CN101432281A - 6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling - Google Patents
6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling Download PDFInfo
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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 cross reference of related application
The application in full introduces the application as a reference at this with both according to the rights and interests that 35 U.S.C. § 119 (e) require U.S. Provisional Application sequence number of applying on April 19th, 2,006 60/793,517 and the sequence number of applying on March 8th, 2,007 60/893,857.
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 and be combined in purposes in prevention or the treatment cancer separately or with at least a other therapeutical agent.
Prior art
CSF-1R is the acceptor of M-CSF (macrophage colony stimulating factor is also referred to as CSF-1) and the biological effect (Sherr1985) that mediates this cytokine.The cloning of colony-stimulating factor-1 acceptor (being also referred to as c-fms) is described in people such as Roussel first, among the Nature 325:549-552 (1987).Show that in this publication CSF-1R has the conversion potential that depends on the terminal afterbody variation of proteic C-, comprises the forfeiture in conjunction with inhibition tyrosine 969 phosphorylations of Cbl, regulates the downward adjusting (Lee 1999) of acceptor thus.
CSF-1R is a kind of strand transmembrane receptor Tyrosylprotein kinase (RTK), and is the member of immunoglobulin (Ig) (Ig) the primitive family that contains RTK, it is characterized in that having multiple Ig structural domain in the extracellular of acceptor part.Intracellular protein tyrosine kinase structural domain is interrupted by a kind of insert structure territory of uniqueness, this insert structure territory also is present among 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 is expressed on the monocytic cell and in female reproductive tract and the placenta.In addition, also reported the youth lattice Chinese cell of CSF-1R, the expression in a kind of subgroup of smooth muscle cell (Inaba 1992), B cell (Baker 1993) and the microglia (Savada 1990) at skin.
The main biological effect of CSF-1R signal conduction is differentiation, propagation, the mobile and survival from monocytic precursor scavenger cell and osteoclast.The activation of CSF-1R is to be mediated by its unique part M-CSF.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 respectively with the p85 subunit of PI3K/AKT and the channel attached PI3K of Ras/MAPK and Grb2 mediation.These two kinds of important signalling channels can be regulated propagation, survival and apoptosis.Can comprise STAT1, STAT3, PLC γ and Cbl (Bourette 2000) 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 (Dai 2002) show and have 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 have the importance of medicine of " cleaner " of the more specific mechanism of action.These medicines can minimize adverse events, have bigger predictability, can give doctor's greater flexibility and can make the researchist understand specific target spot better in therapeutic process.In addition, targeted therapy can be treated the multiple indication that influenced by same signalling channel, has toxicity (BioCentury, V.14 in February, (10) 2006) less and that be easy to control.The inhibition of single kinases such as CSF-1R (it is included in the passage relevant with cancer or other disease) can be regulated the downstream kinases effectively, influences whole passage thus.Yet the avtive spot of 491 human protein kinase structural domains is high conservatives, and this makes that the design of 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, inhibition tumor growth, treatment cancer, adjusting cell cycle to stop and/or particularly suppressing the compound of molecule such as CSF-1R, and need contain the pharmaceutical preparation and the medicine of this compound always.Also need optionally CSF-1R inhibition compound.Also need with 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), and its pharmacologically acceptable salt with relevant composition and method, its Chinese style (I) is:
And wherein X is O, S or S (O);
R
1And R
2Be independently selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of aryl, heterocyclic radical, the replacement of cycloalkenyl group, aryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of alkyl, acyl group, cycloalkyl, the replacement of hydrogen, alkyl, 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
6Be alkoxyl group, the amino of alkyl, alkoxyl group, the replacement of alkyl, replacement, the amino or the halogen of replacement independently;
N is 0,1 or 2; And
When X is O, R
4Be the alkynyl of alkenyl, alkynyl or replacement of alkyl, alkenyl, the replacement of hydrogen, replacement, and R
5Be 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, 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
4Be the 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 (IIb) be
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
12Be independently selected from the heteroaryl of aryl, heteroaryl and replacement of heterocyclic radical, aryl, the replacement of cycloalkyl, heterocyclic radical, the replacement of amino, cycloalkyl, the replacement of alkoxyl group, amino, the replacement of alkyl, alkoxyl group, the replacement of hydrogen, halogen, hydroxyl, alkyl, 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.
Compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (IIIa) that another embodiment relates to formula (IIIa) are
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
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.
Compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (IIIb) that another embodiment relates to formula (IIIb) are
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
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.
Compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (IV) that another embodiment relates to formula (IV) are
And wherein X is O or S;
R
7Be independently selected from alkoxyl group, halogenated alkoxy, halogen and formonitrile HCN;
P is 0,1 or 2;
R
1Be-LR
8Or be 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 by 0,1,2 or 3;
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 randomly is the 2-p-methoxy-phenyl.
Another embodiment relates to compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and the relevant composition and the method for formula V, and wherein formula V is
And wherein X is O or S;
R
1Be-LR
9Or be 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 by 0,1,2 or 3;
L is the alkylidene group of covalent linkage, alkylidene group or replacement; And
R
9Be selected from cycloalkyl, THP trtrahydropyranyl, morpholino and the pyridyl of cycloalkyl, replacement.
Another embodiment relates to the method that suppresses the illness of compounds for treating CSF-1R mediation with formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or CSR-1R (V).
In a more particular embodiment, described compound is gone up substantially and is not suppressed the Raf kinases.In a more particular embodiment, described compound preferentially suppresses CSF-1R with respect to the Raf kinases.In a more particular embodiment, described compound is with IC
50Concentration greater than about 1 μ M suppresses the Raf kinases.In a more particular embodiment, described compound is with IC
50Concentration less than about 1 μ M suppresses CSF-1R.More particularly, described compound is with IC
50Concentration less than about 0.1 μ M suppresses CSF-1R.
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 the various embodiments that this paper provided can be the eclipsed scope.Embodiment discussed in this article only is indicative, and does not mean that and limit the scope of the invention.
Definition
Unless concrete definition is arranged in addition, otherwise term used herein is as following definition.
＂ alkyl ＂ is meant the unit price radical of saturated aliphatic alkyl with 1 to 10 carbon atom, preferred 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 is meant to have 1 to 5; preferred 1 to 3 or more preferably 1 to 2 be selected from following substituent alkyl: alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; 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 that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; azido-; carboxyl; carboxyl ester; (carboxyl ester) amino; (carboxyl ester) oxygen base; cyano group; cyanate; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; cycloalkylthio; the cycloalkylthio that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfenyl; the cycloalkenyl group sulfenyl that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; hydroxyl amino; alkoxy amino; diazanyl; the diazanyl that replaces; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; heteroarylthio; the heteroarylthio that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfenyl; the heterocyclic radical sulfenyl that replaces; 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 " is meant the divalence radical of saturated aliphatic alkyl with 1 to 10 carbon atom, preferred 1 to 6 carbon atom.Alkylidene group comprises side chain and straight-chain alkyl.
" alkylidene group of replacement " is meant to have 1 to 5; preferred 1 to 3 or more preferably 1 to 2 be selected from following substituent alkylidene group: alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; 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 that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; azido-; carboxyl; carboxyl ester; (carboxyl ester) amino; (carboxyl ester) oxygen base; cyano group; cyanate; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; cycloalkylthio; the cycloalkylthio that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfenyl; the cycloalkenyl group sulfenyl that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; hydroxyl amino; alkoxy amino; diazanyl; the diazanyl that replaces; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; heteroarylthio; the heteroarylthio that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfenyl; the heterocyclic radical sulfenyl that replaces; 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 ＂ is meant 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 is meant group-O-(alkyl of replacement), and wherein the alkyl of Qu Daiing as defined herein.
＂ acyl group ＂ be meant group H-C (O)-; alkyl-C (O)-; alkyl-the C (O) that replaces-; alkenyl-C (O)-; alkenyl-the C (O) that replaces-; alkynyl-C (O)-; alkynyl-the C (O) that replaces-; cycloalkyl-C (O)-; cycloalkyl-the C (O) that replaces-; cycloalkenyl group-C (O)-; cycloalkenyl group-the C (O) that replaces-; aryl-C (O)-; aryl-the C (O) that replaces-; diazanyl-the C (O) that replaces-; heteroaryl-C (O)-; heteroaryl-the C (O) that replaces-; heterocycle-C (O)-and heterocycle-C (O) of replacing-; alkyl wherein; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl; the alkynyl that replaces; cycloalkyl; the cycloalkyl that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; aryl; the aryl that replaces; the diazanyl that replaces; heteroaryl; the heteroaryl that replaces; the heterocycle of heterocycle and replacement as defined herein.Acyl group comprise " ethanoyl " CH3C (O)-.
＂ acyl amino ＂ is meant 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 ＂ is meant group alkyl-C (O) O-, alkyl-C (O) O-that replaces, alkenyl-C (O) O-, alkenyl-C (O) O-that replaces, alkynyl-C (O) O-, alkynyl-C (O) O-that replaces, aryl-C (O) O-, aryl-C (O) O-that replaces, cycloalkyl-C (O) O-, cycloalkyl-C (O) O-that replaces, cycloalkenyl group-C (O) O-, cycloalkenyl group-C (O) O-that replaces, heteroaryl-C (O) O-, heteroaryl-C (O) O-that replaces, heterocycle-C (O) O-of heterocycle-C (O) O-and replacement, wherein alkyl, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement as defined herein.
" amino " is meant group-NH
2
" amino of replacement " is meant group-NR
21R
22, R wherein
21And R
22Be independently selected from heteroaryl, heterocycle, the replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement heterocycle ,-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
22Randomly form the heterocyclic radical of heterocycle or replacement with the nitrogen that they connected, 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
21Be hydrogen and R
22When being alkyl, the amino of replacement is known as alkylamino in this article sometimes.Work as R
21And R
22When 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 a hydrogen, but not all be hydrogen.When mentioning dibasic amino, mean R
21And R
21Not hydrogen.
" hydroxyl amino " is meant group-NHOH.
" alkoxy amino " is meant group-NHO-alkyl, and wherein alkyl as defined herein.
＂ aminocarboxyl ＂ is meant group-C (O) NR
23R
24, R wherein
23And R
24Be independently selected from alkoxyl group, the amino of heterocyclic radical, hydroxyl, alkoxyl group, 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, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, the amino and the acyl amino of replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement with the nitrogen that they connected, 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 " is meant group-C (S) NR
23R
24, R wherein
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement, 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 with the nitrogen that they connected.
" amino carbonyl amino " is meant group-NR
20C (O) NR
23R
24, R wherein
20Be hydrogen or alkyl and R
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly with the nitrogen that they connected 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 " is meant group-NR
20C (S) NR
23R
24, R wherein
20Be hydrogen or alkyl and R
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement with the nitrogen that they connected, 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 " is meant group-O-C (O) NR
23R
24, R wherein
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement, 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 with the nitrogen that they connected.
" amino-sulfonyl " is meant group-SO
2NR
23R
24, R wherein
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement, 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 with the nitrogen that they connected.
" amino-sulfonyl oxygen base " is meant group-O-SO
2NR
23R
24, R wherein
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement, 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 with the nitrogen that they connected.
" amino-sulfonyl amino " is meant group-NR
20-SO
2NR
23R
24, R wherein
20Be hydrogen or alkyl and R
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement, 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 with the nitrogen that they connected.
" amidino groups " is meant group-C (=NR
25) NR
23R
24, R wherein
25, R
23And R
24Be independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement, and R wherein
23And R
24Randomly form the heterocyclic radical of heterocycle or replacement, 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 with the nitrogen that they connected.
＂ aryl ＂ or ＂ Ar ＂ are meant the unit price aromatic carbocyclic group of 6 to 14 carbon atoms of have single ring (for example phenyl) or a plurality of condensed ring (for example naphthyl or anthryl), described condensed ring can the yes or no aromaticity (for example 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-ketone-7-bases etc.), condition is that tie point is on aromatic carbon atom.Preferred aryl groups comprises phenyl and naphthyl.
" aryl of replacement " is meant by 1 to 5; preferred 1 to 3 or more preferably 1 to 2 be selected from the following aryl that substituting group replaced: alkyl; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl; the alkynyl that replaces; alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; 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 that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; azido-; carboxyl; carboxyl ester; (carboxyl ester) amino; (carboxyl ester) oxygen base; cyano group; cyanate; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; cycloalkylthio; the cycloalkylthio that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfenyl; the cycloalkenyl group sulfenyl that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; hydroxyl amino; alkoxy amino; diazanyl; the diazanyl that replaces; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; heteroarylthio; the heteroarylthio that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfenyl; the heterocyclic radical sulfenyl that replaces; 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 ＂ is meant group-O-aryl, wherein aryl as defined herein, it comprises for example phenoxy group and naphthyloxy.
The aryloxy ＂ that ＂ replaces is meant group-O-(aryl of replacement), and wherein the aryl of Qu Daiing as defined herein.
" arylthio " is meant group-S-aryl, and wherein aryl as defined herein.
" arylthio of replacement " is meant group-S-(aryl of replacement), and wherein the aryl of Qu Daiing as defined herein.
＂ alkenyl ＂ be meant have 2 to 6 carbon atoms, preferred 2 to 4 carbon atoms and have the unsaturated position of at least 1, preferred 1 to 2 vinyl (〉 C=C＜) alkenyl.Described group is vinyl, allyl group and fourth-3-thiazolinyl for example.
The alkenyl ＂ that ＂ replaces is meant to have 1 to 3; preferred 1 to 2 is selected from following substituent alkenyl: alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; 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 that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; carboxyl; carboxyl ester; (carboxyl ester) amino; (carboxyl ester) oxygen base; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; cycloalkylthio; the cycloalkylthio that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfenyl; the cycloalkenyl group sulfenyl that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; heteroarylthio; the heteroarylthio that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfenyl; the heterocyclic radical sulfenyl that replaces; nitro; SO
3The alkylthio of the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, wherein said substituting group as defined herein, condition is that any hydroxyl or mercaptan replace and all is free of attachment on vinyl (undersaturated) carbon atom.
＂ alkynyl ＂ be meant have 2 to 6 carbon atoms, preferred 2 to 3 carbon atoms and have the alkyl of the unsaturated position of at least 1, preferred 1 to 2 acetylene series (C ≡ C-).
The alkynyl ＂ that ＂ replaces is meant to have 1 to 3; preferred 1 to 2 is selected from following substituent alkynyl: alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; 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 that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; carboxyl; carboxyl ester; (carboxyl ester) amino; (carboxyl ester) oxygen base; cyano group; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; cycloalkylthio; the cycloalkylthio that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfenyl; the cycloalkenyl group sulfenyl that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; heteroarylthio; the heteroarylthio that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfenyl; the heterocyclic radical sulfenyl that replaces; nitro; SO
3The alkylthio of the alkylsulfonyl of H, replacement, alkylsulfonyl oxygen base, sulfo-acyl group, mercaptan, alkylthio and replacement, wherein said substituting group as defined herein, condition is that any hydroxyl or mercaptan replace and all is free of attachment on the alkynyl carbon atom.
" azido-" is meant group-N
3
" diazanyl " is meant group-NHNH
2
" diazanyl of replacement " is meant group-NR
26NR
27R
28, R wherein
26, R
27And R
28Be independently selected from heteroaryl, heterocycle, the replacement of cycloalkenyl group, heteroaryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of aryl, carboxyl ester, cycloalkyl, the replacement of alkynyl, aryl, the replacement of alkenyl, alkynyl, the replacement of alkyl, alkenyl, the replacement of hydrogen, alkyl, replacement heterocycle ,-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
28Randomly form the heterocyclic radical of heterocycle or replacement with the nitrogen that they connected, 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 " is meant group-CN.
" cyanate " is meant group-OCN.
" carbonyl " be meant divalent group-C (O)-, it is equal to-C (=O)-.
" carboxyl " is meant-COOH or its salt.
" carboxyl ester " is meant 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, wherein alkyl, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement as defined herein.
" (carboxyl ester) amino " is meant 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 " is meant 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, wherein alkyl, the alkyl that replaces, alkenyl, the alkenyl that replaces, alkynyl, the alkynyl that replaces, cycloalkyl, the cycloalkyl that replaces, cycloalkenyl group, the cycloalkenyl group that replaces, aryl, the aryl that replaces, heteroaryl, the heteroaryl that replaces, the heterocyclic radical of heterocyclic radical and replacement as defined herein.
" cycloalkyl " be meant have single or multiple rings, comprise condensed, the cyclic alkyl of 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 " is meant to have single or multiple cyclic rings and have at least one〉the unsaturated position of C=C＜ring, preferably have 1 to 2〉the non-aromatic cyclic alkyl with 4 to 10 carbon atoms of unsaturated of C=C＜ring.
" cycloalkyl of replacement " and " cycloalkenyl group of replacement " is meant that having 1 to 5 or preferred 1 to 3 is selected from following substituent cycloalkyl or cycloalkenyl group: oxo; thioketones; alkyl; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl; the alkynyl that replaces; alkoxyl group; the alkoxyl group that replaces; acyl group; acyl amino; acyloxy; amino; the amino that replaces; 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 that replaces; aryloxy; the aryloxy that replaces; arylthio; the arylthio that replaces; azido-; carboxyl; carboxyl ester; (carboxyl ester) amino; (carboxyl ester) oxygen base; cyano group; cyanate; cycloalkyl; the cycloalkyl that replaces; cycloalkyl oxy; the cycloalkyl oxy that replaces; cycloalkylthio; the cycloalkylthio that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; cycloalkenyl oxy; the cycloalkenyl oxy that replaces; the cycloalkenyl group sulfenyl; the cycloalkenyl group sulfenyl that replaces; guanidine radicals; the guanidine radicals that replaces; halogen; hydroxyl; hydroxyl amino; alkoxy amino; diazanyl; the diazanyl that replaces; heteroaryl; the heteroaryl that replaces; heteroaryloxy; the heteroaryloxy that replaces; heteroarylthio; the heteroarylthio that replaces; heterocycle; the heterocycle that replaces; the heterocyclyloxy base; the heterocyclyloxy base that replaces; the heterocyclic radical sulfenyl; the heterocyclic radical sulfenyl that replaces; 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 " is meant-the O-cycloalkyl.
" cycloalkyl oxy of replacement is meant-O-(cycloalkyl of replacement).
" cycloalkylthio " is meant-the S-cycloalkyl.
" cycloalkylthio of replacement " is meant-S-(cycloalkyl of replacement).
" cycloalkenyl oxy " is meant-the O-cycloalkenyl group.
" cycloalkenyl oxy of replacement " is meant-O-(cycloalkenyl group of replacement).
" cycloalkenyl group sulfenyl " is meant-the S-cycloalkenyl group.
" the cycloalkenyl group sulfenyl of replacement " is meant-S-(cycloalkenyl group of replacement).
" guanidine radicals " is meant group-NHC (=NH) NH
2
" guanidine radicals of replacement " is meant-NR29C (=NR29) N (R29)
2, wherein each R29 is independently selected from the heterocyclic radical of heteroaryl, heterocyclic radical and replacement of aryl, heteroaryl, the replacement of alkyl, aryl, the replacement of hydrogen, alkyl, replacement, and is connected to two R on the common guanidine radicals nitrogen-atoms
29Group randomly forms the heterocyclic radical of heterocycle or replacement with the nitrogen that they connected, condition is at least one R
29Be not hydrogen, and wherein said substituting group as defined herein.
" halogen " is meant fluorine, chlorine, bromine and iodine.
" hydroxyl " is meant group-OH.
" heteroaryl " is meant 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 condensed ring (for example indolizine base or benzothienyl), that wherein the condensed ring can the yes or no aromaticity and/or contain or do not contain heteroatoms, condition is that the atom by the aromatics heteroaryl connects.In one embodiment, the nitrogen of heteroaryl and/or sulphur annular atoms randomly are oxidized to N-oxide compound (N → O), sulfinyl or alkylsulfonyl part.Preferred heteroaryl comprises pyridyl, pyrryl, indyl, thiophene and furyl.
" heteroaryl of replacement " be meant by 1 to 5, preferred 1 to 3 or more preferably 1 to 2 be selected from and the defined identical heteroaryl that substituting group replaced of the aryl that replaces.
" heteroaryloxy " is meant-the O-heteroaryl.
" heteroaryloxy of replacement " is meant group-O-(heteroaryl of replacement).
" heteroarylthio " is meant group-S-heteroaryl.
" heteroarylthio of replacement " is meant group-S-(heteroaryl of replacement).
" heterocycle " or " Heterocyclylalkyl " or " heterocyclic radical " are meant in ring to have single ring or a plurality of condensed ring, 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, nitrogen and/or the sulphur atom with heterocyclic radical randomly is oxidized to N-oxide compound, sulfinyl, alkylsulfonyl part.
" heterocycle of replacement " or " Heterocyclylalkyl of replacement " or " heterocyclic radical of replacement " are meant by 1 to 5 or preferred 1 to 3 and are selected from and the defined identical heterocyclic radical that substituting group replaced of the cycloalkyl that replaces.
" heterocyclyloxy base " is meant group-O-heterocyclic radical.
" the heterocyclyloxy base of replacement " is meant group-O-(heterocyclic radical of replacement).
" heterocyclic radical sulfenyl " is meant group-S-heterocyclic radical.
" the heterocyclic radical sulfenyl of replacement " is meant 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 " is meant group-NO
2
" oxo " be meant atom (=O).
" oxide compound " is meant the formed product of one or more heteroatoms oxidations.Its example comprises N-oxide compound, sulfoxide and sulfone.
" volution base " is meant 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 " is meant divalent group, and it comprises and has as above about the described spiral bonded of volution base cycloalkyl ring.
" alkylsulfonyl " is meant divalent group-S (O)
2-.
" alkylsulfonyl of replacement " is meant 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 that replaces comprises that group is such as methyl-SO
2-, phenyl-SO
2-and 4-aminomethyl phenyl-SO
2-.
" alkylsulfonyl oxygen base " is meant 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 " be meant group H-C (S)-; alkyl-C (S)-; alkyl-the C (S) that replaces-; alkenyl-C (S)-; alkenyl-the C (S) that replaces-; alkynyl-C (S)-; alkynyl-the C (S) that replaces-; cycloalkyl-C (S)-; cycloalkyl-the C (S) that replaces-; cycloalkenyl group-C (S)-; cycloalkenyl group-the C (S) that replaces-; aryl-C (S)-; aryl-the C (S) that replaces-; heteroaryl-C (S)-; heteroaryl-the C (S) that replaces-; heterocycle-C (S)-and heterocycle-C (S) of replacing-, alkyl wherein; the alkyl that replaces; alkenyl; the alkenyl that replaces; alkynyl; the alkynyl that replaces; cycloalkyl; the cycloalkyl that replaces; cycloalkenyl group; the cycloalkenyl group that replaces; aryl; the aryl that replaces; heteroaryl; the heteroaryl that replaces; the heterocycle of heterocycle and replacement as defined herein.
" mercaptan " is meant group-SH.
" alkylthio " is meant group-S-alkyl, and wherein alkyl as defined herein.
" alkylthio of replacement " is meant group-S-(alkyl of replacement), and wherein the alkyl of Qu Daiing as defined herein.
" thiocarbonyl " be meant divalent group-C (S)-, it is equal to-C (=S)-.
" thioketones " be meant atom (=S).
" thiocyanic ester " are meant group-SCN.
" solvate " is meant the solvent bonded compound or its salt with stoichiometry or nonstoichiometry amount.Preferred solvent is volatile, nontoxic and/or delivers medicine to the people with trace is acceptable.The The suitable solvent thing comprises water.
" steric isomer " is meant the compound that the chirality at one or more three-dimensional centers is different.Steric isomer comprises enantiomorph and diastereomer.
" tautomer " is meant the change form of the compound that the position of proton is different, such as enol-ketone and imine-enamine tautomerism body, or contain tautomeric form such as pyrazoles, imidazoles, benzoglyoxaline, triazole and the tetrazolium of the heteroaryl that is connected to ring-NH-part and ring=N-annular atoms partly simultaneously.
" prodrug " is meant any derivative that the 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 are when this compound administration can be increased the material (for example can make the compound of oral administration be easier to absorb in the blood) of the bioavailability of The compounds of this invention or can improve the convective material that parent compound enters biology compartment (for example brain or lymphsystem) with respect to parent material 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 general introduction of prodrug can be referring to T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, the 14th volume and the Edward B.Roche of A.C.S.Symposium Series compile, Bioreversible Carriersin Drug Design, American Pharmaceutical Association and PergamonPress, 1987, at this they are incorporated herein by reference.
" pharmacologically acceptable salt " is meant 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 " is meant Mammals, and comprises people and inhuman Mammals.
" treatment " of patient disease is meant 1) prevent to tend 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 be meant the target that preferential inhibition is specific or compound, composition or the chemical type of target class." selectivity of CSF-1R suppresses " expression selectivity inhibition CSF-1R that mentions and randomly similar kinases receptors are such as PDGFR.In certain embodiments, the inhibition of the selectivity of CSF-1R is meant with respect to the Raf kinases and preferentially suppresses CSF-1R." selectivity ", " target ", " specific " or " preferentially " suppress and do not mean that other kinases or acceptor do not have the activity of inhibition fully for all.
" CSF-1R inhibitor " is meant the compound that can suppress CSF-1R.Preferred 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 be meant compound of the present invention 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, the substituent name that does not clearly define in this article names the adjacent functional group that points to tie point to obtain by the terminal part of the functional group of name earlier then.For example, substituting group " arylalkyl oxygen base carbonyl " be meant group (aryl)-(alkyl)-O-C (O)-.
Be appreciated that, in the group of all replacements defined above, (for example have the aryl of the aryl of replacement by definition with the resulting polymkeric substance of further substituting group replacement self 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 have aryl-(aryl of replacement)-replacement that two other continuous replacements of aryl of replacement of aryl of replacement are limited in-replace.
Similarly, be appreciated that, above-mentioned definition does not comprise unallowed substitute mode (for example methyl that is replaced by 5 fluorin radicals).This unallowed substitute mode is well known by persons skilled in the art.
Compound, steric isomer, tautomer, solvate, oxide compound, ester and prodrug, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (I) that a kind of embodiment relates to formula (I) are:
And wherein X is O, S or S (O);
R
1And R
2Be independently selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of aryl, heterocyclic radical, the replacement of cycloalkenyl group, aryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of alkyl, acyl group, cycloalkyl, the replacement of hydrogen, alkyl, 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
6Be alkoxyl group, the amino of alkyl, alkoxyl group, the replacement of alkyl, replacement, the amino or the halogen of replacement independently;
N is 0,1 or 2; And
When X is O, R
4Be the alkynyl of alkenyl, alkynyl or replacement of alkyl, alkenyl, the replacement of hydrogen, replacement, and R
5Be 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, 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
4Be the 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.
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
2Be hydrogen or methyl.
In certain embodiments, R
1Be independently selected from the following alkyl that substituting group replaced by 0,1,2 or 3: 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
1aBe that 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] [1,4] two oxa-s
, pyrazinyl, pyrrolidyl, piperidyl, piperidone, pyrrolidone, pyridine-2 (1H)-ketone, 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 azepan-2-ketone, wherein each R
1aBe that replace or unsubstituted.In some aspects, L is a covalent linkage.
In certain embodiments, L is a covalent linkage.
In some embodiment of formula (I) compound, L is independently selected from the following alkylidene group that substituting group replaced by 0,1,2 or 3: the alkyl of alkyl, replacement, hydroxyl, alkoxyl group, halogenated alkoxy, aminocarboxyl, carboxyl ester and carboxyl.
In some embodiment of formula (I) compound, R
1Be
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
12Be independently selected from the heteroaryl of aryl, heteroaryl and replacement of heterocyclic radical, aryl, the replacement of cycloalkyl, heterocyclic radical, the replacement of amino, cycloalkyl, the replacement of alkoxyl group, amino, the replacement of alkyl, alkoxyl group, the replacement of hydrogen, halogen, hydroxyl, alkyl, 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
10Be hydrogen.
In certain embodiments, dotted line is a saturated bond, forms cyclohexyl thus.
In some embodiment of formula (I) compound, L is a 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 was not covalent linkage, L was replaced by the alkyl of alkyl, replacement, carboxyl, aminocarboxyl and carboxyl ester.
In some embodiment of formula (I) compound, R
10, R
11And R
12Be independently selected from the alkyl and the alkoxyl group of 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
12Be independently selected from the alkyl and the alkoxyl group of 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
1Be the alkyl that replaces, 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
1Be the 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
1Be the alkyl that replaces, R wherein
1Substituting group be the cycloalkyl of cycloalkyl or replacement.
