic group have the saturated mono cyclic group with 3-7 ring members, as cycloalkyl.
A concrete cycloalkyl is a cyclopropyl.
Usually to the various functional groups of composition formula (I) compound with substituting group selects so that the molecular weight of formula (I) compound is no more than 1000.More generally, the molecular weight of compound is less than 750, for example less than 700 or less than 650 or less than 600 or less than 550.More preferably, molecular weight is less than 525, and for example molecular weight is 500 or littler.
Concrete The compounds of this invention is described in hereinafter embodiment.
The compound group that a group of concrete The compounds of this invention is embodiment 1-132.In this compound group, a subgroup is made up of the compound of embodiment 1-114.Another subgroup is made up of the compound of embodiment 115-132.Another subgroup is made up of the compound of embodiment 133-137.
Preferred The compounds of this invention comprises:
4-(2,3-two chloro-6-methoxyl group-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides;
4-(3-chloro-2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides;
4-(2-chloro-3,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides;
With and salt, solvate, tautomer and N-oxide compound.
Salt, solvate, tautomer, isomer, N-oxide compound, ester, prodrug and isotropic substance
Mentioning of compound to formula (I) and its subgroup also comprises its ionic species, salt, solvate, isomer, tautomer, N-oxide compound, ester, prodrug, isotropic substance and protected form, as discussed below those of example.Preferred its salt or tautomer or isomer or N-oxide compound or solvate; More preferably its salt or tautomer or N-oxide compound or solvate.
Many formulas (I) compound can exist with the form of salt, for example acid salt, perhaps can exist with salt such as carboxylate salt, sulfonate and the phosphatic form of organic or inorganic alkali in some cases.All these class salt include within the scope of the invention, to the salt form that comprises compound of mentioning of formula (I) compound.
Can use conventional chemical process such as Pharmaceutical Salts:Properties, Selection, and Use, P.Heinrich Stahl (editor), G.Wermuth (editor), ISBN:3-90639-026-8, Hardcover, 388 pages, described method is by the synthetic salt of the present invention of the parent compound that contains alkalescence or acidic moiety in 2002 8 months.Generally speaking, free acid that this class salt can be by making these compounds or alkali form and suitable alkali or acid are reacted in water or in organic solvent or in the mixture of the two and are prepared; General non-aqueous media such as ether, ethyl acetate, ethanol, Virahol or the acetonitrile of using.
Can form acid salt with various acid (mineral acid and organic acid).The example of acid salt comprises the salt that forms with the acid that is selected from down group: acetate; 2; the 2-dichloro acetic acid; hexanodioic acid; Lalgine; xitix (for example L-xitix); the L-aspartic acid; Phenylsulfonic acid; phenylformic acid; the 4-acetylamino benzoic acid; butyric acid; (+) dextrocamphoric acid; camphor-sulfonic acid; (+)-(1S)-camphor-10-sulfonic acid; capric acid; caproic acid; sad; styracin; citric acid; cyclohexane sulfamic acid; dodecyl sulphate; ethane-1; the 2-disulfonic acid; ethyl sulfonic acid; the 2-ethylenehydrinsulfonic acid; formic acid; fumaric acid; tetrahydroxyadipic acid; 2; the 5-resorcylic acid; glucoheptonic acid; the D-glyconic acid; glucuronic acid (for example D-glucuronic acid); L-glutamic acid (for example L-L-glutamic acid); α-Yang Daiwuersuan; oxyacetic acid; urobenzoic acid; Hydrogen bromide; hydrochloric acid; hydroiodic acid HI; isethionic acid; (+)-L-lactic acid; (±)-DL-lactic acid; lactobionic acid; toxilic acid; oxysuccinic acid; (-)-L MALIC ACID; propanedioic acid; (±)-DL-amygdalic acid; methylsulfonic acid; naphthalene-2-sulfonic acid; naphthalene-1; the 5-disulfonic acid; 1-hydroxyl-2-naphthoic acid; nicotinic acid; nitric acid; oleic acid; vitamin B13; oxalic acid; palmitinic acid; pamoic acid; phosphoric acid; propionic acid; the L-Pyrrolidonecarboxylic acid; Whitfield's ointment; 4-amino-Whitfield's ointment; sebacic acid; stearic acid; succsinic acid; sulfuric acid; tannic acid; (+)-L-tartrate; thiocyanic acid; right-toluenesulphonic acids; undecylenic acid and valeric acid, and the amino acid of acidylate and Zeo-karb.
A concrete group of salt is made up of the salt that forms with acetate, hydrochloric acid, hydroiodic acid HI, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succsinic acid, toxilic acid, oxysuccinic acid, isethionic acid, fumaric acid, Phenylsulfonic acid, toluenesulphonic acids, methylsulfonic acid (methanesulfonic), ethyl sulfonic acid, naphthene sulfonic acid, valeric acid, acetate, propionic acid, butyric acid, propanedioic acid, glucuronic acid and lactobionic acid.
A subgroup of salt is made up of the salt that forms with hydrochloric acid, acetate, methylsulfonic acid, hexanodioic acid, L-aspartic acid and DL-lactic acid.
Another subgroup of salt is made up of acetate, mesylate, esilate, DL-lactic acid salt, adipate, D-glucuronate, D-gluconate and hydrochloride.
The preferred salt of liquid (for example water-based) composition that is used for preparing the compound of formula as herein described (I) and subgroup and example is to have greater than 10mg/ml liquid vehicle (for example water), more generally greater than 15mg/ml, be preferably greater than the salt of the solubleness of 20mg/ml at given liquid vehicle (for example water).
In one embodiment of the invention, a kind of pharmaceutical composition is provided, and it comprises and contains concentration greater than 10mg/ml, usually greater than the aqueous solution of the compound of 15mg/ml, the formula as herein described (I) of salt form that is preferably greater than 20mg/ml and subgroup and example.
If compound is an anionic property, perhaps have can be anionic property functional group (for example-COOH can be-COO-), then can with suitable salt forming cation.The example of suitable inorganic cation includes but not limited to alkalimetal ion such as Na +And K +, alkaline earth metal cation such as Ca 2+And Mg 2+And other positively charged ion such as Al 3+Suitable organic cations example includes but not limited to ammonium ion (that is NH, 4 +) and substituted ammonium ion (for example, NH 3R +, NH 2R 2 +, NHR 3 +, NR 4 +).The example of the substituted ammonium ion that some are suitable is derived from those of following material: ethamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, quadrol, thanomin, diethanolamine, piperazine, benzylamine, phenylbenzyl amine, choline, meglumine and tromethane, and amino acid, as Methionin and arginine.An example of common quaternary ammonium ion is N (CH 3) 4 +
Contain under the situation of amine functional group at formula (I) compound, these compounds can form quaternary ammonium salt, for example by according to well known to a person skilled in the art that method and alkylation reactions form quaternary ammonium salt.This class quaternary ammonium compound is in the scope of formula (I).
The salt form of compound of the present invention is pharmacologically acceptable salt normally, and the example of pharmacologically acceptable salt is at Berge etc., and 1977, " Pharmaceutically Acceptable Salts, " J.Pharm.Sci., the 66th volume has discussion in the 1-19 page or leaf.Yet pharmaceutically unacceptable salt also can be produced with intermediate forms, can convert it into pharmacologically acceptable salt then.The pharmaceutically unacceptable salt form of this class may be useful, for example is used for purifying or separates compound of the present invention, and they have also formed a part of the present invention.
Formula (I) compound that contains amine functional group also can form the N-oxide compound.This paper also comprises the N-oxide compound to the mentioning of formula (I) compound of containing amine functional group.
Contain at compound under the situation of several amine functional groups, one or more nitrogen-atoms can oxidized formation N-oxide compound.The object lesson of N-oxide compound has the N-oxide compound of tertiary amine or nitrogenous heterocyclic nitrogen-atoms.
Can form the N-oxide compound by handling corresponding amine with oxygenant such as hydrogen peroxide or peracid (for example peroxycarboxylic acid), referring to for example Advanced Organic Chemistry, Jerry March, the 4th edition, Wiley Interscience, page or leaf.More specifically, can pass through L.W.Deady (Syn.Comm.1977,7, working method 509-514) prepares the N-oxide compound, wherein amine compound and-chlorine peroxybenzoic acid (MCPBA) reaction, for example in inert solvent such as methylene dichloride, react.
Formula (I) compound can exist with many different rotamerism form and tautomeric forms, and mentioning of formula (I) compound comprised all these class forms.For fear of doubt, can exist and only specifically describe or provided under a kind of situation with one of several rotamerism forms or tautomeric form at compound, all other rotamerism forms or tautomeric form are also included within the formula (I).
For example, in formula (I) compound, the pyrazoles ring can exist with the form of following two kinds of tautomeric form A and B.For easy, general formula (I) has provided form A, but should think that described general formula comprises two kinds of tautomeric forms.
Figure A20068000923800871
Other example of tautomeric form for example comprise ketone group-, enol-and enolate-form, for example following tautomer centering: ketone group/enol (providing below), imines/enamine, acid amides/imino-alcohol, amidine/amidine, nitroso-group/oxime, thioketones/alkene mercaptan and nitro/acid-nitro (aci-nitro).
The ketoenoles enolate
Unless context has requirement in addition, otherwise formula (I) compound contain one or single chiral centre and the situation that can exist with the form of two or more optically active isomer under, mentioning of formula (I) compound comprised its all rotational isomerism forms (for example enantiomorph, epimer and diastereomer), the mixture that described rotational isomerism form is single optically active isomer or two or more optically active isomer (for example racemic mixture).
Can characterize and differentiate optically active isomer (promptly with its optically active, for+and-isomer, or d and l isomer) or can characterize them with " R and S " nomenclature that Cahn, Ingold and Prelog set up according to its absolute stereo chemistry, referring to Advanced Organic Chemistry, JerryMarch, the 4th edition, John Wiley ﹠amp; Sons, New York, 1992, the 109-114 pages or leaves, also referring to Cahn, Ingold ﹠amp; Prelog, Angew.Chem.Int.Ed.Engl., 1966,5,385-415.
Can be with comprise that chiral chromatography (chromatography of carrying out) separates optically active isomer in interior many technology on chiral support, this class technology is known in those skilled in the art.
Alternative as chiral chromatography; separating optical isomers by the following method: form diastereomeric salt as (+)-tartrate, (-)-Pyrrolidonecarboxylic acid, (-)-two-toluyl-L-tartrate, (+)-amygdalic acid, (-)-oxysuccinic acid and (-)-camphorsulfonic acid with chiral acid; separate diastereomer with selective freezing (preferentialcrystallisation), then salt is dissociated into the single enantiomer of free alkali.
Under the situation that formula (I) compound exists with two or more optically active isomer form, a kind of enantiomorph in a pair of enantiomorph can be better than another kind of enantiomorph, for example, is better than another kind of enantiomorph aspect biologic activity.Therefore, in some cases, only may need with a kind of in a pair of enantiomorph or only use a kind of in the multiple diastereomer as therapeutical agent.Therefore, the invention provides and contain formula (I) compound compositions with one or more chiral centres, wherein at least 55% formula (I) compound of (for example at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) exists with the form of single optical isomer (for example enantiomorph or diastereomer).In a general embodiment, 99% or more (for example whole basically) of formula (I) total amount of compound can exist with the form of single optical isomer (for example enantiomorph or diastereomer).
Compound of the present invention comprises having the compound that one or more isotropic substances replace, to all isotropic substances that comprise this element in its scope of mentioning of concrete element.For example, mentioning in its scope of hydrogen comprised 1H, 2H (D) and 3H (T).Similarly, mentioning in its scope of carbon and oxygen comprised respectively 12C, 13C and 14C with 16O and 18O.
Isotropic substance can be radioactive or inactive.In one embodiment of the invention, compound does not contain radio isotope.Preferably this compounds is used for the treatment of purposes.Yet in another embodiment, compound can contain one or more radio isotope.Containing the radioisotopic compound of this class may be useful under the situation of diagnosis.
Ester is also included within formula (I) scope as the carboxylicesters and the acyloxyate of formula (I) compound that has hydroxy-acid group or hydroxyl.The example of ester has and contains group-C (=O) compound of OR, wherein R is ester substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The object lesson of ester group includes but not limited to-C (=O) OCH 3,-C (=O) OCH 2CH 3,-C (=O) OC (CH 3) 3With-C (=O) OPh.The example of acyloxy (oppositely ester) group with-OC (=O) R represents, wherein R is acyloxy substituting group, for example C 1-7Alkyl, C 3-20Heterocyclic radical or C 5-20Aryl, preferred C 1-7Alkyl.The object lesson of acyloxy includes but not limited to-OC (=O) CH 3(acetoxyl group) ,-OC (=O) CH 2CH 3,-OC (=O) C (CH 3) 3,-OC (=O) Ph and-OC (=O) CH 2Ph.
Formula (I) also comprise any polymorphic form of compound, the solvate of compound (for example hydrate), mixture (for example with such as the inclusion complex of compounds such as cyclodextrin or inclusion compound or with the mixture of metal) and the prodrug of compound." prodrug " means any compound of the biologically active cpds that for example is converted to formula (I) in vivo.
For example, some prodrugs are esters (for example, physiology acceptable be easy to metabolic ester) of active compound.In metabolic process, the cleaved generation active medicine of ester group (C (=O) OR).This class ester can form by the esterification of any hydroxy-acid group in the parent compound for example (C (=O) OH), under suitable situation, any other active group in the parent compound is protected in advance, if desired, goes protection afterwards again.
The example that this class is easy to metabolic ester comprises that (=O) those of OR, wherein R is formula-C: C 1-7Alkyl
(for example ,-Me ,-Et ,-nPr ,-iPr ,-nBu ,-sBu ,-iBu ,-tBu);
C 1-7Aminoalkyl group
(for example, amino-ethyl; 2-(N, N-diethylamino) ethyl; 2-(4-morpholino) ethyl); With
Acyloxy-C 1-7Alkyl
(for example, acyloxy methyl;
The acyloxy ethyl;
Oxy acid methyl neopentyl;
Acetoxy-methyl;
1-acetoxyl group ethyl;
1-(1-methoxyl group-1-methyl) ethyl-carbon acyloxy ethyl;
1-(benzoyloxy) ethyl; Isopropoxy-phosphinylidyne oxygen ylmethyl;
1-isopropoxy-carbon acyloxy ethyl; Cyclohexyl-phosphinylidyne oxygen ylmethyl;
1-cyclohexyl-carbon acyloxy ethyl;
Cyclohexyl oxygen base-phosphinylidyne oxygen ylmethyl;
1-cyclohexyl oxygen base-carbon acyloxy ethyl;
(4-THP trtrahydropyranyl oxygen base) phosphinylidyne oxygen ylmethyl;
1-(4-THP trtrahydropyranyl oxygen base) carbon acyloxy ethyl;
(4-THP trtrahydropyranyl) phosphinylidyne oxygen ylmethyl; With
1-(4-THP trtrahydropyranyl) carbon acyloxy ethyl).
In addition, some prodrugs are produced the compound (for example, in ADEPT, GDEPT, LIDEPT etc.) of active compound or the further chemical reaction generation of warp active compound by the enzymatic activation.For example, prodrug can be sugar derivatives or other glucosides conjugate, perhaps can be amino acid ester derivative.
Biologic activity
The compound of formula (I) and its subgroup is the inhibitor of cell cycle protein dependent kinase.For example, compound of the present invention be cell cycle protein dependent kinase, particularly be selected from CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK9, more especially be selected from the inhibitor of the cell cycle protein dependent kinase of CDK1, CDK2, CDK3, CDK4, CDK5 and CDK9.
Preferred compound is to suppress one or more to be selected from the compound of CDK kinases, for example CDK1 and/or the CDK2 of CDK1, CDK2, CDK4 and CDK9.
Compound of the present invention also has the activity of anti-glycogen synthase kinase-3 (GSK3).
Because their are being regulated or are suppressing activity in CDK and the glycogen synthase kinase, estimate that compound of the present invention can be used for being provided in the cell of abnormal division the retardance cell cycle or recovers the means of the control of cell cycle.Therefore, expectation will prove that described compound can be used for treatment or prevention proliferative disorder such as cancer.Estimate that also compound of the present invention will can be used for treatment such as paralysis, corticobasal degeneration and Pick's disease illnesss such as (Pick ' s disease), for example autoimmune disorder and neurodegenerative disease on virus infection, II type or non insulin dependent diabetes, autoimmune disorder, head trauma, apoplexy, epilepsy, neurodegenerative disease such as alzheimer's disease, motor neurone disease, the carrying out property nuclear.
Estimate that morbid state and illness subgroup that compound of the present invention is useful therein be made up of virus infection, autoimmune disorder and neurodegenerative disease.
CDK at cell cycle regulation, apoptosis, transcribe, play a role in differentiation and the CNS function.Therefore, the CDK inhibitor can be used for treating the disorders such as cancers that wherein has propagation, apoptosis or dysdifferentiation.Particularly the RB+ve tumour can be responsive especially to the CDK inhibitor.The RB-ve tumour also can be to CDK inhibitor sensitivity.
Example that can repressed cancer includes but not limited to: cancer, for example bladder cancer, mammary cancer, colorectal carcinoma (for example colorectal carcinoma such as adenocarcinoma of colon and adenoma of colon), kidney, epidermal carcinoma, liver cancer, lung cancer, for example exocrine pancreas cancer (exocrine pancreatic carcinoma), cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer or skin carcinoma, for example squamous cell carcinoma of gland cancer, small cell lung cancer and nonsmall-cell lung cancer, esophagus cancer, carcinoma of gallbladder, ovarian cancer, carcinoma of the pancreas for example; The hematopoietic system cancer of lymph pedigree (hematopoietic tumors of lymphoid lineage), for example leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma (as the diffuse type large B cell lymphoid tumor), T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, hairy cell lymphoma (hairy celllymphoma) or Burkitt lymphoma; The hematopoietic system cancer of marrow pedigree (hematopoietictumour of myeloid lineage), for example acute and chronic myelogenous leukemia, myelodysplastic syndromes or promyelocytic leukemia; Follicular carcinoma of thyroid; The tumour of mesenchyme origin, for example fibrosarcoma or rhabdosarcoma; The tumour of central or peripheral nervous system, for example astrocytoma, neuroblastoma, neurospongioma or schwannoma; Melanoma; Spermocytoma; Teratocarcinoma; Osteosarcoma; Xeroderma pitmentosum; Keratoacanthoma (keratoctanthoma); Follicular carcinoma of thyroid; Or Kaposi sarcoma.
Cancer can be to the cell cycle protein dependent kinase of any or multiple CDK1 of being selected from, CDK2, CDK3, CDK4, CDK5 and CDK6, for example one or more are selected from the cancer of inhibition sensitivity of CDK kinases, for example CDK1 and/or the CDK2 of CDK1, CDK2, CDK4 and CDK5.
Can utilize the cell growth measurement method or the title that provide among the embodiment hereinafter to determine for the method that provides in the part of " diagnostic method " whether a kind of specific cancer is the cancer of the inhibition sensitivity of cell cycle protein dependent kinase.
Also known CDK apoptosis, propagation, break up and transcribe in play a role, therefore the CDK inhibitor also can be used for treating cancer following disease in addition: virus infection, for example simplexvirus, poxvirus, Epstein-Barr virus, sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; Prevention AIDS in the HIV-infected individuals takes place; Chronic inflammatory disease, for example glomerulonephritis, rheumatoid arthritis, psoriatic, inflammatory bowel and the autoimmune diabetes of systemic lupus erythematous, autoimmunization mediation; Cardiovascular disorder is cardiac hypertrophy, restenosis, atherosclerosis for example; Neurodegenerative disease, for example alzheimer's disease, dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, Duchenne-Arandisease and the cerebellar degeneration relevant with AIDS; Glomerulonephritis; Myelodysplastic syndrome, myocardial infarction, apoplexy and the reperfusion injury relevant, irregular pulse, atherosclerosis, toxin-bring out with ischemia injury or with alcohol relevant hepatopathy, blood disease, for example chronic anaemia and aplastic anemia; The degenerative disease of musculoskeletal system, for example osteoporosis and sacroiliitis, aspirin sensitive sinusitis paranasal sinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.
Have been found that also some cell cycle protein dependent kinase inhibitors can be used in combination with other carcinostatic agent.For example, the cell cycle protein dependent kinase inhibitor good fortune draws benefit to be used from combined therapy with other carcinostatic agent one.
Therefore, in pharmaceutical composition, purposes or the method that is used for the treatment of the disease that comprises abnormal cell growth or illness of the present invention, comprise that the disease of abnormal cell growth or illness are cancer in one embodiment.
One group of cancer comprises human breast carcinoma (for example primary breast cancer, lymphoglandula negative breast cancer, mammary gland infiltration duct adenocarcinoma, non-endometrial-like mammary cancer (non-endometrioid breast cancers)); And lymphoma mantle cell.In addition, other cancer has colorectal carcinoma and carcinoma of endometrium.
Another subgroup of cancer comprises the hematopoietic system cancer of lymph pedigree, for example leukemia, chronic lymphocytic leukemia, lymphoma mantle cell and B-cell lymphoma (as the diffuse type large B cell lymphoid tumor).
A kind of concrete cancer is a chronic lymphocytic leukemia.
Another kind of concrete cancer is a lymphoma mantle cell.
Another kind of concrete cancer is the dispersivity large B cell lymphoid tumor.
Another subgroup of cancer comprises mammary cancer, ovarian cancer, colorectal carcinoma, prostate cancer, esophagus cancer, squamous cell carcinoma and nonsmall-cell lung cancer.
Can measure the activity of compound of the present invention as the inhibitor of cell cycle protein dependent kinase and glycogen synthase kinase-3 with the assay method that provides among the embodiment hereinafter, the activity level that given compound showed can be used IC 50Value defines.Preferred The compounds of this invention is IC 50Value less than 1 micromole, be more preferably less than 0.1 micromolar compound.
The advantage of The compounds of this invention
The compound of formula defined herein (I) and its subgroup has the advantage that is better than the prior art compound.
Compound of the present invention may have the physico-chemical property that is suitable for oral exposure.
Compound of the present invention is higher than IC50 to propagation, for example high～100 times to the IC50 that transcribes in the HCT-116 cell.This is favourable, because compound can be tolerated better, thereby makes that it can be with higher dosed administration and administration longer time.
Particularly formula (I) compound is compared the oral administration biaavailability that demonstrates improvement with the compound of prior art.The ratio (F) of the plasma exposure value of compound and the plasma exposure value of compound when intravenously (i.v.) administration when oral administration biaavailability may be defined as the by oral route administration of representing with per-cent.
The compound particularly advantageous of oral administration biaavailability (F value) greater than 30%, more preferably greater than 40% because they can be used by Orally administered but not parenteral, perhaps can be used by Orally administered and parenteral.
The method of preparation formula (I) compound
Unless context has explanation in addition, otherwise, in this part, will be understood that mentioning of formula (I) compound also comprised its all subgroups and example defined herein with the same in all other parts of the application.Unless context has requirement in addition, otherwise mentioning radicals R 1, R 3, R 4, R 7aOr under the situation of any other " R " group, the definition of the group of being discussed as indicated above and as the application with as described in the lower section.
Can be according to well known to a person skilled in the art synthetic method and come preparation formula (I) compound by the method described in the given application PCT/GB2004/003179 with us hereinafter, the content of described application is incorporated herein by reference.
For example, can come preparation formula (I) compound by the reaction sequence shown in the schema 1.
