CN101432281B

CN101432281B - 6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling

Info

Publication number: CN101432281B
Application number: CN200780013974.1A
Authority: CN
Inventors: J·C·苏顿; M·维斯曼; W·王; M·K·林德瓦尔; J·兰; S·拉默西; A·夏尔马; E·J·米厄利; L·M·克利万斯基; W·P·利纳恩; S·考夫曼; H·杨; S·C·额; K·菲斯特; A·韦格曼; V·松; M·森齐克
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2006-04-19
Filing date: 2007-04-18
Publication date: 2013-08-28
Anticipated expiration: 2027-04-18
Also published as: CN101432281A; ZA200808105B

Abstract

Benzoxazole and benzothiazole compounds and the stereoisomers, tautomers, solvates, oxides, esters, and prodrugs thereof and pharmaceutically acceptable salts thereof are disclosed. Compositions of the compounds, either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier, and uses of the compounds, either alone or in combination with at least one additional therapeutic agent are also disclosed. The embodiments are useful for inhibiting cellular proliferation, inhibiting the growth and/or metathesis of tumors, treating or preventing cancer, treating or preventing degenerating bone diseases such as rheumatoid arthritis, and/or inhibiting molecules such as CSF-1R.

Description

The benzo * azoles that 6-0-replaces and benzothiazole compound and the method that suppresses the conduction of CSF-1R signal

The cross reference of related application

The rights and interests that the application requires the U.S. Provisional Application sequence number 60/793,517 of applying on April 19th, 2006 and the sequence number 60/893,857 of applying on March 8th, 2007 according to 35U.S.C. § 119 (e), introduce the application as a reference at this in full by both.

Background of invention

Invention field

The present invention relates to benzoxazole and benzothiazole compound, its tautomer, steric isomer, solvate, oxide compound, ester, metabolite and prodrug and pharmacologically acceptable salt thereof that 6-O-replaces.The invention still further relates to the composition of this compound and pharmaceutically acceptable carrier.On the other hand, the present invention relates to this compound separately or with the purposes of at least one other therapeutic combination in prevention or treatment cancer.

Prior art

CSF-1R is the acceptor of M-CSF (macrophage colony stimulating factor, also referred to as CSF-1) and the biological effect (Sherr1985) that mediates this cytokine.The cloning of colony-stimulating factor-1 acceptor (also referred to as c-fms) is described in the people such as Roussel first, in Nature325:549-552 (1987).In this publication, show, CSF-1R has the conversion potential of the C-end afterbody variation that depends on albumen, comprises the forfeiture in conjunction with inhibition tyrosine 969 phosphorylations of Cbl, regulates thus the downward adjusting (Lee1999) of acceptor.

CSF-1R is a kind of strand transmembrane receptor Tyrosylprotein kinase (RTK), and is the member containing immunoglobulin (Ig) (Ig) the primitive family of RTK, it is characterized in that having in the extracellular of acceptor part the Ig structural domain of repetition.Intracellular protein tyrosine kinase structural domain is interrupted by a kind of insert structure territory of uniqueness, this insert structure territory also is present in other relevant RTK III family member, comprises platelet-derived growth factor receptors (PDGFR), stem cell factor acceptor (c-Kit) and fms type cytokines acceptor (FLT3).Although have structural homology in the family of this growth factor receptors, they have visibly different tissue-specific function.CSF-1R mainly expresses on monocytic cell and in female reproductive tract and placenta.In addition, also reported the youth lattice Chinese cell of CSF-1R at skin, the expression in a kind of subgroup of smooth muscle cell (Inaba1992), B cell (Baker1993) and microglia (Savada1990).

The main biological effect of CSF-1R signal conduction is differentiation, propagation, movement and the survival from monocytic precursor scavenger cell and osteoclast.The activation of CSF-1R is that the part M-CSF unique by it mediates.The zygotic induction of M-CSF and CSF-1R the formation of homodimer and the kinase whose activation of being undertaken by tyrosine phosphorylation.Further the signal conduction is by mediating with p85 subunit and the Grb2 of PI3K/AKT and the channel attached PI3K of Ras/MAPK respectively.These two kinds of important signalling channels can be regulated propagation, survival and apoptosis.Can comprise STAT1, STAT3, PLC γ and Cbl (Bourette2000) in conjunction with other signaling molecule of the cell intracellular domain of the phosphorylation of CSF-1R.

The conduction of CSF-1R signal has physiological role in immunne response, bone reconstruct and reproductive system.M-CSF-1 (op/op mouse; Pollard1996) or the animal that knocks out of CSF-1R (Dai2002) show and there is osteosclerotic, hematopoiesis, tissue macrophages and reproduction phenotype, this is consistent with the effect of CSF-1R in corresponding cell type.

Targeted therapy such as

with

recent one-tenth work hardening exploitation there is the importance of medicine of " cleaner " of the more specific mechanism of action.These medicines can minimize adverse events, have larger predictability, in therapeutic process, can give doctor's greater flexibility and can make the researchist understand better specific target spot.In addition, targeted therapy can be treated the multiple indication that affected by same signalling channel, has less and is easy to the toxicity (BioCentury, V.14 in February, (10) 2006) of controlling.Single kinases can be regulated the downstream kinases effectively as the inhibition of CSF-1R (it is included in the passage relevant with cancer or Other diseases), affects thus whole passage.Yet the avtive spot of 491 human protein kinase structural domains is high conservatives, this design that makes selective depressant is a difficult challenge (Cohen (2005)).Therefore, need optionally kinase inhibitor, such as CSF-1R inhibitor optionally.

Summary of the invention

Need propagation capable of inhibiting cell always, suppress tumor growth, the treatment cancer, regulate that the cell cycle stops and/or the compound of Inhibitory molecules such as CSF-1R particularly, and need to contain pharmaceutical preparation and the medicine of this compound.Also need optionally CSF-1R inhibition compound.Also need by described compound, pharmaceutical preparation and drug administration in needs its patient or individual method.

A kind of embodiment relates to compound, steric isomer, tautomer, solvate, oxide compound, ester and the prodrug of formula (I), its pharmacologically acceptable salt and relevant composition and method, and its Chinese style (I) is:

And wherein X is O, S or S (O);

R ¹and R ²heteroaryl independently selected from heterocyclic radical, heteroaryl and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkyl of hydrogen, alkyl, replacement, acyl group, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heterocyclic radical, replacement; Or R ¹and R ²connect together to form and be selected from following group: the heteroaryl of the heterocyclic radical of heterocyclic radical, replacement, heteroaryl or replacement;

R ³be selected from alkoxyl group, carboxyl, the carboxyl ester of amino, acyl group, acyl amino, alkoxyl group, the replacement of heterocyclic radical, amino, the replacement of heteroaryl, heterocyclic radical, the replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, formonitrile HCN, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, halogen, replacement, alkylsulfonyl, amino-sulfonyl and the aminocarboxyl of replacement;

Each R ⁶alkoxyl group, the amino of alkyl, alkoxyl group, the replacement of alkyl, replacement, amino or the halogen of replacement independently;

N is 0,1 or 2; And

When X is O, R ⁴the alkynyl of alkenyl, alkynyl or replacement of alkyl, alkenyl, the replacement of hydrogen, replacement, and R ⁵the cycloalkyl of heteroaryl, cycloalkyl or replacement of alkynyl, aminocarboxyl, halogen, heteroaryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, or R ⁴and R ⁵connect together to form and be selected from following group: the heteroaryl of the aryl of the cycloalkyl of the heterocyclic radical of heterocyclic radical, replacement, cycloalkyl, replacement, aryl, replacement, heteroaryl and replacement; And

When X is S or S (O), R ⁴the alkynyl of alkenyl, alkynyl or replacement of alkyl, alkenyl, the replacement of hydrogen, replacement, and R ⁵it is the cycloalkyl of heteroaryl, cycloalkyl or replacement of alkynyl, aminocarboxyl, halogen, heteroaryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement.

Another embodiment relates to formula (IIa) or compound (IIb), steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (IIa) and be (IIb)

And wherein X is O or S;

Dotted line is saturated bond or unsaturated link(age);

L is the alkylidene group of covalent linkage or alkylidene group or replacement;

R ¹⁰, R ¹¹and R ¹²heteroaryl independently selected from aryl, heteroaryl and the replacement of the heterocyclic radical of the cycloalkyl of the amino of the alkoxyl group of the alkyl of hydrogen, halogen, hydroxyl, alkyl, replacement, alkoxyl group, replacement, amino, replacement, cycloalkyl, replacement, heterocyclic radical, replacement, aryl, replacement; Or R ¹¹with R ¹²connect together to form and be selected from following group: the heteroaryl of the heterocyclic radical of the aryl of aryl, replacement, heterocyclic radical, replacement, heteroaryl and replacement; And

R ³be selected from alkoxyl group, carboxyl, the carboxyl ester of amino, acyl group, acyl amino, alkoxyl group, the replacement of heterocyclic radical, amino, the replacement of heteroaryl, heterocyclic radical, the replacement of aryl, heteroaryl, the replacement of alkyl, formonitrile HCN, aryl, the replacement of hydrogen, halogen, replacement, alkylsulfonyl, amino-sulfonyl and the aminocarboxyl of replacement.

Another embodiment relates to compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and the method for formula (IIIa), and its Chinese style (IIIa) is

And wherein X is O or S;

R ¹be alkyl or be selected from the following alkyl that substituting group replaced: the heteroaryl of the heterocyclic radical of aryl, cycloalkyl, heterocyclic radical, replacement, heteroaryl and replacement; And

Another embodiment relates to compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and the method for formula (IIIb), and its Chinese style (IIIb) is

And wherein X is O or S;

R ¹be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkenyl group, heterocyclic radical, the replacement of cycloalkyl, cycloalkenyl group, the replacement of acyl group, cycloalkyl, replacement; And

Another embodiment relates to compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and the method for formula (IV), and its Chinese style (IV) is

And wherein X is O or S;

R ⁷independently selected from alkoxyl group, halogenated alkoxy, halogen and formonitrile HCN;

P is 0,1 or 2;

R ¹be-LR ⁸or by 0,1,2 or 3 independently selected from the following alkyl that substituting group replaced: the alkylsulfonyl of halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryloxy, aminocarboxyl, carboxyl ester, carboxyl and replacement;

L is the alkylidene group of covalent linkage, alkylidene group or replacement; And

R ⁸be selected from cycloalkyl, THP trtrahydropyranyl, morpholino, the pyridyl of cycloalkyl, replacement, and when p is 0, R ⁸it is optionally the 2-p-methoxy-phenyl.

Another embodiment relates to compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and the method for formula (V), and its Chinese style (V) is

And wherein X is O or S;

R ¹be-LR ⁹or by 0,1,2 or 3 independently selected from the following alkyl that substituting group replaced: the alkylsulfonyl of halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryloxy, aminocarboxyl, carboxyl ester, carboxyl and replacement;

R ⁹be selected from cycloalkyl, THP trtrahydropyranyl, morpholino and the pyridyl of cycloalkyl, replacement.

Another embodiment relates to the method by the illness of formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or the treatment of CSR-1R Inhibitor (V) CSF-1R mediation.

In a more particular embodiment, described compound does not suppress the Raf kinases basically.In a more particular embodiment, described Compound Phase preferentially suppresses CSF-1R for the Raf kinases.In a more particular embodiment, described compound is with IC ₅₀be greater than the approximately control of the concentration Raf kinases of 1 μ M.In a more particular embodiment, described compound is with IC ₅₀be less than the approximately control of the concentration CSF-1R of 1 μ M.More particularly, described compound is with IC ₅₀be less than the approximately control of the concentration CSF-1R of 0.1 μ M.

Detailed Description Of The Invention

In whole application, this paper relates to the various embodiments of compound, composition and method.Described various embodiment is for multiple indicative example being provided, should not be viewed as the description of alternative type.Should be noted that, the description of various embodiments provided in this article can be overlapping scope.Embodiment discussed in this article is only indicative, and does not mean that and limit the scope of the invention.

Definition

Unless concrete definition is separately arranged, otherwise term used herein defined as following.

＂ alkyl ＂ refer to there is 1 to 10 carbon atom, the preferred unit price radical of saturated aliphatic alkyl of 1 to 6 carbon atom.This term comprises that for example straight chain and branched hydrocarbyl are such as methyl (CH ₃-), ethyl (CH ₃cH ₂-), n-propyl (CH ₃cH ₂cH ₂-), sec.-propyl ((CH ₃) ₂cH-), normal-butyl (CH ₃cH ₂cH ₂cH ₂-), isobutyl-((CH ₃) ₂cHCH ₂-), sec-butyl ((CH ₃) (CH ₃cH ₂) CH-), the tertiary butyl ((CH ₃) ₃c-), n-pentyl (CH ₃cH ₂cH ₂cH ₂cH ₂-) and neo-pentyl ((CH ₃) ₃cCH ₂-).

The alkyl ＂ that ＂ replaces refers to have 1 to 5, preferably 1 to 3 or more preferably 1 to 2 be selected from following substituent alkyl: alkoxyl group, the alkoxyl group replaced, acyl group, acyl amino, acyloxy, amino, the amino replaced, aminocarboxyl, amino thiocarbonyl, amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base, amino-sulfonyl, amino-sulfonyl oxygen base, amino-sulfonyl amino, amidino groups, aryl, the aryl replaced, aryloxy, the aryloxy replaced, arylthio, the arylthio replaced, azido-, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxygen base, cyano group, cyanate, cycloalkyl, the cycloalkyl replaced, cycloalkyl oxy, the cycloalkyl oxy replaced, cycloalkylthio, the cycloalkylthio replaced, cycloalkenyl group, the cycloalkenyl group replaced, cycloalkenyl oxy, the cycloalkenyl oxy replaced, the cycloalkenyl group sulfenyl, the cycloalkenyl group sulfenyl replaced, guanidine radicals, the guanidine radicals replaced, halogen, hydroxyl, hydroxyl amino, alkoxy amino, diazanyl, the diazanyl replaced, heteroaryl, the heteroaryl replaced, heteroaryloxy, the heteroaryloxy replaced, heteroarylthio, the heteroarylthio replaced, heterocycle, the heterocycle replaced, the heterocyclyloxy base, the heterocyclyloxy base replaced, the heterocyclic radical sulfenyl, the heterocyclic radical sulfenyl replaced, nitro, inferior spiro cycloalkyl group, SO ₃the alkylthio of the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, thiocyanic ester, mercaptan, alkylthio and replacement, wherein said substituting group as defined herein.

" alkylidene group " refer to there is 1 to 10 carbon atom, the preferred divalence radical of saturated aliphatic alkyl of 1 to 6 carbon atom.Alkylidene group comprises side chain and straight-chain alkyl.

" alkylidene group of replacement " refers to have 1 to 5, preferably 1 to 3 or more preferably 1 to 2 be selected from following substituent alkylidene group: alkoxyl group, the alkoxyl group replaced, acyl group, acyl amino, acyloxy, amino, the amino replaced, aminocarboxyl, amino thiocarbonyl, amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base, amino-sulfonyl, amino-sulfonyl oxygen base, amino-sulfonyl amino, amidino groups, aryl, the aryl replaced, aryloxy, the aryloxy replaced, arylthio, the arylthio replaced, azido-, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxygen base, cyano group, cyanate, cycloalkyl, the cycloalkyl replaced, cycloalkyl oxy, the cycloalkyl oxy replaced, cycloalkylthio, the cycloalkylthio replaced, cycloalkenyl group, the cycloalkenyl group replaced, cycloalkenyl oxy, the cycloalkenyl oxy replaced, the cycloalkenyl group sulfenyl, the cycloalkenyl group sulfenyl replaced, guanidine radicals, the guanidine radicals replaced, halogen, hydroxyl, hydroxyl amino, alkoxy amino, diazanyl, the diazanyl replaced, heteroaryl, the heteroaryl replaced, heteroaryloxy, the heteroaryloxy replaced, heteroarylthio, the heteroarylthio replaced, heterocycle, the heterocycle replaced, the heterocyclyloxy base, the heterocyclyloxy base replaced, the heterocyclic radical sulfenyl, the heterocyclic radical sulfenyl replaced, nitro, oxo, thioketones, inferior spiro cycloalkyl group, SO ₃the alkylthio of the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, thiocyanic ester, mercaptan, alkylthio and replacement, wherein said substituting group as defined herein.

＂ alkoxyl group ＂ refers to group-O-alkyl, and wherein alkyl as defined herein.Alkoxyl group comprises for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy and n-pentyloxy.

The alkoxyl group ＂ that ＂ replaces refers to group-O-(alkyl of replacement), and the alkyl wherein replaced as defined herein.

＂ acyl group ＂ refer to group H-C (O)-, alkyl-C (O)-, alkyl-the C (O) replaced-, alkenyl-C (O)-, alkenyl-the C (O) replaced-, alkynyl-C (O)-, alkynyl-the C (O) replaced-, cycloalkyl-C (O)-, cycloalkyl-the C (O) replaced-, cycloalkenyl group-C (O)-, cycloalkenyl group-the C (O) replaced-, aryl-C (O)-, aryl-the C (O) replaced-, diazanyl-the C (O) replaced-, heteroaryl-C (O)-, heteroaryl-the C (O) replaced-, heterocycle-C (O)-and heterocycle-C (O) of replacing-, alkyl wherein, the alkyl replaced, alkenyl, the alkenyl replaced, alkynyl, the alkynyl replaced, cycloalkyl, the cycloalkyl replaced, cycloalkenyl group, the cycloalkenyl group replaced, aryl, the aryl replaced, the diazanyl replaced, heteroaryl, the heteroaryl replaced, the heterocycle of heterocycle and replacement as defined herein.Acyl group comprises " ethanoyl " CH ₃c (O)-.

＂ acyl amino ＂ refers to group-NR ²⁰c (O) alkyl ,-NR ²⁰the alkyl that C (O) replaces ,-NR ²⁰c (O) cycloalkyl ,-NR ²⁰the cycloalkyl that C (O) replaces ,-NR ²⁰c (O) cycloalkenyl group ,-NR ²⁰the cycloalkenyl group that C (O) replaces ,-NR ²⁰c (O) alkenyl ,-NR ²⁰the alkenyl that C (O) replaces ,-NR ²⁰c (O) alkynyl ,-NR ²⁰the alkynyl that C (O) replaces ,-NR ²⁰c (O) aryl ,-NR ²⁰the aryl that C (O) replaces ,-NR ²⁰c (O) heteroaryl ,-NR ²⁰the heteroaryl that C (O) replaces ,-NR ²⁰c (O) heterocycle and-NR ²⁰the heterocycle that C (O) replaces, wherein R ²⁰be cycloalkenyl group, aryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of alkynyl, cycloalkyl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen or alkyl and wherein alkyl, replacement aryl, heteroaryl, replacement heteroaryl, heterocycle and replacement heterocycle as defined herein.

＂ acyloxy ＂ refers to group alkyl-C (O) O-, alkyl-C (O) O-replaced, alkenyl-C (O) O-, alkenyl-C (O) O-replaced, alkynyl-C (O) O-, alkynyl-C (O) O-replaced, aryl-C (O) O-, aryl-C (O) O-replaced, cycloalkyl-C (O) O-, cycloalkyl-C (O) O-replaced, cycloalkenyl group-C (O) O-, cycloalkenyl group-C (O) O-replaced, heteroaryl-C (O) O-, heteroaryl-C (O) O-replaced, heterocycle-C (O) O-of heterocycle-C (O) O-and replacement, alkyl wherein, the alkyl replaced, alkenyl, the alkenyl replaced, alkynyl, the alkynyl replaced, cycloalkyl, the cycloalkyl replaced, cycloalkenyl group, the cycloalkenyl group replaced, aryl, the aryl replaced, heteroaryl, the heteroaryl replaced, the heterocyclic radical of heterocyclic radical and replacement as defined herein.

" amino " refers to group-NH ₂.

" amino of replacement " refers to group-NR ²¹r ²², R wherein ²¹and R ²²independently selected from the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle, replacement ,-SO ₂-alkyl ,-SO ₂the alkyl of-replacement ,-SO ₂-alkenyl ,-SO ₂the alkenyl of-replacement ,-SO ₂-cycloalkyl ,-SO ₂the cycloalkyl of-replacement ,-SO ₂-cycloalkenyl group ,-SO ₂the cycloalkenyl group of-replacement ,-SO ₂-aryl ,-SO ₂the aryl of-replacement ,-SO ₂-heteroaryl ,-SO ₂the heteroaryl of-replacement ,-SO ₂-heterocycle and-SO ₂the heterocycle of-replacement, wherein R ²¹and R ²²form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, condition is R ²¹and R ²²be not hydrogen, and the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.Work as R ²¹hydrogen and R ²²while being alkyl, the amino of replacement is known as alkylamino in this article sometimes.Work as R ²¹and R ²²while being alkyl, the amino of replacement is known as dialkyl amido in this article sometimes.When mentioning mono-substituted amino, mean R ²¹or R ²²in any is hydrogen, but be not all hydrogen.When mentioning dibasic amino, mean R ²¹and R ²¹not hydrogen.

" hydroxyl amino " refers to group-NHOH.

" alkoxy amino " refers to group-NHO-alkyl, and wherein alkyl as defined herein.

＂ aminocarboxyl ＂ refers to group-C (O) NR ²³r ²⁴, R wherein ²³and R ²⁴independently selected from amino and the acyl amino of the alkoxyl group of the heterocyclic radical of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocyclic radical, replacement, hydroxyl, alkoxyl group, replacement, amino, replacement, and R wherein ²³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, wherein the heterocycle of the heteroaryl of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement, heterocycle and replacement as defined herein.

" amino thiocarbonyl " refers to group-C (S) NR ²³r ²⁴, R wherein ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R2 wherein ³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

" amino carbonyl amino " refers to group-NR ²⁰c (O) NR ²³r ²⁴, R wherein ²⁰hydrogen or alkyl and R ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R wherein ²³and R ²⁴together with the nitrogen optionally connected with them, form cycloalkenyl group, aryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of alkynyl, cycloalkyl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of the heterocyclic radical of heterocycle or replacement and wherein alkyl, replacement aryl, heteroaryl, replacement heteroaryl, heterocycle and replacement heterocycle as defined herein.

" amino thio-carbonyl-amino " refers to group-NR ²⁰c (S) NR ²³r ²⁴, R wherein ²⁰hydrogen or alkyl and R ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R wherein ²³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, wherein the heterocycle of the heteroaryl of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement, heterocycle and replacement as defined herein.

" aminocarboxyl oxygen base " refers to group-O-C (O) NR ²³r ²⁴, R wherein ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R wherein ²³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

" amino-sulfonyl " refers to group-SO ₂nR ²³r ²⁴, R wherein ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R wherein ²³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

" amino-sulfonyl oxygen base " refers to group-O-SO ₂nR ²³r ²⁴, R wherein ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R wherein ²³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

" amino-sulfonyl amino " refers to group-NR ²⁰-SO ₂nR ²³r ²⁴, R wherein ²⁰hydrogen or alkyl and R ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R wherein ²³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

" amidino groups " refers to group-C (=NR ²⁵) NR ²³r ²⁴, R wherein ²⁵, R ²³and R ²⁴independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, and R wherein ²³and R ²⁴form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, and the heterocycle of heteroaryl, heterocycle and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

＂ aryl ＂ or ＂ Ar ＂ refer to the unit price aromatic carbocyclic group of 6 to 14 carbon atoms of have single ring (for example phenyl) or a plurality of ring condensed (for example naphthyl or anthryl), described condensed ring can the yes or no aromaticity (for example 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-one-7-bases etc.), condition is that tie point is on aromatic carbon atom.Preferred aryl comprises phenyl and naphthyl.

" aryl of replacement " refers to by 1 to 5, preferably 1 to 3 or more preferably 1 to 2 be selected from the aryl that following substituting group replaces: alkyl, the alkyl replaced, alkenyl, the alkenyl replaced, alkynyl, the alkynyl replaced, alkoxyl group, the alkoxyl group replaced, acyl group, acyl amino, acyloxy, amino, the amino replaced, aminocarboxyl, amino thiocarbonyl, amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base, amino-sulfonyl, amino-sulfonyl oxygen base, amino-sulfonyl amino, amidino groups, aryl, the aryl replaced, aryloxy, the aryloxy replaced, arylthio, the arylthio replaced, azido-, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxygen base, cyano group, cyanate, cycloalkyl, the cycloalkyl replaced, cycloalkyl oxy, the cycloalkyl oxy replaced, cycloalkylthio, the cycloalkylthio replaced, cycloalkenyl group, the cycloalkenyl group replaced, cycloalkenyl oxy, the cycloalkenyl oxy replaced, the cycloalkenyl group sulfenyl, the cycloalkenyl group sulfenyl replaced, guanidine radicals, the guanidine radicals replaced, halogen, hydroxyl, hydroxyl amino, alkoxy amino, diazanyl, the diazanyl replaced, heteroaryl, the heteroaryl replaced, heteroaryloxy, the heteroaryloxy replaced, heteroarylthio, the heteroarylthio replaced, heterocycle, the heterocycle replaced, the heterocyclyloxy base, the heterocyclyloxy base replaced, the heterocyclic radical sulfenyl, the heterocyclic radical sulfenyl replaced, nitro, SO ₃the alkylthio of the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, thiocyanic ester, mercaptan, alkylthio and replacement, wherein said substituting group as defined herein.

＂ aryloxy ＂ refers to group-O-aryl, and wherein as defined herein, it comprises for example phenoxy group and naphthyloxy to aryl.

The aryloxy ＂ that ＂ replaces refers to group-O-(aryl of replacement), and the aryl wherein replaced as defined herein.

" arylthio " refers to group-S-aryl, and wherein aryl as defined herein.

" arylthio of replacement " refers to group-S-(aryl of replacement), and the aryl wherein replaced as defined herein.

＂ alkenyl ＂ refer to there are 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms and have at least 1, preferably the unsaturated position of 1 to 2 vinyl (> C=C<) alkenyl.Described group is vinyl, allyl group and fourth-3-thiazolinyl for example.

The alkenyl ＂ that ＂ replaces refers to have 1 to 3, preferably 1 to 2 is selected from following substituent alkenyl: alkoxyl group, the alkoxyl group replaced, acyl group, acyl amino, acyloxy, amino, the amino replaced, aminocarboxyl, amino thiocarbonyl, amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base, amino-sulfonyl, amino-sulfonyl oxygen base, amino-sulfonyl amino, amidino groups, aryl, the aryl replaced, aryloxy, the aryloxy replaced, arylthio, the arylthio replaced, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxygen base, cyano group, cycloalkyl, the cycloalkyl replaced, cycloalkyl oxy, the cycloalkyl oxy replaced, cycloalkylthio, the cycloalkylthio replaced, cycloalkenyl group, the cycloalkenyl group replaced, cycloalkenyl oxy, the cycloalkenyl oxy replaced, the cycloalkenyl group sulfenyl, the cycloalkenyl group sulfenyl replaced, guanidine radicals, the guanidine radicals replaced, halogen, hydroxyl, heteroaryl, the heteroaryl replaced, heteroaryloxy, the heteroaryloxy replaced, heteroarylthio, the heteroarylthio replaced, heterocycle, the heterocycle replaced, the heterocyclyloxy base, the heterocyclyloxy base replaced, the heterocyclic radical sulfenyl, the heterocyclic radical sulfenyl replaced, nitro, SO ₃the alkylthio of the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, as defined herein, condition is that any hydroxyl or mercaptan replacement all are free of attachment on vinyl (undersaturated) carbon atom to wherein said substituting group.

＂ alkynyl ＂ refer to there are 2 to 6 carbon atoms, preferred 2 to 3 carbon atoms and there is at least 1, the preferred alkyl of the unsaturated position of 1 to 2 acetylene series (C ≡ C-).

The alkynyl ＂ that ＂ replaces refers to have 1 to 3, preferably 1 to 2 is selected from following substituent alkynyl: alkoxyl group, the alkoxyl group replaced, acyl group, acyl amino, acyloxy, amino, the amino replaced, aminocarboxyl, amino thiocarbonyl, amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base, amino-sulfonyl, amino-sulfonyl oxygen base, amino-sulfonyl amino, amidino groups, aryl, the aryl replaced, aryloxy, the aryloxy replaced, arylthio, the arylthio replaced, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxygen base, cyano group, cycloalkyl, the cycloalkyl replaced, cycloalkyl oxy, the cycloalkyl oxy replaced, cycloalkylthio, the cycloalkylthio replaced, cycloalkenyl group, the cycloalkenyl group replaced, cycloalkenyl oxy, the cycloalkenyl oxy replaced, the cycloalkenyl group sulfenyl, the cycloalkenyl group sulfenyl replaced, guanidine radicals, the guanidine radicals replaced, halogen, hydroxyl, heteroaryl, the heteroaryl replaced, heteroaryloxy, the heteroaryloxy replaced, heteroarylthio, the heteroarylthio replaced, heterocycle, the heterocycle replaced, the heterocyclyloxy base, the heterocyclyloxy base replaced, the heterocyclic radical sulfenyl, the heterocyclic radical sulfenyl replaced, nitro, SO ₃the alkylthio of the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, as defined herein, condition is that any hydroxyl or mercaptan replacement all are free of attachment on the alkynyl carbon atom to wherein said substituting group.

" azido-" refers to group-N ₃.

" diazanyl " refers to group-NHNH ₂.

" diazanyl of replacement " refers to group-NR ²⁶nR ²⁷r ²⁸, R wherein ²⁶, R ²⁷and R ²⁸independently selected from the heterocycle of the heteroaryl of the cycloalkenyl group of the cycloalkyl of the aryl of the alkynyl of the alkenyl of the alkyl of hydrogen, alkyl, replacement, alkenyl, replacement, alkynyl, replacement, aryl, replacement, carboxyl ester, cycloalkyl, replacement, cycloalkenyl group, replacement, heteroaryl, replacement, heterocycle, replacement ,-SO ₂-alkyl ,-SO ₂the alkyl of-replacement ,-SO ₂-alkenyl ,-SO ₂the alkenyl of-replacement ,-SO ₂-cycloalkyl ,-SO ₂the cycloalkyl of-replacement ,-SO ₂-cycloalkenyl group ,-SO ₂the cycloalkenyl group of-replacement ,-SO ₂-aryl ,-SO ₂the aryl of-replacement ,-SO ₂-heteroaryl ,-SO ₂the heteroaryl of-replacement ,-SO ₂-heterocycle and-SO ₂-the heterocycle that replaces, and R wherein ²⁷and R ²⁸form the heterocyclic radical of heterocycle or replacement together with the nitrogen optionally connected with them, condition is R ²⁷and R ²⁸be not hydrogen, and the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

" cyano group " or " formonitrile HCN " refers to group-CN.

" cyanate " refers to group-OCN.

" carbonyl " refer to divalent group-C (O)-, its be equal to-C (=O)-.

" carboxyl " refer to-COOH or its salt.

" carboxyl ester " refers to group-C (O) O-alkyl, the alkyl that-C (O) O-replaces,-C (O) O-alkenyl, the alkenyl that-C (O) O-replaces,-C (O) O-alkynyl, the alkynyl that-C (O) O-replaces,-C (O) O-aryl, the aryl that-C (O) O-replaces,-C (O) O-cycloalkyl, the cycloalkyl that-C (O) O-replaces,-C (O) O-cycloalkenyl group, the cycloalkenyl group that-C (O) O-replaces,-C (O) O-heteroaryl, the heteroaryl that-C (O) O-replaces,-C (O) O-heterocycle and-heterocycle that C (O) O-replaces, alkyl wherein, the alkyl replaced, alkenyl, the alkenyl replaced, alkynyl, the alkynyl replaced, cycloalkyl, the cycloalkyl replaced, cycloalkenyl group, the cycloalkenyl group replaced, aryl, the aryl replaced, heteroaryl, the heteroaryl replaced, the heterocyclic radical of heterocyclic radical and replacement as defined herein.

" (carboxyl ester) amino " refers to group-NR ²⁰-C (O) O-alkyl ,-NR ²⁰the alkyl that-C (O) O-replaces ,-NR ²⁰-C (O) O-alkenyl ,-NR ²⁰the alkenyl that-C (O) O-replaces ,-NR ²⁰-C (O) O-alkynyl ,-NR ²⁰the alkynyl that-C (O) O-replaces ,-NR ²⁰-C (O) O-aryl ,-NR ²⁰the aryl that-C (O) O-replaces ,-NR ²⁰-C (O) O-cycloalkyl ,-NR ²⁰the cycloalkyl that-C (O) O-replaces ,-NR ²⁰-C (O) O-cycloalkenyl group ,-NR ²⁰the cycloalkenyl group that-C (O) O-replaces ,-NR ²⁰-C (O) O-heteroaryl ,-NR ²⁰the heteroaryl that-C (O) O-replaces ,-NR ²⁰-C (O) O-heterocycle and-NR ²⁰the heterocycle that-C (O) O-replaces, wherein R ²⁰be alkyl or hydrogen, and the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of wherein alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement as defined herein.

" (carboxyl ester) oxygen base " refers to group-O-C (O) O-alkyl, the alkyl that-O-C (O) O-replaces,-O-C (O) O-alkenyl, the alkenyl that-O-C (O) O-replaces,-O-C (O) O-alkynyl, the alkynyl that-O-C (O) O-replaces,-O-C (O) O-aryl, the aryl that-O-C (O) O-replaces,-O-C (O) O-cycloalkyl, the cycloalkyl that-O-C (O) O-replaces,-O-C (O) O-cycloalkenyl group, the cycloalkenyl group that-O-C (O) O-replaces,-O-C (O) O-heteroaryl, the heteroaryl that-O-C (O) O-replaces,-O-C (O) O-heterocycle and-heterocycle that O-C (O) O-replaces, alkyl wherein, the alkyl replaced, alkenyl, the alkenyl replaced, alkynyl, the alkynyl replaced, cycloalkyl, the cycloalkyl replaced, cycloalkenyl group, the cycloalkenyl group replaced, aryl, the aryl replaced, heteroaryl, the heteroaryl replaced, the heterocyclic radical of heterocyclic radical and replacement as defined herein.

" cycloalkyl " refers to have single or multiple rings, comprise cyclic alkyls that condense, bridge joint and 3 to 10 carbon atoms volution system.In the condensed ring system, one or more rings can be cycloalkyl, heterocycle, aryl or heteroaryl, and condition is to connect by cycloalkyl ring.The example of suitable cycloalkyl comprises for example adamantyl, cyclopropyl, cyclobutyl, cyclopentyl and ring octyl group.

" cycloalkenyl group " refers to have single or multiple cyclic rings and have at least one > the unsaturated position of C=C<encircle, preferably there is 1 to 2 > C=C<the encircle non-aromatic cyclic alkyl with 4 to 10 carbon atoms of unsaturated position.

" cycloalkyl of replacement " and " cycloalkenyl group of replacement " refer to have 1 to 5 or preferably 1 to 3 be selected from following substituent cycloalkyl or cycloalkenyl group: oxo, thioketones, alkyl, the alkyl replaced, alkenyl, the alkenyl replaced, alkynyl, the alkynyl replaced, alkoxyl group, the alkoxyl group replaced, acyl group, acyl amino, acyloxy, amino, the amino replaced, aminocarboxyl, amino thiocarbonyl, amino carbonyl amino, amino thio-carbonyl-amino, aminocarboxyl oxygen base, amino-sulfonyl, amino-sulfonyl oxygen base, amino-sulfonyl amino, amidino groups, aryl, the aryl replaced, aryloxy, the aryloxy replaced, arylthio, the arylthio replaced, azido-, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxygen base, cyano group, cyanate, cycloalkyl, the cycloalkyl replaced, cycloalkyl oxy, the cycloalkyl oxy replaced, cycloalkylthio, the cycloalkylthio replaced, cycloalkenyl group, the cycloalkenyl group replaced, cycloalkenyl oxy, the cycloalkenyl oxy replaced, the cycloalkenyl group sulfenyl, the cycloalkenyl group sulfenyl replaced, guanidine radicals, the guanidine radicals replaced, halogen, hydroxyl, hydroxyl amino, alkoxy amino, diazanyl, the diazanyl replaced, heteroaryl, the heteroaryl replaced, heteroaryloxy, the heteroaryloxy replaced, heteroarylthio, the heteroarylthio replaced, heterocycle, the heterocycle replaced, the heterocyclyloxy base, the heterocyclyloxy base replaced, the heterocyclic radical sulfenyl, the heterocyclic radical sulfenyl replaced, nitro, SO ₃the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, thiocyanic ester, mercaptan, alkylthio and the alkylthio of replacement, wherein said substituting group are as defined herein.

" cycloalkyl oxy " refer to-O-cycloalkyl.

" refer to-O-of the cycloalkyl oxy of replacement (cycloalkyl of replacement).

" cycloalkylthio " refer to-S-cycloalkyl.

" cycloalkylthio of replacement " refers to-S-(cycloalkyl of replacement).

" cycloalkenyl oxy " refer to-O-cycloalkenyl group.

" cycloalkenyl oxy of replacement " refers to-O-(cycloalkenyl group of replacement).

" cycloalkenyl group sulfenyl " refer to-S-cycloalkenyl group.

" the cycloalkenyl group sulfenyl of replacement " refers to-S-(cycloalkenyl group of replacement).

" guanidine radicals " refers to group-NHC (=NH) NH ₂.

" guanidine radicals of replacement " refers to-NR29C (=NR29) N (R29) ₂, wherein each R29 is independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and the replacement of the aryl of the alkyl of hydrogen, alkyl, replacement, aryl, replacement, heteroaryl, replacement, and is connected to two R on common guanidine radicals nitrogen-atoms ²⁹form the heterocyclic radical of heterocycle or replacement together with the nitrogen that group optionally connects with them, condition is at least one R ²⁹be not hydrogen, and wherein said substituting group as defined herein.

" halogen " refers to fluorine, chlorine, bromine and iodine.

" hydroxyl " refers to group-OH.

" heteroaryl " refers in ring to have 1 to 10 carbon atom and 1 to 4 heteroatomic aromatic group that is selected from oxygen, nitrogen and sulphur.Described heteroaryl can have single ring (for example pyridyl or furyl) or a plurality of ring condensed (for example indolizine base or benzothienyl), the ring wherein condensed can the yes or no aromaticity and/or containing or containing heteroatoms, condition is the former sub-connection by the aromatics heteroaryl.In one embodiment, the nitrogen of heteroaryl and/or sulphur annular atoms optionally are oxidized to N-oxide compound (N → O), sulfinyl or alkylsulfonyl part.Preferred heteroaryl comprises pyridyl, pyrryl, indyl, thiophene and furyl.

" heteroaryl of replacement " refer to by 1 to 5, preferably 1 to 3 or more preferably 1 to 2 be selected from and the defined identical heteroaryl that substituting group replaced of the aryl replaced.

" heteroaryloxy " refer to-O-heteroaryl.

" heteroaryloxy of replacement " refers to group-O-(heteroaryl of replacement).

" heteroarylthio " refers to group-S-heteroaryl.

" heteroarylthio of replacement " refers to group-S-(heteroaryl of replacement).

" heterocycle " or " Heterocyclylalkyl " or " heterocyclic radical " refer in ring to have single ring or a plurality of ring condensed, comprise that condense bridge joint and heteroatomic saturated, fractional saturation or the unsaturated group (but not being aromaticity) that 1 to 10 carbon atom and 1 to 4 are selected from nitrogen, sulphur or oxygen that the have volution system, wherein in the condensed ring system, one or more rings can be cycloalkyl, aryl or heteroaryl, and condition is to connect by non-aromatic ring.In one embodiment, the nitrogen of heterocyclic radical and/or sulphur atom optionally are oxidized to N-oxide compound, sulfinyl, alkylsulfonyl part.

" heterocycle of replacement " or " Heterocyclylalkyl of replacement " or " heterocyclic radical of replacement " refer to by 1 to 5 or preferably 1 to 3 be selected from and the defined identical heterocyclic radical that substituting group replaced of the cycloalkyl replaced.

" heterocyclyloxy base " refers to group-O-heterocyclic radical.

" the heterocyclyloxy base of replacement " refers to group-O-(heterocyclic radical of replacement).

" heterocyclic radical sulfenyl " refers to group-S-heterocyclic radical.

" the heterocyclic radical sulfenyl of replacement " refers to group-S-(heterocyclic radical of replacement).

The example of heterocycle and heteroaryl includes but not limited to azetidine, the pyrroles, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indoline, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, the naphthyl pyridine, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, the bifurcation pyridine, phenanthroline, isothiazole, azophenlyene, isoxazole, phenoxazine, thiodiphenylamine, imidazolidine, tetrahydroglyoxaline, piperidines, piperazine, indoline, phthalic imidine, 1, 2, 3, the 4-tetrahydroisoquinoline, 4, 5, 6, 7-tetrahydro benzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thio-morpholinyl, 1, 1-dioxo thio-morpholinyl, piperidyl, tetramethyleneimine and tetrahydrofuran base.

" nitro " refers to group-NO ₂.

" oxo " refers to atom (=O).

" oxide compound " refers to the formed product of one or more heteroatoms oxidations.Its example comprises N-oxide compound, sulfoxide and sulfone.

" volution base " refers to the bivalent cyclic group with 3 to 10 carbon atoms, and it comprises and has cycloalkyl ring or the heterocycle of spiral in conjunction with (this combination is formed by single atom, and this atom is the unique cross membership who respectively encircles), and for example, it has following structure:

" spiro cycloalkyl group " or " inferior spiro cycloalkyl group " refers to divalent group, and it comprises the cycloalkyl ring had as above about the described spiral combination of volution base.

" alkylsulfonyl " refers to divalent group-S (O) ₂-.

" alkylsulfonyl of replacement " refers to group-SO ₂-alkyl ,-SO ₂the alkyl of-replacement ,-SO ₂-alkenyl ,-SO ₂the alkenyl of-replacement ,-SO ₂-cycloalkyl ,-SO ₂the cycloalkyl of-replacement ,-SO ₂-cycloalkenyl group ,-SO ₂the cycloalkenyl group of-replacement ,-SO ₂-aryl ,-SO ₂the aryl of-replacement ,-SO ₂-heteroaryl ,-SO ₂the heteroaryl of-replacement ,-SO ₂-heterocycle ,-SO ₂the heterocycle of-replacement, wherein the heterocycle of the heteroaryl of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement, heterocycle and replacement as defined herein.The alkylsulfonyl replaced comprises that group is such as methyl-SO ₂-, phenyl-SO ₂-and 4-aminomethyl phenyl-SO ₂-.