In certain embodiments, R
1Be the alkyl that replaces, 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
3Be acyl amino or aminocarboxyl.
In certain embodiments, R
3Be-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
3Be-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-base, 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
3Be that replace or unsubstituted.
In certain embodiments, R
4Be hydrogen.
In certain embodiments, R
5Be hydrogen.
Some embodiment and with above-mentioned embodiment in the embodiment of any combination in, n is 0, R
4And R
5Be hydrogen, 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,
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;
R
10, R
11And R
12Be independently selected from the heteroaryl of aryl, heteroaryl and replacement of heterocyclic radical, aryl, the replacement of cycloalkyl, heterocyclic radical, the replacement of amino, cycloalkyl, the replacement of alkoxyl group, amino, the replacement of alkyl, alkoxyl group, the replacement of hydrogen, halogen, hydroxyl, alkyl, 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.
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 a saturated bond, forms cyclohexyl thus.
In formula (IIa) or (IIb) in some embodiment of compound, L is a 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
12Be independently selected from the alkyl and the alkoxyl group of 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
12Be independently selected from the alkyl and the alkoxyl group of 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
3Be acyl amino or aminocarboxyl.
In formula (IIa) or (IIb) in some embodiment of compound, R
3Be-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.
Compound, steric isomer, tautomer and solvate, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (IIIa) that another embodiment relates to formula (IIIa) are
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
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 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 that is substituted by cycloalkyl.
In some embodiment of formula (IIIa) compound, R
3Be acyl amino or aminocarboxyl.
In some embodiment of formula (IIIa) compound, R
3Be-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 relate to formula (IIIb) compound, steric isomer, tautomer, moltenly be with thinner thing, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (IIIb)
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
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 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
3Be acyl amino or aminocarboxyl.
In some embodiment of formula (IIIb) compound, R
3Be-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
3Be-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-base, 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
3Be that replace or unsubstituted.
Compound, steric isomer, tautomer, solvate, oxide compound, ester and prodrug, its pharmacologically acceptable salt and relevant composition and method, its Chinese style (IV) that another embodiment relates to formula (IV) are
And wherein X is O or S;
R
7Be independently selected from alkoxyl group, halogenated alkoxy, halogen and formonitrile HCN;
P is 0,1 or 2;
R
1Be-LR
8Or be 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 by 0,1,2 or 3;
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
1aIt randomly is 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 the relevant composition and the method for formula V, and wherein formula V is
Wherein X is O or S;
R
1Be-LR
9Or be 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 by 0,1,2 or 3;
L is the alkylidene group of covalent linkage, alkylidene group or replacement; And
R
9Be selected from cycloalkyl, THP trtrahydropyranyl, morpholino and the pyridyl of cycloalkyl, replacement.
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 | H | H | -C(O)NHCH 3 |
| 24 | O | Cyclohexyl | H | H | H | -C(O)NHCH 3 |
| 25 | O | (2-morpholine-4-ylmethyl) | H | H | H | -C(O)NHCH 3 |
| 26 | O | Phenyl | H | H | H | -C(O)NHCH 3 |
| 27 | O | (4-benzyl chloride base) | H | H | H | -C(O)NHCH 3 |
| 28 | O | 2, the 4-Dimethoxyphenyl | H | H | H | -C(O)NHCH 3 |
| 29 | O | Cyclohexyl | H | H | H | -NHC(O)CH 3 |
| 30 | O | Tetrahydropyran-4-base | H | H | H | -C(O)NHCH 3 |
| 31 | O | 2-(R)-1-(2-p-methoxy-phenyl) | H | H | H | -C(O)NHCH 3 |
| 32 | O | 2-benzyl chloride base | H | H | H | -C(O)NHCH 3 |
| 33 | O | 2, the 5-difluorobenzyl | H | H | H | -NHC(O)CH 3 |
| 34 | O | Cyclohexyl methyl | H | H | H | -NHC(O)CH 3 |
| 35 | O | 2-(R)-phenylacetic acid | H | H | H | -C(O)NHCH 3 |
| 36 | O | 2-(R)-formic acid methyl nitrosourea | H | H | H | -C(O)NHCH 3 |
| 37 | O | 2-(R)-hydroxyl-1-phenyl-ethyl | H | H | H | -C(O)NHCH 3 |
| 38 | O | 2-(S)-phenylacetic acid | H | H | H | -C(O)NHCH 3 |
| 39 | O | 2-(S)-formic acid methyl nitrosourea | H | H | H | -C(O)NHCH 3 |
| 40 | O | Pyridine-2-ylmethyl | H | H | H | -C(O)NHCH 3 |
| 41 | O | Benzyl | H | H | H | -C(O)NHCH 3 |
| 42 | O | 3-benzyl chloride base | H | H | H | -C(O)NHCH 3 |
| 43 | O | 2-(2-tetramethyleneimine-1-base ethyl) phenyl | H | H | H | -C(O)NHCH 3 |
| The compound sequence number | X | R 1 | R 2 | R 4 | R 5 | R 3 |
| 44 | O | 2-(2-piperidines-1-base ethyl) phenyl | H | H | H | -C(O)NHCH 3 |
| 45 | O | 2-(4-methyl-imidazoles-1-yl) phenyl | H | H | H | -C(O)NHCH 3 |
| 46 | O | 2-oxazole-5-base phenyl | H | H | H | -C(O)NHCH 3 |
| 47 | O | 2-(glyoxal ethyline-1-yl) phenyl | H | H | H | -C(O)NHCH 3 |
| 48 | O | 2-morpholine-4-base-ethyl | H | H | H | -C(O)NHCH 3 |
| 49 | O | (1S, 2R)-2-hydroxyl-indane-1-base | H | H | H | -C(O)NHCH 3 |
| 50 | O | (1R, 2S)-2-hydroxyl-indane-1-base | H | H | H | -C(O)NHCH 3 |
| 51 | O | 2-(R)-3-hydroxyl-1-phenyl propyl | H | H | H | -C(O)NHCH 3 |
| 52 | O | (1S, 2S)-the 2-hydroxy-cyclohexyl | H | H | H | -C(O)NHCH 3 |
| 53 | O | 2-(R)-phenylacetic acid methyl ester | H | H | H | -C(O)NHCH 3 |
| 54 | O | 2-(R)-cyclohexyl ethyl | H | H | H | -C(O)NHCH 3 |
| 55 | O | 2-(S)-phenylacetic acid methyl esters | H | H | H | -C(O)NHCH 3 |
| 56 | O | 2-(S)-hydroxyl-1-phenylethyl | H | H | H | -C(O)NHCH 3 |
| 57 | O | The pyridin-4-yl methyl | H | H | H | -C(O)NHCH 3 |
| 58 | O | 2-piperidines-1-base ethyl | H | H | H | -C(O)NHCH 3 |
| 59 | O | The pyridin-3-yl methyl | H | H | H | -C(O)NHCH 3 |
| 60 | O | Cyclohexyl methyl | H | H | H | -C(O)OH |
| The compound sequence number | X | R 1 | R 2 | R 4 | R 5 | R 3 |
| 61 | O | Styroyl | H | H | H | -C(O)NHCH 3 |
| 62 | O | 2-(R)-cyclohexyl methyl-carbamyl ylmethyl | H | H | H | -C(O)NHCH 3 |
| 63 | O | 2-tetramethyleneimine-1-base ethyl | H | H | H | -C(O)NHCH 3 |
| 64 | O | 2-piperidines-1-base ethyl | H | H | H | -C(O)NHCH 3 |
| 65 | O | 2,3-dihydrobenzo [1,4] dioxin-5-ylmethyl | H | H | H | -C(O)NHCH 3 |
| 66 | O | 2-(S)-1-cyclohexyl-2-hydroxyethyl | H | H | H | -C(O)NHCH 3 |
| 67 | O | 2-(R)-1-cyclohexyl-2-hydroxyethyl | H | H | H | -C(O)NHCH 3 |
| 68 | O | Cyclohexyl methyl | H | H | H | -C(O)NHNHC(O)O C(CH 3) 3 |
| 69 | O | Cyclohexyl methyl | H | H | H | -C(O)NH 2 |
| 70 | O | Hexamethylene-3-thiazolinyl | H | H | H | -C(O)NHCH 3 |
| 71 | O | 2, the 4-difluorobenzyl | H | H | H | -C(O)NHCH 3 |
| 72 | O | The 2-bromobenzyl | H | H | H | -C(O)NHCH 3 |
| 73 | O | 2-fluoro-5-methoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 74 | O | 3-(2-morpholine-4-base ethyl) phenyl | H | H | H | -C(O)NHCH 3 |
| 75 | O | The naphthenic acid ethyl ester | H | H | H | -C(O)NHCH 3 |
| 76 | O | 2, the 6-dichloro benzyl | H | H | H | -C(O)NHCH 3 |
| 77 | O | 2, the 3-dichloro benzyl | H | H | H | -C(O)NHCH 3 |
| 78 | O | 2-chloro-6-luorobenzyl | H | H | H | -C(O)NHCH 3 |
| 79 | O | 2, the 3-difluorobenzyl | H | H | 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 | H | H | -CH 2OH |
| 81 | O | Cyclohexyl methyl | H | H | H | The oxadiazole base |
| 82 | O | Cyclohexyl methyl | H | H | H | -CN |
| 83 | O | 2, the 5-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 84 | O | 2, the 6-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 85 | O | 2-dimethylamino benzyl | H | H | H | -C(O)NHCH 3 |
| 86 | O | The 2-aminobenzyl | H | H | H | -C(O)NHCH 3 |
| 87 | O | 2, the 6-difluorobenzyl | H | H | H | -C(O)NHCH 3 |
| 88 | O | 2-morpholine-4-base benzyl | H | H | H | -C(O)NHCH 3 |
| 89 | O | The 2-methyl-benzyl | H | H | H | -C(O)NHCH 3 |
| 90 | O | 3, the 4-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 91 | O | 2, the 3-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 92 | O | 2, the 4-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 93 | O | Naphthenic acid-methyl | H | H | H | -C(O)NHCH 3 |
| 94 | O | 2,3-dihydrobenzo [1,4] dioxin-5-base | H | H | H | -C(O)NHCH 3 |
| 95 | O | Benzo [1,3] dioxole-5-base | H | H | H | -C(O)NHCH 3 |
| 96 | O | The 2-ethoxy benzyl | H | H | H | -C(O)NHCH 3 |
| 97 | O | The 2-trifluoromethyl benzyl | H | H | H | -C(O)NHCH 3 |
| 98 | O | Sec.-propyl | H | H | H | -C(O)NHCH 3 |
| 99 | O | Isobutyl- | H | H | H | -C(O)NHCH 3 |
| 100 | O | The tertiary butyl | H | H | H | -C(O)NHCH 3 |
| 101 | O | The suberyl methyl | H | H | H | -C(O)NHCH 3 |
| 102 | O | Tetrahydrofuran (THF)-2-ylmethyl | H | H | 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 [1,4] dioxin-6-ylmethyl | H | H | H | -C(O)NHCH 3 |
| 123 | O | 2-(2, and the 3-dihydrobenzo [1,4] dioxin-5-yl) ethyl | H | H | H | -C(O)NHCH 3 |
| 124 | O | 2,3-Dihydrobenzofuranes-5-ylmethyl | H | H | H | -C(O)NHCH 3 |
| 125 | O | 2-(2, and the 3-dihydrobenzo [1,4] dioxin-5-yl) ethyl | H | H | H | -C(O)NHCH 3 |
| 126 | S | 4-chloro-3-trifluoromethyl | H | H | H | -C(O)NHCH 3 |
| 127 | S | 2-benzyl chloride base | H | H | H | -C(O)NHCH 3 |
| 128 | S | Cyclohexyl methyl | H | H | H | -C(O)NHCH 3 |
| 129 | S | 2-(R)-1-(2-p-methoxy-phenyl) ethyl | H | H | H | -C(O)NHCH 3 |
| 130 | S | 2, the 4-dichloro benzyl | H | H | H | -C(O)NHCH 3 |
| 131 | S | 2-(R)-1-phenylethyl | H | H | H | -C(O)NHCH 3 |
| 132 | S | The 2-methoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 133 | S | The 2-styroyl | H | H | H | -C(O)NHCH 3 |
| 134 | S | 2, the 3-dichloro benzyl | H | H | H | -C(O)NHCH 3 |
| 135 | S | Cyclohexyl | H | H | H | -C(O)NHCH 3 |
| 136 | S | The 3-methylcyclohexyl | H | H | H | -C(O)NHCH 3 |
| 137 | S | (1S, 2S)-the 2-hydroxy-cyclohexyl | H | H | H | -C(O)NHCH 3 |
| 138 | S | 2-(R)-cyclohexyl ethyl | H | H | H | -C(O)NHCH 3 |
| 139 | S | 2, the 5-difluorobenzyl | H | H | 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 | H | H | -C(O)NHCH 3 |
| 141 | S | The tetrahydropyran-4-base methyl | H | H | H | -C(O)NHCH 3 |
| 142 | S | 2-morpholine-4-base benzyl | H | H | H | -C(O)NHCH 3 |
| 143 | S | 2-pyrazol-1-yl-benzyl | H | H | H | -C(O)NHCH 3 |
| 144 | S | 2-dimethylamino benzyl | H | H | H | -C(O)NHCH 3 |
| 145 | S | 2, the 6-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 146 | S | 2, the 5-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 147 | S | 2, the 3-difluorobenzyl | H | H | H | -C(O)NHCH 3 |
| 148 | S | The suberyl methyl | H | H | H | -C(O)NHCH 3 |
| 149 | S | 2, the 6-difluorobenzyl | H | H | H | -C(O)NHCH 3 |
| 150 | S | Pyridine-2-ylmethyl | H | H | H | -C(O)NHCH 3 |
| 151 | S | 3, the 4-dimethoxy-benzyl | H | H | H | -C(O)NHCH 3 |
| 152 | S | 2,3-dihydrobenzo [1,4] dioxin-5-ylmethyl | H | H | H | -C(O)NHCH 3 |
| 153 | S | 2-piperidines-1-base-benzyl | H | H | H | -C(O)NHCH 3 |
| 154 | S | The pyridin-3-yl methyl | H | H | H | -C(O)NHCH 3 |
| 155 | S | (1R, 2R)-2-benzyloxy cyclohexyl | H | H | H | -C(O)NHCH 3 |
| 156 | S | (1S, 2S)-2-benzyloxy cyclohexyl | H | H | H | -C(O)NHCH 3 |
| 157 | S | (1R, 2R)-the 2-hydroxy-cyclohexyl | H | H | H | -C(O)NHCH 3 |
| 158 | S | 2, the 6-dichloro benzyl | H | H | H | -C(O)NHCH 3 |
| 159 | S | Cyclohexyl methyl | H | H | H | -C(O)NH(CH 2) 2OCH 3 |
| The compound sequence number | X | R 1 | R 2 | R 4 | R 5 | R 3 |
| 160 | S | Cyclohexyl methyl | H | H | H | -C(O)NH(CH 2) 2N(C H 3) 2 |
| 161 | S | 4-sulfamyl-benzyl | H | H | H | -C(O)NHCH 3 |
Representational formula (I) compound for example comprises
4-[2-(4-bromo-phenyl amino)-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 [1,4] dioxin-6-yl)-[6-(6,7-dimethoxy-quinolyl-4 oxygen base)-benzoxazoles-2-yl]-amine,
4-[2-(2,3-dihydro-benzo [1,4] dioxin-6-base is 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-(2-chloro-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,4-two chloro-benzylaminos)-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-two ring [3.1.1] heptan-the 3-base is 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-two ring [2.2.1] heptan-2-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-fluoro-benzylamino)-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-(4-chloro-benzylamino)-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 is amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(R)-and 1-(2-methoxyl group-phenyl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
N-{4-[2-(2-chloro-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-yl }-ethanamide,
4-[2-(2,5-two fluoro-benzylaminos)-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 is 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 is 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)-and 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-(3-chloro-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[2-(2-tetramethyleneimine-1-base-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-{2-[2-(2-piperidines-1-base-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 is amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-((1R, 2S)-2-hydroxyl-indane-1-base is 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 is 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 is 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)-and amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-{2-[3-(2-piperidines-1-base-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(pyridin-3-yl methyl)-and 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-tetramethyleneimine-1-base-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-piperidines-1-base-ethylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(2,3-dihydro-benzo [1,4] 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-(2,4-two fluoro-benzylaminos)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-bromo-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-fluoro-5-methoxyl group-benzylamino)-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 is amino]-methyl }-the naphthenic acid ethyl ester,
4-[2-(2,6-two chloro-benzylaminos)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,3-two chloro-benzylaminos)-benzoxazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-chloro-6-fluoro-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,3-two fluoro-benzylaminos)-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] oxadiazole-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-(2,6-two fluoro-benzylaminos)-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 is amino]-methyl }-naphthenic acid,
4-[2-(2,3-dihydro-benzo [1,4] dioxin-5-base is amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(benzo [1,3] dioxole-5-base is 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-(amino-benzoxazoles of 2-sec.-propyl-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)-and 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 is 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-piperidin-4-yl amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(3,4-dihydro-2H-benzo [b] [1,4] two oxa-s
-6-ylmethyl)-and 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 [1,4] 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)-and 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-(5-chloro-2-methoxyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(5-fluoro-2-methoxyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-fluoro-6-methoxyl group-benzylamino)-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-piperidines-1-base-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(4-benzyl-morpholine-2-ylmethyl)-and amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-chloro-6-methoxyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-{2-[2-(2,3-dihydro-benzo [1,4] 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 [1,4] dioxin-5-yl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea
4-[2-(4-chloro-3-trifluoromethyl-phenyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-chloro-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(cyclohexyl methyl-amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(R)-1-(2-methoxyl group-phenyl)-ethylamino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,4-two chloro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-((R)-1-phenyl-ethylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-methoxyl group-benzylamino)-benzothiazole-6-base 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-(2,3-two chloro-benzylaminos)-benzothiazole-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)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-((R)-1-cyclohexyl-ethylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,5-two fluoro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-fluoro-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(tetrahydrochysene-pyrans-4-ylmethyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-morpholine-4-base-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-pyrazol-1-yl-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-dimethylamino-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,6-dimethoxy-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,5-dimethoxy-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,3-two fluoro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(suberyl methyl-amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,6-two fluoro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(pyridine-2-ylmethyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-[2-(3,4-dimethoxy-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(2,3-dihydro-benzo [1,4] dioxin-5-ylmethyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2-piperidines-1-base-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-{2-[(pyridin-3-yl methyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
4-[2-((1R, 2R)-2-benzyloxy-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-((1S, 2S)-2-benzyloxy-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-((1R, 2R)-2-hydroxyl-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea,
4-[2-(2,6-two chloro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea and
4-[2-(4-sulfamyl-benzylamino)-benzothiazole-6-base 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 ﹠amp; Sons, 69-74 page or leaf (1992).
Embodiment preferred, comprise formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or compound (V) or its tautomer and any pharmacologically acceptable salt, ester, meta-bolites and prodrug can comprise asymmetric replacement in them carbon atom.The carbon atom of described asymmetric replacement can produce the compound of the preferred embodiment that exists with enantiomorph, diastereomer and other stereoisomeric forms in any ratio (can define according to the absolute stereo chemistry), such as (R)-or (S)-form.As a result, the mixture and the single diastereomer of 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 "), diastereomer all will be taken into account.Term ＂ S ＂ used herein and ＂ R ＂ configuration such as IUPAC 1974
Pure Appl.Chem.45:13-30 (1976) defines.Term α and β are used for the ring position of ring compound.α-the side of reference plane is sides that preferred substituted 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 ＂ be meant ＂ on the plane following ＂ and expression absolute configuration.Term α used herein and beta comfiguration as
The 203rd section of IV (1987) define.
The method that is used for the treatment of the disease of CSF-1R mediation
The conduction of CSF-1R signal participates in growth of tumor and transfer by 3 kinds of different mechanism.First kind is, CSF-part and receptor expression have seen the tumour cell that originates from female reproductive system (mammary gland, ovary, uterine endometrium, uterine neck) (Scholl 1994; Kacinski 1997; Nagan 199; And should express relevant Kirma2007), with the xenotransplantation growth of mammary cancer and patient with breast cancer's poor prognosis.Two kinds of point mutation are found among the about 10-20% acute myelocytic leukemia, chronic granulocytic leukemia and the myelodysplasia patient's that test in a research the CSF-1R, and find that a kind of sudden change can interrupt the upset of acceptor (Ridge 1990).Yet, in research subsequently, fail to confirm the incidence (Abu-Duhier 2003) of suddenling change.Under some case of liver cancer (Yang 2004) and idiopathic myelofibrosis (Abu-Duhier 2003), also found sudden change.
The result of the transposition that pigmented villonodular synovitis (PVNS) and Tenosynovial giant cells tumour (TGCT) are the M-CSF gene fusion to the glue protogene COL6A3, and cause the overexpression (West 2006) of M-CSF.It is relevant with formed tumor mass that lateral effect is considered to, and this tumor mass is made of the monocyte that cell attracted of being expressed M-CSF.TGCT is the less tumour of can be relatively easily removing the finger of normal existence from them.PVNS has more aggressiveness, controls by surgical operation because it can appear at big joint part and be not easy to.
Second kind of mechanism is based in the transferring position blocking-up of the bone signal conduction by 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 transferring to bone and cause the cancer of the molten osteopathia that causes the bone complication.The M-CSF that is discharged by tumour cell and matter induces the hematopoiesis myelomonocyte to be divided into sophisticated osteoclast with the receptor activator RANKL of nf κ-B part.In this process, M-CSF plays licensing factor, provides survival signal (Tanaka 1993) to osteoclast.Suppressing the CSF-1R kinase activity with micromolecular inhibitor in the differentiation of osteoclast and ripening process might suppress to cause the osteoclast activity of molten osteopathia in the metastatic disease and associated bone incident unbalance.Though mammary cancer, lung cancer and multiple myeloma cause molten bone damage usually, but in prostate cancer, has the scleroblast presentation at first to the transfer of bone, wherein, the bone forming activity that increases 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 tangible molten bone component and high serum level, and the anti-absorption of prompting therapy may be useful.Confirmed that bisphosphonates only can suppress the formation of molten bone damage and the quantity of minimizing bone dependency incident 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.Still (Choueiri 2006 in the clinical study stage in the effect of anti-absorption agent in the molten bone of mixed type/scleroblast prostate cancer; Vessella 2006).
The third mechanism is based on nearest discovery: the tumor-associated macrophage of finding in the solid tumor of mammary gland, prostate gland, ovary and cervical cancer (TAM) is relevant with poor prognosis, and (Bingle 2002; Pollard 2004).Scavenger cell is raised in the 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 block by suppressing the conduction of CSF-1R signal.Recently, people such as Zins confirm (Zins 2007), behind 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% in tumour.Can reduce the M-CSF of mouse and cause the minimizing of scavenger cell in the 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 anti-M-CSF antigen-binding fragments of antibodies treatment MCF7 tumor xenogeneic graft and suppress, reverse the resistance of chemotherapeutics and improve the survival (Paulus 2006) of mouse.
TAMs is a unique example that contact takes place between chronic inflammatory diseases and cancer.For the contact between inflammation and the cancer, also there is other evidence, because many chronic diseases are all relevant with the risk of cancer that increases, 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 experiment type cancer, and the life-time service anti-inflammatory agent has reduced the risk of some cancer.Be present in many inflammatory conditions with getting in touch of cancer, Hp inductive gastritis, schistosomicide relevant and bladder cancer is relevant, HHV8 is relevant with the Kaposi sarcoma, endometriosis is relevant with ovarian cancer, prostatitis relevant with prostate cancer (Balkwill 2005) wherein with cancer of the stomach.Scavenger cell is the key cells in the chronic inflammatory diseases, and their microenvironment is had different responses.Have two types scavenger cell to be considered to the end of a successive functional status: the M1 scavenger cell participates in the reaction of 1 type.These reactions relate to the activation of microbial product, kill the invasive organism body that produces the reactive oxygen intermediate subsequently.The other end endways is the M2 scavenger cell that participates in the reaction of 2 types, and it promotes cell proliferation, regulates inflammation and adaptive immunity and promotion reconstructed tissue, vasculogenesis and repairing (Mantovani 2004).Cause the chronic inflammatory diseases of the tumour of establishing relevant with the M2 scavenger cell usually.The key cytokines of inducing inflammatory reaction is TNF-α, and is 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 by tumor cells expression, and (Zins 2007; 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.
Rabello 2006 has proved that SNPs in the CSFl gene and aggressive periodontitis are proportionate, and this disease is a kind of inflammatory periodontal tissue disease that causes the tooth loss owing to frontal resorption.
(also being known as youth's lattice Chinese cell tissue cytosis, LCH) is the proliferative disease of a kind of youth's lattice Chinese dendritic cell, the LCH damage that osteoclast in this cytodifferentiation skeletonization and bone are outer in histiocytosis X.Youth's lattice Chinese cell is from round-robin monocyte (Ginoux 2006).Have been found that the increase of the M-CSF level that records in serum and damage and the severity relevant (da Costa2005) of disease.This disease mainly occurs among the child patient group, and become general when disease or when recurrence, must carry out chemotherapy.
The physiopathology of osteoporosis is mediated by osteoblastic minimizing that forms bone and the dependent bone resorption increase of osteoclast.The supportive evidence of Cenci shows, injects anti--M-CSF antibody and can keep bone density and suppress bone resorption (Cenci 2000) in OO mouse.Recent findings potential contact the between the bone loss after estrogen deficiency and the menopause, and the existence of finding to produce the T cell of TNF α can influence bone metabolism (Roggia 2004).A possible mechanism is that TNF α induces M-CSF in vivo.The antibody of anti-M-CSF-inhibitor is blocked TNF α inductive osteolysis in mouse effect has confirmed that M-CSF lures the vital role of splitting in the generation at TNF-α inductive bone, 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 second kind of modal bone after osteoporosis, and the local anomaly of the bone renewal that wherein increases causes complication such as bone pain, distortion, pathologic fracture and deafness.Confirmed four kinds of transgenations of regulating normal osteoclast function and making individual easy trouble PDB and relative disease: the inactivation of the insertion sudden change among the TNFRSF11A of the receptor activator (RANK) (the crucial conditioning agent of osteoclast function) of coding nf (NF) κ B, the TNFRSF11B of coding osteoprotegerin (the bait acceptor of RANK part) suddenlys change, the sudden change of Sequestosome 1 gene (SQSTM1) of the important scaffolding protein of encoding in NF κ B passage, and contains the sudden change in valosin albumen (VCP) gene.This genes encoding VCP, it makes NF kB inhibitor target work (Daroszewska, 2006) in the degraded that proteasome causes.The CSF-1R inhibitor of target provides chance for the imbalance of blocking the conduction of RANKL signal indirectly, and has increased other treatment option for present used bisphosphonates.
Especially be another kind of indication by cancer therapy inductive bone loss in mammary gland and patients with prostate cancer, wherein, the CSF-1R inhibitor of target can prevent bone loss (Lester 2006).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 influences bone metabolism by reducing bone mineral density, cause the risk increase (Lester 2006) 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 (Stoch 2001) of the fracture relevant with osteoporosis.
When target cell type comprised 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 caused implant failure of loss of the bone of Periprosthetic and the prosthetic loosening that comes next is the major complications of joint replacement and need undergos surgery repeatedly, thereby caused the high social economy of individual patients and healthcare system to bear.Up to the present, also there is not the pharmacological agent of permission 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 (Guzman-Clark 2007 in the loss of life-time service glucocorticosteroid (because various illnesss comprise chronic obstructive pulmonary disease, asthma and rheumatoid arthritis) back prevention bone; Feldstein 2005).
Rheumatoid arthritis, psoriatic arthritis and inflammatory arthropathy also are the potential indications of CSF-1R signal conduction depressant drug, because their scavenger cell becomes branch to cause in various degree osteoclasia (Ritchlin 2003).Osteoarthritis and rheumatoid arthritis are to be assembled in reticular tissue and scavenger cell invades caused inflammatory autoimmune disease in the synovia by scavenger cell, and it is mediated by M-CSF to small part.People such as Campbell (2000) are produced by people's joint tissue cell (chondrocyte, synovial membrane fibrocyte) at the external M-CSF that confirmed, and be found in the patient's who suffers from rheumatoid arthritis the 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 might control the scavenger cell quantity in the joint and alleviate the relevant caused pain of osteoclasia.For disadvantageous effect being minimized and further understand the CSF-1R signal conduction influence in these indications, a kind of method is to suppress CSF-1R specifically and other numerous kinases of target not, such as the Raf kinases.