The starting raw material that is used for the synthesis path shown in the schema 1 is 4-nitro-pyrazoles-3-carboxylic acid (X), and it can be commercially available or can be by the unsubstituted pyrazoles carboxylic compound of corresponding 4-is carried out nitrated the preparation.
Figure A20068000923800951
Schema 1
By under the situation that has acid catalyst or thionyl chloride, reacting nitro-pyrazole carboxylic acid (X) is changed into corresponding ester (XI), for example methyl esters or ethyl ester (wherein having provided ethyl ester) with suitable alcohol such as ethanol.This reaction can use esterifying alcohol to carry out at ambient temperature as solvent.
Can nitro-ester (XI) be reduced into corresponding amine (XII) by nitro being changed into amino standard method.Therefore, for example, can nitroreduction be become amine by carrying out hydrogenation with Pd/carbon catalyst.This hydrogenation can carry out in solvent such as ethanol at ambient temperature.
Can by with formula R 1The amine (XII) that the acyl chlorides of COCl reacts under the situation that has glitch-free alkali such as triethylamine gained changes into acid amides (XIII).This reaction can carried out in polar solvent such as diox under about room temperature.Can be by handling carboxylic acid R with thionyl chloride 1CO 2H or by reacting under the situation of the dimethyl formamide that has catalytic amount with oxalyl chloride or reacting and prepare acyl chlorides by sylvite and the oxalyl chloride that makes acid.
As the alternative of using above-mentioned acyl chlorides method, can by with carboxylic acid R 1CO 2H reacts under having the situation that forms the acid amides coupling reagent of common type in the peptide bond amine (XII) is changed into acid amides (XIII).The example of this class reagent comprises 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan etc., J.Amer.Chem Soc.1955, 771067), 1-ethyl-3-(3 '-dimethylaminopropyl)-carbodiimide (is referred to herein as EDC or EDAC, but be also referred to as EDCI and WSCDI in the art) (Sheehan etc., J.Org.Chem., 1961,26,2525), based on the coupling agent such as O-(7-azepine benzo the triazol-1-yl)-N of urea, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU) and based on the coupling agent such as 1-benzo-triazolyl oxygen base three-(pyrrolidino) phosphorus hexafluorophosphate (PyBOP) (Castro etc., the Tetrahedron Letters of phosphorus, 1990 31, 205).Advantageously will based on the coupling agent of carbodiimide and 1-hydroxyl-7-azepine benzotriazole (HOAt) (L.A.Carpino, J.Amer.Chem.Soc., 1993, 115, 4397) or I-hydroxybenzotriazole (HOBt) (Konig etc., Chem.Ber., 103,708,2024-2034) be used in combination.Preferred coupling reagent comprises EDC (EDAC) and the DCC with HOAt or HOBt combination.
This linked reaction is carried out in nonaqueous aprotic solvent such as acetonitrile, diox, dimethyl sulfoxide (DMSO), methylene dichloride, dimethyl formamide or N-crassitude or in the optional aqueous solvent that contains the cosolvent that one or more can be miscible usually.Reaction can at room temperature be carried out, and perhaps (is for example having under the situation of aniline of electron deficiency of electron-withdrawing group such as sulfamoyl group) under the relatively poor situation of reactant activity, and reaction can be carried out under the temperature that suitably raises.Reaction can be carried out under the situation of N-diisopropylethylamine having glitch-free alkali for example tertiary amine such as triethylamine or N.
Subsequently by acid amides (XIII) being hydrolyzed into carboxylic acid (XIV) with alkali metal hydroxide aqueous solution such as sodium-hydroxide treatment.Saponification reaction can use organic cosolvent to carry out as alcohol (for example methyl alcohol), and reaction mixture is heated to non-extreme temperature usually, for example is heated to about 50-60 ℃ at the most.
Then can be by using the condition and the amine R of formation acid amides mentioned above 3-NH 2Reaction transforms an accepted way of doing sth (I) compound with carboxylic acid (XIV).Therefore, for example, this acid amides linked reaction can carried out in polar solvent such as DMF under the situation that have EDC and HOBt.
The general path of the selective formula that obtains (I) compound is as shown in schema 2.
Figure A20068000923800971
Schema 2
In schema 2, use the condition of above-mentioned formation acid amides to make nitro-pyrazoles-carboxylic acid (X) or its reactive derivative such as acyl chlorides and amine R 3-NH 2Reaction obtains nitro-pyrazoles-acid amides (XV), uses the standard method of reduction nitro for example to relate to then and above-mentionedly carries out the hydrogenant method with the Pd/C catalyzer it is reduced into corresponding aminocompound (XVI).
Make amine (XVI) and formula R then 1-CO 2The carboxylic acid of H or its reactive derivative such as acyl chlorides or acid anhydrides carry out coupling above under at the condition of schema 1 described formation acid amides.Therefore, for example, as the alternative of using acyl chlorides, linked reaction can be carried out in solvent such as DMF under the situation that has EDAC (EDC) and HOBt, obtains formula (I) compound.
R wherein 3For formula (I) compound of alkylsulfonyl piperidyl (i) or acylpiperidine base can pass through method for preparing, perhaps can by with suitable acidylate or sulfonylation agent reaction and by the compound of formula (XVII) they:
Figure A20068000923800972
Therefore; for example; the alkylsulfonyl piperidinyl compounds can by with suitable SULPHURYL CHLORIDE such as methylsulfonyl chloride prepared in reaction, and acylpiperidine compounds and carbamate derivatives can be respectively compound by making formula (XVII) and suitable acyl chlorides or chloroformate derivative react and prepare.
The alkylsulfonyl of the compound conversion accepted way of doing sth (I) of display type (XVII) and the illustrative reaction sequence of acyl group and carbamate derivatives are as shown in schema 3.
Figure A20068000923800981
Schema 3
As shown in schema 3, R wherein 3For having alkylsulfonyl-SO 2XR 4Formula (I) compound (being the compound of formula (XIX)) of piperidine ring can be by compound and the SULPHURYL CHLORIDE R that makes formula (XVII) 4SO 2Cl or R 4aSO 2Cl (as methylsulfonyl chloride) reacts under the situation that has glitch-free alkali such as diisopropyl ethyl amine and prepares.This reaction is at room temperature carried out in nonaqueous aprotic solvent such as diox and methylene dichloride usually.
Formula R 4SO 2Cl or R 4aSO 2The SULPHURYL CHLORIDE of Cl can obtain from commercial source, perhaps can prepare by many working method.For example, alkyl sulfonyl chloride can prepare by the following method: alkylogen and S-WAT are reacted to form corresponding sulfonic acid in water-containing organic solvent such as water/diox under heating, handle existing under the situation of DMF then, generate SULPHURYL CHLORIDE with thionyl chloride.
In a selective preparation method, mercaptan R 4SH/R 4aSH can react with saltpetre and sulfuryl chloride, generates required SULPHURYL CHLORIDE.
In a variant in this path, the piperidine compounds of formula (XVII) can react under the situation that has alkali such as triethylamine with 2-chloroethyl SULPHURYL CHLORIDE, generates vinylsulfonyl derivative (XX).The vinylsulfonyl derivative can be in the addition reaction of Michael-type and formula HNR then 5R 6Amine reaction, the compound of production (XXI), wherein NR 5R 6Part defines as this paper other parts.This addition reaction is at room temperature for example carried out in the ethanol at polar solvent such as alcohol usually.In another variant, amine HNHR 5R 6Can be replaced the methoxyl group amino-ethyl alkylsulfonyl of the compound of production (XXI) or methyl (methoxyl group) amino-sulfonyl analogue by methoxyl group amine or methyl (methoxyl group) amine.
Vinylsulfonyl compound (XX) also can be by reacting with borine-dimethyl sulfide, changing into corresponding 2-hydroxyethyl compound with the alkaline hydrogen peroxide reaction then.The adding of borine-dimethyl sulfide is for example at room temperature being carried out in polar aprotic solvent such as THF under the covering of rare gas element such as nitrogen usually.The oxidation step that carries out with hydrogen peroxide subsequently also can at room temperature carry out.
R wherein 3For having carbamate groups-C (O) OR 7Or-C (O) OR 7aThe compound (being the compound of formula (XVIII)) of piperidine ring can be by making formula (XVII) compound and formula R 7-O-C (O)-Cl or R 7aThe chloro-formic ester of-O-C (O)-Cl exists in polar solvent such as THF under the situation of glitch-free alkali such as diisopropyl ethyl amine usually at room temperature or is reacting under about room temperature and preparing.In a variant of this working method, the compound of formula (XVII) can with radicals R wherein 7/ R 7aContain for example chloro-formic ester reaction of bromotrifluoromethane of bromoalkane base section.Then the carboxylamine bromo alkyl ester of gained can with nucleophilic reagent such as HNR 5R 6Or methoxyl group amine or the reaction of methyl (methoxyl group) amine, generate wherein R 7/ R 7aContain group NR 5R 6Or methoxyl group amino or the amino compound of methyl (methoxyl group).
In another variant of flow process synthesis path shown in Figure 3, the piperidine compounds of formula (XVII) can be handled the carboxylamine chloromethyl ester intermediate (not providing) of gained with chloromethylchloroformate reaction and with potassium acetate, forms carboxylamine acetoxyl group methyl compound.Usually in polar solvent such as DMF, under for example being heated to the situation of the high temperature (for example up to about 110 ℃) that surpasses 100 ℃, heating carries out with the reaction of potassium acetate.Other variant of the synthesis path that flow process is shown in Figure 3 can find among the embodiment hereinafter.
In many above-mentioned reactions, may protect preventing one or more groups on undesirable position of molecule, to react.The example of protecting group and to functional group protect with de-protected method can be at Protective Groupsin Organic Synthesis (T.Green and P.Wuts; The 3rd edition; John Wiley and Sons, 1999) find in.
Hydroxyl protection precedent such as ether (OR) or ester (OC (=O) R), for example, can be protected into tertbutyl ether; Benzyl, diphenyl-methyl (diphenyl methyl) or trityl (trityl group) ether; TMS or tertiary butyl dimethylsilyl ether; Or ethanoyl ester (OC (=O) CH 3,-OAc).The aldehydes or ketones group can be protected precedent such as acetal (R-CH (OR) respectively 2) or ketal (R 2C (OR) 2), wherein by reacting carbonyl (〉 C=O with for example primary alconol) change into diether (〉 C (OR) 2).By under the situation that has acid with a large amount of excessive water aldehydes or ketones group of can easily regenerating that is hydrolyzed.Amine groups can be protected precedent such as acid amides (NRCO-R) or urethane (NRCO-OR), for example protect: methyl nitrosourea (NHCO-CH 3); Benzyloxy acid amides (NHCO-OCH 2C 6H 5,-NH-Cbz); Tert.-butoxy acid amides (NHCO-OC (CH 3) 3,-NH-Boc); 2-xenyl-2-propoxy-acid amides (NHCO-OC (CH 3) 2C 6H 4C 6HX;-NH-Bpoc), (NH-Fmoc), (NH-Nvoc), 2-TMS ethyl oxygen base acid amides (NH-Teoc), 2 for 6-nitro veratryl oxygen base acid amides for 9-fluorenyl methoxy acid amides; 2,2-three chloroethyl oxygen base acid amides (NH-Troc), allyl group oxygen base acid amides (NH-Alloc) or 2 (phenyl sulfonyl) ethyl oxygen base acid amides (NH-Psec).Other protecting group that is used for amine such as cyclic amine and heterocycle N-H group comprises tosyl group (tolylsulfonyl-base) and methylsulfonyl (methane sulfonyl) and benzyl such as right-methoxy-benzyl (PMB).Hydroxy-acid group can be protected into ester, for example protect: C 1-7Alkyl ester (for example, methyl ester; Tertiary butyl ester); C 1-7Haloalkyl ester (for example, C 1-7The tri haloalkyl ester); Three C 1-7Alkyl tin groups, alkyl silane groups-C 1-7Alkyl ester; Or C 5-20Aryl-C 1-7Alkyl ester (for example, benzyl ester; The nitrobenzyl ester); Or acid amides, for example methyl nitrosourea.Thiol group can be protected precedent such as thioether (SR), for example to protect: the benzyl thioether; Acetylamino methyl ether (S-CH 2NHC (=O) CH 3).
Above-mentioned many midbody compounds are new.Therefore, on the other hand, the invention provides new chemical intermediate, for example formula (XIII), (XIV), (XV), (XVI) or new compound (XVII), wherein R 1And R 3As defined herein.
Purification process
Can well known to a person skilled in the art that many methods separate and purifying compound, the example of these class methods comprises chromatographic technique such as column chromatography (for example flash chromatography) and HPLC.Preparation type LC-MS be used for purifying organic molecule compound as described herein standard and effective means.Can change be used for liquid phase chromatography (LC) and mass spectroscopy (MS) method to separate thick material better and to improve the detection of MS to sample.The optimization of preparation type gradient LC method relates to change chromatographic column, volatility eluent and properties-correcting agent and gradient.The method that optimization prepares the method for type LC-MS, use it for purifying compounds then is known in the art.These class methods are at Rosentreter U, Huber U.; Optimal fraction collecting in preparativeLC/MS; J Comb Chem.; 2004; 6 (2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a customhigh-throughput preparative liquid chromatography/mass spectrometerplatform for the preparative purification and analytical analysis ofcompound libraries; JComb Chem.; 2003; 5 (3); Description is arranged among the 322-9.
A kind of this class is used at following experimental section description being arranged through the system of preparation type LC-MS purifying compounds, but those skilled in the art should be understood that alternative system and the method that can use described system and method.Particularly, can use the method replacement inversion method described herein for preparing type LC based on positive.Most of preparation type LC-MS system uses anti-phase LC and volatile acidic properties-correcting agent because this method is very effective for the purifying small molecules, and because eluent and positive ion electrospray atomize mass spectroscopy is compatible.For example buffering moving phase, the alkaline properties-correcting agent of positive LC, selection as an alternative wait purifying compounds perhaps can to use other chromatographic solution of being summarized in the analytical procedure hereinafter described.
Pharmaceutical preparation
Though active compound can be used separately, but preferably its form with pharmaceutical composition (for example preparation) is given, described composition comprises at least a active compound of the present invention and one or more pharmaceutically useful carriers, assistant agent, vehicle, thinner, weighting agent, buffer reagent, stablizer, sanitas, lubricant or other material well known to those skilled in the art, and randomly comprises other treatment or prophylactic substance; For example reduce or alleviate the material of some side effects relevant with chemotherapy.The object lesson of this class material comprises that extended period that antiemetic and prevention or the minimizing neutrophilic leukocyte relevant with chemotherapy reduce and prevention result from the material of the complication that red corpuscle or leucocyte level reduce, for example erythropoietin (EPO), rHuGM-CSF (GM-CSF), granulocyte colony-stimulating factor (G-CSF).
Therefore, the present invention also provides the method for pharmaceutical composition and pharmaceutical compositions as defined above, and it comprises at least a active compound is as defined above mixed mutually with one or more pharmaceutically useful carriers as herein described, vehicle, buffer reagent, assistant agent, stablizer or other material.
Term used herein " pharmaceutically useful " relates to and is suitable for contacting with the tissue of individual (for example people) in the rational medicine determination range and does not produce over-drastic toxicity, stimulation, transformation reactions or other problem or complication, have compound, material, composition and/or the formulation of rational benefit/risk ratio.Every kind of carrier, vehicle etc. also must with preparation in the compatible meaning of other composition on be " acceptable ".
Therefore, on the other hand, the invention provides the formula defined herein (I) of pharmaceutical compositions and the compound of its subgroup.
Pharmaceutical composition can be anyly be suitable in oral, parenteral, part, the nose, the form of eye, ear and rectum, intravaginal or transdermal administration.Under composition was used for situation that parenteral uses, they can be used for intravenously, intramuscular, intraperitoneal, subcutaneous administration or directly be delivered to target organ or tissue by injection, infusion or other delivery means by preparation.Send and to realize by bolus injection, short-term infusion or long-term infusion, and can send or by utilizing suitable infusion pump to realize via passive.
Be suitable for the pharmaceutical preparation that parenteral uses and comprise water-based and non-aqueous aseptic parenteral solution, its can contain antioxidant, buffer reagent, fungistat, cosolvent, ORGANIC SOLVENT MIXTURES, cyclodextrin complexing agent, emulsifying agent (being used to form and stable emulsion) but, be used to form the liposome component of liposome, the gelation polymer that is used to form polymeric gel, freezing drying protective agent and in particular for the activeconstituents of stable meltable form and combinations of substances that preparation and expection recipient's blood etc. is opened.Be used for the form that pharmaceutical preparation that parenteral uses also can adopt water-based and non-aqueous sterile suspension, it can comprise suspending agent and thickening material (R.G.Strickly, Solubilizing Excipients in oral and injectableformulations.Pharmaceutical Research, 21 volumes (2) 2004, the 201-230 page or leaf).
If the pH value difference of the pKa of medicine and preparation is apart from enough big, then can make ionogenic drug molecule dissolving reach desired concn by adjusting pH.For intravenously and intramuscular administration, acceptable scope is pH2-12, but the acceptable scope of subcutaneous administration is pH2.7-9.0.PH value of solution by medicine salt form, strong acid/alkali example hydrochloric acid or sodium hydroxide or control by the buffered soln that glycine, Citrate trianion, acetate, maleate, succinate, Histidine, phosphoric acid salt, three (methylol) aminomethane (TRIS) or carbonate form by including but not limited to.
The normal combination of using aqueous solution and water-miscible organic solvent/tensio-active agent (being cosolvent) in injection formulations.Being used in water-miscible organic solvent in the injection formulations and tensio-active agent comprises but is not limited to propylene glycol, ethanol, Liquid Macrogol, poly(oxyethylene glycol) 400, glycerine, N,N-DIMETHYLACETAMIDE (DMA), N-N-methyl-2-2-pyrrolidone N-(NMP; Pharmasolve), methyl-sulphoxide (DMSO), Solutol HS15, Cremophor EL, Cremophor RH 60 and Polysorbate 80.This class preparation is usually can (but not always) not diluted before injection.
Be used in propylene glycol, PEG 300, ethanol, CremophorEL, Cremophor RH 60 and Polysorbate 80 in the injection formulations of commercially available acquisition and be fully and can and can combination with one another use with the miscible organic solvent of water and tensio-active agent.The gained organic formulations dilutes at least 2 times usually before dense notes of intravenously or intravenous infusion.
Perhaps, can be by reaching the water-soluble of increase with the cyclodextrin complexing.
The spherical vesicle of sealing of that liposome is made up of the water-based core of outer field lipid duplicature and internal layer and have＜overall diameter of 100 microns.According to the hydrophobicity degree, if medicine is enclosed or embedded in the liposome, appropriate hydrophobic medicine can be by liposome dissolving.If drug molecule becomes the part of lipid duplicature, hydrophobic drug also can be by liposome dissolving, and in the case, hydrophobic drug is dissolved in the lipid part of lipid bilayer.Common Liposomal formulation contain water and-phosphatide of 5-20mg/ml, isotonic agent (isotonicifier), pH5-8 damping fluid, and randomly contain cholesterol.
Preparation may reside in the ampoule and bottle that unitary dose or multi-dose container for example seal, and can be stored under lyophilize (freeze-drying) condition, only needs add at once before use for example water for injection of sterile liquid carrier.
Pharmaceutical preparation can prepare by lyophilize formula (I) compound or its acid salt.Lyophilize refers to the working method of freeze-dried composition.Therefore, freeze-drying and lyophilize are in this article as synonym.Usual method is with compound dissolution and with the clarification of gained preparation, sterile filtration and change under aseptic condition and be suitable in the cryodesiccated container (for example bottle).Under the situation of bottle, they by with the freeze-drying plug portion clog.Can be cooled to preparation freezing and carry out lyophilize under standard conditions, sealing be added a cover to form stable exsiccant lyophily preparation then.Composition has low residual moisture content usually, for example based on the weight of lyophile, less than 5 weight % for example less than the residual moisture content of 1 weight %.
Freeze-dried preparation can contain other vehicle, for example thickening material, dispersion agent, buffer reagent, antioxidant, sanitas and tension regulator.Common buffer reagent comprises phosphoric acid salt, acetate, Citrate trianion and glycine.Examples of antioxidants comprises xitix, sodium bisulfite, sodium metabisulphite, thioglycerin, thiocarbamide, Yoshinox BHT, butylated hydroxyanisol and edetate.Sanitas can comprise alkyl ester, phenol, butylene-chlorohydrin, benzylalcohol, Thiomersalate, benzalkonium chloride and the cetylpyridinium chloride of phenylformic acid and its salt, Sorbic Acid and its salt, right-hydroxy-benzoic acid.If necessary, aforementioned buffer reagent and glucose and sodium-chlor can be used for tension adjustment.
Extender (bulking agent) generally is used for Freeze Drying Technique to help to process and/or provide the volume and/or the mechanical integrity of lyophilize piece.Extender means the thinner of solid granular soluble in water, and when with the compound or its salt lyophilize, it provides physically stable lyophilize piece, more excellent freeze-drying method and rapidly and reconstruct completely.Extender also can be used for making solution etc. to open.
Water-soluble bulk can be any cryodesiccated pharmaceutically useful inert solids that are generally used for.This class extender comprises that for example sugar is as glucose, maltose, sucrose and lactose; Polyvalent alcohol such as sorbyl alcohol or N.F,USP MANNITOL; Amino acid such as glycine; Polymkeric substance such as polyvinylpyrrolidone; With polysaccharide such as dextran.
The weight of extender and the weight ratio of active compound are generally about 1 to about 5, for example about 1 to about 3, for example about 1 to 2.
Perhaps, they can be provided with the solution form that can be concentrated and be sealed in the suitable bottle.The sterilization of formulation can be by filtering or realizing at the autoclaving in the suitable stage of process for preparation by bottle and its content.The preparation that is provided may need further dilution or preparation before sending, for example be diluted to suitable aseptic infusion bag.
Interim blending type injection solution and suspension can be from aseptic powder, particle and tablet preparation.
In an embodiment preferred of the present invention, pharmaceutical composition is to be suitable for intravenously to use the form of for example using by injection or infusion intravenously.
Be used for the sterilized powder that the pharmaceutical composition of the present invention of parenteral injection also can comprise pharmaceutically useful sterile aqueous or non-aqueous solution, dispersion liquid, suspension or emulsion and be reconstructed into aseptic parenteral solution or dispersion liquid before use at once.The example of suitable water-based and non-aqueous carrier, thinner, solvent or medium comprises water, ethanol, polyvalent alcohol (as glycerine, propylene glycol, polyoxyethylene glycol etc.), carboxymethyl cellulose and their suitable mixture, vegetables oil (as sweet oil) and injection organic ester such as ethyl oleate.Can be for example by use coating substance such as Yelkin TTS, in the dispersive situation by keeping required granular size and by using tensio-active agent to keep suitable flowability.
Composition of the present invention also can contain assistant agent such as sanitas, wetting agent, emulsifying agent and dispersion agent.The prevention of microbial process can for example p-Hydroxybenzoate, butylene-chlorohydrin, phenol, Sorbic Acid wait and guarantee by comprising various antibacteriums and anti-mycotic agent.May need also to comprise that isotonic agent is as sugar, sodium-chlor etc.The prolongation of injectable medicament forms absorbs and can postpone the material that absorbs such as aluminum monostearate and gelatin and realize by comprising.
