CN101589036A

CN101589036A - Aminopyrimidines useful as inhibitors of protein kinases

Info

Publication number: CN101589036A
Application number: CNA2007800502720A
Authority: CN
Inventors: J-M·吉米内兹; P·克里尔; A·米勒
Original assignee: Vertex Pharmaceuticals Inc
Current assignee: Vertex Pharmaceuticals Inc
Priority date: 2006-12-19
Filing date: 2007-12-19
Publication date: 2009-11-25

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Description

The aminopyrimidine that can be used as kinases inhibitor

Technical field

[0001] the present invention relates to can be used as the compound of kinases inhibitor.The present invention also provides the pharmaceutically acceptable composition that comprises The compounds of this invention and use these method for compositions in the treatment of various illness.The present invention also provides the method for preparing The compounds of this invention.

Background of invention

[0002] glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kitase, comprises the α of each free different genes coding and β obform body [people such as Coghlan, Chemistry; Biology 2000,7,793-803; And Kim and Kimmel, Curr.OpinionGenetics Dev., 2,000 10,508-514].GSK-3 involves in various diseases, illness and illness, comprise diabetes, Alzheimer, central nervous system disease such as bipolar disorder, schizophrenia, cerebral apoplexy, Huntington Chorea and other neurodegenerative diseases, leukopenia and myocardial cell's hypertrophy [PCT application Nos.:WO 99/65897 and WO 00/38675; With people such as Haq, J.Cell Biol.2000,151,117-130].These diseases, illness and illness are relevant with the operation irregularity of some cell signal approach that GSK-3 wherein works.Discovery GSK-3 makes many adjusting protein phosphorylations and regulates and control their activity.Above-mentioned albumen comprises Glycogensynthase, it is the synthetic required rate limiting enzyme of glycogen, the tau protein matter relevant with microtubule, the gene transcription factor beta-catenin is white, translation initiation factor e1F2B, and ATP Citrate trianion lyase, axin (axin), heat shock factor-1, c-Jun, c-myc, c-myb, CREB and CEPB α.These different protein targets are in cellular metabolism, propagation, differentiation and developmentally involve GSK-3 aspect many.

[0003] in the approach that the relevant type ii diabetes of GSK-3 mediation is treated, the caused signal of Regular Insulin causes grape cell Sugar intake and glycogen to synthesize.Along this approach, GSK-3 is the down regulator of the caused signal of Regular Insulin.Usually, the existence of Regular Insulin causes the phosphorylation of the Glycogensynthase that GSK-3 is mediated and the inhibition of inactivation.To the inhibition of GSK-3 cause the synthetic and glucose uptake of the glycogen that increases [people such as Klein, PNAS 1996,93,8455-8459; People such as Cross, Biochem.J.1994,303,21-26); Cohen, Biochem.Soc.Trans.1993,21,555-567; With people such as Massillon, Biochem J.1994,299,123-128].Yet insulin response suffers damage in the diabetic subject, although there is the Regular Insulin of high relatively haemoconcentration, glycogen is synthetic still can not to be increased with glucose uptake.This causes unusual high glucose haemoconcentration, and its acute and secular effect may finally cause cardiovascular disorder, renal failure and blind.In such patient, the caused normal inhibition to GSK-3 of Regular Insulin does not take place.Also be reported among the patient who suffers from type ii diabetes, GSK-3 is by overexpression [referring to, PCT application: WO 00/38675].So the treatment inhibitor of GSK-3 can be used for the treatment of suffers from the impaired diabetic subject of insulin response.

[0004] GSK-3 is active relevant with Alzheimer.The sign of this disease is that neurofibril forms in the outer spot of born of the same parents that formed by the accumulative beta amyloid peptide and the born of the same parents that tangle via tau protein.

Show that [0005] in the animal model of Alzheimer, the inhibition of GSK-3 reduces amyloid-β peptide.Referring to people such as Phiel, the 435th, 438 page of Nature 423, the 435-439 pages or leaves (2003).The mouse of the overexpression amyloid antecedent albumen of handling with lithium (GSK-3 alpha inhibitor) during three weeks (APP) shows that amyloid-β peptide tissue concentration surpasses 50% reduction.

[0006] neurofibrillary tangle comprises the tau protein of hyperphosphorylation, wherein tau protein in unusual site by phosphorylation.Known GSK-3 is these unusual sites of phosphorylation in cell and animal model.The condition transgenic mice of overexpression GSK-3 develops and the AD feature, comprises tau protein hyperphosphorylation, neuronal cell apoptosis and space learning defective.In these mouse, block GSK-3 and recover normal behaviour, reduce tau protein hyperphosphorylation and neuronal cell apoptosis (people such as Engel T, J Neuro Sci, 2006,26, people such as 5083-5090 and Lucas, EMBO J, 2001,20,27-39).The inhibitor of GSK-3 also is presented in the cell hyperphosphorylation [people such as Lovestone, Current Biology 1994,4, the 1077-86 of prevention tau protein; With people such as Brownlees, Neuroreport 1997,8,3251-55].

[0007] reported the target of GSK-3 as psychosis and mood disorder in the literature, each is naturally such as schizophrenia and bipolar disorder.Identify the AKT haplocype and lack in schizophreniac's subgroup, this is active relevant with the GSK-3 that increases.The single allelotrope of GSK-3 β knocks out the overactivity that causes weakening in response to amphetamine in manic behavior model.

[0008] being used for treating schizophrenia and bipolar disorder patient's several antipsychotics and mood stabilizers shows and suppresses GSK-3 (people such as Emamian, Nat Genet, 2004,36,131-137; People such as Obrien, J Neurosci, 2004,24,6791-6798; People such as Beaulieu, PNAS, 2004,101,5099-5104; People Int JNeuropsychopharmacol such as Li, 2006, the 1-13 pages or leaves; Gould TD, Expert OpinTher Targets, 2006,10,377-392).In addition, recent patent disclosure US2004/0039007 has described the GSK-3 inhibitor that shows anti-schizophrenia and angst resistance effect in relevant mouse behavior model.

[0009] GSK-3 is active relevant with apoplexy.People such as Wang show IGF-1 (insulin-like growth factor-1), and promptly known GSK-3 inhibitor reduces the infraction size in the rat brain afterwards at transience middle cerebral artery occlusion (MCAO, a kind of rat apoplexy model).[people such as Wang, BraiRes 2000,859,381-5; People such as Sasaki, Neurol Res 2001,23,588-92; People such as Hashimoto, J.Biol.Chem 2002,277,32985-32991].US 2004/0039007 has described the GSK-3 inhibitor at MCAO, the effect in promptly a kind of rat apoplexy model.These GSK-3 inhibitor reduce the striatum ischemic brain injury significantly and reduce edema and form in rat.In addition, rat " has shown the remarkable improvement of nervous function during experiment is carried out.”

[0010] the active inhibition of GSK-3 is relevant with stem cells hyperplasia, differentiation and neuron plasticity.The inhibitor of GSK-3 shows the self of embryo support stem cell, promotes neurone, beta cell, marrow and osteoblast differentiation.(people such as Sato, Nature Medicine 10,55-63,2004; People PNAS 100 such as Ding, 7632-37,2003; People JCell Science 117 such as Branco, 5731-37,2004; People such as Trowbridge, NatureMedicine 12,89-98,2006; People such as Mussmann, JBC (electronic publication before composing and printing) 2007; People Journal of Bone and Mineral Res.21 such as Kulkarni, 910-920,2006).About neuron plasticity, the inhibition of GSK-3 shows that to regulating that polarity, long-term increase effect (LTP) and neurite (neurite)/neurite (axon) grow be important (people Eur opean J of Neuroscience 25 such as Hooper, 81-86,2007; People such as Kim, Neuron 52,981-996,2006; People Cell 120 such as Jiang, 123-135,2005; ).Generally speaking, the GSK-3 micromolecular inhibitor can serve as cytodifferentiation and plastic chemical regulator, and its sex change illness that involves many types is such as neurodegenerative disease (apoplexy, Alzheimer, Parkinson, huntington, ALS and multiple sclerosis), leukopenia, diabetes and osteoporosis.

[0011] therefore, press for the compound that exploitation can be used as kinases inhibitor.Particularly, wish that exploitation can be used as the compound of GSK-3 inhibitor, the especially present obtainable treatment deficiency of most of illness that their activation is involved.

Summary of the invention

[0012] the invention provides formula I compound:

Wherein variable as defined herein.

[0013] the present invention also provides the method for these compounds of preparation, composition, pharmaceutical composition, and uses this compound and composition to come the kinase whose method of arrestin.These compounds especially can be used as the GSK-3 inhibitor.

[0014] these compounds and its pharmaceutically acceptable composition can be used for treatment or prevent multiple disease, illness or illness, include but not limited to the disease of autoimmunization, inflammatory, propagation or hyperproliferation disease, neurodegenerative disease or immunity-mediation.

[0015] kinases that also be can be used in biological and the pathological phenomenon by compound provided by the invention is studied; Research by the intracellular signal transduction approach of this class kinases-mediation; Comparative evaluation with new kinase inhibitor.

Detailed Description Of The Invention

[0016] the invention provides formula I compound:

Or its pharmacy acceptable salt, wherein:

Ht is

Ring D is 4-7 unit's monocycle or the 8-10 unit dicyclo that is selected from heterocyclic radical or carbocyclic ring basic ring; Described heterocyclic ring has 1-4 the ring hetero atom that is selected from nitrogen, oxygen or sulphur, each the commutable ring carbon that wherein encircles D independently by oxo or-R ⁵Replace, and commutable any ring nitrogen is independently by-R ⁴Replace;

X is sulphur, oxygen or NR ²';

Y is nitrogen or CR ²

Z ¹And Z ²Be N or CR independently of one another ⁹Condition is Z ¹Or Z ²In at least one is N;

R ^XBe T ¹-R ³

R ^YBe T ²-R ¹⁰

R ²And R ²' be independently selected from-R or-T ³-W-R ⁶Or R ²And R ²' form the undersaturated or undersaturated ring of part of condensed 5-8 unit with the atom that separates them, have 0-3 the ring hetero atom that is selected from nitrogen, oxygen or sulphur, wherein said R ²And R ²' on the condensed ring that forms each substitutable carbon by halogeno-group, oxo ,-CN ,-NO ₂,-R ⁷Or-V-R ⁶Replace, and described R ²And R ²' can replace nitrogen arbitrarily by R on the condensed ring that forms ⁴Replace;

T, T ¹And T ³Be key or C independently of one another _1-4Alkylidene chain;

T ²Be key or C independently _1-4Alkylidene chain, three methylene units at the most of wherein said alkylidene chain alternatively by-O-,-C (=O)-,-S (O)-,-S (O) ₂-,-S-or-N (R ⁴)-replace;

R ³Be selected from-R ,-halogeno-group ,-OR ,-C (=O) R ,-CO ₂R ,-COCOR ,-COCH ₂COR ,-NO ₂,-CN ,-S (O) R ,-S (O) ₂R ,-SR ,-N (R ⁴) ₂,-CON (R ⁷) ₂,-SO ₂N (R ⁷) ₂,-OC (=O) R ,-N (R ⁷) COR ,-N (R ⁷) CO ₂R " ,-N (R ⁴) N (R ⁴) ₂,-C (=NH) N (R ⁴) ₂,-C (=NH)-OR ,-N (R ⁷) CON (R ⁷) ₂,-N (R ⁷) SO ₂N (R ⁷) ₂,-N (R ⁴) SO ₂R or-OC (=O) N (R ⁷) ₂

R ⁴Be selected from independently of one another-R ⁷,-COR ⁷,-CO ₂(the C of optional replacement _1-6Aliphatic series (aliphatic)) ,-CON (R ⁷) ₂Or-SO ₂R ⁷, two R on the perhaps identical nitrogen ⁴Form 3-8 unit's heterocyclic radical or heteroaryl ring together;