The circulation M-CSF that nearest bibliographical information will increase and the poor prognosis and the progression of atherosclerosis of chronic coronary artery disease connect that (Saitoh 2000; Ikonomidis 2005); M-CSF influences Atherosclerosis by the formation that helps foam cell (scavenger cell with oxidation LDL of absorption), this cell expressing CSF-1R and represented initial patch (Murayama 1999).
The expression of M-CSF and CSF-1R and signal conduction are found in the activatory microgliacyte.Microgliacyte (it is the resident scavenger cell of central nervous system) can be activated by various damages, comprises infecting and traumatic damage.M-CSF is considered to the crucial conditioning agent of the Inflammatory response in the brain, and the M-CSF level increases in HIV-1 encephalitis, Alzheimer (AD) and cerebral tumor.Through experiment type nerve injury model validation, the nervelet cellula adhesiae hyperplasia that is caused by the autocrine signal of M-CSF/CSF-1R can be induced inflammatory cytokine and nitric oxide production release, and (Hao 2002; Murphy1998).Alzheimer in the amyloid precursor protein V717F of the transgene mouse model of patch and Alzheimer, found that CSF-1R expresses the microgliacyte (Murphy 2000) that increases.On the other hand; the op/op mouse that has a small amount of microgliacyte in brain is compared the A β that is produced with normal control fiber-like deposition and neurone loss show that microgliacyte has the neuroprotective function really in the progress of Alzheimer, then lack this function (Kaku 2003) in the op/op mouse.
On the one hand, embodiment preferred 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 this method comprises using to described individuality and alleviates 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 the individuality.
On the other hand, embodiment preferred 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 this method comprises using to described individuality and alleviates or prevent individual bone to lure formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or the compound (V) that splits generation, bone resorption and/or bone injury significant quantity.
On the other hand, embodiment preferred 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 this 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 a other promoting agent.In a more preferred embodiment, described other promoting agent is a 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, embodiment preferred 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 about 5 times or about 10 times or about 20 times or about 30 times or about 50 times or about 100 times or about 250 times or about 500 times or about 750 times or about 1 than suppressing Raf, 000 times or about 2,000 inhibition activity is (for example, with regard to IC
50Value) suppresses CSF-1R.
The method that suppresses CSF-1R is provided on the other hand, and this method comprises cell is contacted with formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or compound (V).In some aspects, this compound is 4-{2-[(2,3-dihydro-cumarone-5-ylmethyl)-and amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea or 4-[2-((1R, 2R)-2-benzyloxy-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea.
On the one hand, this compound is determined the biological test below the inhibition effect utilization of Raf.The kinase whose activity of Raf is by providing ATP, reorganization 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 behind purifying.With MEK cDNA N-end (His)
6Mark subclone and at expression in escherichia coli, then with the MEK substrate of reorganization by nickel affinity chromatography purifying from the intestinal bacteria lysate, carry out anionresin then.With final MEK substrate preparation biotinylation (Pierce EZ-LinkSulfo-NHS-LC-Biotin) and be concentrated into about 11.25 μ M.Reorganization Raf (comprising c-Raf and mutant B-Raf isoform) obtains from the sf9 insect cell that infects with corresponding people Raf recombinant expression vector by purifying.The Raf isoform of reorganization is passed through the interaction of Glu antibody or passes through the metal ion chromatogram purification.
For each test, this compound is for example diluted in DMSO with 3-times of diluent continuously since 25 μ M, mix mutually with various Raf isoforms (every kind of about 0.50nM) then.Kinases inactivation vitamin H-MEK substrate (50nM) adding is contained in the reaction buffer of ATP (1 μ M).This reaction buffer contains 30mM Tris-HCl
2PH 7.5,10mM MgCl
2, 2mM DTT, 4mMEDTA, 25mM β-glycerophospholipids, 5mM MnCl
2With 0.01% BSA/PBS.Subsequently reaction solution at room temperature is incubated about 2 hours, by adding 0.5M EDTA termination reaction.Transfer to the mixture of termination reaction on the plate that has applied Neutradavin and be incubated about 1 hour.With the product of phosphorylation with DELFIA time difference type fluorescing system, utilize rabbit anti--p-MEK (Cell Signaling) measures as secondary antibody as one-level antibody and with the resisting of europium mark-rabbit.Time difference type fluorescence can be on Wallac 1232 DELFIA photofluorometers reading.50% inhibition concentration (IC of compound
50) utilize XL Fit data analysis software to calculate by non-linear regression.
On the other hand, embodiment preferred provides the method that human or animal's individual treatment of the described treatment of needs is related to the CSF-1R disease, and this method comprises to described individuality uses formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or compound (V) and at least a other promoting agent that is used for the treatment of cancer that alleviates or prevent individual tumors growth significant quantity.In a more preferred embodiment, described other promoting agent is a 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; With anticarcinogen bonded monoclonal antibody, toxin and/or radionuclide; Biological response modifier (for example Interferon, rabbit [for example IFN-α etc.] and interleukin [for example I1-2 etc.] etc.); The adoptive immunotherapy promoting agent; Hemopoieticgrowth factor; The medicament of inducing tumor cell differentiation (for example alltrans-vitamin A acid 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 that is used in combination with the compound of preferred embodiment comprises and inducing 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 [for example 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)]; With cancer chemotherapy medicine [for example irinotecan (Camptosar), CPT-11, fludarabine (Fludara), Dacarbazine (DTIC), dexamethasone, mitoxantrone, Mai Luota, VP-16, cis-platinum, 5-FU, Zorubicin, taxotere or taxol; The cell signal molecule; Ceramide and cytokine; With star-like spore rhzomorph etc.
The compound of preferred embodiment can be used for the growth of anticancer in external or body.This compound can use separately or be used in combination with pharmaceutically acceptable carrier or vehicle.
On the other hand, embodiment preferred provides and has comprised at least a formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or compound (V) and the suitable medicine group composition that delivers medicine to pharmaceutically acceptable carrier of human or animal's individuality or also comprise other carcinostatic agent separately.
On the other hand, embodiment preferred 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 preferentially suppresses CSF-1R with respect to the Raf kinases.More particularly, described compound suppresses the Raf kinases with the concentration greater than about 1 μ M.
On the other hand, it further comprises other promoting agent.More particularly, described other promoting agent is a bisphosphonates.
On the other hand, the active formula of CSF-1R (I) that when to its administration, can effectively suppress human or animal's individuality, (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) compound are provided.More particularly, the IC that shows for the CSF-1R restraining effect of described compound
50Value is less than about 1 μ M.More particularly, the IC that shows for the Raf restraining effect of described compound
50Value is greater than about 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 used for the growth of anticancer in external or body.This compound can use separately or be used in combination with pharmaceutically acceptable carrier or vehicle.Suitable pharmaceutically acceptable carrier or vehicle comprise for example 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. among the NewJersey (1991), is introduced into as a reference at this.
Administration and pharmaceutical composition
Usually with the compound of preferred embodiment with any administration in the generally acknowledged administering mode of the medicament of treatment significant quantity by playing 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 effectiveness, 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, preferred 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 in the 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 effect and be enough to suppress the active any amount of CSF-1R with detecting.
Can will change along with the ad hoc fashion of the main body of treatment and administration with the combined amount with the activeconstituents that produces single formulation of carrier substance.Yet, should be appreciated that, the concrete dosage level that is used for any particular patient will depend on various factors, comprise the combination of speed, medicine of activity, age, body weight, general health situation, sex, diet, administration time, route of administration, the discharge of used particular compound and the severity of the specified disease for the treatment of.Be used for being easy to determine by normal experiment to the treatment significant quantity of stable condition, 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 about 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.
Various factors such as administering mode and bioavailability of medicament are 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 the 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.The another kind of mode that preferably is used to use the compound of preferred embodiment is an inhalation.This is a kind of effective ways (referring to US 5,607,915) that are used for therapeutical agent directly is sent to respiratory tract.
Suitable pharmaceutically acceptable carrier or vehicle comprise for example 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, comprise water, salt solution, D/W and glycols in particular for the liquid vehicle of injection solution.Other suitable pharmaceutically acceptable vehicle is at ＂ Remington ' s PharmaceuticalSciences, and ＂ Mack Pub.Co. describes among the New Jersey (1991) to some extent, is introduced into as a reference at this.
Term used herein " pharmacologically acceptable salt " is meant formula (I), (IIa), (IIb), (IIIa), (IIIb), (IV) or (V) the 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 the purge process, or by in 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; Sulfuric acid dialkyl such 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 such as benzyl and phenethyl bromide etc.Obtain water or oil soluble or dispersed product thus.
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 the purge process, or reacts by oxyhydroxide, carbonate or supercarbonate with carboxylic moiety and suitable alkali such as pharmaceutically useful metallic cation in addition or obtain with ammonia or organic primary, second month in a season or reactive tertiary amine.Pharmacologically acceptable salt includes but not limited to include but not limited to the salt of ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethyl amine, Trimethylamine, triethylamine, ethylamine etc. based on positively charged ion of basic metal and alkaline-earth metal such as sodium, lithium, potassium, calcium, magnesium, aluminium salt etc. and nontoxic ammonium, quaternary ammonium and amine positively charged ion.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 " is meant the ester of hydrolysis 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 has and is 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 " is meant and is applicable in rational medical judgment scope and contacts with the tissue of people and rudimentary animal and do not have unsuitable toxicity, stimulation, atopic reaction etc., have reasonably and be benefited/risk-ratio and amphoteric form of the compound of the prodrug of the compound of the effective preferred embodiment of desirable application and this embodiment under possible situation to it simultaneously.Term " prodrug " is meant the compound that can change rapidly in vivo with the parent compound that obtains following formula, for example by hydrolysis in blood.At T.Higuchi and V.Stella, Pro-drugs as NovelDelivery Systems, the 14th volume and the Edward B.Roche of A.C.S.Symposium Series compile, Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987 in that 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 the body processing to produce metabolite by metabolism.Term used herein " metabolite " is meant the structural formula of any derivative that produces 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, people such as G., J.Med.Chem.40:2011-2016 (1997); 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 Press 1985); And Larsen, I.K., Design andApplication of Prodrugs, Drug Design and 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 the preferred embodiment.
The compound of preferred embodiment can be by oral, parenteral, hypogloeeis, by aerosol or suck spraying, rectum or 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 the 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 prepared according to the suitable dispersion agent of methods known in the art utilization or wetting agent and suspending agent.Aseptic injection preparation can also be at nontoxic parenteral acceptable diluent or aseptic injectable solution or the suspension in the solvent, for example, 1, the solution of ammediol.Spendable acceptable carrier and solvent are water, Ringer solution and isotonic sodium chlorrde solution.In addition, aseptic fixed oil is also usually as solvent or suspension medium.For this purpose, the fixed 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 make by this medicine is mixed mutually with suitable non-irritating excipient such as theobroma oil and polyoxyethylene glycol, described vehicle is solid at normal temperatures, but under rectal temperature, be liquid, therefore can and discharge medicine in the internal rectum fusing.
The solid dosage that is used for oral administration can comprise capsule, tablet, pill, powder and granula.In solid dosage, active compound is mixed mutually with at least a inert diluent such as sucrose, lactose or starch.Usually, this formulation also can comprise other material except that inert diluent, and for example lubricant is such as Magnesium Stearate.Under the situation of capsule, tablet and pill, this formulation also can comprise buffer reagent.In addition, tablet and pill can have casing.
The liquid dosage form that is used 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.Be that liposome is usually derived from phosphatide or other lipid material as known in the art.Liposome by be dispersed in list in the water-bearing media-or the crystallization of multilayer hydration liquid 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.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, this compound can be prepared and load to the suitable dispersion agent that is used for administration with the form of liquor, suspension, aerosol propellants or dry powder.Medicinal inhalation devices-the aerohaler, metered-dose inhaler (MDI) and the Diskus (DPI) that have several types.Spraying plant produces and to make the high-speed air flow of therapeutical agent (liquid absorption member) with the mist spraying of the respiratory tract that can enter the patient.Usually MDI is carried out preparation packing with pressurized gas.In case 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 distributed in patient's the suction air-flow by device in respiratory.In order to obtain free-pouring powder, therapeutical agent is prepared such as lactose with vehicle.The therapeutical agent of measured quantity is stored with capsular form, when each the startup, distribute then.
Recently, can be based on bioavailability by increasing surface-area, promptly reducing the principle that granularity increases, be in particular the bioavailability difference drug development pharmaceutical preparation.For example, US 4,107, and 288 to have described granularity be about 10 to about 1, and the pharmaceutical preparation of 000nm wherein loads to active substance on the macromolecular crosslinked matrix.US 5,145,684 have described the preparation of pharmaceutical preparation, wherein medicine are ground to form nano particle (mean particle size is about 400nm) in the presence of surface-modifying agent, are dispersed in then in the liquid medium to obtain showing the pharmaceutical preparation of significant high bioavailability.
Combined therapy
Though the form administration that the compound of preferred embodiment can the single-activity medicament, they also can be used in combination with used one or more other medicaments of treatment cancer.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 the 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 bonded compound that can disturb or suppress 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 male sex hormone and androgen receptor bonded compound.The example of representational androgen receptor modifier comprises finasteride and other 5 inhibitor, Nilutamide, flutamide, bicalutamide, liarozole and acetic acid Abiraterone.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 bexarotene, vitamin A acid, 13-cis-vitamin A acid, 9-cis-vitamin A acid, alpha-difluoromethyl ornithine, LX23-7553, trans-N-(4 '-hydroxy phenyl) look 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 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 inhibitor/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; heptan platinum; Emcyt; the improsulfan tosylate; trofosfamide; nimustine; dibrospidium chloride; pumitepa; Lip river platinum; husky platinum; methylmitomycin; Platinol; irofulven; right ifosfamide; cis-amine dichloro (2-methyl-pyridine) platinum; the benzyl guanine; glufosfamide; GPX100; (trans; trans; trans)-two-mu-(hexane-1; the 6-diamines)-and mu-[diamines-platinum (II)] two [diamines (chlorination) platinum (II)] tetrachloride; diazacyclo propyl group spermine; white arsenic; 1-(11-dodecyl amino-10-hydroxyl undecyl)-3, the 7-dimethyl xanthine; 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 WO 00/50032).The representative example of anoxic activated form compound is a Win-59075.Proteasome inhibitor includes but not limited to lactacystin and Velcade.The example of microtubule inhibitor/microtubule stabilizer comprises taxol, Vindesine Sulfate, 3 ', 4 '-two dehydrogenations-4 '-deoxy-8 '-navelbine, Docetaxel, rhizocholic acid, dolastatin, the mivobulin isethionate, Auristatin, Cemadotin, RPR109881, BMS184476, Vinflunine, Cryptophycin, 2,3,4,5,6-five fluoro-N-(3-fluorine 4-p-methoxy-phenyl) benzsulfamide, F 81097, N, N-dimethyl-L-Xie Ansuan-L-Xie Ansuan-N-methyl-L-Xie Ansuan-L-proline(Pro)-L-proline(Pro)-tert-butylamides, TDX258, the ebormycine class is (referring to for example US 6,284,781 and US 6,288,237) and BMS188797.The representational example of topoisomerase enzyme inhibitor comprises that the holder pool is for bank; Hycaptamine; irinotecan; rubitecan; 6-ethoxy-c acyl group-3 '; 4 '-O-is outer-benzylidene-chartreuse mycin; 9-methoxyl group-N; N-dimethyl-5-nitropyrazole also [3; 4; 5-kl] bifurcation pyridine-2-(6H) propylamine; 1-amino-9-ethyl-5-fluoro-2; 3-dihydro-9-hydroxy-4-methyl-1H; 12H-benzo [de] pyrans also [3 '; 4 ': b; 7]-indolizine also [1; 2b] quinoline-10; 13 (9H; 15H) diketone; lurtotecan; 7-[2-(N-sec.-propyl amino) ethyl]-(20S) camptothecine; BNP1350; BNPI1100; BN80915; BN80942; Etoposide phosphoric acid salt; moor sweet for the Buddhist nun; 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-two [(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 WO 01/30768 and WO01/98278, WO 03/050,064 (on June 19th, 2003), WO 03/050,122 (on June 19th, 2003), WO 03/049,527 (on June 19th, 2003), WO 03/049,679 (on June 19th, 2003), WO 03/049,678 (on June 19th, 2003) and WO 03/39460 (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; the 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-Mi Dingbing [5; 4-b] [1; 4] thiazine-6-base-(S)-ethyl]-2; 5-Thenoyl-L-L-glutamic acid; 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-ammonioformaldehyde thiocarbamide.The example of monoclonal antibody target therapeutical agent comprise have 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.To the HMG-CoA reductase enzyme have suppress active compound can be at an easy rate by utilizing test known in the art to discern, such as US 4,231,938 and WO 84/02131 test that describe or that quote.The example of spendable HMG-CoA reductase inhibitor include but not limited to lovastatin (
Referring to US 4,231,938,4,294,926 and 4,319,039), Simvastatin (
Referring to US 4,444,784,4,820,850 and 4,916,239), Pravastatin (
Referring to US 4,346,227,4,537,859,4,410,629,5,030,447 and 5,180,589), fluvastatin (
Referring to US 5,354,772,4,911,165,4,929,437,5,189,164,5,118,853,5,290,946 and 5,356,896) and atorvastatin (
Referring to US 5,273,995,4,681,893,5,489,691 and 5,342,952).The structural formula of these and other HMG-CoA reductase inhibitor that can be used for present method is at M.Yalpani, ＂ CholesterolLowering Drugs ＂, Chemistry ﹠amp; Among the Industry, the 87th page of pp.85-89 (on February 5th, 1996) and US 4,782,084 and 4,885,314 description is arranged.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 is also referred to as Rab GGPTase).The example that the isopentene group protein transferase suppresses compound comprises (±)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H) quinolinone; (-)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone; (+)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl)]-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-piperazine ketone; (S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-2-piperazine ketone; 5 (S)-normal-butyl-1-(2-aminomethyl phenyl)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone; 1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-2-methyl-5-imidazolyl methyl]-2-piperazine ketone; 1-(2; the 2-diphenyl-ethyl)-and 3-[N-(1-(4-cyano group benzyl)-1H-imidazoles-5-base ethyl) formamyl] piperidines; 4-{-[4-hydroxymethyl-4-(4-chloropyridine-2-ylmethyl)-piperidines-1-ylmethyl]-glyoxal ethyline-1-ylmethyl } cyanobenzene; 4-{-5-[4-hydroxymethyl-4-(3-benzyl chloride base)-piperidines-1-ylmethyl]-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)-and 3H-imidazol-4 yl methyl] cyanobenzene; 18; 19-dihydro-19-oxo-5H; 17H-6; 10:12; 16-two endo-methylene groups-1H-imidazo [4; 3-c] [1; 11; 4] two oxa-s 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-two endo-methylene groups-22H-imidazo [3; 4-h] [1; 8; 11; 14] oxa-three nitrogen heterocyclics 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--three nitrogen heterocyclic-9-formonitrile HCN.Other example of isopentene group-protein transferase inhibitor can be referring to following publication and patent: WO 96/30343, WO97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, US 5,420,245, US 5,523,430, US 5,532,359, US 5,510,510, US 5,589,485, US 5,602,098, EP0 618 221, EP 0 675 112, EP 0 604 181, EP 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, US 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, US 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436 and US 5,532,359.Can be referring to European J.of Cancer 35 (9): 1394-1401 (1999) about isopentene group-protein transferase inhibitor to the example of vascularization role.
Angiogenesis inhibitor is meant 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-deutero-, the inhibitor of inoblast-deutero-or platelet-derived somatomedin, MMP (matrix metalloproteinase) inhibitor, the integrin retarding agent, interferon-' alpha ', il-1 2, piperylene gathers vitriol, cyclooxygenase-2 inhibitors comprises that NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) is as acetylsalicylic acid and Ibuprofen BP/EP and optionally COX-2 inhibitors such as celecoxib and rofecoxib (PNAS 89:7384 (1992); JNCI69:475 (1982); Arch.Ophthalmol.108:573 (1990); Anat.Rec., (238): 68 (1994); FEBS Letters 372:83 (1995); Clin, Orthop.313:76 (1995); J.Mol.Endocrinol.16:107 (1996); Jpn.J.Pharmacol.75:105 (1997); Cancer Res.57:1625 (1997); Cell 93:705 (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, the 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 (October 1999); Kim etc., Nature, 362:841-844 (1993); WO 00/44777; With WO 00/61186).Other therapeutical agent that can regulate or suppress vasculogenesis and can be used in combination with the compound of preferred embodiment comprises can adjusting or the promoting agent (referring to the summary among the 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 open WO 03/013,526 of PCT and United States Patent (USP) sequence number 60/349,925 (in application on January 18th, 2002).Embodiment preferred also comprises the combination of the compound and the NSAIDs of preferred embodiment, NSAIDs is that optionally cox 2 inhibitor (is normally defined, compare with COX-1, the specificity that suppresses COX-2 is at least about 100 times compound, with the IC that suppresses COX-2
50With the IC that suppresses COX-1
50Ratio weigh, assess by cell or microsome test).This compound includes but not limited to the compound of following patent disclosure: December 12 nineteen ninety-five disclosed US5,474,995, on January 19th, 1999 disclosed US 5,861,419, on December 14th, 1999 disclosed US 6,001,843, on February 1st, 2000 disclosed US 6,020,343, April 25 nineteen ninety-five disclosed US 5,409,944, July 25 nineteen ninety-five disclosed US 5,436,265, on July 16th, 1996 disclosed US 5,536,752, on August 27th, 1996 disclosed US 5,550,142, on February 18th, 1997 disclosed US 5,604,260, on December 16th, 1997 disclosed US 5,698,584, on January 20th, 1998 disclosed US 5,710,140, on July 21st, 1994 disclosed WO94/15932, on June 6th, 1994 disclosed US 5,344,991, on July 28th, 1992 disclosed US 5,134,142, January 10 nineteen ninety-five disclosed US 5,380,738, February 20 nineteen ninety-five disclosed US 5,393,790, November 14 nineteen ninety-five disclosed US 5,466,823, on May 27th, 1997 disclosed US 5,633, on August 3rd, 272 and 1999 disclosed US 5,932,598, 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 5-chloro-3-(4-methyl sulphonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine.That describe and compound and synthetic method thereof that can be used for preferred embodiment thus can be referring to following patents as the specific inhibitor of COX-2; pending application and patent disclosure; at this they are incorporated herein by reference: on July 21st, 1994 disclosed WO 94/15932; on June 6th, 1994 disclosed US 5; 344; 991; on July 28th, 1992 disclosed US 5; 134; 142; January 10 nineteen ninety-five disclosed US 5; 380; 738; February 20 nineteen ninety-five disclosed US 5; 393; 790; November 14 nineteen ninety-five disclosed US 5; 466; 823; on May 27th, 1997 disclosed US 5; 633; 272; on August 3rd, 1999 disclosed US 5; 932; 598; December 12 nineteen ninety-five disclosed US 5; 474; 995; on January 19th, 1999 disclosed US5; 861; 419; on December 14th, 1999 disclosed US 6; 001; 843; on February 1st, 2000 disclosed US 6; 020; 343; April 25 nineteen ninety-five disclosed US 5; 409; 944; July 25 nineteen ninety-five disclosed US 5; 436; 265; on July 16th, 1996 disclosed US 5; 536; 752; on August 27th, 1996 disclosed US 5; 550; 142; on February 18th, 1997 disclosed US 5; 604; 260; on December 16th, 1997 disclosed US 5; 698; on January 20th, 584 and 1998 disclosed US 5; 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; 5-two chloro-4-(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-two [imino--N-methyl-4,2-pyrrolo-carbonyl imino-[N-methyl-4,2-pyrroles]-carbonyl imino-]-two-(1; the 3-napadisilate) and 3-[(2, methylene radical 4-dimethyl pyrrole-5-yl)]-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 makes 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 inhibitor such as the WO 02/083064 of Akt, WO02/083139, inhibitor described in WO 02/083140 and the WO 02/083138), 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).
In some present embodiment preferred, be used for comprising that with the combined representative promoting agent of the compound of preferred embodiment of treatment cancer for example irinotecan, holder pool are for bank, gemcitabine, 5 FU 5 fluorouracil, formyl tetrahydrofolic acid, carboplatin, cis-platinum, taxanes, Te Zhata shore (tezacitabine), endoxan, catharanthus alkaloid, imatinib (Gleevec), anthracene nucleus class, Rituximab, Herceptin and other cancer chemotherapeutic agents.
Be used for above-claimed cpd that the compound with preferred embodiment is used in combination can Physicians ' Desk Reference (PDR) therapeutic dose shown in the 47th edition (1993) use, be introduced into as a reference at this, perhaps this treatment consumption is that those of ordinary skills are known.
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 the 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 form administration of combination, therapeutical agent is prepared with the form of independent composition, in identical time or different time administration, or with the form administration of therapeutical agent with single composition.
General synthetic method
The compound of preferred embodiment can make from the general method below the facile prepared using.Should be appreciated that other processing condition also can be used, except as otherwise noted under the situation that provides typical or preferred processing condition (promptly, mol ratio of temperature of reaction, time, reactant, solvent, pressure etc.).Optimum reaction condition can be along with used specific reactants or solvent and is changed, but this condition can be determined by the optimization routine method 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 unwanted reaction to take place to prevent some functional group.It is known in the art being used for the suitable protecting group of various functional groups and being used to protect 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, be introduced into as a reference at this.
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, promptly, make or separate with the form of independent enantiomorph or diastereomer or 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 indication is arranged in addition.The pure stereoisomers mixture of steric isomer (or be rich in) can utilize optically-active raw material for example known in the art or stereoselectivity reagent to make.Perhaps, the racemic mixture of this compound for example can utilize that separation such as chiral column chromatogram, chiral separation agent obtains.
The raw material that is used for following reaction normally known compound maybe can make by currently known methods or its conspicuous improving one's methods.For example, many raw materials buy 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 conspicuous 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 separate 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 whole bag of tricks that the compound of the present embodiment utilizes those skilled in the art to be familiar with usually makes, for example U.S. Patent Application Publication No. US20040087626 A1 and the disclosed method of US20040122237 A1 introduce with following description and embodiment to combine at this full text with its disclosure.The compound of this embodiment makes according to following reaction process 1-8 usually, and flow process 1-8 has detailed description in following examples.
Flow process 1-8 explains and understands and to be used to prepare 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 only is for indicative purpose.
Flow process 1
In flow process 1,2-hydroxyanilines or derivatives thereof and ethyl xanthogenate are reacted to obtain mercaptan-benzoxazoles.The reaction of mercaptan-benzoxazoles and thionyl chloride is changed into the chloro-benzoxazole.Perhaps, also can be with the mercaptan benzoxazole with one group of halogenating agent, change into the halo benzoxazole such as but not limited to phosphorus trichloride, phosphorus tribromide, phosgene or oxalyl chloride.Then with chloro-benzoxazole and benzyl amine such as the reaction of 2-benzyl chloride base amine to obtain benzylamino-benzoxazoles.With benzylamino-benzoxazoles and chloro-pyridine in the presence 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, with mercaptan-benzoxazole or derivatives thereofs in the thiol moiety alkylation.Alkylating mercaptan-benzoxazoles and corresponding haloperidid such as chloro-pyridine are carried out the compound that coupling obtains the present embodiment in the presence of alkali such as cesium carbonate.The benzoxazolyl oxygen base-pyridine that forms is utilized for example mCPBA oxidation.Other oxygenant also can be used for mercaptan oxidation is become 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 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, the crystallization to form 1-cyano group-naphthenic acid ethyl ester.This product is reduced with hydrogen and Raney nickel.Also available other reductive agent is reduced into amine with 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.With reduzate and sulfinyl-benzoxazolyl oxygen base-pyridine couplings mutually.With the further functionalized or derivatize of the formed product of linked reaction.For example, in flow process 3, ester group can be changed into carboxylic acid by hydrolysis, change into acid amides with the amine reaction then.These reactions are conversion reactions well known by persons skilled in the art.