" alkylsulfonyl oxygen base " refers to group-OSO ₂-alkyl ,-OSO ₂the alkyl of-replacement ,-OSO ₂-alkenyl ,-OSO ₂the alkenyl of-replacement ,-OSO ₂-cycloalkyl ,-OSO ₂the cycloalkyl of-replacement ,-OSO ₂-cycloalkenyl group ,-OSO ₂the cycloalkenyl group of-replacement ,-OSO ₂-aryl ,-OSO ₂the aryl of-replacement ,-OSO ₂-heteroaryl ,-OSO ₂the heteroaryl of-replacement ,-OSO ₂-heterocycle ,-OSO ₂the heterocycle of-replacement, wherein the heterocycle of the heteroaryl of the aryl of the cycloalkenyl group of the cycloalkyl of the alkynyl of the alkenyl of the alkyl of alkyl, replacement, alkenyl, replacement, alkynyl, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement, aryl, replacement, heteroaryl, replacement, heterocycle and replacement as defined herein.

" sulfo-acyl group " refer to group H-C (S)-, alkyl-C (S)-, alkyl-the C (S) replaced-, alkenyl-C (S)-, alkenyl-the C (S) replaced-, alkynyl-C (S)-, alkynyl-the C (S) replaced-, cycloalkyl-C (S)-, cycloalkyl-the C (S) replaced-, cycloalkenyl group-C (S)-, cycloalkenyl group-the C (S) replaced-, aryl-C (S)-, aryl-the C (S) replaced-, heteroaryl-C (S)-, heteroaryl-the C (S) replaced-, heterocycle-C (S)-and heterocycle-C (S) of replacing-, alkyl wherein, the alkyl replaced, alkenyl, the alkenyl replaced, alkynyl, the alkynyl replaced, cycloalkyl, the cycloalkyl replaced, cycloalkenyl group, the cycloalkenyl group replaced, aryl, the aryl replaced, heteroaryl, the heteroaryl replaced, the heterocycle of heterocycle and replacement as defined herein.

" mercaptan " refers to group-SH.

" alkylthio " refers to group-S-alkyl, and wherein alkyl as defined herein.

" alkylthio of replacement " refers to group-S-(alkyl of replacement), and the alkyl wherein replaced as defined herein.

" thiocarbonyl " refer to divalent group-C (S)-, its be equal to-C (=S)-.

" thioketones " refers to atom (=S).

" thiocyanic ester " refer to group-SCN.

" solvate " refers to the compound or its salt of being combined with the solvent of stoichiometry or nonstoichiometry amount.Preferred solvent is volatile, nontoxic and/or delivers medicine to the people with trace is acceptable.Suitable solvate comprises water.

" steric isomer " refers to the compound that the chirality of one or more Stereocenters is different.Steric isomer comprises enantiomorph and diastereomer.

" tautomer " refers to the change form of the compound that the position of proton is different, such as enol-one and imine-enamine tautomerism body, or tautomeric form such as pyrazoles, imidazoles, benzoglyoxaline, triazole and the tetrazolium of the heteroaryl that contains the annular atoms that simultaneously is connected to ring-NH-part and ring=N-part.

" prodrug " refers to any derivative that the compounds of this invention of the compounds of this invention or its active metabolite or its residue can be provided directly or indirectly when delivering medicine to individuality.Particularly preferred derivative and prodrug for example are, for example, when this compound administration can be increased to the material (can make the compound of oral administration be easier to absorb in blood) of the bioavailability of the compounds of this invention or can improve with respect to parent material the convective material that parent compound enters biology compartment (brain or lymphsystem) during in individuality.Prodrug comprises the ester-formin of the compounds of this invention.The example of ester prodrugs comprises manthanoate, acetic ester, propionic ester, butyric ester, acrylate and ethyl succinate derivative.The General Introduction of prodrug can be referring to T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, the 14th volume of A.C.S.Symposium Series and Edward B.Roche compile, Bioreversible Carriersin Drug Design, American Pharmaceutical Association and PergamonPress, 1987, at this, they are incorporated herein by reference.

" pharmacologically acceptable salt " refers to the pharmacologically acceptable salt of compound, and described salt is derived from various organic and inorganic counter ion known in the art, and comprises for example sodium salt, potassium, calcium, magnesium, ammonium and tetra-allkylammonium; And, when molecule contains basic group, the salt of organic or inorganic acid such as hydrochloride, hydrobromate, tartrate, mesylate, acetate, maleate and oxalate.This term also comprises the pharmacologically acceptable salt of steric isomer, tautomer, ester and the prodrug of this compound.

" patient " refers to Mammals, and comprises people and inhuman Mammals.

" treatment " of patient disease refers to 1) prevent from tending to sick or also not show the patient of disease symptoms sick; 2) suppress disease or stop its development; Or 3) improve or cause the degeneration of disease.

" selectivity " mentioned suppresses to refer to compound, composition or the chemical type of the specific target of preferential inhibition or target class.The selectivity that means " CSF-1R selectivity suppress " mentioned suppress CSF-1R and optionally similar kinases receptors such as PDGFR.In certain embodiments, the inhibition of the selectivity of CSF-1R refers to respect to the Raf kinases and preferentially suppresses CSF-1R." selectivity ", " target ", " specific " or " preferentially " suppress and do not mean that for all other kinases or acceptors not have suppress active fully.

" CSF-1R inhibitor " refers to the compound that can suppress CSF-1R.Preferably the CSF-1R inhibitor optionally suppresses CSF-1R with respect to other target spot.In one embodiment, the CSF-1R inhibitor optionally suppresses CSF-1R with respect to the Raf kinases.In a preferred embodiment, described selectivity suppresses to refer to that Compound Phase of the present invention is for the Raf kinases, to CSF-1R be at least 2:1 in conjunction with selectivity, preferably be at least 5:1, more preferably be at least 10:1.

Except as otherwise noted, do not have in this article clearly defined substituent name then to name the adjacent functional group that points to tie point to obtain by the terminal part of first naming functional group.For example, substituting group " arylalkyl oxygen base carbonyl " refer to group (aryl)-(alkyl)-O-C (O)-.

Can be understood as, in the group of all replacements defined above, by definition, use the resulting polymkeric substance of further substituting group replacement self (for example to there is the aryl of the aryl of replacement as substituent replacement, the substituted aryl of this substituting group itself replaces, its further substituted aryl replacement etc.) be not included in the scope of this paper.In this case, described substituent maximum number is 3.The aryl that for example, will there is aryl-(aryl of replacement) that two other continuous replacements of aryl of replacement of aryl of replacement are limited in-replace-replacement.

Similarly, can be understood as, above-mentioned definition does not comprise unallowed substitute mode (methyl for example replaced by 5 fluorin radicals).This unallowed substitute mode is well known by persons skilled in the art.

A kind of embodiment relates to compound, steric isomer, tautomer, solvate, oxide compound, ester and prodrug, its pharmacologically acceptable salt and relevant composition and the method for formula (I), and its Chinese style (I) is:

And wherein X is O, S or S (O);

N is 0,1 or 2; And

In certain embodiments, X is O.

In certain embodiments, X is S.

In certain embodiments, X is S (O).

In certain embodiments, the oxide compound of formula (I) is that X wherein is S (O) ₂oxide compound.

In certain embodiments, R ²hydrogen or methyl.

In certain embodiments, R ¹by 0,1,2 or 3 independently selected from the following alkyl that substituting group replaced: the alkylsulfonyl of halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryloxy, aminocarboxyl, carboxyl ester, carboxyl and replacement.That replace or unsubstituted R ¹alkyl comprises that branched hydrocarbyl is such as penta-2-base.

In certain embodiments, R ¹be-LR ^1a, wherein L is the alkylidene group of covalent linkage, alkylidene group or replacement, and R _1abe selected from cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and heteroaryl, wherein each R ^1athat replace or unsubstituted.

In some aspects, R ^1abe selected from phenyl, furans-2-base, furans-3-base, tetrahydropyrans-2-base, tetrahydropyran-3-base, tetrahydropyran-4-base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclohexenyl, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, 2,3-Dihydrobenzofuranes, 2,3-dihydrobenzo [b] [1,4] dioxin, 3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] dioxa

, pyrazinyl, pyrrolidyl, piperidyl, piperidone, pyrrolidone, pyridine-2 (1H)-one, morpholino, naphthyl, two ring [3.1.1] heptane, two ring [2.2.1] heptane, 1,2,3,4-naphthane, 2,3-dihydro-1H-indenes and azacycloheptan-2-one, wherein each R ^1athat replace or unsubstituted.In some aspects, L is covalent linkage.

In certain embodiments, L is covalent linkage.

In some embodiment of formula (I) compound, L by 0,1,2 or 3 independently selected from the following alkylidene group that substituting group replaced: the alkyl of alkyl, replacement, hydroxyl, alkoxyl group, halogenated alkoxy, aminocarboxyl, carboxyl ester and carboxyl.

In some embodiment of formula (I) compound, R ¹be

or

Wherein dotted line is saturated bond or unsaturated link(age);

Wherein L is the alkylidene group of covalent linkage or alkylidene group or replacement; And

R ¹⁰, R ¹¹and R ¹²heteroaryl independently selected from aryl, heteroaryl and the replacement of the heterocyclic radical of the cycloalkyl of the amino of the alkoxyl group of the alkyl of hydrogen, halogen, hydroxyl, alkyl, replacement, alkoxyl group, replacement, amino, replacement, cycloalkyl, replacement, heterocyclic radical, replacement, aryl, replacement; Or R ¹¹with R ¹²connect together to form and be selected from following group: the heteroaryl of the heterocyclic radical of the aryl of aryl, replacement, heterocyclic radical, replacement, heteroaryl and replacement.In some aspects, R ¹⁰hydrogen.

In certain embodiments, dotted line is saturated bond, forms thus cyclohexyl.

In some embodiment of formula (I) compound, L is covalent linkage.

In some embodiment of formula (I) compound, L is the methylene radical of methylene radical or replacement.

In some embodiment of formula (I) compound, when L is not covalent linkage, L is replaced by the alkyl of alkyl, replacement, carboxyl, aminocarboxyl and carboxyl ester.

In some embodiment of formula (I) compound, R ¹⁰, R ¹¹and R ¹²alkyl and alkoxyl group independently selected from hydrogen, halogen, hydroxyl, alkyl, replacement.

In some embodiment of formula (I) compound, R ¹⁰, R ¹¹and R ¹²in at least one be hydroxyl.

In certain embodiments, R ¹¹and R ¹²alkyl and alkoxyl group independently selected from hydrogen, halogen, alkyl, replacement.

In certain embodiments, R ¹¹with R ¹²connect together and form the aryl of aryl or replacement.

In certain embodiments, R ¹it is the alkyl of alkyl or replacement.

In certain embodiments, R ¹the alkyl replaced, wherein R ¹substituting group be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkyl, heterocyclic radical, the replacement of aryl, cycloalkyl, the replacement of alkyl, aryl, replacement.

In certain embodiments, R ¹the alkyl that replaces, R wherein ¹substituting group be selected from the heteroaryl of heterocyclic radical, heteroaryl and the replacement of alkyl, aryl, cycloalkyl, heterocyclic radical, replacement.

In certain embodiments, R ¹the alkyl that replaces, R wherein ¹substituting group be the cycloalkyl of cycloalkyl or replacement.

In certain embodiments, R ¹the alkyl replaced, wherein R ¹substituting group be the cycloalkyl of cycloalkyl or replacement.

In certain embodiments, R ¹be selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of cycloalkenyl group, heterocyclic radical, the replacement of cycloalkyl, cycloalkenyl group, the replacement of cycloalkyl, replacement.

In certain embodiments, R ¹be selected from the heterocyclic radical of cycloalkyl, heterocyclic radical and the replacement of cycloalkyl, replacement.

In certain embodiments, R ³acyl amino or aminocarboxyl.

In certain embodiments, R ³-C (O) NH-LR ^3a, wherein L is the alkylidene group of covalent linkage, alkylidene group or replacement, and R ^3abe selected from the heterocyclic radical of cycloalkyl, heterocyclic radical and replacement of alkoxyl group, cycloalkyl, the replacement of alkyl, haloalkyl, amino, acyl amino, (carboxyl ester) amino, hydroxyl, alkoxyl group, replacement.

In certain embodiments, R ³-C (O) NHCH ₃.

In certain embodiments, R ³it is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.

In certain embodiments, R ³be selected from pyrazol-1-yl, pyrazole-3-yl, pyrazoles-4-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-yl, pyrimidin-3-yl, pyrimidine-2-base, thiazolyl, tetrazyl, imidazoles-1-base, imidazoles-2-base, imidazo-3-yl, pyrazinyl, phenyl, tetrahydropyridine, 1H-pyrrolo-[2,3-b] pyridine, furyl, oxazole, oxadiazole, cyclopropyl, cyclohexyl, cyclohexenyl, piperidyl, morpholino, tetrahydrochysene-1H-benzo [d] imidazoles, pyrrolidyl, piperazinyl and piperazine-2-ketone, wherein each R ³that replace or unsubstituted.

In certain embodiments, R ⁴hydrogen.

In certain embodiments, R ⁵hydrogen.

Some embodiment and with above-mentioned embodiment in the embodiment of any combination in, n is 0, R ⁴and R ⁵hydrogen, and R ³be selected from alkoxyl group, carboxyl, the carboxyl ester of amino, acyl group, acyl amino, alkoxyl group, the replacement of heterocyclic radical, amino, the replacement of heteroaryl, heterocyclic radical, the replacement of aryl, heteroaryl, the replacement of alkyl, formonitrile HCN, aryl, the replacement of hydrogen, halogen, replacement, alkylsulfonyl, amino-sulfonyl and the aminocarboxyl of replacement.

In certain embodiments, R ⁴and R ⁵connect together and form the aryl of aryl or replacement.

Another embodiment relates to formula (IIa) or compound (IIb), steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and method,

or

Wherein X is O or S;

Wherein dotted line is saturated bond or unsaturated link(age);

Wherein L is the alkylidene group of covalent linkage or alkylidene group or replacement;

In formula (IIa) or (IIb) in some embodiment of compound, X is O.

In formula (IIa) or (IIb) in some embodiment of compound, X is S.

In certain embodiments, dotted line is saturated bond, forms thus cyclohexyl.

In formula (IIa) or (IIb) in some embodiment of compound, L is covalent linkage.

In formula (IIa) or (IIb) in some embodiment of compound, L is the methylene radical of methylene radical or replacement.

In formula (IIa) or (IIb) in some embodiment of compound, L is replaced by the alkyl of alkyl, replacement, carboxyl, aminocarboxyl or carboxyl ester.

In formula (IIa) or (IIb) in some embodiment of compound, R ¹⁰, R ¹¹and R ¹²alkyl and alkoxyl group independently selected from hydrogen, halogen, hydroxyl, alkyl, replacement.

In formula (IIa) or (IIb) in some embodiment of compound, R ¹⁰, R ¹¹and R ¹²in at least one be hydroxyl.

In formula (IIa) or (IIb) in some embodiment of compound, R ¹¹and R ¹²alkyl and alkoxyl group independently selected from hydrogen, halogen, alkyl, replacement.

In formula (IIa) or (IIb) in some embodiment of compound, R ¹¹with R ¹²connect together and form the aryl of aryl or replacement.

In formula (IIa) or (IIb) in some embodiment of compound, R ³acyl amino or aminocarboxyl.

In formula (IIa) or (IIb) in some embodiment of compound, R ³-C (O) NHCH ₃.

In formula (IIa) or (IIb) in some embodiment of compound, R ³it is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.

Wherein X is O or S;

In some embodiment of formula (IIIa) compound, X is O.

In some embodiment of formula (IIIa) compound, X is S.

In some embodiment of formula (IIIa) compound, R ¹it is the alkyl be substituted by cycloalkyl.

In some embodiment of formula (IIIa) compound, R ³acyl amino or aminocarboxyl.

In some embodiment of formula (IIIa) compound, R ³-C (O) NHCH ₃.

In some embodiment of formula (IIIa) compound, R ³it is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.

Another embodiment relates to compound, steric isomer, tautomer, molten and agent compound, its pharmacologically acceptable salt and relevant composition and the method for formula (IIIb), and its Chinese style (IIIb) is

Wherein X is O or S;

In some embodiment of formula (IIIb) compound, X is O.

In some embodiment of formula (IIIb) compound, X is S.

In some embodiment of formula (IIIb) compound, R ¹be selected from the heterocyclic radical of cycloalkyl, heterocyclic radical and the replacement of cycloalkyl, replacement.

In some embodiment of formula (IIIb) compound, R ³acyl amino or aminocarboxyl.

In some embodiment of formula (IIIb) compound, R ³-C (O) NHCH ₃.

In some embodiment of formula (IIIb) compound, R ³it is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.

In some embodiment of formula (IIIb) compound, R ³-C (O) NH-LR ^3a, wherein L is the alkylidene group of covalent linkage, alkylidene group or replacement, and R ^3abe selected from the heterocyclic radical of cycloalkyl, heterocyclic radical and replacement of alkoxyl group, cycloalkyl, the replacement of alkyl, haloalkyl, amino, acyl amino, (carboxyl ester) amino, hydroxyl, alkoxyl group, replacement.

In some embodiment of formula (IIIb) compound, R ³be selected from pyrazol-1-yl, pyrazole-3-yl, pyrazoles-4-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-yl, pyrimidin-3-yl, pyrimidine-2-base, thiazolyl, tetrazyl, imidazoles-1-base, imidazoles-2-base, imidazo-3-yl, pyrazinyl, phenyl, tetrahydropyridine, 1H-pyrrolo-[2,3-b] pyridine, furyl, oxazole, oxadiazole, cyclopropyl, cyclohexyl, cyclohexenyl, piperidyl, morpholino, tetrahydrochysene-1H-benzo [d] imidazoles, pyrrolidyl, piperazinyl and piperazine-2-ketone, wherein each R ³that replace or unsubstituted.

Another embodiment relates to compound, steric isomer, tautomer, solvate, oxide compound, ester and prodrug, its pharmacologically acceptable salt and relevant composition and the method for formula (IV), and its Chinese style (IV) is

And wherein X is O or S;

P is 0,1 or 2;

R ⁸be selected from cycloalkyl, THP trtrahydropyranyl, morpholino, the pyridyl of cycloalkyl, replacement, and when p is 0, R ^1ait is optionally the 2-p-methoxy-phenyl.

In certain embodiments, X is S.

In certain embodiments, p is 0.

Another embodiment relates to compound, steric isomer, tautomer, solvate, oxide compound, ester and prodrug, its pharmacologically acceptable salt and relevant composition and the method for formula (V), and its Chinese style (V) is

Wherein X is O or S;

In certain embodiments, X is S.

In certain embodiments, L is covalent linkage or alkylidene group.

In certain embodiments, R ⁹it is the cyclohexyl of cyclohexyl or replacement.

Representational compound is as shown in table 1.

Table 1

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

23

O

Cyclopentyl

H

-C(O)NHCH ₃

24

O

Cyclohexyl

H

-C(O)NHCH ₃

25

O

(2-morpholine-4-ylmethyl)

H

-C(O)NHCH ₃

26

O

Phenyl

H

-C(O)NHCH ₃

27

O

(4-chlorobenzyl)

H

-C(O)NHCH ₃

28

O

2,4-Dimethoxyphenyl

H

-C(O)NHCH ₃

29

O

Cyclohexyl

H

-NHC(O)CH ₃

30

O

Tetrahydropyran-4-base

H

-C(O)NHCH ₃

31

O

2-(R)-1-(2-p-methoxy-phenyl)

H

-C(O)NHCH ₃

32

O

The 2-chlorobenzyl

H

-C(O)NHCH ₃

33

O

2,5-difluorobenzyl

H

-NHC(O)CH ₃

34

O

Cyclohexyl methyl

H

-NHC(O)CH ₃

35

O

2-(R)-phenylacetic acid

H

-C(O)NHCH ₃

36

O

2-(R)-formic acid methyl nitrosourea

H

-C(O)NHCH ₃

37

O

2-(R)-hydroxyl-1-phenyl-ethyl

H

-C(O)NHCH ₃

38

O

2-(S)-phenylacetic acid

H

-C(O)NHCH ₃

39

O

2-(S)-formic acid methyl nitrosourea

H

-C(O)NHCH ₃

40

O

Pyridine-2-ylmethyl

H

-C(O)NHCH ₃

41

O

Benzyl

H

-C(O)NHCH ₃

42

O

The 3-chlorobenzyl

H

-C(O)NHCH ₃

43

O

2-(2-pyrrolidin-1-yl ethyl) phenyl

H

-C(O)NHCH ₃

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

44

O

2-(2-piperidin-1-yl ethyl) phenyl

H

-C(O)NHCH ₃

45

O

2-(4-methyl-imidazoles-1-yl) phenyl

H

-C(O)NHCH ₃

46

O

2-oxazole-5-base phenyl

H

-C(O)NHCH ₃

47

O

2-(glyoxal ethyline-1-yl) phenyl

H

-C(O)NHCH ₃

48

O

2-morpholine-4-base-ethyl

H

-C(O)NHCH ₃

49

O

(1S, 2R)-2-hydroxyl-indane-1-base

H

-C(O)NHCH ₃

50

O

(1R, 2S)-2-hydroxyl-indane-1-base

H

-C(O)NHCH ₃

51

O

2-(R)-3-hydroxyl-1-phenyl propyl

H

-C(O)NHCH ₃

52

O

(1S, 2S)-2-hydroxy-cyclohexyl

H

-C(O)NHCH ₃

53

O

2-(R)-phenylacetic acid methyl ester

H

-C(O)NHCH ₃

54

O

2-(R)-cyclohexyl ethyl

H

-C(O)NHCH ₃

55

O

2-(S)-phenylacetic acid methyl esters

H

-C(O)NHCH ₃

56

O

2-(S)-hydroxyl-1-phenylethyl

H

-C(O)NHCH ₃

57

O

The pyridin-4-yl methyl

H

-C(O)NHCH ₃

58

O

2-piperidin-1-yl ethyl

H

-C(O)NHCH ₃

59

O

The pyridin-3-yl methyl

H

-C(O)NHCH ₃

60

O

Cyclohexyl methyl

H

-C(O)OH

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

61

O

Styroyl

H

-C(O)NHCH ₃

62

O

2-(R)-cyclohexyl methyl-carbamyl ylmethyl

H

-C(O)NHCH ₃

63

O

2-pyrrolidin-1-yl ethyl

H

-C(O)NHCH ₃

64

O

2-piperidin-1-yl ethyl

H

-C(O)NHCH ₃

65

O

2,3-dihydrobenzo [Isosorbide-5-Nitrae] dioxin-5-ylmethyl

H

-C(O)NHCH ₃

66

O

2-(S)-1-cyclohexyl-2-hydroxyethyl

H

-C(O)NHCH ₃

67

O

2-(R)-1-cyclohexyl-2-hydroxyethyl

H

-C(O)NHCH ₃

68

O

Cyclohexyl methyl

H

-C(O)NHNHC(O)OC(CH ₃) ₃

69

O

Cyclohexyl methyl

H

-C(O)NH ₂

70

O

Hexamethylene-3-thiazolinyl

H

-C(O)NHCH ₃

71

O

2,4-difluorobenzyl

H

-C(O)NHCH ₃

72

O

The 2-bromobenzyl

H

-C(O)NHCH ₃

73

O

The fluoro-5-methoxy-benzyl of 2-

H

-C(O)NHCH ₃

74

O

3-(2-morpholine-4-base ethyl) phenyl

H

-C(O)NHCH ₃

75

O

The naphthenic acid ethyl ester

H

-C(O)NHCH ₃

76

O

2,6-dichloro benzyl

H

-C(O)NHCH ₃

77

O

2,3-dichloro benzyl

H

-C(O)NHCH ₃

78

O

The chloro-6-luorobenzyl of 2-

H

-C(O)NHCH ₃

79

O

2,3-difluorobenzyl

H

-C(O)NHCH ₃

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

80

O

Cyclohexyl methyl

H

-CH ₂OH

81

O

Cyclohexyl methyl

H

Oxadiazolyl

82

O

Cyclohexyl methyl

H

-CN

83

O

2,5-dimethoxy-benzyl

H

-C(O)NHCH ₃

84

O

2,6-dimethoxy-benzyl

H

-C(O)NHCH ₃

85

O

2-dimethylamino benzyl

H

-C(O)NHCH ₃

86

O

The 2-aminobenzyl

H

-C(O)NHCH ₃

87

O

2,6-difluorobenzyl

H

-C(O)NHCH ₃

88

O

2-morpholine-4-base benzyl

H

-C(O)NHCH ₃

89

O

The 2-methyl-benzyl

H

-C(O)NHCH ₃

90

O

3,4-dimethoxy-benzyl

H

-C(O)NHCH ₃

91

O

2,3-dimethoxy-benzyl

H

-C(O)NHCH ₃

92

O

2,4-dimethoxy-benzyl

H

-C(O)NHCH ₃

93

O

Naphthenic acid-methyl

H

-C(O)NHCH ₃

94

O

2,3-dihydrobenzo [Isosorbide-5-Nitrae] dioxin-5-base

H

-C(O)NHCH ₃

95

O

Benzo [1,3] dioxole-5-base

H

-C(O)NHCH ₃

96

O

The 2-ethoxy benzyl

H

-C(O)NHCH ₃

97

O

The 2-trifluoromethyl benzyl

H

-C(O)NHCH ₃

98

O

Sec.-propyl

H

-C(O)NHCH ₃

99

O

Isobutyl-

H

-C(O)NHCH ₃

100

O

The tertiary butyl

H

-C(O)NHCH ₃

101

O

The suberyl methyl

H

-C(O)NHCH ₃

102

O

Tetrahydrofuran (THF)-2-ylmethyl

H

-C(O)NHCH ₃

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

103

O

Benzyl-piperidin-4-yl

H

-C(O)NHCH ₃

104

O

1,2,3,4-naphthane-1-base

H

-C(O)NHCH ₃

105

O

2-pyrazol-1-yl benzyl

H

-C(O)NHCH ₃

106

O

Benzyl

CH3

H

-C(O)NHCH ₃

107

O

1-phenyl-piperidines-4-base

H

-C(O)NHCH ₃

108

O

3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] dioxa

-6-ylmethyl

H

-C(O)NHCH ₃

109

O

Cyclohexyl methyl

H

5-methyl isophthalic acid H-imidazoles-2-base

110

O

2,3-dihydrobenzo [Isosorbide-5-Nitrae] dioxin-5-carbonyl

H

-C(O)NHCH ₃

111

O

Cyclohexyl methyl

H

-CH ₂NH ₂

112

O

The formic acid methyl nitrosourea

H

-C(O)NHCH ₃

113

O

2,4,6-trimethoxy benzyl

H

-C(O)NHCH ₃

114

O

The chloro-2-methoxy-benzyl of 5-

H

-C(O)NHCH ₃

115

O

The fluoro-2-methoxy-benzyl of 5-

H

-C(O)NHCH ₃

116

O

The fluoro-6-methoxy-benzyl of 2-

H

-C(O)NHCH ₃

117

O

2-is chloro-3, the 4-dimethoxy-benzyl

H

-C(O)NHCH ₃

118

O

2-piperidin-1-yl benzyl

H

-C(O)NHCH ₃

119

O

2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-2-ylmethyl

H

-C(O)NHCH ₃

120

O

4-benzyl-morpholine-2-ylmethyl

H

-C(O)NHCH ₃

121

O

The chloro-6-methoxy-benzyl of 2-

H

-C(O)NHCH ₃

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

122

O

2,3-dihydrobenzo [Isosorbide-5-Nitrae] dioxin-6-ylmethyl

H

-C(O)NHCH ₃

123

O

2-(2,3-dihydrobenzo [Isosorbide-5-Nitrae] dioxin-5-yl) ethyl

H

-C(O)NHCH ₃

124

O

2,3-Dihydrobenzofuranes-5-ylmethyl

H

-C(O)NHCH ₃

125

O

2-(2,3-dihydrobenzo [Isosorbide-5-Nitrae] dioxin-5-yl) ethyl

H

-C(O)NHCH ₃

126

S

The chloro-3-trifluoromethyl of 4-

H

-C(O)NHCH ₃

127

S

The 2-chlorobenzyl

H

-C(O)NHCH ₃

128

S

Cyclohexyl methyl

H

-C(O)NHCH ₃

129

S

2-(R)-1-(2-p-methoxy-phenyl) ethyl

H

-C(O)NHCH ₃

130

S

2,4-dichloro benzyl

H

-C(O)NHCH ₃

131

S

2-(R)-1-phenylethyl

H

-C(O)NHCH ₃

132

S

The 2-methoxy-benzyl

H

-C(O)NHCH ₃

133

S

The 2-styroyl

H

-C(O)NHCH ₃

134

S

2,3-dichloro benzyl

H

-C(O)NHCH ₃

135

S

Cyclohexyl

H

-C(O)NHCH ₃

136

S

The 3-methylcyclohexyl

H

-C(O)NHCH ₃

137

S

(1S, 2S)-2-hydroxy-cyclohexyl

H

-C(O)NHCH ₃

138

S

2-(R)-cyclohexyl ethyl

H

-C(O)NHCH ₃

139

S

2,5-difluorobenzyl

H

-C(O)NHCH ₃

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

140

S

The 2-luorobenzyl

H

-C(O)NHCH ₃

141

S

The tetrahydropyran-4-base methyl

H

-C(O)NHCH ₃

142

S

2-morpholine-4-base benzyl

H

-C(O)NHCH ₃

143

S

2-pyrazol-1-yl-benzyl

H

-C(O)NHCH ₃

144

S

2-dimethylamino benzyl

H

-C(O)NHCH ₃

145

S

2,6-dimethoxy-benzyl

H

-C(O)NHCH ₃

146

S

2,5-dimethoxy-benzyl

H

-C(O)NHCH ₃

147

S

2,3-difluorobenzyl

H

-C(O)NHCH ₃

148

S

The suberyl methyl

H

-C(O)NHCH ₃

149

S

2,6-difluorobenzyl

H

-C(O)NHCH ₃

150

S

Pyridine-2-ylmethyl

H

-C(O)NHCH ₃

151

S

3,4-dimethoxy-benzyl

H

-C(O)NHCH ₃

152

S

2,3-dihydrobenzo [Isosorbide-5-Nitrae] dioxin-5-ylmethyl

H

-C(O)NHCH ₃

153

S

2-piperidin-1-yl-benzyl

H

-C(O)NHCH ₃

154

S

The pyridin-3-yl methyl

H

-C(O)NHCH ₃

155

S

(1R, 2R)-2-benzyloxy cyclohexyl

H

-C(O)NHCH ₃

156

S

(1S, 2S)-2-benzyloxy cyclohexyl

H

-C(O)NHCH ₃

157

S

(1R, 2R)-2-hydroxy-cyclohexyl

H

-C(O)NHCH ₃

158

S

2,6-dichloro benzyl

H

-C(O)NHCH ₃

159

S

Cyclohexyl methyl

H

-C(O)NH(CH ₂) ₂OCH3

The compound sequence number

X

R ¹

R ²

R ⁴

R ⁵

R ³

160

S

Cyclohexyl methyl

H

-C(O)NH(CH ₂) ₂N(CH ₃) ₂

161

S

4-sulfamyl-benzyl

H

-C(O)NHCH ₃

Representational formula (I) compound for example comprises

4-[2-(the bromo-phenyl amino of 4-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-1-phenyl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-morpholine-4-base-phenyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-6-yl)-[6-(6,7-dimethoxy-quinolyl-4 oxygen base)-benzoxazoles-2-yl]-amine,

4-[2-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-6-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(1-thiazol-2-yl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((S)-1-phenyl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 2,4-bis-)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(3-methyl-cyclohexyl base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-methoxyl group-phenyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-oxyethyl group-phenyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1S, 2S, 3S, 5R)-2,6,6-trimethylammonium-bis-ring [3.1.1] heptan-3-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

[6-(6,7-dimethoxy-quinolyl-4 oxygen base)-benzoxazoles-2-yl]-((R)-1-phenyl-ethyl)-amine,

4-{2-[((1S, 2R, 4R)-7,7-dimethyl-bis-ring [2.2.1] heptan-2-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-methoxyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-1-naphthalene-1-base-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-1-phenyl-propyl group amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((S)-1-naphthalene-2-base-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-(amino-benzoxazoles of 2-cyclobutyl-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-(amino-benzoxazoles of 2-cyclopentyl-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-(amino-benzoxazoles of 2-cyclohexyl-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-morpholine-4-ylmethyl-phenyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-(2-phenylamino-benzoxazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 4-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2,4-dimethoxy-phenyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

N-[4-(amino-benzoxazoles of 2-cyclohexyl-6-base oxygen base)-pyridine-2-yl]-ethanamide,

4-[2-(tetrahydrochysene-pyrans-4-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(R)-1-(2-methoxyl group-phenyl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

N-{4-[2-(the chloro-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-yl }-ethanamide,

4-[2-(the fluoro-benzylamino of 2,5-bis-)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

N-{4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-yl }-ethanamide,

(R)-[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-phenyl-acetic acid,

4-{2-[((R)-methylamino formyl radical-phenyl-methyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-2-hydroxyl-1-phenyl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

(S)-[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-phenyl-acetic acid,

4-{2-[((S)-methylamino formyl radical-phenyl-methyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(pyridine-2-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-(2-benzylamino-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 3-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[2-(2-pyrrolidin-1-yl-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[2-(2-piperidin-1-yl-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[2-(4-methyl-imidazoles-1-yl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-oxazole-5-base-phenyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[2-(2-methyl-imidazoles-1-yl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-(amino-benzoxazoles of 2--6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-(2-hydroxyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-{2-[2-(2-morpholine-4-base-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1S, 2R)-2-hydroxyl-indane-1-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1R, 2S)-2-hydroxyl-indane-1-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-3-hydroxyl-1-phenyl-propyl group amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

(R)-[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-phenyl-acetic acid methyl ester,

4-[2-((R)-1-cyclohexyl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea; (S)-[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-phenyl-acetic acid methyl ester

4-[2-((S)-2-hydroxyl-1-phenyl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(pyridin-4-yl methyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[3-(2-piperidin-1-yl-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(pyridin-3-yl methyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid,

4-(amino-benzoxazoles of 2-styroyl-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-{2-[((R)-cyclohexyl-methylamino formyl radical-methyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-pyrrolidin-1-yl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-piperidin-1-yl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-((S)-1-cyclohexyl-2-hydroxyl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-1-cyclohexyl-2-hydroxyl-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

N '-4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-carbonyl }-the hydrazine t-butyl formate,

4-[2-(cyclohexylmethyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-benzoic acid amides,

4-[2-(hexamethylene-3-alkenyl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2,4-bis-)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the bromo-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-5-methoxyl group-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[3-(2-morpholine-4-base-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-methyl }-the naphthenic acid ethyl ester,

4-[2-(the chloro-benzylamino of 2,6-bis-)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 2,3-bis-)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of the chloro-6-of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2,3-bis-)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-yl }-methyl alcohol,

Cyclohexyl methyl-[6-(2-[1,3,4] oxadiazoles-2-base-pyridin-4-yl oxygen base)-benzoxazoles-2-yl]-amine,

4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formonitrile HCN,

4-[2-(2,5-dimethoxy-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2,6-dimethoxy-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-dimethylamino-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-amino-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2,6-bis-)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-morpholine-4-base-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-methyl-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(3,4-dimethoxy-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2,3-dimethoxy-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2,4-dimethoxy-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-methyl }-naphthenic acid,

4-[2-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(benzo [1,3] dioxole-5-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-oxyethyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-trifluoromethyl-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-(2-isopropylamino-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-(2-isobutylamino-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-(amino-benzoxazoles of the 2-tertiary butyl-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-[2-(suberyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(tetrahydrochysene-furans-2-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(1-benzyl-piperidin-4-yl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(1,2,3,4-tetrahydrochysene-naphthalene-1-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-pyrazol-1-yl-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(benzyl-methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(1-phenyl-piperidines-4-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(3,4-dihydro-2H-benzo [b] [Isosorbide-5-Nitrae] dioxa

-6-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

Cyclohexyl methyl-and 6-[2-(5-methyl isophthalic acid H-imidazoles-2-yl)-pyridin-4-yl oxygen base]-benzoxazoles-2-yl }-amine,

4-{2-[(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-carbonyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

[6-(2-amino methyl-pyridin-4-yl oxygen base)-benzoxazoles-2-yl]-cyclohexyl methyl-amine,

4-{2-[(1-methylamino formyl radical-cyclohexyl methyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2,4,6-trimethoxy-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-2-methoxyl group-benzylamino of 5-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-2-methoxyl group-benzylamino of 5-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-6-methoxyl group-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-chloro-3,4-dimethoxy-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-piperidin-1-yl-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-2-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(4-benzyl-morpholine-2-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-6-methoxyl group-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-6-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[2-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(2,3-dihydro-cumarone-5-ylmethyl)-amino]-benzoxazoles-6-base oxygen base-pyridine-2-formic acid methyl nitrosourea and

4-{2-[1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea

4-[2-(the chloro-3-trifluoromethyl-phenyl of 4-amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 2-)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(cyclohexyl methyl-amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(R)-1-(2-methoxyl group-phenyl)-ethylamino]-benzothiazol-6-yl oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 2,4-bis-)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-1-phenyl-ethylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-methoxyl group-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-(2-styroyl amino-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 2,3-bis-)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-(2-cyclohexyl amino-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea,

4-[2-(3-methyl-cyclohexyl base amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((R)-1-cyclohexyl-ethylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2,5-mono-or two)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2-)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(tetrahydrochysene-pyrans-4-ylmethyl)-amino]-benzothiazol-6-yl oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-morpholine-4-base-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-pyrazol-1-yl-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-dimethylamino-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2,6-dimethoxy-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2,5-dimethoxy-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2,3-bis-)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(suberyl methyl-amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the fluoro-benzylamino of 2,6-bis-)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(pyridine-2-ylmethyl)-amino]-benzothiazol-6-yl oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(3,4-dimethoxy-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-ylmethyl)-amino]-benzothiazol-6-yl oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-(2-piperidin-1-yl-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-{2-[(pyridin-3-yl methyl)-amino]-benzothiazol-6-yl oxygen base }-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1R, 2R)-2-benzyloxy-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1S, 2S)-2-benzyloxy-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-((1R, 2R)-2-hydroxyl-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea,

4-[2-(the chloro-benzylamino of 2,6-bis-)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, and

4-[2-(4-sulfamyl-benzylamino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea or its pharmacologically acceptable salt, tautomer, solvate or steric isomer.

In other embodiments, table 2,3 or 4 compound or steric isomer, tautomer, solvate, oxide compound, ester, prodrug or its pharmacologically acceptable salt are provided.

It will be evident to one skilled in the art that, the compounds of this invention, comprise formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) compound of compound or its steric isomer and any pharmacologically acceptable salt, ester, meta-bolites and the prodrug in them can carry out tautomerization, therefore can exist with various tautomeric forms, wherein the proton of molecule atom moves on another atom, and the chemical bond between the atom of this molecule rearranges thus.Referring to for example March, Advanced Organic Chemistry:Reactions, Mechanisms andStructures, the 4th edition, John Wiley & Sons, 69-74 page (1992).

Preferred embodiment, comprise formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or compound (V) or its tautomer and carbon atom that in them, any pharmacologically acceptable salt, ester, meta-bolites and prodrug can comprise Asymmetrical substitute.The carbon atom of described Asymmetrical substitute can produce the compound of the preferred embodiment existed with enantiomorph, diastereomer and other stereoisomeric forms in any ratio (can be defined according to the absolute stereo chemistry), such as (R)-or (S)-form.As a result, the independent steric isomer of all possible isomer of the compound of preferred embodiment, the pure form of its optically-active, its mixture, racemic mixture (or " racemize ladder "), the mixture of diastereomer and single diastereomer all will be taken into account.Term ＂ S ＂ used herein and ＂ R ＂ configuration are as IUPAC1974

pure Appl.Chem.45:13-30 (1976) defines.Term α and β are for the ring position of ring compound.α-the side of reference plane is sides that preferred substituting group is positioned at low numbered positions.Those substituting groups that are positioned at a relative side of reference plane are described to the β side.Should be noted that, this usage is different from the three-dimensional parent compound of ring-type, wherein ＂ α ＂ refer to ＂ on plane following ＂ and mean absolute configuration.Term α used herein and beta comfiguration as

the 203rd section institute of IV (1987) defines.

The method that is used for the treatment of the disease of CSF-1R mediation

The conduction of CSF-1R signal participates in growth and the transfer of tumour by 3 kinds of different mechanism.The first is that the expression of CSF-part and acceptor has seen the tumour cell (Scholl1994 that originates from female reproductive system (mammary gland, ovary, uterine endometrium, uterine neck); Kacinski1997; Nagan199; Kirma2007), and this express relevant with the xenotransplantation growth of mammary cancer and patient with breast cancer's poor prognosis.Two kinds of point mutation are found in the approximately 10-20% acute myelocytic leukemia, chronic granulocytic leukemia and the myelodysplasia patient's that are tested in a research CSF-1R, and find that a kind of sudden change can interrupt the upset of acceptor (Ridge1990).Yet, fail to confirm the incidence (Abu-Duhier2003) of suddenling change in research subsequently.Also found sudden change under some case of liver cancer (Yang2004) and idiopathic myelofibrosis (Abu-Duhier2003).

Pigmented villonodular synovitis (PVNS) and Tenosynovial giant cells tumour (TGCT) are the M-CSF gene fusion to the result of the transposition on glue protogene COL6A3, and cause the overexpression (West2006) of M-CSF.It is relevant with formed tumor mass that lateral effect is considered to, and the monocyte that this tumor mass is attracted by the cell that is expressed M-CSF forms.TGCT is the less tumour of removing the finger that can relatively easily the most often exist from them.PVNS has more aggressiveness, because it can appear at large joint part and be not easy to control by surgical operation.