R ⁵Be selected from independently of one another-R, halogeno-group ,-OR ,-C (=O) R ,-CO ₂R ,-COCOR ,-NO ₂,-CN ,-S (O) R ,-SO ₂R ,-SR ,-N (R ⁴) ₂,-CON (R ⁴) ₂,-SO ₂N (R ⁴) ₂,-OC (=O) R ,-N (R ⁴) COR ,-N (R ⁴) CO ₂R " ,-N (R ⁴) N (R ⁴) ₂,-C=NN (R ⁴) ₂,-C=N-OR ,-N (R ⁴) CON (R ⁴) ₂,-N (R ⁴) SO ₂N (R ⁴) ₂,-N (R ⁴) SO ₂R or-OC (=O) N (R ⁴) ₂

V is-O-,-S-,-SO-,-SO ₂-,-N (R ⁶) SO ₂-,-SO ₂N (R ⁶)-,-N (R ⁶)-,-CO-,-CO ₂-,-N (R ⁶) CO-,-N (R ⁶) C (O) O-,-N (R ⁶) CON (R ⁶)-,-N (R ⁶) SO ₂N (R ⁶)-,-N (R ⁶) N (R ⁶)-,-C (O) N (R ⁶)-,-OC (O) N (R ⁶)-,-C (R ⁶) ₂O-,-C (R ⁶) ₂S-,-C (R ⁶) ₂SO-,-C (R ⁶) ₂SO ₂-,-C (R ⁶) ₂SO ₂N (R ⁶)-,-C (R ⁶) ₂N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) C (O)-,-C (R ⁶) ₂N (R ⁶) C (O) O-,-C (R ⁶)=NN (R ⁶)-,-C (R ⁶)=N-O-,-C (R ⁶) ₂N (R ⁶) N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) SO ₂N (R ⁶)-or-C (R ⁶) ₂N (R ⁶) CON (R ⁶)-;

W is-C (R ⁶) ₂O-,-C (R ⁶) ₂S-,-C (R ⁶) ₂SO-,-C (R ⁶) ₂SO ₂-,-C (R ⁶) ₂SO ₂N (R ⁶)-,-C (R ⁶) ₂N (R ⁶)-,-CO-,-CO ₂-,-C (R ⁶) ₂OC (O)-,-C (R ⁶) ₂OC (O) N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) CO-,-C (R ⁶) ₂N (R ⁶) C (O) O-,-C (R ⁶)=NN (R ⁶)-,-C (R ⁶)=N-O-, * C (R ⁶) ₂N (R ⁶) N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) SO ₂N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) CON (R ⁶)-or-CON (R ⁶)-;

R ⁶Be selected from hydrogen or optional independently of one another by 0-3 J ⁶The C that replaces _1-4Aliphatic group; Two R on the perhaps identical nitrogen-atoms ⁶Group forms 4-6 unit's heterocyclic radical or heteroaryl ring with described nitrogen-atoms, and wherein said heterocyclic radical or heteroaryl ring are alternatively by 0-4 J ⁶Replace;

R ⁷Be selected from hydrogen or R independently of one another "; Two R on the perhaps identical nitrogen ⁷Form 4-8 unit's heterocyclic radical or heteroaryl ring with described nitrogen, wherein said heterocyclic radical or heteroaryl ring are alternatively by 0-4 J ⁷Replace;

R ⁹Each naturally-R ' ,-halogeno-group ,-OR ' ,-C (=O) R ' ,-CO ₂R ' ,-COCOR ', COCH ₂COR ' ,-NO ₂,-CN ,-S (O) R ' ,-S (O) ₂R ' ,-SR ' ,-N (R ') ₂,-CON (R ') ₂,-SO ₂N (R ') ₂,-OC (=O) R ' ,-N (R ') COR ' ,-N (R ') CO ₂(C _1-6Aliphatic series) ,-N (R ') N (R ') ₂,-N (R ') CON (R ') ₂,-N (R ') SO ₂N (R ') ₂, * N (R ') SO ₂R ' ,-OC (=O) N (R ') ₂,=NN (R ') ₂,=N-OR ' or=O;

R ¹⁰Each is 4-unit heterocycle naturally, comprises 1-2 and is selected from O, NR ¹¹Heteroatoms with S; R ¹⁰Replaced by the J of 0-3 appearance alternatively separately;

R ¹¹Respectively naturally-R ⁷,-COR ⁷,-CO ₂(the C of optional replacement _1-6Aliphatic series) ,-CON (R ⁷) ₂Or-SO ₂R ⁷

R is selected from the C that is selected from of hydrogen or optional replacement independently of one another _1-6Aliphatic series, C _6-10Virtue, have the heteroaryl ring of 5-10 annular atoms or have the group of the heterocyclic ring of 4-10 annular atoms; R is separately alternatively by 0-5 R ⁹Replace;

R ' is hydrogen or the optional C that is replaced by 0-4 J ' independently of one another _1-6Aliphatic group; Perhaps the atom that connects with their of two R ' forms 3-6 unit's carbocylic radical or heterocyclic radical, and wherein said carbocylic radical or heterocyclic radical are alternatively by 0-4 J ' replacement;

R " be alternatively by 0-4 J independently of one another " C that replaces _1-6Aliphatic series;

J ' and J " independently be NH separately ₂, NH (C _1-4Aliphatic series), N (C _1-4Aliphatic series) ₂, halogen, C _1-4Aliphatic series, OH, O (C _1-4Aliphatic series), NO ₂, CN, CO ₂H, CO ₂(C _1-4Aliphatic series), O (halo C _1-4Aliphatic) or halo C _1-4Aliphatic series;

J, J ⁶And J ⁸Independently be separately-halogeno-group ,-OR, oxo, C _1-6Aliphatic series ,-C (=O) R ,-CO ₂R ,-COCOR, COCH ₂COR ,-NO ₂,-CN ,-S (O) R ,-S (O) ₂R ,-SR ,-N (R ⁴) ₂,-CON (R ⁷) ₂,-SO ₂N (R ⁷) ₂,-OC (=O) R ,-N (R ⁷) COR ,-N (R ⁷) CO ₂(C _1-6Aliphatic series) ,-N (R ⁴) N (R ⁴) ₂,=NN (R ⁴) ₂,=N-OR ,-N (R ⁷) CON (R ⁷) ₂,-N (R ⁷) SO ₂N (R ⁷) ₂,-N (R ⁴) SO ₂R or-OC (=O) N (R ⁷) ₂

J ⁷Independently be separately-halogeno-group ,-OR, oxo, C _1-6Aliphatic series ,-C (=O) R ,-CO ₂R ,-COCOR, COCH ₂COR ,-NO ₂,-CN ,-S (O) R ,-S (O) ₂R ,-SR ,-N (R ¹²) ₂,-CON (R ¹²) ₂,-SO ₂N (R ¹²) ₂,-OC (=O) R ,-N (R ¹²) COR ,-N (R ¹²) CO ₂(C _1-6Aliphatic series) ,-N (R ¹²) N (R ¹²) ₂,=NN (R ¹²) ₂,=N-OR ,-N (R ¹²) CON (R ¹²) ₂,-N (R ¹²) SO ₂N (R ¹²) ₂,-N (R ¹²) SO ₂R or-OC (=O) N (R ¹²) ₂Perhaps

On the same atoms or 2 J groups, 2 J on homoatomic not ⁶Group, 2 J ⁷Group or 2 J ⁸The atom that group connects with them forms saturated, fractional saturation or the undersaturated 0-2 of having of 3-8 unit heteroatomic ring that is selected from O, N or S;

R ¹²Be independently selected from hydrogen or R "; Or two R on the identical nitrogen ¹²Form 4-8 unit's heterocyclic radical or heteroaryl ring with described nitrogen, wherein said heterocyclic radical or heteroaryl ring are optional by 0-4 J " replace.

[0017] The compounds of this invention comprises those of general description above, and kind disclosed herein, group and kind can further be set forth.As used herein, should be suitable for following definition.For purposes of the present invention, chemical element will be identified for the 75th edition according to periodic table of elements CAS version Handbook ofChemistry and Physics.In addition, vitochemical General Principle is described in " Organic Chemistry ", Thomas Sorrell, UniversityScience Books, Sausalito:1999 and " March ' s Advanced OrganicChemistry ", the 5th edition, Ed.:Smith, M.B. and March, J., John Wiley﹠amp; Sons, among the New York:2001, its complete content is quoted at this as a reference.

[0018] as described herein, specified atomic quantity scope comprises arbitrary integer wherein.For example, the group with 1-4 atom may have 1,2,3 or 4 atom.

[0019] as described herein, The compounds of this invention can be replaced by one or more substituting groups alternatively, and for example above-outlined is set forth, perhaps as specific big class of the present invention, group and kind institute illustration.To be figured out, wording " optional substituted " is used interchangeably with wording " replacement or unsubstituted ".Generally speaking, no matter the front has or not term " optional " to term " replacement ", represents that all rolling into a ball designated substituent atomic group to the hydrogen atom in the fixed structure replaces.Unless indication is arranged in addition, optional substituted group can have substituting group on each commutable position of this group, if substituting group that can be selected from designated groups more than one for arbitrarily in the fixed structure an above position replaces, then substituting group can be identical or different on each position.Those of the stable or chemically feasible compound of substituting group combination preferably can formation that the present invention paid close attention to.

[0020] term used herein " stablize " be illustrated in be subjected to being used for their preparations, detect, preferably reclaim, the condition of purifying and constant basically compound when being used for one or more purposes disclosed herein.In some embodiment, stable compound or chemically feasible compound be do not have moisture or other chemical reactivity conditions in the presence of, under 40 ℃ or following temperature, keep at least one week and the compound that do not change basically.

[0021] term used herein " aliphatic group " or " aliphatic group " expression straight chain (promptly not branch) or ring-type, branch or not ramose, replacement or unsubstituted hydrocarbon chain, it is saturated fully or contains one or more unsaturated units that it has the single point that is connected with the molecule rest part.Unless otherwise specified, aliphatic group contains 1-20 aliphatic carbon atom.In some embodiment, aliphatic group contains 1-10 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-8 aliphatic carbon atom.In other embodiments, aliphatic group contains 1-6 aliphatic carbon atom, and in other embodiments, aliphatic group contains 1-4 aliphatic carbon atom.The aliphatic group that is fit to includes but not limited to replacement or unsubstituted alkyl, alkenyl or the alkynyl of straight or branched.Specific examples includes but not limited to methyl, ethyl, sec.-propyl, n-propyl, sec-butyl, vinyl, n-butene base, ethynyl and the tertiary butyl.

[0022] term " cyclic aliphatic base " (perhaps " carbocyclic ring " or " carbocylic radical " or " cycloalkyl " etc.) expression monocycle C ₃-C ₈Hydrocarbon or two ring C ₈-C ₁₂Hydrocarbon, it is fully saturated or contains one or more unsaturated units, but aromatics whether has the single point that is connected with the molecule rest part, wherein said bicyclic ring be in any discrete ring have 3-7 member.The cycloaliphatic groups that is fit to includes but not limited to cycloalkyl and cycloalkenyl group.Specific examples includes but not limited to cyclohexyl, cyclopropenyl radical and cyclobutyl.

[0023] the monocyclic, bicyclic or tricyclic ring system of the non-aromatics of expression such as term used herein " heterocycle ", " heterocyclic radical " or " heterocyclic ", wherein one or more ring memberses are independent heteroatomss of selecting.In some embodiment, " heterocycle ", " heterocyclic radical " or " heterocyclic " group have three to 14 ring memberses, and wherein one or more ring memberses are the heteroatomss that independently are selected from oxygen, sulphur, nitrogen or phosphorus, and each ring contains 3 to 7 ring memberses in the system.

[0024] heterocycle of Shi Heing includes but not limited to 3-1H-benzimidazolyl-2 radicals-ketone, 3-(1-alkyl)-benzimidazolyl-2 radicals-ketone, the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-tetrahydro-thienyl, the 3-tetrahydro-thienyl, 2-morpholino base, 3-morpholino base, 4-morpholino base, the 2-parathiazan is for base, the 3-parathiazan is for base, the 4-parathiazan is for base, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, 1-tetrahydrochysene piperazinyl, 2-tetrahydrochysene piperazinyl, 3-tetrahydrochysene piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 1-pyrazolinyl, the 3-pyrazolinyl, the 4-pyrazolinyl, the 5-pyrazolinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 2-thiazolidyl, the 3-thiazolidyl, the 4-thiazolidyl, the 1-imidazolidyl, the 2-imidazolidyl, the 4-imidazolidyl, the 5-imidazolidyl, indolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, the benzo thiacyclopentane, benzo dithiane and 1,3-dihydro-imidazol--2-ketone.