If compound is unstable or have low solubility in aqueous vehicles in aqueous vehicles, it can be mixed with the enriched material in organic solvent.Then enriched material is diluted to low concentration in aqueous systems, and can be enough stable in the short period of time in the administration process.Therefore, on the other hand, a kind of pharmaceutical composition is provided, and it comprises the non-aqueous solution of being made up of one or more organic solvents fully, its can with this form carry out administration or more generally before using with suitable intravenous vehicles (salt solution, glucose; Buffered or buffered not) dilute (Solubilizing excipients in oraland injectable formulations, Pharmaceutical Research, 21 (2), 2004, the 201-230 pages or leaves).The example of solvent and tensio-active agent has propylene glycol, PEG300, PEG400, ethanol, N,N-DIMETHYLACETAMIDE (DMA), N-N-methyl-2-2-pyrrolidone N-(NMP, Pharmasolve), glycerine, Cremophor EL, Cremophor RH 60 and polysorbate.Concrete non-aqueous solution is made up of 70-80% propylene glycol and 20-30% ethanol.A concrete non-aqueous solution is made up of 70% propylene glycol and 30% ethanol.Another is 80% propylene glycol and 20% ethanol.Usually these solvents are used in combination and dilute at least 2 times usually before intravenously bolus injection or intravenous infusion.The common amount of intravenously bolus injection preparation be～50% glycerine, propylene glycol, PEG300, PEG400 and～20% ethanol.The common amount of intravenous infusion preparation be～15% glycerine, 3%DMA and～10% propylene glycol, PEG300, PEG400 and ethanol.
In an embodiment preferred of the present invention, pharmaceutical composition is to be suitable for intravenously to use the form of for example using by injection or infusion intravenously.Use for intravenously, can with solution with itself form administration or can before using, inject in the infusion bag and (contain pharmaceutically useful vehicle) as 0.9% salt solution or 5% glucose.
In another preferred embodiment, pharmaceutical composition is to be suitable for the form that subcutaneous (s.c.) uses.
Be suitable for Orally administered pharmaceutical dosage form and comprise tablet, capsule, Caplet, pill, lozenge, syrup, solution, powder, granule, elixir and suspensoid, Sublingual tablet, wafer or patch and buccal bioadhesive tablet.
The pharmaceutical composition that contains formula (I) compound can be prepared according to known technology, for example referring to Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
Therefore, tablet composition can contain unit dose of active compound and inert diluent or carrier such as sugar or sugar alcohol, for example lactose, sucrose, sorbyl alcohol or N.F,USP MANNITOL; And/or non-sugared deutero-thinner such as yellow soda ash, calcium phosphate, lime carbonate or Mierocrystalline cellulose or derivatives thereof such as methylcellulose gum, ethyl cellulose, Vltra tears and starch such as W-Gum.Tablet also can contain this class standard composition such as tackiness agent and granulation agent such as polyvinylpyrrolidone, disintegrating agent (for example expandable cross-linked polymer such as cross-linked carboxymethyl cellulose), lubricant (for example stearate), sanitas (for example p-Hydroxybenzoate), antioxidant (for example BHT), buffer reagent (for example phosphoric acid salt or citrate buffer agent) and effervescent such as Citrate trianion/bicarbonate mixture.This class vehicle is known, need not to go through at this.
Capsule can be various glutoid or soft gelatin form and the active ingredient that can contain solid, semisolid or liquid form.Gelatine capsule can be formed by the Equivalent of animal gelatin or its synthetic or plant derivation.
Solid dosage (for example tablet, capsule etc.) can be by dressing or dressing not, but has dressing usually, for example the dressing of protectiveness film coating (for example wax or paint film) or sustained release.Dressing (Eudragit for example TMThe type polymkeric substance) desired location that can be designed in gi tract discharges active ingredient.Therefore, can select so that in gi tract, degrade under certain pH condition dressing, thereby optionally discharge compound under one's belt or in ileum or duodenum.
Replace dressing or except dressing, medicine can be present in the solid substrate, this solid substrate comprises the material of sustained release, for example is adapted at optionally discharging under different acidity or alkaline condition in the gi tract material that the delay of compound discharges.Perhaps, the dressing that substrate material or retardance discharge can adopt the form of erodible polymkeric substance (for example maleic anhydride polymkeric substance), when formulation during by gi tract its basically by continuously by corrosion.As another kind of alternative, active compound can be formulated in the delivery system of infiltration control compound release.Infiltration discharges and other postpones to discharge or extended release preparation can be according to well known to a person skilled in the art the method preparation.
Pharmaceutical composition comprises about 1% to about activeconstituents of 95%, preferred about 20% to about 90%.Pharmaceutical composition of the present invention can be a unit dosage form for example, as the form of ampoule, bottle, suppository, drageeing, tablet or capsule.
Being used for Orally administered pharmaceutical composition can obtain by activeconstituents is mixed with solid carrier, if desired with the gained granulating mixture, and if desired or essential, after adding suitable vehicle, mixture is processed into tablet, drageeing core or capsule.Also it may be incorporated in and allow in the plastic carrier of activeconstituents with metered amount diffusion or release.
Also compound of the present invention can be mixed with solid dispersion.Solid dispersion is two or more solid superfine disperse phase uniformly.Solid solution (molecularity dispersion system)-a kind of solid dispersion type-known can be used in the pharmaceutical technology (referring to (Chiou and Riegelman, J.Pharm.Sci., 60, and can be used for increasing dissolution rate and increase the bioavailability of medicament of poorly water-soluble 1281-1300 (1971)).
The solid dispersion of medicine is generally by scorification or solvent evaporated method preparation.For scorification, heating character be generally semi-solid and waxy material (vehicle) so that drug melt and dissolving then harden by being cooled to extremely low temperature.The comminuted solids dispersion is sieved then, with mixed with excipients, encloses in the hard gelatin capsule or is pressed into tablet.Perhaps, use and to have surface-active and carrier self-emulsifying makes solid dispersion directly enclose in the hard gelatin capsule with the form of melt.When the melt cool to room temperature, in capsule, form solid filler.
Solid solution also can be by being dissolved in medicine and required vehicle in aqueous solution or the pharmaceutically useful organic solvent, using pharmaceutically acceptable method such as spraying drying to remove then to desolvate and make.If desired, can adjust gained solid granular size, randomly with mixed with excipients and make tablet or be packed in the capsule.
A kind of particularly suitable polymkeric substance auxiliary material for preparing this class solid dispersion or solid solution is polyvinylpyrrolidone (PVP).
The invention provides a kind of pharmaceutical composition, it comprises is unbodied solid solution basically, and described solid solution comprises
(a) formula (I) compound, for example compound of embodiment 1; With
(b) be selected from down the polymkeric substance of organizing:
Polyvinylpyrrolidone (polyvidone), cross-linked polyvinylpyrrolidone (Crospovidone), Vltra tears, hydroxypropylcellulose, polyoxyethylene, gelatin, cross linked polyacrylate (carbomer), carboxymethyl cellulose, cross-linked carboxymethyl cellulose (croscarmellose), methylcellulose gum, Sipacril 2739OF, the sodium of alkylmethacrylate polymer and water-soluble salt such as methacrylic acid and alkylmethacrylate polymer and ammonium salt, cellacefate, hydroxypropylmethylcellulose phthalate and propylene glycol alginate;
Wherein said compound is about 1: 1 to about 1: 6 with the ratio of described polymkeric substance, for example 1: 3, and the methylene dichloride/alcoholic acid mixture spraying drying of its mixture, preferred 1: 1 ratio and getting by one of chloroform or methylene dichloride and one of methyl alcohol or ethanol.
The present invention also provides the solid dosage that comprises above-mentioned solid solution.Solid dosage comprises tablet, capsule and chewable tablet.Known vehicle can mix with solid solution so that required formulation to be provided.For example, capsule can contain and (a) disintegrating agent and lubricant or (b) disintegrating agent, lubricant and tensio-active agent blended solid solution.Tablet can contain and at least a disintegrating agent, lubricant, tensio-active agent and glidant blended solid solution.Chewable tablet can contain and extender, lubricant and other if desired sweeting agent (as artificial sweetening agent) and suitable correctives blended solid solution.
Pharmaceutical preparation can be with the form of " patient's bag " passs the patient, and it contains the whole course of treatment in unitary package (being generally Blister Package).Tell the tradition prescription of patient's medicine supply with pharmacist wherein and compare from supply in enormous quantities, patient's bag has advantage because patient's total energy is used the package insert that is included in patient's bag, and in patient's prescription this specification sheets not usually.Proved that package insert can improve the compliance of patient to doctor's indication.
Be used for the local composition that uses and comprise ointment, ointment, sprays, patch, gelifying agent, liquid drops and implant (insert) (for example intraocular implant).This based composition can be prepared according to currently known methods.
Being used for the composition that parenteral uses provides with the form of sterile aqueous or oily solution or particulate suspension usually, perhaps can provide to be reconstructed with sterile water for injection temporarily with the sterilized powder form of porphyrize.
The example that is used for the preparation that rectum or intravaginal use comprises vaginal suppository and suppository, and it can be for example formed by the plasticity-or the waxy substance of the shaping that contains active compound.
Be used to suck the composition of using and adopt the form that can suck powder composition or liquid or powder spray agent, and can use powder inhalation device or aerosol drug delivery device to use with standard form.This class device is known.In order to use by suction, powder formulation comprises active compound and Powdered thinner of inert solid such as lactose usually.
Formula (I) compound generally provides with unit dosage form, like this since, it contains enough compounds usually so that the biologic activity of desired level to be provided.For example, preparation can contain the activeconstituents of 1 nanogram to 2 gram, for example the activeconstituents of 1 nanogram to 2 milligram.In this scope, the inferior scope of concrete compound be 0.1 milligram of activeconstituents to 2 grams (more generally be 10 milligrams to 1 gram, for example 50 milligrams to 500 milligrams), or 1 microgram to 20 milligram (for example 1 microgram to 10 milligram, for example 0.1 milligram to 2 milligrams activeconstituents).
For oral compositions, unit dosage form can contain 1 milligram to 2 the gram, more generally 10 milligrams to 1 the gram, for example 50 milligrams to 1 the gram, for example 100 milligrams to 1 the gram active compounds.
Active compound will be applied to the patient (for example human or animal patient) who needs it with the amount that enough reaches required result of treatment.
Methods of treatment
The compound of estimating formula (I) defined herein and subgroup can be used for preventing or treating by cell cycle protein dependent kinase and glycogen synthase kinase-3 disease states mediated or illness.This class morbid state or examples of disorders are as mentioned above.
The general individuality that compound administration is used in this class of needs, for example human or animal patient, preferably people.
Usually with treatment or the effective and general nontoxic amount administered compound of prevention.Yet, in some situation situation of life-threatening disease (for example), the benefit of using formula (I) compound may be more important than the shortcoming of any toxic effect or side effect, in this case, can think the compound that need use the amount relevant with toxicity to a certain degree.
But the long-term application compound with keep useful result of treatment or only short-term use.Perhaps can use them with pulse mode or continuous mode.
The common per daily dose of formula (I) compound can be every kg body weight 100 piks to 100 milligram, more generally be every kg body weight 5 nanograms to 25 milligram, more generally be every kg body weight 10 nanograms to 15 milligram (10 nanograms to 10 milligram for example, more generally be that every kilogram 1 microgram is to 20 milligrams every kilogram, every kilogram 1 microgram to 10 milligram for example), but, also can use higher or lower dosage as needing.Formula (I) compound can or repeat on every day basis to use on the basis, uses once in for example per 2 or 3 or 4 or 5 or 6 or 7 or 10 or 14 or 21 or 28 days.
Compound of the present invention can be Orally administered in dosage range, for example uses with the oral dose of 1-1500mg, 2-800mg or 5-500mg, for example 2-200mg or 10-1000mg, and the object lesson of dosage comprises 10,20,50 and 80mg.But compound is used once every day or once.But compound continuous administration (promptly do not use less than interrupting every day during treatment plan).Perhaps, compound can be interrupted and use (promptly during whole treatment plan, given for some time as a week in continuous administration, interrupt for some time then as a week, and then continuous administration for some time is as week etc.).Relate to the example that is interrupted the treatment plan use and comprise wherein and using a week to cyclicity, interrupt a week; Or used for two weeks, interrupt a week; Or used for three weeks, interrupt a week; Or used for two weeks, interrupted for two weeks; Or around using, interrupted for two weeks; Or use a week, interrupted for three weeks, for example carry out one or more these circulations, for example 2,3,4,5,6,7,8,9 or 10 or more a plurality of this round-robin scheme.
For 60 kilograms people, the example of dosage comprises with the initial dose of 4.5-10.8mg/60kg/ days (equaling 75-180 μ g/kg/ days), uses formula defined herein (I) compound with the effective dose of 44-97mg/60kg/ days (equaling 0.7-1.6mg/kg/ days) or the effective dose of 72-274mg/60kg/ days (equaling 1.2-4.6mg/kg/ days) subsequently, but, if desired, can use higher or lower dosage.For any given body weight, mg/kg dosage in proportion converts.
In a concrete drug dosage schedule table, the patient will be given the transfusion of little up-to-date style (I) compound every day, and administration reaches 10 days, particularly reaches 5 days weekly, and with required time at interval as two to around, particularly per three weeks are once carried out repetitive therapy.
More specifically, the transfusion that the patient can be given little up-to-date style (I) compound every day reaches 5 days, and per three weeks are once carried out repetitive therapy.
In another concrete drug dosage schedule table, the patient is given 30 minutes to 1 hour transfusion, give then variable period for example 1-5 hour for example 3 hours keep infusion.
In another concrete drug dosage schedule table, the patient is given 12 hours to 5 days continuous infusion, particularly 24 hours to 72 hours continuous infusion.
At last, however the amount of institute's administered compound and the type of composition therefor should match with the character of disease or physiological conditions to be treated, and are decided by the doctor.
The compound of formula defined herein (I) and subgroup can be used as the single therapy agent and is applied, perhaps they can with other other be used for the treatment of particular disease states for example one of the compound of neoplastic disease cancer as hereinbefore defined use in the combined therapy mode.Other can with compound of the present invention together (no matter be simultaneously or with the different timed intervals) use or the therapeutical agent that uses or the example of therapy include, but are not limited to topoisomerase enzyme inhibitor, alkylating agent, metabolic antagonist, DNA wedding agent, microtubule inhibitor (agent of tubulin target), monoclonal antibody and signal transduction inhibitor, concrete example has cis-platinum, endoxan, Zorubicin, irinotecan, fludarabine, 5FU, taxanes, ametycin and radiotherapy.
For with the situation of the CDK inhibitor of other therapeutic combination, can give two or more therapy with different separately dose plans and via different approach.
Formula (I) compound and one, two, three, four or the situation of more kinds of (preferred one or two kind, more preferably a kind of) other therapeutical agent combined administration under, compound can be simultaneously or sequential application.When sequential application, they can be with the in-plant timed interval (for example going through 5-10 minute time) or with the longer timed interval (for example at interval 1,2,3,4 or more hours, use perhaps if desired at interval for more time), the character of accurate dose scheme and therapeutical agent matches.
Compound of the present invention also can with non-chemotherapeutic treatment such as radiotherapy, photodynamic therapy, gene therapy; Perform the operation and keep on a diet and use together.
For with the combined therapy of another kind of chemotherapeutics, can with formula (I) compound and one, two, three, four or more other therapeutical agents for example be mixed with together and contain one, two, three, four or the formulation of more kinds of therapeutical agents.In a yes-no decision, each therapeutical agent can be separated to prepare and provide together with the form of medicine box, and described medicine box randomly has their working instructions.
Those skilled in the art can understand used dosage regimen and combined therapy by his or her common sense.
Diagnostic method
Before using formula (I) compound, whether the screening patient is disease or the illness that use is had the treatment sensitivity that the active compound of anti-cell cyclin-dependent kinase carries out to determine that this patient is suffering from the disease that maybe may suffer from or illness.
Whether for example, can analyze the biological specimen of taking from the patient is to be the disease or the illness of feature unusually to cause the CDK overactivity or to cause the gene unconventionality or the protein expression of the active path enhanced sensitivity of normal CDK to determine that this patient is suffering from the illness that maybe may suffer from or disorders such as cancers.Cause the unusual example of this class of the activation of CDK2 signal or enhanced sensitivity to comprise rise (HarwellRM, Mull BB, Porter DC, the Keyomarsi K. of cyclin E; J Biol Chem.2004 March 26; 279 (13): 12695-705) or p21 or p27 disappearance, or have CDC4 variant (Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, LengauerC.; Nature.2004 March 4; 428 (6978): 77-81).Rise with CDC4 sudden change or cyclin E is particularly crossed the tumour of expression or p21 or p27 disappearance to CDK inhibitor sensitivity especially.Term " rise " comprises and express to raise or cross and express, and comprises gene amplification (being a plurality of gene copies) and transcribes effect and expression increase that high reactivity and activation (comprising the activation that sudden change causes) cause.
Therefore, can carry out diagnostic test to detect the mark characteristics that cyclin E rise or p21 or p27 lacked or existed the CDC4 variant to the patient.Term " diagnosis " comprises screening.We comprise genetic marker with " mark " speech, comprise that for example measuring DNA forms to identify the sudden change of CDC4.Term " mark " also comprises and embodies the mark that cyclin E raises characteristics, comprises enzymic activity, enzyme level, enzyme state (for example whether phosphorylation) and aforementioned proteinic mRNA level.Tumour with cyclin E rise or p21 or p27 disappearance may be responsive especially to the CDK inhibitor.Can before treatment, preferentially screen at the rise of cyclin E or the disappearance of p21 or p27 tumour.Therefore, can carry out diagnostic test to detect the mark characteristics of cyclin E rise or p21 or p27 disappearance to the patient.
Diagnostic test is usually with carrying out on the biological specimen that is selected from tumor biopsy sample, blood sample (separation of the tumour cell that comes off and enrichment), ight soil biopsy, phlegm, chromosome analysis, Pleural fluid, peritoneal fluid or urine.
People such as Rajagopalan find (Nature.2004 March 4; 428 (6978): 77-81) there be sudden change (people such as Spruck, Cancer Res.2002 August 15 in CDC4 (being also referred to as Fbw7 or Archipelago) in human colorectal cancer and carcinoma of endometrium; 62 (16): 4535-9).The evaluation of carrying the individuality of CDC4 sudden change means that this patient is particularly suitable for treating with the CDK inhibitor.Can before treatment, preferentially screen tumour at the existence of CDC4 variant.Screening method is usually directed to direct order-checking, oligonucleotide microarray analysis or mutant specific antibody.
The evaluation and the sudden change of analysing protein and the method for rise are well known to a person skilled in the art.Screening method includes, but are not limited to standard method such as reversed transcriptive enzyme polymerase chain reaction (RT-PCR) or in situ hybridization.
In the screening of using RT-PCR to carry out, the mRNA level in the tumour is to estimate with pcr amplification cDNA then by the cDNA copy that produces mRNA.The method of pcr amplification, selection of primers and amplification condition are well known by persons skilled in the art.Nucleic acid operation and PCR carry out according to standard method, as for example Ausubel, and people such as F.M., Current Protocols in MolecularBiology, 2004, John Wiley ﹠amp; Sons Inc., or Innis, people such as M.A., PCR Protocols:a guide to methods and applications, 1990, Academic Press is described in the San Diego.Relate to the reaction of nucleic acid technology and operate in people such as Sambrook, 2001, the 3 editions, Molecular
Cloning:A Laboratory Manual also has description among the Cold Spring Harbor Laboratory Press.Perhaps, can use the test kit (Roche for example of the commercially available acquisition of RT-PCR
Or U.S. Patent No. 4,666,828 Molecular Biochemicals); 4,683,202; 4,801,531; 5,192,659,5,272,057,5,882,864 and 6,218, the method described in 529 is incorporated herein by reference them.
An example estimating the hybridization in situ technique that mRNA expresses be fluorescence in situ hybridization (FISH) (referring to Angerer, 1987Meth.EnzymoL, 152:649).
Generally speaking, in situ hybridization comprises following key step: (1) fixes tissue to be analyzed; (2) sample is carried out accessibility and the minimizing non-specific binding of prehybridization processing to increase target nucleic acid; (3) with the nucleic acid hybridization in nucleic acid mixture and biological structure or the tissue; (4) carry out post-hybridization washing to remove the nucleic acid fragment that unconjugated nucleic acid fragment and (5) in the hybridization detect hybridization.The probe that uses in this class is used is mark normally, for example carries out mark with radio isotope or fluorescent indicator.Preferred probes is answered sufficiently long, and for example, about 50,100 or 200 Nucleotide are to about 1000 or more a plurality of Nucleotide, so that can carry out specific hybrid with target nucleic acid under stringent condition.The standard method of carrying out FISH is at Ausubel, people such as F.M., Current Protocols in Molecular Biology, 2004, John Wiley ﹠amp; Sons Ine and Fluorescence In Situ Hybridization:Technical Overview by John M.S.Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, the 2nd edition; ISBN:1-59259-760-2; In March, 2004, the 077-088 page or leaf; Among the Series:Methods in Molecular Medicine description is arranged.
Perhaps, can be used for the proteinic currently known methods analysis of detection specificity by mRNA expressed protein product by the immunohistochemistry of tumor sample, solid-phase immunoassay, Western blotting, two-dimentional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and this area of use microtiter plate.Detection method comprises the use site-specific antibodie.The technology that it will be understood by a person skilled in the art that the disappearance of the known rise that is used to detect cyclin E of all these classes or p21 or p27 or CDC4 variant is all applicable to this situation.
Therefore, all these technology also can be used for identifying the tumour that is particularly suitable for compounds for treating of the present invention.
Tumour with the rise of CDC4 sudden change or cyclin E, particularly mistake expression or p21 or p27 disappearance may be responsive especially to the CDK inhibitor.Preferentially before treatment, express (Harwell RM, Mull BB, Porter DC, Keyomarsi K. at the rise of cyclin E, particularly mistake; J Biol Chem.2004 March 26; 279 (13): 12695-705) or p21 or p27 disappearance or CDC4 variant tumour is screened (Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C.; Nature.2004 March 4; 428 (6978): 77-81).
The diagnostic test of available this paper general introduction selects to suffer from the patient of lymphoma mantle cell (MCL) to treat with compound of the present invention.MCL is a kind of special clinicopathologic entity of non-Hodgkin lymphoma, and what it is characterized in that having CD5 and CD20 coexpression is little of medium sized lymphopoiesis, invasive and the clinical disease course that can not cure and frequent t (11; 14) (q13; Q32) transposition.Expressing excessively of the cyclin D1 mRNA that finds in lymphoma mantle cell (MCL) is a kind of important diagnostic mark.People such as Yatabe (Blood.2000 April 1; 95 (7): 2253-61) propose to comprise cyclin D1-positive, and proposal should be the innovative treatments that this incurable disease is probed on the basis with this new standard as one of standard of MCL.People such as Jones (J Mol Diagn.2004 May; 6 (2): 84-9) developed a kind of real-time quantitative reverse transcription PCR that is used for cyclin D1 (CCND1) expression and analyzed with assisted diagnosis lymphoma mantle cell (MCL).People such as Howe (ClinChem.2004 January; 50 (1): 80-7) quantitative RT-PCR that uses real-time quantitative RT-PCR to assess the expression of cyclin D1 mRNA and the cyclin D1 mRNA that discovery is normalized to CD19mRNA is used in blood, marrow and the tissue and diagnoses MCL.Perhaps, can use the diagnostic test of above-outlined to select to suffer from the patient of mammary cancer to treat with the CDK inhibitor.Tumour cell common overexpressing cell cyclin E and showed cell cyclin E in mammary cancer, cross to express (people such as Harwell, Cancer Res, 2000,60,481-489).Therefore, particularly mammary cancer can be treated with the CDK inhibitor that this paper provided.