Flow process 4
In flow process 4,3-(2-piperidines-1-base-ethyl)-phenyl amine is an example that can be used for forming the compound of the present embodiment.3-(2-piperidines-1-base-ethyl)-phenyl amine forms from 2-(3-nitrophenyl)-alcoholic acid sulfonation reaction, then with methylsulfonic acid 2-(3-the nitrophenyl)-ethyl ester amination that forms, subsequently with formed 1-[2-(3-nitrophenyl)-ethyl]-the piperidines reduction.
Flow process 5
In flow process 5, with 4-(2-(methylsulfinyl) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide with the amination of cyclohexyl methylamine.Then with 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 with 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 reaction to be to form 4-(2-(cyclohexyl methyl amino) benzo [the basic oxygen base of d] oxazole-6-) 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, 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 with borane reduction.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 become 4-(2-(cyclohexyl methyl amino) benzo [the basic oxygen base of d] oxazole-6-) pyridine-2-formaldehyde with the Dess-Martin reagent oxidation.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 with 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formaldehyde by changing into cyclohexyl methyl-{ 6-[2-(5-methyl isophthalic acid H-imidazoles-2-yl)-pyridin-4-yl oxygen base]-benzoxazoles-2-yl }-amine with the pyruvic aldehyde reaction.
Flow process 7
In flow process 7, the compound of this embodiment synthesizes by the reaction of 4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (from embodiment 2) and 1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamine.In one case, 1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamine synthesizes by resin.
With the amine and 2 that is connected on the resin, [1,4] dioxin-5-formaldehyde reaction obtains C-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-benzylidene amino to 3-dihydro-benzo thus.C-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-benzylidene amino at imino-site derivatize, is for example used methyl-magnesium-bromide by alkylation.Can use other alkylating agent according to required molecule.1-(2,3-dihydro-benzo [1,4] dioxin-5-the yl)-ethylamine that forms is dissociated out from resin.The dissociate example of agent of resin is trifluoroacetic acid (TFA).Formed 1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamine can be used for compound synthetic of this embodiment.For example; can be with 1-(2; 3-dihydro-benzo [1; 4] dioxin-5-yl)-ethylamine and 4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea reaction to be to form 4-{2-[1-(2; 3-dihydro-benzo [1,4] 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 US 4,873, and 346 described methods make.Then 2-sulfydryl-benzothiazole-6-alcohol is changed into 2-methylthio group-benzothiazole-6-alcohol to remove the ether protecting group by ordinary method.The reaction of 2-methylthio group-benzothiazole-6-alcohol and methyl iodide provides the alkylation in the mercaptan position.2-methylthio group-benzothiazole-6-alcohol obtains 4-(2-methylthio group-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea with the reaction of 4-chloro-pyridine-2-formic acid methyl nitrosourea.Obtain 4-(2-methanesulfinyl-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea with rear oxidation 4-(2-methylthio group-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea.4-(2-methanesulfinyl-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea can be the substrate that is used for various amine reactions.For example, 4-(2-methanesulfinyl-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea and cyclohexyl methyl amine are reacted to obtain 4-[2-(cyclohexyl methyl-amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea.
Flow process 9
In flow process 9, the benzoxazole of formula 9.1 or benzothiazole can react to obtain the intermediate of formula 9.2 with the amine that replaces.With the intermediate of formula 9.2 with reagent BBr for example
3Processing obtains the phenol of formula 9.3.Subsequently with the intermediate of formula 9.3 with the 4-haloperidid of formula 9.4 usually but be not limited in the presence of alkali such as salt of wormwood or cesium carbonate, handle the formula of obtaining 9.5 compounds under the temperature of room temperature to 130 ℃.Under well known by persons skilled in the art and Suzuki or Stille reacting phase condition together, obtain formula 9.6 compounds with boric acid or further processing of stannic hydride.In addition, formula 9.5 compounds can also be handled the formula of obtaining 9.7 compounds with the amine that replaces under well known by persons skilled in the art and Buchwald reaction or SnAr reacting phase condition together.
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, and raw material (1) is reacted to obtain the intermediate of formula 10.3 under Buchwald reaction well known by persons skilled in the art or SnAr reaction conditions with the amine that replaces at the intermediate of handling the formula of obtaining 10.2 under Suzuki well known by persons skilled in the art or the Stille reaction conditions or (2) with boric acid or stannic hydride.Subsequently with the phenol intermediate of the intermediate of formula 10.2 or 10.3 and formula 10.4 alkali for example salt of wormwood or cesium carbonate in the presence of solvent for example in dimethyl formamide, acetonitrile or the dioxan reaction obtain the compound of formula 10.5 and 10.6.
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.
Compound and/or intermediate are had 2695 Separation Module by high performance liquid chromatography (HPLC) utilization, and (Milford, Waters Millenium chromatographic system MA) characterizes.Analytical column is anti-phase Phenomenex Luna C18-5 μ, 4.6 x 50mm, buy from Alltech (Deerfield, IL).Adopt gradient elution (flow velocity 2.5mL/min), start from 5% acetonitrile/95% water usually, in 10 minutes, proceed to 100% acetonitrile.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 buy from Burdick and Jackson (Muskegan, MI) or Fisher Scientific (Pittsburgh, PA).
In some cases, purity by thin-layer chromatography (TLC) utilize glass or plastics silica-gel plate for example Baker-Flex Silica Gel 1B2-F film determine.TLC result is easy to detect by range estimation under ultraviolet ray, or by using known iodine vapor and other various dye technologies to detect.
Mass spectroscopy is carried out on one of two LCMS instruments: Waters System (Alliance HTHPLC and Micromass ZQ mass spectrograph; Post: Eclipse XDB-C18,2.1 x 50mm; Gradient: contain the aqueous solution of 5-95% (or 35-95%, or 65-95% or the 95-95%) acetonitrile of 0.05% TFA, in 4 minutes; Flow velocity 0.8mL/min; Molecular weight ranges 200-1500; Awl voltage 20V; 40 ℃ of column temperatures) or Hewlett Packard System (Series 1100 HPLC; Post: EclipseXDB-C18,2.1 x 50mm; 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; Awl voltage 50V; 30 ℃ of column temperatures).All quality all are to report 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 HP 190915-443, size: carry out 30.0m x 25m x 0.25m).
(PaloAlto CA) carries out with Varian 300MHz NMR on some compound in nucleus magnetic resonance (NMR) analysis.The spectrum reference is the known chemical displacement of TMS or solvent.Some compound sample is tested under the temperature (for example 75 ℃) that raises to increase the solubleness of sample.
(Desert Analytics, Tucson AZ) determines the purity of some compound by ultimate analysis.
(Holliston determines on MA) fusing point at Laboratory Devices Mel-Temp equipment.
The separation of preparation type utilizes Flash 40 chromatographic systems and KP-Sil, 60A (Biotage, Charlottesville VA) or by the flash column chromatography of use silica gel (230-400 order) weighting material or by the HPLC that adopts Waters 2767 Sample Manager, C-18 reversed-phase column, 30 X 50mm, flow velocity 75mL/min carries out.The common solvent that is used for Flash 40 Biotage systems and flash column chromatography is methylene dichloride, methyl alcohol, ethyl acetate, hexane, acetone, ammoniacal liquor (or ammonium hydroxide) and triethylamine.The common solvent that is used for reversed-phase HPLC is acetonitrile and the water that contains the change concentration of 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 is only represented a kind of possible tautomeric form, therefore, should be appreciated that preferred embodiment comprises any tautomeric form of drawn structure.
Should be appreciated that, the invention is not restricted to the listed embodiment that is used for task of explanation of this paper, but be included in the form of ownership in the above-mentioned open scope.
In following examples and whole application, following abbreviation has following implication.If not definition, these terms have its general art-recognized meanings.
Abbreviation
The ACN acetonitrile
BINAP 2,2 '-two (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
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
DPPF 1,1 '-two (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
NMP N-N-methyl-2-2-pyrrolidone N-
The RT room temperature
The THF tetrahydrofuran (THF)
Formula I compound
Embodiment 1
4-[2-(2-chloro-benzylamino)-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
In the ethanolic soln of 4-aminoresorcinol (1 equivalent) and xanthogenic acid (3 equivalent), add potassium hydroxide (2.1 equivalent).Mixture was refluxed 2 hours, and dilute with water also is acidified to pH4 with 1N HCl then.With the product ethyl acetate extraction, concentrate then.The solid that forms is obtained pure products with the methylene dichloride development, and yield is 90%.MH+＝168.1。
Synthesizing of step 2.2-chloro-benzoxazole-6-alcohol
2-sulfydryl-benzoxazoles-6-alcohol (1 equivalent) is dissolved in thionyl chloride (10 equivalent).DMF (0.6 equivalent) is at room temperature slowly joined in this solution.With mixture heating up to 80 ℃ and refluxed 15 minutes.Reaction mixture is cooled to room temperature also except that desolvating.With solid dimethylbenzene component distillation 3 times that form.This solid is dissolved in the ethyl acetate solution of 10% THF and with saturated sodium bicarbonate aqueous solution washing 1 time.With the organic layer anhydrous sodium sulfate drying, filter and remove and desolvate.Solid is obtained pure products with the acetonitrile development, and yield is 68%.MH+＝170.0。
Synthesizing of step 3.2-(2-chloro-benzylamino)-benzoxazoles-6-alcohol
2-chloro-benzoxazole-6-alcohol (1 equivalent) and 2-chloro-benzyl amine (2 equivalent) are dissolved in NMP.Utilize Personal Chemistry microwave system, mixture was reacted 6 minutes down at 180 ℃.Crude product mixture is diluted with ethyl acetate, with salt water washing 1 time, with 1N HCl washing 1 time, perhaps use the salt water washing 2 times, this depends on used amine.With the organic layer anhydrous sodium sulfate drying, filter and concentrate.This material is utilized hexane and ethyl acetate purifying by silica gel column chromatography.MH+＝275.1。
Step 4.4-[2-(2-chloro-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea synthetic
In the DMSO solution of 2-(2-chloro-benzylamino)-benzoxazoles-6-alcohol (1 equivalent), add 4-chloro-pyridine-2-formic acid methyl nitrosourea (1 equivalent).It was at room temperature stirred 15 minutes, add cesium carbonate (1.2 equivalent) at this point.Solution was heated down totally 30 minutes at 150 ℃ in Personal Chemistry microwave reactor.Crude product mixture is diluted with ethyl acetate,, use anhydrous sodium sulfate drying, filter and concentrate with salt water washing 3 times.Then crude product is obtained 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 the following table 2 is synthetic according to the similar approach among the embodiment 1.
Embodiment 2
4-[2-((1S, 2R)-2-hydroxyl-indane-1-base is 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
[at room temperature add triethylamine (1.87g, 18.56mmol, 2.0 equivalents) and methyl iodide (1.77g, 13.92mmol, 1.5 equivalents) in the 20mL dichloromethane solution of d] oxazole-6-alcohol (1.55g, 9.28mmol, 1.0 equivalents) to 2-sulfydryl benzo.Reaction mixture was at room temperature stirred 3 hours.Mixture is diluted with the 100mL methylene dichloride.With mixture water (10mL), salt solution (10mL) washing that forms, use MgSO then
4Drying is filtered and reduction vaporization obtains crude product, and it by silica gel chromatography, is obtained 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 [the 80mL N of d] oxazole-6-alcohol (8.5g, 46.7mmol, 1 equivalent), add 4-chloro-N-picoline-2-methane amide (16.0g, 93.4mmol, 2.0 equivalents) and cesium carbonate (45.7g in the dinethylformamide solution, 140.1mmol, 3.0 equivalents).Reaction mixture was stirred 6 hours down at 75 ℃.After mixture is cooled to room temperature, in mixture, add 120mL water.After the filtration solid is passed through the silicagel column purifying, obtain title compound with ethyl acetate and hexane wash-out.MH+＝316。
Step 3.4-(2-(methylsulfinyl) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide synthetic
In the 40mL dichloromethane solution of 4-(2-(methylthio group) benzo [d] oxazole-6-base oxygen base)-N-picoline-2-methane amide (1.26g, 4.0mmol, 1.0 equivalents), add 3-chlorine peroxybenzoic acid (70%, 989mg, 4.4mmol, 1.1 equivalents).Reaction mixture was at room temperature stirred 5 hours, then with the dilution of 200mL methylene dichloride.With mixture sodium bicarbonate aqueous solution and the salt water washing that forms, use MgSO then
4Drying is filtered and reduction vaporization obtains crude product, and it promptly can be used for next step without being further purified.MH+＝332。
Step 4.4-[2-((1S, 2R)-2-hydroxyl-indane-1-base is amino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea
With 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-dihydro-1H-indenes-2-alcohol (30mg; 0.2mml, 4.0 equivalents) 1mL N,N-dimethylacetamide solution in microwave 90 ℃ of following 600 seconds of heating.Crude product is obtained title compound by anti-phase preparation HPLC purifying.MH+＝417.0。
Compound 45,46 in the following table 2 and 47 synthetic according to the similar approach of embodiment 2 is with temperature variation to 140 ℃.Compound 42,57,59 in the following table 2 and 94 synthetic according to the similar approach of embodiment 2 is with temperature variation to 120 ℃.
Embodiment 3
1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base is amino] methyl }-naphthenic acid ethyl ester (table 2, compound 75) synthetic
Synthesizing of step 1.1-cyano group-naphthenic acid ethyl ester
In the DMF solution of cyan-acetic ester (1 equivalent), slowly add cesium carbonate (2.5 equivalent) down, slowly add pentamethylene bromide then at 0 ℃.This mixture was stirred 30 minutes down at 0 ℃, at room temperature stirred 2 hours.Crude product mixture with ethyl acetate dilution and wash with water 3 times, use anhydrous sodium sulfate drying, filter also concentrated.The purity of this compound is enough to proceed reaction and need not 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 under nitrogen atmosphere in the ethanolic soln of 1-cyano group-naphthenic acid ethyl ester.Nitrogen atmosphere is spent the night with excessive hydrogen replacement and with the mixture stirring.With reaction mixture by diatomite filtration and remove and to desolvate.The purity of this compound is enough to proceed reaction and need not purifying.80% yield.MH+＝186.2。
Step 3.1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base is amino] methyl }-naphthenic acid ethyl ester synthetic
In the THF solution of 1-amino methyl-naphthenic acid ethyl ester, add 4-(the 2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea that obtains from the step 3 of embodiment 2.After at room temperature reacting 2 hours, except that desolvating and crude product being diluted with ethyl acetate and a small amount of methylene dichloride, use the salt water washing then 3 times, use anhydrous sodium sulfate drying, filtration also concentrates.End product is passed through anti-phase preparation HPLC purifying.MH+＝453.1。
Embodiment 4
1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base is amino]-methyl }-naphthenic acid (table 2, compound 93) synthetic
1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base is 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 at room temperature reacted spend the night.Remove and desolvate.Crude product is acidified to pH 4 with 1N HCl, alkalizes to pH 7 with saturated sodium bicarbonate aqueous solution then.This solution is saturated with solid sodium chloride, use ethyl acetate extraction then 3 times.With organic extract liquid salt water washing 1 time that merges, use anhydrous sodium sulfate drying, filter also concentrated.With product by silica gel column chromatography with Virahol and methylene dichloride (50%) purifying, MH+=425.1.
Embodiment 5
4-{2-[(1-methylamino formyl radical-cyclohexyl methyl)-and amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea (table 2, compound 112) synthetic
Amino to 1-{[6-(2-methylamino formyl radical-pyridin-4-yl oxygen base)-benzoxazoles-2-base]-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 was at room temperature stirred 2 hours, add the THF solution (5 equivalent) of 2M methylamine then and descend reaction to spend the night at 70 ℃.Mixture with the ethyl acetate dilution and with saturated aqueous ammonium chloride washing 2 times, with salt water washing 1 time, is used anhydrous sodium sulfate drying then, filter and concentrate, then by preparation type reversed-phase HPLC purifying.MH+＝438.1。
Embodiment 6
4-{2-[3-(2-piperidines-1-base-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
In the dichloromethane solution of 2-(3-nitro-phenyl)-ethanol (1 equivalent), add pyridine (4 equivalent) and methylsulfonyl chloride (2 equivalent) down at 0 ℃.After stirring 1 hour under 0 ℃, 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, filtration also concentrates.This product is not purified just enough pure and be used 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 piperidines (20 equivalent) and THF and stirred 1 hour down at 60 ℃.Remove and desolvate.Crude product is diluted with 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-piperidines-1-base-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 stirring is spent the night, filter then and concentrate.This product is enough pure and be used for next reaction.60% yield.MH+＝205.1。
Step 4.4-{2-[3-(2-piperidines-1-base-ethyl)-phenyl amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea synthetic
4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea that the step 3 of embodiment 2 is obtained and 3-(2-piperidines-1-base-ethyl)-phenyl amine is dissolved in DMAC and in the CEM microwave reactor 120 ℃ of heating 10～20 minutes down.With crude product mixture by preparation type 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 [1,4] dioxin-5-carbonyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea (table 2, compound 110) synthetic
With 4-(amino-benzoxazoles of 2--6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (1 equivalent) and 2,3-dihydro-1,4-benzdioxan-5-formic acid (1 equivalent) is dissolved in DMF.In this solution, add DIPEA (3 equivalent) and phosphofluoric acid [dimethylamino-([1,2,3] triazolo [4,5-b] pyridin-3-yl oxygen base)-methylene radical]-dimethyl-ammonium (1 equivalent).Mixture stirred down at 40 ℃ spend the night,, use anhydrous sodium sulfate drying at last, filter also and concentrate then with the ethyl acetate dilution and use 1N HCl, saturated sodium bicarbonate aqueous solution respectively and salt water washing 1 time.With it by preparation type reversed-phase HPLC purifying.MH+＝447.0。
Embodiment 9
Synthesizing of cyclohexyl methyl-[6-(2-[1,3,4] oxadiazole-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)-(1.40g, 4.23mmol at room temperature add cyclohexyl methylamine (955mg, 8.46mmol, 2.0 equivalents) to N-picoline-2-methane amide in 15mL THF solution 1.0eq).Reaction mixture was stirred 2 hours under this temperature.After the removal of solvent under reduced pressure, resistates is dissolved in the 150mL ethyl acetate.With mixture water (20mL), salt solution (20mL) washing that forms, use MgSO then
4Drying is filtered, and reduction vaporization obtains crude product, and it by silica gel chromatography, is obtained 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
With 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base)-(1.0eq) solution in the 10mL10M aqueous hydrochloric acid stirred 24 hours down at 100 ℃ N-picoline-2-methane amide for 300mg, 0.79mmol.Reaction mixture is cooled to room temperature.Most water is removed in decompression.Then sodium bicarbonate aqueous solution is joined in the mixture to pH 7.0.After the filtration, solid is washed with water, drying obtains title compound then.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 2mL N 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 the dinethylformamide solution, 0.36mmol, 1.2 equivalent) and triethylamine (60mg, 0.60mmol, 2.0 equivalents).Reaction mixture was stirred 2 hours under this temperature.In mixture, add 20mL water then.After the filtration, solid is passed through silicagel column purifying once more, 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 1mL methyl alcohol.The dioxan solution that in mixture, adds 3mL 4M hydrogenchloride then.Reaction mixture at room temperature stirred spend the night.Removing desolvates obtains title compound, and it promptly can be used for next step without being further purified.MH+＝382.0。
Synthesizing of step 4. cyclohexyl methyl-[6-(2-[1,3,4] oxadiazole-2-base-pyridin-4-yl oxygen base)-benzoxazoles-2-yl]-amine
With 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formyl hydrazine (8mg, 0.019mmol, 1.0eq) and the 1mL trimethyl orthoformate solution of 0.1mL4M hydrogenchloride in microwave 120 ℃ of 1200 seconds of heating down.Crude product is obtained title compound by anti-phase preparation HPLC purifying.MH
+＝392.0。
Compound 81 also can separate from reaction solution and obtains.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).2mL dichloromethane solution with 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-carboxamide (25mg, 0.068mmol, 1.0 equivalents) after 15 minutes joins in the reaction mixture.After stirring 20 minutes under this temperature, triethylamine (83mg, 0.83mmol, 12 equivalents) is joined in the mixture.Reaction mixture was stirred 2 hours down at-78 ℃, use the aqueous ammonium chloride solution termination reaction then.With the mixture ethyl acetate extraction (2 * 20mL) that forms.With organic layer water (5mL), salt solution (5mL) washing that merges, use MgSO then
4Drying is filtered and reduction vaporization obtains crude product, and it is obtained 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
To 4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-formic acid (120mg, 0.33mmol, in 5mL THF solution 1.0eq) 0 ℃ add down borine-tetrahydrofuran (THF) mixture (1M, 1mL, 1mmol).Reaction mixture was stirred 5 hours under this temperature.With 1M hydrochloric acid termination reaction.With the mixture ethyl acetate extraction (2 * 60mL) that forms.With organic layer water (10mL), salt solution (10mL) washing that merges, use MgSO then
4Drying is filtered and reduction vaporization obtains crude product, and it by silica gel chromatography, is obtained 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 was stirred 4 hours under this temperature.Then mixture is diluted with the 50mL ethyl acetate.The mixture that forms is washed with sodium bicarbonate aqueous solution (5mL), water (5mL), salt solution (5mL), use MgSO then
4Drying is filtered and reduction vaporization obtains crude product, and it is obtained title compound by preparation type 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, at room temperature add in 0.6mL methanol solution 1.0eq) pyruvic aldehyde (40%, 0.1mL) and 0.15mL ammonium hydroxide.Reaction mixture was stirred 2 hours under this temperature.Crude product is obtained 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 was stirred 16 hours under this temperature.Remove then and desolvate.Crude product is obtained 2-((4-(2-(cyclohexyl methyl amino) benzo [d] oxazole-6-base oxygen base) pyridine-2-yl) methyl by preparation type TLC purifying) isoindoline-1, the 3-diketone.
With 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 the reaction mixture.Mixture was at room temperature stirred 3 hours.Remove then and desolvate.Crude product is obtained title compound by anti-phase preparation HPLC purifying.MH+＝353.0。
Embodiment 14
4-{2-[1-(2,3-dihydro-benzo [1,4] 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 [1,4] dioxin-5-yl)-benzylidene amino synthetic
Add 2 in the trimethyl orthoformate suspension of the amine on being attached to the Rink resin (1 equivalent), 3-dihydro-benzo [1,4] dioxin-5-formaldehyde (2 equivalent).With this mixture shaken overnight, filter and solid drying.
Step 2.1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamine synthetic
The dry resin that is combined with C-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-benzylidene amino (1 equivalent) on it is suspended in the exsiccant toluene.The diethyl ether solution that under nitrogen atmosphere, adds the 3M of methyl-magnesium-bromide (150 equivalent).This mixture was vibrated 24 hours down at 60 ℃, filter then, respectively wash 3 times with toluene, water, methyl alcohol and methylene dichloride.Finally use methanol wash.With solid vacuum-drying.
Step 3. is cracking 1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamine from the resin
Add trifluoroacetic acid (20 volume %) in the resin that is combined with 1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamine in being suspended in methylene dichloride.With the mixture shaken overnight, make mixture be alkalescence by adding 3M sodium hydroxide then.Solution is filtered to remove resin, then with methylene dichloride and water dilution.With water layer dichloromethane extraction 3 times.With organic extract liquid salt water washing 1 time that merges, use anhydrous sodium sulfate drying, filter also concentrated.The material that reclaims is not purified just enough pure and proceed to react.MH+＝180.1。
Step 4.4-{2-[1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea synthetic
In the THF solution of 1-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-ethylamine (3 equivalent), add 4-(2-methanesulfinyl-benzoxazoles-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (1 equivalent).It was at room temperature stirred 8 hours, concentrates, and with resistates by preparation type reversed-phase HPLC purifying.MH+＝447.1。
Compound 41,42,57,59,65,90,94,113 in the following table 2 and 122 synthesizes according to the similar approach of embodiment 14.
Embodiment 15 (flow process 8)
4-[2-(cyclohexyl methyl-amino)-benzothiazole-6-base 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 US 4,873, the description of 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.10
Th, 1989.M+H＝184.0。
The preparation of step 2.2-methylthio group-benzothiazole-6-alcohol
DCM (the 40mL of the ice-cold 2-sulfydryl-benzothiazole-6-alcohol (3.80g, 20.76mmol, 1.0 equivalents) that obtains to step 1,0.5M) add triethylamine (7.29mL, 51.91mmol, 2.5 equivalents) down at 0 ℃ in the solution, add then methyl iodide (1.93mL, 31.14mmol, 1.5eq).Reaction solution was stirred 3 hours down at 0 ℃～-10 ℃.Solvent removed in vacuo.Add entry (about 200mL) and with water layer with ethyl acetate extraction (3 X 150mL).With the organic layer dried over sodium sulfate, filtration and vacuum-evaporation obtain 2-methylthio group-benzothiazole-6-alcohol, are shallow green powder (3.76g, 92%).Can not be used for next step with crude product is purified.M+H＝198.0。
The preparation of step 3.4-(2-methylthio group-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea
(3.76g, 19.08mmol at room temperature add CsCO in DMF 1.0eq) (25mL) solution to 2-methylthio group-benzothiazole-6-alcohol
3(15.54g, 47.70mmol, 2.5 equivalents).After stirring a little while, (4.86g, 28.62mmol 1.5eq) add in the mixture and mixture are spent the night stirring under reflux exchanger under 70 ℃ with 4-chloro-pyridine-2-formic acid methyl nitrosourea.Reaction mixture is cooled off in ice bath, add entry (100mL) and with water layer with ethyl acetate extraction (3 X 150mL).With the organic layer dried over sodium sulfate, filter and vacuum-evaporation.With crude product 20g ISCO silicagel column (0%-50%-80%-100% ethyl acetate-hexanes mixtures, 45 minutes, flow velocity 40mL/min) purifying obtains 4-(2-methylthio group-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (3.88g, 62%) of white solid.M+H＝332.1。
The preparation of step 4.4-(2-methanesulfinyl-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea
The 4-that obtains to step 3 (2-methylthio group-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea (3.88g, 11.72mmol, in DCM 1.0eq) (20mL) solution 0 ℃ add down MCPBA (77%, 2.88g, 1.1eq).Mixture was stirred 1 hour under this temperature.Add saturated sodium bicarbonate solution (100mL).Water layer is extracted (3 X 150mL) with DCM.With the organic layer dried over sodium sulfate, filter also vacuum-evaporation obtains white powder with quantitative yield 4-(2-methanesulfinyl-benzothiazole-6-base oxygen base)-pyridine-2-formic acid methyl nitrosourea.Crude product is not purified can be used for next step M+H=348.0.
Step 5.4-[2-(cyclohexyl methyl-amino)-benzothiazole-6-base oxygen base]-preparation of pyridine-2-formic acid methyl nitrosourea
To 4-(2-methanesulfinyl-benzothiazole-6-base 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 stir down at 70 ℃ 2.0eq) and with reaction solution and to spend the night.With reaction mixture with anti-phase preparation HPLC purifying.Purified fraction lyophilize is obtained tfa salt.M+H＝397.1。
Embodiment 16
4-(the preparation of 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-benzothiazole-6-base 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), add then diisopropyl ethyl amine (0.21mL, 1.21mmol).Reaction solution was heated 24 hours down at 110 ℃.With reaction mixture with anti-phase preparation HPLC purifying.Purified fraction lyophilize is obtained tfa salt.M+H＝398
Embodiment 17
Compound in the following table 2 makes by above-described general method.