[0025] cyclic group (for example cyclic aliphatic base and heterocycle) can be linear condensed, bridging or volution.

[0026] one or more oxygen, sulphur, nitrogen, phosphorus or silicon (any oxidised form that comprises nitrogen, sulphur, phosphorus or silicon represented in term " heteroatoms "; Basic nitrogen or heterocycle can replace the quaternized form of nitrogen, for example N (as 3, in the 4-dihydro-2 h-pyrrole base), NH (as in pyrrolidyl) or NR arbitrarily ⁺(in the pyrrolidyl that replaces at N-)).

[0027] term used herein " undersaturated " means that this part has one or more unsaturated units.

[0028] term used herein " alkoxyl group " or " alkylthio " expression is connected with the main body carbochain by oxygen (" alkoxyl group ") or sulphur (" alkylthio ") atom as the defined alkyl of preamble.

[0029] term " haloalkyl ", " halogenated alkenyl " and " halogenated alkoxy " expression are depended on the circumstances by alkyl, alkenyl or alkoxyl group that one or more halogen atoms replace.Term " halogen ", " halogeno-group " and " hal " expression F, Cl, Br or I.

[0030] has monocycle, two rings and the three ring ring systems that amount to five to 14 ring memberses separately or as term " aryl " expression that the part of more most of " aralkyl ", " aralkoxy " or " aryloxy alkyl " is used, wherein at least one ring is an aromatics in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " aryl " can exchange with term " aryl rings " and use.Term " aryl " also is expressed as follows the heteroaryl ring system of definition.

[0031] has the monocyclic, bicyclic or tricyclic ring system that amounts to five to 14 ring memberses separately or as term " heteroaryl " expression that the part of more most of " heteroaralkyl " or " heteroaryl alkoxyl group " is used, wherein at least one ring is an aromatics in this system, at least one ring contains one or more heteroatomss in this system, and wherein in this system each ring contain 3 to 7 ring memberses.Term " heteroaryl " can exchange with term " heteroaryl ring " or term " heteroaromatic base " and use.The heteroaryl ring that is fit to includes but not limited to the 2-furyl, the 3-furyl, the TMSIM N imidazole base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, benzimidazolyl-, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the N-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, pyridazinyl (for example 3-pyridazinyl), the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, tetrazyl (for example 5-tetrazyl), triazolyl (for example 2-triazolyl and 5-triazolyl), the 2-thienyl, the 3-thienyl, benzofuryl, benzothienyl, indyl (for example 2-indyl), pyrazolyl (for example 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazole base, 1,2,5-oxadiazole base, 1,2,4-oxadiazole base, 1,2, the 3-triazolyl, 1,2, the 3-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, purine radicals, pyrazinyl, 1,3, the 5-triazinyl, quinolyl (2-quinolyl for example, the 3-quinolyl, the 4-quinolyl) and isoquinolyl (1-isoquinolyl for example, 3-isoquinolyl or 4-isoquinolyl).

[0032] term blocking group feeding used herein and protectiveness group feeding represent to be used for temporarily sealing the composition of the one or more required reactive positions of polyfunctional compound.In some embodiment, blocking group has one or more in the following feature or all preferred: a) with good yield selective reaction, obtain protected substrate, b) it is stable for the reaction that occurs in one or more other reactive positions; And c) reagent place's selectivity of not attacked regenerated functional group of institute with good yield is removed.Exemplary blocking group is referring to Greene, T.W., Wuts, P.Gin " the Protective Groups in OrganicSynthesis " third edition, John Wiley ﹠amp; Sons, other versions of New York:1999 and this book, its complete content is quoted at this as a reference.Term nitrogen-protecting group used herein is rolled into a ball the composition that feeding represents to be used for temporarily sealing the reactive position of the one or more required nitrogen of polyfunctional compound.Preferred nitrogen-protecting group is rolled into a ball also possesses above-mentioned feature, and some exemplary nitrogen-protecting group is rolled into a ball also referring to Chapter 7 in Greene, T.W., Wuts, P.Gin " the ProtectiveGroups in Organic Synthesis " third edition, John Wiley ﹠amp; Sons, NewYork:1999, its complete content is quoted at this as a reference.

[0033] in some embodiment, the one or more MU (methylene unit) in alkyl or aliphatic chain can be replaced by other atom or group alternatively.This class atom or examples of groups will include but not limited to-NR-,-O-,-S-,-CO ₂-,-OC (O)-,-C (O) CO-,-C (O)-,-C (O) NR-,-C (=N-CN) ,-NRCO-,-NRC (O) O-,-SO ₂NR-,-NRSO ₂-,-NRC (O) NR-,-OC (O) NR-,-NRSO ₂NR-,-SO-or-SO ₂-, wherein R is as defined herein.

[0034] unless otherwise specified, optionally replace generating chemically stable compound.Optionally replacement can occur in the chain, also can occur in the end of chain; Just and/or also endways at tie point.Two optional replacements also can be adjacent one another are in chain, as long as cause chemically stable compound.Optionally replacement also can replace all carbon atoms in the chain fully.For example, C ₃Aliphatic group can be alternatively by-NR-,-C (O)-and-NR-replaces generation-NRC (O) NR-(urea).

[0035] unless otherwise specified, if replace occurring in end, replace the hydrogen atom of atomic linkage on end.For example, if-CH ₂CH ₂CH ₃MU (methylene unit) replaced by-O-alternatively, the gained compound may be-OCH ₂CH ₃,-CH ₂OCH ₃Or-CH ₂CH ₂OH.

[0036] unless otherwise prescribed, the structure that this paper described also means all isomeries (for example enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism)) form that comprises this structure; The for example R of each asymmetric center and S configuration are (Z) with (E) double bond isomer and (Z) and (E) conformer.Therefore, the single three-dimensional chemical isomer of these compounds and enantiomerism, diastereo-isomerism and rotamerism (or conformational isomerism) mixture all belong to scope of the present invention.

[0037] unless otherwise prescribed, all tautomeric forms of The compounds of this invention all belong to scope of the present invention.

[0038] unless otherwise prescribed, substituting group can rotate freely around any rotatable key.For example, be depicted as

Substituting group also represent

[0039] in addition, unless otherwise prescribed, the structure that this paper described also means and only comprises compound different in the existence of one or more isotopic enrichment atoms.For example, replaced or the carbon quilt by deuterium or tritium except hydrogen ¹³C-or ¹⁴The compound that has structure of the present invention beyond the carbon of C-enrichment replaces all belongs to scope of the present invention.This compounds for example can be used as analysis tool or the probe in the biological assay.

[0040] also will be figured out, The compounds of this invention can exist for treatment with free form, perhaps takes the circumstances into consideration to be its pharmacy acceptable salt or its mixture.

[0041] salt of term used herein " pharmacy acceptable salt " expression compound, in rational medical judgment scope, they are suitable for contacting with the lower animal tissue with human body, do not have unsuitable toxicity, pungency, transformation reactions etc., match with rational interests/risk ratio.

[0042] pharmacy acceptable salt is well known in the art.For example, S.M.Berge etc. are at J.Pharmaceutical Sciences, and 1977,66, describe pharmacy acceptable salt among the 1-19 in detail, quote as a reference at this.The pharmacy acceptable salt of The compounds of this invention comprise from the inorganic and organic acid that is fit to and alkali deutero-those.These salt can be by in-situ preparing during the final separation of compound and purifying.Acid salt can be prepared as follows: 1) make the free alkali form and the organic or inorganic acid-respons that is fit to of the compound of purifying, with 2) separate the salt that is generated.

[0043] example of pharmaceutically acceptable non-toxic acid addition salt is the amide that generates with mineral acid or organic acid, mineral acid is hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid for example, organic acid is acetate, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid for example, perhaps utilize the used additive method in this area, for example the salt of ion-exchange formation.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, glucoheptose salt, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, the 2-isethionate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, right-tosylate, the undecane hydrochlorate, valerate etc.Comprise basic metal, alkaline-earth metal, ammonium and N from suitable alkali deutero-salt ⁺(C _1-4Alkyl) ₄Salt.The quaternization of any alkaline nitrogen-containing group of compound is as disclosed herein also contained in the present invention.Can obtain water soluble or the oily product that maybe can be dispersed in water or the oil by this class quaternization.

[0044] base addition salt can be prepared as follows: 1) make the sour form and the organic or inorganic alkali reaction that is fit to of the compound of purifying, with 2) separate the salt that is generated.Base addition salt comprises basic metal or alkaline earth salt.Representative basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.In due course, other pharmacy acceptable salts comprise nontoxic ammonium salt, quaternary ammonium salt and amine cationic salts, utilize counter ion to generate, for example halogenide, oxyhydroxide, carboxylate salt, vitriol, phosphoric acid salt, nitrate, low-grade alkane sulfonate and arylsulphonate.Other bronsted lowry acids and bases bronsted lowries although itself be not pharmaceutically acceptable, can be used to prepare the salt that can be used as intermediate when obtaining The compounds of this invention and their pharmaceutically acceptable acid or base addition salt.

[0045] use following abbreviation:

LiHMDS hexamethyl two silicon Lithium Azides

The DCM methylene dichloride

The EtOAc ethyl acetate

The DMSO dimethyl sulfoxide (DMSO)

The ATP Triphosaden

The DTT dithiothreitol (DTT)

The NMR nucleus magnetic resonance

The HPLC high performance liquid chromatography

The LCMS liquid chromatography-mass spectrography

The TLC thin-layer chromatography

The Rt retention time

[0046] a kind of embodiment provides formula formula I compound

Or its pharmacy acceptable salt, wherein:

Ht is

X is sulphur, oxygen or NR ²';

Y is nitrogen or CR ²

R ^XBe T ¹-R ³

R ^YBe T ²-R ¹⁰

T, T ¹And T ³Be key or C independently of one another _1-4Alkylidene chain;

R ⁴Be selected from independently of one another-R ⁷,-COR ⁷,-CO ₂(the C of optional replacement _1-6Aliphatic series) ,-CON (R ⁷) ₂Or-SO ₂R ⁷, two R on the perhaps identical nitrogen ⁴Form 3-8 unit's heterocyclic radical or heteroaryl ring together;

W is-C (R ⁶) ₂O-,-C (R ⁶) ₂S-,-C (R ⁶) ₂SO-,-C (R ⁶) ₂SO ₂-,-C (R ⁶) ₂SO ₂N (R ⁶)-,-C (R ⁶) ₂N (R ⁶)-,-CO-,-CO ₂-,-C (R ⁶) ₂OC (O)-,-C (R ⁶) ₂OC (O) N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) CO-,-C (R ⁶) ₂N (R ⁶) C (O) O-,-C (R ⁶)=NN (R ⁶)-,-C (R ⁶)=N-O-,-C (R ⁶) ₂N (R ⁶) N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) SO ₂N (R ⁶)-,-C (R ⁶) ₂N (R ⁶) CON (R ⁶)-or-CON (R ⁶)-;

R ⁶Be selected from hydrogen or optional independently of one another by 0-3 J ⁶The C that replaces _1-4Aliphatic group; Two R on the perhaps identical nitrogen-atoms ⁶Group forms 5-6 unit's heterocyclic radical or heteroaryl ring with described nitrogen-atoms, and wherein said heterocyclic radical or heteroaryl ring are alternatively by 0-4 J ⁶Replace;

R ⁷Be selected from hydrogen or R independently of one another "; Two R on the perhaps identical nitrogen ⁷Form 5-8 unit's heterocyclic radical or heteroaryl ring with described nitrogen, wherein said heterocyclic radical or heteroaryl ring are alternatively by 0-4 J ⁷Replace;