The blocking-up of the transferring position of the second mechanism based at bone is by the signal conduction of M-CSF/CSF-1R, and it is induced bone to lure to split generation, bone resorption and molten bone and damages.Mammary gland, kidney and lung cancer are to have found the example of transferring to bone and causing the cancer of the molten osteopathia that causes the bone complication.The M-CSF discharged with interstitial by tumour cell induces the hematopoiesis myelomonocyte to be divided into ripe osteoclast together with the receptor activator RANKL of Nuclear factor kappa-B part.In this process, M-CSF plays licensing factor, to osteoclast, provides survival signal (Tanaka1993).Suppress the osteoclast activity of the molten osteopathia of CSF-1R kinase activity in likely suppressing to cause metastatic disease and associated bone event with micromolecular inhibitor unbalance in the differentiation of osteoclast and ripening process.Although mammary cancer, lung cancer and multiple myeloma cause molten bone damage usually, but, in prostate cancer, there is at first the scleroblast presentation to the transfer of bone, wherein, the bone forming activity increased causes producing " woven bone ", and this bone is different from the typical laminate structure of normal bone.In the progression of disease, bone injury shows the bone resorption of obvious molten bone component and high serum level, and it may be useful pointing out anti-absorption therapy.Confirmed that bisphosphonates only can suppress the formation of molten bone damage the quantity of minimizing bone dependency event in the male sex who suffers from hormone resistance metastasized prostate cancer, but its effect to the scleroblast damage remains now controversial and bisphosphonates shifts for the prevention bone or the hormone-sensitive prostate cancer is invalid.The effect of anti-absorption agent in the molten bone of mixed type/scleroblast prostate cancer is still at clinical study stage (Choueiri2006; Vessella2006).

The discovery of the third mechanism based on nearest: the tumor-associated macrophage of finding in the solid tumor of mammary gland, prostate gland, ovary and cervical cancer (TAM) (Bingle2002 relevant to poor prognosis; Pollard2004).Scavenger cell is raised in tumour by M-CSF and other chemokine.Then, scavenger cell can promote tumor growth by secretion angiogenesis factor, proteolytic enzyme and other somatomedin and cytokine, and can be blocked by suppressing the conduction of CSF-1R signal.Recently, the people such as Zins confirm (Zins2007), in tumour, after the corresponding siRNA of injection heterograft, the tumor growth that the expression of the siRNA of tumor necrosis factor alpha (TNF α), M-CSF or the combination of the two can reduce in the mouse heteroplastic transplantation model reaches 34% to 50%.Can reduce the M-CSF of mouse and cause the minimizing of scavenger cell in tumour by the siRNA of the target TNF α of people SW620 emiocytosis.In addition, when with the chemotherapeutics Combined Preparation, can produce 40% tumor growth with the Fab of anti-M-CSF antibody treatment MCF7 tumor xenogeneic graft and suppress, reverse the resistance of chemotherapeutics and improve the survival (Paulus2006) of mouse.

TAMs is a unique example that contact occurs between chronic inflammatory diseases and cancer.For the contact between inflammation and cancer, also there is other evidence, because many chronic diseases are all relevant with the risk of cancer increased, cancer appears at the position of chronic inflammatory diseases, has found the chemical mediator of inflammation in many cancers; The cell of inflammation or the removal of chemical mediator have suppressed the development of test-type cancer, and the life-time service anti-inflammatory agent has reduced the risk of some cancer.With contacting of cancer, be present in many inflammatory conditions, the gastritis that wherein Hp is induced is relevant with cancer of the stomach, schistosomicide and bladder cancer is relevant, HHV8 is relevant with the Kaposi sarcoma, endometriosis is relevant with ovarian cancer, prostatitis relevant with prostate cancer (Balkwill2005).Scavenger cell is the key cells in chronic inflammatory diseases, and their microenvironment is had to different responses.Have the scavenger cell of two types to be considered to the end of a continuous functional status: the M1 scavenger cell participates in 1 type reaction.These reactions relate to the activation of microbial product, kill subsequently the invasive organism body that produces the reactive oxygen intermediate.The other end endways is the M2 scavenger cell that participates in 2 type reactions, and it promotes cell proliferation, regulates inflammation and adaptive immunity and promotion reconstructed tissue, vasculogenesis and repairing (Mantovani2004).Cause the chronic inflammatory diseases of the tumour of establishing usually relevant with the M2 scavenger cell.The key cytokines of inducing inflammatory reaction is TNF-α, the same just as its title, and it can stimulate antineoplastic immune and hemorrhagic necrosis under high dosage, but recent findings, it can and serve as tumor promoter (Zins2007 by tumor cells expression; Balkwill2006).Still need to understand better the concrete effect of scavenger cell for tumour, comprise its function latent space and to its temporary transient dependency and with the dependency of specific tumors type.

In another embodiment, the bone loss that the Paget's disease (PDB) that is used for the treatment of periodontitis, histiocytosis X, osteoporosis, bone is provided, has caused because of cancer therapy, prosthese week osteolysis, glucocorticoid inducible the method for osteoporosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, inflammatory arthropathy and inflammation.

Rabello2006 proves, and SNPs and aggressive periodontitis in the CSFl gene are proportionate, and this disease is a kind of inflammatory periodontal tissue disease that causes the tooth loss due to frontal resorption.

(also being known as youth's lattice Chinese cell tissue cytosis, is LCH) proliferative disease of a kind of youth's lattice Chinese dendritic cell, the LCH damage that the osteoclast in this cytodifferentiation skeletonization and bone are outer in histiocytosis X.Youth's lattice Chinese cell carrys out the monocyte (Ginoux2006) of self-circulation.Have been found that the increase relevant to the severity of disease (da Costa2005) with the M-CSF level recorded in damage at serum.This disease mainly occurs in the child patient group, and become general when disease or when recurrence, must carry out chemotherapy.

The physiopathology of osteoporosis is to be increased and mediated by the osteoblastic minimizing that forms bone and the dependent bone resorption of osteoclast.The supportive evidence of Cenci shows, injects anti-M-CSF antibody and can in OO mouse, keep bone density and suppress bone resorption (Cenci2000).Recent findings potential contact the between bone loss after estrogen deficiency and menopause, and the existence of finding to produce the T cell of TNF α can affect bone metabolism (Roggia2004).A possible mechanism is that TNF α induces M-CSF in vivo.The effect that the antibody of anti-M-CSF-inhibitor is blocked the osteolysis that TNF α induces in mouse has confirmed that the bone that M-CSF induces at TNF-α lures the vital role in splitting generation, thereby makes the inhibitor of CSF-1R signal conduction become the potential target spot (Kitaura2005) of inflammatory arthritis.

The Paget's disease of bone (PDB) is the metabolic disorder of the modal bone of the second after osteoporosis, and the local anomaly that the bone wherein increased upgrades causes complication such as bone pain, distortion, pathologic fracture and deafness.Confirmed four kinds of transgenations of regulating normal osteoclast function and making the individual easy PDB of suffering from and relative disease: the sudden change of the Sequestosome1 gene (SQSTM1) of the insertion mutation in the TNFRSF11A of the receptor activator (RANK) (the crucial conditioning agent of osteoclast function) of coding nf (NF) κ B, the inactivation sudden change of the TNFRSF11B of coding osteoprotegerin (the bait acceptor of RANK part), the important scaffolding protein of encoding in NF κ B passage, and containing the sudden change in valosin albumen (VCP) gene.This genes encoding VCP, its in the degraded that NF kB inhibitor target is caused in proteasome, work (Daroszewska, 2006).The CSF-1R inhibitor of target provides chance for the imbalance of indirectly blocking the conduction of RANKL signal, and is the treatment option that current bisphosphonates used has increased other.

Especially the loss of the bone of being induced by cancer therapy in mammary gland and patients with prostate cancer is another kind of indication, and wherein, the CSF-1R inhibitor of target can prevent bone loss (Lester2006).Improvement along with the prognosis of breast carcinoma of early stage, the long-term consequence of assisting therapy becomes more and more important, because some therapies, comprise that chemotherapy, radiotherapy, aromatase inhibitor and oophorectomize meeting affects bone metabolism by reducing bone mineral density, cause the risk increase (Lester2006) of osteoporosis and relevant fracture.Suitable with the aromatase inhibitor adjuvant therapy of mammary cancer is the androgen ablation therapy of prostate cancer, and it can cause bone mineral density to descend and significantly increase the risk (Stoch2001) of the fracture relevant to osteoporosis.

When target cell type comprises osteoclast and scavenger cell, the target inhibitor of CSF-1R signal conduction also may produce beneficial effect in other indication, for example, and the caused specific complication of joint replacement that treatment is carried out because of rheumatoid arthritis.Because the loss of the bone of Periprosthetic and the caused implant of prosthetic loosening that comes next are unsuccessfully the major complications of joint replacement and need to be repeatedly performed the operation, thereby caused the high social economical burden of individual patients and healthcare system.Up to the present, also do not have the pharmacological agent of license can prevent or suppress prosthese week osteolysis (Drees2007).

The osteoporosis of glucocorticoid inducible (GIOP) is another kind of indication, wherein, the CSF-1R inhibitor can lose (Guzman-Clark2007 by the prevention bone after life-time service glucocorticosteroid (due to various illnesss, comprising chronic obstructive pulmonary disease, asthma and rheumatoid arthritis); Feldstein2005).

Rheumatoid arthritis, psoriatic arthritis and inflammatory arthropathy are also the potential indications of CSF-1R signal transduction inhibitor, because their scavenger cell becomes branch to cause osteoclasia (Ritchlin2003) in various degree.Osteoarthritis and rheumatoid arthritis are by scavenger cell, in reticular tissue, to be assembled and scavenger cell invades caused inflammatory autoimmune disease in synovia, and it is mediated by M-CSF at least partly.The people such as Campbell (2000) have confirmed that M-CSF is produced by people's joint tissue cell (chondrocyte, synovial membrane fibrocyte) in vitro, and be found in the patient's who suffers from rheumatoid arthritis synovia, this shows that it has caused the synovial tissue hyperplasia relevant with the pathogeny of disease and the intrusion of scavenger cell.Suppressing the conduction of CSF-1R signal likely controls the scavenger cell quantity in joint and alleviates the caused pain of relevant osteoclasia.For disadvantageous effect being minimized and further understanding the CSF-1R signal conduction impact in these indications, a kind of method is to suppress specifically CSF-1R and other numerous kinases of target not, such as the Raf kinases.

Nearest bibliographical information connects (Saitoh2000 by poor prognosis and the progression of atherosclerosis of the circulation M-CSF of increase and chronic coronary artery disease; Ikonomidis2005); M-CSF affects Atherosclerosis by the formation that helps foam cell (scavenger cell with oxidation LDL of absorption), this cell expressing CSF-1R and represented initial patch (Murayama1999).

The expression of M-CSF and CSF-1R and signal conduction are found in the microgliacyte of activation.Microgliacyte (it is the resident scavenger cell of central nervous system) can be activated by various damages, comprises and infecting and traumatic damage.M-CSF is considered to the crucial conditioning agent of the Inflammatory response in brain, and the M-CSF level increases in HIV-1 encephalitis, Alzheimer (AD) and cerebral tumor.Through test-type nerve injury model validation, the nervelet cellula adhesiae hyperplasia caused by the autocrine signal of M-CSF/CSF-1R can be induced inflammatory cytokine and nitric oxide production release (Hao2002; Murphy1998).In the amyloid precursor protein V717F of the transgene mouse model around patch and Alzheimer of Alzheimer, found that CSF-1R expresses the microgliacyte (Murphy2000) increased.On the other hand; the op/op mouse that has the small amount microgliacyte in brain is compared produced A β fiber-like deposition and neurone loss with normal control show that microgliacyte has the neuroprotective function really in the progress of Alzheimer, lacks this function (Kaku2003) in the op/op mouse.

On the one hand, preferred embodiment provides the method that human or animal's individual treatment of the described treatment of needs is related to the disease of CSF-1R, and the method comprises to described individuality to be used and alleviate or formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or the compound (V) of preventing disease significant quantity.In preferred embodiments, described illness is tumor growth and/or the transfer in individuality.

On the other hand, preferred embodiment provides the method that human or animal's individual treatment of the described treatment of needs is related to the disease of CSF-1R, and the method comprises to described individuality uses formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or the compound (V) that alleviates or prevent individual bone to lure to split generation, bone resorption and/or bone injury significant quantity.

On the other hand, preferred embodiment provides the method that human or animal's individual treatment of the described treatment of needs is related to the disease of CSF-1R, and the method comprises to formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or the compound (V) of described individual administering therapeutic disease significant quantity and at least one other promoting agent.In a more preferred embodiment, described other promoting agent is bisphosphonates.In one embodiment, this illness is that tumor growth and/or transfer, bone lure and split generation, bone resorption and/or bone injury.

On the other hand, preferred embodiment provides formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or the compound (V) that optionally or preferentially suppresses CSF-1R.In preferred embodiments, the selective depressant of CSF-1R can be with kinase whose active higher approximately 5 times or approximately 10 times or approximately 20 times or approximately 30 times or approximately 50 times or approximately 100 times or approximately 250 times or approximately 500 times or approximately 750 times or approximately 1 than suppressing Raf, 000 times or approximately 2,000 inhibition is active (for example,, with regard to IC ₅₀value) suppress CSF-1R.

The method that suppresses CSF-1R is provided on the other hand, and the method comprises cell is contacted with formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or Compound Phase (V).In some aspects, this compound is 4-{2-[(2,3-dihydro-cumarone-5-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea or 4-[2-((1R, 2R)-2-benzyloxy-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea.

On the one hand, to the inhibition of Raf, utilize following biological test to determine this compound.The kinase whose activity of Raf is by providing ATP, restructuring kinases deactivation MEK substrate and measuring the phosphate radical part and determine to the transfer of MEK residue.The recombinant full-lenght MEK that will contain deactivation K97R ATP-binding site sudden change (making the kinases inactivation) uses biotin labeling at expression in escherichia coli and after purifying.By N-end (His) for MEK cDNA ₆mark subclone at expression in escherichia coli, then by the MEK substrate of restructuring by nickel affinity chromatography purifying from the intestinal bacteria lysate, then carry out anionresin.By final MEK substrate preparation biotinylation (Pierce EZ-LinkSulfo-NHS-LC-Biotin) and be concentrated into approximately 11.25 μ μ M.Restructuring Raf (comprising c-Raf and mutant B-Raf isoform) obtains from the sf9 insect cell infected with corresponding people Raf recombinant expression vector by purifying.The Raf isoform of restructuring is interacted by Glu antibody or passes through the metal ion chromatogram purification.

For each test, this compound, for example since 3-times of diluent dilution continuously in DMSO for 25 μ M, is then mixed with various Raf isoforms (every kind of about 0.50nM) mutually.Kinases inactivation vitamin H-MEK substrate (50nM) is added in the reaction buffer that contains ATP (1 μ M).This reaction buffer contains 30mM Tris-HCl ₂pH7.5,10mM MgCl ₂, 2mM DTT, 4mMEDTA, 25mM β-glycerophospholipids, 5mM MnCl ₂and 0.01%BSA/PBS.Subsequently reaction solution at room temperature is incubated to approximately 2 hours, by adding 0.5M EDTA termination reaction.The mixture of termination reaction transferred on the plate that has applied Neutradavin and be incubated approximately 1 hour.By DELFIA time difference type fluorescing system for the product of phosphorylation, utilize the anti-p-MEK of rabbit (Cell Signaling) as one-level antibody and measured as secondary antibody with the anti-rabbit of europium mark.Time difference type fluorescence can be on the Wallac1232DELFIA photofluorometer reading.50% inhibition concentration (IC of compound ₅₀) by non-linear regression, utilize XL Fit data analysis software to calculate.

On the other hand, preferred embodiment provides the method that human or animal's individual treatment of the described treatment of needs is related to the CSF-1R disease, and the method comprises to described individuality to be used and alleviate or prevent formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or the compound (V) of individual tumors growth significant quantity to be used for the treatment of other promoting agent of cancer with at least one.In a more preferred embodiment, described other promoting agent is bisphosphonates.

The method that all can be used for preferred embodiment as the many suitable carcinostatic agent of combined therapy agent.In fact, preferred embodiment comprises uses multiple other carcinostatic agent, such as but not limited to the promoting agent of cell death inducing; Polynucleotide (for example ribose enzyme); Polypeptide (for example enzyme); Medicine; The biosimulation thing; Alkaloid; Alkylating agent; Antineoplastic microbiotic; Metabolic antagonist; Hormone; Platinic compound; The monoclonal antibody of being combined with anticarcinogen, toxin and/or radionuclide; Biological response modifier (such as Interferon, rabbit [such as IFN-α etc.] and interleukin [such as I1-2 etc.] etc.); The adoptive immunotherapy promoting agent; Hemopoieticgrowth factor; The medicament of inducing tumor cell differentiation (such as ATRA etc.); Gene therapy reagent; Antisense therapy agent and Nucleotide; Tumor vaccine; Angiopoietic inhibitor etc.Be suitable for that the chemotherapy compound of compound co-administered and multiple other example of anticancer therapeutic agent are well known by persons skilled in the art with disclosed formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V).

In preferred embodiments, other carcinostatic agent used with the compound combination of preferred embodiment comprises induces or the promoting agent of irritation cell apoptosis.The promoting agent of cell death inducing includes but not limited to radiation (for example ω); Kinase inhibitor (for example EGF-R ELISA [EGFR] kinase inhibitor, vascular endothelial growth factor receptor [VEGFR] kinase inhibitor, fibroblast growth factor acceptor [FGFR] kinase inhibitor, platelet-derived growth factor receptors [PDGFR] I kinase inhibitor and Bcr-Abl kinase inhibitor such as STI-571, Gleevec and Glivec]); Antisense molecule; Antibody [Yin is as Herceptin and Rituxan]; Antiestrogen [for example raloxifene and tamoxifen]; Antiandrogen [for example flutamide, bicalutamide, finasteride, aminoglutethimide, KETOKONAZOL and reflunomide]; Cyclooxygenase 2 (COX-2) inhibitor [for example celecoxib, meloxicam, NS-398 and NSAID (non-steroidal anti-inflammatory drug) (NSAIDs)]; For example, with cancer chemotherapy medicine [irinotecan (Camptosar), CPT-11, fludarabine (Fludara), Dacarbazine (DTIC), dexamethasone, mitoxantrone, Gemtuzumab ozogamicin, VP-16, cis-platinum, 5-FU, Zorubicin, taxotere or taxol; Cell signaling molecule; Ceramide and cytokine; With staurosporine etc.

The compound of preferred embodiment can be in vitro or body in for the growth of anticancer.This compound can be used alone or is used in combination together with pharmaceutically acceptable carrier or vehicle.

On the other hand, preferred embodiment provides the pharmaceutically acceptable carrier that comprises separately at least one formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or compound (V) and the suitable human or animal's of delivering medicine to individuality or has also comprised the medicine group composition of other carcinostatic agent.

On the other hand, preferred embodiment provides preparation formula as herein described (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) method of compound.

The formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or compound (V), steric isomer, tautomer, solvate, oxide compound, ester or the prodrug that comprise significant quantity or the composition of its pharmacologically acceptable salt and pharmaceutically acceptable carrier are provided on the other hand.In some aspects, this Compound Phase preferentially suppresses CSF-1R for the Raf kinases.More particularly, described compound is to be greater than the approximately control of the concentration Raf kinases of 1 μ M.

On the other hand, it further comprises other promoting agent.More particularly, described other promoting agent is bisphosphonates.

On the other hand, the formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) of the CSF-1R activity that can effectively suppress human or animal's individuality when to its administration or (V) compound are provided.More particularly, the IC that described compound shows for the CSF-1R restraining effect ₅₀value is less than approximately 1 μ M.More particularly, the IC that described compound shows for the Raf restraining effect ₅₀value is greater than approximately 1 μ M.

Another embodiment provides the method that suppresses CSF-1R, and wherein said compound selective ground suppresses CSF-1R.

The compound of this embodiment can be in vitro or body in for the growth of anticancer.This compound can be used alone or is used in combination together with pharmaceutically acceptable carrier or vehicle.Suitable pharmaceutically acceptable carrier or vehicle comprise such as machining agent and useful for drug delivery properties-correcting agent and toughener such as calcium phosphate, Magnesium Stearate, talcum, monose, disaccharides, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, glucose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, low melt wax, ion exchange resin etc., and any two or more combination wherein.Other suitable pharmaceutically acceptable vehicle is described in ＂ Remington ' s Pharmaceutical Sciences, and ＂ Mack Pub.Co., in NewJersey (1991), be introduced into as a reference at this.

Administration and pharmaceutical composition

Usually by the compound of preferred embodiment with any administration in the generally acknowledged administering mode of the medicament for the treatment of significant quantity by can play similar effectiveness.The compound of preferred embodiment, be the actual amount of the activeconstituents severity that will depend on various factors such as disease to be treated, individual age and effect, route of administration and the form of relative health degree, compound used therefor, and other factors.Medicine can administration every day more than 1 time, preferably every day 1 time or 2 times.These all factors are all in clinicist's skill.

The significant quantity of the compound of preferred embodiment generally include by test described herein any one, by other CSF-1R kinase inhibition test well known by persons skilled in the art or the restraining effect by detecting cancer symptoms or alleviate any amount that effect is enough to suppress the CSF-1R activity with detecting.

Can will change along with the ad hoc fashion of the main body for the treatment of and administration with the combined amount with the activeconstituents that produces single formulation of carrier substance.Yet, should be appreciated that, various factors be will depend on for the concrete dosage level of any particular patient, the combination of speed, medicine of activity, age, body weight, general health situation, sex, diet, administration time, route of administration, the discharge of particular compound used and the severity of the specified disease of being treated comprised.For the treatment significant quantity to stable condition, be easy to determine by normal experiment, and in common clinician's technical ability and judgement.

For preferred embodiment, the treatment significant quantity normally is administered to total per daily dose of host with dosage single or that separate, can be for example approximately 0.001 to about 1000mg/kg body weight/day, 1.0 amounts to about 30mg/kg body weight/day more preferably from about.Dosage unit compositions can contain the amount of its approximate number to reach per daily dose.

The bioavailability of various factors such as administering mode and medicine depended in the selection of preparation.Generally speaking, the form that the compound of preferred embodiment can pharmaceutical composition is carried out administration by any in following approach: oral, whole body (for example in skin, nose or suppository) or parenteral (for example intramuscular, intravenously or subcutaneous).Preferred administering mode is the oral administration that adopts conventional per daily dose scheme, and this dosage regimen can be regulated according to the degree of disease.Composition can be tablet, pill, capsule, semisolid, powder, sustained release preparation, solution, suspensoid, elixir, aerosol or any other suitable composition.Another kind of is preferably inhalation for the mode of the compound of using preferred embodiment.This is a kind of for therapeutical agent directly being sent to the effective ways (referring to US5,607,915) of respiratory tract.

Suitable pharmaceutically acceptable carrier or vehicle comprise such as machining agent and useful for drug delivery properties-correcting agent and toughener such as calcium phosphate, Magnesium Stearate, talcum, monose, disaccharides, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, glucose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, low melt wax, ion exchange resin etc., and any two or more combination wherein.Liquid and semisolid excipient can be selected from glycerine, propylene glycol, water, ethanol and various oil, comprise oil, animal, plant or synthetic oil, for example peanut oil, soybean oil, mineral oil, sesame wet goods.Preferred liquid vehicle, in particular for the liquid vehicle of injection solution, comprise water, salt solution, D/W and glycols.Other suitable pharmaceutically acceptable vehicle is at ＂ Remington ' s PharmaceuticalSciences, and ＂ Mack Pub.Co., describe in New Jersey (1991) to some extent, at this, is introduced into as a reference.

Term used herein " pharmacologically acceptable salt " refers to formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) nontoxic acid or the alkaline earth salt of compound.These salt can be in formulas (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) are made on the spot in the final separation of compound and purge process, or by addition alkali or acid functional group being made with suitable organic or inorganic acid or alkali reaction respectively.Representational salt includes but not limited to acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, bisul-phate, butyrates, camphorate, camsilate, digluconate, cyclopentane propionate, dodecyl sulfate, esilate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosilate and undecylate.In addition, alkaline nitrogen-containing group can be quaternized with following reagent: such as alkylogen such as methyl, ethyl, propyl group and Butyryl Chloride, bromine and iodine; The sulfuric acid dialkyl as sulfuric acid dimethyl, diethyl, dibutyl and diamyl ester, long-chain halogenide such as decyl, dodecyl, myristyl and stearyl chloride, bromine and iodine, aralkyl halide as benzyl and phenethyl bromide etc.Obtain thus water or oil soluble or dispersed product.

The example that can be used for forming the acid of pharmaceutically acceptable acid additive salt comprises all example hydrochloric acids of mineral acid, sulfuric acid and phosphoric acid and organic acid such as oxalic acid, toxilic acid, methylsulfonic acid, succinic acid and citric acid.The alkalescence additive salt can be in formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) is made on the spot in the final separation of compound and purge process, or in addition by carboxylic moiety is reacted or reacted to obtain with ammonia or organic primary, secondary or tertiary amine with oxyhydroxide, carbonate or the supercarbonate of suitable alkali such as pharmaceutically useful metallic cation.Pharmacologically acceptable salt includes but not limited to positively charged ion based on alkali and alkaline earth metal ions such as sodium, lithium, potassium, calcium, magnesium, aluminium salt etc. and nontoxic ammonium, quaternary ammonium and amine positively charged ion, includes but not limited to the salt of ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethyl amine, Trimethylamine, triethylamine, ethylamine etc.Other the representational organic amine that is used to form alkaline additive salt comprises diethylamide, quadrol, thanomin, diethanolamine, piperazine etc.

Term used herein " pharmaceutically acceptable ester " refers to the ester that can be hydrolyzed in vivo, and comprises and be easy in human body fracture to stay those esters of parent compound or its salt.Suitable ester group for example comprises those esters derived from pharmaceutically useful aliphatic carboxylic acid, especially paraffinic acid, alkenoic acid, naphthenic acid and chain docosandioic acid, and wherein each alkyl or alkenyl part preferably have and be no more than 6 carbon atoms.The example of specific ester comprises manthanoate, acetic ester, propionic ester, butyric ester, acrylate and ethyl succinate.

Term used herein " pharmaceutically acceptable prodrug " refers to and is applicable to contact with the tissue of people and rudimentary animal in rational medical judgment scope and there is no unsuitable toxicity, stimulation, atopic reaction etc., have reasonably be benefited/risk-ratio and to prodrug and in the situation that the amphoteric form of the compound of this possible embodiment of the compound of the effective preferred embodiment of its desirable application simultaneously.Term " prodrug " refers to the compound of the parent compound that can change rapidly in vivo to obtain above formula, for example, by being hydrolyzed in blood.At T.Higuchi and V.Stella, Pro-drugs as NovelDelivery Systems, the 14th volume of A.C.S.Symposium Series and Edward B.Roche compile, Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987 sufficient description is arranged, and at this, both is incorporated herein by reference.

It will be apparent to one skilled in the art that preferred embodiment compound, comprise formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) compound or its tautomer, prodrug and steric isomer and any pharmacologically acceptable salt, ester and the prodrug in them can be in human or animal body or cell carry out in body processing to produce metabolite by metabolism.Term used herein " metabolite " refers to the structural formula of any derivative produced in individual after the administration of parent compound.This derivative can produce by intraindividual various biochemical conversions, for example oxidation, reduction, hydrolysis or conjugation reaction from parent compound, and comprises for example oxide compound and demethylation derivative.The metabolite of the compound of the present embodiment can utilize routine techniques known in the art to identify.Referring to for example Bertolini, the people such as G., J.Med.Chem.40:2011-2016 (1997); The people such as Shan, D., J.Pharm.Sci.86 (7): 765-767; Bagshawe K., Drug Dev.Res.34:220-230 (1995); Bodor, N., Advances in Drug Res.13:224-331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press1985); And Larsen, I.K., Design andApplication of Prodrugs, Drug Designand Development (people such as Krogsgaard-Larsen compiles, Harwood Academic Publishers, 1991).Should be appreciated that, belong to formula (I), (IIa), (IIb) or (III) the independent compound of the metabolite of compound or its tautomer, prodrug and steric isomer and any pharmacologically acceptable salt, ester and prodrug in them be also included within preferred embodiment.

The compound of preferred embodiment can be by oral, parenteral, hypogloeeis, by aerosol or suck spraying, rectum or the local form administration with the dosage unit preparations that contains required commonly used nontoxic pharmaceutically acceptable carrier, auxiliary and vehicle.Topical also comprises and adopts percutaneous dosing such as through skin patch or iontophoresis device.Term used herein " parenteral " comprises in subcutaneous injection, intravenously, sheath, intramuscular, breastbone inner injection or infusion techn.

Injection formulations, for example aseptic injection aqueous solution or oil-based suspension can be suitable according to the methods known in the art utilization dispersion agent or wetting agent and suspending agent prepared.Aseptic injection preparation can also be aseptic injectable solution or the suspension in the acceptable thinner of nontoxic parenteral or solvent, for example, and the solution of 1,3-PD.Spendable acceptable carrier and solvent are water, Ringer solution and isotonic sodium chlorrde solution.In addition, aseptic fixedly oil also is typically used as solvent or suspension medium.For this purpose, the fixedly oil of any gentleness all can be used, and comprises synthetic list-or two-glyceride.In addition, lipid acid such as oleic acid also can be used for the preparation of injection formulations.

The suppository that is used for the rectal administration of medicine can be by mixing this medicine to make such as theobroma oil and polyoxyethylene glycol with suitable non-irritating excipient mutually, described vehicle is solid at normal temperatures, therefore but be liquid under rectal temperature, can melt and discharge medicine at internal rectum.

Solid dosage for oral administration can comprise capsule, tablet, pill, powder and granula.In solid dosage, active compound is mixed mutually with at least one inert diluent such as sucrose, lactose or starch.Usually, this formulation also can comprise other material except inert diluent, and for example lubricant is such as Magnesium Stearate.In the situation that capsule, tablet and pill, this formulation also can comprise buffer reagent.In addition, tablet and pill can be with casing.

Liquid dosage form for oral administration can comprise pharmaceutically useful emulsion, solution, suspension, syrup and elixir, and they contain the normally used inert diluent in this area such as water.Said composition also can comprise auxiliary such as wetting agent, emulsifying agent and suspending agent, cyclodextrin and sweeting agent, correctives and flavouring agent.

The form administration of all right liposome of the compound of preferred embodiment.As known in the art that, liposome is usually derived from phosphatide or other lipid material.Liposome by be dispersed in list in water-bearing media-or multilayer hydration liquid crystalization form.Can use any nontoxic, physiologically acceptable and metabolizable lipid material that can form liposome.Except the compound of preferred embodiment, the said composition of liposome form also can contain stablizer, sanitas, vehicle etc.Preferred lipid material is phosphatide and phosphatidylcholine (Yelkin TTS), comprises natural and synthetic.The method that forms liposome is known in the art.Compile Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33et seq. (1976) referring to for example Prescott.

Pressurized gas can be used for the compound of the preferred embodiment of dispersed gas solation.Being suitable for this purpose rare gas element is nitrogen, carbonic acid gas etc.The pharmaceutical excipient that other is suitable and preparation thereof are recorded in the Remington ' s Pharmaceutical Sciences (MackPublishing Company, the 18th edition, 1990) that E.W.Martin edits.

For the inhalation administration, the suitable dispersion agent for administration can be prepared and loaded to this compound with the form of liquor, suspension, aerosol propellants or dry powder.There are medicinal inhalation devices-aerohaler, metered-dose inhaler (MDI) and the Diskus (DPI) of several types.Spraying plant produces and to make the high-speed air flow of therapeutical agent (preparation of liquid form) with the mist spraying of the respiratory tract that can enter the patient.Usually MDI being carried out to preparation with pressurized gas packs.Once start, this device discharges quantitative therapeutical agent by pressurized gas, and the reliable method of using the set amount medicament is provided thus.DPI disperses therapeutical agent with free-pouring powder type, and this powder can be in the suction air-flow that is distributed to the patient in respiratory by device.In order to obtain free-pouring powder, therapeutical agent is prepared such as lactose with vehicle.Form by the therapeutical agent of measured quantity with capsule stores, and then when each the startup, is distributed.

Recently, can be by increasing surface-area, reducing the principle that granularity increases based on bioavailability, the pharmaceutical preparation that has been in particular the poor drug development of bioavailability.For example, US4,107,288 to have described granularity be approximately 10 to approximately 1, the pharmaceutical preparation of 000nm, wherein load to active substance on macromolecular crosslinked matrix.US5,145,684 have described the preparation of pharmaceutical preparation, wherein medicine are ground to form under the existence of surface-modifying agent to nano particle (mean particle size is about 400nm), then are dispersed in liquid medium to obtain showing the pharmaceutical preparation of significant high bioavailability.

Combined therapy

Although the form administration that the compound of preferred embodiment can the single-activity medicament, one or more other medicaments that they also can be used with the treatment cancer are used in combination.The compound of preferred embodiment also can be used for known therapeutical agent and carcinostatic agent combined, and the combination of compound disclosed herein and other carcinostatic agent or chemotherapeutic is also in the scope of preferred embodiment.The example of described promoting agent can be referring to Cancer Principles and Practice of Oncology, V.T.Devitaand S.Hellman (editors), the 6th edition (February 15 calendar year 2001), Lippincott Williams; Wilkins Publishers.Those of ordinary skill in the art can determine that according to concrete property and the related cancer of medicine which kind of combination of promoting agent is useful.Described carcinostatic agent includes but not limited to following material: the promoting agent of the inhibitor of estrogenic agents, androgen receptor modifier, retinoid receptor conditioning agent, cytotoxic agent/cytostatics, antiproliferative, isopentene group-protein transferase inhibitor, HMG-CoA reductase inhibitor and other angiogenesis inhibitor, cell proliferation and survival signal, cell death inducer and interference cell cycle checkpoint.The compound of preferred embodiment also can be used jointly with radiotherapy.

Therefore, in one embodiment, this compound also can be used in combination with known carcinostatic agent, and described carcinostatic agent comprises for example estrogenic agents, androgen receptor modifier, retinoid receptor conditioning agent, cytotoxic agent, antiproliferative, isopentene group-protein transferase inhibitor, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors and other angiogenesis inhibitor.

Estrogenic agents is the compound that can disturb or suppress the combination of oestrogenic hormon and acceptor, regardless of its mechanism.The example of estrogenic agents includes but not limited to tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(piperidino) oxyethyl group] phenyl]-2H-1-chromene-3-yl)-phenyl-2,2-dimethyl-propionic ester, 4,4 '-dihydroxy benaophenonel-2,4-dinitrophenyl-hydrazone and SH646.

Androgen receptor modifier is to disturb or to suppress the compound that male sex hormone is combined with androgen receptor.The example of representational androgen receptor modifier comprises finasteride and other 5α-reductase inhibitor, Nilutamide, flutamide, bicalutamide, liarozole and Abiraterone acetate.The retinoid receptor conditioning agent is to disturb or to suppress the compound that retina combines with the retina acceptor.The example of retinoid receptor conditioning agent comprises that bexarotene, vitamin A acid, 13CRA, RETINOIC ACID, alpha-difluoromethyl ornithine, LX23-7553, trans-N-(4 '-hydroxy phenyl) are looked yellow acid amides and the N4-carboxyl phenyl is looked yellow acid amides.

Cytotoxic agent and/or cytostatics be can cause necrocytosis or mainly the functionalization by the direct interference cell suppress cell proliferation or inhibition or the mitotic compound of interference cell, comprise the kinase whose inhibitor, the metabolic antagonist that relate in the inhibitor, mitotic division process of alkylating agent, tumour necrosis factor, intercalator, anoxic activated form compound, microtubule inhibitors/microtubule stabilizer, mitotic kinesins; Biological response modifier; Hormone/hormone antagonist therapeutical agent, hemopoieticgrowth factor, monoclonal antibody target therapeutic agent, topoisomerase enzyme inhibitor, proteasome inhibitor and ubiquitin ligase inhibitor.The example of cytotoxic agent includes but not limited to Sertenef, cachectin, ifosfamide, Ta Suonamin, lonidamine, carboplatin, altretamine, PM, Elobromol, ranomustine, fotemustine, S 254, oxaliplatin, Temozolomide, Eptaplatin, Emcyt, the improsulfan tosylate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, Satraplatin, methylmitomycin, Platinol, irofulven, right ifosfamide, cis-amine dichloro (2-methyl-pyridine) platinum, the benzyl guanine, glufosfamide, GPX100, (trans, trans, trans)-bis--mu-(hexane-1,6-diamines)-mu-[diamines-platinum (II)] two [diamines (chlorination) platinum (II)] tetrachloride, diazacyclo propyl group spermine, white arsenic, 1-(11-dodecyl amino-10-hydroxyl undecyl)-3,7-dimethylxanthine, zorubicin, the jaundice element, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, galarubicin, 3 '-deaminizating-3 '-morpholino-13-deoxidation-10-hydroxyl carminomycin, Annamycin, galarubicin, Elinafide, MEN10755 and 4-demethoxylation-3-deaminizating-3-nitrogen heterocyclic propyl group-4-methyl sulphonyl-daunorubicin (referring to WO00/50032).The representative example of anoxic activated form compound is Win-59075.Proteasome inhibitor includes but not limited to lactacystin and Velcade.The example of microtubule inhibitors/microtubule stabilizer comprises taxol, Vindesine Sulfate, 3 ', 4 '-bis-dehydrogenations-4 '-deoxy-8 '-navelbine, Docetaxel, rhizocholic acid, dolastatin, the mivobulin isethionate, Auristatin, Cemadotin, RPR109881, BMS184476, Vinflunine, Cryptophycin, 2, 3, 4, 5, the fluoro-N-of 6-five (3-fluorine 4-p-methoxy-phenyl) benzsulfamide, F 81097, N, N-dimethyl-Valine-Valine-N-methyl-Valine-L-PROLINE-L-PROLINE-tert-butylamides, TDX258, the ebormycine class is (referring to for example US6, 284, 781 and US6, 288, 237) and BMS188797.The representational example of topoisomerase enzyme inhibitor comprises topotecan, Hycaptamine, irinotecan, rubitecan, 6-ethoxy-c acyl group-3 ', 4 '-O-is outer-benzylidene-chartreuse mycin, 9-methoxyl group-N, N-dimethyl-5-nitropyrazole is [3,4,5-kl] bifurcation pyridine-2-(6H) propylamine also, 1-amino-9-ethyl-5-is fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrans also [3 ', 4 ': b, 7]-indolizine [1,2b] quinoline-10,13 (9H, 15H) diketone also, lurtotecan, 7-[2-(N-isopropylamino) ethyl]-(20S) camptothecine, BNP1350, BNPI1100, BN80915, BN80942, Etoposide phosphoric acid salt, for the Buddhist nun, moor sweet, sobuzoxane, 2 '-dimethylamino-2 '-deoxy-Etoposide, GL331, N-[2-(dimethylamino) ethyl]-9-hydroxyl-5,6-dimethyl-6H-pyrido [4,3-b] carbazole-1-methane amide, Asulacrine, (5a, 5aB, 8aa, 9b)-9-[2-[N-[2-(dimethylamino) ethyl]-the N-methylamino] ethyl]-5-[4-hydroxyl-3, the 5-Dimethoxyphenyl]-5,5a, 6, 8,8a, the 9-hexahydro furyl also (3 ', 4 ': 6, 7) naphtho-(2,3-d)-1,3-dioxole-6-ketone, 2,3-(methylene radical dioxy base)-5-methyl-7-hydroxyl-8-methoxyl group benzo [c]-phenanthridines, 6,9-bis-[(2-amino-ethyl) amino] benzo [g] isoguinoline-5, the 10-diketone, 5-(3-amino propyl amino)-7,10-dihydroxyl-2-(2-hydroxyethyl amino methyl)-6H-pyrazolo [4,5,1 '-de] bifurcation pyridine-6-ketone, N-[1-[2 (diethylamino) ethylamino]-7-methoxyl group-9-oxo-9H-thioxanthene-4-ylmethyl] methane amide, N-(2-(dimethylamino) ethyl) bifurcation pyridine-4-methane amide, 6-[[2-(dimethylamino) ethyl] amino]-3-hydroxyl-7H-indeno [2,1-c] quinoline-7-ketone and dimesna.The example of the inhibitor of mitotic kinesins such as people's mitotic kinesins KSP is recorded in WO01/30768 and WO01/98278, WO03/050, 064 (on June 19th, 2003), WO03/050, 122 (on June 19th, 2003), WO03/049, 527 (on June 19th, 2003), WO03/049, 679 (on June 19th, 2003), WO03/049, 678 (on June 19th, 2003) and WO03/39460 (on May 15th, 2003) and unsettled PCT application number US03/06403 (in application on March 4th, 2003), US03/15861 (in application on May 19th, 2003), US03/15810 (in application on May 19th, 2003), US03/18482 (in application on June 12nd, 2003) and US03/18694 (in application on June 12nd, 2003).In one embodiment, the example of the inhibitor of mitotic kinesins includes but not limited to the inhibitor of KSP, the inhibitor of MKLP1, the inhibitor of CENP-E, the inhibitor of MCAK, the inhibitor of Kif14, the inhibitor of Mphosph1 and the inhibitor of Rab6-KIFL.