Table 2
Embodiment 162
4-(the preparation of 2-((1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-base is 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; 0.86mmo1) 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 was stirred 24 hours down at 105 ℃.Crude reaction solution is obtained 4-with preparation HPLC purifying and vacuum-evaporation, and (((1R, 2S)-2-hydroxyl-2,3-dihydro-1H-indenes-1-base is amino) benzo [d] thiazole-6-base oxygen base)-(347mg 0.63mmol), is tfa salt to N-picoline methane amide to 2-.ES/MS?m/z?433.1(MH
+)。
Embodiment 163
4-(the preparation of 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
Step 1.4-(the preparation of 2-((1R, 2R)-2-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
In 400 μ L nmp solutions of N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (15mg, 43 μ mol), add (1R, 2R)-hexanaphthene-1,2-diamines (17mg, 150 μ mol).Reaction soln was stirred 24 hours down at 105 ℃.Crude reaction solution is obtained 4-with preparation HPLC purifying and vacuum-evaporation, and (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
+)。
Step 2.4-(the preparation of 2-((1R, 2R)-2-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
(add diacetyl oxide (5 μ L, 50 μ mol) in the 300 μ L DMF solution of 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) to 4-.Reaction soln was at room temperature stirred 1.5 hours.Crude reaction solution is obtained 4-with preparation HPLC purifying and vacuum-evaporation, and (2-((1R, 2R)-2-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (5.1mg, 12 μ mol) is white powder.ES/MS?m/z?440.2(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, add in 2ml nmp solution 0.3mmol) (S)-tertiary butyl 3-amino piperidine-1-manthanoate (240mg, 1.2mmol).Reaction soln was stirred 5 days down at 105 ℃.Crude reaction solution is obtained (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) with preparation HPLC purifying and vacuum-evaporation, and (56mg 0.12mmol), is white powder to piperidines-1-manthanoate.ES/MS?m/z?484.2(MH
+)。
The preparation of step 2. (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide
(56mg 0.12mmol) is dissolved in the dioxan solution (16mmol) of 4ml 4M HCl with (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate.Reaction soln was at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base), and (46mg 0.12mmol), is white solid to pyridine carboxamide.ES/MS?m/z?384.0(MH
+)。
The preparation of step 3. (S)-N-methyl-4-(2-(1-(methyl sulphonyl) piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide
To (S)-N-methyl-4-(2-(piperidines-3-base is 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 the 300 μ L nmp solutions.Reaction soln was stirred 46 hours down at 105 ℃.Crude reaction solution is obtained (S)-N-methyl-4-(2-(1-(methyl sulphonyl) piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (4.5mg, 9.8 μ mol) with preparation HPLC purifying and vacuum-evaporation, be white powder.ES/MS?m/z?462.1(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
To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (104mg, add in 2ml nmp solution 0.3mmol) (S)-tertiary butyl 3-amino piperidine-1-manthanoate (240mg, 1.2mmol).Reaction soln was stirred 5 days down at 105 ℃.Crude reaction solution is obtained (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) with preparation HPLC purifying and vacuum-evaporation, and (56mg 0.12mmol), is white powder to piperidines-1-manthanoate.ES/MS?m/z?484.2(MH
+)。
The preparation of step 2. (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide
(56mg 0.12mmol) is dissolved in the dioxan solution (16mmol) of 4ml 4M HCI with (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate.Reaction soln was at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base), and (46mg 0.12mmol), is white solid to pyridine carboxamide.ES/MS?m/z?384.0(MH
+)。
The preparation of step 3. (S)-4-(2-(1-ethanoyl piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
In 300 μ L DMA solution of (S)-N-methyl-4-(2-(piperidines-3-base is 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).Reaction soln was at room temperature stirred 1.5 hours.Crude reaction solution is obtained (S)-4-(2-(1-ethanoyl piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (4.8mg, 11 μ mol) with preparation HPLC purifying and vacuum-evaporation, be white powder.ES/MS?m/z?426.2(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 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, add in 2ml nmp solution 0.3mmol) (S)-tertiary butyl 3-amino piperidine-1-manthanoate (240mg, 1.2mmol).Reaction soln was stirred 5 days down at 105 ℃.Crude reaction solution is obtained (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) with preparation HPLC purifying and vacuum-evaporation, and (56mg 0.12mmol), is white powder to piperidines-1-manthanoate.ES/MS?m/z?484.2(MH
+)。
The preparation of step 2. (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide
(56mg 0.12mmol) is dissolved in the dioxan solution (16mmol) of 4ml 4M HCl with (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate.Reaction soln was at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base), and (46mg 0.12mmol), is white solid to pyridine carboxamide.ES/MS?m/z?384.0(MH
+)。
The preparation of step 3. (S)-4-(2-(1-isobutyryl piperidines-3-base is 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 is amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (13mg in the 400 μ L DMA solution, 30 μ mol) and DIPEA (6 μ L, 30 μ mol).Reaction soln was at room temperature stirred 16 hours.Crude reaction solution is obtained (S)-4-(2-(1-isobutyryl piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (6.8mg, 15 μ mol) with preparation HPLC purifying and vacuum-evaporation, be white powder.ES/MS?m/z?454.2(MH
+)。
Embodiment 167
(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 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
To N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (104mg, add in 2ml nmp solution 0.3mmol) (S)-tertiary butyl 3-amino piperidine-1-manthanoate (240mg, 1.2mmol).Reaction soln was stirred 5 days down at 105 ℃.Crude reaction solution is obtained (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) with preparation HPLC purifying and vacuum-evaporation, and (56mg 0.12mmol), is white powder to piperidines-1-manthanoate.ES/MS?m/z?484.2(MH
+)。
The preparation of step 2. (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide
(56mg 0.12mmol) is dissolved in the dioxan solution (16mmol) of 4ml 4M HCl with (S)-tertiary butyl 3-(6-(2-(methylamino formyl radical) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate.Reaction soln was at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained (S)-N-methyl-4-(2-(piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base), and (46mg 0.12mmol), is white solid to pyridine carboxamide.ES/MS?m/z?384.0(MH
+)。
The preparation of step 3. (S)-4-(2-(1-(sec.-propyl formamyl) piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
In the 300 μ L nmp solutions of (S)-N-methyl-4-(2-(piperidines-3-base is 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).Reaction soln was at room temperature stirred 18 hours.Crude reaction solution is obtained (S)-4-(2-(1-(sec.-propyl formamyl) piperidines-3-base is amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (5.9mg, 12 μ mol) with preparation HPLC purifying and vacuum-evaporation, be white powder.ES/MS?m/z?469.2(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
The preparation of step 1.6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole
To 2-(methylthio group) benzo [d] thiazole-6-alcohol (1g, 5.08mmol) and cesium carbonate (4.55g, add in 15ml NMP mixture 14mmol) 2-chloro-4-fluorine pyridine (1.32mg, 10mmol).Reaction mixture stirring under 55 ℃ is spent the night.Pour reaction mixture into 80ml saturated NaHCO
3Also use ethyl acetate extraction (2 x 150ml) in the aqueous solution.With the organic layer 0.1M NaHSO that merges
4MgSO is used in the aqueous solution (60ml), water (2 x 60ml) and salt solution (60ml) washing then
4Drying is filtered and vacuum-evaporation obtains brown buttery 6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole (1.72g), and it is not purified can be used for next step.ES/MS?m/z?308.9(MH
+)。
The preparation of step 2.6-(2-chloropyridine-4-base oxygen base)-2-(methylsulfinyl) benzo [d] thiazole
To 6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole (1.72g, under 0 ℃, add in 32ml DCM solution 5.08mmol) in batches 3-chlorine peroxybenzoic acid (77%, 1.3g, 5mmol).After at room temperature stirring 2 hours, mixture is diluted with 80ml DCM.With the mixture 0.2M Na that forms
2S
2O
3The aqueous solution (25ml), saturated NaHCO
3Na is used in the aqueous solution (25ml), water (25ml) and salt water washing then
2SO
4Drying is filtered and vacuum-evaporation obtains yellowish brown solid (1.72g).Resistates is obtained 6-by flash column chromatography purifying and vacuum-evaporation, and (2-chloropyridine-4-base oxygen base)-(970mg 3mmol), is off-white powder to 2-(methylsulfinyl) benzo [d] thiazole.ES/MSm/z?325.0(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
In 400 μ L nmp solutions of 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, 250 μ mol) and DIPEA (17 μ L, 100 μ mol).Reaction soln was stirred 18 hours down at 100 ℃.Crude reaction solution is obtained pulverous (R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)-4-methylpent-1-alcohol (12mg, 31 μ mol) with preparation HPLC purifying and vacuum-evaporation.ES/MS?m/z?378.1(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) add 1-methyl-4-(4 in the reaction mixture of 400 μ L DME, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-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 was stirred 24 hours down at 90 ℃.Reaction mixture is filtered, obtain 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-alcohol (4.2mg) with preparation HPLC purifying and vacuum-evaporation.ES/MS?m/z?424.1(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
The preparation of step 1.6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole
To 2-(methylthio group) benzo [d] thiazole-6-alcohol (1g, 5.08mmol) and cesium carbonate (4.55g, add in 15ml NMP mixture 14mmol) 2-chloro-4-fluorine pyridine (1.32mg, 10mmol).Reaction mixture stirring under 55 ℃ is spent the night.Pour reaction mixture into 80ml saturated NaHCO
3Also use ethyl acetate extraction (2 x 150ml) in the aqueous solution.With the organic layer 0.1M NaHSO that merges
4MgSO is used in the aqueous solution (60ml), water (2 x 60ml) and salt solution (60ml) washing then
4Drying is filtered and vacuum-evaporation obtains brown buttery 6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole (1.72g), and it is not purified can be used for next step.ES/MS?m/z?308.9(MH
+)。
The preparation of step 2.6-(2-chloropyridine-4-base oxygen base)-2-(methylsulfinyl) benzo [d] thiazole
To 6-(2-chloropyridine-4-base oxygen base)-2-(methylthio group) benzo [d] thiazole (1.72g, under 0 ℃, add in 32ml DCM solution 5.08mmol) in batches 3-chlorine peroxybenzoic acid (77%, 1.3g, 5mmol).After at room temperature stirring 2 hours, mixture is diluted with 80ml DCM.With the mixture 0.2M Na that forms
2S
2O
3The aqueous solution (25ml), saturated NaHCO
3Na is used in the aqueous solution (25ml), water (25ml) and salt water washing then
2SO
4Drying is filtered and vacuum-evaporation obtains yellowish brown solid (1.72g).Resistates is obtained 6-by flash column chromatography purifying and vacuum-evaporation, and (2-chloropyridine-4-base oxygen base)-(970mg 3mmol), is off-white powder ES/MSm/z 325.0 (MH to 2-(methylsulfinyl) benzo [d] thiazole
+).
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 was stirred 5 days down at 95 ℃.Crude reaction solution is obtained (S)-tertiary butyl 3-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (160mg) with preparation HPLC purifying and vacuum-evaporation, be tfa salt.ES/MS?m/z?461.1(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) add 1-methyl-4-(4 in the 1.2ml DME reaction mixture, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-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 was stirred 72 hours down or finishes until LC demonstration reaction at 85 ℃.Pour reaction mixture into 40ml saturated NaHCO
3Also use ethyl acetate extraction (2 x 80ml) in the solution.With organic layer water (2 x 20ml) and salt solution (20ml) washing that merges, use Na then
2SO
4Dry, filtration and vacuum-evaporation obtain brown jelly (77mg), and it is obtained 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 the preparation HPLC purifying.ES/MS?m/z?507.1(MH
+)。
The preparation of step 5. (S)-N-methyl-4-(2-(piperidines-3-base is 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 the dioxan solution (4mmol) of 1ml 4M HCl.Reaction soln was at room temperature stirred 1 hour.Crude reaction solution vacuum-evaporation is obtained (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), be white solid.ES/MS?m/z?407.1(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 the 400 μ L nmp solutions.Reaction soln was stirred 16 hours down at 55 ℃.Crude reaction solution is obtained (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 with preparation HPLC purifying and vacuum-evaporation; 12 μ mol), be white powder.ES/MS?m/z?511.2(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, add in 400 μ L NMP reaction solns 0.03mmol) DIPEA (9 μ L, 0.05mmol) and the aqueous solution of 70% ethylamine (200 μ L, 2.51mmol).Reaction mixture was stirred 96 hours down or finishes until LC demonstration reaction at 110 ℃.Crude product mixture is filtered, obtain N-(cyclohexyl methyl)-6-(2-(ethylamino) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine, be tfa salt (1.8mg) with preparation HPLC purifying and vacuum-evaporation.ES/MS?m/z?383.1(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 3
Step 1. tertiary butyl 4-(2-(methylthio group) benzo [d] thiazole-6-base oxygen base) picolinic acid ester
25mlN to 2-(methylthio group) benzo [d] thiazole-6-alcohol (5.0g, 25.38mmol, 1.0 equivalents), add tertiary butyl 4-chloropyridine manthanoate (8.13g, 38.07mmol, 1.5 equivalents) and cesium carbonate (20.67g in the dinethylformamide solution, 63.45mmol, 2.5 equivalents).Reaction mixture was stirred 6 hours down at 75 ℃.After mixture is cooled to room temperature, in mixture, add 120mL water, with water with ethyl acetate extraction (3 X 150mL), with the organic layer dried over sodium sulfate that merges.After the filtration, solid by the silicagel column purifying, is obtained 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
In the 25ml dichloromethane solution of tertiary butyl 4-(2-(methylthio group) benzo [d] thiazole-6-base oxygen base) picolinic acid ester (5.84g, 15.61mmol, 1.0 equivalents), add 3-chlorine peroxybenzoic acid (77%, 3.84g, 17.17mmol, 1.1 equivalents).Reaction mixture was at room temperature stirred 1.5 hours, then with the dilution of 200ml methylene dichloride.With mixture sodium bicarbonate aqueous solution and the salt water washing that forms, use MgSO then
4Drying is filtered and reduction vaporization obtains crude product, and it promptly can be used for next step without being further purified.MH+＝391.0。
The step 3. tertiary butyl 4-(preparation of 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 was stirred 3 days down at 100 ℃.Crude reaction solution is obtained tertiary butyl 4-with preparation HPLC purifying and vacuum-evaporation, and ((240mg 0.544mmol), is white powder to picolinic acid ester to 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base).ES/MS?m/z?442.5(MH
+)。
Step 4.4-(the preparation of 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxylic acid
To tertiary butyl 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) picolinic acid ester (and 250mg, add in 10ml acetonitrile solution 0566mmol) 6M hydrochloric acid (1ml, 6mmol).Reaction soln was at room temperature stirred 1 hour, stirred 2 hours down at 60 ℃ then.With the concentrated 10ml acetonitrile that also is dissolved in again of crude reaction solution.With the solution for vacuum evaporation that forms obtain light brown oily product 4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxylic acid (and 215mg, 0.56mmol).ES/MS?m/z?386.5(MH
+)。
Step 5.N-cyclopropyl-4-(preparation of 2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-benzo [d] thiazole-6-base oxygen base) pyridine carboxamide
To 4-(2-((1R, 2R)-and 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 the 1mlNMP reaction soln.Reaction soln was at room temperature stirred 12 hours.Crude reaction solution is obtained N-cyclopropyl-4-with preparation HPLC purifying and vacuum-evaporation, and (2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (1mg, 2.3 μ mol) is white powder.ES/MS?m/z?425.2(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
With N-methyl-4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) pyridine carboxamide (15mg, 43 μ mol) and 500 μ L hexahydrobenzyl alcohols and cesium carbonate (42mg, 0.13mmol) mixing mutually.The reaction mixture that forms was stirred 12 hours down at 90 ℃.With the crude product mixture drying, filter and use the preparation HPLC purifying, 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) then.ES/MS?m/z398.1(MH
+)。
Embodiment 173
(1R, 2R)-preparation of 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 1
Step 3
Step 1. (1R, 2R)-preparation of 2-(6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin
To 2-chloro-6-methoxyl group benzo [d] thiazole (1.0g, add in 5.5ml nmp solution 5mmol) (1R, 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (910mg, 6mmol) and DIPEA (2.44ml, 14mmol).Reaction soln was stirred 96 hours down at 115 ℃.Crude reaction solution is obtained the fraction of purifying by the preparation HPLC purifying, this fraction is merged, use solid NaHCO
3Neutralization.With the solution ethyl acetate extraction (2 x 300ml) that forms.With organic layer water (60ml) and salt solution (60ml) washing that merges, use Na then
2SO
4Dry and vacuum-evaporation obtain (1R, 2R)-(1.06g 3.81mmol), is Off-white solid to hexalin to 2-(6-methoxyl group benzo [d] thiazol-2-yl amino).ES/MS?m/z279.1(MH
+)。
Step 2.2-(the preparation of (1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol
To (1R, 2R)-2-(6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin (1.06g, in 16ml DCM solution 3.81mmol) 0 ℃ of DCM solution that adds down slowly the 1M boron tribromide (8ml, 8mmol).Reaction soln was at room temperature stirred 2 hours.Vacuum is removed all solvents, then water (about 30ml) and rare NaHCO
3The solution termination reaction, and with water ethyl acetate extraction (3 x 100ml), with the organic extract liquid Na that merges
2SO
4Drying is removed ethyl acetate with final vacuum and is obtained the required product of pink solid shape (1.16g).Resistates is obtained 2-by the flash column chromatography purifying, and ((1R, 2R)-2-hydroxy-cyclohexyl amino) (1.0g 3.78mmol), is brown solid to benzo [d] thiazole-6-alcohol.ES/MS?m/z?265.1(MH
+)。
Step 3. (1R, 2R)-preparation of 2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (and 265mg, 1mmol) and cesium carbonate (651mg, add in 3ml NMP mixture 2mmol) 2-chloro-4-fluorine pyridine (263mg, 2mmol).Reaction mixture was stirred 20 hours down at 60 ℃.With the crude product mixture drying, filter, then with the preparation HPLC purifying obtain pulverous (1R, 2R)-2-(6-(the basic oxygen base of 2-chloropyridine-4-) benzo [d] thiazol-2-yl amino) hexalin (341mg, 0.9mmol).ES/MS?m/z376.0(MH
+)。
Embodiment 174
(1R, 2R)-preparation of 2-(6-(2-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
Step 4. (1R, 2R)-preparation of 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) add 1-methyl-4-(4 in the 400 μ L DME reaction mixtures, 4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-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 was being stirred 24 hours down at 90 ℃.Pour reaction mixture into 10ml saturated NaHCO
3Also use ethyl acetate extraction (2 x 30ml) in the solution.With organic layer water (2 x 10ml) and salt solution (20ml) washing that merges, use Na then
2SO
4Dry and vacuum-evaporation obtains brown solid (65mg), with its with the preparation HPLC purifying 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).ES/MS?m/z?422.2(MH
+)。
Embodiment 175
(1R, 2R)-preparation of 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:
(1R, 2R)-preparation of 2-(6-(2-(1-methyl isophthalic acid H-imidazoles-5-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To (1R, 2R)-(11mg adds Pd (dppf) in 0.5ml DMF reaction mixture 0.029mmol) to hexalin to 2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)
2Cl
2(7.2mg, 0.0088mmol), LiCl (19mg, 0.44mmol) and 1-methyl-5-(tributyl stannyl)-1H-imidazoles (44mg, 0.117mmol).Reaction soln is finished in 105-110 ℃ of following stirring 18 hours or LC demonstration reaction.Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (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/z?422.1(MH
+)。
Embodiment 176
(1R, 2R)-preparation of 2-(6-(2-(1-(2,2-two 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:
(1R, 2R)-preparation of 2-(6-(2-(1-(2,2-two fluoro ethyls)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To 4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles (210mg, add in 2.0ml NMP reaction mixture 1.08mmol) cesium carbonate (672mg, 2.06mmol).Reaction mixture was stirred 5 minutes, add 1 then, (197mg 1.03mmol) also at room temperature stirred 40 hours 1-two fluoro-2-iodoethane.From above-mentioned crude product mixture, take out 0.8ml (0.432mol) and use (remaining 1.2ml is stored in the refrigerator).In this 0.8ml reaction mixture, add (1R, 2R)-2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin (20mg, 0.053mmol), Pd (dppf)
2Cl
2(15.2mg is 0.019mmol) with 2M Na
2CO
3(0.150ml, 0.3mmol).With reaction mixture 140 ℃ of 720 seconds of following microwave heating.Crude product mixture is filtered, obtain (1R with preparation HPLC purifying and lyophilize, 2R)-and 2-(6-(2-(1-(2,2-two fluoro ethyls)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (4.6mg).ES/MS?m/z?472.0(MH
+)。
Embodiment 177
(1R, 2R)-preparation of 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
Step 1.4-(the preparation of 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 (and 90mg, add in 1.9ml NMP reaction mixture 0.34mmol) cesium carbonate (232mg, 0.71mmol) and 4-chloropyridine formaldehyde (125mg, 0.883mmol).Reaction mixture was at room temperature stirred 10 minutes, then 150 ℃ of 750 seconds of following microwave heating.Crude product mixture is filtered, and (2-((1R, 2R)-2-hydroxy-cyclohexyl amino) the basic oxygen base of benzo [d] thiazole-6-) pyridylaldehyde is tfa salt (88mg) to obtain 4-with preparation HPLC purifying and lyophilize.ES/MS m/z 388.1 (MH
+), be hydrate (+18).