R ⁹Each naturally-R ' ,-halogeno-group ,-OR ' ,-C (=O) R ' ,-CO ₂R ' ,-COCOR ', COCH ₂COR ' ,-NO ₂,-CN ,-S (O) R ' ,-S (O) ₂R ' ,-SR ' ,-N (R ') ₂,-CON (R ') ₂,-SO ₂N (R ') ₂,-OC (=O) R ' ,-N (R ') COR ' ,-N (R ') CO ₂(C _1-6Aliphatic series) ,-N (R ') N (R ') ₂,-N (R ') CON (R ') ₂,-N (R ') SO ₂N (R ') ₂,-N (R ') SO ₂R ' ,-OC (=O) N (R ') ₂,=NN (R ') ₂,=N-OR ' or=O;

R is selected from the C that is selected from of hydrogen or optional replacement independently of one another _1-6Aliphatic series (aliphatic), C _6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the group of the heterocyclic ring of 4-10 annular atoms; R is separately alternatively by 0-5 R ⁹Replace;

J, J ⁶, J ⁷And J ⁸Independently be separately-halogeno-group ,-OR, oxo, C _1-6Aliphatic series ,-C (=O) R ,-CO ₂R ,-COCOR, COCH ₂COR ,-NO ₂,-CN ,-S (O) R ,-S (O) ₂R ,-SR ,-N (R ⁴) ₂,-CON (R ⁷) ₂,-SO ₂N (R ⁷) ₂,-OC (=O) R ,-N (R ⁷) COR ,-N (R ⁷) CO ₂(C _1-6Aliphatic series) ,-N (R ⁴) N (R ⁴) ₂,=NN (R ⁴) ₂,=N-OR ,-N (R ⁷) CON (R ⁷) ₂,-N (R ⁷) SO ₂N (R ⁷) ₂,-N (R ⁴) SO ₂R or-OC (=O) N (R ⁷) ₂Perhaps

On the same atoms or 2 J groups, 2 J on homoatomic not ⁶Group, 2 J ⁷Group or 2 J ⁸The atom that group connects with them forms saturated, fractional saturation or the undersaturated 0-2 of having of 3-8 unit heteroatomic ring that is selected from O, N or S.

[0047] in some embodiments of the present invention, Ht is Or

In some embodiment, Ht is

In other embodiments, Ht is

[0048] in another embodiment of the invention, X is S.In another embodiment, X is NR ²'.In some embodiment, Y is N or CR ²In other embodiments, Y is N.In going back other embodiment, Y is CR ²In some embodiments, X is that S and Y are N.In other embodiments, X is that S and Y are CR ²

[0049] in some embodiment, T ²Be key or C independently _1-4Alkylidene chain, three MU (methylene unit) at the most of wherein said alkylidene chain alternatively by-O-,-C (=O)-,-S (O)-,-S (O) ₂-,-S-or-N (R ⁴)-replace.In some embodiment, the described optional replacement of the MU (methylene unit) of T is selected from-CO ₂-,-COCO-,-COCH ₂CO-,-S (O)-,-S (O) ₂-,-S-,-N (R ⁴)-,-CON (R ⁷)-,-SO ₂N (R ⁷)-,-OC (=O)-,-N (R ⁷) CO-,-N (R ⁷) CO ₂-,-N (R ⁴) N (R ⁴)-,-N (R ⁷) CON (R ⁷)-,-N (R ⁷) SO ₂N (R ⁷)-,-N (R ⁴) SO ₂-or-OC (=O) N (R ⁷)-.

[0050] in some embodiment of the present invention, Z ¹And Z ²All be nitrogen.In other embodiments, Z ¹Be CR ⁹And Z ²Be nitrogen.In going back other embodiment, Z ¹Be nitrogen and Z ²Be CH.

[0051] in some embodiment of the present invention, R ²' be hydrogen or methyl. in some embodiment, R ²' be hydrogen.

[0052] in other embodiments, R ²Be T ³-W-R ⁶Or R; Wherein W is-C (R ⁶) ₂O-,-C (R ⁶) ₂N (R ⁶)-,-CO-,-CO ₂-,-C (R ⁶) ₂OC (O)-,-C (R ⁶) ₂N (R ⁶) CO-,-C (R ⁶) ₂N (R ⁶) C (O) O-or-CON (R ⁶)-, and R is the C that is selected from of optional replacement _1-6Aliphatic series or phenyl groups.In going back other embodiment, R ²Be hydrogen or be selected from aryl, heteroaryl or C _1-6The group that be substituted or that be unsubstituted of aliphatic group.In some embodiments, R ²Be hydrogen or be selected from aryl or C _1-6The group that be substituted or that be unsubstituted of aliphatic group.

[0053] in some embodiment of the present invention, R ²And R ²' form undersaturated 6-unit's carbocyclic ring of the benzo, pyrido, Mi Dingbing or the part that are substituted or be unsubstituted and ring with the atom that separates them.In other embodiments, R ²And R ²' form benzo or the pyrido ring that is substituted or be unsubstituted with the atom that separates them.In some embodiments, described benzo or pyrido ring are replaced by 1-2 halogeno-group substituting group.

[0054] in another aspect of this invention, R ^XBe hydrogen, C _1-4Aliphatic series or halogeno-group.In some embodiments, R ^XBe hydrogen, fluorine, methyl, ethyl, cyclopropyl or sec.-propyl.In other embodiments, R ^XBe hydrogen.

[0055] in another aspect of this invention in, R ^YRepresent by formula ii-a:

[0056] in still another aspect of the invention in, R ^YBe T ²-R ¹⁰, T wherein ²It is key.In some embodiments, R ¹⁰It is the azetidine of optional replacement.

[0057] in still another aspect of the invention in, R ^YRepresent by formula i:

[0058] in still another aspect of the invention, R ^YRepresent by formula iii:

[0059] in some embodiment, R ¹¹Be H.

[0060] in one aspect of the invention in, the ring D be the ring of optional replacement, be selected from piperidyl, piperazinyl, pyrrolidyl, morpholinyl, 1,2,3,4-tetrahydro isoquinolyl, 1,2,3,4-tetrahydric quinoline group, 2,3-dihydro-1H-pseudoindoyl, 2,3-dihydro-1H-indyl or isoquinolyl.In some embodiments, ring D is tetralyl, Ben Bing dioxin base (benzodioxinyl), indanyl, indoline base or the isoquinolyl of optional replacement.In some embodiment, ring D is a 5-8 unit cycloalkyl.In some embodiments, ring D is cyclopentyl, cyclohexyl or suberyl.In some embodiment, ring D is a cyclohexyl.

[0061] in another aspect of this invention, R ¹Be-halogeno-group, the C of optional replacement _1-6Aliphatic group, phenyl ,-COR ⁶,-OR ⁶,-CN ,-SO ₂R ⁶,-SO ₂NH ₂,-N (R ⁶) ₂,-CO ₂R ⁶,-CONH ₂,-NHCOR ⁶,-OC (O) NH ₂Or-NHSO ₂R ⁶In some embodiments, R ¹Be-halogeno-group, C _1-6The C of halogenated aliphatic group, optional replacement _1-6Aliphatic group, phenyl or-CN.In other embodiments, R ¹Be-halogeno-group, the optional C that is replaced by halogen _1-4Aliphatic group, or-CN.

[0062] in some embodiment, J, J ⁶And J ⁸Be independently of one another-halogeno-group ,-OR, oxo, C _1-6Aliphatic series ,-C (=O) R ,-CO ₂R ,-COCOR, COCH ₂COR ,-NO ₂,-CN ,-S (O) R ,-S (O) ₂R ,-SR ,-N (R ⁴) ₂,-CON (R ⁷) ₂,-SO ₂N (R ⁷) ₂,-OC (=O) R ,-N (R ⁷) COR ,-N (R ⁷) CO ₂(C _1-6Aliphatic series) ,-N (R ⁴) N (R ⁴) ₂,=NN (R ⁴) ₂,=N-OR ,-N (R ⁷) CON (R ⁷) ₂,-N (R ⁷) SO ₂N (R ⁷) ₂,-N (R ⁴) SO ₂R or-OC (=O) N (R ⁷) ₂

[0063] in some embodiment, J ⁷Be independently of one another-halogeno-group ,-OR, oxo, C _1-6Aliphatic series ,-C (=O) R ,-CO ₂R ,-COCOR, COCH ₂COR ,-NO ₂,-CN ,-S (O) R ,-S (O) ₂R ,-SR ,-N (R ¹²) ₂,-CON (R ¹²) ₂,-SO ₂N (R ¹²) ₂,-OC (=O) R ,-N (R ¹²) COR ,-N (R ¹²) CO ₂(C _1-6Aliphatic series) ,-N (R ¹²) N (R ¹²) ₂,=NN (R ¹²) ₂,=N-OR ,-N (R ¹²) CON (R ¹²) ₂,-N (R ¹²) SO ₂N (R ¹²) ₂,-N (R ¹²) SO ₂R, or-OC (=O) N (R ¹²) ₂R wherein ¹²Be independently selected from hydrogen or R "; Or two R on the identical nitrogen ¹²Form 4-8 unit's heterocyclic radical or heteroaryl ring with described nitrogen, wherein said heterocyclic radical or heteroaryl ring are alternatively by 0-4 J " replace.

[0064] in some embodiment, two R on the identical nitrogen ⁴Form 3-8 unit's heterocyclic radical or heteroaryl ring together.In other embodiments, R ⁴Be selected from independently of one another-R ⁷,-COR ⁷,-CO ₂(the C of optional replacement _1-6Aliphatic series) ,-CON (R ⁷) ₂Or-SO ₂R ⁷In some embodiment, described C _1-6Aliphatic series is optional by 0-2 J " replace.In some embodiment, described C _1-6Aliphatic series is unsubstituted.

[0065] in some embodiment, R ⁶Be selected from hydrogen independently of one another or alternatively by 0-3 J ⁶The C that replaces _1-4Aliphatic group; Or two R on the identical nitrogen-atoms ⁶Group forms 4-6 unit's heterocyclic radical or heteroaryl ring with described nitrogen-atoms, and wherein said heterocyclic radical or heteroaryl ring are alternatively by 0-4 J ⁶Replace.In some embodiment, two R on the identical nitrogen-atoms ⁶Group forms 5-6 unit's heterocyclic radical or heteroaryl ring with described nitrogen-atoms, and wherein said heterocyclic radical or heteroaryl ring are alternatively by 0-4 J ⁶Replace.

[0066] one embodiment of the present invention are represented by formula Ia:

[0067] another embodiment of the invention is represented by formula Ib:

[0068] another embodiment of the invention is represented by formula Ic:

[0069] another embodiment of the invention is represented by formula Id:

[0070] another embodiment of the invention is represented by formula Ie:

[0071] another embodiment of the invention is represented by formula If:

R wherein ²And R ²' form benzo or the pyrido ring that is substituted or be unsubstituted with the atom that separates them.

[0072] in some embodiment, each variable is to describe as compound in the table 1.

[0073] in some embodiment, The compounds of this invention is as shown in table 1:

Table 1

Universal synthesis method

[0074] The compounds of this invention generally can by following generalized flowsheet and subsequently those methods of describing of preparation example prepared.Unless indication is arranged in addition, all variablees in the following flow process all are as defined herein.

Flow process 1

[0075] Reagent and condition:(i) EtONa, EtOH refluxes; (ii) POCl ₃, reflux; (iii) HtNH ₂, LiHMDS ,-60 ℃ to 0 ℃ (iv) azetidines, propyl carbinol, 108 ℃.

[0076] above-mentioned flow process 1 shows the general synthetic route that is used to prepare compound 5.Formula 5 compounds can be from intermediate 3 preparations.Intermediate 3 reacts formation by malonic ester and corresponding amidine in backflow ethanol in the presence of as the EtONa of alkali.Crude product is used POCl subsequently ₃Handle and produce dichloro pyrimidine intermediate 3.Thereby handle this dichloro pyrimidine intermediate with heterocyclic amine and azetidine derivatives successively then and produce final compound 5.These two reaction process are applicable to various heterocyclic amines and the azetidine that is substituted.

[0077] the invention provides compound and the composition that can be used as kinases inhibitor.In some embodiment, described protein kinase is the GSK-3 kinases.