The kinase whose inhibitor that mitotic division relates in carrying out comprises but is not limited to the inhibitor of aurora kinase, the inhibitor of Polo-class kinases (PLK) (for example inhibitor of PLK-1), the inhibitor of bub-1 and the inhibitor of bub-1R.Antiproliferative comprises that anti-meaning RNA and DNA oligonucleotide are such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 and metabolic antagonist are such as enocitabine, fluorine-based pyrimidine, Ftorafur, pentoside, doxifluridine, trimetrexate, fludarabine, capecitabine, capecitabine, arabinosylcytosine, Fosteabine hydration sodium, Raltitrexed, Paltitrexid, emitefur, Tiazofurin, Decitabine, Nolatrexed, pemetrexed, Nelzarabine, 2 '-deoxy-2 '-the methylene radical cytidine, 2 '-fluorine methylene radical-2 '-the deoxy cytidine, N-[5-(2,3-dihydro-benzofuryl) alkylsulfonyl]-N '-(3,4-dichlorophenyl) urea, N6-[4-deoxy-4-[N2-[2 (E), 4 (E)-14 carbon two enoyl-s] glycyl amino]-L-glycerine-B-1-sweet dew-pyrans heptose base] VITAMIN B4, Aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydrochysene-3H-Kui Linpyrimido quinoline [5,4-b] [Isosorbide-5-Nitrae] thiazine-6-base-(S)-ethyl]-2,5-Thenoyl-Pidolidone, aminopterin, 5 FU 5 fluorouracil, alanosin, 11-ethanoyl-8-(formamyl oxygen ylmethyl)-4-formyl radical-6-methoxyl group-14-oxa--1,1-diaza Fourth Ring (7.4.1.0.0)-14 carbon-2,4,6-triolefin-9-yl acetate, trihydroxyoctahydroindolizidine, lometrexol, dexrazoxane, methioninase, 2 '-cyano group-2 '-deoxy-N4-palmitoyl-L-B-D-furyl glycosyl cytosine(Cyt) and 3-aminopyridine-2-formaldehyde Thioacetazone.The example of monoclonal antibody target therapeutical agent comprise there is cytotoxic agent be connected to the cancer cells specificity or the target cell monoclonal antibody specific on radioisotopic those therapeutical agents.Example comprises for example Bexxar.The HMG-CoA reductase inhibitor is the inhibitor of 3-hydroxy-3-methyl glutaryl base-CoA reductase enzyme.The HMG-CoA reductase enzyme is had to the compound that suppresses active can be at an easy rate by utilizing test known in the art to be identified, such as US4, and 231,938 and WO84/02131 is that describe or test that quote.The example of spendable HMG-CoA reductase inhibitor include but not limited to lovastatin (

referring to US4,231,938,4,294,926 and 4,319,039), Simvastatin (

; Referring to US4,444,784,4,820,850 and 4,916,239), Pravastatin ( ; Referring to US4,346,227,4,537,859,4,410,629,5,030,447 and 5,180,589), fluvastatin (

referring to US5,354,772,4,911,165,4,929,437,5,189,164,5,118,853,5,290,946 and 5,356,896) and atorvastatin (

referring to US5,273,995,4,681,893,5,489,691 and 5,342,952).Can be used for the structural formula of these and other HMG-CoA reductase inhibitor of present method at M.Yalpani, ＂ CholesterolLowering Drugs ＂, Chemistry & Industry, the 87th page and the US4 of pp.85-89 (on February 5th, 1996), have description in 782,084 and 4,885,314.In one embodiment, the HMG-CoA reductase inhibitor is selected from lovastatin or Simvastatin.

Isopentene group-protein transferase inhibitor is the compound that can suppress any or any combination in isopentene group-protein transferase, comprise farnesyl-protein transferase (FPTase), geranyl geranyl-protein transferase I type (GGPTase-I) and geranyl geranyl-protein transferase II type (GGPTase-II, also referred to as Rab GGPTase).The example of isopentene group protein transferase Inhibitor comprises amino (4-chloro-phenyl-) (the 1-methyl isophthalic acid H-imidazoles-5-yl) methyl of (±)-6-[]-4-(3-chloro-phenyl-)-1-methyl-2 (1H) quinolinone, amino (4-chloro-phenyl-) (the 1-methyl isophthalic acid H-imidazoles-5-yl) methyl of (-)-6-[]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone, amino (4-chloro-phenyl-) (the 1-methyl isophthalic acid H-imidazoles-5-yl) of (+)-6-[]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone, 5 (S)-normal-butyl-1-(2, the 3-3,5-dimethylphenyl)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl-2-piperazinones, (S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-the 2-piperazinones, 5 (S)-normal-butyl-1-(2-aminomethyl phenyl)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-the 2-piperazinones, 1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-2-methyl-5-imidazolyl methyl]-the 2-piperazinones, 1-(2, the 2-diphenyl-ethyl)-3-[N-(1-(4-cyano group benzyl)-1H-imidazoles-5-base ethyl) formamyl] piperidines, 4-{-[4-hydroxymethyl-4-(4-chloropyridine-2-ylmethyl)-piperidin-1-yl methyl]-glyoxal ethyline-1-ylmethyl } cyanobenzene, 4-{-5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidin-1-yl methyl]-glyoxal ethyline-1-ylmethyl } cyanobenzene, 4-{3-[4-(2-oxo-2H-pyridine-1-yl) benzyl]-3H-imidazol-4 yl methyl } cyanobenzene, 4-{3-[4-(5-chloro-2-oxo-2H-[1, 2 '] two pyridines-5 '-ylmethyl)-3H-imidazol-4 yl methyl] cyanobenzene, 4-{3-[4-(2-oxo-2H-[1, 2 '] two pyridines-5 '-ylmethyl)-3H-imidazoles 4-ylmethyl] cyanobenzene, 4-[3-(2-oxo-1-phenyl-1, 2-dihydropyridine-4-ylmethyl)-3H-imidazol-4 yl methyl] cyanobenzene, 18, 19-dihydro-19-oxo-5H, 17H-6, 10:12, 16-bis-endo-methylene groups-1H-imidazo [4, 3-c] [1, 11, 4] dioxa nitrogen heterocyclic-ninth of the ten Heavenly Stems decine-9-formonitrile HCN, (±)-19, 20-dihydro-19-oxo-5H-18, 21-ethano--12, 14-ethano--6, 10-endo-methylene group-22H-benzo [d] imidazo [4, 3-k] [1, 6, 9, 12] oxa-three azepines-encircle hot decine-9-formonitrile HCN, 19, 20-dihydro-19-oxo-5H, 17H-18, 21-ethano--6, 10:12, 16-bis-endo-methylene groups-22H-imidazo [3, 4-h] [1, 8, 11, 14] oxa-three nitrogen heterocyclic 20 carbynes-9-formonitrile HCN and (±)-19, 20-dihydro-3-methyl isophthalic acid 9-oxo-5H-18, 21-ethano--12, 14-ethano--6, 10-endo-methylene group-22H-benzo [d] imidazo [4, 3-k] [1, 6, 9, 12] the hot decine of oxa--tri-nitrogen heterocyclic-9-formonitrile HCN.Other example of isopentene group-protein transferase inhibitor can be referring to following publication and patent: WO96/30343, WO97/18813, WO97/21701, WO97/23478, WO97/38665, WO98/28980, WO98/29119, WO95/32987, US5,420,245, US5,523,430, US5,532,359, US5,510,510, US5,589,485, US5,602,098, EP0618221, EP0675112, EP0604181, EP0696593, WO94/19357, WO95/08542, WO95/11917, WO95/12612, WO95/12572, WO95/10514, US5,661,152, WO95/10515, WO95/10516, WO95/24612, WO95/34535, WO95/25086, WO96/05529, WO96/06138, WO96/06193, WO96/16443, WO96/21701, WO96/21456, WO96/22278, WO96/24611, WO96/24612, WO96/05168, WO96/05169, WO96/00736, US5,571,792, WO96/17861, WO96/33159, WO96/34850, WO96/34851, WO96/30017, WO96/30018, WO96/30362, WO96/30363, WO96/31111, WO96/31477, WO96/31478, WO96/31501, WO97/00252, WO97/03047, WO97/03050, WO97/04785, WO97/02920, WO97/17070, WO97/23478, WO97/26246, WO97/30053, WO97/44350, WO98/02436 and US5,532,359.Can be referring to European J.of Cancer35 (9): 1394-1401 (1999) to the example of vascularization role about isopentene group-protein transferase inhibitor.

Angiogenesis inhibitor refers to the compound that can suppress neovascularization, regardless of its mechanism.The example of angiogenesis inhibitor includes but not limited to the inhibitor of tyrosine kinase inhibitor such as tyrosine kinase receptor Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR2), epithelium-derivative, the inhibitor of inoblast-derivative or platelet-derived somatomedin, MMP (matrix metalloproteinase) inhibitor, the integrin retarding agent, interferon-' alpha ', IL-12, piperylene gathers vitriol, cyclooxygenase-2 inhibitors, comprise NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) as acetylsalicylic acid and Ibuprofen BP/EP and optionally COX-2 inhibitors as celecoxib and rofecoxib (PNAS89:7384 (1992), JNCI69:475 (1982), Arch.Ophthalmol.108:573 (1990), Anat.Rec., (238): 68 (1994), FEBS Letters372:83 (1995), Clin, Orthop.313:76 (1995), J.Mol.Endocrinol.16:107 (1996), Jpn.J.Pharmacol.75:105 (1997), Cancer Res.57:1625 (1997), Cell93:705 (1998), Intl.J.Mol.Med.2:715 (1998), J.Biol.Chem.274:9116 (1999)), the steroidal anti-inflammatory medicine is (such as reflunomide, Mineralocorticoid, dexamethasone, prednisone, prednisolone, methylprednisolone, Betamethasone Valerate), carboxyl amido triazole, combretastatin A4, squalamine, 6-O-chloracetyl-carbonyl)-aspergillus fumigatus cedrol (fumagillol), the Sa Li polyamines, his spit of fland of blood vessel, troponin-1, angiotensin-ii antagonist is (referring to Fernandez etc., J.Lab.Clin.Med.105:141-145 (1985)) and the antibody of anti-VEGF (referring to NatureBiotechnology, 17:963-968 (October1999), Kim etc., Nature, 362:841-844 (1993), WO00/44777, and WO00/61186).Can regulate or suppress vasculogenesis and can comprise with other therapeutical agent that the compound combination of preferred embodiment is used can adjusting or the promoting agent (referring to the summary in Clin.Chem.La.Med.38:679-692 (2000)) of anticoagulant and fibrinolytic system.Can adjusting or the example of the promoting agent of anticoagulant and fibrinolysis approach include but not limited to heparin (referring to Thromb.Haemost.80:10-23 (1998)), low molecular weight heparin and carboxypeptidase U inhibitor (also being known as the inhibitor of active enzyme thrombin activated form fibrinolysis inhibitor [TAFIa]) (referring to Thrombosis Res.101:329-354 (2001)).The TAFIa inhibitor is recorded in the open WO03/013 of PCT, and 526 and United States Patent (USP) sequence number 60/349,925 (in application on January 18th, 2002).Preferred embodiment also comprises the combination of compound and the NSAIDs of preferred embodiment, NSAIDs is that optionally cox 2 inhibitor (is normally defined, with COX-1, compare, the specificity that suppresses COX-2 is at least the approximately compound of 100 times, with the IC that suppresses COX-2 ₅₀with the IC that suppresses COX-1 ₅₀ratio weigh, by cell or microsome test, assess).This compound includes but not limited to the disclosed compound of following patent: December 12 nineteen ninety-five disclosed US5,474,995, on January 19th, 1999 disclosed US5,861,419, on December 14th, 1999 disclosed US6,001,843, on February 1st, 2000 disclosed US6,020,343, April 25 nineteen ninety-five disclosed US5,409,944, July 25 nineteen ninety-five disclosed US5,436,265, on July 16th, 1996 disclosed US5,536,752, on August 27th, 1996 disclosed US5,550,142, on February 18th, 1997 disclosed US5,604,260, on December 16th, 1997 disclosed US5,698,584, on January 20th, 1998 disclosed US5,710,140, on July 21st, 1994 disclosed WO94/15932, on June 6th, 1994 disclosed US5,344,991, on July 28th, 1992 disclosed US5,134,142, January 10 nineteen ninety-five disclosed US5,380,738, February 20 nineteen ninety-five disclosed US5,393,790, November 14 nineteen ninety-five disclosed US5,466,823, on May 27th, 1997 disclosed US5, on August 3rd, 633,272 and 1999 disclosed US5,932,598, at this, it all is incorporated herein by reference.The representative inhibitor of COX-2 that can be used for the method for preferred embodiment comprises 3-phenyl-4-(4-(methyl sulphonyl) phenyl)-2-(5H)-furanone; With the chloro-3-of 5-(4-methyl sulphonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine.As the specific inhibitor of COX-2, that describe and compound and synthetic method thereof that can be used for thus preferred embodiment can be referring to following patents, pending application and patent are open, at this, they are incorporated herein by reference: on July 21st, 1994 disclosed WO94/15932, on June 6th, 1994 disclosed US5,344,991, on July 28th, 1992 disclosed US5,134,142, January 10 nineteen ninety-five disclosed US5,380,738, February 20 nineteen ninety-five disclosed US5,393,790, November 14 nineteen ninety-five disclosed US5,466,823, on May 27th, 1997 disclosed US5,633,272, on August 3rd, 1999 disclosed US5,932,598, December 12 nineteen ninety-five disclosed US5,474,995, on January 19th, 1999 disclosed US5,861,419, on December 14th, 1999 disclosed US6,001,843, on February 1st, 2000 disclosed US6,020,343, April 25 nineteen ninety-five disclosed US5,409,944, July 25 nineteen ninety-five disclosed US5,436,265, on July 16th, 1996 disclosed US5,536,752, on August 27th, 1996 disclosed US5,550,142, on February 18th, 1997 disclosed US5,604,260, on December 16th, 1997 disclosed US5, on January 20th, 698,584 and 1998 disclosed US5,710,140, other example of angiogenesis inhibitor includes but not limited to his spit of fland of endothelium, Ukrain, ranpirnase, IM862, 5-methoxyl group-4-[2-methyl-3-(3-methyl-2-butene base) oxa-cyclopropyl]-1-oxaspiro [2,5] suffering-6-base (chloracetyl) carbamate, ethanoyl Dinanaline, 5-amino-1-[[3, the chloro-4-of 5-bis-(4-chlorobenzene formacyl) phenyl] methyl]-1H-1,2,3-triazole-4-methane amide, CM101, squalamine, combretastatin, RPI4610, NX31838, Sulfated sweet dew pentose phosphate ester, 7,7-(carbonyl-bis-[imino--N-methyl-4,2-pyrrolo-carbonyl imino-[N-methyl-4,2-pyrroles]-carbonyl imino-]-bis--(1, the 3-napadisilate) and 3-[(2,4-dimethyl pyrrole-5-yl) methylene radical]-2-indolone (SU5416).

But the promoting agent of the interference cell cycle checkpoint kinase whose compound that is arrestin, the signal of the convertible cell cycle check point of this protein kinase, make cancer cells to DNA infringement agent sensitivity thus.This promoting agent comprises the kinase whose inhibitor of ATR, ATM, Chk1 and Chk2 and cdk and cdc kinase inhibitor, and its object lesson is Staurosporine, Flavopiridol, CYC202 (Cyclacel) and BMS-387032.

The inhibitor of cell proliferation and survival signalling channel is the medicament in the signal transduction series connection downstream of surface receptor capable of inhibiting cell and this surface receptor.This medicament comprises the inhibitor (for example Gefitinib and erlotinib) of EGFR, the inhibitor of ERB-2 (for example Herceptin), the inhibitor of IGFR, the inhibitor of cytokine receptor, the inhibitor of MET, the inhibitor of PI3K (for example LY294002), serine/threonine kinase (includes but not limited to that the inhibitor of Akt is such as WO02/083064, WO02/083139, inhibitor described in WO02/083140 and WO02/083138), the kinase whose inhibitor of Raf (for example BAY-43-9006), the inhibitor (for example Wyeth CCI-779) of the inhibitor of MEK (for example CI-1040 and PD-098059) and mTOR.This medicament comprises micromolecular inhibitor compound and antibody antagonist.

Cell death inducer comprises TNF receptor family member's activator (comprising the TRAIL acceptor).

At some at present in preferred embodiment, for the representative promoting agent of the Compound Phase combination of the preferred embodiment with the treatment cancer, comprise for example irinotecan, topotecan, gemcitabine, 5 FU 5 fluorouracil, formyl tetrahydrofolic acid, carboplatin, cis-platinum, taxanes, Te Zhata shore (tezacitabine), endoxan, catharanthus alkaloid, imatinib (Gleevec), anthracycline, Rituximab, Herceptin and other cancer chemotherapeutic agents.

For the above-claimed cpd that uses with the compound combination of preferred embodiment can Physicians ' Desk Reference (PDR) therapeutic dose shown in the 47th edition (1993) use, at this, be introduced into as a reference, or this treatment consumption is known to persons of ordinary skill in the art.

The maximum clinical dosage that the compound of preferred embodiment and other carcinostatic agent can be recommended or with lower dosed administration.In the composition of preferred embodiment, the dosage level of active compound can change according to severity and the reaction of route of administration, disease, thereby obtains required therapeutic response.Described combination separately composition form or with the form administration of the single formulation that contains two kinds of promoting agents.When with the combination form administration the time, therapeutical agent is prepared with the form of independent composition, in same time or different time administration, or by therapeutical agent the form administration with single composition.

General synthetic method

The compound of preferred embodiment can make by the general method below facile prepared using.Should be appreciated that in the situation that provide typical or preferred processing condition (, mol ratio of temperature of reaction, time, reactant, solvent, pressure etc.), other processing condition also can be used, except as otherwise noted.Optimum reaction condition can be along with specific reactants used or solvent and is changed, but this condition can be determined by classical algorithm by those skilled in the art.

In addition, it will be apparent to one skilled in the art that and need the GPF (General Protection False base, to prevent some functional group, unwanted reaction occurs.For the suitable protecting group of various functional groups and be known in the art for the protection of the suitable condition with the deprotection particular functional group.For example, various protecting groups are recorded in T.W.Greene and G.M.Wuts, Protecting Groups in OrganicSynthesis, and the 3rd edition, Wiley, New York, 1999, at this, be introduced into as a reference.

In addition, the compound of preferred embodiment also contains one or more chiral centres.Therefore, if necessary, the form that this compound can pure stereoisomers,, with the form of independent enantiomorph or diastereomer or make or separate with the form of mixtures that is rich in steric isomer and obtain.All these steric isomers (and the mixture that is rich in steric isomer) all are included in the scope of the present embodiment, unless otherwise directed.The pure stereoisomers mixture of steric isomer (or be rich in) for example can utilize optically-active raw material known in the art or stereoselectivity reagent to make.Perhaps, the racemic mixture of this compound can utilize separation such as chiral column chromatogram, chiral resolving agent to obtain.

For the raw material of following reaction normally known compound maybe can make by currently known methods or its apparent improving one's methods.For example, many raw materials are bought from supplier such as Aldrich ChemicalCo. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St.Louis, Missouri, USA).Other raw material can make by the described method of canonical reference document or its apparent improving one's methods: such as Fieser and Fieser ' sReagents for Organic Synthesis, 1-15 rolls up (John Wiley and Sons, 1991), Rodd ' s Chemistry of Carbon Compounds, 1-5 rolls up and augments volume (ElsevierScience Publishers, 1989), Organic Reactionsm, 1-40 rolls up (John Wiley and Sons, 1991), March ' s Advanced Organic Chemistry (John Wiley and Sons, the 4th edition) and Larock ' s Comprehensive Organic Transformations (VCHPublishers Inc., 1989).

Various raw materials, intermediate and the compound of preferred embodiment can utilize routine techniques such as precipitation, filtration, crystallization, evaporation, distillation and chromatogram to be separated and purifying in due course.The sign of these compounds can utilize ordinary method to carry out, such as being undertaken by fusing point, mass spectrum, nucleus magnetic resonance and various other spectroscopy analysis method.

The compound of the present embodiment utilizes the familiar the whole bag of tricks of those skilled in the art to make usually, for example the disclosed method of U.S. Patent Application Publication No. US20040087626A1 and US20040122237A1, introduce the full text of its disclosure to combine with following description and embodiment at this.The compound of this embodiment makes according to following reaction process 1-8 usually, and flow process 1-8 is described later in detail in following examples.

Flow process 1-8 explains and understands for the preparation of the intermediate of the present embodiment and the general method of compound.These compounds make from the raw material that maybe can buy known in the art.Concrete compound is only for indicative purpose.

Flow process 1

In flow process 1,2-hydroxyanilines or derivatives thereof is reacted to obtain mercaptan-benzoxazoles with ethyl xanthogenate.Mercaptan-benzoxazoles are reacted with thionyl chloride and change into chloro-benzoxazole.Perhaps, also can be by one group of halogenating agent for the mercaptan benzoxazole, change into the halo benzoxazole such as but not limited to phosphorus trichloride, phosphorus tribromide, phosgene or oxalyl chloride.Then chloro-benzoxazole is reacted to obtain benzylamino-benzoxazoles with benzyl amine as 2-chlorobenzyl amine.By benzylamino-benzoxazoles and chloro-pyridine under the existence of alkali such as cesium carbonate coupling to obtain the compound of the present embodiment.Perhaps, haloperidid also can be used for linked reaction.

Flow process 2

In flow process 2, by mercaptan-benzoxazole or derivatives thereofs in the thiol moiety alkylation.Alkylating mercaptan-benzoxazoles and corresponding haloperidid are carried out to the compound that coupling obtains the present embodiment under the existence of alkali such as cesium carbonate as chloro-pyridine.The benzoxazolyl oxygen base-pyridine of formation is utilized to for example mCPBA oxidation.Other oxygenant also can be used for mercaptan oxidation is become to sulfoxide.Other oxygenant comprises but is not limited to hydrogen peroxide, sodium periodate, Pyridinium chlorochromate on silica gel or chromium trioxide.The sulfoxide of benzoxazolyl oxygen base-pyridine is carried out to nucleophilic reaction to obtain compound of the present invention with amine.

Flow process 3

In flow process 3, cyan-acetic ester and pentamethylene bromide are carried out after coupling, crystallization to form 1-cyano group-naphthenic acid ethyl ester.By hydrogen and Raney nickel reduction for this product.Also available other reductive agent is reduced into amine by itrile group.Other reductive agent includes but not limited to utilize the catalytic hydrogenation of platinum oxide or Raney nickel; Or lithium aluminum hydride, diisobutyl aluminium hydride, sodium borohydride or lithium triethylborohydride.By reduzate and sulfinyl-benzoxazolyl oxygen bases-pyridine phase coupling.By the further functionalized or derivatize of the formed product of linked reaction.For example, in flow process 3, ester group can be become to carboxylic acid by hydrolysis, then with amine, react and change into acid amides.These reactions are conversion reactions well known by persons skilled in the art.

Flow process 4

In flow process 4,3-(2-piperidin-1-yl-ethyl)-phenyl amine is an example that can be used for forming the compound of the present embodiment.3-(2-piperidin-1-yl-ethyl)-phenyl amine forms from the sulfonation reaction of 2-(3-nitrophenyl)-ethanol, then by the methylsulfonic acid 2-(3-nitrophenyl) of formation-ethyl ester amination, subsequently by formed 1-[2-(3-nitrophenyl)-ethyl]-the piperidines reduction.

Flow process 5

In flow process 5, by cyclohexyl methylamine amination for 4-(2-(methylsulfinyl) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide.Then by the 4-that forms (2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide hydrogenation to form 4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid.Then by 4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid and benzotriazole-1-base oxygen base three (dimethylamino)-Phosphonium hexafluorophosphates, tert-butyl carbazate and triethylamine react to form 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formyl hydrazine.Then 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formyl hydrazine is reacted to form the compound of this embodiment with trimethyl orthoformate.

Flow process 6

In flow process 6, can the compound of this embodiment is further functionalized.For example, borane reduction for 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formic acid is become 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-yl }-methyl alcohol.Other suitable reductive agent includes but not limited to lithium aluminum hydride, aluminum hydride, diisobutyl aluminium hydride, sodium borohydride or lithium triethylborohydride.Then will { 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-yl }-methyl alcohol by the Dess-Martin reagent oxidation, become 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formaldehyde.Other suitable oxygenant comprises but is not limited to Pyridinium chlorochromate on silica gel, SO ₃the condition of the DMSO solution of pyridine or so-called Swern or Moffet oxidation.Then 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formaldehyde is changed into to cyclohexyl methyl-{ 6-[2-(5-methyl isophthalic acid H-imidazoles-2-yl)-pyridin-4-yl oxygen base]-benzoxazoles-2-yl }-amine by reacting with pyruvic aldehyde.

Flow process 7

In flow process 7; the compound of this embodiment is by 4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (from embodiment 2) and 1-(2; 3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-reaction of ethylamine synthesizes.In one case, 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamine synthesizes by resin.

By being connected to amine on resin and 2,3-dihydro-benzo, [Isosorbide-5-Nitrae] dioxin-5-formaldehyde reaction obtains C-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-benzylidene amino thus.C-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-benzylidene amino at imino-site derivatize, is for example used to methyl-magnesium-bromide by alkylation.Can use other alkylating agent according to required molecule.The 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl) of formation-ethylamine is dissociated out from resin.The dissociate example of agent of resin is trifluoroacetic acid (TFA).Formed 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamine can be used for compound synthetic of this embodiment.For example; can be by 1-(2; 3-dihydro-benzo [1; 4] dioxin-5-yl)-ethylamine reacts to form 4-{2-[1-(2 with 4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea; 3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea.

Flow process 8

In flow process 8,2-sulfydryl-benzothiazole-6-alcohol can be according to US4, and 873,346 described methods make.Then 2-sulfydryl-benzothiazole-6-alcohol is changed into to 2-methylthio group-benzothiazole-6-alcohol to remove the ether protecting group by ordinary method.2-methylthio group-benzothiazole-6-alcohol provides the alkylation in the mercaptan position with reacting of methyl iodide.2-methylthio group-benzothiazole-6-alcohol obtains 4-(2-methylthio group-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea with reacting of the chloro-pyridine of 4--2-formic acid methyl nitrosourea.Obtain 4-(2-methanesulfinyl-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea with rear oxidation 4-(2-methylthio group-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea.4-(2-methanesulfinyl-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea can be the substrate for reacting with various amine.For example, 4-(2-methanesulfinyl-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea is reacted to obtain 4-[2-(cyclohexyl methyl-amino)-benzothiazol-6-yl oxygen base with cyclohexyl methyl amine]-pyridine-2-formic acid methyl nitrosourea.

Flow process 9

In flow process 9, the benzoxazole of formula 9.1 or benzothiazole can react with the amine replaced the intermediate of the formula that obtains 9.2.By reagent BBr for example for the intermediate of formula 9.2 ₃processing obtains the phenol of formula 9.3.Subsequently by the intermediate of formula 9.3 with the 4-haloperidid of formula 9.4 usually but be not limited to process the formula of obtaining 9.5 compounds under the existence such as salt of wormwood or cesium carbonate at alkali at the temperature of room temperature to 130 ℃.Further process and obtain formula 9.6 compounds with boric acid or stannic hydride under well known by persons skilled in the art and Suzuki or Stille reacting phase condition together.In addition, can also by formula 9.5 compounds with the amine replaced well known by persons skilled in the art with Buchwald, react or SnAr reacting phase condition together under process the formula of obtaining 9.7 compounds.

Flow process 10

In flow process 10, formula 10.5 and 10.6 benzoxazole or benzothiazole can make as raw material with the 4-haloperidid of formula 10.1, by raw material (1) with boric acid or stannic hydride under Suzuki well known by persons skilled in the art or Stille reaction conditions, process the intermediate of the formula of obtaining 10.2 or (2) and the amine replaced Buchwald well known by persons skilled in the art react or the SnAr reaction conditions under reacted the intermediate of the formula that obtains 10.3.Subsequently the phenol intermediate of the intermediate of formula 10.2 or 10.3 and formula 10.4 is for example for example reacted to the compound of the formula of obtaining 10.5 and 10.6 in dimethyl formamide, acetonitrile or dioxan at solvent under the existence of salt of wormwood or cesium carbonate at alkali.

Embodiment

With reference to following examples, the compound of preferred embodiment utilizes method as herein described or other method known in the art to synthesize.

The Waters Millenium chromatographic system that compound and/or intermediate are had to 2695Separation Module (Milford, MA) by high performance liquid chromatography (HPLC) utilization is characterized.Analytical column is anti-phase Phenomenex Luna C18-5 μ, and 4.6x50mm buys from Alltech (Deerfield, IL).Adopt gradient elution (flow velocity 2.5mL/min), usually start from 5% acetonitrile/95% water, proceeded to 100% acetonitrile in 10 minutes.All solvents all contain 0.1% trifluoroacetic acid (TFA).By 220 or this compound of ultraviolet ray (UV) absorption detecting at 254nm place.The HPLC solvent is bought from Burdick and Jackson (Muskegan, MI) or Fisher Scientific (Pittsburgh, PA).

In some cases, purity by thin-layer chromatography (TLC) utilize glass or plastic silicon offset plate for example Baker-Flex Silica Gel1B2-F film determined.The TLC result is easy to detect by range estimation under ultraviolet ray, or by using known iodine vapor and other various dye technologies to be detected.

Mass spectroscopy is carried out on one of two LCMS instruments: Waters System (Alliance HTHPLC and Micromass ZQ mass spectrograph; Post: Eclipse XDB-C18,2.1x50mm; Gradient: containing the aqueous solution of the 5-95% of 0.05%TFA (or 35-95%, or 65-95% or 95-95%) acetonitrile, in 4 minutes; Flow velocity 0.8mL/min; Molecular weight ranges 200-1500; Cone voltage 20V; 40 ℃ of column temperatures) or Hewlett Packard System (Series1100HPLC; Post: EclipseXDB-C18,2.1x50mm; Gradient: contain the aqueous solution of the 5-95% acetonitrile of 0.05%TFA, in 4 minutes; Flow velocity 0.8mL/min; Molecular weight ranges 150-850; Cone voltage 50V; 30 ℃ of column temperatures).All quality are reported with the form of protonated parent ion.

GCMS analyzes in Hewlett Packard instrument (the HP6890 series gas-chromatography with Mass Selective Detector5973; Syringe volume: 1 μ L; Initial column temperature: 50 ℃; Final column temperature: 250 ℃; The even change time (ramp time): 20 minutes; Gas flow rate: 1mL/min; Post: 5% phenyl methyl siloxanes, model HP190915-443, size: carry out 30.0m x25m x0.25m).

Nucleus magnetic resonance (NMR) is analyzed on some compound and is carried out with Varian300MHz NMR (PaloAlto, CA).The spectrum reference is the known chemical shift of TMS or solvent.Some compound sample for example, is tested to increase the solubleness of sample at the temperature (75 ℃) raise.

The purity of some compound is determined by ultimate analysis (Desert Analytics, Tucson, AZ).

Fusing point is determined on Laboratory Devices Mel-Temp equipment (Holliston, MA).

Preparative extraction and application Flash40 chromatographic system and KP-Sil, 60A (Biotage, Charlottesville, VA) or the flash column chromatography by using silica gel (230-400 order) weighting material or undertaken by the HPLC that adopts Waters2767Sample Manager, C-18 reversed-phase column, 30X50mm, flow velocity 75mL/min.Common solvent for Flash40Biotage system and flash column chromatography is methylene dichloride, methyl alcohol, ethyl acetate, hexane, acetone, ammoniacal liquor (or ammonium hydroxide) and triethylamine.For the common solvent of reversed-phase HPLC, be acetonitrile and the water of the change concentration that contains 0.1% trifluoroacetic acid.

Should be appreciated that, the organic compound of preferred embodiment can show tautomerism.Because the chemical structure in this specification sheets only represents a kind of possible tautomeric form, therefore, should be appreciated that any tautomeric form that preferred embodiment comprises drawn structure.

Should be appreciated that, the invention is not restricted to the listed embodiment for task of explanation of this paper, but be included in the form of ownership in above-mentioned open scope.

In following examples and whole application, following abbreviation has following implication.If not definition, these terms have its general generally acknowledged implication.

Abbreviation

The ACN acetonitrile

BINAP 2,2 '-bis-(diphenylphosphine)-1,1 '-dinaphthalene

The DCM methylene dichloride

The DIEA diisopropyl ethyl amine

DIPEA N, the N-diisopropyl ethyl amine

DME 1, the 2-glycol dimethyl ether

The DMF DMF

The DMSO dimethyl sulfoxide (DMSO)

DPPF 1,1 '-bis-(diphenylphosphine) ferrocene

The EtOAc ethyl acetate

EtOH ethanol

HATU 2-(7-azepine-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea hexafluoro

Phosphoric acid salt

The HPLC high performance liquid chromatography

The MCPBA metachloroperbenzoic acid

MeOH methyl alcohol

NBS N-bromine succinimide

The NMP METHYLPYRROLIDONE

The RT room temperature

The THF tetrahydrofuran (THF)

Formula I compound

Embodiment 1

4-[2-(the chloro-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea (table 2, compound 8) synthetic

Synthesizing of step 1.2-sulfydryl-benzoxazoles-6-alcohol

Add potassium hydroxide (2.1 equivalent) in the ethanolic soln of 4-aminoresorcinol (1 equivalent) and xanthogenic acid (3 equivalent).Mixture is refluxed 2 hours, and then dilute with water also is acidified to pH4 with 1N HCl.Product is extracted with ethyl acetate, then concentrated.The solid of formation is obtained to pure products with the methylene dichloride development, and yield is 90%.MH+=168.1.

Synthesizing of the chloro-benzoxazole of step 2.2--6-alcohol

2-sulfydryl-benzoxazoles-6-alcohol (1 equivalent) is dissolved in to thionyl chloride (10 equivalent).DMF (0.6 equivalent) is at room temperature slowly joined in this solution.Mixture is heated to 80 ℃ and reflux 15 minutes.Reaction mixture is cooled to room temperature and removes desolventizing.By solid dimethylbenzene component distillation 3 times that form.This solid is dissolved in to the ethyl acetate solution of 10%THF and washs 1 time with saturated sodium bicarbonate aqueous solution.By the organic layer anhydrous sodium sulfate drying, filter and remove desolventizing.Solid is obtained to pure products with the acetonitrile development, and yield is 68%.MH+=170.0.

Synthesizing of step 3.2-(the chloro-benzylamino of 2-)-benzoxazoles-6-alcohol

The chloro-benzoxazole of 2--6-alcohol (1 equivalent) and the chloro-benzyl amine of 2-(2 equivalent) are dissolved in to NMP.Utilize Personal Chemistry microwave system, mixture is reacted 6 minutes under 180 ℃.Crude product mixture is diluted by ethyl acetate, and with salt water washing 1 time, with 1N HCl washing 1 time, or with salt water washing 2 times, this depends on amine used.By the organic layer anhydrous sodium sulfate drying, filter and concentrate.This material is utilized to hexane and ethyl acetate purifying by silica gel column chromatography.MH+=275.1.

Step 4.4-[2-(the chloro-benzylamino of 2-)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea synthetic

Add the chloro-pyridine of 4--2-formic acid methyl nitrosourea (1 equivalent) in the DMSO solution of 2-(the chloro-benzylamino of 2-)-benzoxazoles-6-alcohol (1 equivalent).It is at room temperature stirred 15 minutes, at this point, add cesium carbonate (1.2 equivalent).Solution is heated 30 minutes totally in Personal Chemistry microwave reactor under 150 ℃.Crude product mixture is diluted by ethyl acetate, with salt water washing 3 times, use anhydrous sodium sulfate drying, filter and concentrate.Then crude product is obtained to pure products 8 by anti-phase preparation HPLC purifying.MH+=409.1.

Compound 9,11,12,18,19,20,26,27,28 and 40 in following table 2 is synthetic according to the similar approach in embodiment 1.

Embodiment 2

4-[2-((1S, 2R)-2-hydroxyl-indane-1-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea (table 2, compound 50)

Step 1.2-(methylthio group) benzo [synthesizing of d] oxazole-6-alcohol

[in the 20mL dichloromethane solution of d] oxazole-6-alcohol (1.55g, 9.28mmol, 1.0 equivalents), at room temperature add triethylamine (1.87g to 2-sulfydryl benzo, 18.56mmol, 2.0 equivalent) and methyl iodide (1.77g, 13.92mmol, 1.5 equivalents).Reaction mixture is at room temperature stirred 3 hours.By 100mL methylene dichloride dilution for mixture.By mixture water (10mL), salt solution (10mL) washing formed, then use MgSO ₄drying, filter and reduction vaporization obtains crude product, and it,, by silica gel chromatography, is obtained to title compound with ethyl acetate and hexane wash-out.MH+=182.

Step 2.4-(2-(methylthio group) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide synthetic

To 2-(methylthio group) benzo [d] oxazole-6-alcohol (8.5g, 46.7mmol, 1 equivalent) 80mL N, add the chloro-N-picoline of 4--2-methane amide (16.0g in dinethylformamide solution, 93.4mmol, 2.0 equivalent) and cesium carbonate (45.7g, 140.1mmol, 3.0 equivalents).Reaction mixture is stirred 6 hours under 75 ℃.After mixture is cooled to room temperature, in mixture, add 120mL water.After filtration, solid is passed through to the silicagel column purifying, with ethyl acetate and hexane wash-out, obtain title compound.MH+=316.

Step 3.4-(2-(methylsulfinyl) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide synthetic

To 4-(2-(methylthio group) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide (1.26g, 4.0mmol, 1.0 equivalents) the 40mL dichloromethane solution in add 3-chlorine peroxybenzoic acid (70%, 989mg, 4.4mmol, 1.1 equivalents).Reaction mixture is at room temperature stirred 5 hours, then with the dilution of 200mL methylene dichloride.By sodium bicarbonate aqueous solution and the salt water washing for mixture formed, then use MgSO ₄drying, filter and reduction vaporization obtains crude product, and it can be used for next step without being further purified.MH+=332.

Step 4.4-[2-((1S, 2R)-2-hydroxyl-indane-1-base amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea

By 4-(2-(methylsulfinyl) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide (17mg; 0.05mmol; 1.0eq) and (1S; 2R)-1-amino-2; 3-mono-dihydro-1H-indenes-2-alcohol (30mg; 0.2mml, 4.0 equivalents) 1mL N,N-dimethylacetamide solution in microwave under 90 ℃ the heating 600 seconds.Crude product is obtained to title compound by anti-phase preparation HPLC purifying.MH+=417.0.

Compound 45,46 in following table 2 and 47 similar approach according to embodiment 2 are synthetic, by temperature variation to 140 ℃.Compound 42,57,59 in following table 2 and 94 similar approach according to embodiment 2 are synthetic, by temperature variation to 120 ℃.

Embodiment 3

1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino] methyl }-naphthenic acid ethyl ester (table 2, compound 75) synthetic

Synthesizing of step 1.1-cyano group-naphthenic acid ethyl ester

Slowly add cesium carbonate (2.5 equivalent) under 0 ℃ in the DMF solution of cyan-acetic ester (1 equivalent), then slowly add pentamethylene bromide.This mixture is stirred 30 minutes under 0 ℃, at room temperature stir 2 hours.Crude product mixture diluted by ethyl acetate and wash with water 3 times, using anhydrous sodium sulfate drying, filtering and concentrate.The purity of this compound be enough to proceed the reaction and without purifying.57% yield. ¹h NMR (300MHz, CDCl ₃) δ 4.25 (q, 2H), 2.12-1.68 (m, 10H), 1.31 (t, 3H).

Synthesizing of step 2.1-amino methyl-naphthenic acid ethyl ester

The alcohol suspension of excessive Raney nickel is joined in the ethanolic soln of 1-cyano group-naphthenic acid ethyl ester under nitrogen atmosphere.Nitrogen atmosphere is replaced with excessive hydrogen and mixture is stirred and spends the night.Reaction mixture is also removed to desolventizing by diatomite filtration.The purity of this compound be enough to proceed the reaction and without purifying.80% yield.MH+=186.2.

Step 3.1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino] methyl }-naphthenic acid ethyl ester synthetic

To adding the 4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base) that obtains from the step 3 of embodiment 2-pyridine-2-formic acid methyl nitrosourea in the THF solution of 1-amino methyl-naphthenic acid ethyl ester.After at room temperature reacting 2 hours, except desolventizing and by ethyl acetate and a small amount of methylene dichloride dilution for crude product, then use the salt water washing 3 times, use anhydrous sodium sulfate drying, filter and concentrate.End product is passed through to anti-phase preparation HPLC purifying.MH+=453.1.

Embodiment 4

1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-methyl }-naphthenic acid (table 2, compound 93) synthetic

By 1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino] methyl }-naphthenic acid ethyl ester (1 equivalent) is dissolved in 3M sodium hydroxide (20 equivalent); Add THF and methyl alcohol with homogenize solution.Mixture is at room temperature reacted and spends the night.Except desolventizing.Crude product is acidified to pH4 with 1N HCl, then alkalizes to pH7 with saturated sodium bicarbonate aqueous solution.This solution is saturated with solid sodium chloride, then be extracted with ethyl acetate 3 times.By the salt water washing 1 time for organic extract liquid merged, use anhydrous sodium sulfate drying, filter and concentrate.By product by silica gel column chromatography Virahol and methylene dichloride (50%) purifying, MH+=425.1.

Embodiment 5

4-{2-[(1-methylamino formyl radical-cyclohexyl methyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea (table 2, compound 1] 2) synthetic

To 1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base amino]-methyl }-add DIPEA (3 equivalent) and phosphofluoric acid [dimethylamino-([1 in the DMF solution of naphthenic acid (1 equivalent); 2; 3] triazolo [4,5-b] pyridin-3-yl oxygen base)-methylene radical]-dimethyl-ammonium (1 equivalent).It is at room temperature stirred 2 hours, then add the THF solution (5 equivalent) of 2M methylamine and react and spend the night under 70 ℃.Mixture, with the ethyl acetate dilution and with saturated aqueous ammonium chloride washing 2 times, with salt water washing 1 time, is then used to anhydrous sodium sulfate drying, filter and concentrate, then by preparative reversed-phase HPLC purifying.MH+=438.1.

Embodiment 6

4-{2-[3-(2-piperidin-1-yl-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea (table 2, compound 44) synthetic

Synthesizing of step 1. methylsulfonic acid 2-(3-nitro-phenyl)-ethyl ester

Add pyridine (4 equivalent) and methylsulfonyl chloride (2 equivalent) under 0 ℃ in the dichloromethane solution of 2-(3-nitro-phenyl)-ethanol (1 equivalent).Stir under 0 ℃ after 1 hour, at room temperature stir and spend the night, mixture is diluted with methylene dichloride, wash with water 1 time, with 1N HCl washing 1 time, use anhydrous sodium sulfate drying, filter and concentrate.This product is not purified just enough pure and for next step.MH+=246.0.