Antifungal application
On the other hand, the invention provides the purposes of the compound of formula defined herein (I) and its subgroup as anti-mycotic agent.
The compound of formula defined herein (I) and its subgroup can be used for animal medicine (for example being used for the treatment of Mammals) as the people be used for the treatment of plant (for example in agricultural and the Horticulture) or as anti-mycotic agent, for example be used as sanitas and sterilizing agent.
In one embodiment, the invention provides and be used at Mammals such as people prevention or the formula defined herein (I) of treatment fungi infestation and the compound of its subgroup.
The compound that formula (I) defined herein and its subgroup also be provided is used for purposes in the medicine of Mammals such as people's prevention or treatment fungi infestation in preparation.
For example, can be with compound administration of the present invention in suffering from the human patients that local fungal infects or has the local fungal risk of infection, described local fungal infects and is caused by following biology: mycocandida (Candida), Trichophyton (Trichophyton), Microsporon (Microsporum) or Epidermophyton (Epidermophyton), perhaps under the situation of mucosal infections, cause (for example white mouth and vaginal candidiasis) by Candida albicans (Candida albicans).Also can use the systemic fungal infection that compound of the present invention is caused by for example Candida albicans, Cryptococcus neoformans (Cryptococcusneoformans), flavus (Aspergillus flavus), aspergillus fumigatus (Aspergillus fumigatus), ball spore Pseudomonas (Coccidiodies), Paracoccidioides (Paracoccidioides), Histoplasma (Histoplasma) or Blastomyces (Blastomyces) with treatment or prevention.
On the other hand, the invention provides and be used for the agricultural antifungal composition of (comprising Horticulture), its compound and agricultural that comprises formula defined herein (I) and its subgroup goes up acceptable diluent or carrier.
The present invention also provides treatment to have the method for animal (comprising Mammals such as people), plant or the seed of fungi infestation, and it comprises formula defined herein (I) and the described animal of compound treatment, plant or the seed of its subgroup or the location of described plant or seed with significant quantity.
The present invention also provides the method for treatment plant or seed fungi infestation, and it comprises with the fungicide composition of the compound of containing of antimycotic significant quantity formula defined herein (I) and its subgroup handles plant or seed.
Can use differential screening assay method to select of the present invention those that non-human CDK enzyme is had specific compound.The compound that acts on the CDK enzyme of eukaryotic pathogens specifically can be used as antimycotic or antiparasitic.The kinase whose inhibitor C KSI of mycocandida CDK can be used for treating moniliosis.Anti-mycotic agent can be used for resisting the infection of institute's define styles above or betides weakness usually or immunosuppressed patient is suffered from opportunistic infection such as the patient of illnesss such as diabetes or AIDS as suffering from leukemia and lymphadenomatous patient, the people who accepts immunosuppressant therapy and Yi, and is used for non-immunosuppressed patient.
The described assay method in this area can be used for screening the material of at least a fungi that can be used for suppressing related in the mycosis, and described mycosis is moniliosis, aspergillosis, mucormycosis, blastomycosis, geotrichosis, torulosis, chromoblastomycosis, coccidioidomycosis, conidium bacterium disease (conidiosporosis), histoplasmosis, mycetoma, rhinosporidiosis, nocardiosis, pseudactinomycosis, penicilliosis, monoliasis or sporotrichosis for example.By utilizing CDK gene by yeast clone, differential screening assay method can be used for identifying the anti-mycotic activity that has therapeutic value in the aspergillosis treatment, described yeast is aspergillus fumigatus (Aspergillus fumigatus) for example, yellow aspergillus (Aspergillusflavus), black aspergillus (Aspergillus niger), structure nest aspergillus (Aspergillus nidulans) or terreus (Aspergillus terreus), be under the situation of mucon-mycosis in fungal infection perhaps, the CDK assay method can be derived from yeast rhizopus arrhizus (Rhizopus arrhizus) for example, rice root fungus (Rhizopusoryzae), absidia corymbifera bacterium (Absidia corymbifera), absidia rasmosa bacterium (Absidia ramosa) or mucor pusillus (Mucorpusillus).The source of other CDK enzyme comprises pathogenic agent Pneumocystis carinii (Pneumocystis carinii).
For example, the in-vitro evaluation of the anti-mycotic activity of compound of the present invention can be undertaken by measuring minimal inhibitory concentration (M.I.C.), and it is the test compound concentration that specified microorganisms can't be grown in suitable medium.In practice, inoculate for example type culture of Candida albicans to a series of agar plates that mix the specific concentrations test compound separately, then with each flat board at 37 ℃ of following incubation suitable times.Check then whether fungi growth is arranged on the flat board, the M.I.C. value that record is suitable.Perhaps, but carry out turbidity measurement in the liquid medium within, the scheme of summarizing the example of this assay method can be referring to the following examples.
The interior evaluating of compound can under a series of dosage levels by to inoculated fungi for example in the mouse peritoneum of Candida albicans or aspergillus flavus strain or intravenous injection or Orally administered carrying out.The activity of compound can be assessed by the growth (by histology or by obtaining the fungi of self-infection) of monitor therapy and the fungi infestation of untreated mouse group.Active can provide the 50% dosage level (PD that protects from infection lethal effect according to compound 50) measure.
With regard to human antifungal application, the compound of formula defined herein (I) and its subgroup can use separately or with put into practice selected pharmaceutical carrier according to expection route of administration and standard pharmaceutical and mix and use.Therefore, for example, they can adopt in preparation oral, parenteral, intravenously, intramuscular or the subcutaneous administration described in above-mentioned " pharmaceutical preparation " joint.
With regard to the oral and parenteral of human patients was used, the dosage level of antifungal compound of the present invention was 0.01 to 10mg/kg (a plurality of divided dose), and this especially depends on the effectiveness of compound when using by oral or parenteral approach.The tablet of compound or capsule can for example contain 5mg to 0.5g active compound, take the circumstances into consideration to use a slice (grain), two (grain) or multi-disc (grain) at every turn.In any case the doctor will determine to be suitable for most the actual dose (significant quantity) of individual patient, it will be different because of age, body weight and the response of particular patient.
Perhaps, antifungal compound can be used with the form of suppository or vaginal suppository, and perhaps they can be with the form topical application of lotion, solution, ointment, ointment or dusting.For example, they can be impregnated in the ointment of being made up of the water-based emulsion of polyoxyethylene glycol or whiteruss; Perhaps they can be impregnated in the ointment of being made up of Chinese wax or paraffinum molle alba matrix and the stablizer that adds as required and sanitas, and concentration is 1 to 10%.
Except that above-mentioned therepic use, the anti-mycotic agent of being developed with this differential screening assay method also can be used as sanitas in the food for example, promote the fodder additives that domestic animal weight increases or be used to handle non-living matter for example be used to the to sterilize disinfectant preparation in hospital equipment and room.In a similar manner, side by side relatively the restraining effect of Mammals CDK and insect CDK such as fruit bat CDK5 gene people such as (, (1994) FEBS Lett 356:317-21) Hellmich can be selected the inhibitor of the enzyme that can distinguish people/Mammals and insect from the compound of this paper.Therefore, the present invention comprises purposes and the preparation of compound of the present invention in sterilant clearly, for example is used for the processing of insect such as fruit bat.
In another embodiment, the CDK inhibitor that can select some to be tried with respect to the inhibition specificity of mammalian enzyme according to plant CDK.For example, plant CDK is arranged in the differential screening that contains one or more people's enzymes, to select to suppress those the highest compounds of selectivity of plant enzyme.Therefore, the present invention specifically comprises the preparation that is tried the CDK inhibitor that is used for agricultural application, for example the preparation of form such as defoliant.
For agricultural and gardening purpose, compound of the present invention can be mixed with the composition forms that is suitable for specific end use and intended purposes.Therefore, compound can be used with the form of dusting powder or granule, seed dressing, the aqueous solution, dispersion liquid or emulsion, immersion liquid, sprays, aerosol or smoke substance.Composition also can provide with dispersion powder, granule or particle or with the form of the concentrated solution of preceding dilution.This based composition can contain those known and acceptable conventional carrier, thinner or assistant agents in agricultural and Horticulture, and they can prepare according to conventional methods.Said composition also can be mixed other activeconstituents, for example, has the compound or the another kind of mycocide of weeding or insecticidal activity.Compound and composition can be used in many ways; for example they can be applied directly to plant leaf, stem, branch, seed or root; or may be used on soil or other growth media, and they not only can eradicate disease, and preventability ground protective plant or seed are not under fire.For example, said composition can contain the activeconstituents of 0.01 to 1 weight %.Use for the field, the possible utility ratio of activeconstituents is the 50-5000g/ hectare.
The present invention also comprises the purposes that the compound of formula defined herein (I) and its subgroup is used to control the foxy fungi and handles soil, seedling rice field or the irrigation water of plant-growth.The present invention comprises that also the compound of formula defined herein (I) and its subgroup is used to prevent that stock's cereal and other no plant place from the purposes of fungi infestation taking place.
Embodiment
Set forth the present invention referring now to the specific embodiments described in the following example, but do not limit the present invention.
In an embodiment, used following abbreviation.
AcOH acetate
Uncle BOC-butoxy carbonyl
CDI 1, the 1-carbonyl dimidazoles
DMAW90 solvent mixture: DCM:MeOH, AcOH, H 2O (90: 18: 3: 2)
DMAW120 solvent mixture: DCM:MeOH, AcOH, H 2O (120: 18: 3: 2)
DMAW240 solvent mixture: DCM:MeOH, AcOH, H 2O (240: 20: 3: 2)
The DCM methylene dichloride
The DMF dimethyl formamide
The DMSO methyl-sulphoxide
EDC 1-ethyl-3-(3 '-dimethylaminopropyl)-carbodiimide
Et 3The N triethylamine
The EtOAc ethyl acetate
Et 2The O ether
HOAt 1-hydroxyl azepine benzotriazole
The HOBt I-hydroxybenzotriazole
The MeCN acetonitrile
MeOH methyl alcohol
P.E. sherwood oil
SiO 2Silicon-dioxide
TBTUN, N, N ', N '-tetramethyl--O-(benzotriazole-1-yl) urea a tetrafluoro borate
THF hydrogen furans
The explanation of analysis mode LC-MS system and method
In an embodiment, utilize hereinafter described system and operational condition to characterize prepared compound by liquid phase chromatography and mass spectroscopy.If exist to have different isotopic atoms and to have provided single quality, the quality of given compound be single isotopic mass (promptly 35Cl; 79Br etc.).Use following several system, these systems are assembled and set so that moving under the similar operation condition very much.
Used operational condition also is described in down.
WatersPlatform LC-MS system:
HPLC system: Waters 2795
Mass detector: Micromass Platform LC
PDA detector: Waters 2996 PDA
The acidic conditions of analyzing:
Eluent A:H 2O (0.1% formic acid)
Eluent B:CH 3CN (0.1% formic acid)
Gradient: go through 3.5 minutes 5-95% eluent B
Flow velocity: 0.8ml/min
Chromatographic column: Phenomenex Synergi 4 μ MAX-RP 80A,
2.0×50mm
The alkaline condition of analyzing:
Eluent A:H 2O (10mM NH 4HCO 3Damping fluid is used NH 4OH
Be adjusted to pH=9.2)
Eluent B:CH 3CN
Gradient: go through 3.5 minutes 05-95% eluent B
Flow velocity: 0.8ml/min
Chromatographic column: Phenomenex Luna C18 (2) 5 μ m
2.0×50mm
The polarity condition of analyzing:
Eluent A:H 2O (0.1% formic acid)
Eluent B:CH 3CN (0.1% formic acid)
Gradient: go through 3 minutes 00-50% eluent B
Flow velocity: 0.8ml/min
Chromatographic column: Phenomenex Synergi 4 μ MAX-RP 80A,
2.0×50mm
The lipotropy condition of analyzing:
Eluent A:H 2O (0.1% formic acid)
Eluent B:CH 3CN (0.1% formic acid)
Gradient: go through 3.5 minutes 55-95% eluent B
Flow velocity: 0.8ml/min
Chromatographic column: Phenomenex Synergi 4 μ MAX-RP80A,
2.0×50mm
The long acidic conditions of analyzing:
Eluent A:H 2O (0.1% formic acid)
Eluent B:CH 3CN (0.1% formic acid)
Gradient: go through 15 minutes 05-95% eluent B
Flow velocity: 0.4ml/min
Chromatographic column: Phenomenex Synergi 4 μ MAX-RP 80A,
2.0×150mm
The long alkaline condition of analyzing:
Eluent A:H 2O (10mM NH 4HCO 3Damping fluid is used NH 4OH
Be adjusted to pH=9.2)
Eluent B:CH 3CN
Gradient: go through 15 minutes 05-95% eluent B
Flow velocity: 0.8ml/min
Chromatographic column: Phenomenex Luna C18 (2) 5 μ m
2.0×50mm
Platform MS condition:
Capillary voltage: 3.6kV (3.40kV on negative ES)
Taper hole voltage: 25V
Source temperature: 120 ℃
Sweep limit: 100-800amu
Ionization pattern: positive electron spray(ES) Or
The negative electricity spraying Or
Positive ﹠amp; The negative electricity spraying
Waters Fractionlynx LC-MS system:
HPLC system: 2767 automatic samplers-2525 binary gradient pump
Mass detector: Waters ZQ
PDA detector: Waters 2996 PDA
The acidic conditions of analyzing:
Eluent A:H 2O (0.1% formic acid)
Eluent B:CH 3CN (0.1% formic acid)
Gradient: go through 4 minutes 5-95% eluent B
Flow velocity: 2.0ml/min
Chromatographic column: Phenomenex Synergi 4 μ MAX-RP80A,
4.6×50mm
The polarity condition of analyzing:
Eluent A:H 2O (0.1% formic acid)
Eluent B:CH 3CN (0.1% formic acid)
Gradient: go through 4 minutes 00-50% eluent B
Flow velocity: 2.0ml/min
Chromatographic column: Phenomenex Synergi4 μ MAX-RP80A,
4.6×50mm
The lipotropy condition of analyzing:
Eluent A:HxO (0.1% formic acid)
Eluent B:CH 3CN (0.1% formic acid)
Gradient: go through 4 minutes 55-95% eluent B
Flow velocity: 2.0ml/min
Chromatographic column: Phenomenex Synergi4 μ, MAX-RP80A,
4.6×50mm
Fractionlynx MS condition:
Capillary voltage: 3.5kV (3.2kV on negative ES)
Taper hole voltage: 25V (30V on negative ES)
Source temperature: 120 ℃
Sweep limit: 100-800amu
Ionization pattern: positive electron spray(ES) Or
The negative electricity spraying Or
Positive ﹠amp; The negative electricity spraying
The purifying LC-MS system that quality instructs
Preparation type LC-MS be used for purifying organic molecule compound as described herein standard and effective means.Can change be used for liquid phase chromatography (LC) and mass spectroscopy (MS) method to separate thick material better and to improve the detection of MS to sample.The optimization of preparation type gradient LC method relates to change chromatographic column, volatility eluent and properties-correcting agent and gradient.The method that optimization prepares type LC-MS method, use it for purifying compounds then is known in the art.These class methods are at Rosentreter U, Huber U.; Optimal fraction collecting in preparativeLC/MS; J Comb Chem.; 2004; 6 (2), 159-64 and Leister W, Strauss K, WisnoskiD, Zhao Z, Lindsley C., Development of a customhigh-throughput preparative liquid chromatography/mass spectrometerplatform for the preparative purification and analyticalan alysis ofcompound libraries; J Comb Chem.; 2003; 5 (3); Description is arranged among the 322-9.
A kind of this class is used for through the system of preparation type LC-MS purifying compounds description being arranged hereinafter.Yet those skilled in the art should be understood that alternative system and the method that can use described system and method.Particularly, can use the method replacement inversion method described herein for preparing type LC based on positive.Most of preparation type LC-MS system uses anti-phase LC and volatile acidic properties-correcting agent, because this method is very effective for the purifying small molecules, and because eluent is compatible with the positive ion electron spray mass spectrometry.For example buffering moving phase, the alkaline properties-correcting agent of positive LC, selection as an alternative wait purifying compounds perhaps can to use other chromatographic solution of being summarized in the analytical procedure hereinafter described.
Make various LC-MS system:
Waters Fractionlynx system:
Hardware:
2767 double loops automatic sampler/fraction collector
2525 preparation pumps
Be used for the CFO (chromatographic column fluid tissue device (fluidic organiser)) that chromatographic column is selected
The RMA (Waters reagent manager) of pump (make up pump) as a supplement
Waters ZQ mass spectrograph
Waters 2996 photodiode array detectors
Waters ZQ mass spectrograph
Software:
Masslynx 4.0
Waters MS operational conditions:
Capillary voltage: 3.5kV (3.2kV on negative ES)
Taper hole voltage: 25V
Source temperature: 120 ℃
Multiplier: 500V
Sweep limit: 125-800amu
The ionization pattern: positive electron spray(ES) just Or
The negative electricity spraying
The Agilent1100LC-MS preparation system:
Hardware:
Automatic sampler: 1100 series " prepALS "
Pump: be used for 1100 series " PrepPump " of preparative liquid stream gradient and 1100 series " QuatPump " of the properties-correcting agent that the pumping preparative liquid flows
UV detector: 1100 series " MWD " multiwavelength detector
MS detector: 1100 series " LC-MSD VL "
Fraction collector: 2x " Prep-FC "
Make-up pump: " Waters RMA "
The active demultiplexer of Agilent
Software:
Chemstation：Chem32
Agilent MS operational conditions:
Capillary voltage: 4000V (3500V on negative ES)
Fragmentor/Gain： 150/l
Dry gas: 13.0L/min
Gas temperature: 350 ℃
Atomizer pressure: 50psig
Sweep limit: 125-800amu
Ionization pattern: positive electron spray(ES) Or
The negative electricity spraying
Chromatographic condition:
Chromatographic column:
1. low pH chromatography:
Phenomenex Synergy MAX-RP, l0 μ, 100 * 21.2mm (perhaps uses Thermo Hypersil-KeystoneHyPurity Aquastar, 5 μ, 100 * 21.2mm) for the compound than high polarity
2. high pH chromatography:
Phenomenex Luna C18 (2), 10 μ, 100 * 21.2mm (perhaps uses Phenomenex Gemini, 5 μ, 100 * 21.2mm)
Eluent:
1. low pH chromatography:
Solvent orange 2 A:H 2O+0.1% formic acid, pH～1.5
Solvent B: CH 3CH+0.1% formic acid
2. high pH chromatography:
Solvent orange 2 A:H 2O+10mM NH 4HOH+NH 4OH, pH=9.2
Solvent B:CH 3CN
3. supplementing solvent:
MeOH+0.2% formic acid (being used for two kinds of chromatography types)
Method:
Follow the tracks of according to analyzing, select optimal preparative scale chromatography type.Typical convention is to use chromatography type (low or high pH) the operating analysis type LC-MS that is suitable for compound structure most.Indicate good chromatography in case analyze to follow the tracks of, select the suitable preparation type method of same type.The two typical operational conditions of low and high pH chromatographic process is:
Flow velocity:24ml/min
Gradient:General all gradients all have initial 0.4 minute step using 95%A+5%B.Then according to analyze following the tracks of, selects 3.6 minutes gradients in case realize good separation (for example for keeping compound morning, from 5% to 50%B; For the compound of medium reservation, from 35% to 80%B etc.)
Washing:When finishing, gradient carries out 1.2 minutes washing steps
Reequilibrate:The reequilibrate step of carrying out 2.1 minutes is used for operation next time with preparation system
Replenish flow velocity:1ml/min
Solvent:
All compounds all are dissolved among 100%MeOH or the 100%DMSO usually.
From the information that is provided, those skilled in the art can enough preparation type LC-MS purifying compound as herein described.
Except as otherwise noted, otherwise the starting raw material of each embodiment all is commercially available acquisitions.
The preparation of starting raw material
Preparation I
Synthesizing of trans-4-(2-methoxyl group-oxyethyl group)-cyclo-hexylamine
Step 1. is trans-4-dibenzyl amino-hexalin
Figure A20068000923801271
Merge bromotoluene (12.0g, 70mmol), trans-the 4-Trans-4-Amino Cyclohexanol (4.0g, 35mmol), sodium bicarbonate (7.8g, 93mmol) and ethanol (100ml) and stirring 16 hours under refluxing.Reduce reaction mixture in a vacuum, with methylene dichloride dilution, washing (1M NaOH, salt solution), dry (MgSO 4) and reduce in a vacuum.By column chromatography (SP4-biotage) purifying resistates, the sherwood oil wash-out with containing the 0-50% ethyl acetate produces trans-4-dibenzyl amino-hexalin, is white solid (3.83g, 37%).(LC/MS：R t1.78，[M+H] +296.39)。
Step 2. dibenzyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine
Figure A20068000923801272
(0.240g 6mmol) uses twice of petroleum ether under nitrogen with sodium hydride (60% in mineral oil).(0.590g 2mmol) and with mixture heating up to 95 ℃ reaches 30 minutes to add diox (5ml) and trans-4-dibenzyl amino-hexalin.After being cooled to envrionment temperature, (0.73ml 8mmol), all stirs them 18 hours down in 95 ℃ to add the 2-chloroethyl methyl ether.Make reaction mixture be cooled to envrionment temperature, then with the methylene dichloride dilution, washing (1M NaOH, salt solution), dry (MgSO 4) and reduce in a vacuum.By column chromatography (SP4-biotage) purifying resistates.With the sherwood oil wash-out that contains the 0-50% ethyl acetate, produce dibenzyl-[trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine, be yellow oil (0.275g, 39%).(LC/MS：R t2.08，[M+H] +354.37)。
Step 3. is trans-4-(2-methoxyl group-oxyethyl group)-cyclo-hexylamine
Figure A20068000923801273
With dibenzyl-(0-275g 0.77mmol) is dissolved in the ethanol (10ml) [trans-4-(2-methoxyl group-oxyethyl group)-cyclohexyl]-amine.Under nitrogen gas stream, add palladium hydroxide/charcoal (20%, 0.120mg), with reaction mixture in the Parr hydrogenator under the hydrogen of 40psi the vibration 4 hours.Reaction mixture with other alcohol dilution, is passed through Celite TMFilter, use washing with alcohol, reduce filtrate in a vacuum, produce trans-4-(2-methoxyl group-oxyethyl group)-cyclo-hexylamine, be clarifying colorless oil (0.123g, 92%).