[0078] as the inhibitor of protein kinase, compound of the present invention and composition are particularly useful for treatment a kind of like this disease, illness or illness or alleviate its seriousness, wherein protein kinase implication in this disease, illness or illness.On the one hand, the invention provides the method for the treatment of disease, illness or illness or alleviating its seriousness, wherein protein kinase implication in this morbid state.On the other hand, the invention provides treatment disease, illness or illness or alleviate the method for its seriousness, wherein enzymic activity is suppressed at implication in this treatment of diseases.On the other hand, the invention provides with compounds for treating disease, illness or illness or alleviate the method for its seriousness, this compound is by combining and inhibitory enzyme activity with protein kinase.Provide on the other hand by suppress the method that described kinase whose enzymic activity is treated kinases disease, illness or illness or alleviated its seriousness with kinases inhibitor.

[0079] in some embodiment, described kinases inhibitor is GSK-3.

[0080] as the inhibitor of protein kinase, compound of the present invention and composition also can be used for biological sample.One aspect of the present invention relates to the protein kinase activity that suppresses in the biological sample, and this method comprises to be made described biological sample contact I compound or comprise described compound compositions.Term used herein " biological sample " expression ExternalOr from In the bodySample, comprise cell culture and extract thereof without limitation; Biopsy material from Mammals or the acquisition of its extract; With blood, saliva, urine, ight soil, seminal fluid, tear or other body fluid or its extract.

[0081] protein kinase activity that suppresses in the biological sample can be used for the known purpose of those skilled in the art separately.The example of these purposes includes, but not limited to blood transfusion, organ transplantation and biological samples storage.

[0082] another aspect of the present invention relates to the protein kinase research in biological and the pathological phenomenon; Research by the kinase mediated intracellular signal transduction approach of this proteinoid; Comparative evaluation with new kinases inhibitor.The example of this class purposes includes but not limited to bioassay method, for example enzyme assay and cell class assay method.

[0083] in the present invention as the activity of the compound of kinases inhibitor can External, In the bodyOr measured in the clone. ExternalAssay method comprises the restraining effect of mensuration to the kinase activity or the atpase activity of activated protein kinase.Optionally ExternalBut assay method quantitative assay inhibitor and protein kinase bonded ability.The combination of inhibitor can be measured like this, radio-labeling inhibitor before combination separates inhibitor/kinase complex, measures the radiolabeled amount of institute's bonded again, the experiment that perhaps is at war with is wherein with novel inhibitors with known radioligand bonded kinases incubation.

[0084] another aspect of the present invention provides the compound that can be used for treating disease, illness and illness, includes but not limited to disease, immunodeficiency disorder, immunity modulation or immunosuppression illness, osteopathia, metabolic trouble, neural and neurodegenerative disease, neurotrophic factor, cardiovascular disorder, hormone relative disease, diabetes, transformation reactions, asthma and the Alzheimer of autoimmune disease, inflammatory diseases, propagation and hyperproliferation disease, immunology-mediation.Another aspect of the present invention provides the kinases inhibitor compound, thereby can be used for treating disease, illness and illness, and other purposes as herein described.

[0085] provide the pharmaceutically acceptable composition that comprises any compound described herein also to comprise pharmaceutically acceptable carrier, auxiliary agent or vehicle alternatively on the other hand.In some embodiment, these compositions further comprise one or more additional treatment agent alternatively.

[0086] one aspect of the present invention provides treatment to be selected from following disease, illness and illness or alleviate the method for its seriousness: autoimmune disease, inflammatory diseases, propagation or hyperproliferation disease (for example cancer), the disease of immunology-mediation, immunodeficiency disorder, osteopathia, metabolic trouble, nerve or neurodegenerative disease, cardiovascular disorder, transformation reactions, diabetes, asthma, Alzheimer or hormone relative disease comprise and give the compound of significant quantity or the pharmaceutically acceptable composition of inclusion compound to the curee that these needs are arranged.

[0087] term " cancer " includes but not limited to following cancer: epidermoid Mouthful:Oral cavity, lip, tongue, mouth, pharynx; The heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, do not break up minicell, do not break up maxicell, gland cancer), alveolar (bronchiole) cancer, bronchial adenoma, sarcoma, lymphoma, cartilage progonoma, mesothelioma; Stomach and intestine: oesophagus (squamous cell carcinoma, larynx, gland cancer, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (duct adenocarcinoma, nesidioblastoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (gland cancer, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyoma, vascular tumor, lipoma, neurofibroma, fibroma), large intestine (gland cancer, tubular adenoma, villous adenoma, progonoma, leiomyoma), colon, colon-rectum, colorectum, rectum; Genitourinary tract: kidney (gland cancer, wilm tumor [nephroblastoma], lymphoma, leukemia), bladder and urinary tract (squamous cell carcinoma, transitional cell carcinoma, gland cancer), prostate gland (gland cancer, sarcoma), spermary (spermocytoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, mesenchymal cell cancer, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, adenoma, vascular tumor, biliary tract; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, pernicious giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), optimum chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumor; Neural system: skull (osteoma, vascular tumor, granuloma, vitiligoidea, osteitis deformans), meninx (meningioma, meningosarcoma, neurogliosis), cranial ganglia (astrocytoma, medulloblastoma, neurospongioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerves fibroma, meningioma, neurospongioma, sarcoma); Gynaecology: uterus (carcinoma of endometrium), uterine neck (dysplasia of cervix before cervical cancer, the tumour), ovary (ovarian cancer [serous cystadenocarcinoma, mucous cystoadenocarcinoma, unfiled cancer], granulosa-theca cell knurl, plug Lay two Schwann Cells knurls, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, gland cancer, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), uterine tube (cancer), breast; Blood: blood (myelomatosis [acute and chronic], acute lymphoblastic leukemia, lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), Hokdkin disease, non_hodgkin lymphoma [malignant lymphoma] galley proof cell; Lymph sample illness; Skin: malignant melanoma, rodent cancer, squamous cell carcinoma, Kaposi sarcoma, keratoacanthoma, the hypogenetic mole of mole, lipoma, vascular tumor, dermatofibroma, keloid, chronic eczema; Tiroidina: papillary thyroid carcinoma, folliculus shape thyroid carcinoma; Spinal cord thyroid carcinoma, undifferentiated thyroid carcinoma, multiple internal secretion malignant tumour 2A, multiple internal secretion malignant tumour 2B, familial spinal cord thyroid carcinoma, pheochromocytoma, chromaffinoma; And Suprarenal gland: neuroblastoma.Therefore, term " cancerous cells " provides as this paper, comprises the cell of suffering from any above-mentioned illness.In some embodiment, described cancer is selected from colorectum, Tiroidina or mammary cancer.

[0088] any disease or other the deleterious illness that work of term " illness of mitotic division enzyme-mediation " or " disease of mitotic division enzyme-mediation " known wherein mitotic division of expression as used herein enzyme (mitotic division enzyme A, mitotic division enzyme B and mitotic division enzyme C).Such illness without stint comprises that cancer is such as colorectum, Tiroidina and mammary cancer; And myeloproliferative disease, such as polycythemia vera, thrombocythemia, myeloid metaplasia, chronic granulocytic leukemia (CML), chronic myelomonocytic leukemia, HES, teenager's monocytic leukemia and systemic mast cell disease with myelofibrosis.

[0089] in some embodiment, " significant quantity " of compound or pharmaceutically acceptable composition is effectively to measure in order to treat described disease.Can utilize according to the compound of the inventive method and composition and just to treat described disease or to alleviate with regard to its seriousness effective any amount and in addition administration of route of administration arbitrarily.In some embodiment, described disease is selected from dementia that transformation reactions or the anaphylaxis of I type, asthma, diabetes, Alzheimer, Huntington Chorea, Parkinson's disease, AIDS-occur together, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig disease), multiple sclerosis (MS), schizophrenia, leukopenia, myocardial cell's hypertrophy, perfusion/local asphyxia, apoplexy, alopecia, transplant rejection, graft versus host disease (GVH disease), rheumatoid arthritis and firm and haematological malignancies again.In some embodiment, described disease is selected from diabetes, bipolar disorder, schizophrenia, apoplexy, Huntington Chorea, leukopenia and myocardial cell's hypertrophy.

[0090] in other embodiments of the present invention, described disease is protein kinase mediated illness.In some embodiment, described protein kinase is GSK-3.

[0091] known protein kinases any disease or other harmful illnesss of figure therein represented in term used herein " illness of protein kinase-mediation ".This class illness comprises disease, immunodeficiency disorder, immunity modulation or immunosuppression illness, osteopathia, metabolic trouble, neural and neurodegenerative disease, cardiovascular disorder, hormone relative disease, diabetes, transformation reactions, asthma and the Alzheimer of autoimmune disease, inflammatory diseases, propagation and hyperproliferation disease, immunology-mediation without limitation.

[0092] any disease or other harmful illnesss that GSK-3 works therein represented in term used herein " illness of GSK-3-mediation ".Such illness without stint comprises, the dementia that diabetes, Alzheimer, Huntington Chorea, Parkinson's disease, AIDS-occur together, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig disease), multiple sclerosis (MS), schizophrenia, leukopenia, myocardial cell's hypertrophy, apoplexy and rheumatoid arthritis.

[0093] in some embodiment, described compound is used for treating diabetes by promoting cell regeneration.

[0094] in other embodiments, described compound is used for treating the apoplexy recovery.In some situation, described compound is used for administration after the apoplexy.The treatment phase can be one month to 1 year.

[0095] in going back other embodiment, described compound is used for treating osteoporosis by scleroblast.

[0096] also will be figured out, some The compounds of this invention can exist for treatment with free form, perhaps takes the circumstances into consideration to be its pharmacy acceptable salt or pharmaceutically acceptable derivates.

[0097] should understand mixtures/combinations and the compound of free form and the mixtures/combinations of pharmacy acceptable salt that the present invention includes different pharmacy acceptable salts.

[0098] as described herein, pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, auxiliary agent or vehicle in addition, just as used herein, they comprise be suitable for required particular dosage form arbitrarily and all solvents, thinner or other liquid excipients, dispersion or suspension aids, tensio-active agent, isotonic agent, thickening or emulsifying agent, sanitas, solid binder, lubricant etc.Remington ' s Pharmaceutical Sciences, the 16 edition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1980) known technology that is used to prepare the various carriers of pharmaceutically acceptable composition and is used for its preparation is disclosed.Except any conventional mounting medium is incompatible with The compounds of this invention, for example produce any worthless biological effect or interact in any other component of pharmaceutically acceptable composition in harmful mode, its use is contained within the scope of the invention.

[0099] some examples that can serve as the material of pharmaceutically acceptable carrier include but not limited to ion-exchanger; Aluminum oxide; Aluminum stearate; Yelkin TTS; Serum protein, for example human serum albumin; Buffer substance, for example phosphoric acid salt; Glycine; Sorbic Acid or potassium sorbate; The partial glyceride mixture of saturated vegetable fatty acid; Water; Salt or ionogen, for example protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt; Colloid silica; Magnesium Trisilicate; Polyvinylpyrrolidone; Polyacrylic ester; The wax class; Polyethylene-polyoxytrimethylene-block polymer; Lanolin; Carbohydrate, for example lactose, dextrose plus saccharose; Starch, for example W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and rhodia; The tragacanth gum of pulverizing; Fructus Hordei Germinatus; Gelatin; Talcum; Vehicle, for example theobroma oil and suppository wax; Oils, for example peanut oil, Oleum Gossypii semen, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycol, for example propylene glycol or polyoxyethylene glycol; Ester class, for example ethyl oleate and Laurate ethyl; Agar; Buffer reagent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline solution; Ringer's solution; Ethanol; Phosphate buffer soln; And other nontoxic compatible lubricant, for example Sodium Lauryl Sulphate BP/USP and Magnesium Stearates; According to preparation personnel's judgement, in composition, also can exist toner, releasing agent, Drug coating, sweeting agent, seasonings and spices, sanitas and antioxidant.