Step 2.1-[2-(3-nitro-phenyl)-ethyl]-piperidines synthetic

Methylsulfonic acid 2-(3-nitro-phenyl)-ethyl ester is dissolved in to piperidines (20 equivalent) and THF and stirs 1 hour under 60 ℃.Except desolventizing.Crude product is diluted by ethyl acetate, wash with water 3 times, use anhydrous sodium sulfate drying, filter and concentrate.This product is not purified just enough pure and continue reaction.44% yield.MH+=235.1.

Synthesizing of step 3.3-(2-piperidin-1-yl-ethyl)-phenyl amine

To 1-[2-(3-nitro-phenyl)-ethyl]-add 10% active palladium carbon and excess hydrogen of catalytic amount in the ethanolic soln of piperidines.This mixture is stirred and spends the night, then filter and concentrate.This product is enough pure and for next reaction.60% yield.MH+=205.1.

Step 4.4-{2-[3-(2-piperidin-1-yl-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea synthetic

The 4-that the step 3 of embodiment 2 is obtained (2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea and 3-(2-piperidin-1-yl-ethyl)-phenyl amine are dissolved in DMAC and heat under 120 ℃ 10～20 minutes in the CEM microwave reactor.Crude product mixture is passed through to preparative reversed-phase HPLC purifying.MH+=472.2.

Embodiment 7

4-{2-[3-(2-morpholine-4-base-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea (table 2, compound 74)

This compound (table 2, project 74) is synthetic according to the similar approach of embodiment 6.MH+=474.2.

Embodiment 8

4-{2-[(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-carbonyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea (table 2, compound 110) synthetic

4-(amino-benzoxazoles of 2--6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (1 equivalent) and 2,3-dihydro-Isosorbide-5-Nitrae-benzdioxan-5-formic acid (1 equivalent) are dissolved in to DMF.Add DIPEA (3 equivalent) and phosphofluoric acid [dimethylamino-([1,2,3] triazolos [4,5-b] pyridin-3-yl oxygen base)-methylene radical]-dimethyl-ammonium (1 equivalent) in this solution.Mixture is stirred and spends the night under 40 ℃, then with ethyl acetate dilution and use respectively 1N HCl, saturated sodium bicarbonate aqueous solution and salt water washing 1 time, finally use anhydrous sodium sulfate drying, filter and concentrate.It is passed through to preparative reversed-phase HPLC purifying.MH+=447.0.

Embodiment 9

Synthesizing of cyclohexyl methyl-[6-(2-[1,3,4] oxadiazoles-2-base-pyridin-4-yl oxygen base)-benzoxazoles-2-yl]-amine (table 2, compound 81)

Step 1.4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide synthetic

To 4-(2-(methylsulfinyl) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide (1.40g; 4.23mmol; 1.0eq) 15mL THF solution at room temperature add cyclohexyl methylamine (955mg, 8.46mmol, 2.0 equivalents).Reaction mixture is stirred 2 hours at this temperature.After removal of solvent under reduced pressure, resistates is dissolved in to the 150mL ethyl acetate.By mixture water (20mL), salt solution (20mL) washing formed, then use MgSO ₄drying, filter, and reduction vaporization obtains crude product, and it,, by silica gel chromatography, is obtained to title compound with ethyl acetate and hexane wash-out.MH ⁺=381.

Step 2.4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid synthetic

4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base)-N-picoline-solution of 2-methane amide (300mg, 0.79mmol, 1.0eq) in the 10mL10M aqueous hydrochloric acid is stirred 24 hours under 100 ℃.Reaction mixture is cooled to room temperature.Most water is removed in decompression.Then sodium bicarbonate aqueous solution is joined in mixture to pH 7.0.After filtration, solid is washed with water, then drying obtains title compound.MH+=368.0.

Step 3.4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formyl hydrazine synthetic

To 4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid (110mg, 0.30mmol, 1.0 2mLN equivalent), at room temperature add benzotriazole-1-base oxygen base three (dimethylamino)-Phosphonium hexafluorophosphates (199mg, 0.45mmol, 1.5 equivalents), tert-butyl carbazate (47mg in dinethylformamide solution, 0.36mmol, 1.2 equivalent) and triethylamine (60mg, 0.60mmol, 2.0 equivalents).Reaction mixture is stirred 2 hours at this temperature.Then add 20mL water in mixture.After filtration, solid is passed through to silicagel column purifying again, obtain the title compound of Boc protection with ethyl acetate and hexane wash-out.

The title compound (54mg, 0.112mmol, 1.0 equivalents) of Boc protection is dissolved in to 1mL methyl alcohol.Then to the dioxan solution that adds 3mL4M hydrogenchloride in mixture.Reaction mixture is at room temperature stirred and spends the night.Except desolventizing obtains title compound, it can be used for next step without being further purified.MH+=382.0.

Synthesizing of step 4. cyclohexyl methyl-[6-(2-[1,3,4] oxadiazoles-2-base-pyridin-4-yl oxygen base)-benzoxazoles-2-yl]-amine

By 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formyl hydrazine (8mg, 0.019mmol, 1.0eq) with the 1mL trimethyl orthoformate solution of 0.1mL4M hydrogenchloride, in microwave, under 120 ℃, heated for 1200 seconds.Crude product is obtained to title compound by anti-phase preparation HPLC purifying.MH ⁺=392.0.

Compound 81 also can separate and obtain from reaction solution.MH+=367.0.

Embodiment 10

4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formonitrile HCN (table 2, compound 82) synthetic

Under-78 ℃, in the 1mL dichloromethane solution of methyl sulfoxide (32mg, 0.41mmol, 6.0 equivalents), add oxalyl chloride (2M, 0.135mL, 0.27mmol, 4.0 equivalents).After 15 minutes, the 2mL dichloromethane solution of 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-carboxamide (25mg, 0.068mmol, 1.0 equivalents) is joined in reaction mixture.Stir after 20 minutes triethylamine (83mg, 0.83mmol, 12 equivalents) is joined in mixture at this temperature.Reaction mixture is stirred 2 hours under-78 ℃, then use the aqueous ammonium chloride solution termination reaction.The mixture of formation is extracted with ethyl acetate to (2 * 20mL).By organic layer water (5mL), salt solution (5mL) washing merged, then use MgSO ₄drying, filter and reduction vaporization obtains crude product, and it is obtained to title compound by anti-phase preparation HPLC purifying.MH+=349.0.

Embodiment 11

{ 4-[2-(cyclohexyl methyl-amino)-benzoxazoles-6-base oxygen base]-pyridine-2-yl }-methyl alcohol (table 2, compound 80) synthetic

Add borine-tetrahydrofuran (THF) mixture (1M, 1mL, 1mmol) under 0 ℃ in the 5mL THF solution of 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formic acid (120mg, 0.33mmol, 1.0eq).Reaction mixture is stirred 5 hours at this temperature.By 1M hydrochloric acid termination reaction.The mixture of formation is extracted with ethyl acetate to (2 * 60mL).By organic layer water (10mL), salt solution (10mL) washing merged, then use MgSO ₄drying, filter and reduction vaporization obtains crude product, and it,, by silica gel chromatography, is obtained to title compound with ethyl acetate and hexane wash-out.MH+=354.0.

Embodiment 12

Cyclohexyl methyl-{ 6-[2-(5-methyl isophthalic acid H-imidazoles-2-yl)-pyridin-4-yl oxygen base]-benzoxazoles-2-yl }-amine (table 2, compound 109) synthetic

Step 1.4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formaldehyde synthetic

To 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-yl) methyl alcohol (20mg, 0.057mmol, 1.0eq) the 2mL methylene dichloride and 2mL THF solution at room temperature add Dess-Martin reagent (26mg, 0.062mmol, 1.1eq).Reaction mixture is stirred 4 hours at this temperature.Then by 50mL ethyl acetate dilution for mixture.By sodium bicarbonate aqueous solution for mixture (5mL), water (5mL), salt solution (5mL) washing formed, then use MgSO ₄drying, filter and reduction vaporization obtains crude product, and it is obtained to title compound by preparative TLC purifying.MH+=352.0.

Step 2. cyclohexyl methyl-{ 6-[2-(5-methyl isophthalic acid H-imidazoles-2-yl)-pyridin-4-yl oxygen base]-benzoxazoles-2-yl }-amine synthetic

To 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formaldehyde (5mg, 0.014mmol, 1.0eq) the 0.6mL methanol solution at room temperature add pyruvic aldehyde (40%, 0.1mL) and 0.15mL ammonium hydroxide.Reaction mixture is stirred 2 hours at this temperature.Crude product is obtained to title compound by anti-phase preparation HPLC purifying.MH+=404.0.

Embodiment 13

Synthesizing of [6-(2-amino methyl-pyridin-4-yl oxygen base)-benzoxazoles-2-yl]-cyclohexyl methyl-amine (table 2, compound 111)

To (4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-yl) methyl alcohol (20mg, 0.057mmol, 1.0eq) 2mL THF solution at room temperature add triphenylphosphine (22mg, 0.085mmol, 1.5eq), phthalic imidine (12.5mg, 0.085mmol, 1.5 equivalents) and diisopropyl azodiformate (17mg, 0.085mmol, 1.5 equivalents).Reaction mixture is stirred 16 hours at this temperature.Then except desolventizing.Crude product is obtained to 2-((4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-yl) methyl by preparative TLC purifying) isoindoline-1, the 3-diketone.

By 2-((4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-yl) methyl) isoindoline-1,3-diketone (6.2mg, 0.013mmol, 1 equivalent) is dissolved in 0.5mL ethanol.Then a hydrazine hydrate (6.4mg, 0.13mmol, 10 equivalents) is added in reaction mixture.Mixture is at room temperature stirred 3 hours.Then except desolventizing.Crude product is obtained to title compound by anti-phase preparation HPLC purifying.MH+=353.0.

Embodiment 14

4-{2-[1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea (table 2, compound 125) synthetic

Step 1.C-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-benzylidene amino synthetic

Add 2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-formaldehyde (2 equivalent) in the trimethyl orthoformate suspension that is attached to the amine (1 equivalent) on the Rink resin.By this mixture shaken overnight, filter and by solid drying.

Step 2.1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamine synthetic

The dry resin that is combined with C-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-benzylidene amino (1 equivalent) on it is suspended in dry toluene.The diethyl ether solution that adds the 3M of methyl-magnesium-bromide (150 equivalent) under nitrogen atmosphere.This mixture is vibrated 24 hours under 60 ℃, then filter, respectively wash 3 times with toluene, water, methyl alcohol and methylene dichloride.Finally use methanol wash.By solid vacuum-drying.

Step 3. is cracking 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamine from resin

Add trifluoroacetic acid (20 volume %) in the resin that is combined with 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamine be suspended in methylene dichloride.By the mixture shaken overnight, then by adding 3M sodium hydroxide to make mixture be alkalescence.Solution filter, to remove resin, is then diluted with methylene dichloride and water.By water layer dichloromethane extraction 3 times.By the salt water washing 1 time for organic extract liquid merged, use anhydrous sodium sulfate drying, filter and concentrate.The material reclaimed is not purified just enough pure and proceed to react.MH+=180.1.

Step 4.4-{2-[1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea synthetic

Add 4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (1 equivalent) in the THF solution of 1-(2,3-dihydro-benzo [Isosorbide-5-Nitrae] dioxin-5-yl)-ethylamine (3 equivalent).It is at room temperature stirred 8 hours, concentrated, and resistates is passed through to preparative reversed-phase HPLC purifying.MH+=447.1.

Compound 41,42,57,59,65,90,94,113 in following table 2 and 122 similar approach according to embodiment 14 are synthetic.

Embodiment 15 (flow process 8)

4-[2-(cyclohexyl methyl-amino)-benzothiazol-6-yl oxygen base]-preparation of pyridine-2-formic acid methyl nitrosourea (table 2, compound 128)

The preparation of step 1.2-sulfydryl-benzothiazole-6-alcohol

According to US4, the description of 873,346 (being incorporated herein by reference in its entirety) is prepared: the benzothiazole of replacement, benzoglyoxaline and benzoxazole; Anderson, David J.; The UpjohnCompany, Kalamazoo, Michigan; Oct.10th, 1989.M+H=184.0.

The preparation of step 2.2-methylthio group-benzothiazole-6-alcohol

The ice-cold 2-sulfydryl-benzothiazole obtained to step 1-6-alcohol (3.80g, 20.76mmol, 1.0 DCM (40mL equivalent), 0.5M) add triethylamine (7.29mL in solution under 0 ℃, 51.91mmol, 2.5 equivalents), then add methyl iodide (1.93mL, 31.14mmol, 1.5eq).Reaction solution is stirred 3 hours under 0 ℃～-10 ℃.Solvent removed in vacuo.Add water (about 200mL) and water layer be extracted with ethyl acetate to (3X150mL).By the organic layer dried over sodium sulfate, filter also vacuum-evaporation and obtain 2-methylthio group-benzothiazole-6-alcohol, be shallow green powder (3.76g, 92%).By crude product is not purified can be for next step.M+H=198.0.

The preparation of step 3.4-(2-methylthio group-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea

At room temperature add CsCO in DMF (25mL) solution of 2-methylthio group-benzothiazole-6-alcohol (3.76g, 19.08mmol, 1.0eq) ₃(15.54g, 47.70mmol, 2.5 equivalents).After stirring a little while, the chloro-pyridine of 4--2-formic acid methyl nitrosourea (4.86g, 28.62mmol, 1.5eq) is added in mixture and by mixture and stirs and spend the night under reflux exchanger under 70 ℃.Reaction mixture is cooling in ice bath, add water (100mL) and water layer is extracted with ethyl acetate to (3X150mL).By the organic layer dried over sodium sulfate, filter and vacuum-evaporation.By 20g ISCO silicagel column (0%-50%-80%-100% ethyl acetate-hexanes mixtures for crude product, 45 minutes, flow velocity 40mL/min) purifying obtains the 4-(2-methylthio group-benzothiazol-6-yl oxygen base) of white solid-pyridine-2-formic acid methyl nitrosourea (3.88g, 62%).M+H=332.1.

The preparation of step 4.4-(2-methanesulfinyl-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea

Add MCPBA (77%, 2.88g, 1.1eq) in DCM (20mL) solution of the 4-obtained to step 3 (2-methylthio group-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea (3.88g, 11.72mmol, 1.0eq) under 0 ℃.Mixture is stirred 1 hour at this temperature.Add saturated sodium bicarbonate solution (100mL).By DCM extraction (3X150mL) for water layer.By the organic layer dried over sodium sulfate, filter and vacuum-evaporation obtains the 4-(2-methanesulfinyl-benzothiazol-6-yl oxygen base) of white powder-pyridine-2-formic acid methyl nitrosourea with quantitative yield.Crude product is not purified can be for next step M+H=348.0.

Step 5.4-[2-(cyclohexyl methyl-amino)-benzothiazol-6-yl oxygen base]-preparation of pyridine-2-formic acid methyl nitrosourea

To 4-(2-methanesulfinyl-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea (25mg; 0.072mmol; 1.0eq) DMF (500 μ L) solution in add cyclohexyl methyl amine (18.7 μ L; 0.144mmol, 2.0eq) and by reaction solution under 70 ℃, stir and spend the night.Reaction mixture is purified with anti-phase preparation HPLC.Pure fraction lyophilize is obtained to tfa salt.M+H=397.1.

Embodiment 16

The preparation of 4-(2-((1S, 2S)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (table 2, compound 137)

To 4-(2-methanesulfinyl-benzothiazol-6-yl oxygen base)-pyridine-2-formic acid methyl nitrosourea (70mg; 0.202mmol; 1.0eq) DMA (600 μ L) solution in add (1S; 2S)-2-Trans-4-Amino Cyclohexanol hydrochloride (92mg; 0.606mmol; 3.0eq), then add diisopropyl ethyl amine (0.21mL, 1.21mmol).Reaction solution is heated 24 hours under 110 ℃.Reaction mixture is purified with anti-phase preparation HPLC.Pure fraction lyophilize is obtained to tfa salt.M+H=398

Embodiment 17

Compound in following table 2 makes by above-described general method.

Table 2

Embodiment 162

The preparation of 4-(2-((1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow:

Step 1

To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (300mg; 0.86mmol) the 5ml nmp solution in add (1R; 2S)-1-amino-2; 3-dihydro-1H-indenes-2-alcohol (597mg; 4mmol) and DIPEA (300 μ L, 1.73mmol).Reaction soln is stirred 24 hours under 105 ℃.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains 4-(2-((1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (347mg, 0.63mmol) is tfa salt.ES/MS m/z433.1 (MH ⁺).

Embodiment 163

The preparation of 4-(2-((1R, 2R)-2-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow:

Step 1

Step 2

The preparation of step 1.4-(2-((1R, 2R)-2-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (15mg; 43 μ mol) in 400 μ L nmp solutions, add (1R; 2R)-hexanaphthene-1,2-diamines (17mg, 150 μ mol).Reaction soln is stirred 24 hours under 105 ℃.Crude reaction solution being purified with preparation HPLC and vacuum-evaporation obtains 4-(2-((1R, 2R)-2-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (12mg, 30 μ mol), is white powder.ES/MS m/z398.1 (MH ⁺).

The preparation of step 2.4-(2-((1R, 2R)-2-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To 4-(2-((1R, 2R)-2-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (9mg, 22 μ mol) and triethylamine (11 μ L, 80 μ mol) add diacetyl oxide (5 μ L, 50 μ mol) in 300 μ L DMF solution.Reaction soln is at room temperature stirred 1.5 hours.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains 4-(2-((1R, 2R)-2-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (5.1mg, 12 μ mol), be white powder.ES/MS m/z440.2 (MH ⁺).

Embodiment 164

(S) preparation of-N-methyl-4-(2-(1-(methyl sulphonyl) piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

This motif compound makes according to following general flow:

Step 1

Step 2

Step 3

Step 1. (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate

To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (104mg; 0.3mmol) the 2ml nmp solution in add (S)-tertiary butyl 3-amino piperidine-1-manthanoate (240mg, 1.2mmol).Reaction soln is stirred 5 days under 105 ℃.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (56mg; 0.12mmol), be white powder.ES/MS m/z484.2 (MH ⁺).

The preparation of step 2. (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

(S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (56mg, 0.12mmol) is dissolved in to the dioxan solution (16mmol) of 4ml4M HCl.Reaction soln is at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained to (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (46mg, 0.12mmol), is white solid.ES/MS m/z384.0 (MH ⁺).

The preparation of step 3. (S)-N-methyl-4-(2-(1-(methyl sulphonyl) piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

To (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide hydrochloride (12.5mg, 30 μ mol) and DIPEA (28 μ L, 160 μ mol) add methylsulfonic acid acid anhydride (17mg, 100 μ mol) in 300 μ L nmp solutions.Reaction soln is stirred 46 hours under 105 ℃.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains (S)-N-methyl-4-(2-(1-(methyl sulphonyl) piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (4.5mg; 9.8 μ mol), be white powder.ES/MS m/z462.1 (MH ⁺).

Embodiment 165

(S) preparation of-4-(2-(1-ethanoyl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow:

Step 2

Step 3

The preparation of step 1. (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate

(S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (56mg, 0.12mmol) is dissolved in to the dioxan solution (16mmol) of 4ml4M HCI.Reaction soln is at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained to (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (46mg, 0.12mmol), is white solid.ES/MS m/z384.0 (MH ⁺).

The preparation of step 3. (S)-4-(2-(1-ethanoyl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (13mg, 30 μ mol) and triethylamine (13 μ L, 90 μ mol) add diacetyl oxide (6 μ L, 60 μ mol) in 300 μ L DMA solution.Reaction soln is at room temperature stirred 1.5 hours.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains (S)-4-(2-(1-ethanoyl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (4.8mg; 11 μ mol), be white powder.ES/MS m/z426.2 (MH ⁺).

Embodiment 166

(S) preparation of-4-(2-(1-isobutyryl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow:

Step 1

Step 2

Step 3

The preparation of step 3. (S)-4-(2-(1-isobutyryl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To isopropylformic acid (4 μ L, 40 μ mol), HATU (15mg, 40 μ mol) and DIEA (14 μ L, 80 μ mol) add (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (13mg in 400 μ L DMA solution, 30 μ mol) and DIPEA (6 μ L, 30 μ mol).Reaction soln is at room temperature stirred 16 hours.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains (S)-4-(2-(1-isobutyryl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (6.8mg; 15 μ mol), be white powder.ES/MS m/z454.2 (MH ⁺).

Embodiment 167

This motif compound makes according to following general flow:

Step 2

Step 3

The preparation of step 3. (S)-4-(2-(1-(isopropylamino formyl radical) piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (13mg; 30 μ mol) and DIPEA (17 μ L; 100 μ mol) add 2-isocyanide acyl group propane (5 μ L, 50 μ mol) in 300 μ L nmp solutions.Reaction soln is at room temperature stirred 18 hours.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains (S)-4-(2-(1-(isopropylamino formyl radical) piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (5.9mg; 12 μ mol), be white powder.ES/MS m/z469.2 (MH ⁺).

Embodiment 168

(R) preparation of-4-methyl-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) penta-1-alcohol

This motif compound makes according to following general flow:

Step 1

Step 2

Step 3

The preparation of step 1.6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole

Add 2-chloro-4-fluorine pyridine (1.32mg, 10mmol) in the 15ml NMP mixture of 2-(methylthio group) benzo [d] thiazole-6-alcohol (1g, 5.08mmol) and cesium carbonate (4.55g, 14mmol).Reaction mixture is stirred and spends the night under 55 ℃.Pour reaction mixture into 80ml saturated NaHCO ₃in the aqueous solution and be extracted with ethyl acetate (2x150ml).By the organic layer 0.1M NaHSO merged ₄the aqueous solution (60ml), water (2x60ml) and salt solution (60ml) washing, then use MgSO ₄drying, filter and vacuum-evaporation obtains the 6-(2-chloropyridine-4-base oxygen base) of brown oily-2-(methylthio group) benzo [d] thiazole (1.72g), its not purified can be for next step.ES/MS m/z308.9 (MH ⁺).

The preparation of step 2.6-(2-chloropyridine-4-base oxygen base)-2-(methylsulfinyl) benzo [d] thiazole

Add 3-chlorine peroxybenzoic acid (77%, 1.3g, 5mmol) under 0 ℃ in the 32ml DCM solution of 6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole (1.72g, 5.08mmol) in batches.After at room temperature stirring 2 hours, by 80ml DCM dilution for mixture.By the mixture 0.2M Na formed ₂s ₂o ₃the aqueous solution (25ml), saturated NaHCO ₃the aqueous solution (25ml), water (25ml) and salt water washing, then use Na ₂sO ₄drying, filter and vacuum-evaporation obtains yellowish brown solid (1.72g).Resistates is obtained to 6-(2-chloropyridine-4-base oxygen base)-2-(methylsulfinyl) benzo [d] thiazole (970mg, 3mmol) by flash column chromatography purifying vacuum-evaporation, is off-white powder.ES/MSm/z325.0 (MH ⁺).

The preparation of step 3. (R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)-4-methylpent-1-alcohol

To 6-(2-chloropyridine-4-base oxygen base)-2-(methylsulfinyl) benzo [d] thiazole (26mg; 80 μ mol) add (R)-2-amino-4-methylpent-1-alcohol (33 μ L in 400 μ L nmp solutions; 250 μ mol) and DIPEA (17 μ L, 100 μ mol).Reaction soln is stirred 18 hours under 100 ℃.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains pulverous (R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)-4-methylpent-1-alcohol (12mg, 31 μ mol).ES/MS m/z378.1 (MH ⁺).

The preparation of step 4. (R)-4-methyl-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) penta-1-alcohol

To (R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)-4-methylpent-1-alcohol (12mg, 31 μ mol) in the reaction mixture of 400 μ L DME, add 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1H-pyrazoles (21mg, 100 μ mol), Pd (dppf) ₂cl ₂(7mg, 8 μ mol) and 2M Na ₂cO ₃the aqueous solution (100 μ L, 200 μ mol).Reaction mixture is stirred 24 hours under 90 ℃.Reaction mixture is filtered, purify and vacuum-evaporation obtains pulverous (R)-4-methyl-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) penta-1-pure (4.2mg) with preparation HPLC.ES/MS m/z424.1 (MH ⁺).

Embodiment 169

(S) preparation of-N-(1-(cyclopropyl alkylsulfonyl) piperidines-3-yl)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

This motif compound makes according to following general flow:

Step 2

Step 5

Step 6

Add 3-chlorine peroxybenzoic acid (77%, 1.3g, 5mmol) under 0 ℃ in the 32ml DCM solution of 6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole (1.72g, 5.08mmol) in batches.After at room temperature stirring 2 hours, by 80ml DCM dilution for mixture.By the mixture 0.2M Na formed ₂s ₂o ₃the aqueous solution (25ml), saturated NaHCO ₃the aqueous solution (25ml), water (25ml) and salt water washing, then use Na ₂sO ₄drying, filter and vacuum-evaporation obtains yellowish brown solid (1.72g).Resistates is obtained to 6-(2-chloropyridine-4-base oxygen base)-2-(methylsulfinyl) benzo [d] thiazole (970mg, 3mmol) by flash column chromatography purifying vacuum-evaporation, is off-white powder ES/MSm/z325.0 (MH ⁺).

The preparation of step 3. (S)-tertiary butyl 3-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate

To 6-(2-chloropyridine-4-base oxygen base)-2-(methylsulfinyl) benzo [d] thiazole (100mg; 0.31mmol) the 1.6ml nmp solution in add (S)-tertiary butyl 3-amino piperidine-1-manthanoate (200mg; 1mmol) and DIPEA (70 μ L, 0.4mmol).Reaction soln is stirred 5 days under 95 ℃.Crude reaction solution being purified with preparation HPLC and vacuum-evaporation obtains (S)-tertiary butyl 3-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (160mg), is tfa salt.ES/MS m/z461.1 (MH ⁺).

The preparation of step 4. (S)-tertiary butyl 3-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate

To (S)-tertiary butyl 3-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (68mg, 148 μ mol) in 1.2ml DME reaction mixture, add 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1H-pyrazoles (40mg, 192 μ mol), Pd (dppf) ₂cl ₂(18mg, 22 μ mol) and 2M Na ₂cO ₃the aqueous solution (400 μ L, 800 μ mol).Reaction mixture is stirred 72 hours under 85 ℃ or until LC shows has reacted.Pour reaction mixture into 40ml saturated NaHCO ₃in solution and be extracted with ethyl acetate (2x80ml).By organic layer water (2x20ml) and salt solution (20ml) washing merged, then use Na ₂sO ₄dry, filter also vacuum-evaporation and obtain brown jelly (77mg), it is purified and obtain pulverous (S)-tertiary butyl 3-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (9.6mg) with preparation HPLC.ES/MS m/z507.1 (MH ⁺).

The preparation of step 5. (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

(S)-tertiary butyl 3-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (9.6mg, 19 μ mol) is dissolved in to the dioxan solution (4mmol) of 1ml4M HCl.Reaction soln is at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained to (S)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base)-N-(piperidines-3-yl) benzo [d] thiazole-2-amine (7.6mg, 18 μ mol), is white solid.ES/MS m/z407.1 (MH ⁺).

The preparation of step 6. (S)-N-(1-(cyclopropyl alkylsulfonyl) piperidines-3-yl)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

To (S)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base)-N-(piperidines-3-yl) benzo [d] thiazole-2-amine (7.6mg, 18 μ mol) and DIPEA (35 μ L, 200 μ mol) add cyclopropane SULPHURYL CHLORIDE (10mg, 98 μ mol) in 400 μ L nmp solutions.Reaction soln is stirred 16 hours under 55 ℃.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains (S)-N-(1-(cyclopropyl alkylsulfonyl) piperidines-3-yl)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine (6.2mg; 12 μ mol), be white powder.ES/MS m/z511.2 (MH ⁺).

Embodiment 170

The preparation of N-(cyclohexyl methyl)-6-(2-(ethylamino) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

Step 1

To 6-(2-chloropyridine-4-base oxygen base)-N-(cyclohexyl methyl) benzo [d] thiazole-2-amine (12mg, 0.03mmol) 400 μ L NMP reaction solns in add DIPEA (9 μ L, 0.05mmol) and the aqueous solution (200 μ L, 2.51mmol) of 70% ethylamine.Reaction mixture is stirred 96 hours under 110 ℃ or until LC shows has reacted.Crude product mixture is filtered, purify and vacuum-evaporation obtains N-(cyclohexyl methyl)-6-(2-(ethylamino) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine with preparation HPLC, be tfa salt (1.8mg).ES/MS m/z383.1 (MH ⁺).

Embodiment 171

N-cyclopropyl-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

This motif compound makes according to following general flow:

Step 1

Step 2

Step 1. tertiary butyl 4-(2-(methylthio group) benzo [d] thiazole-6-base oxygen base) picolinic acid ester

To 2-(methylthio group) benzo [d] thiazole-6-alcohol (5.0g, 25.38mmol, 1.0 25mlN equivalent), add tertiary butyl 4-chloropyridine manthanoate (8.13g in dinethylformamide solution, 38.07mmol, 1.5 equivalent) and cesium carbonate (20.67g, 63.45mmol, 2.5 equivalents).Reaction mixture is stirred 6 hours under 75 ℃.After mixture is cooled to room temperature, in mixture, add 120mL water, water is extracted with ethyl acetate (3X150mL), by the organic layer dried over sodium sulfate of merging.After filtration, solid, by the silicagel column purifying, is obtained to 5.84g brown ceramic powder shape title compound (62%) with ethyl acetate-hexane 0%-50% mixture wash-out.MH+=375.

Step 2. tertiary butyl 4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) picolinic acid ester

To tertiary butyl 4-(2-(methylthio group) benzo [d] thiazole-6-base oxygen base) picolinic acid ester (5.84g, 15.61mmol, 1.0 equivalents) the 25ml dichloromethane solution in add 3-chlorine peroxybenzoic acid (77%, 3.84g, 17.17mmol, 1.1 equivalents).Reaction mixture is at room temperature stirred 1.5 hours, then with the dilution of 200ml methylene dichloride.By sodium bicarbonate aqueous solution and the salt water washing for mixture formed, then use MgSO ₄drying, filter and reduction vaporization obtains crude product, and it can be used for next step without being further purified.MH+=391.0.

The preparation of step 3. tertiary butyl 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-benzo [d] thiazole-6-base oxygen base) picolinic acid ester

To tertiary butyl 4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) picolinic acid ester (500mg; 1.25mmol) the 10ml nmp solution in add (1R; 2R)-hexanaphthene-1; 2 diamines (581mg; 3.84mmol) and DIPEA (0.995ml, 5.76mmol).Reaction soln is stirred 3 days under 100 ℃.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains tertiary butyl 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) picolinic acid ester (240mg, 0.544mmol), be white powder.ES/MS m/z442.5 (MH ⁺).

The preparation of step 4.4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxylic acid

Add 6M hydrochloric acid (1ml, 6mmol) in the 10ml acetonitrile solution of tertiary butyl 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) picolinic acid ester (250mg, 0566mmol).Reaction soln is at room temperature stirred 1 hour, then stir 2 hours under 60 ℃.By the concentrated 10ml acetonitrile that also again is dissolved in of crude reaction solution.The evaporation of the solution for vacuum of formation is obtained to light brown oily product 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxylic acid (215mg, 0.56mmol).ES/MS m/z386.5 (MH ⁺).

The preparation of step 5.N-cyclopropyl-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

To 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxylic acid (5mg, 39 μ mol), HATU (15mg, 39 μ mol) and DIPEA (14 μ L, 78 μ mol) add cyclopropylamine (7ul mg, 30 μ mol) in 1mlNMP reaction soln.Reaction soln is at room temperature stirred 12 hours.Crude reaction solution is purified with preparation HPLC and vacuum-evaporation obtains N-cyclopropyl-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (1mg, 2.3 μ mol), be white powder.ES/MS m/z425.2 (MH ⁺).

Embodiment 172

The preparation of 4-(2-(cyclohexyl methoxyl group) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow:

Step 1

The preparation of step 1.4-(2-(cyclohexyl methoxyl group) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (15mg, 43 μ mol) is mixed mutually with 500 μ L hexahydrobenzyl alcohols and cesium carbonate (42mg, 0.13mmol).The reaction mixture formed is stirred 12 hours under 90 ℃.By the crude product mixture drying, filter and purify with preparation HPLC, then vacuum-evaporation obtains pulverous 4-(2-(cyclohexyl methoxyl group) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (7mg, 17.6 μ mol).ES/MS m/z398.1 (MH ⁺).

Embodiment 173

The preparation of (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Step 3

The preparation of step 1. (1R, 2R)-2-(6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin

Add (1R, 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (910mg, 6mmol) and DIPEA (2.44ml, 14mmol) in the 5.5ml nmp solution of 2-chloro-6-methoxyl group benzo [d] thiazole (1.0g, 5mmol).Reaction soln is stirred 96 hours under 115 ℃.Crude reaction solution is obtained to the fraction of purifying by the preparation HPLC purifying, this fraction is merged, use solid NaHCO ₃neutralization.The solution of formation is extracted with ethyl acetate to (2x300ml).By organic layer water (60ml) and salt solution (60ml) washing merged, then use Na ₂sO ₄dry and vacuum-evaporation obtains (1R, 2R)-2-(6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin (1.06g, 3.81mmol), is Off-white solid.ES/MS m/z279.1 (MH ⁺).

The preparation of step 2.2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol

To the DCM solution (8ml, 8mmol) that slowly adds the 1M boron tribromide in the 16ml DCM solution of (1R, 2R)-2-(6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin (1.06g, 3.81mmol) under 0 ℃.Reaction soln is at room temperature stirred 2 hours.Vacuum is removed all solvents, then water (about 30ml) and rare NaHCO ₃the solution termination reaction, and water is extracted with ethyl acetate to (3x100ml), by the organic extract liquid Na of merging ₂sO ₄drying, remove ethyl acetate with final vacuum and obtain the required product of pink solid shape (1.16g).Resistates is obtained to 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (1.0g, 3.78mmol) by the flash column chromatography purifying, is brown solid.ES/MS m/z265.1 (MH ⁺).

The preparation of step 3. (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin

Add 2-chloro-4-fluorine pyridine (263mg, 2mmol) in the 3ml NMP mixture of 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (265mg, 1mmol) and cesium carbonate (651mg, 2mmol).Reaction mixture is stirred 20 hours under 60 ℃.By the crude product mixture drying, filter, then with preparation HPLC, purify and obtain pulverous (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (341mg, 0.9mmol).ES/MS m/z376.0 (MH ⁺).

Embodiment 174

The preparation of (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

The preparation of step 4. (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

To (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (20mg, 40 μ mol) in 400 μ L DME reaction mixtures, add 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1H-pyrazoles (21mg, 100 μ mol), Pd (dppf) ₂cl ₂(4mg, 5 μ mol) and 2M Na ₂cO ₃(100 μ L, 200 μ mol).Reaction mixture is being stirred 24 hours under 90 ℃.Pour reaction mixture into 10ml saturated NaHCO ₃in solution and be extracted with ethyl acetate (2x30ml).By organic layer water (2x10ml) and salt solution (20ml) washing merged, then use Na ₂sO ₄dry and vacuum-evaporation obtains brown solid (65mg), it is purified and obtain pulverous (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin (6.4mg) with preparation HPLC.ES/MS m/z422.2 (MH ⁺).

Embodiment 175

The preparation of (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-imidazoles-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Add Pd (dppf) in the 0.5ml DMF reaction mixture of (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (11mg, 0.029mmol) ₂cl ₂(7.2mg, 0.0088mmol), LiCl (19mg, 0.44mmol) and 1-methyl-5-(tributyl stannyl)-1H-imidazoles (44mg, 0.117mmol).Reaction soln is stirred 18 hours under 105-110 ℃ or LC shows and to have reacted.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-imidazoles-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (3.5mg).ES/MS m/z422.1 (MH ⁺).

Embodiment 176

The preparation of (1R, 2R)-2-(6-(2-(1-(2,2-, bis-fluoro ethyls)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Add cesium carbonate (672mg, 2.06mmol) in the 2.0ml NMP reaction mixture of 4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1H-pyrazoles (210mg, 1.08mmol).Reaction mixture is stirred 5 minutes, then add the fluoro-2-iodoethane of 1,1-bis-(197mg, 1.03mmol) and at room temperature stir 40 hours.Take out 0.8ml (0.432mol) and use (remaining 1.2ml is stored in refrigerator) from above-mentioned crude product mixture.Add (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (20mg, 0.053mmol), Pd (dppf) in this 0.8ml reaction mixture ₂cl ₂(15.2mg, 0.019mmol) and 2M Na ₂cO ₃(0.150ml, 0.3mmol).By reaction mixture 140 ℃ of 720 seconds of lower microwave heating.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, (((1-(2 for 2-for 6-for 2R)-2-, 2-bis-fluoro ethyls)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (4.6mg).ES/MS m/z472.0 (MH ⁺).

Embodiment 177

The preparation of (1R, 2R)-2-(6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Step 1

Step 2

The preparation of step 1.4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde

To 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (90mg, 0.34mmol) 1.9ml NMP reaction mixture in add cesium carbonate (232mg, 0.71mmol) and 4-chloropyridine formaldehyde (125mg, 0.883mmol).Reaction mixture is at room temperature stirred 10 minutes, then 150 ℃ of 750 seconds of lower microwave heating.Crude product mixture is filtered, purify and lyophilize obtains 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde with preparation HPLC, be tfa salt (88mg).ES/MS m/z388.1 (MH ⁺), be hydrate (+18).

The preparation of step 2. (1R, 2R)-2-(6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

To 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde (16mg, 0.041mmol) 0.75ml MeOH reaction mixture in add ammonium acetate (32mg, 0.41mmol) and the aqueous solution (0.037ml, 0.21mmol) of 2-oxopropanal 40%wt.Reaction mixture is stirred 2 hours under 70 ℃.Crude product mixture is concentrated, again be dissolved in 0.8ml DMF, filter, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (3.2mg).ES/MS m/z422.1 (MH ⁺).

Embodiment 178

The preparation of (1R, 2R)-2-(6-(3-bromopyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Add cesium carbonate (39mg, 0.118mmol) and at room temperature stir 1-3 minute in the 0.4ml NMP reaction mixture of 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (12.5mg, 0.047mmol).Add the bromo-4-chloropyridine of 3-(18.2mg, 0.094mmol) in this mixture.Reaction mixture is stirred 4 hours under 90 ℃ or until LC shows has reacted.Crude product mixture is filtered, purify and lyophilize (1R, 2R)-2-(6-(3-bromopyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin with preparation HPLC, be tfa salt (9.2mg).ES/MS m/z420.1/422.0 (MH ⁺).

Embodiment 179

The preparation of (1R, 2R)-2-(6-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Add Pd (dppf) in the 0.5ml NMP mixture of (1R, 2R)-2-(6-(3-bromopyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (15mg, 0.036mmol) ₂cl ₂(8.8mg, 0.0107mmol), 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1H-pyrazoles (30mg, 0.143mmol) and 2M Na ₂cO ₃(0.12ml, 0.24mmol).Reaction soln is stirred 2 hours under 105-110 ℃, or until LC shows has reacted.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (5.5mg).ES/MS m/z422.1 (MH ⁺).

Embodiment 180

The preparation of 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carbonitrile

This motif compound makes according to following general flow:

Step 1

Step 2

Step3

The preparation of step 1.N-(cyclohexyl methyl)-6-methoxyl group benzo [d] thiazole-2-amine

Add cyclohexyl methylamine (865mg, 7.65mmol) and DIPEA (1.57ml, 9.0mmol) in the 4.5ml nmp solution of 2-chloro-6-methoxyl group benzo [d] thiazole (900mg, 4.5mmol).Reaction soln is stirred 66 hours under 105-110 ℃.Reaction solution, by adding the 250ml ethyl acetate to carry out aftertreatment, is used to the saturated NaHCO of 2x60ml ₃, the saturated NaCI washing of 3x60ml water, 1x60ml, use dried over sodium sulfate, drying, filter the N-(cyclohexyl methyl) that vacuum concentration also obtains solid state-6-methoxyl group benzo [d] thiazole-2-amine (1.18 gram).ES/MS m/z277.1 (MH ⁺).

The preparation of step 2.2-(cyclohexyl methyl amino) benzo [d] thiazole-6-alcohol

To DCM (10.6ml, the 10.6mmol) solution that slowly added the 1M boron tribromide in the 12ml DCM solution of N-(cyclohexyl methyl)-6-methoxyl group benzo [d] thiazole-2-amine (1.40g, 5.05mmol) under 0 ℃ in about 3 minutes.Reaction soln is stirred 20 minutes under 0 ℃, then at room temperature stir 2 hours.Reaction mixture is concentrated into to solid.Add 200ml ethyl acetate and 50ml water and at room temperature stir 10 minutes in residual solid.Under agitation add carefully excessive solid NaHCO ₃to being alkalescence.At room temperature stir about 1 hour is with dissolved solids.Remove water layer and extract by the 100ml ethyl acetate.Merge organic layer, with 1x30ml water, the saturated NaCl solution washing of 1x25ml, then use dried over sodium sulfate.This mixture is filtered and uses ethyl acetate rinse by silica gel plug (1.25in.x3in.).By concentrated 2-(cyclohexyl methyl amino) benzo [d] thiazole that obtains solid state of filtrate decompression-6-alcohol (1.32 gram).ES/MS m/z263.1 (MH ⁺).

The preparation of step 3.4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carbonitrile

Add cesium carbonate (56mg, 0.171mmol) and at room temperature stir 1-3 minute in the 0.4mlNMP reaction mixture of 2-(cyclohexyl methyl amino) benzo [d] thiazole-6-alcohol (18mg, 0.068mmol).Add 4-chloropyridine formonitrile HCN (19mg, 0.136mmol) in this mixture.Reaction mixture is stirred 5 hours under 60 ℃ or until LC shows has reacted.Crude product mixture is filtered, purify and lyophilize obtains 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carbonitrile with preparation HPLC, be tfa salt (9.8mg).ES/MS m/z365.1 (MH ⁺).