Preparation II
2-(5-amino-pyridine-2-base oxygen base)-alcoholic acid preparation
Figure A20068000923801281
To the nitro of the 2-[(5-under nitrogen-2-pyridyl) the oxygen base] (0.5g 2.72mmol) adds 10% palladium/charcoal (50mg) to ethane-1-alcohol in the solution in ethanol (10ml), the gained suspension is descended hydrogenation 3 hours in room temperature and constant pressure (RTP).Reaction mixture is passed through Celite TMFilter.Evaporated filtrate produces 2-(5-amino-pyridine-2-base oxygen base)-ethanol in a vacuum, is colorless oil (410mg, 98%).(LC/MS：R t0.36，[M+H] +155.10)。
Preparation III
The preparation of 6-(2-methoxyl group-oxyethyl group)-pyridin-3-yl amine
Figure A20068000923801282
With 2-chloro-5-nitropyridine (1g, 6.31mmol), 2-methyl cellosolve (0.55ml, 6.94mmol) and potassium tert.-butoxide (850mg, 7.57mmol) suspension in DMF (10ml) stirred 2 hours at ambient temperature.Reaction mixture is diluted water (* 3) washing, dry (MgSO with EtOAc (100ml) 4), filter and evaporation in a vacuum, produce 2-(2-methoxyl group-oxyethyl group)-5-nitropyridine, be yellow solid (1.0g, 80%).(LC/MS：R t2.55，[M+H] +199.19)。
To the 2-under nitrogen (2-methoxyl group-oxyethyl group)-5-nitropyridine (1g 5.05mmol) adds 10% palladium/charcoal (100mg) in the solution in methyl alcohol (10ml), under RTP with gained suspension hydrogenation 2 hours.By the Celite filter reaction mixture.Evaporated filtrate produces 6-(2-methoxyl group-oxyethyl group)-pyridin-3-yl amine in a vacuum, is light brown oily thing (0.9g, 100%).(L C/M S：R t0.74，[M+H] +169.13)。
Preparation IV
Synthesizing of 1-methyl-piperidines-3-(S)-Ji amine
Synthesizing of step 1. (S)-(1-methyl-piperidines-3-yl)-carboxylamine uncle-butyl ester
With (S)-3-BOC-amino piperidine (600mg, 3.0mmol), salt of wormwood (470mg, 3.4mmol) and methyl iodide (188 μ l, mixture 3.0mmol) heating 12 hours under refluxing.Reduce mixture in a vacuum, between EtOAc and water, distribute, with salt water washing organic moiety, dry (MgSO 4) and reduce in a vacuum, produce title compound, be yellow solid (450mg).
Synthesizing of step 2.1-methyl-piperidines-3-(S)-Ji amine
Figure A20068000923801292
The mixture of (S)-(1-methyl-piperidines-3-yl)-carboxylamine uncle-butyl ester (440mg) in trifluoroacetic acid (5ml) and DCM (5ml) stirred 1 hour at ambient temperature, reduce (* 3) with methylbenzene azeotropic in a vacuum then, produce title compound, be orange.
Preparation V
Synthesizing of 1-methyl-piperidines-3-(R)-Ji amine
Figure A20068000923801293
This series of compounds prepares to be similar to 1-methyl-piperidines-3-(S)-described mode of Ji amine, and different being to use (R)-3-BOC-amino piperidine is as starting raw material.
Preparation VII
Synthesizing of trans-4-(2-dimethylamino-oxyethyl group)-cyclo-hexylamine
Step 1. is trans-4-dibenzyl amino-hexalin synthetic
Figure A20068000923801301
With trans-4-Trans-4-Amino Cyclohexanol (3.80g, 33mmol), benzyl chloride (11.5ml, 100mmol) and sodium bicarbonate (11.2g, the 133mmol) heating 14 hours under refluxing of the mixture in ethanol (100ml) reduces then in a vacuum.Resistates is distributed between DCM and water, separate each layer, with the 1M NaOH aqueous solution and salt water washing organic moiety, dry (MgSO 4) and reduce in a vacuum.By column chromatography purifying resistates, use P.E.-EtOAc (1: 2) system, produce title compound, be white solid (4.38g).
Step 2. is trans-dibenzyl-[4-(2--dimethylamino-oxyethyl group)-cyclohexyl]-amine synthetic
Figure A20068000923801302
To 60% dispersion liquid of the NaH that under nitrogen, stirs at ambient temperature in mineral oil (167mg, 2.5mmol) add in the mixture in no Shui diox (5ml) trans-4-dibenzyl amino-hexalin (590mg, 2mmol).Stirred the mixture 5 minutes, add then (2-chloro-ethyl)-dimethyl-amine (753mg, 7mmol).In 95 ℃ of following heated mixt 2 hours, be cooled to envrionment temperature and dilute with DCM.Add the 1M NaOH aqueous solution carefully, separate each layer, with salt water washing organic moiety, dry (MgSO 4) and reduce in a vacuum, produce orange (739mg).Find that by analysis product is about 1: 1 mixture of title compound and starting raw material.
Step 3. is trans-4-(2-dimethylamino-oxyethyl group)-cyclo-hexylamine synthetic
Figure A20068000923801303
Vibration VIIb product (400mg) and Pd (OH) under nitrogen atmosphere (40psi) 2The mixture of/C (200mg) in methyl alcohol (15ml) 3 hours filters by the Celite plug, reduces in vacuum, produces about 1: 1 mixture (184mg) of title compound and trans-4-Trans-4-Amino Cyclohexanol.
Preparation VIII
Synthesizing of 4-amino-1H-pyrazoles-3-carboxylic acid, ethyl ester
Step 1.4-nitro-1H-pyrazoles-3-carboxylic acid, ethyl ester
Figure A20068000923801311
(2.90ml, (5.68g 36.2mmol) in the mixture in EtOH (100ml), stirred the mixture 48 hours 39.8mmol) to add to 4-nitro-3-pyrazole carboxylic acid at leisure with thionyl chloride at ambient temperature.Reduce mixture in a vacuum, by with the methylbenzene azeotropic drying, obtain 4-nitro-1H-pyrazoles-3-carboxylic acid, ethyl ester, be white solid (6.42g, 96%).( 1H NMR(400MHz，DMSO-d 6)δ14.4(s，1H)，9.0(s，1H)，4.4(q，2H)，1.3(t，3H))。
Step 2.4-amino-1H-pyrazoles-3-carboxylic acid, ethyl ester
Figure A20068000923801312
With 4-nitro-1H-pyrazoles-3-carboxylic acid, ethyl ester (6.40g, 34.6mmol) and the mixture of 10%Pd/C (650mg) in EtOH (150ml) under nitrogen atmosphere, stirred 20 hours.Mixture filters through Celite plug, reduce in a vacuum, by with the methylbenzene azeotropic drying, obtain 4-amino-1H-pyrazoles-3-carboxylic acid, ethyl ester, be pink solid (5.28g, 98%).( 1H NMR(400MHz，DMSO-d 6)δ12.7(s，1H)，7.1(s，1H)，4.8(s，2H)，4.3(q，2H)，1.3(t，3H))。
Preparation IX
Synthesizing of 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid
Figure A20068000923801313
With 2,6-dichlorobenzoyl chloride (8.2g; 39.05mmol) be added to 4-amino-1H-pyrazoles-3-carboxylate methyl ester (to be similar to the method preparation for preparing VIII) (5g carefully; 35.5mmol) and triethylamine (5.95ml; 42.6mmol in the solution in the) Zai diox (50ml), at room temperature stirred then 5 hours.Filter reaction mixture is handled filtrate with methyl alcohol (50ml) and 2M sodium hydroxide solution (100ml), heats 4 hours down in 50 ℃, then evaporation.100ml water is added in the resistates, use the concentrated hydrochloric acid acidifying then.By solid collected by filtration, water (100ml) washing is blotted, and produces 10.05g4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid, is the lavender solid.(L C/M S：R t2.26，[M+H] +300/302)。
Preparation X
The preparation of 4-(2.6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride Step 1.4-{[4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carbonyl]-amino }-piperidines-1-carboxylic acid The preparation of uncle-butyl ester
At room temperature stir 4-(2; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (6.5g; 21.6mmol) (preparation IX), 4-amino-1-BOC-piperidines (4.76g; 23.8mmol), EDC (5.0g; 25.9mmol) and HOBt (3.5g, 25.9mmol) mixture in DMF (75ml) is 20 hours.Reduce reaction mixture in a vacuum, resistates is distributed between ethyl acetate (100ml) and saturated sodium bicarbonate aqueous solution (100ml).With salt water washing organic layer, dry (MgSO 4) and reduce in a vacuum.With resistates 5%MeOH-DCM (～30ml) absorption.Collect undissolved material by filtering, dry in a vacuum with the DCM washing, produce 4-{[4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carbonyl]-amino }-piperidines-1-carboxylic acid uncle-butyl ester (5.38g), be white solid.Reduce filtrate in a vacuum; by column chromatography purifying resistates, use gradient elution 1: the 2EtOAc/ hexane obtains other 4-{[4-(2 to EtOAc; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carbonyl]-amino }-piperidines-1-carboxylic acid uncle-butyl ester (2.54g), be white solid.
Step 2.4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride
Figure A20068000923801321
Handle 4-{[4-(2 with saturated HCl-EtOAc (40ml); 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carbonyl]-amino }-solution of piperidines-1-carboxylic acid uncle-butyl ester (7.9g) in MeOH (50ml) and EtOAc (50ml), at room temperature stir then and spend the night.So owing to exist the methyl alcohol product not have crystallization, so evaporation reaction mixture, resistates is ground with EtOAc.Collect the gained pale solid by filtering,, on sintered filter (sinter), blot, produce 6.3g4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride with the EtOAc washing.(L C/M S：R t5.89，[M+H] +328/384)。
Preparation XI
Synthesizing of step 1.4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid, ethyl ester
Figure A20068000923801331
Stir 2 at ambient temperature, the 6-difluoro-benzoic acid (6.32g, 40.0mmol), 4-amino-1H-pyrazoles-3-carboxylic acid, ethyl ester (5.96g, 38.4mmol), EDC (8.83g, 46.1mmol) and HOBt (6.23g, 46.1mmol) mixture in DMF (100ml) is 6 hours.Reduce mixture in a vacuum, add water, collect formed solid by filtering, air-dry, the generation main component is the mixture (15.3g) of 4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid, ethyl ester.(LC/MS：R t3.11[M+H] +295.99)。
Synthesizing of step 2.4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid
Figure A20068000923801332
(1: 1,250ml) mixture in was 14 hours at the 2M NaOH aqueous solution/MeOH to stir 4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid, ethyl ester (10.2g) at ambient temperature.Remove volatile matter in a vacuum, add water (300ml), use the 1M HCl aqueous solution to make mixture to pH5.By filter collecting the gained throw out, by with the methylbenzene azeotropic drying, produce 4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid, be pink solid (5.70g).(LC/MS：R t2.33，[M+H] +267.96)。
Preparation XII
N-is trans-(4-amino-cyclohexyl)-Toluidrin hydrochloride synthetic
Figure A20068000923801341
Step 1: trans-(N-Boc-4-amino-cyclohexyl)-Toluidrin synthetic
Figure A20068000923801342
At room temperature stir N-Boc-trans-4-aminocyclohexane (860mg; 4mmol) with methylsulfonic acid acid anhydride (1.05g; 6mmol) the mixture overnight in pyridine (10ml).Evaporation reaction is distributed between EtOAc and 2M hydrochloric acid then.By filter collecting undissolved solid, wash with water, blot, then by the flash column chromatography purifying, with 2% 5%MeOH/DCM wash-out then.Isolate 185mg trans-(N-Boc-4-amino-cyclohexyl)-Toluidrin, be white solid.
Step 2:N-is trans-(4-amino-cyclohexyl)-Toluidrin hydrochloride synthetic
Figure A20068000923801343
Be dissolved in trans-(N-Boc-4-amino-cyclohexyl)-Toluidrin (180mg) in the saturated HCl/ ethyl acetate solution and at room temperature stirred 4 hours.By solid collected by filtration, dry under vacuum with ether washing, produce 85mg N-trans-(4-amino-cyclohexyl)-Toluidrin hydrochloride, be rose pink solid.
Preparation XIII
2-fluoro-6-(2-methoxyl group-oxyethyl group)-benzoic synthetic
Synthesizing of step 1:2-fluoro-6-(2-methoxyl group-oxyethyl group)-methyl benzoate
Figure A20068000923801351
To the 6-fluorosalicylic acid methyl esters that under nitrogen, is stirring (1g, 5.88mmol) add in the solution in DMF (10ml) sodium hydride (282mg, 7.06mmol).Stirred gained solution at ambient temperature 10 minutes.(591 μ l 6.47mmol) add in the reaction mixture, heat gained solution 24 hours down in 85 ℃ with the 2-chloroethyl methyl ether.Use the ethyl acetate diluted reaction mixture, use sodium hydroxide solution (2N, secondary), water (secondary) then, wash with the salt brine solution order then.Dry (MgSO 4) organic moiety, to filter, evaporation in a vacuum produces 2-fluoro-6-(2-methoxyl group-oxyethyl group)-methyl benzoate, is colorless oil (600mg, 45%).(LC/MS：R t2.73，[M+H] +229.17)。
Step 2:2-fluoro-6-(2-methoxyl group-oxyethyl group)-benzoic synthetic
Figure A20068000923801352
(2N, (600mg 2.63mmol) in the solution in methyl alcohol (10ml), heated gained solution 2 hours down in 50 ℃ 10ml) to be added to 2-fluoro-6-(2-methoxyl group-oxyethyl group)-methyl benzoate that is stirring with sodium hydroxide solution.Evaporate methyl alcohol in a vacuum.Resistates is distributed between EtOAc and water.(2N) is acidified to pH2 with water section with HCl solution, washs with EtOAc then.Dry (MgSO 4) this organic moiety, to filter, evaporation in a vacuum produces 2-fluoro-6-(2-methoxyl group-oxyethyl group)-phenylformic acid, is colorless oil (400mg, 71%).(LC/MS：R t2.13，[M+H] +215.17)。
Preparation XIV
2,3-two fluoro-6-methoxyl groups-benzoic synthetic
Figure A20068000923801353
(27.5%w/w 4ml) is added to 2, and (0.5g 2.91mmol) in the suspension in potassium hydroxide solution (3g KOH is in 20ml water), heated 2 hours down in 70 ℃ 3-two fluoro-6-methoxybenzaldehydes then with superoxol., wash with ethyl acetate then to pH2 with dense HCl acidified reaction mixture.Dry (MgSO 4) organic moiety, to filter, evaporation in a vacuum then with the toluene azeotropic, produces 2,3-two fluoro-6-methoxyl group-phenylformic acid (500mg, 91%).(LC/MS:R t2.08, do not observe molion).
Preparation XV
2-methoxyl group-6-methyl-benzoic synthetic
Figure A20068000923801361
(2N, (5g is 25.77mmol) in the solution in ethanol (20ml) 20ml) to be added to 2-methoxyl group-6-ethyl benzoate with sodium hydroxide solution.In 70 ℃ of following reacting by heating mixtures 24 hours.(10g 0.25mmol) adds in the reaction mixture, heats gained solution down 4 hours in addition in 70 ℃ with sodium hydroxide.Remove ethanol in a vacuum.Resistates is distributed between ethyl acetate and water.With dense HCl water section is acidified to pH2, washs with ethyl acetate then.Dry (MgSO 4) this organic moiety, to filter, evaporation in a vacuum produces 2-methoxyl group-6-methyl-phenylformic acid, is faint yellow solid (3g, 70%).(LC/MS：R t2.21，[M+H] +167.11)。
Preparation XVI
2-chloro-6-fluoro-3-methoxyl group-benzoic synthetic
Figure A20068000923801362
To the 2-chloro-4-fluoroanisole under-70 ℃ under nitrogen (1.9ml, 15mmol) dropwise add in the solution in THF (50ml) n-BuLi solution (1.6M, 13ml, 21mmol).After adding, in-70 ℃ of following stirred reaction mixtures 1.5 hours in addition.Several dry ice pellet are added in the reaction mixture, stirred 10 minutes.Reaction mixture is poured in the 250ml beaker that half dry ice is housed then.Make reaction mixture be warming to room temperature then, between ethyl acetate and sodium hydroxide solution (2N), distribute.With dense HC1 water section is acidified to pH2, washs with ethyl acetate then.Dry (MgSO 4) this organic moiety, filter, in a vacuum evaporation.Resistates and toluene is azeotropic in a vacuum, produces 2-chloro-6-fluoro-3-methoxyl group-phenylformic acid, is white solid (2.9g, 95%).(LC/MS:R t1.91, do not observe molion).
Preparation XVII:2-chloro-6-dimethylaminomethyl-phenylformic acid
Synthesizing of step 1.2-brooethyl-6-chloro-methyl benzoate
Figure A20068000923801371
(5.8g 34.0mmol) is suspended in the methylene dichloride (100ml) with 2-chloro-6-tolyl acid.With DMF (250mg 3.4mmol) is added in the suspension, dropwise add then oxalyl chloride (3.9ml, 44.2mmol).Stirred gained solution at ambient temperature 24 hours.With other DMF (250mg, 3.4mmol) and oxalyl chloride (3.9ml 44.2mmol) adds in the reaction mixture, stirs gained solution at ambient temperature other 24 hours.Concentrated reaction mixture in a vacuum.Be dissolved in resistates in the methyl alcohol (100ml) and stirred at ambient temperature 3 hours.Concentrated reaction mixture in a vacuum.Resistates is distributed between ethyl acetate and sodium hydroxide solution (2N).With sodium hydroxide solution (2N), use salt water washing organic moiety then, dry (MgSO 4), filter, concentrate in a vacuum.(eluent 3: 5EtOAc: purifying gasoline), generation 2-chloro-6-methyl-methyl benzoate is yellow oil (4.5g, 72%) resistates by flash chromatography.
With N-bromine succinimide (4.3g, 24.4mmol) and benzoyl peroxide (50mg, (4.5g is 24.4mmol) at CCl 0.2mmol) to be added to 2-chloro-6-methyl-methyl benzoate 4In the solution (50ml), heated the gained suspension 24 hours down in 70 ℃.(50mg 0.2mmol) adds in the reaction mixture, stirs 3 hours in addition in 70 ℃ with other benzoyl peroxide.Reaction mixture is cooled to envrionment temperature and filtration.Concentrated filtrate in a vacuum.By flash chromatography (Biotage SP4,40M, flow velocity 40ml/min, gradient gasoline to 2: 3EtOAc: purifying resistates gasoline), produce 2-brooethyl-6-chloro-methyl benzoate, be yellow oil (6.2g, 97%).
Synthesizing of step 2.2-chloro-6-dimethylaminomethyl-methyl benzoate
Figure A20068000923801372
(2g, 7.6mmol) (5.6M, 13.6ml) solution in is 24 hours at the ethanolic soln of dimethylamine to stir 2-brooethyl-6-chloro-methyl benzoate at ambient temperature.Concentrated reaction mixture in a vacuum.Resistates is distributed between ethyl acetate and hydrochloric acid soln (1N)., distribute with ethyl acetate then to pH12 with sodium hydroxide solution (2N) alkalization water.Dry (MgSO 4) organic moiety, filter, concentrate in a vacuum, produce 2-chloro-6-dimethylaminomethyl-methyl benzoate, be colorless oil (300mg, 17%).(LC/MS：R t1.55，[M+H] +228.10)。
Step 3.2-chloro-6-dimethylaminomethyl-benzoic synthetic
(2N, (300mg 1.32mmol) in the solution in methyl alcohol (10ml), stirred gained solution 1 hour at ambient temperature, stirred 72 hours in 50 ℃ then 10ml) to be added to 2-chloro-6-dimethylaminomethyl-methyl benzoate with sodium hydroxide solution.Evaporate methyl alcohol in a vacuum, to pH4, concentrate in a vacuum then with hydrochloric acid (2N) acidifying resistates.Resistates in a vacuum with methyl alcohol and toluene coevaporation.Resistates is ground with methyl alcohol, filter.Evaporated filtrate in a vacuum, with 1: 4MeOH:EtOAc grinds, and filters then.Evaporated filtrate produces 2-chloro-6-dimethylaminomethyl-phenylformic acid in a vacuum, is white solid (200mg, 71%).
Preparation XVIII:2-chloro-6-methoxymethyl-phenylformic acid
Figure A20068000923801382
(912mg, (2g is 7.60mmol) in the solution in methyl alcohol (20ml) 22.80mmol) to be added to 2-brooethyl-6-chloro-methyl benzoate with sodium hydride under nitrogen.In 50 ℃ of following reacting by heating mixtures 2 hours.After being cooled to envrionment temperature, reaction mixture is distributed between ethyl acetate and water.Dry (MgSO4) organic moiety is filtered, in a vacuum evaporation.By flash chromatography (Biotage SP4,40S, flow velocity 40ml/min, gradient 3: 17EtOAc: gasoline to 1: 1EtOAc: purifying resistates gasoline), produce 2-chloro-6-methoxymethyl-methyl benzoate, be colorless oil (400mg, 25%).(2N, (400mg 1.86mmol) in the solution in methyl alcohol (10ml), stirred gained solution 24 hours down in 50 ℃ 10ml) to be added to 2-chloro-6-methoxymethyl-methyl benzoate with sodium hydroxide solution.Add other sodium hydroxide solution (2N, 10ml), in 50 ℃ of following reacting by heating mixtures 24 hours in addition.Remove methyl alcohol by evaporating in a vacuum.Resistates is distributed between ethyl acetate and water.Partly arrive pH2 with the concentrated hydrochloric acid acidified water, distribute with ethyl acetate then.Dry (MgSO 4) organic moiety, to filter, evaporation in a vacuum produces 2-chloro-6-methoxymethyl-phenylformic acid, is white solid (340mg, 91%).(LC/MS：R t2.23，[M+Na] +223.11)。
Preparation XIX
Synthesizing of 4-amino-1H-pyrazoles-3-carboxylic acid (trans-4-methoxymethoxy-cyclohexyl)-acid amides Step 1. is trans-4-methoxymethoxy-cyclo-hexylamine synthetic
Figure A20068000923801391
(1.6g, 40mmol) (preparation I, (4.0g 13.6mmol) is heated to 95 ℃ and reaches 30 minutes step 1) with trans-4-dibenzyl amino-hexalin with the sodium hydride in the Zai diox (50ml).After being cooled to envrionment temperature, (3ml, 40mmol), stirred reaction mixture is 5 hours at ambient temperature, with the methylene dichloride dilution, washs by (1M NaOH, salt solution) dry (MgSO then to add the chloromethyl methyl ether 4), reduce in a vacuum, produce dibenzyl-(trans-4-methoxymethoxy-cyclohexyl)-amine crude product, be yellow gel shape thing (4.84g).(LC/MS：R t2.01，[M+H] +340.28)。
Crude product dibenzyl-(trans-4-methoxymethoxy-cyclohexyl)-amine is absorbed with ethanol (100ml).Under nitrogen gas stream, add palladium hydroxide/charcoal (20%, 2.5g), in the Parr hydrogenator under the hydrogen of 48psi oscillatory reaction mixture 5 hours.Use the ethyl acetate diluted reaction mixture, pass through Celite TMFilter, the ethyl acetate washing with other reduces filtrate in a vacuum, produces trans-4-methoxymethoxy-cyclo-hexylamine, is sticky white solid (2.95g).( 1H NMR(400MHz，MeOD-d 4)δ4.6(s，2H)，3.5(m，1H)，3.35(s，3H)，2.7(m，1H)，1.9-2.1(m，4H)，1.2-1.4(m，4H)。
Synthesizing of step 2.4-nitro-1H-pyrazoles-3-carboxylic acid (trans-4-methoxymethoxy-cyclohexyl)-acid amides
Stir 4-nitro-3-pyrazole carboxylic acid (2.32g at ambient temperature, 14.8mmol), trans 4-Trans-4-Amino Cyclohexanol (2.95g, 18.5mmol), EDAC (3.55g, 18.5mmol) and HOBt (2.50g, 18.5mmol) mixture in DMF (75ml) is 16 hours.Reduce mixture in a vacuum, between saturated sodium bicarbonate aqueous solution and ethyl acetate, distribute.Washing (water, salt solution) organic layer, dry (MgSO 4), reduce in a vacuum, produce yellow oil (3.25g), it is passed through the column chromatography purifying, with the sherwood oil wash-out that contains 0-100%EtOAc, with the EtOAc wash-out that contains 1-25%MeOH, produce 4-nitro-1H-pyrazoles-3-carboxylic acid (trans-4-methoxymethoxy-cyclohexyl)-acid amides then, be faint yellow solid (1.25g).(LC/MS：R t2.11[M+H] +297.25)。
Step 3.4-amino-1H-pyrazoles-3-carboxylic acid (trans-4-methoxymethoxy-cyclohexyl)-acid amides
Figure A20068000923801401
(1.25g, 4.2mmol) solution in DMF (100ml) is handled with 10% palladium/charcoal (0.125g), is vibrating 5 hours under hydrogen under room temperature and the constant pressure then with 4-nitro-1H-pyrazoles-3-carboxylic acid (4-methoxymethoxy-cyclohexyl)-acid amides.Use the ethyl acetate diluted reaction mixture, pass through Celite TMFilter, the ethyl acetate washing with other reduces filtrate in a vacuum, and generation 4-amino-1H-pyrazoles-3-carboxylic acid (4-methoxymethoxy-cyclohexyl)-acid amides is trans-4-methoxymethoxy-cyclo-hexylamine crude product, be brown oil (1.45g).(LC/MS：R t1.41[M+H] +269.37)。
The general operation method
General operation method A
Prepare acid amides by pyrazole carboxylic acid
Figure A20068000923801402
Stir at ambient temperature suitable benzoyl-amido-1H-pyrazoles-3-carboxylic acid (0.50mmol), EDAC (104mg, 0.54mmol), HOBt (73.0mg, 0.54mmol) and the corresponding mixture of amine (0.45mmol) in DMF (3ml) 16 hours.Reduce mixture in a vacuum, resistates is absorbed with EtOAc, use saturated sodium bicarbonate aqueous solution, water and salt water washing continuously.Dry (MgSO 4) organic moiety, reduce in a vacuum, produce desired product.