[00100] kinases inhibitor or its drug salts can be formulated into pharmaceutical composition, to animal or human's administration.These pharmaceutical compositions comprise the kinases inhibitor and the pharmaceutically acceptable carrier of effective treatment or prevention kinases-mediation illness amount, are another embodiment of the invention.In some embodiment, the illness of described protein kinase-mediation is the illness of GSK-3-mediation.It in some embodiment the illness of GSK-3-mediation.

[00101] the definite amount of treatment required compound will be different because of the curee, depend on seriousness, the certain drug of curee's kind, age and general state, infection, the mode of its administration etc.The compounds of this invention preferably is formulated into dosage unit form, and the consistence of administration of being easy to and dosage is arranged.The drug unit that phraseology used herein " dosage unit form " expression is physically discrete is suitable for the patient who is treated.But will be appreciated, total every day of the consumption of The compounds of this invention and composition will reasonably determined in the medical judgment scope by the attending doctor.The concrete effective dose level of any specific patient or organism will depend on multiple factor, comprise the illness of being treated and the seriousness of illness; The activity of the particular compound that is adopted; The concrete composition that is adopted; Patient's age, body weight, general health situation, sex and diet; The discharge rate of the approach of time of administration, administration and the particular compound that is adopted; The time length of treatment; With particular compound associating of being adopted or the medicine that uses simultaneously; Other factors of knowing with field of medicaments.Term used herein " patient " expression animal, preferred mammal, optimum is chosen.

[00102] pharmaceutically acceptable composition of the present invention can be oral to people and other animals, in the rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (with pulvis, ointment or drops), oral cavity, with mouth with or mode administration such as nasal spray, this depends on the seriousness that infection is treated by institute.In some embodiment, The compounds of this invention can be by oral or administered parenterally, dosage level be every day about 0.01mg/kg to about 50mg/kg, preferred about 1mg/kg about 25mg/kg curee's body weight extremely, once a day or repeatedly, to obtain required result of treatment.

[00103] liquid dosage form of oral administration includes but not limited to pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.Except active compound, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent, for example ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, phenylformic acid benzyl ester, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, wheat germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and the fatty acid ester of anhydro sorbitol and their mixture.Except inert diluent, oral compositions also can comprise auxiliary agent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and spices.

[00104] uses dispersion or wetting agent and the suspension agent that is fit to, can prepare the injectable prepared product according to known technique, for example the water-based of sterile injectable or oiliness suspension.The sterile injectable prepared product also can be at nontoxic parenteral acceptable diluent or sterile injectable solution, suspension or the emulsion in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's solution, U.S.P. and isotonic sodium chlorrde solution.In addition, routine adopts aseptic fixed oil as solvent or suspension medium.For this reason, can adopt the fixed oil of any gentleness, comprise synthetic list-or two-glyceryl ester.In addition, in the preparation of injection, also can use lipid acid, for example oleic acid.

[00105] injectable formulation can be sterilized like this, for example filters by the bacterium property held back filter, perhaps mixes the disinfectant of aseptic solid composite form, can be before use with its dissolving be dispersed in aseptic water or other sterile injectable medium in.

[00106] in order to prolong the effect of The compounds of this invention, often need delay the absorption of compound after subcutaneous or intramuscularly.This can utilize the crystallinity of poorly water-soluble or the liquid suspension of amorphous substance to realize.The uptake rate of compound depends on its dissolution rate, and the latter may be depended on crystallographic dimension and crystal formation.Instead select, with compound dissolution or be suspended in the oils carrier, realize that the delay of administered parenterally compound form absorbs.Injectable depot forms is like this preparation, and in Biodegradable polymeric, polylactide-polyglycolide for example generates the microencapsulation matrix of compound.According to the ratio of compound and polymkeric substance and the attribute of the particular polymers that adopts, can control the rate of release of compound.The example of other biological degradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).The depot injectable formulation also can prepare the compound inclusion in liposome compatible with body tissue or micro emulsion.

[00107] rectum or vagina administration composition suppository preferably, they can prepare like this, The compounds of this invention is mixed with the nonirritant excipient or the carrier that are fit to, for example theobroma oil, polyoxyethylene glycol or suppository wax, they are solid at ambient temperature, but under body temperature, be liquid, therefore in rectum or vaginal canal, melt, discharge active compound.

[00108] solid dosage of oral administration comprises capsule, tablet, pill, pulvis and granule.In this class solid dosage, active compound is mixed with pharmaceutically acceptable vehicle of at least a inert or carrier, for example Trisodium Citrate or Lin Suanergai, and/or a) weighting agent or expanding material, starch for example, lactose, sucrose, glucose, mannitol and silicic acid, b) tackiness agent, carboxymethyl cellulose for example, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) wetting agent, glycerine for example, d) disintegrating agent, for example agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash, e) dissolving retarding agent, paraffin for example, f) absorption enhancer, for example quaternary ammonium compound, g) wetting agent, for example hexadecanol and Zerol, h) absorption agent, for example kaolin and wilkinite, and i) lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and composition thereof.Under the situation of capsule, tablet and pill, described formulation also can comprise buffer reagent.

[00109] solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft or hard filling, and the capsule used excipient is lactose or toffee and high molecular weight polyethylene glycol etc. for example.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example other dressings of knowing of enteric coating and medicine formulation art.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.The solids composition that also can adopt similar type is as the weighting agent in the gelatine capsule agent of soft and hard filling, and the capsule used excipient is lactose or toffee and macromolecule polyethylene glycol etc. for example.

[00110] active compound also can be the form of microencapsulation, wherein contains one or more above-mentioned vehicle.Solid dosages such as tablet, lozenge, capsule, pill and granule can have dressing and shell, for example enteric coating, discharge other dressings that controlled dressing and medicine formulation art are known.In this class solid dosage, active compound can be mixed with at least a inert diluent, for example sucrose, lactose or starch.Under normal circumstances, this class formulation also can comprise other materials except that inert diluent, for example compressing tablet lubricant and other compression aids, for example Magnesium Stearate and Microcrystalline Cellulose.Under the situation of capsule, tablet and pill, formulation also can comprise buffer reagent.They can contain opalizer alternatively, also can be only or preferentially at the composition of a part of release of active ingredients of enteron aisle, alternatively the mode for postponing.The example of operable embedding composition comprises polymeric material and wax class.

[00111] part of The compounds of this invention or transdermal administration formulation comprise ointment, paste, creme, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.Active ingredient is mixed with pharmaceutically acceptable carrier and any essential sanitas or buffer reagent under aseptic condition, decide as required.Ophthalmic preparation, ear drop and eye drops also covered in the scope of the present invention.In addition, the use of transdermal patch is contained in the present invention, and they have the attendant advantages that the control compound is sent to body.This class formulation can be by with compound dissolution or be dispersed in the appropriate medium and prepare.Also can use absorption enhancer to increase the flux that compound passes skin.Can control speed by rate controlling membranes being provided or compound being dispersed in polymeric matrix or the gel.

[00112] except compound of the present invention, in treatment or prevent also can adopt in the composition of above-mentioned illness the pharmaceutically acceptable derivates or the prodrug of The compounds of this invention.

[00113] salt or other derivatives of any pharmacy acceptable salt of " pharmaceutically acceptable derivates or prodrug " expression The compounds of this invention, ester, ester can directly or indirectly provide The compounds of this invention or its to suppress active metabolite or resistates after to recipient's administration.Desirable especially derivative and prodrug are such, they increase the bioavailability (for example allowing the easier absorption of compound of oral administration to enter blood) of The compounds of this invention during to the Mammals administration at this compounds, perhaps strengthen send (for example brain or the lymphsystem) of parent compound to body cavity of organism with respect to the parent kind.

[00114] the pharmaceutically acceptable prodrug of The compounds of this invention comprises ester, amino acid ester, phosphoric acid ester, metal-salt and sulphonate without limitation.

[00115] the pharmaceutically acceptable carrier that can be used in these compositions includes but not limited to ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein (for example human serum albumin), buffer substance (for example phosphoric acid salt), glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen (for example protamine sulfate), Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silica, Magnesium Trisilicate, polyvinylpyrrolidone, cellulose substances, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, the wax class, polyethylene-polypropylene-block polymer, polyoxyethylene glycol and lanolin.

[00116] administration of the present composition can be oral, parenteral, suction spraying, part, rectum, nose, cheek, vagina or via implanting bank.That term used herein " parenteral " comprises is subcutaneous, in the intravenously, intramuscular, intraarticular, synovial membrane, in the breastbone, in the sheath, in the liver, in the damage location and intracranial injection or infusion techniques.Preferably, composition is oral, intraperitoneal or intravenous administration.

[00117] the sterile injectable formulation of the present composition can be water-based or oiliness suspension.These suspensions can use suitable dispersion or wetting agent and suspension agent to be prepared according to technology known in the art.Sterile injectable preparation also can be at nontoxic parenteral acceptable diluent or sterile injectable solution or the suspension in the solvent, for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's solution and isotonic sodium chlorrde solution.In addition, routine adopts aseptic fixed oil as solvent or suspension medium.For this reason, can adopt the fixed oil of any brand, comprise synthetic list-or two-glyceryl ester.Lipid acid, for example oleic acid and glyceride derivative thereof can be used for preparing injection, because they are natural pharmaceutically acceptable oil, and for example sweet oil or Viscotrol C, especially their polyoxy ethylization form.These oil solutions or suspension also can contain long-chain alcohol thinner or dispersion agent, for example carboxymethyl cellulose or similar dispersion agent, and they are usually used in preparing pharmaceutically acceptable formulation, comprise emulsion and suspension.For the purpose of preparation, also can use other tensio-active agents commonly used, for example Tweens, spans and other emulsifying agents or bioavailability toughener, they are usually used in making pharmaceutically acceptable solid, liquid or other formulations.

[00118] pharmaceutically acceptable composition of the present invention can be taken orally, and any oral acceptable forms includes but not limited to capsule, tablet, aqueous suspensions or solution.With under the situation of tablet, carrier commonly used comprises lactose and W-Gum at mouth.Usually also add lubricant, for example Magnesium Stearate.With regard to the oral capsule administration, useful thinner comprises lactose and exsiccant W-Gum.Very moment mixes activeconstituents during with the needs aqueous suspensions with emulsifying and suspending agent.If necessary, also can add some sweeting agent, correctives or tinting material.

[00119] instead select, pharmaceutical composition of the present invention can be with the suppository form administration, for rectal administration.They can prepare like this, and medicine is mixed with the nonirritant excipient that is fit to, and the latter at room temperature is a solid, but is liquid under rectal temperature, therefore will melt at internal rectum, discharges medicine.This class material comprises theobroma oil, beeswax and polyoxyethylene glycol.

[00120] pharmaceutical composition of the present invention also can topical, especially when therapeutic goal comprises local application easy to reach position or organ, comprises the disease of eye, skin or lower intestinal tract.The topical formulations that is fit to is prepared according to each these position or organ easily.

[00121] lower intestinal tract local application can utilize rectal suppository (on seeing) or suitable enema to carry out.Also can use the topical transdermal patch.

[00122] with regard to local application, pharmaceutical composition can be formulated in the suitable ointment, wherein contains to suspend or be dissolved in active ingredient in one or more carriers.The topical carrier of The compounds of this invention includes but not limited to mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Instead select, pharmaceutical composition can be formulated into suitable lotion or creme, wherein contains to suspend or be dissolved in active ingredient in one or more pharmaceutically acceptable carriers.The carrier that is fit to includes but not limited to mineral oil, Arlacel-60, polysorbate60, spermaceti ester type waxes, cetostearyl alcohol, 2-Standamul G, benzyl alcohol and water.

[00123] with regard to eye with regard to, pharmaceutical composition can be formulated into micronization suspension or the solution in the Sterile Saline of isoosmotic pH regulator preferably in the Sterile Saline of isoosmotic pH regulator, the two all contains or does not have sanitas, for example a benzalkonium chloride.Instead select, with regard to eye was used, pharmaceutical composition can be formulated in the ointment, for example vaseline.

[00124] pharmaceutical composition of the present invention also can pass through nose aerosol or inhalation administration.This based composition is to prepare according to the technology that field of pharmaceutical preparations is known, can make salt brine solution, adopt absorption enhancer, fluorocarbon and/or other the conventional solubilizing agent or the dispersion agent of phenylcarbinol or other sanitass that is fit to, raising bioavailability.