Embodiment 181

The preparation of 6-(2-(1H-TETRAZOLE-5-yl) pyridin-4-yl oxygen base)-N-(cyclohexyl methyl) benzo [d] thiazole-2-amine

This motif compound makes according to following general flow:

Add ZnCl in the 0.6ml NMP reaction mixture of 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carbonitrile (20mg, 0.055mmol) ₂(37mg, 0.274mmol) and sodiumazide (35.5mg, 0.55mmol).By reaction soln 170 ℃ of 800 seconds of lower microwave heating.Crude product mixture is filtered, purify and lyophilize obtains 6-(2-(1H-TETRAZOLE-5-yl) pyridin-4-yl oxygen base)-N-(cyclohexyl methyl) benzo [d] thiazole-2-amine with preparation HPLC, be tfa salt (6.6mg).ES/MS m/z408.2 (MH ⁺).

Embodiment 182

This motif compound of preparation of 6-(quinolyl-4 oxygen base)-N-(2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) benzo [d] thiazole-2-amine makes according to following general flow:

The preparation of step 1.2-(methylthio group)-6-(quinolyl-4 oxygen base) benzo [d] thiazole

Add cesium carbonate (3.2g, 9.5mmol) and at room temperature stir 3 minutes in the 10ml NMP reaction mixture of 2-(methylthio group) benzo [d] thiazole-6-alcohol (750mg, 3.79mmol).Add 4-chloroquinoline (682mg, 4.17mmol) in this mixture.Reaction mixture is stirred 24 hours under 110 ℃.Reaction solution, by adding the 250ml ethyl acetate to carry out aftertreatment, is used to the saturated NaHCO of 75ml ₃, the saturated NaCl washing of 2x60ml water, 1x50ml, use dried over sodium sulfate, filter also vacuum concentration.The solid residue that forms, by silica gel chromatography, is obtained to the 2-(methylthio group) of solid state-6-(quinolyl-4 oxygen base) benzo [d] thiazole (980mg) with (40%EtOAc:60% hexane) wash-out vacuum concentration.ES/MS m/z325.1 (MH ⁺).

The preparation of step 2.2-(methylsulfinyl)-6-(quinolyl-4 oxygen base) benzo [d] thiazole

The reaction mixture of 2-(methylthio group)-6-(quinolyl-4 oxygen base) benzo [d] thiazole (460mg, 1.415mmol) is dissolved in to 8ml DCM and is cooled to-5 ℃.The solution that preparation is comprised of 77%MCPBA (333mg, 1.486mmol) and 6ml DCM.This solution was added drop-wise in above cooling reaction mixture in 3-4 minute.Reaction solution is stirred 10 minutes under-5 ℃, at room temperature stir 90 minutes.The LC monitoring shows that 95% reaction completes and stops.The standby solution formed by 77%MCPBA (25mg, 0.1132mmol) and 1ml DCM of new system.This solution is added drop-wise in the reaction mixture under above-mentioned room temperature.Reaction solution was stirred more than 90 minutes, and the LC demonstration has been reacted.Reaction solution, by adding 80ml DCM and 25ml10% hypo solution to carry out aftertreatment, and is at room temperature stirred 10 minutes.By the water layer extraction, by the saturated NaHCO of 25ml for the DCM layer ₃, 2x25ml5%NaHCO ₃solution, 1x25ml water, the saturated NaCl washing of 1x25ml, use dried over sodium sulfate.Add approximately 1 gram silica gel and stir 10 minutes.Mixture is filtered and vacuum concentration obtains the 2-(methylsulfinyl) of solid state-6-(quinolyl-4 oxygen base) benzo [d] thiazole (357mg).ES/MS m/z341.0 (MH ⁺).

The preparation of step 3.6-(quinolyl-4 oxygen base)-N-(2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) benzo [d] thiazole-2-amine

To 2-(methylsulfinyl)-6-(quinolyl-4 oxygen base) benzo [d] thiazole (11.5mg; 0.034mmol) 0.4ml NMP reaction mixture in add (DIPEA) diisopropyl ethyl amine (15uL; 0.084mmol) and 2-(tetrahydrochysene-2H-pyrans-4-yl) ethamine (17.4mg, 0.134mmol).Reaction mixture is stirred 20 hours under 100 ℃ or until LC shows has reacted.Crude product mixture is filtered, purify and lyophilize obtains 6-(quinolyl-4 oxygen base)-N-(2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) benzo [d] thiazole-2-amine with preparation HPLC, be tfa salt (5.1mg).ES/MS m/z406.1 (MH ⁺).

Embodiment 183

The preparation of (1R, 2R)-2-(6-(2-morpholino pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

To (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (14mg, 0.037mmol) 0.4ml NMP reaction mixture in add (DIPEA) diisopropyl ethyl amine (13ul, 0.074mmol) and morpholine (49mg, 0.558mmol).Reaction mixture is stirred 48 hours under 110 ℃ or until LC shows has reacted.Crude product mixture is filtered, purify and lyophilize obtains (1R, 2R)-2-(6-(2-morpholino pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin with preparation HPLC, be tfa salt (3.7mg).ES/MS m/z427.1 (MH ⁺).

Embodiment 184

(S)-6-(2-chloropyridine-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine

This motif compound makes according to following general flow:

Step 1

Step 2

Step 3

The preparation of step 1. (S)-N-(1-cyclohexyl ethyl)-6-methoxyl group benzo [d] thiazole-2-amine

Add (S)-1-cyclohexyl ethamine (2.3g, 18mmol) and DIPEA (3.5ml, 20mmol) in the 10ml nmp solution of 2-chloro-6-methoxyl group benzo [d] thiazole (2.0g, 10mmol).Reaction soln is stirred 96 hours under 110 ℃.Reaction solution, by adding the 170ml ethyl acetate to carry out aftertreatment, is used to the saturated NaHCO of 1x60ml ₃, 1x60ml5%NaHCO ₃the saturated NaCl of solution, 1x60ml water, 1x60ml processes, and use dried over sodium sulfate, filters (S)-N-(1-cyclohexyl ethyl) that vacuum concentration also obtains thick solid state-6-methoxyl group benzo [d] thiazole-2-amine (3.39 gram).ES/MSm/z291.1 (MH ⁺).

The preparation of step 2. (S)-2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-alcohol

To the DCM solution (20ml, 20mmol) that adds the 1M boron tribromide in the 30ml DCM solution of (S)-N-(1-cyclohexyl ethyl)-6-methoxyl group benzo [d] thiazole-2-amine (3.39g, 10mmol) under 0 ℃.Reaction soln is stirred under 0 ℃, then at room temperature stir 2 hours.Reaction mixture is concentrated into to solid.Add 400ml ethyl acetate and 90ml water and at room temperature stir 10 minutes in this residual solid.Under agitation add carefully excessive solid NaHCO ₃to being alkalescence.At room temperature stir about 1 hour is with dissolved solids.Remove water layer and extract by the 100ml ethyl acetate.Merge organic layer, with 1x50ml water, the saturated NaCl solution washing of 1x50ml, use dried over sodium sulfate, filter and concentrating under reduced pressure.The solid that forms, by silica gel chromatography, is obtained to (S)-2-(1-cyclohexyl ethylamino) benzo [d] thiazole of solid state-6-alcohol (2.0 gram) with (30%EtOAc:70% hexane) wash-out vacuum concentration.ES/MS m/z277.1 (MH ⁺).

The preparation of step 3. (S)-6-(2-chloropyridine-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine

To (S)-2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-alcohol (270mg, 0.974mmol) and cesium carbonate (794mg, 2.44mmol) 3.6ml NMP mixture in add 2-chloro-4-fluorine pyridine (254mg, 1.95mmol).Reaction mixture is stirred 18 hours under 60 ℃ or until LC shows has reacted.Crude product mixture is filtered, purify and lyophilize obtains (S)-6-(2-chloropyridine-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine with preparation HPLC, be tfa salt (298mg).ES/MS m/z388.1 (MH ⁺).

Embodiment 185

(S) preparation of-6-(2,3 '-dipyridyl-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine

To (S)-6-(2-chloropyridine-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine (15mg, 0.039mmol) 0.6ml DME reaction mixture in add 3-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) pyridine (32mg, 0.155mmol), Pd (dppf) ₂cl ₂(7.9mg, 0.0096mmol) and 2M Na ₂cO ₃(0.18ml, 0.36mmol).Reaction soln is stirred 90 minutes under 100-105 ℃ or until LC shows has reacted.Crude product mixture is concentrated into to solid, again be dissolved in 0.8ml DMF, filter, purify and lyophilize obtains (S)-6-(2 with preparation HPLC, 3 '-dipyridyl-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine, be tfa salt (5.2mg).ES/MS m/z431.2 (MH ⁺).

Embodiment 186

(S)-N-(1-cyclohexyl ethyl)-6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

This motif compound makes according to following general flow:

The preparation of step 1. (S)-4-(2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde

To (S)-2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-alcohol (110mg, 0.40mmol) 2.0ml NMP reaction mixture in add cesium carbonate (272mg, 0.834mmol) and 4-chloropyridine formaldehyde (146mg, 1.03mmol).Reaction mixture is at room temperature stirred 20 minutes, then 150 ℃ of 750 seconds of lower microwave heating.Crude product mixture is filtered, purify and lyophilize obtains (S)-4-(2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde with preparation HPLC, be tfa salt (105mg).ES/MS m/z400.2 (MH ⁺), be hydrate (+18).

The preparation of step 2. (S)-N-(1-cyclohexyl ethyl)-6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

To (S)-4-(2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde (15mg, 0.038mmol) 0.6ml methyl alcohol reaction mixture in add ammonium acetate (29mg, 0.38mmol) and the aqueous solution (0.034ml, 0.19mmol) of 2-oxopropanal 40%wt.Reaction mixture is stirred 2 hours under 70 ℃.Crude product mixture is concentrated into to solid, again be dissolved in 0.8ml DMF, filter, purify and lyophilize obtains (S)-N-(1-cyclohexyl ethyl)-6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine with preparation HPLC, be tfa salt (6.5mg).ES/MSm/z434.2 (MH ⁺).

Embodiment 187

The preparation of (1R, 2R)-2-(6-(2-(1H-imidazoles-1-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

To (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (12mg, 0.032mmol) 0.55ml NMP reaction mixture in add (DIPEA) diisopropyl ethyl amine (17ul, 0.096mmol) and 1H-imidazoles (180mg, 2.64mmol).Reaction mixture is monitored and also carried out in the following order microwave heating by LC, LCMS: (heated for 750 seconds under 150 ℃, heated for 750 seconds under 230 ℃, heating for 1000 seconds at 250 ℃, again heated for 1000 seconds under 250 ℃).Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(2-(1H-imidazoles-1-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (1.4mg).ES/MS m/z408.2 (MH ⁺).

Embodiment 188

The preparation of (1R, 2R)-2-(6-(2-(1,2,3,6-tetrahydropyridine-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

Step 1. tertiary butyl 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-5, the preparation of 6-dihydropyridine-1 (2H)-manthanoate

To (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (11mg, 0.029mmol) 0.5ml DME reaction mixture in add tertiary butyl 4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-5,6-dihydropyridine-1 (2H)-manthanoate (36mg, 0.117mmol), Pd (dppf) ₂cl ₂(7.2mg, 0.0088mmol) and 2M Na ₂cO ₃(0.125ml, 0.25mmol).Reaction soln is stirred 24 hours under 105-110 ℃ or until LC shows has reacted.Crude product mixture is concentrated into to solid, again be dissolved in 0.8ml DMF, filter, with preparation HPLC, purify and lyophilize obtains tertiary butyl 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-manthanoate is tfa salt (2.5mg).ES/MS m/z523.1 (MH ⁺).

The preparation of step 2. (1R, 2R)-2-(6-(2-(1,2,3,6-tetrahydropyridine-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

To tertiary butyl 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-manthanoate (2.5mg, 0.0039mmol) solid in add the dioxan solution (1ml, 4.0mmol) of 4M HCl.Reaction mixture is at room temperature stirred 45 minutes.Crude product mixture is concentrated into to solid and lyophilize obtains (1R, ((2-(1,2,3 for 6-for 2R)-2-, 6-tetrahydropyridine-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is HCl salt (1.4mg).ES/MS m/z423.1 (MH ⁺).

Embodiment 189

The preparation of 4-(2-((1s, 4s)-4-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow

The preparation of step 1. (1s, 4s)-4-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexyl t-butyl carbamate

To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (15mg; 0.043mmol) 0.4ml NMP reaction mixture in add (1s; 4s)-4-aminocyclohexyl t-butyl carbamate (47mg; 0.215mmol) and (DIPEA) diisopropyl ethyl amine (22ul, 0.129mmol).Reaction mixture is stirred 20 hours under 105-100 ℃ or until LC shows has reacted.Crude reaction solution is obtained to (1s by preparation HPLC purifying lyophilize; 4s)-4-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexyl t-butyl carbamate (16mg) is tfa salt.ES/MS m/z498.2 (MH ⁺).

The preparation of step 2.4-(2-((1s, 4s)-4-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To (1s; 4s)-4-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexyl t-butyl carbamate (16mg; 0.032mmol) solid in add ether (2ml, the 4.0mmol) solution of 2M HCl.Reaction mixture is at room temperature stirred 60 minutes.Crude product mixture is concentrated into to solid and lyophilize obtains 4-(2-((1s, 4s)-4-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide, is HCl salt (12.0mg).ES/MS m/z398.1 (MH ⁺).

Embodiment 190

The preparation of 4-(2-((1s, 4s)-4-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow

To 4-(2-((1s, 4s)-4-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (9.0mg, 0.0226mmol) 0.6ml NMP reaction mixture in add (TEA) triethylamine (19ul, 0.136mmol) and diacetyl oxide (7.0mg, 0.0678mmol).Reaction mixture is at room temperature stirred 90 minutes.Crude reaction solution is obtained to 4-(2-((1s, 4s)-4-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (8.7mg) by preparation HPLC purifying lyophilize, is tfa salt.ES/MS m/z440.2 (MH ⁺).

Embodiment 191

The preparation of 4-(2-((1s, 4s)-4-isobutyryl aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

This motif compound makes according to following general flow:

To adding HATU (17.1mg, 0.045mmol) and (DIPEA) diisopropyl ethyl amine (11ul, 0.0625mmol) in the 0.3ml NMP reaction mixture of isopropylformic acid (4.4mg, 0.050mmol).Reaction mixture is at room temperature stirred to 10-15 minute.Add 4-(2-((1s in above-mentioned reaction mixture, 4s)-4-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (10mg, 0.025mmol) and (DIPEA) the 0.3ml nmp solution of diisopropyl ethyl amine (13ul, 0.075mmol).Reaction soln is at room temperature stirred 18 hours.Crude reaction solution is obtained to 4-(2-((1s, 4s)-4-isobutyryl aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (4.0mg) by preparation HPLC purifying lyophilize, is tfa salt.ES/MS m/z468.3 (MH ⁺).

Embodiment 192

The preparation of (1R, 2R)-2-(6-(6-fluorine quinolyl-4 oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Add cesium carbonate (47mg, 0.143mmol) and at room temperature stir 1-3 minute in the 0.4ml NMP reaction mixture of 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (15.1mg, 0.057mmol).Add 4-chloro-6-fluorine quinoline (21mg, 0.114mmol) in this mixture.Reaction mixture is stirred 18 hours under 105-110 ℃ or until LC shows has reacted.Crude product mixture is filtered, purify and lyophilize obtains (1R, 2R)-2-(6-(6-fluorine quinolyl-4 oxygen base) benzo [d] thiazol-2-yl amino) hexalin with preparation HPLC, be tfa salt (9.2mg).ES/MSm/z410.1 (MH ⁺).

Embodiment 193

4-(2-(cyclohexyl methyl amino)-4-methyl benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Synthesizing of step 1.4-(4-amino-3-methylphenoxy)-N-picoline methane amide

At room temperature add the chloro-N-picoline of 4-methane amide (189mg, 1.11mmol, 1.1eq) and cesium carbonate (658mg, 2.02mmol, 2.0eq) in the 1mL nmp solution of 4-amino-m-cresol (125mg, 1.01mmol, 1.0eq).Reaction mixture is stirred 12 hours under 75 ℃, then, by mixture water (about 50mL) dilution, water layer is extracted with ethyl acetate to (about 50mLX3).By the organic layer dried over sodium sulfate merged, filter also concentrating under reduced pressure and obtain enough pure crude product, this crude product can be used for next step without being further purified.LC/MS (m/z) [258.1] (MH ⁺).

Synthesizing of step 2.4-(2-amino-4-methyl benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Add ammonium thiocyanate (11mg, 0.145mmol, 1.5eq) in the cold acetic acid solution of 1mL of 4-(4-amino-3-methylphenoxy)-N-picoline methane amide (25mg, 0.097mmol, 1.0eq).After stirring several minutes, injection drips bromine (6 μ L, 0.116mmol, 1.2eq) and reaction solution is at room temperature stirred 3 hours.Then use NaHCO ₃saturated solution (about 10mL) termination reaction also is extracted with ethyl acetate (about 25mLX3), the organic extract liquid of merging is obtained to enough pure crude product with dried over sodium sulfate concentrating under reduced pressure, and this crude product can be used for next step without being further purified.LC/MS (m/z) [315.1] (MH ⁺).

Synthesizing of step 3.4-(2-(cyclohexyl methyl amino)-4-methyl benzo [d] thiazole-6-base oxygen base) picoline methane amide

To 4-(2-amino-4-methyl benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (30mg, 0.095mmol, 1.0 at room temperature add brooethyl hexanaphthene (20 μ L in 1mL nmp solution equivalent), 0.142mmol, 1.5 equivalent) and salt of wormwood (40mg, 0.285mmol, 3.0 equivalents).Reaction mixture is stirred 12 hours under 80 ℃, then by the reversed-phase HPLC purifying.LC/MS (m/z) [411.1] (MH ⁺)

Embodiment 194

4-(the chloro-2-of 4-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Synthesizing of step 1.4-(4-amino-3-chlorophenoxy)-N-picoline methane amide

According to the described method of the step 1 of embodiment 1, make.LC/MS (m/z) [278.1] (MH ⁺).

Synthesizing of step 2.4-(2-amino-4-chlorobenzene is [d] thiazole-6-base oxygen base also)-N-picoline methane amide

According to the described method of the step 2 of embodiment 1, make.LC/MS (m/z) [335.0] (MH ⁺).

Synthesizing of step 3.4-(the chloro-2-of 4-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To 4-(2-amino-4-chlorobenzene is [d] thiazole-6-base oxygen base also)-N-picoline methane amide (30mg, 0.089mmol, 1.0 at room temperature add brooethyl hexanaphthene (18 μ L in 2mL nmp solution equivalent), 0.134mmol, 1.5 equivalent) and salt of wormwood (36mg, 0.267mmol, 3.0 equivalents).Reaction mixture is stirred 2 hours under 80 ℃, then by the reversed-phase HPLC purifying.LC/MS (m/z) [431.0] (MH+).

Embodiment 195

4-(the bromo-2-of 7-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Synthesizing of the chloro-6-methoxyl group of the bromo-2-of step 1.7-benzo [d] thiazole

At room temperature add N-bromine succinimide (213mg, 1.20mmol, 1.2 equivalents) in the 5mL nmp solution of the chloro-6-methoxyl group-benzothiazole of 2-(200mg, 1.0mmol, 1.0 equivalents).Reaction mixture is stirred under 75 ℃ 24 hours, the carrying out along with reaction adds NBS with short run subsequently, then by mixture water (about 100mL) dilution and water layer is extracted with ethyl acetate to (about 150mLX3).By the organic layer dried over sodium sulfate merged, filter and concentrating under reduced pressure.Purify and obtain 336mg rice white fine hair sprills product with gradient 0%-50% ethyl acetate-hexane on ISCO, yield is 60%, passes through H ⁺nMR confirms its structure.LC/MS (m/z) [279.9] (MH ⁺).

Synthesizing of step 2. (1R, 2R)-2-(the bromo-6-methoxyl group of 7-benzo [d] thiazol-2-yl amino) hexalin

To the bromo-2-of 7-chloro-6-methoxyl group benzo [d] thiazole (150mg, 0.539mmol, 1.0 at room temperature add (1R in 1mL nmp solution equivalent), 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (0.123mg, 0.809mmol, 1.5 equivalent) and DIPEA (263 μ L, 1.503mmol, 2.8 equivalents).Reaction mixture is stirred 12 hours under 125 ℃, then by saturated sodium bicarbonate solution for mixture (about 100mL) dilution and water layer is extracted with ethyl acetate to (about 200mLX3).By the organic layer dried over sodium sulfate merged, filter also concentrating under reduced pressure and obtain brown oily crude product, this crude product is enough pure and can be used for next step without being further purified.LC/MS (m/z) [359.0] (MH ⁺).

Synthesizing of the bromo-2-of step 3.7-((1R, 2R)-2-hydroxy-cyclohexyl amino)-benzo [d] thiazole-6-alcohol

To (1R, at room temperature add 1M boron tribromide solution (about 3.0mL in the 10mL DCM solution of 2R)-2-(the bromo-6-methoxyl group of 7-benzo [d] thiazol-2-yl amino) hexalin (191mg, 0.537mmol, 1.0 equivalents), 2.68mmol, 5.0 equivalents).By reaction mixture refluxed 12 hours, then saturated sodium bicarbonate for mixture (about 100mL) is diluted to pH=7 and water layer is extracted with ethyl acetate to (about 150mLX3).By the organic layer dried over sodium sulfate merged, filter also concentrating under reduced pressure and obtain enough pure crude product, this crude product can be used for next step without being further purified.LC/MS (m/z) [345.0] (MH ⁺).

Synthesizing of step 4.4-(the bromo-2-of 7-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To bromo-the 2-((1R of 7-, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (50mg, 0.145mmol, 1.0 at room temperature add the chloro-N-picoline of 4-methane amide (29mg in 1mL nmp solution equivalent), 0.174mmol, 1.2 equivalent) and cesium carbonate (165mg, 0.507mmol, 3.5 equivalents).Reaction mixture, 80 ℃ of lower stir abouts 12 hours, is then purified mixture with reversed-phase HPLC.LC/MS (m/z) [479.0] (MH ⁺).

Embodiment 196

4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-7-methyl benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Synthesizing of step 1.2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-7-methyl benzo [d] thiazole-6-alcohol

To bromo-the 2-((1R of 7-in the microwave bottle, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (117mg, 0.34mmol, 1.0 at room temperature add trimethylammonium boraxine (128mg in 1mL DMF solution equivalent), 1.02mmol, 3.0 equivalents), Pd (Cl ₂) dPPf (27mg, 0.034mmol, 0.1 equivalent) and 1mL2M Na ₂cO ₃solution.Then reaction mixture is heated 15 minutes in microwave under 120 ℃.Use saturated NaHCO ₃solution (25ml) termination reaction also is extracted with ethyl acetate water (50mLX3), by the organic layer Na of merging ₂sO ₄drying, filter and concentrating under reduced pressure.On ISCO, utilizing the gradient purifying of 0%-18% methyl alcohol-DCM to obtain 17mg brown ceramic powder shape product, is 17% yield.LC/MS (m/z) [279.1] (MH ⁺).

Synthesizing of step 2.4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-7-methyl benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Method according to embodiment 543 steps 4 makes.LC/MS (m/z) [413.1] (MH ⁺)

Embodiment 197

4-(the chloro-2-of 7-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Synthesizing of the chloro-2-of step 1.7-(methylthio group) benzo [d] thiazole-6-alcohol

At room temperature add N-chloro-succinimide (507mg, 3.80mmol, 1.5 equivalents) in the 10mLNMP solution of 2-(methylthio group) benzo [d] thiazole-6-alcohol (500mg, 2.53mmol, 1.0 equivalents).Reaction mixture is at room temperature stirred 1 hour, then by saturated sodium bicarbonate solution for mixture (about 100mL) dilution and by DCM extraction (about 150mLX3) for water layer.By the organic layer dried over sodium sulfate merged, filter and concentrating under reduced pressure.On ISCO, utilize the gradient purifying of 0%-100% ethyl acetate-hexane to obtain the 283.39mg product, yield is 48%, passes through H ⁺nMR confirms the structure of product.LC/MS (m/z) [232.0] (MH ⁺).

Synthesizing of step 2.4-(the chloro-2-of 7-(methylthio group) benzo [d] thiazole-6-base oxygen base)-N picoline methane amide

To the chloro-2-of 7-(methylthio group) benzo [d] thiazole-6-alcohol (80mg, 0.346mmol, 1.0 at room temperature add the chloro-N-picoline of 4-methane amide (88mg in 1mL nmp solution equivalent), 0.519mmol, 1.5 equivalent) and cesium carbonate (281mg, 0.865mmol, 2.5 equivalents).Reaction mixture is stirred under 85 ℃ the reactions to about 75%-80% in 48 hours complete, then by mixture water (about 50mL) dilution and water layer is extracted with ethyl acetate to (about 50mLX3).By the organic layer dried over sodium sulfate merged, filter also concentrating under reduced pressure and obtain crude product, on ISCO, utilize the gradient purifying of 0%-100% ethyl acetate-hexanes mixtures to obtain the 64mg product this crude product, yield is 50%.LC/MS (m/z) [366.0] (MH ⁺).

Synthesizing of step 3.4-(the chloro-2-of 7-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To 4-(the chloro-2-of 7-(methylthio group) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (64mg, 0.175mmol, 1.0 add MCPBA (33mg in 5ml DCM solution equivalent) under 0 ℃, 0.192mmol, 1.1 equivalents) and reaction solution is stirred to 30-45 minute.Then water (10mL) termination reaction water is extracted with ethyl acetate to (25mLX5), by the organic layer dried over sodium sulfate merged, filter and concentrating under reduced pressure obtains crude product, this crude product is enough pure and can be used for next step without being further purified.LC/MS (m/z) [382.0] (MH ⁺).

Synthesizing of step 4.4-(the chloro-2-of 7-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

To 4-(the chloro-2-of 7-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (10mg; 0.026mmol; 1.0 add (1R in nmp solution equivalent); 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (6mg; 0.039mmol; 1.5 equivalent) and DIPEA (13 μ L, 0.078mmol, 3.0 equivalents) and by reaction mixture under 160 ℃ in microwave the heating 15 minutes.Then product is passed through to the reversed-phase HPLC purifying.LC/MS (m/z) [433.1] (MH ⁺).

Embodiment 198

4-(2-(cyclohexyl methyl amino)-5-fluorobenzene is [d] thiazole-6-base oxygen base also)-N-picoline methane amide

Synthesizing of the fluoro-6-methoxyl group of step 1.5-benzo [d] thiazole-2-amine

Reference used: " the synthetic and biologic activity of α-[(the fluoro-2-[4-morpholinodithio base of the chloro-5-of 6-) amino] Acetanilide " .Pattan, S.R.; Narendra, Babu S.N.; Angadi, J.S.Dept.ofMechanical Chemistry, K.L.E.S ' s College of Pharmacy, Belg.Indian Drugs (2002), 39 (10), 515-517.

Add ammonium thiocyanate (1.07g, 14.18mmol, 2.0 equivalents) in the cold acetic acid solution of 30ml of the fluoro-p-methyl oxyaniline of 3-(1.00g, 7.09mmol, 1.0 equivalents).After stirring several minutes, by feed hopper, slowly inject the 6mL acetic acid solution that drips bromine (437 μ L, 8.50mmol, 1.2 equivalents) and reaction solution is at room temperature stirred 3 hours.Then decompression is removed acetic acid and by NaHCO ₃saturated solution (100mL) joins in resistates, be extracted with ethyl acetate (125mLX3), the organic extract liquid of merging is obtained to crude product with dried over sodium sulfate concentrating under reduced pressure, and this crude product is enough pure and can be used for next step without being further purified.

NMR (H ⁺) (DMSO) 1H (d) 7.51,7.48,2H (s) 7.34,1H (d) 7.17,7.13,3H (s) 3.78.LC/MS (m/z) [199.0] (MH ⁺).

Synthesizing of step 2.N-(the cyclohexyl methyl)-fluoro-6-methoxyl group of 5-benzo [d] thiazole-2-amine

At room temperature add brooethyl hexanaphthene (370 μ L in the 2mLNMP solution of the fluoro-6-methoxyl group of 5-benzo [d] thiazole-2-amine (350mg, 1.76mmol, 1.0 equivalents), 2.65mmol, 1.5 equivalent) and salt of wormwood (366mg, 2.65mmol, 1.5 equivalents).Reaction mixture is stirred 24 hours under 80 ℃, add subsequently reagent to having reacted, then use saturated sodium bicarbonate solution (100mL) termination reaction, then be extracted with ethyl acetate (125mLX3), by the organic layer dried over sodium sulfate merged, filter and concentrating under reduced pressure.Crude product is utilized on ISCO the slow gradient purifying of 0%-50% ethyl acetate-hexane obtain the 310mg product, yield is 60%.LC/MS (m/z) [295.1] (MH+).

Step 3.2-(cyclohexyl methyl amino)-5-fluorobenzene is synthesizing of [d] thiazole-6-alcohol also

At room temperature add 1M boron tribromide solution (about 1.0mL, 0.775mmol, 2.0 equivalents) in the 10mL DCM solution of N-(the cyclohexyl methyl)-fluoro-6-methoxyl group of 5-benzo [d] thiazole-2-amine (114mg, 0.387mmol, 1.0 equivalents).Reaction mixture is stirred 2 hours, then saturated sodium bicarbonate solution for mixture (about 100mL) is diluted to pH=7 and water layer is extracted with ethyl acetate to (about 150mLX3).By the organic layer dried over sodium sulfate merged, filter also concentrating under reduced pressure and obtain crude product, this crude product is enough pure and can be used for next step without being further purified.LC/MS (m/z) [281.1] (MH ⁺).

Synthesizing of step 4.4-(2-(cyclohexyl methyl amino)-5-fluorobenzene is [d] thiazole-6-base oxygen base also)-N-picoline methane amide

To 2-(cyclohexyl methyl amino)-5-fluorobenzene [d] thiazole-6-alcohol (25mg also, 0.089mmol, 1.0 at room temperature add the chloro-N-picoline of 4-methane amide (18mg in 2mL nmp solution equivalent), 0.107mmol, 1.2 equivalent) and cesium carbonate (86mg, 0.267mmol, 3.0 equivalents).Reaction mixture being stirred 12 hours under 85 ℃, then mixture is obtained to the 1.6mg product by the reversed-phase HPLC purifying, is tfa salt, and yield is about 3.5%.LC/MS (m/z) [415.1] (MH ⁺).

Embodiment 199

N-methyl-4-(2-(4-((4-methylpiperazine-1-yl) methyl) benzylamino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (25mg; 0.072mmol; 1.0 add (4-((4-methylpiperazine-1-yl) methyl) phenyl) methylamine (23mg in 2ml nmp solution equivalent); 0.108mmol; 1.5 equivalent) and DIPEA (37 μ L; 0.216mmol, 3.0 equivalents) and reaction mixture is heated 12 hours under 80 ℃ in oil bath.Then product is passed through to the reversed-phase HPLC purifying.LC/MS (m/z) [503.1] (MH ⁺).

Embodiment 200

N-methyl-4-(2-(2-(2-(4-methylpiperazine-1-yl) oxyethyl group) phenyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide

To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (25mg; 0.072mmol; 1.0 add 2-(2-(4-methylpiperazine-1-yl) oxyethyl group) aniline (25mg in the dense HCl solution of 1ml IPA equivalent) and 1mL; 0.108mmol, 1.5 equivalents) and reaction mixture is heated 2 hours under 80 ℃ in oil bath.Then product is passed through to the reversed-phase HPLC purifying.The method can be used for other similar method, wherein, and by the process of LC-MS monitoring reaction and regulate as required amount and the reaction times of aniline.LC/MS (m/z) [519.1] (MH ⁺).

Embodiment 201

4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] oxazole-6-base oxygen base)-N-picoline methane amide

To N-methyl-4-(2-(methylsulfinyl) benzo [d] oxazole-6-base oxygen base) pyridine carboxamide (25mg; 0.075mmol; 1.0 add (1R in 1ml nmp solution equivalent); 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (17mg; 0.112mmol; 1.5 equivalent) and DIPEA (40 μ L, 0.225mmol, 3.0 equivalents) reaction mixture is at room temperature stirred 48 hours.Then product is passed through to the reversed-phase HPLC purifying.LC/MS (m/z) [383.1] (MH ⁺).

Intermediate

Synthesizing of the chloro-N-picoline of 4--3-methane amide

Step 1. at room temperature adds thionyl chloride (1.8mL, 25.0mmol, 2.5 equivalents) in the 25ml toluene suspension of 4-chlorine apellagrin (1.57g, 10.0mmol, 1.0 equivalents).Reaction mixture is stirred 3 hours under 100 ℃.By the mixture concentrating under reduced pressure, be dissolved in 25mL toluene, again concentrate and obtain crude product 4-chloronicotinoyl chloride hydrochloride, it can be used for next step without being further purified.

Step 2. adds methylamine solution (the THF solution of 2M, 20mL, 40mmol, 4.0 equivalents) in the 25ml THF suspension of crude product 4-chloronicotinoyl chloride hydrochloride under 0 ℃.Reaction mixture is at room temperature stirred 1 hour and concentrating under reduced pressure.By crude product be dissolved in ethyl acetate (75mL) and water/salt solution/saturated sodium bicarbonate solution (1/1/1,75mL).Isolated water layer is extracted with EtOAc.By organic layer water/salt solution of merging/saturated sodium bicarbonate solution (1/1/1,25mL) and salt solution (25mL) wash and use dried over sodium sulfate.Removal of solvent under reduced pressure obtains orange solids shape title compound (400mg, 24%), and it can use without being further purified.MH+=171.0, Rt=0.55min.

The chloro-N ' of 4-, N '-lutidine-2-formyl hydrazine synthetic

At room temperature add N in the 10ml THF suspension of 4-chloropyridine formyl chloride hydrochloride (352mg, 2.0mmol, 1,0 equivalent), N-dimethylhydrazine (120mg, 2.0mmol, 1.0 equivalents) and N, N-diisopropyl ethyl amine (383 μ L, 2.2mmol, 1.1 equivalents).Reaction mixture is stirred 15 minutes and water (25mL) and EtOAc (50mL) dilution.By isolated for organic layer salt solution (25mL), saturated sodium bicarbonate solution (25mL) wash and use dried over sodium sulfate.Concentrating under reduced pressure obtains colorless solid shape title compound (223mg, 56%), and it can use without being further purified.MH+=200, Rt=1.42min.

Synthesizing of 4-chloro-N-picoline methane amide and 4-chloropyridine formyl chloride

According to " A Scaleable Synthesis of BAY43-9006:A Potent Raf Kinaseinhibitor for the treatment of cancer " .Donald Bankston, Jacques Dumas, Reina Natero, Bernd Riedl, Mary-Katherine Monahan, Robert Sibley.; The described method of Bayer Research Center.Pharmaceutical Division.Organic ProcessResearch and Development2002 (6) 777-781 makes.

Synthesizing of (1R, 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride

To cooling amine (1R in ice bath, 2R)-(-)-2-benzyloxy cyclo-hexylamine (20g, 97.4mmol) dry MeOH (390mL) solution in slowly add the dioxan solution (49mL, 195mmol) of 4.0M HCl by syringe.Remove ice bath, by the solution N of formation ₂spray 10 minutes.By 10%Pd/C (3g, 28mmol), join in this solution and by reaction solution H ₂purify and maintain H ₂in atmosphere.After 4 hours, add the dioxan solution of 10ml4.0M HCl and reaction solution is maintained to H ₂in atmosphere, spend the night.Once complete (detecting by LCMS), just reaction solution is filtered by thin, Celite pad tight filling, and the solid of collecting is washed with MeOH and EtOAc successively.The organic filtrate merged is evaporated to (1R, 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (13.8g, 91mmol, 93%) that also vacuum-drying obtains light solid state.LCMS m/z116.0 (MH ⁺), t _r=0.37min.

(1S, 2S)-2-Trans-4-Amino Cyclohexanol hydrochloride makes according to identical mode.

Embodiment 202

The chloro-N-isobutoxy of 4-pyridine carboxamide

To 4-chloropyridine formyl chloride hydrochloride (1.0g, 5.68mmol, 1.0 at room temperature add O-isobutyl-hydroxy amine hydrochloric acid salt (785mg in 25ml THF suspension equivalent), 6.25mmol, 1.1 equivalent) and N, N-mono-diisopropyl ethyl amine (2.97ml, 17.0mmol, 3.0 equivalents).Reaction mixture is stirred 30 minutes and water (25mL) and EtOAc (50mL) dilution.By isolated for organic layer salt solution (25mL), saturated sodium bicarbonate solution (2x25mL) wash and use dried over sodium sulfate.Concentrating under reduced pressure obtains colorless solid shape title compound (870mg, 67%), and it can use without being further purified.ES/MS m/z229.0 (MH ⁺), Rt=2.61 minute.

Embodiment 203

4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base)-N-isobutoxy pyridine carboxamide

To 2-(cyclohexyl methyl amino) benzo [d] thiazole-6-alcohol (30mg, 0.114mmol) and cesium carbonate (326mg, 0.228mmol) 1.2ml DMF reaction mixture in add 4-chloro-N-isobutoxy pyridine carboxamide (40mg, 0.171mmol).Reaction mixture is at room temperature stirred 10 minutes, then at 130 ℃ of lower microwave heating 3x20 minute.Crude product mixture is filtered, purify and lyophilize obtains the white solid title compound with preparation HPLC, be its tfa salt (15mg, 23%).ES/MS m/z455.1 (MH ⁺), Rt=2.90 minute.

Embodiment 204

4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-isobutoxy pyridine carboxamide

Method according to previous embodiment makes.ES/MS m/z457.0 (MH ⁺), Rt=2.35 minute.

Embodiment 205

N-(cyclohexyl methyl)-6-(2-(4,5-dimethyl-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

This motif compound makes according to following general flow:

Step 1

Step 2

Step 3

Step 4

To 4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) the pyridine carboxylic acid tert-butyl ester (500mg; 1.28mmol) the 8.0ml nmp solution in add cyclohexyl methylamine (407mg; 3.6mmol) and DIPEA (0.887ml, 5.12mmol).Reaction soln is stirred 12 hours under 110 ℃ or LCMS shows and to have reacted.Crude product mixture is filtered, purify and lyophilize obtains 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) the pyridine carboxylic acid tert-butyl ester with preparation HPLC, be tfa salt (420mg).ES/MS m/z440.2 (MH ⁺).

The preparation of step 2. (4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) methyl alcohol

To 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxylic acid tertiary butyl ester (420mg, 1.14mmol) 50ml THF solution in add THF (3.41ml, the 3.41mmol) solution of 1M LAH under room temperature under argon gas.Reaction mixture is at room temperature stirred 30 minutes.Under stirring at room by crude product mixture by adding carefully methyl alcohol (5ml), 6M NaOH (5ml) and water (5ml) to carry out aftertreatment.Aluminium salt Precipitation.Add ethyl acetate (200ml) and decant is out from salt by organic layer.This salt is used to ethyl acetate (100ml) washing decant again, organic layer is merged, with salt water washing (2x50ml), use Na ₂sO ₄drying, filter and concentrate.The solid residue formed is passed through to silica gel chromatography, obtain (4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) methyl alcohol (157mg) of solid state with (5% methyl alcohol 95%DCM) wash-out vacuum concentration.ES/MS m/z370.2 (MH ⁺).

The preparation of step 3.4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde

To (4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) methyl alcohol (30mg, 0.081mmol) 2ml THF and 2ml DCM solution in add Dess-MartinPeriodinane (38mg, 0.089mmol).Reaction mixture is at room temperature stirred 30 minutes.By ethyl acetate for crude product mixture (60ml) dilution, with saturated sodium bicarbonate (2x15ml), salt solution (1x15ml) washing, use Na ₂sO ₄drying, filtration vacuum concentration obtain 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde (29mg) of solid state.ES/MS m/z386.1 (MH ⁺), be hydrate (+18).

The preparation of step 4.N-(cyclohexyl methyl)-6-(2-(4,5-dimethyl-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

To 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde (15mg, 0.041mmol) the 1.0ml methanol solution in add ammonium acetate (32mg, 0.41mmol) and biacetyl (14mg, 0.163mmol).Reaction mixture is stirred 2 hours under 70 ℃ or extremely monitored by LCMS.Crude product mixture is concentrated into to solid, again be dissolved in 0.8ml NMP, filter, with preparation HPLC, purify and lyophilize obtains N-(cyclohexyl methyl)-6-(2-(4,5-dimethyl-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine is tfa salt (3.0mg).ES/MS m/z434.2 (MH ⁺).

Embodiment 206

N-(cyclohexyl methyl)-6-(2-(4-(trifluoromethyl)-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

This motif compound makes according to following general flow:

To adding in the 1.6ml aqueous solution of sodium acetate (300mg, 3.7mmol) 3,3-bis-bromo-1,1,1-trifluoro penta-2-ketone (500mg, 1.85mmol).Reaction mixture is stirred 1 hour under 100 ℃.Take out about 0.5ml (0.46mol) from above-mentioned reaction mixture, be cooled to room temperature.This crude mixture is joined in the 2ml methanol solution of 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde (15mg, 0.041mmol).Add ammonium hydroxide (28%-30%) solution (0.5ml, 4mmol) in crude product mixture.Reaction mixture is at room temperature stirred 18 hours or extremely complete by the LCMS monitoring reaction.Crude product mixture is concentrated into to solid, again be dissolved in 0.8ml NMP, filter, purify and lyophilize obtains N-(cyclohexyl methyl)-6-(2-(4-(trifluoromethyl)-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine with preparation HPLC, be tfa salt (3.0mg).ES/MS m/z474.2 (MH ⁺).