General operation method B
Prepare acid amides by amino-pyrazoles
Figure A20068000923801411
Corresponding carboxylic acid (0.25mmol) is added to suitable 4-amino-1H-pyrazoles-3-carboxylic acid amide (0.23mmol), the EDAC (52mg that is stirring; 0.27mmol) and HOBt (37mg; 0.27mmol) at 5ml N, in the solution in the dinethylformamide, mixture is kept somewhere at room temperature spent the night then.Evaporation reaction mixture by preparation type L C/M S purifying resistates, produces product.
General operation method C
Synthesizing of the acid amides of 4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid
Stir 4-(2 at ambient temperature; 6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (134mg; 0.50mmol), amine (0.45mmol), EDAC (104mg, 0.54mmol) and HOBt (73.0mg, 0.54mmol) mixture in DMF (3ml) is 16 hours.Reduce mixture in a vacuum, resistates is absorbed with EtOAc, use saturated sodium bicarbonate aqueous solution, water and salt water washing continuously.Dry (MgSO 4) organic moiety, reduce in a vacuum, produce the acid amides of 4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid.
General operation method D
The preparation of protected 4-amino-pyrazole-3-yl carboxylic acid 4-hydroxyl-cyclohexyl amide
Step D (i):
Stir 4-nitro-3-pyrazole carboxylic acid (4.98g at ambient temperature, 31.7mmol), trans 4-Trans-4-Amino Cyclohexanol (3.65g, 31.7mmol), EDAC (6.68g, 34.8mmol) and HOBt (4.7g, 34.8mmol) mixture in DMF (120ml) is 16 hours.Reduce mixture in a vacuum, with resistates CH 2Cl 2Absorb, use 5% citric acid, saturated sodium bicarbonate aqueous solution, water and salt water washing continuously.The discovery product mainly in the citric acid washing lotion, extracts with its alkalization and with EtOAc.Use MgSO 4Dry organic layer filters, and evaporation produces white solid, with itself and CHCl 3Grind together, produce 1.95g4-nitro-1H-pyrazoles-3-carboxylic acid 4-hydroxyl-cyclohexyl amide.(LC/MS：R t1.62，[M+H] +255)。
Step D is (ii):
The introducing of tetrahydrochysene-pyrans-2-base protecting group
With 4-nitro-1H-pyrazoles-3-carboxylic acid 4-hydroxyl-cyclohexyl amide (1.95g; 7.67mmol) solution in the mixture of THF (50ml) and chloroform (100ml) is with 3,4-dihydro-2H-pyrans (1.54ml, 15.34mmol) and right-toluenesulphonic acids monohydrate (100mg) handle.At room temperature stirred reaction mixture spends the night, and the excessive pyrans (0.9ml) of disposable then adding is so that react completely.Use the DCM diluted reaction mixture, use saturated sodium bicarbonate aqueous solution, water and salt water washing continuously.Reduce gained solution in a vacuum, carry out the Biotage column chromatography, with hexane (2 column lengths), use 30% ethyl acetate then: hexane (10 column lengths), 70% ethyl acetate: hexane (10 column lengths) wash-out produces 1.25g4-nitro-1-(tetrahydrochysene-pyrans-2-base-1H-pyrazoles-3-carboxylic acid [4-(tetrahydrochysene-pyrans-2-base oxygen base)-cyclohexyl]-acid amides.(LC/MS：R t2.97，[M+H] +423)。
Step D is (iii):
With 4-nitro-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3-carboxylic acid [4-(tetrahydrochysene-pyrans-2-base oxygen base)-cyclohexyl]-acid amides (0.3g; 0.71mmol) solution in methyl alcohol (25ml) handles with 10% palladium/charcoal (30mg), hydrogenation is spent the night under room temperature and constant pressure then.By removing by filter catalyzer, use methanol wash three times.Evaporated filtrate produces the desired product of 0.264g.(LC/MS：R t2.39，[M+H] +393)。
General operation method E
Synthesizing of the acid amides of 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid
At room temperature stir 4-(2; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (preparation IX) (6.5g; 21.6mmol), amine (23.8mmol), EDC (5.0g, 25.9mmol) and HOBt (3.5g, 25.9mmol) mixture in DMF (75ml) is 20 hours.Reduce reaction mixture in a vacuum, resistates is distributed between ethyl acetate (100ml) and saturated sodium bicarbonate aqueous solution (100ml).With salt water washing organic layer, dry (MgSO 4), reduce in a vacuum.With resistates 5%MeOH-DCM (～30ml) absorption.Collect undissolved material by filtering, dry in a vacuum with the DCM washing, the acid amides of generation 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid.If desired, reduce filtrate in a vacuum, by using gradient elution 1: the 2EtOAc/ hexane produces other acid amides to the column chromatography purifying resistates of EtOAc.
General operation method F
Prepare urea by 4-amino-pyrazoles-3-carboxylic acid amide
Suitably substituted phenylcarbimide (0.24mmol) is added in 4-amino-pyrazol-3-carboxylic acid amide or the solution of its protected derivative (0.2mmol) in toluene (2ml).In 70 ℃ of following reacting by heating mixtures 1 hour.Reaction mixture is diluted with EtOAc, continuously water and salt water washing.Reduce gained solution in a vacuum, produce oily matter, perhaps use dried over mgso, produce desired urea.
General operation method G
The sulfonylation of piperidines or acidylate
To 4-(2; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride (preparation X) (1mmol) adds diisopropyl ethyl amine (2.2mmol) in the mixture in acetonitrile (10ml), adds suitable SULPHURYL CHLORIDE or acyl chlorides (1mmol) then.Stirred the mixture at ambient temperature 16 hours, and reduced in a vacuum then.Resistates is distributed between ethyl acetate and water, separate each layer, with salt water washing organic moiety, dry (MgSO 4), reduce in a vacuum, produce desired sulphonamide or amide derivatives.
General operation method H
Figure A20068000923801441
Heat alkyl chloride (10mmol) and S-WAT (15mmol) 1 under refluxing, (1: 1,16ml) mixture in was 16 hours, makes to be cooled to envrionment temperature, reduces with methylbenzene azeotropic (* 3) in a vacuum then for 4-diox/water.Thionyl chloride (10ml) and 2 DMF are added in the resistates, and heated mixt is 2 hours under refluxing, and makes to be cooled to envrionment temperature, reduces with methylbenzene azeotropic in a vacuum then.Resistates is distributed between EtOAc and water, separate each layer, with salt water washing organic moiety, dry (MgSO 4), reduce in a vacuum, produce desired sulfonyl chloride derivatives.
To 4-(2; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride (preparation X) (2mmol) adds diisopropyl ethyl amine (4.2mmol) in the mixture in acetonitrile (10ml), adds suitable SULPHURYL CHLORIDE (about 2mmol) then.Stirred the mixture at ambient temperature 16 hours, and reduced in a vacuum then.Resistates is distributed between ethyl acetate and water, separate each layer, with salt water washing organic moiety, dry (MgSO 4), reduce in a vacuum, produce desired sulfone amide derivative.
General operation method I
In the solution of the mercaptan under 0 ℃ (5mmol) in acetonitrile (50ml), add saltpetre (12.5mmol), any dropping sulfuryl chloride (12.5mmol).Under 0 ℃, stirred the mixture 2 hours, by adding saturated NaHCO 3Aqueous solution neutralise mixt.Extract mixture with EtOAc, separate each layer, with salt water washing organic moiety, dry (MgSO 4), reduce in a vacuum, produce desired SULPHURYL CHLORIDE.
To 4-(2; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride (preparation X) (2mmol) adds diisopropyl ethyl amine (4.2mmol) in the mixture in acetonitrile (10ml), adds suitable SULPHURYL CHLORIDE (about 2mmol) then.Stirred the mixture at ambient temperature 16 hours, and reduced in a vacuum then.Resistates is distributed between ethyl acetate and water, separate each layer, with salt water washing organic moiety, dry (MgSO 4), reduce in a vacuum, produce desired sulfone amide derivative.
General operation method J
The preparation of 4-amino-1H-pyrazoles-3-carboxylic acid amide
The preparation of step J (i) .4-nitro-1H-pyrazoles-3-carboxylic acid amide
Figure A20068000923801451
With 4-nitropyrazole-3-carboxylic acid (10g; 63.66mmol, 1 equivalent) and add to the amine RNH that is stirring 2(70mmol, 1.1 equivalents), EDC (14.6g; 76.4mmol, 1.2 equivalents) and HOBt (10.3g; 76.4mmol, 1.2 equivalents) in the solution in DMF (250ml), at room temperature stir then and spend the night., except that desolvating resistates is ground with ethyl acetate/saturated brine solution by vapourisation under reduced pressure.Collect the solid that is produced by filtering, dry under vacuum then with 2M salt acid elution, produce the 15.5g amide compound.
Step J is .4-amino-1H-pyrazoles-3-carboxylic acid (4-fluoro-phenyl)-acid amides (ii)
Figure A20068000923801452
4-nitro-1H-pyrazoles-3-carboxylic acid amide (15g) of step J (i) is dissolved in the 200ml ethanol, handles with 1.5g10% palladium/charcoal under nitrogen, hydrogenation is spent the night under room temperature and constant pressure then.Remove by filter catalyzer by Celite, evaporated filtrate.Crude product is dissolved in acetone (100ml: 100ml), after slowly evaporating acetone, by the product of solid collected by filtration form.
Embodiment 1
Closing of 4-(2,3,6-three chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-methyl-piperidin-4-yl)-acid amides Become
Figure A20068000923801461
Heat 2,3 under refluxing, (282mg, 1.25mmol) mixture in thionyl chloride (4ml) is 3 hours, reduces with toluene (* 3) azeotropic in a vacuum then for the 6-trichlorobenzoic acid.Resistates Yong diox (8ml) is absorbed, add 4-amino-1H-pyrazoles-3-carboxylic acid (1-methyl-piperidin-4-yl)-acid amides (283mg, 1mmol), add then triethylamine (280 μ l, 2mmol).Stirred the mixture at ambient temperature 14 hours, and reduced in a vacuum, with resistates at EtOAc and saturated NaHCO 3Distribute between the aqueous solution.Separate each layer, with salt water washing organic moiety, dry (MgSO 4) and reduce in a vacuum.By preparation type LC/MS purifying resistates, produce title compound, be white solid (60mg).(LC/MS:r.t.2.06 minute; M/z430).
Embodiment 2
4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [1-(2-cyano group-ethyl)-piperidin-4-yl]-acyl Synthesizing of amine
(2A.[1-2-cyano group-ethyl)-piperidin-4-yl]-carboxylamine uncle-butyl ester
Figure A20068000923801462
Will the 4-Boc-amino-piperadine among the THF (15ml) (1.0g, 5mmol), 3-bromo-propionitrile (0.80g, 6mmol) and salt of wormwood (1.04g, 7.5mmol) heating 16 hours under refluxing.Reaction mixture is cooled to envrionment temperature, pours in the water, use ethyl acetate extraction three times.The organism that washing (salt solution) merges, dry (MgSO 4), reduce to the emulsus solid in a vacuum.The NMR display part changes into desired product.The solid that is obtained is dissolved among the THF (15ml) again, add other 3-bromo-propionitrile (0.80g, 6mmol), then potassium tert.-butoxide (0.84g, 7.5mmol).The reacting by heating mixture is 16 hours in addition under refluxing, and is cooled to envrionment temperature, pours in the water, uses ethyl acetate extraction three times.The organism that washing (salt solution) merges, dry (MgSO 4) and reduce in a vacuum, produce [1-(2-cyano group-ethyl)-piperidin-4-yl]-carboxylamine uncle-butyl ester, be yellow solid (0.704g, 56%).
(2B.4-2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [1-(2-cyano group-ethyl)-piperidines-4- Base]-acid amides
Figure A20068000923801471
Be stirred in [1-(2-cyano group-ethyl)-piperidin-4-yl]-carboxylamine uncle-butyl ester (0.230g, 0.9mmol) 20 minutes in 1: 5 mixture (3ml) of TFA:DCM.Use the methyl alcohol diluted reaction mixture, reduce in a vacuum, resistates with methyl alcohol revaporization twice, is produced yellow oil.With 4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (preparation XI) (200mg, 0.75mmol), EDC (173mg, 0.9mmol), HOBT (122mg, 0.9mmol) and DMF (4ml) be added to wherein.Stirred reaction mixture is 16 hours at ambient temperature, reduces in a vacuum, at ethyl acetate and saturated NaHCO 3Distribute between the solution.Washing (water, salt solution) organic layer, dry (MgSO 4) and reduce in a vacuum.With resistates by with 100% ethyl acetate-contain column chromatography (SP4-biotage) purifying of the eluent ethyl acetate of 5% methyl alcohol; produce 4-(2; 6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [1-(2-cyano group-ethyl)-piperidin-4-yl]-acid amides; be pale solid (55mg, 18%).(LC/MS：R t1.79，[M+H] +403.23)。
Embodiment 3
4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [6-(piperidin-4-yl oxygen base)-pyridin-3-yl]- Acid amides
Figure A20068000923801481
At room temperature stir 4-(5-{4-(two chloro-benzoyl-amidos)-1H-pyrazoles-3-carbonyl }-amino)-pyridine-2-base oxygen base)-piperidines-1-carboxylic acid uncle-butyl ester (this starting raw material is referring to embodiment 45) (260mg; 0.45mmol) (4M, 10ml) solution in is 24 hours at HCl De dioxane solution.Evaporation reaction mixture in a vacuum.With resistates and toluene: carbinol mixture (1: 1) azeotropic.Resistates is ground with ether, filter, produce 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [6-(piperidin-4-yl oxygen base)-the pyridin-3-yl]-acid amides (213mg, 93%) of white hydrochloride salt solid form.(LC/MS：R t2.10，[M+H] +475.22)。
Embodiment 4
4-(2-chloro-6-fluoro-benzoyl-amido)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides Preparation
4A.4-amino-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides
Figure A20068000923801482
To the 4-that is stirring (N-BOC amino) piperidines (2.5g, 12.5mmol) add in the solution in methylene dichloride (30ml) triethylamine (2.1ml, 15.0mmol), drip then methylsulfonyl chloride (1.06ml, 13.8mmol).At room temperature stirred formed solution 1 hour.Reaction mixture is distributed between EtOAc and water.Water, 2N HCl, salt water washing organic moiety, dry (MgSO 4), to filter, evaporation in a vacuum produces 4-(N-BOC-amino)-1-methylsulfonyl piperidines, is white solid (3.1g, 89%).
(3.1g, 11.15mmol) (4M, 40ml) solution in is 24 hours at HCl De dioxane solution at room temperature to stir 4-(N-BOC-amino)-1-methylsulfonyl piperidines.Evaporation reaction mixture in a vacuum.With resistates and toluene: carbinol mixture (1: 1) azeotropic produces the 1-methylsulfonyl-piperidin-4-yl amine (2.4g, 100%) of white hydrochloride salt form.
At room temperature stir 1-methylsulfonyl-piperidin-4-yl amine hydrochlorate (2.4g; 11.1mmol), 4-nitro-1H-pyrazoles-3-carboxylic acid (1.8g; 11.1mmol), EDC (2.6g; 13.5mmol), HOBt (1.8g; 13.3mmol) and triethylamine (3.4ml, 24.6mmol) solution in DMF (30ml) is 24 hours.Reaction mixture is distributed between the saturated solution of EtOAc and sodium bicarbonate.Dry (MgSO 4) organic moiety, to filter, evaporation in a vacuum produces 4-nitro-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides, is greenish orange look solid (1.7g, 48%).
Under nitrogen, 10% palladium/charcoal (150mg) is added to 4-nitro 1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides (1.7g, 5.36mmol) in the solution in ethanol (20ml), hydrogenation 2 hours under RTP then.Add other palladium/charcoal (150mg), hydrogenation gained suspension is 2 hours in addition under RTP.Reaction mixture is filtered by Celite.Evaporated filtrate produces 4-amino-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl) acid amides in a vacuum, is yellow/brown oily matter (1.5g, 98%) (LC/MS:R t0.33, [M+H] +288.21).
(4B.4-2-chloro-6-fluoro-benzoyl-amido)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acyl Amine
Figure A20068000923801491
Stir 4-amino-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl) acid amides (150mg at ambient temperature; 5.23mmol), 2-chloro-6-fluorobenzoic acid (91mg; 0.523mmol), HOBt (85mg; 0.627mmol) and EDC (120mg, 0.627mmol) solution in DMF (10ml) is 3 hours.Reaction mixture is distributed between the saturated solution of EtOAc and sodium bicarbonate.Water (* 2), salt water washing organic moiety, dry (MgSO 4), filter, in a vacuum evaporation.By flash chromatography (Biotage SP4; 25S; flow velocity 25ml/min; gradient EtOAc/ gasoline (1: 1) is to EtOAc) the purifying resistates; produce 4-(2-chloro-6-fluoro-benzoyl-amido)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides; be white solid (25mg, 11%).(LC/MS：R t2.57，[M+H] +444.22)。
Embodiment 5
4-(2-chloro-6-methoxyl group-benzoyl-amido)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)- The preparation of acid amides
(5A.4-{[4-2-chloro-6-methoxyl group-benzoyl-amido)-1H-pyrazoles-3-carbonyl]-amino }-piperidines-1-carboxylic Acid uncle-butyl ester
4ml superoxol (30%w/w) is added to 2-methoxyl group-6-benzyl chloride nitrile, and (1.0g is 5.97mmol) in the suspension in potassium hydroxide solution (the 3g KOH in 20ml water).In 70 ℃ of following reacting by heating mixtures 20 hours, then in 100 ℃ of heating 6 hours.Reaction mixture is cooled to envrionment temperature, produces white suspension.Filter reaction mixture produces white solid.This solid is dissolved in the acetonitrile (2ml), and (10ml) is added in the formed solution carefully with the vitriol oil.Stirred reaction mixture below 30 ℃ 30 minutes.(2.58g 37mmol) adds in the reaction mixture by part with Sodium Nitrite.Stirred reaction mixture is 16 hours at ambient temperature, is poured on ice then.Then with EtOAc washing ice mixture (* 3).Merge organic moiety, dry (MgSO 4), to filter, evaporation in a vacuum produces 2-chloro-6-methoxybenzoic acid (786mg, 71%).
Under 70 ℃ with 4-[4-amino-1H-pyrazoles-3-carbonyl]-amino]-piperidines-1-carboxylic acid uncle-butyl ester (100mg, 0.324mmol), 2-chloro-6-methoxybenzoic acid (60mg, 0.324mmol), (53mg, 0.389mmol) solution stirring in DMF (5ml) is 48 hours for EDC75mg (0.389mmol) and HOBt.With EtOAc (50ml) diluted reaction mixture, with saturated solution, water (* 3), the salt water washing of sodium bicarbonate, dry (MgSO 4), filter, in a vacuum evaporation.By flash chromatography (BiotageSP4; 25S; flow velocity 25ml/min; gradient EtOAc/ gasoline arrives EtOAc at 1: 1) the purifying resistates; produce 4-{[4-(2-chloro-6-methoxyl group-benzoyl-amido)-1H-pyrazoles-3-carbonyl]-amino }-piperidines-1-carboxylic acid uncle-butyl ester; be faint yellow solid (100mg, 65%).(L C/M S：R t3.18，[M+H] +478.29)。
(5B.4-2-chloro-6-methoxyl group-benzoyl-amido)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidines-4- Base)-acid amides
Figure A20068000923801511
With 4-{[4-(2-chloro-6-methoxyl group-benzoyl-amido)-1H-pyrazoles-3-carbonyl]-amino-piperidines-1-carboxylic acid uncle-butyl ester (100mg, 0.21mmol) be dissolved in HCl De dioxane solution (4M, 10ml) in, at room temperature stirred 30 minutes.Evaporation reaction in a vacuum.Resistates and toluene: carbinol mixture (1: 1) azeotropic.Resistates is dissolved among methylene dichloride (10ml) and the DMF (1ml).With diisopropyl ethyl amine (84 μ l, 0.46mmol) and methylsulfonyl chloride (17 μ l 0.21mmol) are added in the gained solution.Stirred reaction mixture is 30 minutes at ambient temperature; then at first by flash chromatography (BiotageSP4; 25S; flow velocity 25ml/min; gradient EtOAc/ gasoline (1: 1) is to EtOAc), carry out purifying by grinding then with ether; produce 4-(2-chloro-6-methoxyl group-benzoyl-amido)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides, be white solid (34mg, 36%).(LC/MS：R t2.56，[M+H] +456.23)。
Embodiment 6
4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [1-(2-dimethylamino-ethylsulfonyl)-piperazine Pyridine-4-yl]-preparation of acid amides
(6A.4-2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-ethene alkylsulfonyl-piperidin-4-yl)- Acid amides
Figure A20068000923801512
To 4-(2; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride (preparation X) (2g, 4.78mmol) add in the solution in DMF (20ml) triethylamine (2.7ml, 19.12mmol); add then 2-chloro-1-ethyl sulfonyl chloride (0.5ml, 4.78mmol).Stirred reaction mixture is 30 minutes at ambient temperature.(175 μ l, 1.67mmol), stirred reaction mixture is 1 hour in addition at ambient temperature to add other 2-chloro-1-ethyl sulfonyl chloride.Use the EtOAc diluted reaction mixture, water (* 3), use the salt water washing then.Dry (MgSO 4) organic moiety, filter, in a vacuum evaporation.Resistates is passed through flash chromatography (Biotage SP4; 40S; flow velocity 40ml/min; gradient 1: 1EtOAc/ gasoline is to EtOAc) purifying; produce 4-(2; 6-two chloro-benzoyl-amidos)-and 1H-pyrazoles-3-carboxylic acid (1-ethene alkylsulfonyl-piperidin-4-yl)-acid amides, be white solid (500mg, 22%).(LC/MS：R t2.94，[M+H] +472.15)。
(6B.4-2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [1-(2-dimethylamino-second sulphonyl Base)-piperidin-4-yl]-acid amides
Figure A20068000923801521
(100mg, 0.212mmol) (10ml, 35%w/v) solution in is 10 minutes at the ethanolic soln of dimethylamine to stir 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-ethylsulfonyl-piperidin-4-yl)-acid amides at ambient temperature.Evaporating solvent in a vacuum.By flash chromatography (BiotageSP4; 25S; flow velocity 25ml/min; gradient 1: 20MeOH/DCM to 1: 10MeOH/DCM) purifying resistates; produce 4-(2; 6-two chloro-benzoyl-amidos)-and 1H-pyrazoles-3-carboxylic acid [1-(2-dimethylamino-ethylsulfonyl)-piperidin-4-yl]-acid amides, be white solid (30mg, 27%).(LC/MS：R t2.16，[M+H] +517.22)。
Embodiment 7
4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid [1-(2-hydroxyl-ethylsulfonyl)-piperidines-4- Base]-preparation of acid amides
Figure A20068000923801531
Borine-dimethyl sulfide (2M that will be in THF under nitrogen; 106 μ l; 0.212mmol) be added to 4-(2; 6-two chloro-benzoyl-amidos)-(100mg is 0.212mmol) in the solution in THF (10ml) for 1H-pyrazoles-3-carboxylic acid (1-ethene alkylsulfonyl-piperidin-4-yl)-acid amides (embodiment 6A).Stirred gained solution at ambient temperature 30 minutes.With superoxol (5ml, 30%w/v) and sodium hydroxide solution (5ml 2N) adds in the reaction mixture.Stirred reaction mixture is 24 hours at ambient temperature.The reaction mixture branch is dissolved between EtOAc and the water distributes.Dry (MgSO 4) organic moiety, filter, in a vacuum evaporation.By flash chromatography (Biotage SP4; 25S; flow velocity 25ml/min; gradient 1: 1EtOAc/ gasoline is to EtOAc) the purifying resistates; produce 4-(2; 6-two chloro-benzoyl-amidos)-and 1H-pyrazoles-3-carboxylic acid [1-(2-hydroxyl-ethylsulfonyl)-piperidin-4-yl]-acid amides, be white solid (10mg, 10%).(LC/MS：R t2.66，[M+H] +490.16)。
Embodiment 8
4-(2,6-two chloro-benzoyl-amidos)-1-H-pyrazoles-3-carboxylic acid [1-(2,2,2-three fluoro-ethanoyl)-piperidines-4 Base]-acid amides synthetic
Figure A20068000923801532
With trifluoroacetic anhydride (0.1ml; 0.71mmol) be added to 4-(2; 6-two chloro-benzoyl-amidos)-and 1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride (preparation X) (0.3g, 0.71mmol), (0.213ml is 1.42mmol) in the suspension in THF (5ml) for triethylamine.At room temperature stirred reaction mixture is 15 hours.Crude product is distributed between EtOAc and water, with organic phase MgSO 4Drying is filtered, in a vacuum evaporation.Resistates is ground with ether, obtain title compound, be faint yellow solid (0.1g, 30%) (LC/MS:R t2.96, [M+H] +478).