[00125] can merge the amount of the kinase inhibitor make single formulation with solid support material will be different because of the host that treated, specific administering mode.Preferably, composition should be preparation like this, so that can give the inhibitor of dosage between the 0.01-100mg/kg body weight/day to the patient who accepts these compositions.

[00126] also is to be understood that, concrete dosage and treatment system with regard to any particular patient will depend on multiple factor, comprise activity, age, body weight, general health situation, sex, diet, administration time, discharge rate, drug regimen, attending doctor's judgement and the seriousness of the specified disease for the treatment of of the particular compound that is adopted.The amount of inhibitor also will depend on the specific compound in the composition.

[00127] in other embodiments, the invention provides the method for treatment or prophylaxis of protein kinase-mediation illness (in some embodiment, being GSK-3-mediation illness), comprise the step that the patient is given one of aforementioned pharmaceutical compositions.Term used herein " patient " expression animal, preferred people.

[00128] in some embodiment, this method is used for the treatment of or prevents to be selected from following illness: cancer, for example the cancer of mammary gland, colon, prostate gland, skin, pancreas, brain, urogenital tract, lymphsystem, stomach, larynx and lung comprises adenocarcinoma of lung and small cell lung cancer; Apoplexy, diabetes, melanoma, hepatomegaly, megalocardia, Alzheimer, cystic fibrosis and virus disease, perhaps above-mentioned any specific disease or illness.

[00129] in other embodiments, this method is used for treating or prevent to be selected from the illness of dementia, bipolar disorder, amyotrophic lateral sclerosis (ALS, Lou Gehrig disease), multiple sclerosis (MS), schizophrenia, leukopenia, myocardial cell's hypertrophy, apoplexy or rheumatoid arthritis that diabetes, Alzheimer, Huntington Chorea, Parkinson's disease, AIDS-occur together.

[00130] in some embodiment, this method is used for treating diabetes by cell regeneration.

[00131] in other embodiments, this method is used for treating the apoplexy recovery.In some situation, said composition is used for administration after the apoplexy.The treatment phase can be one month to 1 year.

[00132] in going back other embodiment, said composition is used for treating osteoporosis by scleroblast.

[00133] another aspect of the present invention relates to the protein kinase activity that suppresses among the patient, and this method comprises this patient's giving construction I compound or comprises described compound compositions.

[00134] depends on the specific protein kinase-mediation illness that to treat or to prevent, under normal circumstances drug treatment or prevent the medication of this illness can be with inhibitor administration of the present invention.For example, chemotherapeutics or other anti-proliferating agents can with kinases inhibitor combination therapy hyperplasia of the present invention.

[00135] these medications can with compound that contains kinases inhibitor or composition separate administration, as the part of polynary dosage regimen.Instead select, these medicines can be the parts of single formulation, are mixed together in the single composition with kinases inhibitor.

[00136] in some embodiment, described kinases inhibitor is the GSK-3 kinase inhibitor.

[00137] the present invention also can be used in those methods that do not involve patient's administration.

[00138] The compounds of this invention generally can be prepared by method known to those skilled in the art.These compounds can include but not limited to LCMS (liquid chromatography mass) and NMR (nucleus magnetic resonance) by the currently known methods analysis.The compounds of this invention also can be tested according to these embodiment.Should be appreciated that down and show that actual conditions only is example, does not represent to limit the scope that can be used in preparation, analyzes or test the condition of The compounds of this invention.On the contrary, the present invention comprises that also those skilled in the art become known for preparing, analyzing and test the condition of The compounds of this invention.

Embodiment

[00139] term used herein " Rt (branch) expression HPLC or LCMS retention time, in minute, relevant with compound.

[00140] unless indication is arranged in addition, the HPLC method that is used to obtain the retention time reported is as follows:

Pillar: ACE C8 post, 4.6x150mm

Gradient: 0-100% acetonitrile+methyl alcohol 60: 40 (20mM Tris phosphoric acid salt)

Flow velocity: 1.5mL/ branch

Detect: 225nm.

[00141] on MicroMass Quattro Micro mass spectrograph, analyzes mass spectrum sample, work in the single MS pattern of using electro-spray ionization.Utilize chromatography to introduce sample to mass spectrograph.The moving phase that is used for whole mass spectroscopy is that composition is ammonium acetate and 1: 1 acetonitrile-carbinol mixture of 10mM pH 7, and the post gradient condition is 5%-100% acetonitrile-methyl alcohol and 5 minute working time on ACE C8 3.0x75mm post in 3.5 minutes gradient time.Flow velocity is the 1.2ml/ branch.

[00142] utilizes Bruker DPX 400 instruments record under 400MHz ¹H-NMR spectrum.Be prepared as follows and analyze following formula I compound.

Intermediate 1

Hexanaphthene formyl imines amide hydrochloride

Under [00143] 0 ℃, under agitation (60g is 550mmol) at MeOH (33ml) and Et by cyclohexane nitrile with the hydrogen chloride gas bubbling ₂Solution in the mixture of O (150ml).Bubbling 1 as a child moves to refrigerator with flask, spends the night.Use Et then ₂The O diluted reaction mixture filters the gained solid.Thick solid is dissolved in the mixture of the ethanolic soln (100mL) of ethanol (400mL) and 2N ammonia.The ammonia bubbling was passed through this suspension 1 hour, then reaction mixture is moved to refrigerator, spend the night.Filter reaction mixture charges into viscous solid in the flask with methyl alcohol.Vacuum concentrated mixture adds Et ₂O crosses filter solid.This solid is dissolved in methyl alcohol again, concentrates until solid and begin precipitation, add Et in this stage ₂O.Crossing filter solid, place high vacuum to spend the night, provide title compound, is solid (87.8g, 98%). ¹H?NMR：(DMSO)1.00-1.88(10H，m)，2.35-2.57(1H，m)，8.86(1H，s)，9.02(1H，s)。

Intermediate 2

2-cyclohexyl pyrimidine-4, the 6-glycol

[00144] under the envrionment temperature, under agitation use diethyl malonate (6.1mL, 40.2mmol) handle sodium ethylate ethanolic soln [by with sodium (2.12g 92.2mmol) is dissolved in ethanol (200mL) prepared beforehand].Then at room temperature, under agitation drip hexanaphthene formyl imines amide hydrochloride (5g, ethanol 31mmol) (100mL) solution.Add when finishing, the reacting by heating mixture is 8 hours under refluxing, and placement is spent the night.The vacuum concentration reaction mixture adds water, with 2N HCl with pH regulator to pH 7-8.Filtering the solid that gained forms, with the ether washing, provide title compound, is solid (5.53g, 93%).MS(ES+)m/e＝195。 ¹H?NMR：(DMSO)1.09-1.81(10H，m)，2.40-2.53(1H，m)，5.09(1H，s)，11.61(2H，brs)。

Intermediate 3

4,6-two chloro-2-cyclohexyl pyrimidines

[00145] heating contains 2-cyclohexyl pyrimidine-4 under refluxing, the 6-glycol (5.53g, 28.5mmol) and phosphoryl chloride (70mL, mixture 751mmol) 3 hours is cooled to room temperature and vacuum concentration subsequently.Then with ice-water, saturated NaHCO ₃Handle formed semisolid, use Et ₂The O extraction, dry (Na ₂SO ₄) and vacuum concentration.Institute's resistates that obtains provides title compound by column chromatography (EtOAc/ gasoline, 1/9 wash-out) purifying, is oily matter (5.74g, 87%).MS(ES+)m/e＝231。 ¹H?NMR：(DMSO)1.15-2.00(10H，m)，2.70-2.84(1H，m)，7.86(1H，s)。

Intermediate 4

N-(6-chloro-2-cyclohexyl pyrimidine-4-yl)-5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-amine

[00146] THF (5.46mL of usefulness 1M two (trimethyl silyl) Lithamide, 5.46mmol) solution dropwise handles and be cooled to-60 ℃ and comprise 4,6-two chloro-2-cyclohexyl pyrimidine (505mg, 2.19mmol), 5-fluoro-1H-pyrazolo [3,4-b] and pyridine-3-amine (400mg, 2.63mmol) and the mixture of THF (20mL).Make reaction mixture be warmed to 0 ℃ in 1 hour, add water subsequently.Reaction mixture distributes between water and EtOAc, with saturated NaCl solution washing, and dry (Na ₂SO ₄), vacuum concentration.Institute's resistates that obtains provides title compound by column chromatography (MeOH/DCM, 5/95 wash-out) purifying, is solid (380mg, 50%).MS(ES+)m/e＝347。 ¹H?NMR：(DMSO)1.10-1.96(10H，m)，2.56-2.69(1H，m)，7.65(1H，brs)，8.27-8.39(1H，m)，8.58(1H，s)，10.72(1H，s)，13.34(1H，s)。

Embodiment 1

N-(6-(azetidine-1-yl)-2-cyclohexyl pyrimidine-4-yl)-5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-amine

[00147] in microwave, heating contains N-(6-chloro-2-cyclohexyl pyrimidine-4-yl)-5-fluoro-1H-pyrazolo [3 under 125 ℃, 4-b] pyridine-3-amine (78mg, 0.22mmol), N, N-diisopropylethylamine (158 μ L, 0.91mmol), azetidine (45 μ L, 0.67mmol) and the mixture of propyl carbinol (6mL) 20 minutes.Reaction mixture is cooled to room temperature, filters the gained solid, use Et ₂O, saturated NH ₄Cl and Et ₂O washs solid.Dry air gained solid provides title compound, is white solid (48mg, 58%).MS(ES+)m/e＝368。 ¹H?NMR：(DMSO)1.08-1.92(10H，m)，2.26-2.58(3H，m)，3.89-4.06(4H，m)，6.50(1H，brs)，8.32-8.62(2H，m)，9.79(1H，s)，13.03(1H，s)

[00148] following compound is according to the method preparation that is used for preparing Compound I-1.

Embodiment 2

[00149] the total synthetic flow process that is used for synthetic 5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-amine (5a) is described below.

Reagent and condition: i.Pd (OAc) ₂ , PPh ₃ , Et ₃ N, H ₂ CO ₂ Ii.1) (COCl) ₂ , CH ₂ Cl ₂ , catalytic amount DMF; 2) NH ₃ (g), dioxane, iii.TFAA, Et ₃ N, CH ₂ Cl ₂ , 0 ℃; Iv.H ₂ NNH ₂ .H ₂ O, propyl carbinol, backflow.

2-chloro-5-fluorine nicotinic acid (6a)

[00150] to N ₂Add the degassing DMF (270mL), Pd (OAc) in the round-bottomed flask under the atmosphere ₂(0.05 equivalent, 2.7g, 11.9mmol), PPh ₃(0.1 equivalent, 6.2g, 23.8mmol) and degassing Et ₃N (6 equivalents, 200mL, 1428.6mmol).Stirred the mixture 20 minutes, (3 equivalents, 28mL 714.3mmol), add 2 after 5 minutes, and (50g 238.1mmol), stirs this mixture down at 50 ℃ in 6-two chloro-5-villiaumite acid to add HCOOH subsequently.Follow the tracks of reaction by analyzing (1H NMR) treated sample.(24 hours) are cooled to 0 ℃ with mixture after whole raw materials exhaust, and add water (500mL).After 20 minutes, mixture is filtered C salt pad, the water flushing.With the 30%NaOH aqueous solution mixture is alkalized to pH 9, with EtOAc (2x) washing.Slowly adding HCl (12N) is 1 up to pH, with saturated this solution of NaCl.Extract this mixture with EtOAc (3x).The organic extract salt water washing that merges, dry (Na ₂SO ₄), concentrating under reduced pressure provides 37g (88%) beige solid, does not add to be further purified to be used for subsequent step.