Embodiment 207

(1R, 2R)-2-(6-(6 '-(pyrrolidin-1-yl)-2,3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Step 2

Step 1. (1R, 2R)-2-(6-(6 '-fluoro-2,3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) preparation of hexalin

To (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (130mg, 0.345mmol) 5.0ml DME reaction mixture in add the fluoro-5-(4 of 2-, 4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) pyridine (268mg, 1.21mmol), Pd (dppf) ₂cl ₂(56mg, 0.069mmol) and 2M Na ₂cO ₃(1.05ml, 2.1mmol).Reaction soln is stirred 2 hours or until completes by the LC detection reaction at 105 ℃.Crude product mixture is concentrated into to solid, again be dissolved in 3ml DMF, filter, with preparation HPLC, purify and lyophilize obtains (1R, (6-(6 '-fluoro-2 for 2R)-2-, 3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (149mg).ES/MS m/z437.1 (MH ⁺).

Step 2. (1R, 2R)-2-(6-(6 '-(pyrrolidin-1-yl)-2,3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) preparation of hexalin

To (1R, (6-(6 '-fluoro-2 for 2R)-2-, 3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (11mg, 0.0252mmol) 0.4ml NMP reaction mixture in add (DIPEA) diisopropyl ethyl amine (13ul, 0.0756mmol) and tetramethyleneimine (14.4mg, 0.202mmol).Reaction mixture is stirred 20 hours or until completes by the LC detection reaction under 105-110 ℃.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(6 '-(pyrrolidin-1-yl)-2,3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (2.3mg).ES/MS m/z488.1 (MH ⁺).

Embodiment 208

(1R, 2R)-2-(6-(2-(4-(pyrrolidin-1-yl methyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

The preparation of step 1.4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl aldehyde

To (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (70mg, 0.186mmol) 2.5ml NMP reaction mixture in add 4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl aldehyde (130mg, 0.558mmol), Pd (dppf) ₂cl ₂(38mg, 0.0465mmol) and 2M Na ₂cO ₃(0.56ml, 1.12mmol).Reaction soln is stirred 4 hours or until completes by the LC detection reaction under 110 ℃.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl aldehyde is tfa salt (61mg).ES/MS m/z446.0 (MH ⁺).

The preparation of step 2. (1R, 2R)-2-(6-(2-(4-(pyrrolidin-1-yl methyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

To 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl aldehyde (12mg, 0.027mmol) 0.6ml NMP reaction mixture in add successively tetramethyleneimine (19.2mg, 0.27mmol), excessive acetic acid (0.060ml, 1.0mmol) and triethyl orthoformate (20mg, 0.135mmol).Reaction mixture is at room temperature stirred 20 minutes.Add sodium triacetoxy borohydride (14.3mg, 0.0675mmol) in this reaction mixture.Reaction mixture is at room temperature stirred 18 hours.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(2-(4-(pyrrolidin-1-yl methyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (2.8mg).ES/MS m/z501.2 (MH ⁺).

Embodiment 209

(1R, 2R)-2-(6-(2-(1-(2-(pyrrolidin-1-yl) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

Step 1.2-(4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-1H-pyrazol-1-yl) acetaldehyde

To (1R, (((1-((1 for 2-for 6-for 2R)-2-, 3-dioxolane-2-yl) methyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin (195mg, 0.395mmol) solid in add 3M HCl (6.0ml, 18mmol).Reaction soln is stirred 6 hours or until completes by the LC detection reaction under 95 ℃.By the crude product mixture lyophilize to solid, then again be dissolved in 2ml water and 2ml NMP, with preparation HPLC, purify and lyophilize obtains 2-(4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-1H-pyrazol-1-yl) acetaldehyde is tfa salt (50mg).ES/MS m/z468.2 (MH ⁺).

The preparation of step 2. (1R, 2R)-2-(6-(2-(1-(2-(pyrrolidin-1-yl) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

To 2-(4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-1H-pyrazol-1-yl) acetaldehyde (12.5mg, 0.0267mmol) 0.5ml NMP reaction mixture in add tetramethyleneimine (19mg, 0.267mmol) and stir 10 minutes.Add excessive acetic acid (0.070ml, 1.16mmol) and stir 20 minutes in this reaction mixture.Add sodium triacetoxy borohydride (13mg, 0.0614mmol) in this reaction mixture.Reaction mixture is at room temperature stirred 90 minutes.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(2-(1-(2-(pyrrolidin-1-yl) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (1.4mg).ES/MS m/z505.2 (MH ⁺).

Embodiment 210

The preparation of N-(cyclohexyl methyl)-6-(pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

To N-(cyclohexyl methyl)-6-(pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine (20mg, 0.076mmol, 1.0 at room temperature add cesium carbonate (61mg in nmp solution equivalent), 0.190mmol, 2.5 equivalent), 4-chloropyridine HCl (12.5mg, 0.083mmol, 1.1 equivalents) and DIPEA (33 μ L, 0.190mmol, 2.5 equivalents) and reaction solution is stirred 72 hours under 80 ℃.Then isolate product by preparation HPLC, pure fraction lyophilize is obtained to title compound, be tfa salt (1.4mg).ES/MS m/z340.1 (MH ⁺).

Embodiment 211

The preparation of 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-1-oxo-benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide

Will

(KHSO ₅380mg, mmol) water (4ml) solution at room temperature is added drop-wise in methyl alcohol (4ml) solution of 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (25mg, mmol).Stir after 23 hours, suspension water (50ml) is diluted and be extracted with ethyl acetate (2x10ml).By the organic layer salt water washing merged, concentrated, obtain the white solid title compound by the preparation HPLC purifying.Yield: 2.4mg.ES/MSm/z415.1 (MH ⁺), Rt=1.81 minute.

Embodiment 212

(S) preparation of-N-(1-cyclohexyl ethyl)-6-(2-(1-ethyl-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

Method according to embodiment 176 (table 3) makes.Reaction mixture is heated 3 hours under 110 ℃, then by the preparation HPLC purifying, obtain title compound.Yield: 13mg.ES/MS m/z448.1 (MH ⁺), Rt=2.79min.

Embodiment 213

(S) preparation of-N-(1-cyclohexyl ethyl)-6-(2-(1-(2-morpholino ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

Method according to embodiment 185 (table 3) makes, and at first crude product is passed through to preparation HPLC purifying lyophilize.Resistates is dissolved in to ethyl acetate/saturated sodium bicarbonate solution (10ml/10ml).By isolated organic layer dried over sodium sulfate, vacuum concentration also utilizes methylene chloride/methanol (95:5) purifying by preparative TLC.Purified product being dissolved in to acetonitrile (3ml) and the 1N HCl aqueous solution (0.5ml) lyophilize and obtaining title compound, is its HCl salt.Yield: 11mg.ES/MS m/z533.1 (MH ⁺), Rt=2.14min.

Embodiment 214

(S) preparation of-6-(2-chloropyridine-4-base oxygen base)-N-(1-(ethylsulfonyl) piperidines-3-yl) benzo [d] thiazole-2-amine

The preparation of step 1. (S)-tertiary butyl 3-(6-methoxyl group benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate

To the chloro-6-methoxyl group of 2-benzo [d] thiazole (2.6g, add (S)-tertiary butyl 3-(6-methoxyl group benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (5g in 25ml nmp solution 13mmol), 25mmol) and DIPEA (2.6ml, 15mmol).Reaction soln is stirred 7 days under 100 ℃.Crude reaction solution is mixed mutually with ethyl acetate (250ml) and dilute aqueous solution of sodium bicarbonate (80ml) and isolate organic phase.By isolated organic layer water (2x60ml) and salt solution (60ml) washing, then obtain brown oily product with dried over sodium sulfate vacuum-evaporation, this product is passed through to the flash chromatography on silica gel purifying, use ethyl acetate: hexane (35:65-50:50) wash-out obtains (S)-tertiary butyl 3-(6-methoxyl group benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (3.33g, 9.16mmol) of Off-white solid shape.ES/MS m/z364.2 (MH ⁺).Rt=2.2 minute.

The preparation of step 2. (S)-6-methoxyl group-N-(piperidines-3-yl) benzo [d] thiazole-2-amine

To (S)-tertiary butyl 3-(6-methoxyl group benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (3.35g, 9.22mmol) methyl alcohol/dioxan (3ml/3ml) solution in slowly add the dioxan solution (60ml, 240mmol) of 4M HCl [to note: emit gas! ].Reaction mixture is at room temperature stirred to 2.5 hours and vacuum concentration to remove methyl alcohol and the dioxan of half.Resistates is suspended in diethyl ether (50ml).Leaching solid, with diethyl ether (50ml) washing vacuum-drying, obtain (S)-6-methoxyl group-N-(piperidines-3-yl) benzo [d] thiazole of white solid-2-amine, is its hydrochloride.Yield: 4.29g.ES/MSm/z264.1 (MH ⁺), Rt=1.62 minute.

The preparation of step 3. (S)-N-(1-(ethylsulfonyl) piperidines-3-yl)-6-methoxyl group benzo [d] thiazole-2-amine

By (S)-6-methoxyl group-N-(piperidines-3-yl) benzo [d] thiazole-2-amine hydrochlorate (2.0g, 5.95mmol), ethyl chloride (1.13ml, 11.91mmol) and NMP (25ml) mixture of DIPEA (4.11ml, 23.8mmol) under 55 ℃, heat 16 hours 50 minutes.Reaction mixture is cooled to room temperature water (150ml) and ethyl acetate (150ml) dilution.After vigorous stirring 1 hour, isolated organic layer water (3x100ml), saturated sodium bicarbonate solution (3x100ml), water (100ml) and salt solution (100ml) are washed and use dried over sodium sulfate.Vacuum concentration by the flash chromatography on silica gel purifying, use ethyl acetate: hexane (20:80-100:0) wash-out obtains (the S)-N-(1-(ethylsulfonyl) piperidines-3-yl) of tawny solid state-6-methoxyl group benzo [d] thiazole-2-amine.Yield: 1.22g.ES/MS m/z356.0 (MH ⁺), Rt=2.12 minute.

The preparation of step 4. (S)-2-(1-(ethylsulfonyl) piperidines-3-base amino) benzo [d] thiazole-6-alcohol

By (S)-N-(1-(ethylsulfonyl) piperidines-3-yl)-6-methoxyl group benzo [d] thiazole-2-amine (1.22g; 3.43mmol) methylene dichloride (25ml) solution under nitrogen atmosphere, with boron tribromide, (dichloromethane solution of 1M 7.5ml) is processed under 0 ℃.Under 0 ℃, continue to stir 10 minutes, at room temperature stir about is 135 minutes.By reaction mixture, water (50ml), ethyl acetate (200ml) are diluted and are processed (until observe, not emitting gas) with solid sodium bicarbonate carefully.Mixture is stirred to each phase transformation clarification.The saturated sodium bicarbonate solution for organic phase (2x75ml), water (75ml), the salt solution (75ml) that separate are washed and use dried over sodium sulfate.Vacuum concentration obtains crude product (S)-2-(1-(ethylsulfonyl) piperidines-3-base amino) benzo [d] thiazole-6-alcohol, and it can be used for next step without being further purified.Yield: 1.15g.ES/MS m/z342.0 (MH ⁺), Rt=1.86 minute.

The preparation of step 5. (S)-6-(2-chloropyridine-4-base oxygen base)-N-(1-(ethylsulfonyl) piperidines-3-yl) benzo [d] thiazole-2-amine

To (S)-2-(1-(ethylsulfonyl) piperidines-3-base amino) benzo [d] thiazole-6-alcohol (1.15g; 3.37mmol) and cesium carbonate (2.20g; 6.74mmol) 12ml NMP mixture in add 2-chloro-4-fluorine pyridine (532mg, 4.05mmol).Reaction mixture is stirred 17 hours under 60 ℃.By reaction mixture water (100ml) and ethyl acetate (100ml) dilution.Isolated organic layer water (3x50ml), saturated sodium bicarbonate solution (3x50ml), water (50ml), salt solution (100ml) are washed and use dried over sodium sulfate.Vacuum concentration also passes through the flash chromatography on silica gel purifying, and use ethyl acetate: hexane (1:1 to 3:1) wash-out obtains title compound.Yield: 671mg.ES/MS m/z453.0 (MH ⁺), Rt=2.59min.

Embodiment 215

(1R, 2R)-2-(6-(2-(3-methoxy propyl-1-alkynyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

The preparation of (1R, 2R)-2-(6-(2-(3-methoxy propyl-1-alkynyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

Add Pd (dppf) in the 0.5ml DMF reaction mixture of (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (18.8mg, 0.05mmol) ₂cl ₂(8.2mg, 0.01mmol), CuI (4.3mg, 0.0225mmol), 3-methoxy propyl-1-alkynes (15.8mg, 0.225mmol), finally add DIPEA (0.026ml, 0.15mmol).Reaction soln is stirred 90 minutes or until completes by the LC detection reaction under 100 ℃.Crude product mixture is filtered, with preparation HPLC, purify and lyophilize obtains (1R, 2R)-2-(6-(2-(3-methoxy propyl-1-alkynyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin is tfa salt (9.2mg).ES/MS m/z410.1 (MH ⁺).

Embodiment 216

(1R, 2R)-2-(6-(2-ethynyl pyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin

This motif compound makes according to following general flow:

The preparation of (1R, 2R)-2-(6-(2-ethynyl pyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin

Add Pd (dppf) in the 0.5ml DMF reaction mixture of (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (16mg, 0.043m mol) ₂cl ₂(8.8mg, 0.0108mmol), CuI (4.5mg, 0.024mmol), ethynyl trimethyl silane (21.1mg, 0.215mmol) also finally add DIPEA (0.023ml, 0.129mmol).Reaction soln is stirred 90 minutes or until completes by the LC detection reaction under 100 ℃.Add 3MNaOH solution (0.175ml, 0.525mmol) in crude product mixture.Crude product mixture is at room temperature stirred 30 minutes or until completes by the LC detection reaction.By dense thick excessive acetic acid for crude product mixture (0.085,1.41mmol) neutralize and add 0.5ml DMF.Mixture is stirred 5 minutes, filter, purify and lyophilize obtains (1R, 2R)-2-(6-(2-ethynyl pyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin with preparation HPLC, be tfa salt (4.6mg).ES/MS m/z366.1 (MH ⁺).

Embodiment 217

(S) preparation of-N-(1-(ethylsulfonyl) piperidines-3-yl)-6-(2-(1-propyl group-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

Method according to embodiment 176 makes.Reaction mixture is heated 18 hours under 85 ℃, and under 90 ℃, heating is 24 hours.Obtain title compound by the preparation HPLC purifying.Yield: 2.1mg.ES/MS m/z527.1 (MH ⁺), Rt=2.24 minute.

Embodiment 218

(S) preparation of-N-(1-(ethylsulfonyl) piperidines-3-yl)-6-(2-(1-(2-fluoro ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine

Method according to embodiment 176 makes.Reaction mixture is heated 18 hours and obtains title compound by the preparation HPLC purifying under 105 ℃.Yield: 9.8mg.ES/MS m/z531.2 (MH ⁺), Rt=1.89min minute.

Embodiment 219

The preparation of (1R, 2R)-2-(6-(pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin

Add cesium carbonate (62mg, 0.189mmol) and at room temperature stir 1-3 minute in the 0.5ml NMP reaction mixture of 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (20mg, 0.0755mmol).Add cesium carbonate (98.5mg, 0.302mmol) and 4-chloropyridine hydrochloride (45.3mg, 0.302mmol) in this mixture.Reaction mixture is stirred 48 hours or until completes by the LC detection reaction under 105-110 ℃.Crude product mixture is filtered, purify and lyophilize obtains (1R, 2R)-2-(6-(pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin with preparation HPLC, be tfa salt (1.1mg).ES/MS m/z342.1 (MH ⁺).

Compound 1-381 in table 3 and compound 1-102,104-106 in table 4 and 112-119 make according to above embodiment, especially according to " Ex Prep " (Preparation Example) described embodiment in hurdle, make.Compound 103 and 107-111 can make according to above embodiment.

Table 3

Table 4

Every kind of compound listing in table 2 is active to the inhibition of CSF-1R is IC ₅₀be less than approximately 10 μ M.The activity that most compounds suppresses to show for CSF-1R is IC ₅₀be less than approximately 1 μ M or be less than approximately 0.1 μ M or be less than approximately 0.01 μ M.The activity of table 3 and 4 compound is less than 1 μ M.Every kind of compound itself in table 2,3 and 4 individually or be all preferred as a member in this group.

Except CSF-1R suppresses activity, chemical compound lot in his-and-hers watches 2,3 and 4 suppresses (according to US10/405 Raf, 945 described biological chemistry screening methods, be incorporated by reference in its entirety) and other kinase whose restraining effect screen, and confirm, the activity that they suppress CSF-1R is greater than the kinase whose activity that (approximately between 2～approximately 1,000 times) suppresses Raf and other screening significantly.More particularly, the activity of most compounds when suppressing Raf is greater than approximately 1 μ M, and the activity of most of same compound when suppressing CSF-1R is less than approximately 0.1 μ M.Therefore the most compounds in table 2,3 and 4 be CSF-1R effectively and be inhibitor optionally.

Biology embodiment

Biology embodiment 1

Vitro kinase test for colony-stimulating factor-1 acceptor (CSF-1R)

The kinase activity of various protein tyrosine kinases can be by providing ATP and the suitable peptide containing tyrosine or protein substrate and measuring the phosphate radical part and measure to the transfer of tyrosine residues.The recombinant protein that is equivalent to the endochylema structural domain of people CSF-1R is bought from Invitrogen Corporation, Carlsbad, CA U.S.A. (#PV3249).For each test, by testing compound since the dilution continuously in 384 orifice plates in DMSO of 3 times of diluents for 25 μ M, then with by 50mMHepes, 5mM MgCl ₂, 10mM MnCl ₂, the suitable kinase reaction buffering liquid-phase mixing that forms of 0.1%BSA, pH7.5,1.0mM dithiothreitol (DTT), 0.01%Tween80 and 1 μ M ATP.With 50nM, add kinase protein and suitable biotinylated peptide substrates take and obtain final volume as 20 μ L, reaction solution at room temperature is incubated to 2 hours, by adding 10 μ L45mM EDTA, 50mMHepes pH7.5 termination reaction.Add 30 μ L PT66Alphascreen beads (Perkin Elmer, Boston, MA, U.S.A.) in the mixture of stopped reaction.By the reaction solution incubated overnight and at the upper reading of Envision (Perkin Elmer).AlphaScreen system for the peptide prod of phosphorylation (Perkin Elmer) utilization is scribbled to the acceptor bead of antiphosphotyrosine antibody PT66 and scribbles the donor bead that can send the streptavidin of fluorescent signal in about 520-620nM transmitted wave strong point and measured.50% inhibition concentration (IC of every kind of compound ₅₀) by non-linear regression, utilize XL Fit data analysis software to calculate.

By the CSF-1R kinases at 50mM Hepes pH7.0,5mM MgCl ₂, 10mM MnCl ₂, 1mM DTT, 1mg/ml BSA, 1.0 μ M ATP and 0.05 μ M vitamin H-GGGGRPRAATF-NH ₂in (SEQ ID NO:2) peptide substrates, tested.Final concentration with 4nM adds the CSF-1R kinases.

Biology embodiment 2

The In-vitro Inhibitory Effect of CSF-1R receptor tyrosine phosphorylation

In order to test the restraining effect of CSF-1R receptor tyrosine phosphorylation, to buy the compound of HEK293H from Invitrogen (Cat.#11631017) (with the cell that is cloned into the total length people CSF-1R acceptor transfection in Mammals additive type transfection carrier) and serial dilution (since 10 μ M, 3 times of dilutions) be incubated together 1 hour, then stimulate 8 minutes with 50ng/ml MCSF.After removing supernatant liquor, cell is being dissolved with dissolving damping fluid (150mM NaCl, 20mM Tris, pH7.5,1mMEDTA, 1mM EGTA, 1%Triton X-100 and NaF, proteolytic enzyme and inhibitors of phosphatases) on ice, then vibration 15-20 minute under 4 ℃.Then lysate is transferred in 96 orifice plates that apply with CSF-1R antibody, this plate uses 3%Blocker A (from Mesoscale Discovery (MSD)) to seal in advance 2 hours, then washing.Lysate, 4 ℃ of lower incubated overnight, is then washed this plate 4 times with MSD Tris Wash Buffer.To be diluted to the 20nM final concentration in 1%Blocker A (MSD) solution from the SULFO-TAGanti-pTyr antibody of MSD, and then join on the plate after washing and be incubated 1.5-2 hour, then add reading damping fluid (MSD).By this plate reading on Sector6000 instrument (MSD).Raw data is inputted to Abase, and calculate EC by the XL-fit data analysis software ₅₀.

Biology embodiment 3

CSF-1R inhibitor in the MNFS-60Pk/Pd model

500 ten thousand MNFS-60 cells are implanted in HBSS/Matrigel solution to the right side abdomen.Approximately measure tumour after 3 weeks at tumor cell injection, and by the mouse selected according to the big or small randomized grouping of its tumour (n=3, except vehicle group, n=6 wherein).

Will be with EC ₅₀in<100nM inhibition MNFS-60 cell, the compound of the phosphorylation of the propagation of M-CSF mediation and CSF-1R is at the homogenic tumor model (5X10 of MNFS-60 ⁶, wherein in Matrigel subcutaneous implantation and the growth 3-4 week, until they reach about 150mm ²) on tested.The single 100mg/kg dosed administration of representative compound disclosed herein is had to the animal of MNFS-60 tumour in length; 1 hour to 24 hours after administration starts at each time point results blood plasma and tumor sample.

By western blotting, measured, result confirms, in administration, after 4 hours, with vehicle Control, compares, and multiple compound disclosed herein can suppress the Tyr723 phosphorylation of CSF-1R in the tumour lysate >=50%.

In addition, also at the severe osteoarthritis mouse model (people such as Terato, K., the Journalof Immunology148:2103-2108 that show effect rapidly; 1992) in, multiple compound disclosed herein is detected, then treatment starts with LPS at injection anticol original antibody mixture in post-stimulatory the 3rd day.In whole 12 days of being treated with the CSF-1R inhibitor, the degree of pawl swelling and the severity of bone resorption are marked.Compare with control group, do not observe the obvious alleviation of swelling, still, the severity of bone resorption is tended to improve.Also do not have at present report to show that the CSF-1R inhibitor is effective in this arthritis model.Unique situation that successfully slows down progression of disease of reporting is conducted (people such as Campbell, J.Leukoc.Biol.68:144-150 with anti-MCSF antibody suppression CSF-1R signal in sacroiliitis mouse model lighter, slowly outbreak; 2000).

Biology embodiment 4

The restraining effect of Raf kinase signal in biochemical test in vitro

Compound utilizes following biological test to be determined to the inhibition of Raf.The kinase whose activity of Raf is by providing ATP, restructuring kinases deactivation MEK substrate and measuring the phosphate radical part and determine to the transfer of MEK residue.The recombinant full-lenght MEK that will contain deactivation K97R ATP-binding site sudden change (making the kinases inactivation) uses biotin labeling at expression in escherichia coli and after purifying.By N-end (His) for MEKcDNA ₆mark subclone at expression in escherichia coli, then by the MEK substrate of restructuring by nickel affinity chromatography purifying from the intestinal bacteria lysate, then carry out anionresin.By final MEK substrate preparation biotinylation (Pierce EZ-LinkSulfo-NHS-LC-Biotin) and be concentrated into approximately 11.25 μ M.Restructuring Raf (comprising c-Raf and mutant B-Raf isoform) obtains from the sf9 insect cell infected with corresponding people Raf recombinant expression vector by purifying.The Raf isoform of restructuring is interacted by Glu antibody or passes through the metal ion chromatogram purification.

For each test, this compound, for example since 3-times of diluent dilution continuously in DMSO for 25 μ M, is then mixed with various Raf isoforms (every kind of about 0.50nM) mutually.Kinases inactivation vitamin H-MEK substrate (50nM) is added in the reaction buffer that contains ATP (1 μ M).This reaction buffer contains 30mM Tris-HCl ₂pH7.5,10mM MgCl ₂, 2mM DTT, 4mMEDTA, 25mM β-glycerophospholipids, 5mM MnCl ₂and 0.01%BSA/PBS.Subsequently reaction solution at room temperature is incubated to approximately 2 hours, by adding 0.5M EDTA termination reaction.The mixture of termination reaction is transferred to the plate (Pierce) that has applied Neutradavin and go up and be incubated approximately 1 hour.By DELFIA time difference type fluorescing system (Wallac) for the product of phosphorylation, utilize the anti-p-MEK of rabbit (Cell Signaling) as one-level antibody and measured as secondary antibody with the anti-rabbit of europium mark.Time difference type fluorescence can be on the Wallac1232DELFIA photofluorometer reading.50% inhibition concentration (IC of compound ₅₀) by non-linear regression, utilize XL Fit data analysis software to calculate.

Biology embodiment 5

The restraining effect of cKIT and PDGFRb kinase signal in biological test in vitro

Measure the IC that suppresses RTK in the Alphascreen system ₅₀value, wherein, measure compound and various enzymes shifted to the restraining effect of phosphate radical to substrate.In brief, buy corresponding RTK structural domain (cKIT Upstate#14-559, PDGFRb Invitrogen#P3082) and it is cultivated under the existence of substrate and ATP with together with the compound of serial dilution with the form of human recombination protein, wherein, the concentration of ATP is in 3 times of the Km of enzyme.

By the kinase domain of cKIT at 50mM Hepes, pH=7.5,5mM MgCl ₂, 10mMMnCl ₂, tested in 1mM DTT, the 0.1%BSA that contains the biotinylated peptide substrates of 0.06uM (GGLFDDPSYVNVQN1-NH2) and 15uM ATP (the apparent KM=15uM of ATP).By the kinase domain of PDGFR at 50mM Hepes, pH=7.5,20mM MgCl ₂, tested in 1mM DTT, the 0.1%BSA that contains the biotinylated peptide substrates of 0.1uM (GGLFDDPSYVNVQN1-NH2) and 10uM ATP (the apparent KM=25uM of ATP).Reaction solution at room temperature is incubated to 3 to 4 hours and uses damping fluid termination reaction (for PDGFRb and cKIT, all using 20mM EDTA, 0.01%Tween-20).Alphascreen PY20 bead is joined in the cKIT reaction solution of stopped reaction, PY20Ab/ albumin A Alphascreen bead is joined in the reaction solution of stopped reaction of PDGFR β.By these two kinds of equal incubated overnight of reaction solution and on the Alphascreen reader reading.50% inhibition concentration (IC of compound ₅₀) utilize non-linear regression to calculate by the XL-Fit data analysis software.Compound in contrast, by staurosporine for each test, and need Z ' 0.5 so that result is effective.

Biology embodiment 6

Cells survival test in the MNFS60 cell relied at MCSF

Cell Titer Glo by Pu Luomaige company (Promega) estimates cells survival.Before adding compound, MNFS60 (mouse AML cell) is seeded in the 96-orifice plate of TC processing with the density of 5,000 cells/well, substratum is RPMI-1640, containing 10%FBS and 1% penicillin/streptomycin.Test compounds is carried out in DMSO to serial dilution (3 times), be diluted to the 500x final concentration.For each concentration of test compounds, the aliquots containig of 2 μ l (500x) compounds or 100%DMSO (contrast) are diluted for 2x concentration in the 500 μ l substratum of the somatomedin MCSF that comprises the 2x final concentration, then on cell, be diluted to 1x.The final concentration of MCSF is 10ng/ml.Cell is at 37 ℃, 5%CO ₂under condition, hatch 72 hours.After hatching, add each hole to measure the cell of survival 100 μ l Cell Titer Glo.This test is that the specification sheets (Pu Luomaige company, Madison, the state of Wisconsin, the U.S.) according to the manufacturer carries out.Each test conditions all carries out in triplicate.Raw data is inputted to Abase and adopt the XL-fit data analysis software to calculate EC ₅₀.Comprise cell in substratum but do not contain each hole that MCSF thereby cell are not grown, its relative light unit is defined as 100% inhibition.

Biology embodiment 7

The osteolysis model of tumor inducing

The osteolysis of tumor inducing (TIO) model has demonstrated and can reappear visible bone destruction in suffering from molten bone metastases patient, and it in the document of diphosphate and new anti-molten bone drug test by wide coverage.There are good cognation (people such as Kim S-J, 2005, Canc.Res., 65 (9): 3707 from the result of this class research and people's clinical activity; Corey, the people such as E, 2003, Clin.Canc.Res., 9:295; Alvarez, the people such as E., 2003, Clin.Canc.Res., 9:5705).The method comprises tumour cell is injected directly into to proximal tibia.Once cell is set up, they are just bred and secrete the somatomedin with osteoclast activity, cause absorbing again of girder and cortex of bone.After tumor cell transplantation, with the drug treating animal of anti-absorption and bone destruction is measured by several different methods in test endpoint.

The tumor cell line used in the method is human origin, has represented this class tumor cell line, changed before them thereby at present expressing luciferase in order to use the Xenogen system to be followed the trail of the tumour cell in animal body.The intensity of optical signal also provides on concrete site nearly how many cellular localizations in this indication.

Inoculate first 30 minutes at cell, to mouse subcutaneous injection 2.5mg/kg flunixin meglumine, so that the analgesic activity after program to be provided.Then mouse is anaesthetized to (if can not get isoflurane, can use ketamine/xylazine) by isoflurane.The animal of anesthesia is placed as to dorsal position, after tumour cell is sucked to the 50 or 100 μ l microsyringes with 26-or No. 27 syringe needles, syringe needle is inserted by the cortex of the front tuberosity of right side shin bone, during insertion, adopt the rotation of " drilling type " to advance, so that the chance of cortex fracture minimizes.If the resistance that syringe needle advances disappears, illustrate that syringe needle is successfully by cortex and entered marrow.Once, through cortex of bone, 10-20 μ l cell suspension (6X10^5MDA-MB-231Luc mammary cancer or 3X10^5PC-3MLuc prostate cancer cell) is injected in the marrow of shin bone.Animal is observed to guarantee its accident-free recovery (heat pad or lamp), until their recoveries from anesthesia.

Tumor growth progress in bone can be divided into 5 stages (0-4 phase).These stage definitions are as described below, and they can compare to monitor by (left side) leg of not injecting with this mouse:

0 phase: normal, in bone without the indication of any change.

1 phase: indefinite or minimal change; Cortex/system architecture is normal.

2 phases: limited damage; The cortex of minimum level/system architecture fracture.

3 phases: a large amount of damages; Cortex/system architecture fracture.

4 phases: havoc; System architecture does not exist, " late period ".The animal that reaches this stage will exclude this test execution.

In research process, estimate the growth of tumour on injection point and farther position with the photon imaging of leg, use the Xenogen system quantitative to the tumour cell in shin bone, and confirm not to be leaked in other zone.It is weekly until off-test is used Faxitron X-ray Unit to take radiograph to leg, to estimate the bone destruction in the cortex of injection point.When using more invasion and attack clone as PC-3M-Luc, we are one to two week and the damage of monitoring once in a week subsequently bone after injection.For the clone with than slow rate formation damage, MDA-MB-231Luc for example, its 4-5 week after transplanting just shows bone injury, according to the model development experimental study, radiograph is animal to be carried out in shin bone transplanting shooting in latter about 4 weeks first, to set up baseline control, the time point that starts to occur from damage subsequently starts, and measures once in a week bone injury.For example, in the mouse of injection MDA-MB-231Luc, will within about 4 weeks, take pictures afterwards in transplanting, take once weekly afterwards.

Can be according to any standard way, once a day or twice uses small molecules, monoclonal antibody or albumen to animal.

The terminal of test is late period (4 phase) the sacrificed time point that the animal of most of untreated (negative controls) has reached disease.At that point, no matter in research, remaining its tumour of animal all was condemned to death in which kind of in stage.According to the difference of clone, research continues about 5-10 week.After final X-line is taken, by cardiac puncture, from animal, draw blood (for measuring the marrow of serum; See below).Then the X-line image of terminal is distributed to 5 volunteers, they are marked to each image according to top described in detail points-scoring system.The mark of every mouse is averaged and is expressed as average molten bone mark or has the per-cent of the animal (mark higher than 2 animal) of serious osteolysis.

Biology embodiment 8

Mouse Trap5b tests (IDS company, Fountain Hills, AZ)

This test is the immunofixation enzymic activity test of the solid phase for determining the TRAP 5b that the mice serum sample is osteoclast-derived.Trap5b is expressed by the resorbent osteoclast of sclerotin, and secretedly enters circulation.Therefore think that serum T rap5b is the resorbent significant notation of osteoclast activity, quantity and sclerotin.

Polyclonal antibody is used in mouse Trap5b test, and it prepares as antigen with recombined small-mouse Trap5b.In this test, in the microtiter well that has applied anti-rabbit igg, hatch antibody.After cleaning, the serum sample of standard substance, contrast and dilution is hatched in hole, in conjunction with the Trap5b activity with chromogenic substrate colour developing, determine.Termination reaction, the absorbancy by microplate reader at 405nm assaying reaction mixture.Colored intensity is directly proportional to amount and the activity of the Trap5b existed in sample.Mean light absorbency by each standard substance with ordinate zou is mapped to X-coordinate concentration, and the numerical value of unknown sample can be read from this typical curve, and means with U/L Trap5b.The sensitivity for analysis of this test is 0.1U/L, and the difference of test bay and test inner analysis is below 10%.Find that Trap5b level and average molten bone scoring mark (through the assessment of x-ray) have good dependency.

Although described the preferred embodiment of the invention and change programme thereof in detail, using other improvement and method should be apparent for those skilled in the art.Correspondingly, be to be understood that various application, improvement and replacement can be comprised of the multiple equivalence that does not break away from the scope of purport of the present invention and claim.

In the described test of biology embodiment, so that approximately 1 μ M is tested, the active per-cent of inhibition of table 2,3,4 compound is presented at respectively in table 5,6 and 7.Be expected at the compound that under 1 μ M, inhibiting rate is 0% and there is the activity of inhibition under higher concentration." N/D " is illustrated in special test and do not test this compound.

The activity of table 5. table 2 compound

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						1	N/D	99	N/D	21	N/D
2	N/D	100	N/D	63	80
						3	N/D	96	N/D	0	N/D
4	N/D	100	N/D	100	91
						5	N/D	99	N/D	100	93
6	N/D	85	N/D	N/D	N/D
						7	N/D	94	N/D	17	21

Cmpd	PDGFRβ	CSF.1R	cKit	M-NFS-60CP	pCSF1R
						8	N/D	99	N/D	60	92
9	N/D	99	N/D	58	75
						10	35	99	N/D	62	79
11	96	99	N/D	26	N/D
						12	12	99	N/D	30	N/D
13	65	99	N/D	76	75
						14	85	99	N/D	56	71
15	88	100	N/D	97	92
						16	20	99	N/D	25	81
17	10	100	85	81	94
						18	35	100	N/D	91	74
19	2	100	N/D	36	N/D
						20	0	15	N/D	N/D	N/D
21	0	99	N/D	55	65
						22	0	21	N/D	N/D	N/D
23	0	50	N/D	N/D	N/D
						24	20	99	N/D	12	N/D
25	7	98	N/D	42	35
						26	100	98	N/D	24	N/D
27	28	99	N/D	97	96
						28	98	99	N/D	98	88
29	51	99	N/D	0	N/D
						30	14	25	N/D	N/D	N/D
31	N/D	100	18	57	79
						32	22	100	N/D	70	93
33	35	98	N/D	35	83
						34	89	99	N/D	68	65
35	9	19	N/D	N/D	N/D
						36	6	78	0	N/D	N/D
37	16	79	N/D	N/D	N/D
						38	14	34	N/D	N/D	N/D
39	10	67	N/D	N/D	N/D
						40	6	99	N/D	0	N/D
41	30	100	N/D	100	94
						42	12	99	N/D	100	97
43	15	26	N/D	N/D	N/D
						44	15	37	N/D	N/D	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						45	14	11	N/D	N/D	N/D
46	15	94	N/D	1	N/D
						47	12	13	N/D	N/D	N/D
48	0	84	N/D	0	N/D
						49	25	55	63	N/D	N/D
50	8	56	59	N/D	N/D
						51	2	95	40	N/D	N/D
52	50	100	12	56	71
						53	0	95	21	N/D	N/D
54	7	100	17	64	60
						55	11	97	21	N/D	N/D
56	0	66	55	N/D	N/D
						57	3	97	35	35	N/D
58	85	98	48	30	N/D
						59	0	97	21	N/D	N/D
60	2	92	6	N/D	N/D
						61	0	94	74	35	N/D
62	5	19	7	N/D	N/D
						63	3	45	6	N/D	N/D
64	21	77	0	N/D	N/D
						65	38	99	98	100	97
66	37	100	55	18	37
						67	1	97	8	10	0
68	3	99	6	18	N/D
						69	0	100	0	0	N/D
70	0	99	0	0	N/D
						71	0	100	27	11	N/D
72	0	100	65	48	N/D
						73	2	100	21	0	N/D
74	31	100	34	14	N/D
						75	0	99	7	0	N/D
76	0	98	9	0	N/D
						77	15	100	92	79	94
78	0	87	9	N/D	N/D
						79	0	100	31	57	94
80	0	87	7	N/D	N/D
						81	0	54	16	N/D	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						82	0	46	9	N/D	N/D
83	0	99	12	26	N/D
						84	0	99	12	32	44
85	N/D	99	79	100	98
						87	N/D	99	42	21	N/D
88	N/D	100	98	100	96
						90	N/D	99	22	18	N/D
91	N/D	99	93	87	97
						92	N/D	99	98	17	N/D
94	N/D	99	14	28	N/D
						95	8	98	40	N/D	N/D
96	3	99	33	75	89
						97	5	99	99	67	84
98	0	26	7	N/D	N/D
						99	9	63	12	N/D	N/D
100	9	99	10	N/D	N/D
						101	91	99	85	85	91
102	0	83	14	N/D	N/D
						103	14	60	8	N/D	N/D
104	10	99	18	47	63
						105	8	99	22	49	70
106	0	99	2	N/D	N/D
						107	0	67	8	N/D	N/D
108	40	99	100	100	98
						109	75	100	53	81	90
110	8	85	16	N/D	N/D
						111	2	25	15	N/D	N/D
112	5	28	0	N/D	N/D
						113	17	97	7	19	N/D
114	15	100	92	36	N/D
						115	18	99	88	21	N/D
116	18	100	100	10	N/D
						117	0	100	96	61	88
118	49	100	95	83	69
						119	32	99	18	13	N/D
120	0	75	5	N/D	N/D
						121	30	100	9	17	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						122	0	100	53	19	N/D
123	2	99	15	0	N/D
						124	0	99	32	51	94
125	0	100	35	44	45
						126	99	68	83	N/D	N/D
127	20	100	81	95	95
						128	83	100	90	95	95
129	34	99	92	94	92
						130	25	99	87	72	85
131	55	99	96	100	98
						132	58	99	98	100	98
133	3	99	53	45	92
						134	0	98	98	93	93
135	20	100	68	96	91
						136	84	100	88	100	97
137	98	100	45	100	98
						138	93	99	93	100	88
139	0	100	21	48	94
						140	0	100	92	52	90
141	0	100	1	22	N/D
						142	97	99	98	100	88
143	4	99	33	97	91
						144	100	99	100	100	N/D
145	25	99	34	100	98
						146	3	99	5	56	86
147	0	98	90	90	97
						148	100	99	99	100	98
149	0	99	4	67	92
						150	1	99	34	49	87
151	0	99	5	26	N/D
						152	82	99	100	100	98
153	91	97	0	63	N/D
						154	18	99	17	48	93
155	8	87	0	N/D	N/D
						156	41	100	27	63	16
157	20	100	20	100	99
						158	2	99	11	1	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						159	1	99	12	17	N/D
160	18	99	13	30	N/D
						161	94	100	0	38	N/D

The activity of table 6. table 3 compound

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						1	7	100	36	34	N/D
2	18	100	64	N/D	N/D
						3	0	100	14	89	72
4	14	99	0	15	N/D
						5	29	100	0	76	79
6	29	100	61	65	74
						7	9	100	12	35	N/D
8	31	95	99	0	N/D
						9	84	100	14	2	N/D
10	9	67	0	N/D	N/D
						11	60	100	0	69	92
12	1	95	0	N/D	N/D
						13	0	93	9	N/D	N/D
14	0	96	3	N/D	N/D
						15	7	99	15	4	N/D
16	9	99	12	30	N/D
						17	12	99	19	23	N/D
18	23	99	80	22	N/D
						19	0	96	8	23	N/D
20	0	76	0	N/D	N/D
						21	7	100	64	11	N/D
22	21	100	6	36	N/D
						23	20	57	48	34	N/D
24	8	100	40	65	80
						25	33	99	65	13	N/D
26	8	100	18	37	N/D
						27	13	100	38	71	95
28	6	100	20	53	83
						29	12	100	64	48	72
30	12	100	25	28	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						31	20	100	50	57	84
32	11	100	45	65	93
						33	2	100	18	54	66
34	0	100	21	43	62
						35	24	100	59	56	57
36	24	100	73	85	80
						37	0	55	19	N/D	N/D
38	21	99	99	N/D	N/D
						39	5	100	60	76	61
40	18	100	92	90	92
						41	0	94	52	N/D	N/D
42	6	100	4	44	87
						43	18	100	8	100	98
44	98	100	87	100	99
						45	11	99	35	58	66
46	30	55	46	N/D	N/D
						47	4	100	0	55	83
48	16	99	14	26
						49	12	100	21	33	77
50	14	99	13	18	N/D
						51	0	95	10	N/D	N/D
52	47	100	61	47	N/D
						53	96	100	100	100	N/D
54	65	100	40	39	N/D
						55	46	100	40	42	53
56	8	96	20	13	N/D
						57	19	95	38	N/D	N/D
58	93	100	96	100	N/D
						59	0	98	12	5	28
60	4	69	0	N/D	N/D
						61	12	95	3	N/D	N/D
62	0	99	14	3	56
						63	7	100	1	28	44
64	0	100	1	16	49
						65	0	87	1	N/D	N/D
66	0	89	13	N/D	N/D
						67	0	55	7	N/D	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						68	0	96	17	19	54
69	0	90	6	N/D	N/D
						70	5	94	16	N/D	N/D
71	1	75	13	N/D	N/D
						72	0	95	8	N/D	N/D
73	5	96	13	N/D	N/D
						74	4	79	3	N/D	N/D
75	2	76	11	N/D	N/D
						76	0	64	5	N/D	N/D
77	2	88	7	N/D	N/D
						78	8	88	11	N/D	N/D
79	0	99	6	22	34
						80	14	99	0	8	19
81	6	100	71	9	18
						82	0	100	31	50	92
83	3	100	8	28	62
						84	14	100	45	80	90
85	0	99	8	24	46
						86	32	63	15	N/D	N/D
87	5	99	30	20	6
						88	1	67	12	N/D	N/D
89	2	100	15	15	65
						90	42	100	64	97	96
91	83	100	86	100	96
						92	25	100	97	100	97
93	0	100	12	23	47
						94	9	100	90	17	38
95	2	100	0	60	65
						96	0	70	29	N/D	N/D
97	0	100	7	50	59
						98	0	60	6	N/D	N/D
99	0	86	0	N/D	N/D
						100	6	81	0	N/D	N/D
101	0	99	5	20	N/D
						102	9	100	0	75	88
103	7	95	0	N/D	N/D
						104	0	86	0	N/D	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						105	6	100	7	31	N/D
107	99	100	19	100	96
						108	4	100	10	70	94
109	16	100	13	67	N/D
						110	0	98	0	34	N/D
111	71	100	76	100	98
						112	5	100	8	46	90
113	0	97	6	14	N/D
						114	0	100	4	86	97
115	55	100	18	97	82
						116	0	100	21	41	N/D
117	48	100	70	63	92
						118	25	100	18	71	67
119	0	94	1	N/D	N/D
						120	0	65	0	N/D	N/D
121	0	61	4	N/D	N/D
						122	0	67	0	N/D	N/D
123	0	62	1	N/D	N/D
						124	10	99	0	18	N/D
125	9	99	2	17	N/D
						126	83	100	36	100	97
127	0	95	0	N/D	N/D
						128	20	100	29	82	88
129	99	100	99	N/D	N/D
						130	70	100	90	79	N/D
131	23	100	35	98	96
						132	30	80	18	N/D	N/D
133	14	67	19	N/D	N/D
						134	13	53	11	N/D	N/D
135	11	75	21	N/D	N/D
						136	0	86	3	N/D	N/D
137	2	71	8	N/D	N/D
						138	37	100	100	105	N/D
139	19	100	24	46	88
						140	100	100	27	25	N/D
141	80	100	100	100	99
						142	84	100	100	97	96