Step 2. (1R, 2R)-preparation of 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)-and 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 of 2-oxopropanal 40%wt (0.037ml, 0.21mmol).Reaction mixture was stirred 2 hours down at 70 ℃.Crude product mixture is concentrated, again be dissolved in 0.8ml DMF, filter, obtain (1R with preparation HPLC purifying and lyophilize, 2R)-and 2-(6-(2-(4-methyl isophthalic acid H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (3.2mg).ES/MS?m/z?422.1(MH
+)。
Embodiment 178
(1R, 2R)-preparation of 2-(6-(3-bromopyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin
This motif compound makes according to following general flow:
(1R, 2R)-preparation of 2-(6-(3-bromopyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (and 12.5mg, add in 0.4ml NMP reaction mixture 0.047mmol) cesium carbonate (39mg, 0.118mmol) and at room temperature stirred 1-3 minute.Adding 3-bromo-4-chloropyridine in this mixture (18.2mg, 0.094mmol).Reaction mixture was stirred 4 hours down or finishes until LC demonstration reaction at 90 ℃.Crude product mixture is filtered, and usefulness preparation HPLC purifying and lyophilize (1R, 2R)-2-(6-(3-bromopyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (9.2mg).ES/MS?m/z420.1/422.0(MH
+)。
Embodiment 179
(1R, 2R)-preparation of 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:
(1R, 2R)-preparation of 2-(6-(3-(1-methyl isophthalic acid H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To (1R, 2R)-(15mg adds Pd (dppf) in 0.5ml NMP mixture 0.036mmol) to hexalin to 2-(6-(3-bromopyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)
2Cl
2(8.8mg, 0.0107mmol), 1-methyl-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls)-1H-pyrazoles (30mg, 0.143mmol) and 2M Na
2CO
3(0.12ml, 0.24mmol).Reaction soln was stirred 2 hours down at 105-110 ℃, or finish until LC demonstration reaction.Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (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/z?422.1(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
Step?3
The preparation of step 1.N-(cyclohexyl methyl)-6-methoxyl group benzo [d] thiazole-2-amine
To 2-chloro-6-methoxyl group benzo [d] thiazole (900mg, add in 4.5ml nmp solution 4.5mmol) the cyclohexyl methylamine (865mg, 7.65mmol) and DIPEA (1.57ml, 9.0mmol).Reaction soln was stirred 66 hours down at 105-110 ℃.Reaction solution is carried out aftertreatment by adding the 250ml ethyl acetate, with the saturated NaHCO of 2 x 60ml
3, the saturated NaCl washing of 3 x 60ml water, 1 x 60ml, use dried over sodium sulfate, drying is filtered and vacuum concentration obtains N-(cyclohexyl methyl)-6-methoxyl group benzo [d] thiazole-2-amine (1.18 restrain) of solid state.ES/MS?m/z?277.1(MH
+)。
The preparation of step 2.2-(cyclohexyl methyl amino) benzo [d] thiazole-6-alcohol
To N-(cyclohexyl methyl)-6-methoxyl group benzo [d] thiazole-2-amine (1.40g, in 12ml DCM solution 5.05mmol) in the DCM (10.6ml, 10.6mmol) solution that in about 3 minutes, slowly add the 1M boron tribromide under 0 ℃.Reaction soln was stirred 20 minutes down at 0 ℃, at room temperature stirred then 2 hours.Reaction mixture is concentrated into solid.Adding 200ml ethyl acetate and 50ml water also at room temperature stirred 10 minutes in residual solid.Under agitation add excessive solid NaHCO carefully
3To being alkalescence.At room temperature stir about 1 hour is with dissolved solids.Remove water layer and use the 100ml ethyl acetate extraction.Merge organic layer,, use dried over sodium sulfate then with 1 x 30ml water, the saturated NaCl solution washing of 1 x 25ml.This mixture is filtered and uses ethyl acetate rinse by silica gel plug (1.25in.x 3in.).Filtrate decompression is concentrated 2-(cyclohexyl methyl amino) benzo [d] thiazole-6-alcohol (1.32 gram) that obtains solid state.ES/MS?m/z?263.1(MH
+)。
The preparation of step 3.4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carbonitrile
(18mg, (56mg 0.171mmol) also at room temperature stirred 1-3 minute to add cesium carbonate in 0.4mlNMP reaction mixture 0.068mmol) to 2-(cyclohexyl methyl amino) benzo [d] thiazole-6-alcohol.Adding 4-chloropyridine formonitrile HCN in this mixture (19mg, 0.136mmol).Reaction mixture was stirred 5 hours down or finishes until LC demonstration reaction at 60 ℃.Crude product mixture is filtered, obtain 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carbonitrile, be tfa salt (9.8mg) with preparation HPLC purifying and lyophilize.ES/MS?m/z?365.1(MH
+)。
Embodiment 181
The preparation of 6-(2-(1H-tetrazolium-5-yl) pyridin-4-yl oxygen base)-N-(cyclohexyl methyl) benzo [d] thiazole-2-amine
This motif compound makes according to following general flow:
The preparation of 6-(2-(1H-tetrazolium-5-yl) pyridin-4-yl oxygen base)-N-(cyclohexyl methyl) benzo [d] thiazole-2-amine
(20mg adds ZnCl in 0.6ml NMP reaction mixture 0.055mmol) to pyridine carbonitrile to 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base)
2(37mg, 0.274mmol) and sodiumazide (35.5mg, 0.55mmol).With reaction soln 170 ℃ of 800 seconds of following microwave heating.Crude product mixture is filtered, obtain 6-(2-(1H-tetrazolium-5-yl) pyridin-4-yl oxygen base)-N-(cyclohexyl methyl) benzo [d] thiazole-2-amine, be tfa salt (6.6mg) with preparation HPLC purifying and lyophilize.ES/MS?m/z?408.2(MH
+)。
Embodiment 182
The preparation of 6-(quinolyl-4 oxygen base)-N-(2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) benzo [d] thiazole-2-amine
This motif compound makes according to following general flow:
The preparation of step 1.2-(methylthio group)-6-(quinolyl-4 oxygen base) benzo [d] thiazole
(750mg, (3.2g 9.5mmol) also at room temperature stirred 3 minutes to add cesium carbonate in 10ml NMP reaction mixture 3.79mmol) to 2-(methylthio group) benzo [d] thiazole-6-alcohol.Adding 4-chloroquinoline in this mixture (682mg, 4.17mmol).Reaction mixture was stirred 24 hours down at 110 ℃.Reaction solution is carried out aftertreatment by adding the 250ml ethyl acetate, with the saturated NaHCO of 75ml
3, the saturated NaCl washing of 2 x 60ml water, 1 x 50ml, use dried over sodium sulfate, filter also vacuum concentration.The solid residue that forms is passed through silica gel chromatography, obtain 2-(methylthio group)-6-(quinolyl-4 oxygen base) benzo [d] thiazole (980mg) of solid state with (40% EtOAc:60% hexane) wash-out and vacuum concentration.ES/MS?m/z?325.1(MH
+)。
The preparation of step 2.2-(methylsulfinyl)-6-(quinolyl-4 oxygen base) benzo [d] thiazole
(460mg, reaction mixture 1.415mmol) are dissolved in 8ml DCM and are cooled to-5 ℃ with 2-(methylthio group)-6-(quinolyl-4 oxygen base) benzo [d] thiazole.Preparation by 77%MCPBA (333mg, 1.486mmol) and the solution formed of 6ml DCM.This solution was added drop-wise in 3-4 minute in the above refrigerative reaction mixture.Reaction solution was stirred 10 minutes down at-5 ℃, at room temperature stirred 90 minutes.The reaction of LC monitoring demonstration 95% is finished and is stopped.New preparation by 77% MCPBA (25mg, 0.1132mmol) and the solution formed of 1ml DCM.This drips of solution is added in the reaction mixture under the above-mentioned room temperature.Reaction solution was stirred more than 90 minutes, and LC demonstration reaction is finished.Reaction solution is carried out aftertreatment by adding 80ml DCM and 25ml 10% hypo solution, and at room temperature stirred 10 minutes.With the water layer extraction, with the DCM layer saturated NaHCO of 25ml
3, 2 x 25ml5% NaHCO
3Dried over sodium sulfate is used in solution, 1 x 25ml water, the saturated NaCl washing of 1 x 25ml.Add about 1 gram silica gel and stirring 10 minutes.Mixture filtered and vacuum concentration obtains 2-(methylsulfinyl)-6-(quinolyl-4 oxygen base) benzo [d] thiazole (357mg) of solid state.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 was stirred 20 hours down or finishes until LC demonstration reaction at 100 ℃.Crude product mixture is filtered, obtain 6-(quinolyl-4 oxygen base)-N-(2-(tetrahydrochysene-2H-pyrans-4-yl) ethyl) benzo [d] thiazole-2-amine, be tfa salt (5.1mg) with preparation HPLC purifying and lyophilize.ES/MS?m/z406.1(MH
+)。
Embodiment 183
(1R, 2R)-preparation of 2-(6-(2-morpholino pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
(1R, 2R)-preparation of 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 was stirred 48 hours down or finishes until LC demonstration reaction at 110 ℃.Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (1R 2R)-2-(6-(2-morpholino pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin, is tfa salt (3.7mg).ES/MS?m/z?427.1(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
To 2-chloro-6-methoxyl group benzo [d] thiazole (2.0g, add in 10ml nmp solution 10mmol) (S)-1-cyclohexyl ethamine (2.3g, 18mmol) and DIPEA (3.5ml, 20mmol).Reaction soln was stirred 96 hours down at 110 ℃.Reaction solution is carried out aftertreatment by adding the 170ml ethyl acetate, with the saturated NaHCO of 1 x 60ml
3, 1 x 60ml, 5% NaHCO
3Solution, 1 x 60ml water, the saturated NaCl of 1 x 60ml handle, and use dried over sodium sulfate, and filtration and vacuum concentration obtain (S)-N-(1-cyclohexyl ethyl)-6-methoxyl group benzo [d] thiazole-2-amine (3.39 gram) of thick solid state.ES/MSm/z?291.1(MH
+)。
The preparation of step 2. (S)-2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-alcohol
To (S)-N-(1-cyclohexyl ethyl)-6-methoxyl group benzo [d] thiazole-2-amine (3.39g, in 30ml DCM solution 10mmol) 0 ℃ of DCM solution that adds down the 1M boron tribromide (20ml, 20mmol).Reaction soln is stirred down at 0 ℃, at room temperature stirred then 2 hours.Reaction mixture is concentrated into solid.Adding 400ml ethyl acetate and 90ml water also at room temperature stirred 10 minutes in this residual solid.Under agitation add excessive solid NaHCO carefully
3To being alkalescence.At room temperature stir about 1 hour is with dissolved solids.Remove water layer and use the 100ml ethyl acetate extraction.Merge organic layer,, use dried over sodium sulfate, filter and concentrating under reduced pressure with 1 x 50ml water, the saturated NaCl solution washing of 1 x 50ml.The solid that forms is passed through silica gel chromatography, obtain (S)-2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-alcohol (2.0 gram) of solid state with (30% EtOAc:70% hexane) wash-out and vacuum concentration.ES/MS?m/z?277.1(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, add in 3.6ml NMP mixture 2.44mmol) 2-chloro-4-fluorine pyridine (254mg, 1.95mmol).Reaction mixture was stirred 18 hours down or finishes until LC demonstration reaction at 60 ℃.Crude product mixture is filtered, obtain (S)-6-(2-chloropyridine-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine, be tfa salt (298mg) with preparation HPLC purifying and lyophilize.ES/MS?m/z?388.1(MH
+)。
Embodiment 185
(S)-preparation of 6-(2,3 '-dipyridyl-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine
(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-two oxa-boron heterocycle pentane-2-yls) pyridine (32mg, 0.155mmol), Pd (dppf)
2Cl
2(7.9mg is 0.0096mmol) with 2M Na
2CO
3(0.18ml, 0.36mmol).Reaction soln was stirred 90 minutes down or finishes until LC demonstration reaction at 100-105 ℃.Crude product mixture is concentrated into solid, again be dissolved in 0.8ml DMF, filter, obtain (S)-6-(2 with preparation HPLC purifying and lyophilize, 3 '-dipyridyl-4-base oxygen base)-N-(1-cyclohexyl ethyl) benzo [d] thiazole-2-amine, be tfa salt (5.2mg).ES/MS?m/z?431.2(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, add in 2.0ml NMP reaction mixture 0.40mmol) cesium carbonate (272mg, 0.834mmol) and 4-chloropyridine formaldehyde (146mg, 1.03mmol).Reaction mixture was at room temperature stirred 20 minutes, then 150 ℃ of 750 seconds of following microwave heating.Crude product mixture is filtered, obtain (S)-4-(2-(1-cyclohexyl ethylamino) benzo [d] thiazole-6-base oxygen base) pyridylaldehyde, be tfa salt (105mg) with preparation HPLC purifying and lyophilize.ES/MS m/z 400.2 (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 of 2-oxopropanal 40% wt (0.034ml, 0.19mmol).Reaction mixture was stirred 2 hours down at 70 ℃.Crude product mixture is concentrated into solid, again be dissolved in 0.8ml DMF, filter, obtain (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, be tfa salt (6.5mg) with preparation HPLC purifying and lyophilize.ES/MSm/z?434.2(MH
+)。
Embodiment 187
(1R, 2R)-preparation of 2-(6-(2-(1H-imidazoles-1-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
(1R, 2R)-preparation of 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 the 1H-imidazoles (180mg, 2.64mmol).Reaction mixture monitored by LC, LCMS and carry out microwave heating in the following order: (150 ℃ of 750 seconds of heating down, 230 ℃ of 750 seconds of heating down, at 250 ℃ in 1000 seconds of heating, once more 250 ℃ of 1000 seconds of heating down).Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (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/z?408.2(MH
+)。
Embodiment 188
(1R, 2R)-preparation of 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-two oxa-boron heterocycle pentane-2-yls)-5, and 6-dihydropyridine-1 (2H)-manthanoate (36mg, 0.117mmol), Pd (dppf)
2Cl
2(7.2mg is 0.0088mmol) with 2M Na
2CO
3(0.125ml, 0.25mmol).Reaction soln was stirred 24 hours down or finishes until LC demonstration reaction at 105-110 ℃.Crude product mixture is concentrated into solid, again be dissolved in 0.8ml DMF, filter, obtain tertiary butyl 4-(4-(2-((1R with preparation HPLC purifying and lyophilize, 2R)-and 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/z?523.1(MH
+)。
Step 2. (1R, 2R)-preparation of 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)-and 2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-5,6-dihydropyridine-1 (2H)-manthanoate (2.5mg, and the dioxan solution of adding 4M HCl in solid 0.0039mmol) (1ml, 4.0mmol).Reaction mixture was at room temperature stirred 45 minutes.Crude product mixture is concentrated into solid and lyophilize obtains that (1R 2R)-2-(6-(2-(1,2,3,6-tetrahydropyridine-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin, is HCl salt (1.4mg).ES/MS?m/z?423.1(MH
+)。
Embodiment 189
4-(the preparation of 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
Step 1. (1s, 4s)-preparation of 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 was stirred 20 hours down or finishes until LC demonstration reaction at 105-100 ℃.Crude reaction solution obtained by preparation HPLC purifying and lyophilize (1s 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/z?498.2(MH
+)。
Step 2.4-(the preparation of 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, ether (2ml, 4.0mmol) solution of adding 2M HCl in solid 0.032mmol).Reaction mixture was at room temperature stirred 60 minutes.Crude product mixture is concentrated into solid and lyophilize to be obtained 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
4-(the preparation of 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
4-(the preparation of 2-((1s, 4s)-4-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
To 4-(2-((1s, 4s)-and 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 was at room temperature stirred 90 minutes.Crude reaction solution is obtained 4-by preparation HPLC purifying and lyophilize, and (2-((1s, 4s)-4-kharophen cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (8.7mg) is tfa salt.ES/MS?m/z?440.2(MH
+)。
Embodiment 191
4-(the preparation of 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:
4-(the preparation of 2-((1s, 4s)-4-isobutyryl aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
To isopropylformic acid (4.4mg, add in 0.3ml NMP reaction mixture 0.050mmol) HATU (17.1mg, 0.045mmol) and (DIPEA) diisopropyl ethyl amine (11ul, 0.0625mmol).Reaction mixture was at room temperature stirred 10-15 minute.In above-mentioned reaction mixture, add 4-(2-((1s, 4s)-and 4-aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (10mg, 0.025mmol) and (DIPEA) diisopropyl ethyl amine (13ul, 0.3ml nmp solution 0.075mmo1).Reaction soln was at room temperature stirred 18 hours.Crude reaction solution is obtained 4-by preparation HPLC purifying and lyophilize, and (2-((1s, 4s)-4-isobutyryl aminocyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (4.0mg) is tfa salt.ES/MS?m/z468.3(MH
+)。
Embodiment 192
(1R, 2R)-preparation of 2-(6-(6-fluorine quinolyl-4 oxygen base) benzo [d] thiazol-2-yl amino) hexalin
This motif compound makes according to following general flow:
(1R, 2R)-preparation of 2-(6-(6-fluorine quinolyl-4 oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (and 15.1mg, add in 0.4ml NMP reaction mixture 0.057mmol) cesium carbonate (47mg, 0.143mmol) and at room temperature stirred 1-3 minute.Adding 4-chloro-6-fluorine quinoline in this mixture (21mg, 0.114mmol).Reaction mixture was stirred 18 hours down or finishes until LC demonstration reaction at 105-110 ℃.Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (1R 2R)-2-(6-(6-fluorine quinolyl-4 oxygen base) benzo [d] thiazol-2-yl amino) hexalin, is tfa salt (9.2mg).ES/MSm/z?410.1(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
To 4-amino--cresols (125mg, 1.01mmol, at room temperature add in 1mL nmp solution 1.0eq) 4-chloro-N-picoline methane amide (189mg, 1.11mmol, 1.1eq) and cesium carbonate (658mg, 2.02mmol, 2.0eq).Reaction mixture was stirred 12 hours down at 75 ℃, then with mixture water (about 50mL) dilution, with water layer ethyl acetate extraction (about 50mL X 3).With the organic layer dried over sodium sulfate that merges, filtration and concentrating under reduced pressure obtain enough pure crude product, and this crude product promptly 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
To 4-(4-amino-3-methylphenoxy)-N-picoline methane amide (25mg, 0.097mmol, add in the cold acetic acid solution of 1mL 1.0eq) ammonium thiocyanate (11mg, 0.145mmol, 1.5eq).After stirring several minutes, (6 μ L, 0.116mmol 1.2eq) and with reaction solution at room temperature stirred 3 hours the injection dripping bromine.Use NaHCO then
3Saturated solution (about 10mL) termination reaction is also used ethyl acetate extraction (about 25mL X 3), and the organic extract liquid that merges is obtained enough pure crude product with dried over sodium sulfate and concentrating under reduced pressure, and this crude product promptly 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 was stirred 12 hours down at 80 ℃, then by the reversed-phase HPLC purifying.LC/MS(m/z)[411.1](MH
+)
Embodiment 194
4-(4-chloro-2-(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
Make according to the described method of the step 1 of embodiment 1.LC/MS(m/z)[2781](MH
+)。
Synthesizing of step 2.4-(2-amino-4-chlorobenzene is [d] thiazole-6-base oxygen base also)-N-picoline methane amide
Make according to the described method of the step 2 of embodiment 1.LC/MS(m/z)[335.0](MH
+)。
Synthesizing of step 3.4-(4-chloro-2-(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 was stirred 2 hours down at 80 ℃, then by the reversed-phase HPLC purifying.LC/MS(m/z)[431.0](MH+)。
Embodiment 195
4-(7-bromo-2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
Synthesizing of step 1.7-bromo-2-chloro-6-methoxyl group benzo [d] thiazole
In the 5mL nmp solution of 2-chloro-6-methoxyl group-benzothiazole (200mg, 1.0mmol, 1.0 equivalents), at room temperature add N-bromine succinimide (213mg, 1.20mmol, 1.2 equivalents).Reaction mixture is stirred down at 75 ℃ 24 hours, the carrying out along with reaction adds NBS with short run subsequently, then with mixture water (about 100mL) dilution and with water layer ethyl acetate extraction (about 150mL X 3).With the organic layer dried over sodium sulfate that merges, filter and concentrating under reduced pressure.Obtain 336mg rice white fine hair sprills product with gradient 0%-50% ethyl acetate-hexane purifying on ISCO, yield is 60%, passes through H
+NMR confirms its structure.LC/MS(m/z)[279.9](MH
+)。
Step 2. (1R, 2R)-2-(7-bromo-6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin synthetic
In the 1mL nmp solution of 7-bromo-2-chloro-6-methoxyl group benzo [d] thiazole (150mg, 0.539mmol, 1.0 equivalents), at room temperature add (1R, 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (0.123mg, 0.809mmol, 1.5 equivalents) and DIPEA (263 μ L, 1.503mmol, 2.8 equivalents).Reaction mixture was stirred 12 hours down at 125 ℃, then with mixture with saturated sodium bicarbonate solution (about 100mL) dilution and with water layer ethyl acetate extraction (about 200mL X 3).With the organic layer dried over sodium sulfate that merges, filter also that concentrating under reduced pressure obtains brown oily crude product, this crude product is enough pure and promptly can be used for next step without being further purified.LC/MS(m/z)[359.0](MH
+)。
Step 3.7-bromo-2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-benzo [d] thiazole-6-alcohol synthetic
To (1R, 2R)-at room temperature add 1M boron tribromide solution (about 3.0mL, 2.68mmol, 5.0 equivalents) in the 10mL DCM solution of 2-(7-bromo-6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin (191mg, 0.537mmol, 1.0 equivalents).With reaction mixture refluxed 12 hours, then mixture is diluted to pH=7 with saturated sodium bicarbonate (about 100mL) and with water layer with ethyl acetate extraction (about 150mL X 3).With the organic layer dried over sodium sulfate that merges, filtration and concentrating under reduced pressure obtain enough pure crude product, and this crude product promptly can be used for next step without being further purified.LC/MS(m/z)[345.0](MH
+)。
Step 4.4-(7-bromo-2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide synthetic
To 7-bromo-2-((1R, 2R)-and 2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (50mg, 0.145mmol, 1.0 at room temperature add 4-chloro-N-picoline 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 following stir abouts 12 hours, is used mixture the reversed-phase HPLC purifying then.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
Step 1.2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-7-methyl benzo [d] thiazole-6-alcohol synthetic
7-bromo-2-((1R in the microwave bottle, 2R)-and 2-hydroxy-cyclohexyl amino) at room temperature add trimethylammonium boraxine (128mg in the 1mL DMF solution of benzo [d] thiazole-6-alcohol (117mg, 0.34mmol, 1.0 equivalents), 1.02mmol, 3.0 equivalents), Pd (Cl
2) dPPf (27mg, 0.034mmol, 0.1 equivalent) and 1mL 2M Na
2CO
3Solution.Then reaction mixture was heated 15 minutes down at 120 ℃ in microwave.Use saturated NaHCO
3Solution (25ml) termination reaction and with water with ethyl acetate extraction (50mL X 3), with the organic layer Na that merges
2SO
4Drying is filtered and concentrating under reduced pressure.Utilizing the gradient purifying of 0%-18% methyl alcohol-DCM to obtain 17mg brown ceramic powder shape product on ISCO, is 17% yield.LC/MS(m/z)[279.1](MH
+)。
Step 2.4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-7-methyl benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide synthetic
Method according to embodiment 543 steps 4 makes.LC/MS(m/z)[413.1](MH
+)
Embodiment 197
4-(7-chloro-2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
Synthesizing of step 1.7-chloro-2-(methylthio group) benzo [d] thiazole-6-alcohol
In the 10mLNMP solution of 2-(methylthio group) benzo [d] thiazole-6-alcohol (500mg, 2.53mmol, 1.0 equivalents), at room temperature add N-chloro-succinimide (507mg, 3.80mmol, 1.5 equivalents).Reaction mixture was at room temperature stirred 1 hour, then mixture is extracted (about 150mL X 3) with saturated sodium bicarbonate solution (about 100mL) dilution and with water layer with DCM.With the organic layer dried over sodium sulfate that merges, filter and concentrating under reduced pressure.Utilize the gradient purifying of 0%-100% ethyl acetate-hexane to obtain the 283.39mg product on ISCO, yield is 48%, passes through H
+NMR confirms the structure of product.LC/MS(m/z)[232.0](MH
+)。
Synthesizing of step 2.4-(7-chloro-2-(methylthio group) benzo [d] thiazole-6-base oxygen base)-N picoline methane amide
In the 1mL nmp solution of 7-chloro-2-(methylthio group) benzo [d] thiazole-6-alcohol (80mg, 0.346mmol, 1.0 equivalents), at room temperature add 4-chloro-N-picoline methane amide (88mg, 0.519mmol, 1.5 equivalent) and cesium carbonate (281mg, 0.865mmol, 2.5 equivalents).Reaction mixture is stirred down at 85 ℃ 48 hours finish to the reaction of about 75%-80%, then mixture water (about 50mL) is diluted and with water layer ethyl acetate extraction (about 50mL X 3).With the organic layer dried over sodium sulfate that merges, filtration and concentrating under reduced pressure obtain crude product, utilize the gradient purifying of 0%-100% ethyl acetate-hexanes mixtures to obtain the 64mg product on ISCO this crude product, and yield is 50%.LC/MS(m/z)[366.0](MH
+)。
Synthesizing of step 3.4-(7-chloro-2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
To 4-(7-chloro-2-(methylthio group) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide (64mg, 0.175mmol, 1.0 stirred 30-45 minute at 0 ℃ of following adding MCPBA (33mg, 0.192mmol, 1.1 equivalents) and with reaction solution in 5ml DCM solution equivalent).Then water (10mL) termination reaction and with water with ethyl acetate extraction (25mL X 5), with the organic layer dried over sodium sulfate that merges, filter also that concentrating under reduced pressure obtains crude product, this crude product is enough pure and promptly can be used for next step without being further purified.LC/MS(m/z)[382.0](MH
+)。
Step 4.4-(7-chloro-2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide synthetic
To 4-(7-chloro-2-(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 with reaction mixture under 160 ℃ in microwave the heating 15 minutes.Then product is passed through 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 step 1.5-fluoro-6-methoxyl group benzo [d] thiazole-2-amine
Used reference: " the synthetic and biologic activity of α-[(6-chloro-5-fluoro-2-[4-morpholinodithio base) 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.
To the 3-fluoro-right-add ammonium thiocyanate (1.07g, 14.18mmol, 2.0 equivalents) in the cold acetic acid solution of 30ml of methyl oxyaniline (1.00g, 7.09mmol, 1.0 equivalents).After stirring several minutes, slowly inject the 6mL acetic acid solution of dripping bromine (437 μ L, 8.50mmol, 1.2 equivalents) and reaction solution was at room temperature stirred 3 hours by feed hopper.Decompression is removed acetate and with NaHCO then
3Saturated solution (100mL) joins in the resistates, with ethyl acetate extraction (125mL X 3), the organic extract liquid that merges is obtained crude product with dried over sodium sulfate and concentrating under reduced pressure, and this crude product is enough pure and promptly 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-(cyclohexyl methyl)-5-fluoro-6-methoxyl group benzo [d] thiazole-2-amine
In the 2mLNMP solution of 5-fluoro-6-methoxyl group benzo [d] thiazole-2-amine (350mg, 1.76mmol, 1.0 equivalents), at room temperature add brooethyl hexanaphthene (370 μ L, 2.65mmol, 1.5 equivalents) and salt of wormwood (366mg, 2.65mmol, 1.5 equivalents).Reaction mixture was stirred 24 hours down at 80 ℃, add reagent to reaction subsequently and finish, use saturated sodium bicarbonate solution (100mL) termination reaction then, use ethyl acetate extraction (125mL X 3) then, with the organic layer dried over sodium sulfate that merges, filter and concentrating under reduced pressure.Utilize the slow gradient purifying of 0%-50% ethyl acetate-hexane to obtain the 310mg product on ISCO crude 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
In the 10mL DCM solution of N-(cyclohexyl methyl)-5-fluoro-6-methoxyl group benzo [d] thiazole-2-amine (114mg, 0.387mmol, 1.0 equivalents), at room temperature add 1M boron tribromide solution (about 1.0mL, 0.775mmol, 2.0 equivalents).Reaction mixture was stirred 2 hours, then mixture is diluted to pH=7 with saturated sodium bicarbonate solution (about 100mL) and water layer usefulness ethyl acetate extraction (about 150mL X 3).With the organic layer dried over sodium sulfate that merges, filter also that concentrating under reduced pressure obtains crude product, this crude product is enough pure and promptly 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
Also at room temperature add 4-chloro-N-picoline methane amide (18mg in the 2mL nmp solution of [d] thiazole-6-alcohol (25mg, 0.089mmol, 1.0 equivalents) to 2-(cyclohexyl methyl amino)-5-fluorobenzene, 0.107mmol, 1.2 equivalent) and cesium carbonate (86mg, 0.267mmol, 3.0 equivalents).Reaction mixture was stirred 12 hours down at 85 ℃, then mixture is obtained the 1.6mg product by the reversed-phase HPLC purifying, be tfa salt, 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 with reaction mixture under 80 ℃ in oil bath the heating 12 hours.Then product is passed through 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 with reaction mixture under 80 ℃ in oil bath the heating 2 hours.Then product is passed through the reversed-phase HPLC purifying.This method can be used for other similar method, wherein, and by the process of LC-MS monitoring reaction and regulate the amount and the reaction times of aniline as required.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) and reaction mixture at room temperature stirred 48 hours.Then product is passed through the reversed-phase HPLC purifying.LC/MS(m/z)[383.1](MH
+)。
Intermediate
Synthesizing of 4-chloro-N-picoline-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 was stirred 3 hours down at 100 ℃.With the mixture concentrating under reduced pressure, be dissolved in 25mL toluene, concentrate once more and obtain crude product 4-chloronicotinoyl chloride hydrochloride, it promptly 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) down at 0 ℃ in the 25ml THF suspension of crude product 4-chloronicotinoyl chloride hydrochloride.Reaction mixture was at room temperature stirred 1 hour and concentrating under reduced pressure.With 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.With organic layer water/salt solution/saturated sodium bicarbonate solution of merging (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。
4-chloro-N ', N '-lutidine-2-formyl hydrazine synthetic
In the 10ml THF suspension of 4-chloropyridine formyl chloride hydrochloride (352mg, 2.0mmol, 1,0 equivalent), at room temperature add N, N-dimethylhydrazine (120mg, 2.0mmol, 1.0 equivalents) and N, N-diisopropyl ethyl amine (383 μ L, 2.2mmol, 1.1 equivalents).Reaction mixture was stirred 15 minutes and water (25mL) and EtOAc (50mL) dilution.Isolated organic layer is washed and uses dried over sodium sulfate with salt solution (25mL), saturated sodium bicarbonate solution (25mL).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 BAY 43-9006: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 Development 2002 (6) 777-781 makes.
(1R, 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride synthetic
Refrigerative amine in ice bath (1R, 2R)-(-)-2-benzyloxy cyclo-hexylamine (20g, in dry MeOH (390mL) solution 97.4mmol) by syringe slowly add 4.0M HCl dioxan solution (49mL, 195mmol).Remove ice bath, with the solution N that forms
2Sprayed 10 minutes.(3g 28mmol) joins in this solution and with reaction solution H with 10%Pd/C
2Purify and maintain H
2In the atmosphere.After 4 hours, add the dioxan solution of 10ml 4.0M HCl and reaction solution is maintained H
2Spend the night in the atmosphere.In case finish (detecting), just reaction solution is filtered by Celite pad thin, tight filling, and the solid of collecting is washed with MeOH and EtOAc successively by LCMS.With organic filtrate evaporation of merging and vacuum-drying obtain light solid state (1R, 2R)-2-Trans-4-Amino Cyclohexanol hydrochloride (13.8g, 91mmol, 93%).LCMS?m/z?116.0(MH
+)，t
R＝0.37min。
(1S, 2S)-2-Trans-4-Amino Cyclohexanol hydrochloride makes according to identical mode.