Embodiment 9
4-(2,6-two chloro-benzoyl-amidos)-1-H-pyrazoles-3-carboxylic acid [1-(morpholine-4-alkylsulfonyl)-piperidines-4 base]- Synthesizing of acid amides
Figure A20068000923801541
With triethylamine (6ml, 40mmol) be added to the chlorination morpholine (0.5g, 4mmol) in, at room temperature stirred the mixture 15 minutes.Add chloroform (10ml), mixture be cooled to-5 ℃, drip chlorsulfonic acid (0.266ml, 4mmol) in case with temperature maintenance below 0 ℃.The evaporation chloroform is used in the 0.03mol NaOH treating mixture in the 16ml water.Evaporating solns obtains morpholine-4-sodium sulfonate (morpholine-4-sodium sulphamate) to doing.Thick substance dissolves 1, in the 2-ethylene dichloride (5ml), is added POCl 3(0.7ml, 8mmol).In 80 ℃ of following reacting by heating mixtures 18 hours.Then sherwood oil and EtOAc are added in the mixture, remove solid by filtration.Evaporated filtrate obtains morpholine-4-SULPHURYL CHLORIDE (morpholine sulphamoyl chloride) to doing.With the thick substance dissolves that produced in DCM (30ml), in 0 ℃ add triethylamine (1ml, 10mmol), add then 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl amide hydrochloride (preparation X) (1g, 4mmol).At room temperature stirred reaction mixture is 16 hours, adds diox (5ml) then, heats 3 hours down in 50 ℃.Crude product is distributed between EtOAc and water.Use MgSO 4Dry organic phase is filtered, in a vacuum evaporation.By using EtOAc: 1: 2 purified by flash chromatography resistates that on silicon-dioxide, carries out of hexane to the 100%EtOAc wash-out, obtain title compound, be white solid (130mg, 3 steps 10%) (LC/MS:R t2.80, [M+H] +531).
Embodiment 10-134
By the compound of embodiment 18-138 that used method for preparing.In following table, provided the general synthesis path that uses in each case and to any adjustment (if adjustment is arranged) of reactant and condition at each embodiment.
Figure A20068000923801551
Figure A20068000923801561
Figure A20068000923801571
Figure A20068000923801581
Figure A20068000923801591
Figure A20068000923801601
Figure A20068000923801611
Figure A20068000923801621
Figure A20068000923801631
Figure A20068000923801641
Figure A20068000923801651
Figure A20068000923801661
Figure A20068000923801671
Figure A20068000923801681
Figure A20068000923801691
Figure A20068000923801701
Figure A20068000923801711
Figure A20068000923801721
Figure A20068000923801731
Figure A20068000923801741
Figure A20068000923801751
Embodiment 112
4-(two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1,1-dioxo-tetrahydrochysene-1 λ * 6*-thiapyran-4- Base)-acid amides synthetic
Figure A20068000923801752
With mCPBA (112mg; 0.50mmol) be added to the 4-(2 that is stirring; 6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (tetrahydrochysene-thiapyran-4-yl)-acid amides (embodiment 102) (100mg; 0.25mmol) in the solution in methylene dichloride (10ml), stirred gained solution at ambient temperature 1 hour.Use the ethyl acetate diluted reaction mixture, use saturated sodium bisulfite solution (twice), saturated sodium bicarbonate solution (twice) successively, wash with salt brine solution then.Dry (MgSO 4) organic moiety, filter, in a vacuum evaporation.By flash chromatography (Biotage SP4; 25S; flow velocity 25ml/min; gradient 1: 1EtOAc/ gasoline is to EtOAc) the purifying resistates; produce 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1,1-dioxo-tetrahydrochysene-1 λ * 6*-thiapyran-4-yl)-acid amides; be white solid (47mg, 44%).(LC/MS：R t2.44，[M+H] +431.14)。
Embodiment 113
Trans-4-(2.6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (4-isopropoxy-cyclohexyl)-acid amides Preparation
113A.4-the preparation of isopropoxy-cyclo-hexylamine
Figure A20068000923801761
(500mg 2.76mmol) vibrated 4 hours under 60 ℃ of hydrogen at 50psi with the mixture of 5%Rh/ aluminum oxide (400mg) in EtOH (10ml) and ice AcOH (200 μ l) with 1-isopropoxy-4-oil of mirbane.Mixture is filtered by the Celite plug, reduce, produce title compound, be isomer mixture in vacuum.
113B. trans-4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (4-isopropoxy-hexamethylene Base)-preparation of acid amides
Figure A20068000923801762
Stirred 4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (600mg), 4-isopropoxy-cyclo-hexylamine (400mg), EDC (573mg) and the mixture of HOBt (405mg) in DMF (20ml) at ambient temperature 18 hours.Reduce mixture in a vacuum, then at EtOAc and NaHCO 3Distribute between the saturated aqueous solution.With salt water washing organic moiety, dry (MgSO 4) and reduce in a vacuum, produce title compound, be isomer mixture.Take out a part of resistates to the preparation type LC/MS that is used for purifying, isolate desired trans-isomer (1.4mg).(LC/MS：R t3.09，[M+H] +439.24)。
Embodiment 114
4-[(2,6-two chloro-benzoyls)-methyl-amino]-1H-pyrazoles-3-carboxylic acid piperidin-4-yl-acid amides synthetic 114A.4-[(2,6-two chloro-benzoyls)-methyl-amino]-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3-carboxylic The preparation of acid methyl esters
Figure A20068000923801771
With 4-amino-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3-carboxylate methyl ester (1g, 4.4mmol) be dissolved in the ethanol (30ml), add triethyl orthoformate (5.3mmol, 0.785g), mixture was refluxed 15 hours, at room temperature add at leisure then sodium borohydride (0.537g, 14.2mmol).With reaction mixture refluxed 1 hour and be cooled to room temperature in addition, evaporating solvent in a vacuum then.By quick SiO 2The thick material of chromatography purification, use hexane: EtOAc (1: 3) wash-out, produce 4-methylamino-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3-carboxylate methyl ester, be white solid (0.238g, 23% productive rate).
With this compound as the starting raw material of next reaction (0.238g 0.99mmol), is dissolved in it among DCM (10ml), add triethylamine (179 μ l 1.18mmol), then add 2,6-two chloro-Benzoyl chlorides (228 μ l, 1.08mmol).Stirred reaction mixture 16 hours reduces solvent then in a vacuum, and crude product is distributed between EtOAc and water.Use saturated NaHCO 3The washing organism is used MgSO 4Drying is filtered, and evaporation obtains title compound in a vacuum, is oil mixt.Crude product is used for next reaction.
114B.4-{[(2,6-two chloro-benzoyls)-methyl-amino]-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3- Carbonyl }-amino }-piperidines-1-carboxylic acid uncle-butyl ester
With 24-[(2,6-two chloro-benzoyls)-methyl-amino]-(0.513g 1.2mmol) is dissolved in the methyl alcohol (5ml) 1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3-carboxylate methyl ester, adds 2N NaOH solution (5ml), stirring reaction 15 hours.Reduce solvent in a vacuum, then crude product is distributed between EtOAc and water.With among the 2N HC1 and water layer, extract in EtOAc.Organism is through MgSO 4Drying is filtered, and evaporation obtains 4-[(2,6-two chloro-benzoyls in a vacuum)-methyl-amino]-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3-carboxylic acid, be white solid.
(0.194mg is a starting raw material in next reaction 0.49mmol), and described next reaction is carried out in the mode that is similar to embodiment 113, but is to use N-Boc-4-amino piperidine (108mg in this pyrazoles acid; 0.53mmol) as initial amine.Crude product is by using the quick SiO of hexane: EtOAc (2: 1) wash-out 2Chromatography purification obtains 4-{[(2,6-two chloro-benzoyls)-methyl-amino]-1-(tetrahydrochysene-pyrans-2-yl)-1H-pyrazoles-3-carbonyl }-amino }-piperidines-1-carboxylic acid uncle-butyl ester, be white solid.With the diethyl ether solution (3ml) of HCl be added to this compound (30mg, 0.05mmol) in, stirred reaction mixture 5 hours reduces solvent then in a vacuum, obtains the title compound of hydrochloride form, is white solid (30mg, 20%) (LC/MS:R t1.52, [M+H] +396).
Embodiment 115-131
By the compound of embodiment 115-131 that used method for preparing.In following table, provided the general synthesis path that uses in each case and to any adjustment (if adjustment is arranged) of reactant and condition at each embodiment.
Figure A20068000923801791
Figure A20068000923801801
Figure A20068000923801811
Figure A20068000923801821
Embodiment 132
4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-pyrimidine-2-base-piperidin-4-yl)-acid amides Synthetic
Figure A20068000923801822
With 4-(2,6-dichloro-benzoyl base amino)-1H-pyrazoles-3-carboxylic acid piperidin-4-yl-acid amides mesylate (use with prepare the similar mode of X prepare) (200mg; 0.42mmol) and 2-chloropyrimide (55mg; 0.46mmol) mixture in the 5ml diox is with cesium carbonate (300mg; 9.2mmol) and the potassiumiodide of catalytic amount handle, then 95 ℃ of following heated overnight.Make the reaction cool to room temperature, handle, remove diox by vaporising under vacuum with water (20ml).By solid collected by filtration, wash drying with water.By flash column chromatography (eluent: 1: 12: 1 then 1 then: 0EtOAc/P.E.) purifying, produce 85mg4-(2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-pyrimidine-2-base-piperidin-4-yl)-acid amides, be white solid.(LC/MS：R t2.78，[M+H] +460/462)。
Embodiment 133-137
By the compound of embodiment 133-137 that used method for preparing.In following table, provided the general synthesis path that uses in each case and to any adjustment (if adjustment is arranged) of reactant and condition at each embodiment.
Figure A20068000923801831
Biologic activity
Embodiment 138
Measure activation CDK2/ cyclin A kinase inhibiting activity assay method (IC 50)
Utilize the kinase inhibiting activity of following scheme test The compounds of this invention.
To activate CDK2/ cyclin A (Brown etc., Nat.Cell Biol., 1, the 438-443 page or leaf, 1999; Lowe, E.D. etc., Biochemistry, 41, the 15625-15634 pages or leaves, 2002) at 2.5X concentration determination damping fluid (50mM MOPS pH7.2,62.5mM β-phospho-glycerol, 12.5mMEDTA, 37.5mM MgCl 2, 112.5mM ATP, 2.5mM DTT, 2.5mM sodium orthovanadate, 0.25mg/ml bovine serum albumin) is diluted to 125pM in, gets 10 μ l and 10 μ l histone substrate mixture (60 μ l ox histone h1 (Upstate Biotechnology, 5mg/ml), 940 μ l H 2O, 35 μ Ci γ 33P-ATP) mix, join in 96 orifice plates with the various diluents of 5 μ l test compounds in DMSO (at the most 2.5%).Reaction was carried out 2 to 4 hours, used excessive ortho-phosphoric acid (5 μ l, 2%) to stop then.On Millipore MAPH filter plate, from the phosphorylation histone h1, separate not and histone h1 bonded γ 33P-ATP.Each hole of MAPH plate is moistening with 0.5% ortho-phosphoric acid, reaction product is filtered with Millipore vacuum filtration unit pass through the hole then.After filtering, with twice of 200 μ l0.5% ortho-phosphoric acid debris.Filter after the drying, adds 20 μ l Microscint, 20 scintillators, then counting 30 seconds on Packard Topcount.
Calculate active % inhibition of CDK2 and drawing and suppress the active needed test compound concentration (IC of 50%CDK2 so that measure 50).
Embodiment 139
Measure activation CDKl/ cell periodic protein B kinase inhibiting activity assay method (IC 50)
CDK1/ cell periodic protein B assay method is identical with above-mentioned CDK2/ cyclin A, and different is to use CDK1/ cell periodic protein B (Upstate Discovery) and enzyme is diluted to 6.25nM.
Compound of the present invention has the IC that is less than 20 μ M 50Value or under 10 μ M concentration, provide at least 50% CDK2 activity inhibition.In CDK2 or CDK1 assay method, preferred The compounds of this invention has the IC less than 1 μ M 50Value.
Embodiment 140
GSK3-B kinase inhibiting activity assay method
With GSK3-β (Upstate Discovery) at 25mM MOPS, pH7.00,25mg/mlBSA, 0.0025%Brij-35,1.25% glycerine, 0.5mM EDTA, 25mM MgCl 2, be diluted to 7.5nM among 0.025% beta-mercaptoethanol, the 37.5mM ATP, get 10 μ l and mix with 10 μ l substrate mixture.Substrate mixture is the 1ml aqueous solution of 12.5 μ M phosphoric acid-glycogen synthetase peptides-2 (Upstate Discovery), contains 35 μ Ci γ 33P-ATP.Enzyme and substrate are joined in 96 orifice plates with the various diluents of 5 μ l test compounds in DMSO (at the most 2.5%).Make reaction carry out 3 hours (GSK3-β), use excessive ortho-phosphoric acid (5 μ l, 2%) to stop then.The filter operation method is with above activating CDK2/ cyclin A assay method.
Embodiment 141
Antiproliferative activity
Measure the antiproliferative activity of compound of the present invention by measuring ability that compound suppresses the cell growth of various kinds of cell system.Utilize Alamar Blue assay method (Nociari, M.M, Shalev, A., Benias, P., Russo, C.Journal of Immunological Methods 1998,213,157-167) restraining effect of measurement cell growth.This method is the ability of its fluorescence-causing substance resorufin based on viable cell reduction resazurin.For each proliferation assay, on 96 orifice plates, it was recovered 16 hours cell inoculation, add inhibitor compound then and reach other 72 hours.When incubation period finishes, add 10% (v/v) Alamar Blue, other 6 hours of incubation is measured fluorescence-causing substance then under 535nM ex/590nM em.Under the situation that non-proliferative cell is measured, cell was kept under converging 96 hours, add inhibitor compound then and reach other 72 hours.As above measure viable count by Alamar Blue assay method.Each clone all obtains from ECACC (European zooblast preservation center, European Collection ofcell Cultures).
Particularly, with HCT-116 clone (the ECACC preserving number: 91091005) test compound of the present invention of derived from human colorectal carcinoma.
Find that in this assay method many compounds of the present invention have the IC less than 20 μ M 50Value, preferred compound has the IC less than 1 μ M 50Value.
Embodiment 142
The mensuration of oral administration biaavailability
Oral administration biaavailability that can following mensuration formula (I) compound.
With test compound according to following dosage level and dosage formulation with solution form intravenously with by oral administration to the balb/c mouse;
1mg/kg, intravenously is formulated in 10%DMSO/90% (2-hydroxypropyl)-beta-cyclodextrin (25%w/v); With
5mg/kg, oral, be formulated among 10%DMSO/20% water/70%PEG200.
Each time point after administration, blood sampling places the heparinization test tube, collects blood plasma and partly is used for analyzing.After carrying out albumen precipitation, analyze, by sample being carried out quantitatively with standard correction curve ratio at the test compound member with LC-MS/MS.With standard method by area (AUC) under blood plasma level-time plot calculated curve.Oral administration biaavailability in order to following Equation for Calculating per-cent form:
AUC OralX dosage IntravenouslyX 100
AUC IntravenouslyDosage Oral
Pharmaceutical preparation
Embodiment 143
(i) tablet
Preparation contains the tablet composition of formula (I) compound by the following method: mix 50mg compound and 197mg as the lactose (BP) of thinner and 3mg as the Magnesium Stearate of lubricant, be pressed into tablet with currently known methods.
(ii) capsule
Prepare capsule by the following method: mix 100mg formula (I) compound and 100mg lactose, the gained mixture is packed in the opaque hard gelatin capsule of standard.
(iii) injection I
Can prepare the parenteral composition of using by injection by the following method: formula (I) compound (for example formula of salt form (I) compound) is dissolved in the water that contains 10% propylene glycol, produces the activity compound concentration of 1.5 weight %.Then by filtering with solution sterilization also sealing in the ampoule of packing into.
(iv) injection II
The preparation parenteral composition that is used for injecting by the following method: with formula (I) compound (for example formula of salt form (I) compound) (2mg/ml) and N.F,USP MANNITOL (50mg/ml) be dissolved in water, with solution sterile filtration, in pack into sealable 1ml bottle or the ampoule.
(v) injection III
Can prepare by the following method and be used for: formula (I) compound (for example formula of salt form (I) compound) is dissolved in water with the concentration of 20mg/ml by injection or the preparation sent of infusion intravenously.Then with bottle sealing and autoclaving.
(vi) injection IV
Can prepare by the following method and be used for: formula (I) compound (for example formula of salt form (I) compound) is dissolved in the water (for example 0.2M acetate pH4.6) that contains buffer reagent with the concentration of 20mg/ml by injection or the preparation sent of infusion intravenously.Then with bottle sealing and autoclaving.
(vii) subcutaneous injection preparation
Preparation is used for the composition of subcutaneous administration by the following method: hybrid (I) compound and pharmaceutical grade Semen Maydis oil, the concentration of generation 5mg/ml.In composition sterilization and threading appropriate containers.
(viii) freeze-dried preparation
The aliquots containig of formula (I) compound of preparation is put into bottle and the lyophilize of 50ml.During lyophilize, use the freezing said composition of a freezing scheme of step down at (45 ℃).Temperature is raised to-10 ℃ to rise again, be reduced to then-45 ℃ down freezing, then in+25 ℃ first down dry about 3400 minutes, succeeded by redrying, if temperature rises to 50 ℃ then increase step.During preliminary and redrying, pressure is set at 80 millitorrs.
(ix) solid solution preparation
The concentration of formula (I) compound with 5-50% (for example 16 or 20%) is dissolved in methylene dichloride/ethanol (1: 1), uses corresponding to condition given in the following table the solution spray drying.Given data comprise the entrance and exit temperature of formula (I) compound concentrations and spray-dryer in the table.
Concentration solution w/v Temperature in Temperature out
16％ 140℃ 80℃
16％ 180℃ 80℃
20％ 160℃ 80℃
20％ 180℃ 100℃
The solid solution of formula (I) compound and PVP directly can be put in glutoid or HPMC (Vltra tears) capsule, or with pharmaceutically acceptable vehicle such as extender, slip agents or dispersant.But this capsule amount is 2mg-200mg, for example 10,20 and formula (I) compound of 80mg.
Embodiment 144
The mensuration of anti-mycotic activity
Can adopt following scheme to measure the anti-mycotic activity of formula (I) compound.
Test the effect that described compound resists one group of fungi, comprise Candida parapsilosis (Candidaparpsilosis), candida tropicalis (Candida tropicalis), Candida albicans (Candidaalbicans)-ATCC 36082 and Cryptococcus neoformans (Cryptococcus neoformans).These are being stored under 4 ℃ on the Sabourahd agar glucose inclined-plane for the examination microorganism.Each biological singlet suspension prepares according to following description: under 27 ℃, on rotary shaker, containing amino acid (Difco, Detroit Mich.) spends the night yeast growth in the yeast nitrogen liquid nutrient medium (YNB) of (pH7.0) and 0.05M morpholine propanesulfonic acid (MOPS).Centrifugal then suspension is used the 0.85%NaCl washed twice, then will through the cell suspension of washing with sonic treatment 4 seconds (Branson Sonifier, 350 types, Danbury, Conn.).Counting singlet blastospore is adjusted to desired concn in 0.85%NaCl in hematimeter.
Use the activity of the modification method mensuration test compound of liquid nutrient medium Microdilution technology.Test compound is diluted to the ratio of 1.0mg/ml in DMSO, in the YNB liquid nutrient medium that contains MOPS (using fluconazole in contrast) of pH7.0, is diluted to 64 μ g/ml then, so that the working solution of every kind of compound to be provided.Use 96 orifice plates, prepare the 1st and 3 to 12 holes, prepare ten times of diluents (concentration range is 64 to 0.125 μ g/ml) of compound solution in the 2nd to 11 hole with the YNB liquid nutrient medium.The 1st hole is as the aseptic contrast and the blank of spectrophotometry.The 12nd hole is as growth control.(final inoculum number is 10 to inoculate 10 μ l to each hole in micro plate the 2nd to 11 hole 4Individual biology/ml).Will be through the plate of inoculation 35 ℃ of following incubations 48 hours.With vortex mixer (Vorte-Genie 2 Mixer, Scientific Industries, Inc., Bolemia, N.Y.) the vibration plate is after 2 minutes, with absorbancy (Automatic MicroplateReader, the DuPont Instruments of metric measurement at 420nm, Wilmington Del.) measures the IC50 value.The IC50 terminal point is defined as comparing with control wells, demonstrating the lowest concentration of drug that growth reduces about 50% (or more than).In turbidity measurement, this is defined as the lowest concentration of drug (IC50) of aperture turbidity for＜50% contrast.Minimum molten born of the same parents' concentration (MCC) is determined by the following method: all apertures of culture transferring 96 orifice plates on Sabourahd agar glucose (SDA) plate, 35 ℃ of following incubations 1 to 2 day, check viability then.