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						143	22	100	63	80	90
144	12	100	38	41	N/D
						145	33	100	39	58	86
146	8	100	24	32	N/D
						147	100	100	93	100	97
148	2	96	23	1	N/D
						149	21	100	29	48	N/D
150	2	100	24	22	N/D
						151	38	100	46	43	N/D
152	21	97	25	13	N/D
						153	23	97	17	15	N/D
154	95	100	96	86	83
						155	18	99	34	0	N/D
156	3	100	36	33	N/D
						157	17	100	43	42	N/D
158	1	99	27	0	N/D
						159	23	100	29	98	96
160	19	100	95	30	N/D
						161	26	54	20	N/D	N/D
162	30	100	20	100	99
						163	39	100	32	100	99
164	87	100	79	100	100
						165	83	100	83	100	98
166	0	100	13	49	78
						167	0	100	16	24	N/D
168	43	100	40	100	99
						169	0	75	12	N/D	N/D
170	23	100	28	100	96
						171	18	100	25	96	95
172	18	100	22	100	97
						173	8	100	18	52	81
174	3	86	18	N/D	N/D
						175	1	100	11	17	N/D
176	0	63	12	N/D	N/D
						177	0	67	15	N/D	N/D
178	-3	82	17	N/D	N/D
						179	16	98	10	27	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						180	12	100	23	96	93
181	17	72	27	N/D	N/D
						182	4	100	16	100	98
183	99	100	100	100	98
						184	84	100	45	100	95
185	29	100	32	100	94
						186	14	100	13	100	99
187	25	100	32	100	98
						188	35	100	55	38	N/D
189	23	100	31	26	N/D
						190	19	98	22	5	N/D
191	15	45	19	N/D	N/D
						192	22	99	56	14	N/D
193	15	95	27	0	N/D
						194	16	77	20	N/D	N/D
195	25	81	90	N/D	N/D
						196	23	100	29	100	98
197	89	100	93	100	98
						198	39	100	48	100	94
199	81	100	61	100	97
						200	19	100	29	69	83
201	22	52	17	N/D	N/D
						202	19	100	32	17	N/D
203	15	98	22	20	N/D
						204	74	100	92	85	N/D
205	39	100	24	96	93
						206	98	100	100	100	N/D
207	72	100	36	100	98
						208	80	100	99	83	N/D
209	1	100	17	36	N/D
						210	26	100	19	26	N/D
211	50	100	85	23	N/D
						212	28	100	37	97	94
213	0	100	30	34	N/D
						214	13	100	30	60	76
215	80	100	100	86	N/D
						216	45	100	59	98	93

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						217	23	99	16	0	N/D
218	23	100	28	16	N/D
						219	85	100	97	53	N/D
220	65	100	48	84	91
						221	88	100	97	52	N/D
222	69	100	52	91	68
						223	28	100	54	100	97
224	0	100	26	33	N/D
						225	0	90	21	N/D	N/D
226	0	80	20	N/D	N/D
						227	47	100	100	65	N/D
228	26	100	70	32	N/D
						229	30	100	21	80	92
230	14	100	6	58	65
						231	49	100	9	100	99
232	64	100	34	100	99
						233	84	100	85	59	N/D
234	56	100	64	78	N/D
						235	81	100	100	100	N/D
236	97	100	100	100	N/D
						237	13	100	24	100	94
238	90	100	100	100	N/D
						239	25	100	100	90	N/D
240	16	100	21	66	71
						241	23	100	25	51	65
242	35	100	97	51	N/D
						243	69	100	100	76	N/D
244	35	100	25	67	85
						245	21	100	16	53	81
246	82	100	100	100	N/D
						247	80	100	100	100	N/D
248	41	100	33	51	39
						249	0	100	69	100	N/D
250	0	97	98	20	N/D
						251	28	100	56	80	74
252	6	100	100	81	N/D
						253	6	100	100	86	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						254	0	100	98	100	N/D
255	8	100	92	69	N/D
						256	3	100	71	87	87
257	11	100	100	100	N/D
						258	62	100	44	100	99
259	6	100	24	100	98
						260	0	100	25	100	98
261	30	100	25	100	98
						262	3	100	20	46	48
263	0	99	12	22	24
						264	4	97	25	3	N/D
265	12	100	9	32	N/D
						266	21	100	18	100	94
267	26	100	16	100	96
						268	29	100	25	84	87
269	13	100	18	75	85
						270	11	98	21	50	74
271	24	98	46	54	55
						272	7	98	24	38	N/D
273	14	100	41	95	88
						274	12	100	28	76	82
275	16	100	45	89	94
						276	26	100	39	100	97
277	5	100	26	24	N/D
						278	12	100	38	82	75
279	7	100	30	60	59
						280	22	100	11	100	65
281	36	100	22	100	96
						282	7	99	23	22	N/D
283	20	99	38	0	N/D
						284	53	100	61	100	N/D
285	8	99	33	0	N/D
						286	0	100	23	71	94
287	20	100	57	35	N/D
						288	24	100	78	70	N/D
289	2	99	28	0	N/D
						290	15	100	10	2	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						291	0	48	4	N/D	N/D
292	0	95	3	N/D	N/D
						293	0	100	22	67	82
294	0	87	1	N/D	N/D
						295	0	85	5	N/D	N/D
296	9	97	1	N/D	N/D
						297	9	98	0	42	90
298	0	98	13	41	N/D
						299	57	100	32	94	95
300	0	99	2	14	N/D
						301	7	55	0	N/D	N/D
302	0	68	20	N/D	N/D
						303	12	74	24	N/D	N/D
304	18	100	9	23	N/D
						305	7	87	15	N/D	N/D
306	0	99	6	48	N/D
						307	6	90	15	N/D	N/D
308	27	100	51	54	81
						309	13	74	6	N/D	N/D
310	13	15	13	N/D	N/D
						311	88	93	22	N/D	N/D
312	14	76	0	N/D	N/D
						313	2	52	23	N/D	N/D
314	12	99	13	20	N/D
						315	0	98	17	27	N/D
316	12	99	8	41	98
						317	12	100	70	50	95
318	13	100	47	24	78
						319	24	100	93	61	91
320	20	100	16	25	N/D
						321	41	100	52	82	97
322	11	99	18	21	N/D
						323	24	100	25	100	98
324	19	99	21	15	N/D
						325	43	100	27	66	N/D
326	7	65	44	33	81
						327	0	47	6	N/D	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						328	0	100	14	63	80
329	17	100	59	84	92
						330	8	99	41	58	50
331	10	100	41	68	79
						332	10	48	38	N/D	N/D
333	6	86	21	N/D	N/D
						334	15	100	20	67	71
335	0	100	21	57	50
						336	14	94	23	17	N/D
337	0	95	14	19	N/D
						338	52	100	51	44	N/D
339	69	100	66	66	84
						340	98	100	100	100	96
341	88	100	99	99	96
						342	61	100	84	75	87
343	28	100	59	57	N/D
						344	65	100	45	100	95
345	13	100	19	97	93
						346	0	100	13	67	84
347	58	100	37	100	99
						348	55	100	47	100	90
349	73	100	77	100	N/D
						350	91	100	100	100	N/D
351	79	100	98	100	N/D
						352	74	100	45	100	97
353	100	100	100	100	N/D
						354	98	100	100	100	N/D
355	27	100	27	100	99
						356	99	100	100	100	N/D
357	44	100	91	100	N/D
						358	99	100	100	100	N/D
359	19	100	31	95	93
						360	16	100	29	100	98
361	75	100	100	N/D	N/D
						362	92	100	99	100	100
363	99	100	100	N/D	N/D
						364	100	100	100	N/D	N/D

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						365	79	100	100	100	97
366	26	100	94	100	98
						367	7	100	13	81	89
368	8	100	24	12	N/D
						369	12	100	26	44	N/D
370	34	100	64	60	81
						371	9	100	29	69	79
372	8	100	21	75	88
						373	0	101	51	100	91
374	41	99	98	3	N/D
						375	38	100	97	19	N/D
376	28	100	72	87	77
						377	49	100	75	93	N/D
378	43	100	62	90	87
						379	36	77	16	N/D	N/D
380	49	100	53	79	94
						381	20	100	30	100	99

The activity of table 7. table 4 compound

Cmpd	PDGFRβ	CSF-1R	cKit	M-NFS-60CP	pCSF1R
						1	13	100	73	50	47
2	8	80	14	N/D	N/D
						3	1	100	15	67	85
4	0	100	29	92	94
						5	8	100	18	91	92
6	26	100	26	100	99
						7	5	100	23	54	N/D
8	35	100	25	100	98
						9	45	100	15	100	98
10	9	100	6	76	83
						11	4	100	8	38	N/D
12	6	100	14	100	95
						13	45	100	73	N/D	N/D
14	85	100	71	N/D	N/D
						15	60	100	59	100	99
16	59	100	41	100	100

17	72	100	61	100	100
						18	28	100	45	100	100
19	19	100	33	100	100
						20	12	100	30	100	99
21	22	100	32	N/D	N/D
						22	90	100	89	N/D	N/D
23	0	100	29	7	N/D
						24	0	100	26	100	100
25	1	100	33	100	86
						26	0	100	29	33	N/D
27	0	100	67	N/D	N/D
						28	0	100	98	N/D	N/D
2g	0	100	65	73	90
						30	0	100	18	73	93
31	0	96	26	N/D	N/D
						32	0	100	71	N/D	N/D
33	0	100	65	100	98
						34	1	100	90	N/D	N/D
35	90	100	46	100	98
						36	26	100	45	5	N/D
37	24	100	88	N/D	N/D
						38	16	100	27	100	99
39	9	100	98	N/D	N/D
						40	0	100	27	83	96
41	19	100	66	100	97
						42	28	100	28	100	99
43	0	95	14	N/D	N/D
						44	24	100	45	94	53
45	44	100	53	100	99
						46	42	100	24	100	99
47	31	100	55	58	79
						4B	98	100	79	100	100
49	1	100	11	100	99
						50	14	100	10	100	99
51	78	100	36	100	100
						52	42	100	27	100	100
53	14	100	12	100	99
						54	1	100	11	100	99

55	2	100	11	100	95
						56	11	100	13	100	99
57	11	100	15	100	99
						58	0	100	11	100	95
59	27	100	25	100	99
						60	0	100	9	100	99
61	23	100	3	100	98
						62	27	100	5	97	97
63	21	100	10	100	99
						64	16	100	7	91	96
65	21	100	6	100	98
						66	28	100	12	100	99
67	42	100	97	100	98
						68	100	100	57	100	99
69	28	100	12	100	99
						70	86	100	26	100	100
71	25	100	5	73	95
						72	20	100	6	65	95
73	20	100	3	56	96
						74	22	100	0	60	97
75	10	99	0	0	N/D
						76	15	100	8	95	96
77	25	100	6	100	99
						78	71	100	7	100	100
79	28	100	2	99	99
						80	25	100	0	46	N/D
81	18	100	4	87	97
						82	24	100	2	92	99
83	36	100	7	100	99
						84	30	100	11	100	97
85	53	100	13	100	53
						86	25	99	22	85	60
87	N/D	100	19	N/D	N/D
						88	N/D	100	14	N/D	N/D
89	N/D	100	18	N/D	N/D
						90	N/D	100	18	N/D	N/D
91	N/D	100	17	N/D	N/D
						92	N/D	100	15	N/D	N/D

93	N/D	99	5	N/D	N/D
						94	N/D	100	12	N/D	N/D
95	N/D	100	42	N/D	N/D
						96	N/D	100	7	N/D	N/D
97	N/D	100	14	N/D	N/D
						98	N/D	100	8	N/D	N/D
99	N/D	100	0	N/D	N/D
						100	N/D	100	5	N/D	N/D
101	N/D	100	10	N/D	N/D
						102	N/D	100	18	N/D	N/D
103	N/D	N/D	N/D	N/D	N/D
						104	N/D	100	4	N/D	N/D
105	N/D	100	10	N/D	N/D
						106	N/D	100	17	N/D	N/D
107	N/D	N/D	N/D	N/D	N/D
						108	N/D	N/D	N/D	N/D	N/D
109	N/D	N/D	N/D	N/D	N/D
						110	N/D	N/D	N/D	N/D	N/D
111	N/D	N/D	N/D	N/D	N/D
						112	N/D	100	11	N/D	N/D
113	N/D	92	10	N/D	N/D
						114	N/D	100	6	N/D	N/D
115	N/D	95	12	N/D	N/D
						116	N/D	100	13	N/D	N/D
117	N/D	100	11	N/D	N/D
						118	N/D	100	11	N/D	N/D
119	N/D	95	16	N/D	N/D

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Claims

1. the compound or pharmaceutically acceptable salt thereof of formula (I):

Wherein X is O or S;

R ¹be

Wherein dotted line is saturated bond;

Wherein L is covalent linkage; And

R ¹⁰, R ¹¹and R ¹²independently selected from hydrogen, halogen, hydroxyl, C _1-6alkyl, there is the C of 1 to 2 substituent replacement _1-6alkyl, C _1-6the amino of alkoxyl group, amino, replacement, C _3-10cycloalkyl, there is the C of 1 to 2 substituent replacement _3-10cycloalkyl, aryl and there is the aryl of 1 to 2 substituent replacement; Or R ¹¹with R ¹²the aryl that connects together and form aryl or there is 1 to 2 substituent replacement;

R ²hydrogen or C _1-6alkyl;

R ³be selected from halogen, there is the C of 1 to 2 substituent replacement _1-6alkyl, C _2-6alkynyl, formonitrile HCN, C _3-10cycloalkyl, there is the C of 1 to 2 substituent replacement _3-10cycloalkyl, C _4-10amino, carboxyl and the aminocarboxyl of cycloalkenyl group, heteroaryl, heteroaryl, heterocyclic radical with 1 to 2 substituent replacement, the heterocyclic radical with 1 to 2 substituent replacement, amino, replacement;

Each R ⁶c independently _1-6alkyl or halogen;

N is 0 or 1; And

When X is O, R ⁴hydrogen and R ⁵hydrogen, or R ⁴and R ⁵the aryl that connects together and form aryl or there is 1 to 2 substituent replacement; And

When X is S, R ⁴hydrogen and R ⁵hydrogen, aminocarboxyl, halogen, heteroaryl or the heteroaryl with 1 to 2 substituent replacement, wherein

" alkyl " refers to the unit price radical of saturated aliphatic alkyl with 1 to 6 carbon atom;

" alkyl of replacement " refers to have and is selected from following substituent alkyl: alkoxyl group, acyl group, amino, carboxyl, cyano group, halogen, hydroxyl, mercaptan and alkylthio;

" alkoxyl group " refers to group-O-alkyl;

" acyl group " refer to group H-C (O)-, alkyl-C (O)-, alkenyl-C (O)-and alkynyl-C (O)-;

" acyl amino " refers to group-NR ²⁰c (O) alkyl ,-NR ²⁰c (O) cycloalkyl ,-NR ²⁰c (O) cycloalkenyl group ,-NR ²⁰c (O) alkenyl and-NR ²⁰c (O) alkynyl, wherein R ²⁰it is hydrogen or alkyl;

" acyloxy " refers to group alkyl-C (O) O-, alkenyl-C (O) O-and alkynyl-C (O) O-;

" amino of replacement " refers to group-NR ²¹r ²², R wherein ²¹and R ²²independently selected from hydrogen, alkyl and-SO ₂-alkyl, condition is R ²¹and R ²²not all hydrogen;

" aminocarboxyl " refers to group-C (O) NR ²³r ²⁴, R wherein ²³and R ²⁴independently selected from hydrogen, alkyl, alkenyl, alkynyl, and R wherein ²³and R ²⁴form heterocyclic radical together with the nitrogen optionally connected with them;

" aryl " refers to the unit price aromatic carbocyclic group of 6 to 14 carbon atoms with single ring or a plurality of rings that condense, what described condensed ring can the yes or no aromaticity, condition is that tie point is on aromatic carbon atom;

" aryl of replacement " refers to and is selected from the following aryl that substituting group replaced: the amino of alkoxyl group, acyl group, acyl amino, acyloxy, amino, replacement, aminocarboxyl, carboxyl, carboxyl ester, cyano group, halogen, hydroxyl, mercaptan and alkylthio;

" alkenyl " refers to the alkenyl that has 2 to 6 carbon atoms and have at least 1 unsaturated position of vinyl (>C=C<);

" alkynyl " refers to the alkyl that has 2 to 6 carbon atoms and have at least 1 unsaturated position of acetylene series (C ≡ C-);

" carboxyl ester " refer to group-C (O) O-alkyl ,-C (O) O-alkenyl and-C (O) O-alkynyl;

" cycloalkyl " refers to have single or multiple rings, comprise cyclic alkyls that condense, bridge joint and 3 to 10 carbon atoms volution system;

" cycloalkenyl group " refer to there are single or multiple cyclic rings and have at least one>the non-aromatic cyclic alkyl with 4 to 10 carbon atoms of the unsaturated position of C=C<encircle;

" cycloalkyl of replacement " refers to have and is selected from following substituent cycloalkyl: the amino of alkoxyl group, acyl group, acyl amino, acyloxy, amino, replacement, aminocarboxyl, carboxyl, carboxyl ester, cyano group, halogen, hydroxyl, mercaptan and alkylthio;

" haloalkyl " refers to the alkyl replaced by 1 to 5 halogen group;

" heteroaryl " refers in ring to have 1 to 10 carbon atom and 1 to 4 heteroatomic aromatic group that is selected from oxygen, nitrogen and sulphur, described heteroaryl has single ring or a plurality of ring condensed, the ring wherein condensed can the yes or no aromaticity and/or containing or do not conform to heteroatoms, condition is the former sub-connection by the aromatics heteroaryl;

" heteroaryl of replacement " refers to and is selected from and the defined identical heteroaryl that substituting group replaced of the aryl replaced;

" heterocyclic radical " refer in ring there is single ring or a plurality of ring condensed, comprise condense bridge joint with the volution system there is heteroatomic saturated, fractional saturation that 1 to 10 carbon atom and 1 to 4 is selected from nitrogen, sulphur or oxygen or unsaturated but be not the group of aromaticity, wherein in the condensed ring system, one or more rings can be cycloalkyl, aryl or heteroaryl, and condition is to connect by non-aromatic ring;

" heterocyclic radical of replacement " refers to and is selected from and the defined identical heterocyclic radical that substituting group replaced of the cycloalkyl replaced; And

" alkylthio " refers to group-S-alkyl.

2. the compound of claim 1, wherein X is O.

3. the compound of claim 1, wherein X is S.

4. the compound of claim 1, wherein R ²hydrogen or methyl.

5. the compound of claim 1, wherein R ¹⁰, R ¹¹and R ¹²independently selected from hydrogen, halogen, hydroxyl, C _1-6alkyl, there is the C of 1 to 2 substituent replacement _1-6alkyl and C _1-6alkoxyl group.

6. the compound of claim 1, wherein R ¹⁰, R ¹¹and R ¹²in at least one be hydroxyl.

7. the compound of claim 1, wherein R ¹¹with R ¹²the aryl that connects together and form aryl or there is 1 to 2 substituent replacement.

8. the compound of claim 1, wherein R ³it is aminocarboxyl.

9. the compound of claim 8, wherein R ³-C (O) NH-LR ^3a, wherein L is covalent linkage or C _1-6alkylidene group, and R ^3abe selected from C _1-6alkyl, halo C _1-6alkyl, C _1-6alkoxyl group, C _3-10cycloalkyl and the C with 1 to 2 substituent replacement _3-10cycloalkyl,

Wherein " alkylidene group " refers to the divalence radical of saturated aliphatic alkyl with 1 to 6 carbon atom.

10. the compound of claim 9, wherein R ³-C (O) NHCH ₃.

11. the compound of claim 1, wherein R ³be carboxyl, there is the C of 1 to 2 substituent replacement _1-6alkyl, formonitrile HCN, heteroaryl or there is the heteroaryl of 1 to 2 substituent replacement.

12. the compound of claim 1, wherein R ³the C with 1 to 2 substituent replacement _1-6alkyl, heteroaryl or there is the heteroaryl of 1 to 2 substituent replacement.

13. the compound of claim 1, wherein R ³be selected from pyrazol-1-yl, pyrazole-3-yl, pyrazoles-4-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-yl, pyrimidin-3-yl, pyrimidine-2-base, thiazolyl, tetrazyl, imidazoles-1-base, imidazoles-2-base, imidazo-3-yl, pyrazinyl, phenyl, tetrahydropyridine, 1H-pyrrolo-[2,3-b] pyridine, furyl,

azoles,

diazole, wherein each R ³by 1 to 2 substituting group replacement or unsubstituted.

14. the compound of claim 1, wherein R ⁴hydrogen.

15. the compound of claim 1, wherein R ⁵hydrogen.

16. the described compound of any one in claim 1 to 15, wherein n is 0, R ⁴and R ⁵hydrogen, and R ³be selected from halogen, there is the C of 1 to 2 substituent replacement _1-6alkyl, formonitrile HCN, heteroaryl, there is heteroaryl, carboxyl and the aminocarboxyl of 1 to 2 substituent replacement.

17. the compound of claim 1, wherein R ⁴and R ⁵the aryl that connects together and form aryl or there is 1 to 2 substituent replacement.

18. there is formula (IIa) or compound or pharmaceutically acceptable salt thereof claimed in claim 1 (IIb):

Wherein X is O or S;

Dotted line is saturated bond;

L is covalent linkage;

R ¹⁰, R ¹¹and R ¹²independently selected from hydrogen, halogen, hydroxyl, C _1-6alkyl and the C with 1 to 2 substituent replacement _1-6alkyl; And

R ³be selected from halogen, there is the C of 1 to 2 substituent replacement _1-6alkyl, formonitrile HCN, heteroaryl, there is heteroaryl, carboxyl and the aminocarboxyl of 1 to 2 substituent replacement.

19. the compound of claim 18, wherein X is O.

20. the compound of claim 18, wherein X is S.

21. the compound of claim 18, wherein R ¹⁰, R ¹¹and R ¹²independently selected from hydrogen, halogen, hydroxyl and C _1-6alkyl.

22. the compound of claim 18, wherein R ³it is aminocarboxyl.

23. the compound of claim 22, wherein R ³-C (O) NHCH ₃.

24. the compound of claim 18, wherein R ³formonitrile HCN, heteroaryl or the heteroaryl with 1 to 2 substituent replacement.

25. there is the compound or pharmaceutically acceptable salt thereof claimed in claim 1 of formula (IIIb):

Wherein X is O or S;

R ¹as claim 1 is defined; And

R ³be selected from amino, carboxyl and the aminocarboxyl of replacement.

26. the compound of claim 25, wherein X is O.

27. the compound of claim 25, wherein X is S.

28. the compound of claim 25, wherein R ³it is aminocarboxyl.

29. the compound of claim 28, wherein R ³-C (O) NHCH ₃.

30. the compound or pharmaceutically acceptable salt thereof of formula (IV):

Wherein X is O or S;

R ⁷independently selected from C _1-6alkoxyl group, halo C _1-6alkoxyl group, halogen and formonitrile HCN;

P is 0,1 or 2;

R ¹be-LR ⁸;

L is covalent linkage; And

R ⁸be selected from C _3-10cycloalkyl, there is the C of 1 to 5 substituent replacement _3-10cycloalkyl, THP trtrahydropyranyl and morpholino,

Wherein the substituting group of " cycloalkyl of replacement " is selected from amino, aminocarboxyl, carboxyl, carboxyl ester, cyano group, halogen, hydroxyl, mercaptan and the alkylthio of alkoxyl group, acyl group, acyl amino, acyloxy, amino, replacement, wherein

" alkoxyl group " refers to group-O-alkyl;

" heteroaryl " refers in ring to have 1 to 10 carbon atom and 1 to 4 heteroatomic aromatic group that is selected from oxygen, nitrogen and sulphur, described heteroaryl has single ring or a plurality of ring condensed, the ring wherein condensed can the yes or no aromaticity and/or containing or containing heteroatoms, condition is the former sub-connection by the aromatics heteroaryl;

" alkylthio " refers to group-S-alkyl.

31. the compound of claim 30, wherein X is S.

32. claim 1,25 or 30 described compounds, this compound is selected from:

4-[2-(3-methyl-cyclohexyl base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S, 3S, 5R)-2,6,6-trimethyl-bis-ring [3.1.1] heptan-3-base amino)-benzo azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-(2-cyclobutyl amino-benzo

azoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea, 4-(2-cyclopenta amino-benzo

azoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea, 4-(2-cyclohexyl amino-benzo

azoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea, N-[4-(2-cyclohexyl amino-benzo

azoles-6-base oxygen base)-pyridine-2-yl]-acetamide, 4-[2-(tetrahydrochysene-pyrans-4-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2R)-2-hydroxyl-dihydroindene-1-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1R, 2S)-2-hydroxyl-dihydroindene-1-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(hexamethylene-3-alkenyl amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(1-benzyl-piperidin-4-yl-amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(1,2,3,4-tetrahydrochysene-naphthalene-1-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(1-phenyl-piperidines-4-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-(2-cyclohexyl amino-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea, 4-[2-(3-methyl-cyclohexyl base amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1R, 2R)-2-benzyloxy-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S)-2-benzyloxy-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1R, 2R)-2-hydroxyl-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d]

azoles-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N, N-lutidines formamide, N-cyclopropyl-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-(tetrahydrochysene-2H-pyrans-4-yl) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-(1-methyl piperidine-4-yl) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-(1-methyl piperidine-3-yl) pyridine carboxamide, N-(2-acetylamino ethyl)-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-(2-(pyrrolidin-1-yl) ethyl) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-((oxolane-2-yl) methyl) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-((tetrahydrochysene-2H-pyrans-4-yl) methyl) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-((1-methyl piperidine-4-yl) methyl) pyridine carboxamide, N-(((S)-1-ethyl pyrrolidine-2-yl) methyl)-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, N-ethyl-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-(2, 2, the 2-trifluoroethyl) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-propyl group pyridine carboxamide, N-(cyclopropyl methyl)-4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-isopropyl pyridine formamide, N-methyl-4-(2-(tetrahydrochysene-2H-pyrans-4-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-(1-ethyl piperidine-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-(cyclohexyl (methyl) amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (2-(4 for 4-, 4-difluoro cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (R)-N-methyl-4-(2-(6-oxo-piperidine-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, (S)-N-methyl-4-(2-(6-oxo-piperidine-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, (R) (2-(1 for-N-methyl-4-, 2, 3, 4-naphthane-1-base amino) benzo] d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-(suberyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (S) (2-(1 for-N-methyl-4-, 2, 3, 4-naphthane-1-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, N-methyl-4-(2-(2-oxo azepan-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-(connection (cyclohexane)-2-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1s, 4s)-4-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1s, 4s)-4-acetylamino cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1r, 4r)-4-acetylamino cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (R)-4-(2-(4-(2-amino-3-hydroxypropyl)-1H-imidazoles-1-yl) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (S)-4-(2-(4-(2-amino-3-hydroxypropyl)-1H-imidazoles-1-yl) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1r, 4r)-4-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R, 4S)-bis-ring [2.2.1] heptane-2-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-(ring octyl group amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1s, 4s)-4-isobutyryl aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, N-methyl-4-(2-((1s, 4s)-4-(3-methylbutyryl amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, N-methyl-4-(2-((1S, 4s)-4-((R)-2-TETRAHYDROFUROYL amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1s, 4s)-4-benzamido cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, N-methyl-4-(2-((1R, 4s)-4-((S)-2-TETRAHYDROFUROYL amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, N-methyl-4-(2-((1R, 4s)-4-((S)-1-methylpyrrolidin-2-formamido group) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1S, 4R)-bis-ring [2.2.1] heptane-2-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2S)-2-hydroxyl-1, 2, 3, 4-naphthane-1-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(pyrazine-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(thiazole-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-imidazoles-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(thiazole-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(thiazol-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, ((2-(1 for 6-for 2R)-2-, 2, 3, 6-tetrahydropyridine-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(5-ethyl-4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-(4-methylpiperazine-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-morpholine-4-base-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(3-(morpholine-4-ylmethyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-cyclohexenyl group pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(4-(morpholine-4-ylmethyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-cyclopropyl pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-methoxyl group-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (6-(2 '-fluoro-2 for 2R)-2-, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(3 '-fluoro-2 '-morpholine-4-base-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (6-(6 '-fluoro-2 for 2R)-2-, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(piperidin-1-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-morpholine-4-yl pyridines-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(4-methylpiperazine-1-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, N-((R)-1-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) pyrrolidin-3-yl) acetamide, N-((S)-1-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) pyrrolidin-3-yl) acetamide, (1R, (6-(2 for 2R)-2-, 2 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-(2-morpholine-4-base ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-ethyl-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-(2-(diethylamino) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (((1-(2 for 2-for 6-for 2R)-2-, 2-bis-fluoro ethyls)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(2-morpholine-4-yl pyrimidines-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(4-(4-methylpiperazine-1-yl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(4-(trifluoromethyl)-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-picoline-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 4-(2-((1R, 6S)-6-carbamoyl hexamethylene-3-alkenyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 6R)-6-carbamoyl hexamethylene-3-alkenyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carbonitrile, (1R, 2R)-2-(6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, ((2-(4 for 6-for 2R)-2-, 5-dimethyl-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, ((2-(4 for 6-for 2R)-2-, 5, 6, 7-tetrahydrochysene-1H-benzo [d] imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-(2-fluoro ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-(2-methoxy ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (6-(6 '-amino-2 for 2R)-2-, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1H-imidazoles-1-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, ((2-(4 for 6-for 2R)-2-, 5-diethyl-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(5-methyl-4-propyl group-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (6-(2 for 2R)-2-, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-propyl group-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-amino-5 '-(trifluoromethyl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, ((2-(1 for 6-for 2R)-2-, 3, 5-trimethyl-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1H-pyrrolo-[2, 3-b] pyridine-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(pyrimidine-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(2-(dimethylamino) pyrimidine-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-2, 3 '-bipyridyl-6 '-formonitrile HCN, (1R, 2R)-2-(6-(2-(4-fluorophenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 4-(2-((1S, 2R)-2-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-(3-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-(3-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1S, 2R)-2-acetylamino cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-(3-acetylamino cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R)-2-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R)-2-acetylamino cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R)-2-(hydroxymethyl) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, N-methyl-4-(2-((1S, 2R)-2-(sulfonyloxy methyl amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1S, 2R)-2-(3-isopropyl urea groups) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (R)-4-(2-(1-acetyl group piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (R)-4-(2-(1-acetyl-pyrrolidine-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (S)-4-(2-(1-acetyl group piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (S)-4-(2-(1-acetyl-pyrrolidine-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-(1-acetyl group piperidin-4-yl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-(1-acetyl group piperidin-4-yl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, N-methyl-4-(2-((1S, 2R)-2-((R)-2-TETRAHYDROFUROYL amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1S, 2R)-2-isobutyryl aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, N-methyl-4-(2-((1S, 2R)-2-(3-methylbutyryl amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1S, 2R)-2-benzamido cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, N-methyl-4-(2-((1S, 2R)-2-((S)-1-methylpyrrolidin-2-formamido group) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, N-methyl-4-(2-((1S, 2S)-2-phenycyclopropyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1S, 2S)-2-hydroxycyclopent base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1S, 2R)-2-hydroxyl-2, 3-dihydro-1H-indenes-1-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1S, 2R)-2-hydroxycyclopent base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2S)-2-hydroxyl-2, 3-dihydro-1H-indenes-1-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R)-2-hydroxycyclopent base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1S, 3R, 4R)-3-(hydroxymethyl) two ring [2.2.1] heptane-2-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, N-methyl-4-(2-((1R, 2R)-2-(sulfonyloxy methyl amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, 4-(2-((1R, 2R)-2-isobutyryl aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (R) (2-(1 for-N-methyl-4-, 2, 3, 4-naphthane-2-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, N-methyl-4-(2-((1S, 2S)-2-(sulfonyloxy methyl amino) cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, (S)-N-methyl-4-(2-(piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide, (S)-4-(2-(1-(isopropylamino formoxyl) piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (S)-4-(2-(1-isobutyryl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (S)-4-(2-(1-(pentamethylene carbonyl) piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (S)-4-(2-(1-benzoyl piperidines-3-base amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (1R, 2R)-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (6-(2 for 2R)-2-, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(2-aminopyrimidine-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2S)-1-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1S, 2R)-1-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2R)-2-(6-(2-(1-isobutyl group-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (S)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base)-N-(1, 2, 3, 4-naphthane-1-yl) benzo [d] thiazole-2-amine, (R)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base)-N-(1, 2, 3, 4-naphthane-1-yl) benzo [d] thiazole-2-amine, N-suberyl-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine, (S)-6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base)-N-(1, 2, 3, 4-naphthane-2-yl) benzo [d] thiazole-2-amine, (1R, 2R)-2-(6-(2-(methylamino) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(ethylamino) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(furans-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(

azoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 4-(bromo-the 2-((1R of 7-, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-7-methyl benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(chloro-the 2-((1R of 7-, 2R)-2-hydroxy-cyclohexyl amino) benzo] d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-isobutoxy pyridine carboxamide, (1R, 2R)-2-(6-(2 '-morpholine-4-base-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2 '-(4-methylpiperazine-1-yl)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 1-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-2, 4 '-bipyridyl-2 '-yl) piperidines-4-alcohol, (1R, 2R)-2-(6-(2 '-((R)-3-(dimethylamino) pyrrolidin-1-yl)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2 '-((S)-3-(dimethylamino) pyrrolidin-1-yl)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2 '-(4-(dimethylamino) piperidin-1-yl)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2 '-(pyrrolidin-1-yl)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2 '-(4-fluorine piperidin-1-yl)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2 '-(dimethylamino)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 1-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-2, 3 '-bipyridyl-6 '-yl) piperidines-4-alcohol, (1R, 2R)-2-(6-(6 '-((R)-3-(dimethylamino) pyrrolidin-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-((S)-3-(dimethylamino) pyrrolidin-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-(4-(dimethylamino) piperidin-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-(pyrrolidin-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-(4-fluorine piperidin-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-(dimethylamino)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-(piperidin-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(6 '-(4-isopropyl piperazine-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, the fluoro-3-of 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-N, the N-dimethyl benzamide, 3-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-N, the N-dimethyl benzamide, (3-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl) (pyrrolidin-1-yl) ketone, (3-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl) (morpholine-4-yl) ketone, (3-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl) (4-methylpiperazine-1-yl) ketone, (4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-2, 3 '-bipyridyl-5 '-yl) (morpholine-4-yl) ketone, 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-N, the N-dimethyl benzamide, (4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl) (pyrrolidin-1-yl) ketone, (4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl) (morpholine-4-yl) ketone, (4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl) (4-methylpiperazine-1-yl) ketone, 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-N-(2-hydroxyethyl) benzamide, 4-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) benzamide, (1R, 2R)-2-(6-(2-(2-(4-methylpiperazine-1-yl) pyrimidine-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1H-pyrazoles-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 3-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-N-(2-hydroxyethyl) benzamide, (1R, 2R)-2-(6-(2-(4-(4-methyl isophthalic acid H-imidazoles-2-yl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (((4-(4 for 2-for 6-for 2R)-2-, 5-dimethyl-1H-imidazoles-2-yl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(4-(4-(trifluoromethyl)-1H-imidazoles-2-yl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(4-(pyrrolidin-1-yl methyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(4-((4-methylpiperazine-1-yl) methyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-1-oxo-benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, ((1S, 2S)-2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexyl) methyl alcohol, (1R, (6-(2 for 2S)-1-, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, (6-(6 '-amino-2 for 2S)-1-, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(6 '-(4-methylpiperazine-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-bis--hydrogen-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(6 '-morpholine-4-base-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, (6-(2 for 2S)-1-, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(1-propyl group-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(1-(2-morpholine-4-base ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(1-ethyl-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(1-(2-methoxy ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(1-(2-(diethylamino) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (4-(4-(2-((1R, 2S)-2-hydroxyl-2, 3-dihydro-1H-indenes-1-base amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) phenyl) (pyrrolidin-1-yl) ketone, (1R, 2S)-1-(6-(2-(1-(2-fluoro ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, (((1-(2 for 2-for 6-for 2S)-1-, 2-bis-fluoro ethyls)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2 '-(4-methylpiperazine-1-yl)-2, 4 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(6 '-((S)-3-(dimethylamino) pyrrolidin-1-yl)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, (6-(5 '-fluoro-2 for 2R)-2-, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(5 '-methoxyl group-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, 5-(4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) pyridine-2 (1H)-one, (1R, 2S)-1-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, 4-(2-((1S, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, 4-(2-((1R, 2S)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline formamide, (1R, 2R)-2-(6-(2-(1-(2-(4-methylpiperazine-1-yl) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-(2-(dimethylamino) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-(2-(pyrrolidin-1-yl) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, 2R)-2-(6-(2-(1-(2-(4-fluorine piperidin-1-yl) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (((1-((1 for 2-for 6-for 2R)-2-, 3-dioxolane-2-yl) methyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, (1R, (6-(6 '-fluoro-2 for 2S)-1-, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(6 '-(dimethylamino)-2, 3 '-bipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, ((2-(4 for 6-for 2S)-1-, 5-dimethyl-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(5-ethyl-4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, ((2-(4 for 6-for 2S)-1-, 5, 6, 7-tetrahydrochysene-1H-benzo [d] imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol, (1R, 2S)-1-(6-(2-(4-(trifluoromethyl)-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino)-2, 3-dihydro-1H-indenes-2-alcohol and (1R, 2R)-2-(6-(2-ethynyl pyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) cyclohexanol, or its officinal salt.

33. the compound of claim 2, this compound is selected from: 4-[2-(3-methyl-cyclohexyl base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S, 3S, 5R)-2,6,6-trimethylammonium-bis-ring [3.1.1] heptan-3-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, [4-(2-cyclobutyl amino-benzo

azoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea, 4-(2-cyclopentyl amino-benzo azoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea, 4-(2-cyclohexyl amino-benzo

azoles-6-base oxygen base)-pyridine-2-yl]-ethanamide, 4-[2-(tetrahydrochysene-pyrans-4-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2R)-2-hydroxyl-indane-1-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1R, 2S)-2-hydroxyl-indane-1-base amino)-benzo azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(hexamethylene-3-alkenyl amino)-benzo azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(1-benzyl-piperidin-4-yl amino)-benzo azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(1,2,3,4-tetrahydrochysene-naphthalene-1-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea and 4-[2-(1-phenyl-piperidines-4-base amino)-benzo

azoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea; Or its pharmacologically acceptable salt.

34. compound claimed in claim 3, this compound is selected from: 4-(2-cyclohexyl amino-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea, 4-[2-(3-methyl-cyclohexyl base amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1R, 2R)-2-hydroxyl-cyclohexyl amino)-benzothiazol-6-yl oxygen base]-pyridine-2-formic acid methyl nitrosourea; Or its pharmacologically acceptable salt.

35. any one the described compound or pharmaceutically acceptable salt thereof in the claims 1 to 34 that comprises significant quantity and the pharmaceutical composition of pharmaceutically acceptable carrier.

36. the described compound of any one in claims 1 to 34 is used for the treatment of the purposes in the medicine of illness of CSF-1R mediation in production.

37. the purposes of claim 36, wherein the illness of CSF-1R mediation is selected from cancer, osteoporosis, sacroiliitis, atherosclerosis and chronic glomerulonephritis.

38. the purposes of claim 36, wherein the illness of CSF-1R mediation is to be selected from following cancer: myelocytic leukemia, idiopathic myelofibrosis, mammary cancer, cervical cancer, ovarian cancer, carcinoma of endometrium, prostate cancer, liver cancer, multiple myeloma, lung cancer, kidney and osteocarcinoma.

39. the purposes of claim 36, wherein the illness of CSF-1R mediation is rheumatoid arthritis.

40. the purposes of claim 36, wherein said composition also comprises other promoting agent that at least one is used for the treatment of the illness of CSF-1R mediation.