¹H?NMR(DMSO-d ₆，300MHz)：δ8.16(dd，1H)；8.58(d，1H)。

2-chloro-5-fluorine niacinamide (3a)

[00151] under 0 ℃, to 2-chloro-5-fluorine nicotinic acid 6a (50g, 285mmol) and DMF (2mL, drip in DCM 28mmol) (400mL) solution oxalyl chloride (64mL, 741mmol).At room temperature stirred reaction mixture spends the night, vacuum concentration.The gained yellow liquid is dissolved in 1, and 4-dioxane (600mL) is cooled to 0 ℃, with NH ₃(g) bubbling passed through this solution 30 minutes.Mixture at room temperature stirred spend the night.Filter the gained mixture, concentrated filtrate provides compound 3a (44g, 89%), is beige solid. ¹H?NMR(DMSO-d ₆，300MHz)：δ7.84(s，1H)，7.96(dd，1H)，8.09(s，1H)，8.49(d，1H)。

2-chloro-5-fluorine nicotine nitrile (nicotinonitrile) (4a)

[00152] with crude compound 3a (65g, 372.4mmol) and Et ₃N (114mL, DCM 819.2mmol) (700mL) suspension is cooled to 0 ℃, dropping TFAA (57mL, 409.6mmol).Stirred the gained yellow solution 90 minutes down at 0 ℃,, use saturated NaHCO with the DCM dilution ₃The aqueous solution and salt water washing, dry (Na ₂SO ₄).Filtering mixt also concentrates.The Kugel Rohr distillation (～70 ℃/1 millibar) of resistates provides 50g (86%) compound 4a, is beige solid.Compound 4a also can pass through column chromatography (SiO ₂, 8: 1 heptane: EtOAc) purifying. ¹H?NMR(CDCl ₃，300MHz)：δ7.78(dd，1H)；8.49(d，1H)。

5-fluoro-1H-pyrazolo [3,4-b] pyridine-3-amine (5a)

[00153] (50g, 321.7mmol) 1-butanols (1L) solution add the hydrazine monohydrate, and (150mL, 3.2mol), this mixture 4 hours refluxes to compound 4a.Mixture is cooled to room temperature and concentrated.Water (2x) and Et on strainer subsequently ₂O (2x) washing precipitation, vacuum-drying is spent the night, and provides compound 5a (44g, 88%), is yellow solid. ¹H?NMR(DMSO-d ₆，300MHz)：δ5.53(s，2H)；7.94(dd，1H)；8.35(dd，1H)；12.02(s，1H)。

Embodiment 3:GSK-3 suppresses test:

[00154] the screening The compounds of this invention suppresses the active ability of GSK-3 β (AA 1-420), uses standard coupling enzyme system people such as (, Protein Sci.1998,7,2249) Fox.Be reflected at and contain 100mM HEPES (pH 7.5), 10mM MgCl ₂, 25mM NaCl, 300 μ MNADH, 1mM DTT and 1.5%DMSO solution in carry out.Final concentration of substrate in test be 20 μ M ATP (Sigma Chemicals, St Louis, MO) and 300 μ M peptides (American Peptide, Sunnyvale, CA).React down and under the 20nM GSK-3 β at 30 ℃.The final concentration of component of described coupling enzyme system is 2.5mM phosphoenolpyruvic acid, 300 μ M NADH, 30 μ g/m l pyruvate kinases and 10 μ g/ml serum lactic dehydrogenases.

[00155] formation determination deposit buffered soln wherein contains whole reagent of as above enumerating, except ATP and the test compound of the present invention.Under 30 ℃, in 30 μ M scopes, in 96 orifice plates, will test deposit buffered soln (175 μ l) and 5 μ l test compound incubation of the present invention 10 minutes at ultimate density 0.002 μ M.Usually, by in daughter board, preparing the serial dilutions of test compound of the present invention, carry out 12 titration with DMSO (from 10mM compound storing solution).By adding 20 μ l Triphosadens (ultimate density 20 μ M) initiation reaction.(Sunnyvale CA) obtains speed of reaction at 30 ℃ in following 10 minutes with MolecularDevices Spectramax plate reader.The inhibitor concentration function of through-rate data is determined K _iValue.Find that Compound I-1 and I-2 suppress GSK-3, Ki value＜50nM.Find that Compound I-3 suppresses GSK-3, the Ki value is between 50 to 100nM.

[00156] although we have described a large amount of embodiment of the present invention, but obviously can change our basic example, other employings to be provided or to contain the embodiment of The compounds of this invention, method and process.So, should understand the scope of the invention and define by appended claims.

Claims

1. formula I compound:

Or its pharmacy acceptable salt, wherein:

Ht is

X is sulphur, oxygen or NR ²';

Y is nitrogen or CR ²

R ^XBe T ¹-R ³

R ^YBe T ²-R ¹⁰

T, T ¹And T ³Be key or C independently of one another _1-4Alkylidene chain;

R is selected from the C that is selected from of hydrogen or optional replacement independently of one another _1-6Aliphatic series, C _6-10Aryl, have the heteroaryl ring of 5-10 annular atoms or have the group of the heterocyclic ring of 4-10 annular atoms; R is separately alternatively by 0-5 R ⁹Replace;

J, J ⁶And J ⁸Independently be separately-halogeno-group ,-OR, oxo, C _1-6Aliphatic series ,-C (=O) R ,-CO ₂R ,-COCOR, COCH ₂COR ,-NO ₂,-CN ,-S (O) R ,-S (O) ₂R ,-SR ,-N (R ⁴) ₂,-CON (R ⁷) ₂,-SO ₂N (R ⁷) 2 ,-OC (=O) R ,-N (R ⁷) COR ,-N (R ⁷) CO ₂(C _1-6Aliphatic series) ,-N (R ⁴) N (R ⁴) ₂,=NN (R ⁴) ₂,=N-OR ,-N (R ⁷) CON (R ⁷) ₂,-N (R ⁷) SO ₂N (R ⁷) ₂,-N (R ⁴) SO ₂R or-OC (=O) N (R ⁷) ₂

2. according to the compound of claim 1, wherein Ht is

3. according to the compound of claim 1, wherein Ht is

4. according to the compound of claim 3, wherein X is N.

5. according to the compound of claim 4, wherein Y is N.

6. according to the compound of claim 4, wherein Y is CR ²

7. according to the compound of claim 3, wherein X is that S and Y are CR ²

8. according to each compound among the claim 1-7, wherein Z ¹And Z ²All be nitrogen.

9. according to each compound among the claim 1-7, wherein Z ¹Be nitrogen and Z ²Be CH.

10. according to each compound among the claim 1-7, wherein Z ¹Be CR ⁹And Z ²Be nitrogen.

11. each compound, wherein R according to Claim 8-10 ²' be hydrogen or methyl.

12. according to the compound of claim 11, wherein R ²' be hydrogen.

13. according to the compound of claim 11 or claim 12, R ²Be T ³-W-R ⁶Or R, wherein W is-C (R ⁶) ₂O-,-C (R ⁶) ₂N (R ⁶)-,-CO-,-CO ₂-,-C (R ⁶) ₂OC (O)-,-C (R ⁶) ₂N (R ⁶) CO-,-C (R ⁶) ₂N (R ⁶) C (O) O-or-CON (R ⁶)-, and R is the C that is selected from of optional replacement _1-6Aliphatic series or phenyl groups.

14. according to the compound of claim 11 or claim 12, wherein R ²Be hydrogen or be selected from aryl, heteroaryl or C _1-6The group that be substituted or that be unsubstituted of aliphatic group.

15. according to the compound of claim 14, wherein R ²Be hydrogen or be selected from aryl or C _1-6The group that be substituted or that be unsubstituted of aliphatic group.

16. according to each compound among the claim 1-10, wherein R ²And R ²' form unsaturated 6-unit's carbocyclic ring of the benzo, pyrido, Mi Dingbing or the part that are substituted or be unsubstituted and ring with the atom that separates them.

17. according to the compound of claim 16, wherein R ²And R ²' form benzo or the pyrido ring that is substituted or be unsubstituted with the atom that separates them.

18. according to the compound of claim 17, wherein said benzo or pyrido ring are replaced by 1-2 halogeno-group substituting group.

19. each compound, wherein R according to Claim 8-18 ^XBe hydrogen, C _1-4Aliphatic series or halogeno-group.

20. according to the compound of claim 19, wherein R ^XBe hydrogen, methyl, ethyl, cyclopropyl or sec.-propyl.

21. according to the compound of claim 20, wherein R ^XBe hydrogen.

22. each compound, wherein R according to Claim 8-21 ^YRepresent by formula ii-a:

23. each compound, wherein R according to Claim 8-21 ^YBe T ²-R ¹⁰, T wherein ²It is key.

24. according to the compound of claim 23, wherein R ¹⁰It is the azetidine of optional replacement.

25. according to the compound of claim 24, wherein R ^YRepresent by formula i:

26. according to the compound of claim 24, wherein R ^YRepresent by formula iii:

27. each compound according to Claim 8-26, wherein encircling D is the ring of optional replacement, be selected from piperidyl, piperazinyl, pyrrolidyl, morpholinyl, 1,2,3,4-tetrahydro isoquinolyl, 1,2,3,4-tetrahydric quinoline group, 2,3-dihydro-1H-pseudoindoyl, 2,3-dihydro-1H-indyl or isoquinolyl.

28. each compound according to Claim 8-26, wherein encircling D is tetralyl, Ben Bing dioxin base, indanyl, indoline base or the isoquinolyl of optional replacement.

29. each compound according to Claim 8-26, wherein encircling D is cyclohexyl.

30. the compound of claim 1 is selected from:

31. a composition comprises according to each compound and pharmaceutically acceptable carrier, auxiliary agent or media among the claim 1-30.

32. compound according to claim 31, comprise the reagent that is selected from chemotherapy or antiproliferative, anti-inflammatory agent, immune modulation or immunosuppressor, neurotrophic factor, is used for the treatment of cardiovascular disorder, the reagent that is used for the treatment of diabetes in addition, perhaps be used for the treatment of the therapeutical agent of the reagent of immune deficiency illness.

Exist 33. use according to each compound among the claim 1-30 Take from live bodyOr Live ExternalBiological sample in suppress the active method of GSK-3.

34. treatment is selected from dementia, bipolar disorder, amyotrophic lateral sclerosis (ALS that diabetes, Alzheimer, Huntington Chorea, Parkinson's disease, AIDS-occur together, Lou Gehrig disease), the disease or the illness of multiple sclerosis (MS), schizophrenia, leukopenia, myocardial cell's hypertrophy, apoplexy and rheumatoid arthritis or alleviate the method for its seriousness, comprise to described patient's administration according to claim 1-30 in each the step of compound.

35. the method for claim 34, wherein said disease is an apoplexy.

36. the method for claim 34, wherein said disease is diabetes.

37. the method for claim 34, wherein said disease is a schizophrenia.

38. the method for claim 34, wherein said disease is a bipolar disorder.

39. the method for claim 34, comprise to described patient's administration and be selected from the reagent that is used for the treatment of diabetes, the reagent that is used for the treatment of Alzheimer, the reagent that is used for the treatment of Huntington Chorea, be used for the treatment of parkinsonian reagent, the reagent that is used for the treatment of the dementia that AIDS-occurs together, the reagent that is used for the treatment of bipolar disorder, be used for the treatment of amyotrophic lateral sclerosis (ALS, the LouGehrig disease) reagent, the reagent that is used for the treatment of multiple sclerosis (MS), be used for the treatment of schizoid reagent, the reagent that is used for the treatment of leukopenia, the reagent that is used for the treatment of myocardial cell's hypertrophy, be used for the treatment of the reagent of apoplexy and the additional step of the other therapeutical agent of the reagent that is used for the treatment of rheumatoid arthritis, wherein:

A) described other therapeutical agent is suitable with regard to the disease of being treated; With

B) described other therapeutical agent separates a part of administration as polynary formulation with described composition as single formulation administration or with described composition.

40. treatment is selected from leukopenia, diabetes, apoplexy recovery or osteoporotic disease or illness or alleviates the method for its seriousness, comprises to the step of described patient's administration according to the compound of claim 1-30.

41. the method for claim 40 comprises to described patient's administration and is selected from the reagent, the reagent that is used for the treatment of leukopenia that are used for the treatment of diabetes, is used for the treatment of reagent that apoplexy recovers or the additional step that is used for the treatment of the other therapeutical agent of osteoporotic reagent.