CN1832929B - 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders - Google Patents
2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders Download PDFInfo
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- CN1832929B CN1832929B CN2004800227255A CN200480022725A CN1832929B CN 1832929 B CN1832929 B CN 1832929B CN 2004800227255 A CN2004800227255 A CN 2004800227255A CN 200480022725 A CN200480022725 A CN 200480022725A CN 1832929 B CN1832929 B CN 1832929B
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- ZWMDEVPYVGQJHU-UHFFFAOYSA-N CN(C)S(c(cccc1)c1Nc(nc(Nc(c(OC)c1)ccc1N1CCOCC1)[n]c1)c1Br)(=O)=O Chemical compound CN(C)S(c(cccc1)c1Nc(nc(Nc(c(OC)c1)ccc1N1CCOCC1)[n]c1)c1Br)(=O)=O ZWMDEVPYVGQJHU-UHFFFAOYSA-N 0.000 description 1
- NRPNUOKRHRYIBP-UHFFFAOYSA-N CNC(c1ccccc1Nc(nc(nc1)Cl)c1Cl)=O Chemical compound CNC(c1ccccc1Nc(nc(nc1)Cl)c1Cl)=O NRPNUOKRHRYIBP-UHFFFAOYSA-N 0.000 description 1
- HJVNHZGCYWWRMV-UHFFFAOYSA-N Cc(cc1)cc(OC)c1Nc(nc1)nc(Nc(cccc2)c2S(NCC(F)(F)F)(=O)=O)c1Cl Chemical compound Cc(cc1)cc(OC)c1Nc(nc1)nc(Nc(cccc2)c2S(NCC(F)(F)F)(=O)=O)c1Cl HJVNHZGCYWWRMV-UHFFFAOYSA-N 0.000 description 1
- GIKMWFAAEIACRF-UHFFFAOYSA-N Clc(c(Cl)n1)cnc1Cl Chemical compound Clc(c(Cl)n1)cnc1Cl GIKMWFAAEIACRF-UHFFFAOYSA-N 0.000 description 1
Abstract
Novel pyrimidine derivatives of formula (I) Wherein R is selected from C16-10 aryl, C5-10 heteroaryl, C3-12 cycloalkyl and C3-10 heterocycloalkyl; R0-R6 as described herein; and their use for the manufacture of a medicament for the treatment or prevention of a disease wich responds to inhibition of FAK and/or ALK and/or ZAP-70 and/or IGF-IR.
Description
The present invention relates to the application of new pyrimidine derivatives, the pyrimidine derivatives that some is new, also relate to its working method, they are as the application of medicine and the compsn that contains them.
More specifically; First aspect present invention provides following formula (I) compound and the purposes of salt in the tyrosine kinase activity diseases associated of a treatment and a modification lymphoma kinases (ALK) thereof; The purposes that perhaps is used for the pharmaceutical composition of the said disease of production for treating; Its purposes in the said disease of treatment is provided simultaneously, also relates to the method for use of this type of pyrimidine derivatives when the said disease of treatment, and the pharmaceutical composition that contains this type of pyrimidine derivatives that is useful on the said disease of treatment.
Said formula (I) compound is:
Wherein:
R is selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Naphthenic base and C
3-10Heterocyclylalkyl;
R
0, R
1, R
2And R
3Independent is hydrogen, C
1-C
8Alkyl, C
2-C
8-thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Naphthenic base, C
3-C
8Naphthenic base C
1-C
8Alkyl, C
5-C
10Aryl C
1-C
8Alkyl, hydroxyl C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, amino C
1-C
8Alkyl, halo C
1-C
8Alkyl, unsubstituted or substituted C
5-C
10Aryl, unsubstitutedly or substituted contain 1,2 or 3 heteroatomic 5 or 6 yuan of heterocyclic radicals, hydroxyl, C that is selected from N, O and S
1-C
8Alkoxyl group, hydroxyl C
1-C
8Alkoxyl group, C
1-C
8Alkoxy C
1-C
8Alkoxyl group, halo C
1-C
8Alkoxyl group, unsubstituted or substituted C
5-C
10Aryl C
1-C
8Alkoxyl group, substituted or substituted heterocyclyloxy base, unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group, unsubstituted or substituted amino, C
1-C
8Alkylthio, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
5-C
10Aryl sulfonyl, halogen, carboxyl, C
1-C
8Alkoxy carbonyl, unsubstituted or substituted formamyl, unsubstituted or substituted sulfamyl, cyanic acid, nitro ,-S (O)
0-2NR
12R
13,-S (O)
0-2R
13,-NR
12S (O)
0-2R
13,-C (O) NR
12R