Embodiment 202
4-chloro-N-isobutoxy pyridine carboxamide
In the 25ml THF suspension of 4-chloropyridine formyl chloride hydrochloride (1.0g, 5.68mmol, 1.0 equivalents), at room temperature add O-isobutyl-hydroxy amine hydrochloric acid salt (785mg, 6.25mmol, 1.1 equivalents) and N, N-diisopropyl ethyl amine (2.97ml, 17.0mmol, 3.0 equivalents).Reaction mixture was stirred 30 minutes and water (25mL) and EtOAc (50mL) dilution.Isolated organic layer is washed and uses dried over sodium sulfate with salt solution (25mL), saturated sodium bicarbonate solution (2 x 25mL).Concentrating under reduced pressure obtains colorless solid shape title compound (870mg, 67%), and it can use without being further purified.ES/MS m/z 229.0 (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, add in 1.2ml DMF reaction mixture 0.228mmol) 4-chloro-N-isobutoxy pyridine carboxamide (40mg, 0.171mmol).Reaction mixture was at room temperature stirred 10 minutes, then 130 ℃ of following microwave heating 3 x 20 minutes.Crude product mixture is filtered, obtain the white solid title compound, be its tfa salt (15mg, 23%) with preparation HPLC purifying and lyophilize.ES/MS m/z 455.1 (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/z 457.0 (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 1. (1R, 2R)-preparation of 2-(6-methoxyl group benzo [d] thiazol-2-yl amino) hexalin
To 4-(2-(methylsulfinyl) benzo [d] thiazole-6-base oxygen base) the pyridine carboxylic acid tert-butyl ester (500mg, add in 8.0ml nmp solution 1.28mmol) the cyclohexyl methylamine (407mg, 3.6mmol) and DIPEA (0.887ml, 5.12mmol).Reaction soln is finished in 110 ℃ of following stirrings 12 hours or LCMS demonstration reaction.Crude product mixture is filtered, obtain 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) the pyridine carboxylic acid tert-butyl ester, be tfa salt (420mg) with preparation HPLC purifying and lyophilize.ES/MS?m/z?440.2(MH
+)。
The preparation of step 2. (4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl) methyl alcohol
(420mg adds THF (3.41ml, 3.41mmol) solution of 1M LAH under room temperature under argon gas in 50ml THF solution 1.14mmol) to 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base) pyridine carboxylic acid tertiary butyl ester.Reaction mixture was at room temperature stirred 30 minutes.Under stirring at room, crude product mixture is carried out aftertreatment by adding methyl alcohol (5ml), 6M NaOH (5ml) and water (5ml) carefully.Aluminium salt precipitation is separated out.Add ethyl acetate (200ml) and organic layer decant from salt is come out.This salt is used ethyl acetate (100ml) washing and decant once more, organic layer is merged,, use Na with salt water washing (2 x 50ml)
2SO
4Drying is filtered and is concentrated.The solid residue that forms is passed through 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 and vacuum concentration.ES/MS?m/z?370.2(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, add in 2ml THF 0.081mmol) and the 2ml DCM solution Dess-MartinPeriodinane (38mg, 0.089mmol).Reaction mixture was at room temperature stirred 30 minutes.Crude product mixture with ethyl acetate (60ml) dilution, with saturated sodium bicarbonate (2 x 15ml), salt solution (1 x 15ml) washing, is used Na
2SO
4Drying, filtration and 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, add in 1.0ml methanol solution 0.041mmol) ammonium acetate (32mg, 0.41mmol) and biacetyl (14mg, 0.163mmol).Reaction mixture was stirred 2 hours down or finishes to monitoring by LCMS at 70 ℃.Crude product mixture is concentrated into solid, again be dissolved in 0.8ml NMP, filter, (2-(4 to obtain N-(cyclohexyl methyl)-6-with preparation HPLC purifying and lyophilize, 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 sodium acetate (300mg adds 3 in 1.6ml aqueous solution 3.7mmol), 3-two bromo-1,1,1-trifluoro penta-2-ketone (500mg, 1.85mmol).Reaction mixture was stirred 1 hour down at 100 ℃.From above-mentioned reaction mixture, take out about 0.5ml (0.46mol), be cooled to room temperature.This crude mixture is joined 4-(2-(cyclohexyl methyl amino) benzo [d] thiazole-6-base oxygen base), and (15mg is in 2ml methanol solution 0.041mmol) for pyridylaldehyde.In crude product mixture, add ammonium hydroxide (28%-30%) solution (0.5ml, 4mmol).Reaction mixture was at room temperature stirred 18 hours or extremely finish by the LCMS monitoring reaction.Crude product mixture is concentrated into solid, again be dissolved in 0.8ml NMP, filter, obtain N-(cyclohexyl methyl)-6-(2-(4-(trifluoromethyl)-1H-imidazoles-2-yl) pyridin-4-yl oxygen base) benzo [d] thiazole-2-amine, be tfa salt (3.0mg) with preparation HPLC purifying and lyophilize.ES/MS?m/z?474.2(MH
+)。
Embodiment 207
(1R, 2R)-2-(6-(6 '-(tetramethyleneimine-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 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 2-fluoro-5-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron heterocycle pentane-2-yls) pyridine (268mg, 1.21mmol), Pd (dppf)
2Cl
2(56mg is 0.069mmol) with 2M Na
2CO
3(1.05ml, 2.1mmol).Reaction soln was stirred 2 hours or until finishing by the LC detection reaction at 105 ℃.Crude product mixture is concentrated into solid, is dissolved in 3ml DMF again, filter, obtain (1R with preparation HPLC purifying and lyophilize, 2R)-2-(6-(6 '-fluoro-2,3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (149mg).ES/MS?m/z?437.1(MH
+)。
Step 2. (1R, 2R)-2-(6-(6 '-(tetramethyleneimine-1-yl)-2,3 '-dipyridyl-4-base oxygen base) benzo [d] thiazol-2-yl amino) preparation of hexalin
To (1R, 2R)-2-(6-(6 '-fluoro-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 was stirred 20 hours down or until finishing by the LC detection reaction at 105-110 ℃.Crude product mixture is filtered, with preparation HPLC purifying and lyophilize obtain (1R, 2R)-2-(6-(6 '-(tetramethyleneimine-1-yl)-2,3 '-the basic oxygen base of dipyridyl-4-) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (2.3mg).ES/MS?m/z?488.1(MH
+)。
Embodiment 208
(1R, 2R)-2-(6-(2-(4-(tetramethyleneimine-1-ylmethyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
This motif compound makes according to following general flow:
Step 1.4-(the preparation of 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-two oxa-boron heterocycle pentane-2-yls) phenyl aldehyde (130mg, 0.558mmol), Pd (dppf)
2Cl
2(38mg is 0.0465mmol) with 2M Na
2CO
3(0.56ml, 1.12mmol).Reaction soln was stirred 4 hours down or until finishing by the LC detection reaction at 110 ℃.Crude product mixture is filtered, and (4-(2-((1R, 2R)-2-hydroxy-cyclohexyl amino) the basic oxygen base of benzo [d] thiazole-6-) pyridine-2-yl) phenyl aldehyde is tfa salt (61mg) to obtain 4-with preparation HPLC purifying and lyophilize.ES/MS?m/z?446.0(MH
+)。
Step 2. (1R, 2R)-preparation of 2-(6-(2-(4-(tetramethyleneimine-1-ylmethyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To 4-(4-(2-((1R, 2R)-and 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 tetramethyleneimine (19.2mg successively, 0.27mmol), excessive acetate (0.060ml, 1.0mmol) and triethyl orthoformate (20mg, 0.135mmol).Reaction mixture was at room temperature stirred 20 minutes.In this reaction mixture, add sodium triacetoxy borohydride (14.3mg, 0.0675mmol).Reaction mixture was at room temperature stirred 18 hours.Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (1R 2R)-2-(6-(2-(4-(tetramethyleneimine-1-ylmethyl) phenyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin, is tfa salt (2.8mg).ES/MS?m/z?501.2(MH
+)。
Embodiment 209
(1R, 2R)-2-(6-(2-(1-(2-(tetramethyleneimine-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)-the 1H-pyrazol-1-yl) acetaldehyde
To (1R, 2R)-(((1-((1 for 2-for 6-for 2-, 3-dioxolane-2-yl) methyl)-and 1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin (195mg, and adding 3M HCl in solid 0.395mmol) (6.0ml, 18mmol).Reaction soln was stirred 6 hours down or until finishing by the LC detection reaction at 95 ℃.With the crude product mixture lyophilize to solid, again be dissolved in 2ml water and 2ml NMP then, obtain 2-(4-(4-(2-((1R with preparation HPLC purifying and lyophilize, 2R)-and 2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-the 1H-pyrazol-1-yl) acetaldehyde, be tfa salt (50mg).ES/MS?m/z?468.2(MH
+)。
Step 2. (1R, 2R)-preparation of 2-(6-(2-(1-(2-(tetramethyleneimine-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)-and 2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base) pyridine-2-yl)-the 1H-pyrazol-1-yl) acetaldehyde (12.5mg, 0.0267mmol) 0.5ml NMP reaction mixture in add tetramethyleneimine (19mg, 0.267mmol) and stirred 10 minutes.In this reaction mixture, add excessive acetic acid (0.070ml, 1.16mmol) and stirred 20 minutes.In this reaction mixture, add sodium triacetoxy borohydride (13mg, 0.0614mmol).Reaction mixture was at room temperature stirred 90 minutes.Crude product mixture is filtered, obtain (1R with preparation HPLC purifying and lyophilize, 2R)-and 2-(6-(2-(1-(2-(tetramethyleneimine-1-yl) ethyl)-1H-pyrazoles-4-yl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin, be tfa salt (1.4mg).ES/MS?m/z?505.2(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 (33L, 0.190mmol, 2.5 equivalents) and reaction solution stirred 72 hours down at 80 ℃.Isolate product by preparation HPLC then, pure fraction lyophilize is obtained title compound, be tfa salt (1.4mg).ES/MS?m/z?340.1(MH
+)。
Embodiment 211
4-(the preparation of 2-((1R, 2R)-2-hydroxy-cyclohexyl amino)-1-oxo-benzo [d] thiazole-6-base oxygen base)-N-picoline methane amide
Will
(KHSO
5, 380mg, water mmol) (4ml) solution at room temperature are added drop-wise to 4-(((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-base oxygen base)-(25mg are in methyl alcohol mmol) (4ml) solution for N-picoline methane amide for 2-.Stir after 23 hours, with suspension water (50ml) dilution and with ethyl acetate extraction (2 x 10ml).With the organic layer salt water washing that merges, concentrate, obtain the white solid title compound by the preparation HPLC purifying.Yield: 2.4mg.ES/MSm/z 415.1 (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 was heated 3 hours down at 110 ℃, obtain title compound by the preparation HPLC purifying then.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 crude product is at first passed through preparation HPLC purifying and lyophilize.Resistates is dissolved in ethyl acetate/saturated sodium bicarbonate solution (10ml/10ml).With isolated organic layer dried over sodium sulfate, vacuum concentration also utilizes methylene chloride (95:5) purifying by preparation type TLC.Purified product is dissolved in the acetonitrile (3ml) and the 1N HCl aqueous solution (0.5ml) and lyophilize obtains title compound, be its HCl salt.Yield: 11mg.ES/MS?m/z?533.1(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 2-chloro-6-methoxyl group benzo [d] thiazole (2.6g, add in 25ml nmp solution 13mmol) (S)-tertiary butyl 3-(6-methoxyl group benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (5g, 25mmol) and DIPEA (2.6ml, 15mmol).Reaction soln was stirred 7 days down at 100 ℃.Crude reaction solution mixed mutually with ethyl acetate (250ml) and dilute aqueous solution of sodium bicarbonate (80ml) and isolate organic phase.With isolated organic layer water (2 x 60ml) and salt solution (60ml) washing, obtain brown oily product with dried over sodium sulfate and vacuum-evaporation then, this product is passed through the flash chromatography on silica gel purifying, use ethyl acetate: hexane (35:65-50:50) wash-out obtain the Off-white solid shape (S)-tertiary butyl 3-(6-methoxyl group benzo [d] thiazol-2-yl amino) piperidines-1-manthanoate (3.33g, 9.16mmol).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 of 4M HCl (60ml 240mmol) [note: emit gas! ].Reaction mixture is at room temperature stirred 2.5 hours and vacuum concentration to remove methyl alcohol and the dioxan of half.Resistates is suspended in the diethyl ether (50ml).Leach solid, wash (S)-6-methoxyl group-N-(piperidines-3-yl) benzo [d] thiazole-2-amine that also vacuum-drying obtains white solid, be its hydrochloride with diethyl ether (50ml).Yield: 4.29g.ES/MSm/z 264.1 (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
With (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 DIPEA (4.11ml, NMP 23.8mmol) (25ml) mixture is 55 ℃ of down heating 16 hours 50 minutes.Reaction mixture is cooled to room temperature and water (150ml) and ethyl acetate (150ml) dilution.After the vigorous stirring 1 hour, isolated organic layer water (3 x 100ml), saturated sodium bicarbonate solution (3 x 100ml), water (100ml) and 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 (20:80-100:0) wash-out obtains (S)-N-(1-(ethylsulfonyl) piperidines-3-yl)-6-methoxyl group benzo [d] thiazole-2-amine of tawny solid state.Yield: 1.22g.ES/MS m/z 356.0 (MH
+), Rt=2.12 minute.
The preparation of step 4. (S)-2-(1-(ethylsulfonyl) piperidines-3-base is amino) benzo [d] thiazole-6-alcohol
((dichloromethane solution of 1M 7.5ml) is handled down at 0 ℃ with boron tribromide under nitrogen atmosphere for 1.22g, methylene dichloride 3.43mmol) (25ml) solution with (S)-N-(1-(ethylsulfonyl) piperidines-3-yl)-6-methoxyl group benzo [d] thiazole-2-amine.Continue down to stir 10 minutes at 0 ℃, at room temperature stir about is 135 minutes.Water (50ml), ethyl acetate (200ml) are diluted and are handled (not emitting gas until observing) with solid sodium bicarbonate carefully with reaction mixture.Mixture is stirred to each phase transformation clarification.Dried over sodium sulfate is washed and used to the organic phase of telling with saturated sodium bicarbonate solution (2 x 75ml), water (75ml), salt solution (75ml).Vacuum concentration obtains crude product (S)-2-(1-(ethylsulfonyl) piperidines-3-base is amino) benzo [d] thiazole-6-alcohol, and it promptly can be used for next step without being further purified.Yield: 1.15g.ES/MS m/z 342.0 (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, adding 2-chloro-4-fluorine pyridine in 12ml NMP mixture 6.74mmol) (532mg, 4.05mmol).Reaction mixture was stirred 17 hours down at 60 ℃.With reaction mixture water (100ml) and ethyl acetate (100ml) dilution.Isolated organic layer water (3 x 50ml), saturated sodium bicarbonate solution (3 x 50ml), 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/z?453.0(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:
(1R, 2R)-preparation of 2-(6-(2-(3-methoxy propyl-1-alkynyl) pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To (1R, 2R)-(18.8mg adds Pd (dppf) in 0.5ml DMF reaction mixture 0.05mmol) to hexalin to 2-(6-(2-chloropyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino)
2Cl
2(8.2mg, 0.01mmol), CuI (4.3mg, 0.0225mmol), 3-methoxy propyl-1-alkynes (15.8mg, 0.225mmol), add at last DIPEA (0.026ml, 0.15mmol).Reaction soln was stirred 90 minutes down or until finishing by the LC detection reaction at 100 ℃.Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (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:
(1R, 2R)-preparation of 2-(6-(2-ethynyl pyridine-4-base oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To (1R, 2R)-add Pd (dppf) in the 0.5ml DMF reaction mixture of 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), the ethynyl trimethyl silane (21.1mg, 0.215mmol) and last add DIPEA (0.023ml, 0.129mmol).Reaction soln was stirred 90 minutes down or until finishing by the LC detection reaction at 100 ℃.Adding 3MNaOH solution in crude product mixture (0.175ml, 0.525mmol).Crude product mixture at room temperature stirred 30 minutes or until finishing by the LC detection reaction.With dense thick crude product mixture with excessive acetic acid (0.085,1.41mmol) neutralization and add 0.5ml DMF.Mixture was stirred 5 minutes, filter, obtain with preparation HPLC purifying and lyophilize that (1R 2R)-2-(6-(the basic oxygen base of 2-ethynyl pyridine-4-) benzo [d] thiazol-2-yl amino) hexalin, is tfa salt (4.6mg).ES/MS?m/z?366.1(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 was heated 18 hours down at 85 ℃, heated 24 hours down at 90 ℃.Obtain title compound by the preparation HPLC purifying.Yield: 2.1mg.ES/MS m/z 527.1 (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 obtained title compound 105 ℃ of following heating 18 hours and by the preparation HPLC purifying.Yield: 9.8mg.ES/MS m/z 531.2 (MH
+), Rt=1.89min minute.
Embodiment 219
(1R, 2R)-preparation of 2-(6-(pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin
To 2-((1R, 2R)-2-hydroxy-cyclohexyl amino) benzo [d] thiazole-6-alcohol (and 20mg, add in 0.5ml NMP reaction mixture 0.0755mmol) cesium carbonate (62mg, 0.189mmol) and at room temperature stirred 1-3 minute.In this mixture, add cesium carbonate (98.5mg, 0.302mmol) and 4-chloropyridine hydrochloride (45.3mg, 0.302mmol).Reaction mixture was stirred 48 hours down or until finishing by the LC detection reaction at 105-110 ℃.Crude product mixture is filtered, obtain with preparation HPLC purifying and lyophilize that (1R 2R)-2-(6-(pyridin-4-yl oxygen base) benzo [d] thiazol-2-yl amino) hexalin, is tfa salt (1.1mg).ES/MS?m/z?342.1(MH
+)。
Compound 1-381 in the table 3 and compound 1-102,104-106 in the table 4 and 112-119 make according to above embodiment, especially make according to " Ex Prep " (preparation embodiment) described embodiment in a hurdle.Compound 103 and 107-111 can make according to above embodiment.
Table 3
Table 4
Every kind of compound listing in the table 2 is active to the inhibition of CSF-1R to be IC
50Less than about 10 μ M.Most compounds is IC for the activity that CSF-1R suppresses to show
50Less than about 1 μ M or less than about 0.1 μ M or less than about 0.01 μ M.The activity of table 3 and 4 compound is less than 1 μ M.Every kind of compound itself in the table 2,3 and 4 all is preferred individually or as a member in this group.
Except CSF-1R suppresses activity, chemical compound lot in the 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 suppresses the kinase whose activity of Raf and other screening significantly greater than (between about 2～about 1,000 times).More particularly, the activity of most compounds when suppressing Raf is greater than about 1 μ M, and the activity of most of same compound when suppressing CSF-1R is less than about 0.1 μ M.Therefore the most compounds in the table 2,3 and 4 be CSF-1R effectively and be inhibitor optionally.
Biology embodiment
Biology embodiment 1
Be used for the vitro kinase test of colony-stimulating factor-1 acceptor (CSF-1R)
The kinase activity of various protein tyrosine kinases can be by providing ATP and the suitable peptide that contains 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, with testing compound since 25 μ M with 3 times of diluents in DMSO in 384 orifice plates continuously the dilution, then with by 50mMHepes, 5mM MgCl
2, 10mM MnCl
2, the suitable kinase reaction buffering liquid-phase mixing formed of 0.1% BSA, pH 7.5,1.0mM dithiothreitol (DTT), 0.01% Tween 80 and 1 μ M ATP.Is 20 μ L with 50nM adding kinase protein and suitable biotinylated peptide substrates to obtain final volume, reaction solution at room temperature is incubated 2 hours, by adding 10 μ L 45mM EDTA, 50mMHepes pH 7.5 termination reactions.Adding 30 μ L PT66Alphascreen beads in the mixture of stopped reaction (Perkin Elmer, Boston, MA, U.S.A.).Go up reading with the reaction solution incubated overnight and at Envision (Perkin Elmer).The peptide prod of phosphorylation is utilized the acceptor bead that scribbles anti-phosphotyrosine antibody PT66 with AlphaScreen system (Perkin Elmer) and scribble and to measure at the donor bead that about 520-620nM transmitted wave strong point is sent the streptavidin of fluorescent signal.50% inhibition concentration (IC of every kind of compound
50) utilize XL Fit data analysis software to calculate by non-linear regression.
With the CSF-1R kinases at 50mM Hepes pH 7.0,5mM MgCl
2, 10mM MnCl
2, 1mM DTT, 1mg/ml BSA, 1.0 μ M ATP and 0.05 μ M vitamin H-GGGGRPRAATF-NH
2Test in (SEQ ID NO:2) peptide substrates.Final concentration with 4nM adds the CSF-1R kinases.
Biology embodiment 2
The vitro inhibition effect of CSF-1R receptor tyrosine phosphorylation
In order to test the restraining effect of CSF-1R receptor tyrosine phosphorylation, the compound that to buy HEK293H from Invitrogen (Cat.#11631017) (with the total length people CSF-1R acceptor cells transfected of being cloned in the Mammals additive type transfection carrier) and serial dilution is (since 10 μ M, 3 times of dilutions) be incubated 1 hour together, stimulated 8 minutes with 50ng/ml MCSF then.After removing supernatant liquor, cell is being dissolved with dissolving damping fluid (150mM NaCl, 20mM Tris, pH 7.5,1mMEDTA, 1mM EGTA, 1% Triton X-100 and NaF, proteolytic enzyme and inhibitors of phosphatases) on ice, vibrating 15-20 minute down at 4 ℃ then.Then lysate is transferred in 96 orifice plates that apply with CSF-1R antibody, this plate is in advance with 3% Blocker A (from Mesoscale Discovery (MSD)) sealing 2 hours, washing then.Lysate 4 ℃ of following incubated overnight, is washed this plate 4 times with MSD Tris Wash Buffer then.To in 1% Blocker A (MSD) solution, be diluted to the 20nM final concentration from the SULFO-TAGanti-pTyr antibody of MSD, and join on the plate after the washing then and be incubated 1.5-2 hour, add reading damping fluid (MSD) then.This plate is gone up reading at Sector6000 instrument (MSD).Raw data is imported Abase, and calculate EC with the XL-fit data analysis software
50
Biology embodiment 3
CSF-1R inhibitor in the MNFS-60 Pk/Pd model
500 ten thousand MNFS-60 cells are implanted the right side abdomen in HBSS/Matrigel solution.Measure tumours in the about 3 week backs of tumor cell injection, and with the mouse selected according to the big or small randomization grouping of its tumour (n=3, except the vehicle group, n=6 wherein).
Will be with EC
50The compound of the phosphorylation of the propagation of M-CSF mediation and CSF-1R is at the homogenic tumor model of MNFS-60 (5 X 10 in＜the 100nM inhibition MNFS-60 cell
6, wherein subcutaneous implantation and growth 3-4 week in Matrigel, reach about 150mm until them
2) on test.The animal that the single 100mg/kg dosed administration of representative compounds disclosed herein is had the MNFS-60 tumour in length; 1 hour to 24 hours after administration begins at each time point results blood plasma and tumor sample.
Measure by western blotting, the result confirms that, compare with vehicle Control after 4 hours in administration, multiple compound disclosed herein can suppress Tyr723 phosphorylation 〉=50% of CSF-1R in the tumour lysate.
In addition, also at the severe osteoarthritis mouse model (people such as Terato, K., the Journalof Immunology 148:2103-2108 that show effect rapidly; 1992) in multiple compound disclosed herein is detected, treatment began with LPS then at injection anticol original antibody mixture in post-stimulatory the 3rd day.In whole 12 days for the treatment of, the degree of pawl swelling and the severity of bone resorption are marked with the CSF-1R inhibitor.Compare with control group, do not observe the obvious alleviation of swelling, still, the severity of bone resorption is tended to improve.Also there is not report to show that the CSF-1R inhibitor is effective in this arthritis model at present.Unique situation of successfully slowing down progression of disease of being reported suppresses the CSF-1R signal with anti-MCSF antibody and conducts (people such as Campbell, J.Leukoc.Biol.68:144-150 in sacroiliitis mouse model lighter, slowly outbreak; 2000).
Biology embodiment 4
The restraining effect of Raf kinase signal in the external biological chemical test
Compound is determined the biological test below the inhibition effect utilization of Raf.The kinase whose activity of Raf is by providing ATP, reorganization 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 behind purifying.With MEKcDNA N-end (His)
6Mark subclone and at expression in escherichia coli, then with the MEK substrate of reorganization by nickel affinity chromatography purifying from the intestinal bacteria lysate, carry out anionresin then.With final MEK substrate preparation biotinylation (Pierce EZ-LinkSulfo-NHS-LC-Biotin) and be concentrated into about 11.25 μ M.Reorganization Raf (comprising c-Raf and mutant B-Raf isoform) obtains from the sf9 insect cell that infects with corresponding people Raf recombinant expression vector by purifying.The Raf isoform of reorganization is passed through the interaction of Glu antibody or passes through the metal ion chromatogram purification.
For each test, this compound is for example diluted in DMSO with 3-times of diluent continuously since 25 μ M, mix mutually with various Raf isoforms (every kind of about 0.50nM) then.Kinases inactivation vitamin H-MEK substrate (50nM) adding is contained in the reaction buffer of ATP (1 μ M).This reaction buffer contains 30mM Tris-HCl
2PH 7.5,10mM MgCl
2, 2mM DTT, 4mMEDTA, 25mM β-glycerophospholipids, 5mM MnCl
2With 0.01% BSA/PBS.Subsequently reaction solution at room temperature is incubated about 2 hours, by adding 0.5M EDTA termination reaction.The mixture of termination reaction is transferred to the plate (Pierce) that has applied Neutradavin to be gone up and is incubated about 1 hour.With the product of phosphorylation with DELFIA time difference type fluorescing system (Wallac), utilize rabbit anti--p-MEK (Cell Signaling) measures as secondary antibody as one-level antibody and with the resisting of europium mark-rabbit.Time difference type fluorescence can be on Wallac 1232 DELFIA photofluorometers reading.50% inhibition concentration (IC of compound
50) utilize XL Fit data analysis software to calculate by non-linear regression.
Biology embodiment 5
The restraining effect of cKIT and PDGFRb kinase signal in the extracorporeal biology test
In the Alphascreen system, measure the IC that suppresses RTK
50Value wherein, is measured compound shifts phosphate radical to substrate to various enzymes restraining effect.In brief, buy corresponding RTK structural domain (cKIT Upstate #14-559, PDGFRb Invitrogen #P3082) and its compound with serial dilution is cultivated in the presence of substrate and ATP with the form of human recombination protein, wherein, the concentration of ATP is in 3 times of the Km of enzyme.
With the kinase domain of cKIT at 50mM Hepes, pH=7.5,5mM MgCl
2, 10mMMnCl
2, test among 1mM DTT, 0.1% BSA that contains the biotinylated peptide substrates of 0.06uM (GGLFDDPSYVNVQN1-NH2) and the 15uM ATP (the apparent KM=15uM of ATP).With the kinase domain of PDGFR at 50mM Hepes, pH=7.5,20mM MgCl
2, test among 1mM DTT, 0.1% BSA that contains the biotinylated peptide substrates of 0.1uM (GGLFDDPSYVNVQN1-NH2) and the 10uM ATP (the apparent KM=25uM of ATP).Reaction solution at room temperature is incubated 3 to 4 hours and uses damping fluid termination reaction (, all using 20mM EDTA, 0.01% Tween-20) for PDGFRb and cKIT.Alphascreen PY20 bead is joined in the cKIT reaction solution of stopped reaction, PY20 Ab/ albumin A Alphascreen bead is joined in the reaction solution of stopped reaction of PDGFR β.With 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 is used for each test with star-like spore rhzomorph, and needs Z ' in contrast〉0.5 so that the result is effective.
Biology embodiment 6
Cells survival test in the MNFS60 cell that MCSF relies on
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, contains 10%FBS and 1% penicillin/streptomycin.Test compounds is carried out serial dilution (3 times) in DMSO, 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) diluted in the 500 μ l substratum of the somatomedin MCSF that comprises the 2x final concentration be 2x concentration, then on cell, be diluted to 1x.The final concentration of MCSF is 10ng/ml.Cell is at 37 ℃, 5%CO
2Hatched under the condition 72 hours.After hatching, 100 μ l Cell Titer Glo are added the cell that survival is measured in each hole.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 imported Abase and adopt the XL-fit data analysis software to calculate EC
50Comprise cell in the substratum but do not contain MCSF thereby each hole that cell is not grown, its relative light unit is defined as 100% to be suppressed.
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.Have 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, people such as E, 2003, Clin.Canc.Res., 9:295; Alvarez, people such as E., 2003, Clin.Canc.Res., 9:5705).This method comprises tumour cell is injected directly into proximal tibia.In case cell is set up, they just breed the somatomedin that justacrine has osteoclast activity, cause the absorption again of girder and cortex of bone.Behind tumor cell transplantation, by several different methods bone destruction is measured with the anti-drug treating animal that absorbs and in test endpoint.
The tumor cell line that uses in this method is a human origin, has represented this class tumor cell line, promptly changed before them thereby at present expressing luciferase so that use the Xenogen system that the intravital tumour cell of animal is followed the trail of.The intensity of optical signal also provides on concrete site nearly how many cellular localizations in this indication.
At cell inoculation preceding 30 minutes, to mouse subcutaneous injection 2.5mg/kg flunixin meglumine, so that the analgesic activity after the program to be provided.Follow mouse by sucking isoflurane anesthesia (, can use ketamine/xylazine) if can not get isoflurane.The animal of anesthesia is placed as dorsal position, after the tumour cell suction is had 50 or 100 μ l microsyringes of 26-or No. 27 syringe needles, syringe needle is inserted by the cortex of the preceding tuberosity of right side shin bone, adopt the rotation of " probing formula " to advance during insertion, so that the chance of cortex fracture minimizes.If syringe needle progressive resistance disappears, illustrate that syringe needle is successfully by cortex and entered marrow.In case the cortex of bone of passing then is injected into 10-20 μ l cell suspension (6X10^5MDA-MB-231Luc mammary cancer or 3X10^5PC-3MLuc prostate cancer cell) in the marrow of shin bone.Animal is observed to guarantee its accident-free recovery (heat pad or lamp), till they are recovered from anesthesia.
Tumor growth progress in the bone can be divided into 5 stages (0-4 phase).These stage definitions are as described below, and they can compare by (left side) leg of not injecting with this mouse and monitor:
0 phase: normal, the indication of no any change in the bone.
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 and execution.
In research process, use the photon imaging of leg to estimate growth of tumor on injection point and farther position, use the Xenogen system quantitative, and confirm not to be leaked in other zone the tumour cell in the shin bone.Up to off-test, use Faxitron X-ray Unit that leg is taken radiograph, once in a week to estimate bone destruction in the cortex of injection point.When using more invasion and attack clone such as PC-3M-Luc, we are one to two week and the damage of monitoring bone subsequently once in a week after injection.For clone to damage than slow rate formation, 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 transplant the about 4 weeks shooting in back in the shin bone first, to set up baseline control, the time point that begins to occur from damage begins subsequently, measures bone injury once in a week.For example, in the mouse of injection MDA-MB-231Luc, will after transplanting, take pictures in about 4 weeks, take once weekly afterwards.
Can be according to any standard way, once a day or use small molecules, monoclonal antibody or albumen to animal twice.
The terminal point of test is that the be untreated animal of (negative control) of great majority has reached the late period (4 phase) and the sacrificed time point of disease.At that point, no matter which kind of is remaining its tumour of animal be in and all be condemned to death in stage in the research.According to the difference of clone, research continues about 5-10 week.After final X-line was taken, drawing blood from animal by cardiac puncture (was used to measure the marrow of serum; See below).Then the X-line image of terminal point is distributed to 5 volunteers, they mark to each image according to the top points-scoring system that describes in detail.The mark of every mouse is averaged and is expressed as average molten bone mark or has the per-cent of the animal (mark is higher than 2 animal) of serious osteolysis.
Biology embodiment 8
Mouse Trap5b test (IDS company, Fountain Hills, AZ)
This test is the immunofixation enzymic activity test that is used for the solid phase of the osteoclast-derived anti-tartaic acid Phosphoric acid esterase 5b of definite mice serum sample.Trap5b is expressed by the resorbent osteoclast of sclerotin, and is entered circulation by secretion.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, its with recombined small-mouse Trap5b as antigen prepd.In this test, in the microtiter well that has applied anti-rabbit igg, hatch antibody.After the cleaning, the serum sample of standard substance, contrast and dilution is hatched in the hole, bonded Trap5b activity is determined with the chromogenic substrate colour developing.Termination reaction is with the absorbancy of microplate reader at 405nm assaying reaction mixture.Amount and the activity of the Trap5b that exists in colored intensity and the sample are directly proportional.By with the mean light absorbency of each standard substance of ordinate zou to the mapping of X-coordinate concentration, the numerical value of unknown sample can be read from this typical curve, and represents 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.