Embodiment 145
The biological assessment method of fungi infestation in the whole strain plant materials of control
In acetone, then use the acetone serial dilution formula (I) compound dissolution to obtain the desired concn scope.Decide according to pathogenic agent, by adding the 0.05%Tween-20 of 9 volumes TMThe aqueous solution or 0.01%Triton X-100 TMObtain the final volume of handling.
Use composition to adopt following method to measure the activity of the anti-tomato eqpidemic disease of The compounds of this invention (phytophthora infestans (Phytophthora infestans)) then.Make the growth in the peat base potting mixtures that does not have soil of tomato (Rutgers kind) seed high up to seedling 10-20 centimetre.Compound to be tried with the 100ppm ratio sprays this plant to flowing out then.After 24 hours, test plants is with the sporocyst aqueous suspension spray inoculation of tomato parasitica, and remains on open-air room and spend the night.Then this plant being transferred to the greenhouse takes place on untreated control plant up to disease.
Also adopt similar method to test the activity of Powdery Mildew, speckled leaf blotch (wheat septoria (Septoria tritici)) and the wheat glume blight (Leptosphaeria nodorum) of The compounds of this invention opposing brown rust of wheat (Puccinia Puccinia), wheat (Ervsiphe vraminis) and wheat (Monon kind).
Equivalents
Provide the purpose of the foregoing description to be to set forth the present invention, it should be interpreted as the scope of the invention is forced any restriction.Obviously, can be under the situation that does not deviate from ultimate principle of the present invention the specific embodiments of the present invention that is exemplified among mentioned above and the embodiment be carried out various modifications and variations.All these class modifications and variations are all contained by the application.

Claims (50)

1. the compound of formula (I):
Figure A2006800092380002C1
Or its salt, tautomer, N-oxide compound or solvate
Wherein:
R 1Be selected from:
(a) 2, the 6-dichlorophenyl;
(b) 2, the 6-difluorophenyl;
(c) 2,3, the 6-trisubstd phenyl, wherein the substituting group of this phenyl is selected from fluorine, chlorine, methyl and methoxyl group;
(d) radicals R 0
(e) radicals R 1a
(f) radicals R 1b
(g) radicals R 1c
(h) radicals R 1dWith
(j) 2,6-difluorophenyl amino;
R 0Be carbocyclic ring or heterocyclic group with 3-12 ring members; Or the C that is randomly replaced by one or more substituting groups 1-8Alkyl, described substituting group is selected from fluorine, hydroxyl, cyano group; C 1-4-oxyl, amino, list-or two-C 1-4Alkyl amino and carbocyclic ring or heterocyclic group with 3-12 ring members, and wherein 1 or 2 carbon atom of alkyl can randomly be selected from O, S, NH, SO, SO 2Atom or group replace;
R 1aBe selected from cyclopropyl-cyano group-methyl; Furyl; Benzisoxa _ azoles base; Methyl is different _ the azoles base; The mono-substituted phenyl of 2-and 2, the dibasic phenyl of 6-, wherein the substituting group on the phenyl moiety is selected from methoxyl group, oxyethyl group, fluorine, chlorine and difluoro-methoxy; Condition is R 1aNot 2,6-difluorophenyl or 2,6-dichlorophenyl;
R 1bBe selected from tetrahydrofuran base; And list-replacement and dibasic phenyl, wherein the substituting group on the phenyl moiety is selected from fluorine; Chlorine; Methoxyl group; Oxyethyl group and methyl sulphonyl;
R 1cBe selected from; Benzisoxa _ azoles base; Contain one or two and be selected from the heteroatomic quinary heteroaryl ring of O and N and contain six of one or two nitrogen heteroatom ring members-first heteroaryl ring, heteroaryl ring is randomly replaced by methyl, fluorine, chlorine or trifluoromethyl in each case; With the phenyl that is selected from the substituting group replacement of bromine, chlorine, fluorine, methyl, trifluoromethyl, oxyethyl group, methoxyl group, methoxy ethoxy, methoxymethyl, dimethylaminomethyl and difluoro-methoxy by, two or three; Condition is R 1aNot 2, the 6-difluorophenyl;
R 1dBe radicals R 1e-CH (CN)-, R wherein 1eBe carbocyclic ring or heterocyclic group with 3-12 ring members;
R 2aAnd R 2bRespectively do for oneself hydrogen or methyl;
And wherein:
If R A. 1Be (a) 2,6-dichlorophenyl and R 2aAnd R 2bBe all hydrogen; R then 3Can be selected from:
(i) group
Figure A2006800092380003C1
R wherein 9Be selected from C (O) NR 5R 6C (O)-R 10With 2-pyrimidyl, wherein R 10Be the C that is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group and methoxyl group 1-4Alkyl; And R 11, R wherein 11Be the C that is replaced by one or more substituting groups that are selected from fluorine, chlorine and cyano group 1-4Alkyl;
(ii) group
Figure A2006800092380003C2
R wherein 12Be C 2-4Alkyl;
(iii) group
Figure A2006800092380003C3
R wherein 13Be selected from methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl and 1-pyrrolidyl;
The (iv) substituted 3-pyridyl or the 4-pyridyl of following formula
Figure A2006800092380004C1
Radicals R wherein 14Position or contraposition and be selected from methyl, methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl, 1-pyrrolidyl, 4-piperidyl oxygen base, 1-C between with the valence link of asterisk mark 1-4Alkoxy carbonyl-piperidin-4-yl oxygen base, 2-hydroxyl-oxethyl and 2-methoxy ethoxy; With
(v) be selected from 2-pyrazinyl, 5-pyrimidyl, cyclohexyl, 1,4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base (4-cyclohexanone ethylene ketal), 4-methyl sulphonyl amino-cyclohexyl, tetrahydric thiapyran-4-group, 1,1-dioxo-tetrahydric thiapyran-4-group, tetrahydropyran-4-base, 4,4-difluoro cyclohexyl and 3, the 5-dimethyl is different _ group of azoles-4-base; With
If R B. 1Be (b) 2,6-difluorophenyl and R 2aAnd R 2bBe all hydrogen; R then 3Can be selected from:
(vi) 1-methyl-piperidines-3-base; 4-(2-dimethylamino ethoxy)-cyclohexyl; With the 4-piperidyl that N-replaces, wherein the N-substituting group is selected from cyano methyl and cyano ethyl; With
(vii) group
Figure A2006800092380004C2
R wherein 13As hereinbefore defined; With
If R C. 1Be (c) 2,3, the 6-trisubstd phenyl, wherein the substituting group of this phenyl is selected from fluorine, chlorine, methyl and methoxyl group; And R 2aAnd R 2bBe all hydrogen; R then 3Can be selected from group defined herein (ii), (xi), (xii) and (xiii); With
(viii) 4-piperidyl and 1-methyl-4-piperidyl;
(ix) tetrahydropyran-4-base; With
(x) group:
Figure A2006800092380004C3
R wherein 4Be C 1-4Alkyl;
If R D. 1Be (d) radicals R 0, R wherein 0Be carbocyclic ring or heterocyclic group with 3-12 ring members; Or the C that is randomly replaced by one or more substituting groups 1-8Alkyl, described substituting group is selected from fluorine, hydroxyl, cyano group; C 1-4-oxyl, amino, list-or two C 1-4Alkyl amino and carbocyclic ring or heterocyclic group with 3-12 ring members, and wherein 1 or 2 carbon atom of alkyl can randomly be selected from O, S, NH, SO, SO 2Atom or group replace; R then 3Can be selected from:
(xi) group:
Figure A2006800092380005C1
R wherein 7For:
● except C 1-4Unsubstituted alkyl outside the alkyl;
● have one or more substituent substituted C 1-4Alkyl, described substituting group is selected from fluorine, chlorine, hydroxyl, methyl sulphonyl, cyano group, methoxyl group, NR 5R 6With contain 4-7 unit saturated carbon ring or the heterocycle that is selected from the heteroatomic ring member of O, N and S to too many by two;
● group NR 5R 6, R wherein 5And R 6Be selected from hydrogen and C 1-4Alkyl, C 1-2Alkoxyl group and C 1-2Alkoxy-C 1-4Alkyl, condition are R 5And R 6In to be no more than one be C 1-2Alkoxyl group, or NR 5R 6Formation contains one or two five or the hexa-atomic saturated heterocyclic that are selected from the heteroatomic ring member of O, N and S, and this heterocycle is randomly by one or more methyl substituted;
● contain one or two and be selected from the heteroatomic ring member of N, S and O and randomly by methyl, methoxyl group, fluorine, chlorine or group NR 5R 6Five or the six membered heteroaryl that replace;
● randomly by methyl, methoxyl group, fluorine, chlorine, cyano group or group NR 5R 6The phenyl that replaces;
● C 3-6Cycloalkyl; With
● contain one or two five or hexa-atomic saturated heterocyclic that is selected from the heteroatomic ring member of O, N and S, this heterocycle is randomly by one or more methyl substituted; With
(xii) group:
Figure A2006800092380005C2
R wherein 12aFor by one or more fluorine, chlorine, C of being selected from 3-6Cycloalkyl, oxa--C 4-6Cycloalkyl, cyano group, methoxyl group and NR 5R 6The C that replaces of substituting group 1-4Alkyl, condition are when there being group NR 5R 6The time, R 12Sauerstoffatom that is connected and group NR 5R 6Between have at least two carbon atoms; With
If R E. 1Be (e) radicals R 1aAnd R 2aAnd R 2bBe all hydrogen, then R 3Can be (xiii) group
Figure A2006800092380006C1
With
If R F. 1Be (f) radicals R 1bAnd R 2aAnd R 2bBe all hydrogen, then R 3Can be (xiv) methyl; With
If R G. 1Be (g) radicals R 1cAnd R 2aAnd R 2bBe all hydrogen, then R 3Can be (xv) group
With:
If R H. 1Be (h) radicals R 1d, R then 3Be group-Y-R 3a, wherein Y is that valence link or length are the alkylidene chain and the R of 1,2 or 3 carbon atom 3aBe selected from hydrogen and carbocyclic ring and heterocyclic group with 3-12 ring members;
If R J. 1Be (j) 2,6-difluorophenyl amino, and R 2aAnd R 2bBe all hydrogen; R then 3Can be methyl; With
If R K. 1Be 2,6-dichlorophenyl and (k) R 2aBe methyl and R 2bBe hydrogen, perhaps (1) R 2aBe hydrogen and R 2bBe methyl; R then 3Can be 4-piperidines group;
Or its salt, tautomer, solvate and N-oxide compound.
2. compound according to claim 1, wherein R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3Be (i) group:
Figure A2006800092380006C3
R wherein 9Be selected from C (O) NR 5R 6C (O)-R 10, R wherein 10Be the C that is randomly replaced by one or more substituting groups that are selected from fluorine, chlorine, cyano group and methoxyl group 1-4Alkyl; And R 11, R wherein 11Be the C that is replaced by one or more substituting groups that are selected from fluorine, chlorine and cyano group 1-4Alkyl.
3. compound according to claim 2, wherein R 9Be C (O) NR 5R 6, and NR 5R 6Be selected from dimethylamino or cyclic amine such as morpholine, piperidines, piperazine, N methyl piperazine, tetramethyleneimine and thiazolidine, a concrete example is a morpholine.
4. compound according to claim 2, wherein R 9Be C (O)-R 10, and R 10Be selected from methyl, trifluoromethyl and methoxymethyl.
5. compound according to claim 2, wherein R 9Be radicals R 11, and R 11Be selected from ethyl such as cyano methyl, 2-cyano ethyl and 2-fluoro ethyl that substituted methyl and 2-replace.
6. compound according to claim 1, wherein R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3Be (ii) group:
Figure A2006800092380007C1
R wherein 12Be C 2-4Alkyl such as ethyl, different-propyl group, just-butyl, different-butyl and tert-butyl.
7. compound according to claim 1, wherein R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3Be (iii) group:
Figure A2006800092380007C2
R wherein 13Be selected from methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl and 1-pyrrolidyl.
8. compound according to claim 1, wherein R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3Be the (iv) substituted 3-pyridyl or the 4-pyridyl of following formula
Figure A2006800092380007C3
Radicals R wherein 14Position or contraposition and be selected from methyl, methyl sulphonyl, 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl, 1-pyrrolidyl, 4-piperidyl oxygen base, 1-C between with the valence link of asterisk mark 1-4Alkoxy carbonyl-piperidin-4-yl oxygen base, 2-hydroxyl-oxethyl and 2-methoxy ethoxy.
9. compound according to claim 1, wherein R 1Be 2,6-dichlorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3For (v) being selected from 2-pyrazinyl, 5-pyrimidyl, cyclohexyl, 1; 4-two oxa-s-spiral shell [4.5] last of the ten Heavenly stems-8-base (4-cyclohexanone ethylene ketal), 4-methyl sulphonyl amino-cyclohexyl, tetrahydric thiapyran-4-group, 1; 1-dioxo-tetrahydric thiapyran-4-group, tetrahydropyran-4-base, 4; 4-difluoro cyclohexyl and 3, the 5-dimethyl is different _ group of azoles-4-base.
10. compound according to claim 1, wherein R 1Be (b) 2,6-difluorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3Be selected from:
(vi) 1-methyl-piperidines-3-base; 4-(2-dimethylamino ethoxy)-cyclohexyl; With the 4-piperidyl that N-replaces, wherein the N-substituting group is selected from cyano methyl and cyano ethyl; With
(vii) group:
Figure A2006800092380008C1
R wherein 13As defined in claim 1.
11. compound according to claim 10, wherein R 1Be 2,6-difluorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3Be selected from 1-methyl-piperidines-3-base; 4-(2-dimethylamino ethoxy)-cyclohexyl; With the 4-piperidyl that N-replaces, wherein the N-substituting group is selected from cyano methyl and cyano ethyl.
12. compound according to claim 10, wherein R 1Be 2,6-difluorophenyl, R 2aAnd R 2bBe all hydrogen, and R 3For (vii) group:
R wherein 13Be selected from 4-morpholino, 4-parathiazan generation, piperidino, 1-methyl-4-piperazinyl and 1-pyrrolidyl.
13. compound according to claim 1, wherein R 1Be 2,3, the 6-trisubstd phenyl, wherein the substituting group of this phenyl is selected from fluorine, chlorine, methyl and methoxyl group; R 2aAnd R 2bBe all hydrogen; And R 3Be selected from (viii) in 4-piperidyl and 1-methyl-4-piperidyl, (ix) tetrahydropyran-4-base and the claim 1 defined group (ii), (x), (xi), (xii) and (xiii).
14. compound according to claim 13, wherein 2,3, the 6-trisubstd phenyl has fluorine, chlorine, methyl or methoxy in the 2-position.
15. compound according to claim 14, wherein 2,3, the 6-trisubstd phenyl has at least two substituting groups that are selected from fluorine and chlorine and exists.
16. compound according to claim 13, wherein 2,3, the 6-trisubstd phenyl is selected from 2,3,6-trichlorophenyl, 2,3,6-trifluorophenyl, 2,3-two fluoro-6-chloro-phenyl-s, 2,3-two fluoro-6-aminomethyl phenyls, 3-chloro-2,6-difluorophenyl, 2-chloro-3,6-difluorophenyl, 2-chloro-3-methoxyl group-6-fluorophenyl and 2-methoxyl group-3-fluoro-6-chloro-phenyl-.
17. according to each described compound, wherein R in the claim 13 to 16 3Be 4-piperidyl or 1-methyl-4-piperidyl.
18. according to each described compound, wherein R in the claim 13 to 16 3Be (x) group:
Figure A2006800092380009C1
R wherein 4As defined in claim 1.
19. according to each described compound, wherein R in the claim 13 to 16 3Be (ii) group:
Figure A2006800092380009C2
R wherein 12As defined in claim 1.
20. according to each described compound, wherein R in the claim 13 to 16 3Be (xi) group:
Figure A2006800092380009C3
R wherein 7As defined in claim 1.
21. according to each described compound, wherein R in the claim 13 to 16 3Be (xii) group:
Figure A2006800092380009C4
R wherein 12aAs defined in claim 1.
22. compound according to claim 1, wherein R 1Be radicals R 1a, R 2aAnd R 2bBe all hydrogen, and R 3Be (xiii) group
Figure A2006800092380010C1
23. compound according to claim 1, wherein R 1Be radicals R 1b, R 2aAnd R 2bBe all hydrogen, and R 3Be (xiv) methyl.
24. compound according to claim 1, wherein R 1Be radicals R 1c, R 2aAnd R 2bBe all hydrogen, and R 3Be (xv) group
25. compound according to claim 1, wherein R 1Be (j) 2,6-difluorophenyl amino, R 2aAnd R 2bBe all hydrogen; And R 3Be methyl.
26. compound according to claim 1, wherein R 1Be 2,6-dichlorophenyl, R 3Be 4-piperidines group, (k) R 2aBe methyl and R 2bBe hydrogen, or (l) R 2aBe hydrogen and R 2bBe methyl.
27. compound according to claim 1, wherein R 1Be (d) radicals R 0, R wherein 0Be carbocyclic ring or heterocyclic group with 3-12 ring members; Or the C that is randomly replaced by one or more substituting groups 1-8Alkyl, described substituting group is selected from fluorine, hydroxyl, cyano group; C 1-4-oxyl, amino, list-or two-C 1-4Alkyl amino and carbocyclic ring or heterocyclic group with 3-12 ring members, and wherein 1 or 2 carbon atom of alkyl can randomly be selected from O, S, NH, SO, SO 2Atom or group replace; And R 3Be selected from:
(xi) group:
Figure A2006800092380010C3
(xii) group:
R wherein 7, R 7aAnd R 12aAs defined herein.
28. compound according to claim 1, it is selected from:
4-(2,6-two chloro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (4-methoxyl group-cyclohexyl)-acid amides;
4-(2,3-two fluoro-6-methoxyl group-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides;
4-(3-chloro-2,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides; With
4-(2-chloro-3,6-two fluoro-benzoyl-amidos)-1H-pyrazoles-3-carboxylic acid (1-methylsulfonyl-piperidin-4-yl)-acid amides;
With its salt, solvate, tautomer and N-oxide compound.
29. according to each described compound in the claim 1 to 28, it is the form of salt, solvate or N-oxide compound.
30. be used for preventing or treat by cell cycle protein dependent kinase or glycogen synthase kinase-3 disease states mediated or illness according to each described compound of claim 1 to 29.
31. prevention or treatment be by the method for cell cycle protein dependent kinase or glycogen synthase kinase-3 disease states mediated or illness, this method comprises the compound of its individuality of needs being used in the claim 1 to 29 each.
32. alleviate or reduce the method by the incidence of cell cycle protein dependent kinase or glycogen synthase kinase-3 disease states mediated or illness, this method comprises the compound of its individuality of needs being used in the claim 1 to 29 each.
33. treatment comprises abnormal cell growth or the disease that caused by abnormal cell growth or the method for illness in Mammals, this method comprises the compound that administration is suppressed in the claim 1 to 29 of abnormal cell growth significant quantity each.
34. alleviate or reduce the method for the incidence of the disease that comprises abnormal cell growth or caused by abnormal cell growth or illness in Mammals, this method comprises the compound that administration is suppressed in the claim 1 to 29 of abnormal cell growth significant quantity each.
35. treatment comprises abnormal cell growth or the disease that caused by abnormal cell growth or the method for illness in Mammals, this method comprises the compound that administration is suppressed in the claim 1 to 29 of cdk kinases (as ckd1 or ckd2) or glycogen synthase kinase-3 active significant quantities each.
36. alleviate or reduce the method for the incidence of the disease that comprises abnormal cell growth or caused by abnormal cell growth or illness in Mammals, this method comprises the compound that administration is suppressed in the claim 1 to 29 of cdk kinases (as ckd1 or ckd2) or glycogen synthase kinase-3 active significant quantities each.
37. suppress the method for cell cycle protein dependent kinase or glycogen synthase kinase-3, this method comprises makes kinases contact with each compound in the kinase whose claim 1 to 29 of inhibition.
38. regulate the method for cell processes (for example cell fission), this method realizes by the activity that suppresses cell cycle protein dependent kinase or glycogen synthase kinase-3 with each compound in the claim 1 to 29.
39. according to each described compound in the claim 1 to 29, it is used for prevention or treats morbid state as herein described.
40. the purposes of each compound in the preparation medicine in the claim 1 to 29, wherein said medicine is used for one or more purposes defined herein.
41. comprise each compound and the pharmaceutical composition of pharmaceutically acceptable carrier in the claim 1 to 29.
42. comprise each compound and the pharmaceutical composition of pharmaceutically acceptable carrier in the claim 1 to 29, it is to be suitable for Orally administered form.
43. according to each described compound in the claim 1 to 29, it is used in the medicine.
44. according to each described compound in the claim 1 to 29, it is used for above-mentioned and described any purposes of this paper other parts and method.
45. diagnosis and treatment be by the method for cell cycle protein dependent kinase disease states mediated or illness, this method comprises that whether (i) screening patient is disease or the illness that use is had the treatment sensitivity that the active compound of anti-cell cyclin-dependent kinase carries out to determine that this patient is suffering from the disease that maybe may suffer from or illness; Therefore (ii) showing that disease of patient or illness are under the situation of susceptibility, using in the claim 1 to 29 each compound then to the patient.
46. the purposes of each compound in the preparation medicine in the claim 1 to 29, described medicine is used for screened and be determined and suffer from disease or illness or have the disease suffered from or the patient of the danger of illness treatment or preventing disease state or illness, and described disease or illness have the treatment sensitivity that the active compound of anti-cell cyclin-dependent kinase carries out to use.
47. according to each described compound in the claim 1 to 29, it is used for suppressing tumor growth Mammals.
48. according to each compound in the claim 1 to 29, it is used for suppressing growth of tumour cell (for example suppressing growth of tumour cell Mammals).
49. suppress the method for tumor growth in Mammals (for example people), this method comprises the compound of Mammals (for example people) being used in the claim 1 to 29 that suppresses the tumor growth significant quantity each.
50. suppress the method for tumour cell (tumour cell that for example is present in Mammals such as philtrum) growth, this method comprises makes tumour cell contact with each compound in the claim 1 to 29 that suppresses the growth of tumour cell significant quantity.
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CN102060772A (en) * 2010-12-17 2011-05-18 中国药科大学 N-(4-substituted phenyl)-1H-3-pyrazolecarboxamide cyclin dependent kinase 2 inhibitors and application thereof
CN110357850A (en) * 2018-03-26 2019-10-22 广东东阳光药业有限公司 A kind of preparation method of sulfur heterocyclic compound
CN111848579A (en) * 2019-04-26 2020-10-30 润佳（苏州）医药科技有限公司 Prodrugs of 4- (2, 6-dichlorobenzamido) -N- (4-piperidinyl) -1H-pyrazole-3-carboxamide
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CN111848579B (en) * 2019-04-26 2023-11-14 君实润佳(上海)医药科技有限公司 Prodrugs of 4- (2, 6-dichlorobenzoylamino) -N- (4-piperidinyl) -1H-pyrazole-3-carboxamide
CN114008058B (en) * 2019-04-26 2024-07-05 润佳（苏州）医药科技有限公司 Prodrugs of CDK inhibitors for the treatment of cancer

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