Though described the preferred embodiment of the invention and variation scheme thereof in detail, being to use other improvement and method should be conspicuous for those skilled in the art.Correspondingly, be to be understood that various application, improvement and replacement can be made up of the multiple equivalence that does not break away from the scope of purport of the present invention and claim.
When testing with about 1 μ M in the described test of biology embodiment, the active per-cent of inhibition of table 2,3,4 compound is presented at respectively in the table 5,6 and 7.Being expected at inhibiting rate under the 1 μ M and being 0% compound has under higher concentration and suppresses active." N/D " is illustrated in and do not test this compound in the special test.
The activity of table 5. table 2 compound
| Cmpd | PDGFRβ | CSF-1R | cKit | M-NFS-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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-60?CP | 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 |
| 29 | 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 |
| 48 | 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 (85)
1, compound, steric isomer, tautomer, solvate, oxide compound, ester or the prodrug of formula (I) or its pharmacologically acceptable salt:
Wherein X is O, S or S (O);
R
1And R
2Be independently selected from the heteroaryl of heterocyclic radical, heteroaryl and replacement of aryl, heterocyclic radical, the replacement of cycloalkenyl group, aryl, the replacement of cycloalkyl, cycloalkenyl group, the replacement of alkyl, acyl group, cycloalkyl, the replacement of hydrogen, alkyl, 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
6Be alkoxyl group, the amino of alkyl, alkoxyl group, the replacement of alkyl, replacement, the amino or the halogen of replacement independently;
N is 0,1 or 2; And
When X is O, R
4Be the alkynyl of alkenyl, alkynyl or replacement of alkyl, alkenyl, the replacement of hydrogen, replacement, and R
5Be 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, 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
4Be the 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.
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
2Be hydrogen or methyl.
5, the compound of claim 1, wherein R
1Be independently selected from the following alkyl that substituting group replaced by 0,1,2 or 3: the alkylsulfonyl of halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, aryloxy, aminocarboxyl, carboxyl ester, carboxyl and replacement.
6, the compound of claim 1, wherein 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
1aBe that replace or unsubstituted.
7, the compound of claim 6, wherein 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] [1,4] two oxa-s
, pyrazinyl, pyrrolidyl, piperidyl, piperidone, pyrrolidone, pyridine-2 (1H)-ketone, 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 azepan-2-ketone, wherein each R
1aBe that replace or unsubstituted.
8, the compound of claim 7, wherein L is a covalent linkage.
9, the compound of claim 6, wherein L is independently selected from the following alkylidene group that substituting group replaced by 0,1,2 or 3: the alkyl of alkyl, replacement, hydroxyl, alkoxyl group, halogenated alkoxy, aminocarboxyl, carboxyl ester and carboxyl.
10, the compound of claim 1, wherein R
1Be
Wherein dotted line is saturated bond or unsaturated link(age);
Wherein L is the alkylidene group of covalent linkage, alkylidene group or replacement; And
R
10, R
11And R
12Be independently selected from the heteroaryl of aryl, heteroaryl and replacement of heterocyclic radical, aryl, the replacement of cycloalkyl, heterocyclic radical, the replacement of amino, cycloalkyl, the replacement of alkoxyl group, amino, the replacement of alkyl, alkoxyl group, the replacement of hydrogen, halogen, hydroxyl, alkyl, 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.
11, the compound of claim 10, wherein dotted line is a saturated bond, forms cyclohexyl thus.
12, the compound of claim 10, wherein L is a covalent linkage.
13, the compound of claim 10, wherein L is the methylene radical of methylene radical or replacement.
14, the compound of claim 13, wherein L is replaced by the alkyl of alkyl, replacement, carboxyl, aminocarboxyl and carboxyl ester.
15, the compound of claim 10, wherein R
10, R
11And R
12Be independently selected from the alkyl and the alkoxyl group of hydrogen, halogen, hydroxyl, alkyl, replacement.
16, the compound of claim 10, wherein R
10, R
11And R
12In at least one be hydroxyl.
17, the compound of claim 10, wherein R
11With R
12Connect together and form the aryl of aryl or replacement.
18, the compound of claim 1, wherein R
1It is the alkyl of alkyl or replacement.
19, the compound of claim 18, wherein R
1Be the alkyl that replaces, 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.
20, the compound of claim 19, wherein R
1Be the alkyl that replaces, wherein R
1Substituting group be the cycloalkyl of cycloalkyl or replacement.
21, the compound of claim 1, wherein 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.
22, the compound of claim 21, wherein R
1Be selected from the heterocyclic radical of cycloalkyl, heterocyclic radical and the replacement of cycloalkyl, replacement.
23, the compound of claim 1, wherein R
3Be acyl amino or aminocarboxyl.
24, the compound of claim 23, wherein R
3Be-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.
25, the compound of claim 24, wherein R
3Be-C (O) NHCH
3
26, the compound of claim 1, wherein R
3It is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.
27, the compound of claim 1, wherein R
3It is the cycloalkenyl group of cycloalkyl, cycloalkenyl group or replacement of heterocyclic radical, cycloalkyl, the replacement of heteroaryl, heterocyclic radical, the replacement of aryl, heteroaryl, the replacement of the alkyl that replaces, aryl, replacement.
28, 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-base, 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 R3 is that replace or unsubstituted.
29, the compound of claim 1, wherein R
4Be hydrogen.
30, the compound of claim 1, wherein R
5Be hydrogen.
31, the described compound of any one in the claim 1 to 30, wherein n is 0, R
4And R
5Be hydrogen, 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.
32, the compound of claim 1, wherein R
4And R
5Connect together and form the aryl of aryl or replacement.
33, have formula (IIa) or the described compound of claim 1 (IIb), steric isomer, tautomer or solvate or its pharmacologically acceptable salt:
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;
R
10, R
11And R
12Be independently selected from the heteroaryl of aryl, heteroaryl and replacement of heterocyclic radical, aryl, the replacement of cycloalkyl, heterocyclic radical, the replacement of amino, cycloalkyl, the replacement of alkoxyl group, amino, the replacement of alkyl, alkoxyl group, the replacement of hydrogen, halogen, hydroxyl, alkyl, 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.
34, the compound of claim 33, wherein dotted line is a saturated bond, forms cyclohexyl thus.35, the compound of claim 33, wherein X is O.
36, the compound of claim 33, wherein X is S.
37, the compound of claim 33, wherein L is a covalent linkage.
38, the compound of claim 33, wherein L is the methylene radical of methylene radical or replacement.
39, the compound of claim 33, wherein L is replaced by the alkyl of alkyl, replacement, carboxyl, aminocarboxyl or carboxyl ester.
40, the compound of claim 33, wherein R
10, R
11And R
12Be independently selected from the alkyl and the alkoxyl group of hydrogen, halogen, hydroxyl, alkyl, replacement.
41, the compound of claim 38, wherein R
10, R
11And R
12In at least one be hydroxyl.
42, the compound of claim 33, wherein R
11With R
12Connect together and form the aryl of aryl or replacement.
43, the compound of claim 33, wherein R3 is acyl amino or aminocarboxyl.
44, the compound of claim 43, wherein R
3Be-C (O) NHCH
3
45, the compound of claim 33, wherein R
3It is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.
46, the described compound of claim 1, steric isomer, tautomer or the solvate or its pharmacologically acceptable salt that have formula (IIIa):
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
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.
47. the compound of claim 46, wherein X is O.
48, the compound of claim 46, wherein X is S.
49, the compound of claim 46, wherein R
1It is the alkyl that is substituted by cycloalkyl.
50, the compound of claim 46, wherein R
3Be acyl amino or aminocarboxyl.
51, the compound of claim 50, wherein R
3Be-C (O) NHCH
3
52, the compound of claim 46, wherein R
3It is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.
53, the described compound of claim 1, steric isomer, tautomer or the solvate or its pharmacologically acceptable salt that have formula (IIIb):
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
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.
54, the compound of claim 53, wherein X is O.
55, the compound of claim 53, wherein X is S.
56, the compound of claim 53, wherein R
1Be selected from the heterocyclic radical of cycloalkyl, heterocyclic radical and the replacement of cycloalkyl, replacement.
57, the compound of claim 53, wherein R
3Be acyl amino or aminocarboxyl.
58, the compound of claim 57, wherein R
3Be-C (O) NHCH
3
59, the compound of claim 53, wherein R
3It is the heteroaryl of alkyl, formonitrile HCN, heteroaryl or the replacement of hydrogen, carboxyl, replacement.
60, compound, steric isomer, tautomer, solvate, oxide compound, ester or the prodrug of formula (IV) or its pharmacologically acceptable salt:
Wherein X is O or S;
R
7Be independently selected from alkoxyl group, halogenated alkoxy, halogen and formonitrile HCN;
P is 0,1 or 2;
R
1Be-LR
8Or be 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 by 0,1,2 or 3;
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 randomly is the 2-p-methoxy-phenyl.
61, the compound of claim 53, wherein X is S.
62, the compound of claim 53, wherein p is 0.
63, the compound of formula V, steric isomer, tautomer, solvate, oxide compound, ester or prodrug or its pharmacologically acceptable salt:
Wherein X is O or S;
R
1Be-LR
9Or be 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 by 0,1,2 or 3;
L is the alkylidene group of covalent linkage, alkylidene group or replacement; And
R
9Be selected from cycloalkyl, THP trtrahydropyranyl, morpholino and the pyridyl of cycloalkyl, replacement.
64, the compound of claim 60, wherein X is S.
65, the compound of claim 60, wherein L is covalent linkage or alkylidene group.
66, the compound of claim 60, wherein R
8It is the cyclohexyl of cyclohexyl or replacement.
67, be selected from table 2,3 or 4 claim 1,60 or 63 described compounds, steric isomer, tautomer, solvate, oxide compound, ester or prodrug or its pharmacologically acceptable salt.
68, The compound claimed in claim 2, which compound is selected from: 4 - [2 - (4 - bromo - phenylamino) - benzo
Oxazolyl -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - ((R) -1 - phenyl - ethyl amino) - benzoxazin
-6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - morpholin-4 - yl - amino phenyl) - benzoxazole
-6 - Yloxy] - pyridin-2 - carboxylic acid methylamide, (2,3 - dihydro - benzo [1,4] dioxin-6 - yl) - [6 - (6,7 -
Dimethoxy - quinolin-4 - yloxy) - benzoxazol-2 - yl] - amine, 4 - [2 - (2,3 - dihydro - benzo [1,4] dioxin
Dioxin-6 - ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (1 - thiazol-2 - yl
- Ethylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - ((S) -1 - phenyl - B
Ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - chloro - benzylamino) -
Benzoxazol -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2,4 - dichloro - benzylamino) - benzo
Oxazolyl -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (3 - methyl - cyclohexylamino) - benzoxazole
-6 - Yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - methoxy - phenyl amino) - benzoxazole -6 -
Yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - ethoxy - phenylamino) - benzoxazole -6 - yloxy
Yl] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - ((1S, 2S, 3S, 5R) -2,6,6 - trimethyl - bicyclo [3.1.1] hept-
-3 - Ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methyl amide, [6 - (6,7 - dimethoxy - quinoline
Morpholin-4 - yloxy) - benzoxazol-2 - yl] - ((R) -1 - phenyl - ethyl) - amine, 4 - {2 - [((1S, 2R, 4R) - 7,7 -
Dimethyl - bicyclo [2.2.1] hept-2 - ylmethyl) - amino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methyl
Amide, 4 - [2 - (2 - fluoro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - (2 - methoxy - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - ((R) -1 - naphthalen-1 - yl - ethylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - ((R) -1 - phenyl - propylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - ((S) -1 - naphthalen-2 - yl - amino-ethyl) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - (cyclohexyl-methyl - amino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methyl amide, 4 - (2 -
Cyclobutylamino - benzoxazol -6 - yloxy) - pyridine-2 - carboxylic acid methyl amide, 4 - (2 - cyclopentyl-amino -
Benzoxazol -6 - yloxy) - pyridine-2 - carboxylic acid methyl amide, 4 - (2 - cyclohexylamino - benzoxazole -6 -
Yloxy) - pyridine-2 - carboxylic acid methylamide, 4 - [2 - (2 - morpholin-4 - yl methyl - phenylamino) - benzoxazole
-6 - Yloxy] - pyridin-2 - carboxylic acid methyl amide, 4 - (2 - phenylamino - benzoxazole -6 - yloxy) - pyridine
2 - carboxylic acid methylamide, 4 - [2 - (4 - chloro - benzylamino) - benzoxazole -6 - yloxy] - pyridine-2 - carboxylic acid methyl
Amide, 4 - [2 - (2,4 - dimethoxy - phenylamino) - benzoxazole -6 - yloxy] - pyridine-2 - carboxylic acid methyl
Amide, N-[4 - (2 - cyclohexylamino - benzoxazol -6 - yloxy) - pyridin-2 - yl] - acetamide,
4 - [2 - (tetrahydro - pyran-4 - ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - {2 - [(R) -1 - (2 - methoxy - phenyl) - ethylamino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methyl
Amide, N-{4 - [2 - (2 - chloro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - yl} - acetamide,
4 - [2 - (2,5 - difluoro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
N-{4 - [2 - (cyclohexyl-methyl - amino) - benzoxazole -6 - yloxy] - pyridin-2 - yl} - acetamide,
(R) - [6 - (2 - methylcarbamoyl - pyridin-4 - yloxy) - benzoxazol-2 - yl-amino] - phenyl - acetic acid,
4 - {2 - [((R) - methylcarbamoyl - phenyl - methyl) - amino] - benzoxazol -6 - yloxy} - pyridin-2 -
Carboxylic acid methylamide, 4 - [2 - ((R) -2 - hydroxy-1 - phenyl - ethyl amino) - benzoxazole -6 - yloxy] - pyridine
-2 - carboxylic acid methylamide, (S) - [6 - (2 - methylcarbamoyl - pyridin-4 - yloxy) - benzoxazol-2 -
Ylamino] - phenyl - acetic acid, 4 - {2 - [((S) - methylcarbamoyl - phenyl - methyl) - amino] - benzoxazole
-6 - Yl oxy} - pyridine-2 - carboxylic acid methylamide, 4 - {2 - [(pyridin-2 - ylmethyl) - amino] - benzoxazole -6 -
Yloxy} - pyridine-2 - carboxylic acid methyl amide, 4 - (2 - benzylamino - benzoxazol -6 - yloxy) - pyridin-2 -
Carboxylic acid methylamide, 4 - [2 - (3 - chloro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methyl
Amide, 4 - {2 - [2 - (2 - pyrrolidin-1 - yl - ethyl) - phenylamino] - benzoxazol -6 - yloxy} - pyridin-2 -
Carboxylic acid methylamide, 4 - {2 - [2 - (2 - piperidin-1 - yl - ethyl) - phenylamino] - benzoxazol -6 - yl oxy} -
Pyridine-2 - carboxylic acid methylamide, 4 - {2 - [2 - (4 - methyl - imidazol-1 - yl) - phenylamino] - benzoxazole -6 -
Yloxy} - pyridine-2 - carboxylic acid methylamide, 4 - [2 - (2 - oxazol-5 - yl - amino phenyl) - benzoxazole -6 -
Yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - {2 - [2 - (2 - methyl - imidazol-1 - yl) - phenylamino] - benzo
Oxazolyl -6 - yl oxy} - pyridine-2 - carboxylic acid methyl amide, 4 - (2 - amino - benzoxazole -6 - yloxy) - pyridine
2 - carboxylic acid methyl amide, 4 - (2 - hydroxy - benzoxazol -6 - yloxy) - pyridine-2 - carboxylic acid methylamide,
4 - {2 - [2 - (2 - morpholin-4 - yl - ethyl) - phenylamino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methyl
Amide, 4 - [2 - ((1S, 2R) -2 - hydroxy - dihydro-inden-1 - ylamino) - benzoxazole -6 - yloxy] - pyridine
-2 - carboxylic acid methylamide, 4 - [2 - ((1R, 2S) -2 - hydroxy - dihydro-inden-1 - ylamino) - benzoxazole -6 -
Yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - ((R) -3 - hydroxy-1 - phenyl - propylamino) - benzoxazin
-6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - ((1S, 2S) -2 - hydroxy - cyclohexylamino) - benzo
Oxazolyl -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, (R) - [6 - (2 - methylcarbamoyl - pyridin -
Yloxy) - benzoxazol-2 - yl-amino] - phenyl - acetic acid methyl ester, 4 - [2 - ((R) -1 - cyclohexyl - ethylamino
Yl) - benzoxazol -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, (S) - [6 - (2 - methylcarbamoyl -
Pyridin-4 - yloxy) - benzoxazol-2 - yl-amino] - phenyl - acetic acid methyl ester, 4 - [2 - ((S) -2 - hydroxy-1 -
Phenyl - ethyl amino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - {2 - [(pyridin-4 -
Ylmethyl) - amino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methylamide, 4 - {2 - [3 - (2 - piperidine
-1 - Yl - ethyl) - phenylamino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methylamide, 4 - {2 - [(pyridin
-3 - yl methyl) - amino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methylamide, 4 - [2 - (cyclohexyl
Yl methyl - amino) - benzoxazole -6 - yloxy] - pyridine-2 - carboxylic acid, 4 - (2 - phenylethyl-amino - benzoxazole
-6 - Yloxy) - pyridine-2 - carboxylic acid methylamide, 4 - {2 - [((R) - cyclohexyl - methylcarbamoyl - A
Yl) - amino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methylamide, 4 - [2 - (2 - pyrrolidin-1 - yl -
Ethylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - piperidin-1 - yl -
Ethylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - {2 - [(2,3 - dihydro - benzo
[1,4] dioxin -5 - ylmethyl) - amino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methylamide,
4 - [2 - ((S) -1 - cyclohexyl-2 - hydroxy - ethyl-amino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methyl
Amide, 4 - [2 - ((R) -1 - cyclohexyl-2 - hydroxy - ethyl-amino) - benzoxazole -6 - yloxy] - pyridin-2 - methyl
Acid methylamide, N'-{4 - [2 - (cyclohexyl-methyl - amino) - benzoxazole -6 - yloxy] - pyridine-2 - carbonyl
Yl} - hydrazinecarboxylate, 4 - [2 - (cyclohexyl-methyl - amino) - benzoxazole -6 - yloxy] - pyridin-2 - methyl
Acid amide, 4 - [2 - (cyclohex-3 - en-ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - (2,4 - difluoro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - (2 - bromo - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 -
Fluoro-5 - methoxy - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - {2 - [3 - (2 - morpholin-4 - yl - ethyl) - phenylamino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methyl
Amide, 1 - {[6 - (2 - methylcarbamoyl - pyridin-4 - yloxy) - benzoxazol-2 - yl-amino] - methyl
Yl} - cyclohexane, ethyl 4 - [2 - (2,6 - dichloro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 -
Carboxylic acid methylamide, 4 - [2 - (2,3 - dichloro - benzylamino) - benzoxazole -6 - yloxy] - pyridine-2 - carboxylic acid
Methylamide, 4 - [2 - (2 - chloro-6 - fluoro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methyl
Amide, 4 - [2 - (2,3 - difluoro - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
{4 - [2 - (cyclohexyl-methyl - amino) - benzoxazole -6 - yloxy] - pyridin-2 - yl} - methanol, cyclohexylmethyl
- [6 - (2 - [1,3,4] oxadiazol-2 - yl - pyridin-4 - yloxy) - benzoxazol-2 - yl] - amine, 4 - [2 - (cyclo hexyl
Methyl - amino) - benzoxazole -6 - yloxy] - pyridine-2 - carbonitrile, 4 - [2 - (2,5 - dimethoxy - benzyl-amino
Yl) - benzoxazol -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2,6 - dimethoxy - benzyl-amino
Yl) - benzoxazol -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - dimethylamino - benzyl-amino
Yl) - benzoxazol -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - amino - benzylamino) - benzene
Benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2,6 - difluoro - benzylamino) - benzoxazin
-6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - morpholin-4 - yl - benzylamino) - benzoxazole
-6 - Yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - methyl - benzylamino) - benzoxazole -6 - yloxy
Yl] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (3,4 - dimethoxy - benzylamino) - benzoxazole -6 - yloxy
Yl] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2,3 - dimethoxy - benzylamino) - benzoxazole -6 - yloxy
Yl] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2,4 - dimethoxy - benzylamino) - benzoxazole -6 - yloxy
Yl] - pyridin-2 - carboxylic acid methyl amide, 1 - {[6 - (2 - methylcarbamoyl - pyridin-4 - yloxy) - benzoxazin
Oxazol-2 - yl-amino] - methyl} - cyclohexanecarboxylic acid, 4 - [2 - (2,3 - dihydro - benzo [1,4] dioxin -5 - ylamino) -
Benzoxazol -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (benzo [1,3] dioxole
-5 - Ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - ethoxy - benzyl
Amino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (2 - (trifluoromethyl) - benzyl-amino
Yl) - benzoxazol -6 - yloxy] - pyridin-2 - carboxylic acid methyl amide, 4 - (2 - isopropylamino - benzoxazole
-6 - Yloxy) - pyridine-2 - carboxylic acid methyl amide, 4 - (2 - butylamino - benzoxazol -6 - yloxy) - pyridine
-2 - carboxylic acid methyl amide, 4 - (2 - tert-butylamino - benzoxazol -6 - yloxy) - pyridine-2 - carboxylic acid methyl
Amide, 4 - [2 - (cycloheptylmethyl - amino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - {2 - [(tetrahydro - furan-2 - ylmethyl) - amino] - benzoxazol -6 - yl oxy} - pyridine-2 - carboxylic acid methyl acid
Amine, 4 - [2 - (1 - benzyl - piperidin-4 - ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - (1,2,3,4 - tetrahydro - naphthalene-1 - ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - (2 - pyrazol-1 - yl - benzylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide,
4 - [2 - (benzyl - methyl - amino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - [2 - (1 -
Phenyl - piperidin-4 - ylamino) - benzoxazole -6 - yloxy] - pyridin-2 - carboxylic acid methylamide, 4 - {2 - [(3,4 -
Dihydro-2H-benzo [b] [1,4] 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 [1, 4] bioxin-5-carbonyls)-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 formoxyl-cyclohexyl methyl)-amino]-benzoxazole-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-(5-chloro-2-methoxyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(5-fluoro-2-methoxyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-fluoro-6-methoxyl group-benzylamino)-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 [1, 4] bioxin-2-ylmethyls)-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-(2-chloro-6-methoxyl group-benzylamino)-benzoxazoles-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-{2-[(2, 3-dihydro-benzo [1, 4] bioxin-6-ylmethyls)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea, 4-{2-[2-(2, 3-dihydro-benzo [1, 4] bioxin-5-yls)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea, 4-{2-[(2, 3-dihydro-benzofuran-5-ylmethyl)-amino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea and 4-{2-[1-(2, 3-dihydro-benzo [1, 4] bioxin-5-yls)-ethylamino]-benzoxazoles-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea,
Or its pharmacologically acceptable salt, tautomer, solvate or steric isomer.
69, the described compound of claim 3, this compound is selected from: 4-[2-(4-chloro-3-trifluoromethyl-phenyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-chloro-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(cyclohexyl methyl-amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-{2-[(R)-1-(2-methoxyl group-phenyl)-ethylamino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2,4-two chloro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((R)-1-phenyl-ethylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-methoxyl group-benzylamino)-benzothiazole-6-base 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-(2,3-two chloro-benzylaminos)-benzothiazole-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)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S)-2-hydroxyl-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((R)-1-cyclohexyl-ethylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2,5-two fluoro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-fluoro-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-{2-[(tetrahydrochysene-pyrans-4-ylmethyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-morpholine-4-base-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-pyrazol-1-yl-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-dimethylamino-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2,6-dimethoxy-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2,5-dimethoxy-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2,3-two fluoro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(suberyl methyl-amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2,6-two fluoro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-{2-[(pyridine-2-ylmethyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea, 4-[2-(3,4-dimethoxy-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-{2-[(2,3-dihydro-benzo [1,4] dioxin-5-ylmethyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2-piperidines-1-base-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-{2-[(pyridin-3-yl methyl)-amino]-benzothiazole-6-base oxygen base }-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1R, 2R)-2-benzyloxy-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1S, 2S)-2-benzyloxy-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-((1R, 2R)-2-hydroxyl-cyclohexyl amino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-[2-(2,6-two chloro-benzylaminos)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea, 4-(2-(cyclohexyl methyl amino) benzothiazole-6-base oxygen base)-N-(2-methoxy ethyl) pyridine-2-carboxamide, 4-(2-(cyclohexyl methyl amino) benzothiazole-6-base oxygen base)-N-(2-(dimethylamino) ethyl) pyridine-2-carboxamide and 4-[2-(4-sulfamyl-benzylamino)-benzothiazole-6-base oxygen base]-pyridine-2-formic acid methyl nitrosourea;
Or its steric isomer, tautomer or solvate or its pharmacologically acceptable salt.
70, comprise any one described compound, steric isomer, tautomer, solvate, oxide compound, ester or prodrug in the claim 1 to 69 of significant quantity or the pharmaceutical composition of its pharmacologically acceptable salt and pharmaceutically acceptable carrier.
71, the composition of claim 70, the IC that wherein said compound shows for the CSF-1R restraining effect
50Value is less than 1 μ M.
72, the composition of claim 70, it also comprises other promoting agent.
73, the composition of claim 72, wherein said other promoting agent is a bisphosphonates.
74, any one described compound in the claim 1 to 30,32 to 66,68 and 69, wherein, with respect to the Raf kinases, described compound preferentially suppresses CSF-1R.
75, the compound of claim 74, wherein, with regard to IC
50Value, about 5 times of the active height the when specific activity when described compound suppresses CSF-1R suppresses the Raf kinases.
76, the compound of claim 74, wherein, with regard to IC
50Value, about 10 times, about 20 times, about 30 times or about 50 times of the active height the when specific activity when described compound suppresses CSF-1R suppresses the Raf kinases.
77, the compound of claim 74, wherein, with regard to IC
50Value, about 100 times, about 250 times, about 500 times, about 750 times, about 1000 times or about 2000 times of the active height the when specific activity when described compound suppresses CSF-1R suppresses the Raf kinases.
78, the compound of claim 74, wherein, described compound suppresses the Raf kinases with the concentration greater than 1 μ M.
79, the method for the illness of the CSF-1R mediation of treatment human or animal individuality, this method comprises to human or animal's individuality uses composition, and said composition comprises any one described compound in the claim 1 to 69 that suppresses the active significant quantity of the individual CSF-1R of human or animal.
80, the method for claim 79, wherein said compound selective ground suppresses CSF-1R.
81, the method for claim 79, wherein the illness of CSF-1R mediation is selected from cancer, osteoporosis, sacroiliitis, atherosclerosis and chronic glomerulonephritis.
82, the method for claim 79, 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.
83, the method for claim 79, wherein the illness of CSF-1R mediation is a rheumatoid arthritis.
84, the method for claim 79, wherein said composition also comprises other promoting agent of the illness of at least a CSF-1R of being used for the treatment of mediation.
85, the method that suppresses CSF-1R, this method comprise cell are contacted with any one described compound in the claim 1,60 or 63.
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| US79351706P | 2006-04-19 | 2006-04-19 | |
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| US60/893,857 | 2007-03-08 | ||
| PCT/US2007/066898 WO2007121484A2 (en) | 2006-04-19 | 2007-04-18 | 6-o-substituted benzoxazole and benzothiazole compounds and methods of inhibiting csf-1r signaling |
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| CN101432281A true CN101432281A (en) | 2009-05-13 |
| CN101432281B CN101432281B (en) | 2013-08-28 |
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| CN105130973A (en) * | 2014-05-26 | 2015-12-09 | 海南国瑞堂中药制药有限公司 | 5-Pyridyl-2-amino-benzo[d]oxazole derivatives, and preparation method and use thereof |
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| AU2003235838A1 (en) * | 2002-05-01 | 2003-11-17 | Kirin Beer Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of macrophage colony stimulating factor receptor |
| EP1711495A2 (en) * | 2004-01-23 | 2006-10-18 | Amgen Inc. | Quinoline, quinazoline, pyridine and pyrimidine counds and their use in the treatment of inflammation, angiogenesis and cancer |
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2007
- 2007-04-18 CN CN200780013974.1A patent/CN101432281B/en active Active
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| ZA200808105B (en) | 2009-06-24 |
| CN101432281B (en) | 2013-08-28 |
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