13,-C (O) R
13With-C (O) OR
13R wherein
12Be selected from hydrogen and C
1-
6Alkyl; R
13Be selected from hydrogen, C
1-6Alkyl and C
3-12Naphthenic base;
Perhaps R
0And R
1, R
1And R
2, and/or R
2And R
3Form with the carbon atom that they connected and to contain 0,1,2 or 3 heteroatomic 5 or 6 yuan of carbocyclic rings or heterocycle that is selected from N, O and S;
R
4Be hydrogen or C
1-C
8Alkyl;
R
5And R
6Independent is hydrogen, C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, halo C
1-C
8Alkyl, C
1-C
8Alkoxyl group, halogen, carboxyl, C
1-C
8Alkoxy carbonyl, unsubstituted or substituted formamyl, cyanic acid or nitro;
R is not substituted or by R
7, R
8, R
9, R
10And R '
10Replace;
R
7, R
8, R
9, R
10Or R '
10Independently be selected from following groups: hydrogen, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Naphthenic base, C
3-C
8Naphthenic base C
1-C
8Alkyl, C
5-C
10Aryl C
1-C
8Alkyl, hydroxyl C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, amino C
1-C
8Alkyl, halo C
1-C
8Alkyl, unsubstituted or substituted C
5-C
10Aryl, unsubstitutedly or substituted contain 1,2 or 3 heteroatomic 5 or 6 yuan of heterocyclic radicals, hydroxyl, C that is selected from N, O and S
1-C
8Alkoxyl group, hydroxyl C
1-C
8Alkoxyl group, C
1-C
8Alkoxy C
1-C
8Alkoxyl group, halo C
1-C
8Alkoxyl group, unsubstituted or substituted amino C
1-C
8Alkoxyl group, unsubstituted or substituted C
5-C
10Aryl C
1-C
8Alkoxyl group, unsubstituted or substituted heterocyclyloxy base, unsubstituted or substituted heterocyclic radical C
1-C
8Alkyl, unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group, unsubstituted or substituted amino, C
1-C
8Alkylthio, C
1-C
8Alkyl sulphinyl, C
1-C
8Alkyl sulphonyl, C
5-C
10Aryl sulfonyl, heterocycle alkylsulfonyl, halogen, carboxyl, C
1-C
8Alkyl-carbonyl, C
1-C
8Alkoxy carbonyl, unsubstituted or substituted formamyl, unsubstituted or substituted sulfamyl, cyanic acid, nitro ,-S (O)
0-2NR
12R
13,-S (O)
0-2R
12,-C (O) R
11,-OXR
11,-NR
12XR
11,-NR
12XNR
12R
13,-OXNR
12R
13,-OXOR
12With-XR
11
Perhaps last two the adjacent substituting groups of R with its connect carbon atom and form unsubstituted or substituted 0,1,2 or 3 heteroatomic 5 or 6 yuan of carbocyclic rings or the heterocycle that is selected from N, O and S that contains;
X is key or C
1-6Alkylidene group; And
R
11Independently be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Naphthenic base and C
3-10Heterocyclylalkyl;
And R
11Any aryl, heteroaryl, naphthenic base or Heterocyclylalkyl can choose wantonly and independently be selected from following group by 1-3 and replace: C
1-6Alkyl, optional by C
1-6The substituted C of alkyl
3-10Heterocyclylalkyl-C
0-4Alkyl ,-C (O) R
12,-C (O) NR
12R
13,-XNR
12R
13,-NR
12XNR
12R
13With-NR
12C (O) R
13Wherein X is key or C
1-6Alkylidene group; R
12And R
13Independently be selected from hydrogen and C
1-6Alkyl.
Unless stated otherwise, employed generic term preferably has following meaning in the context of this specification sheets:
The plural form that is used for compound, salt etc. has also been represented the compound of its singulative, salt etc.
(R)-, (S)-or (R, S)-any unsymmetrical carbon that possibly exist on the configuration is preferably (R)-or (S)-configuration.So compound can exist with the form of isomer mixture or exist with the form of pure isomer, preferably the form with enantiomorph-pure anisomeria exists.
The present invention also relates to the possible tautomer of formula I compound.
C
1-C
8Alkyl represent has the alkyl group of 1-8 (preferred maximum 4) carbon atom, and said group can be straight chain or have single or a plurality of branched side chains; Preferred C
1-C
8Alkyl is butyl (like normal-butyl, sec.-butyl, isobutyl-, the tertiary butyl), propyl group (like n-propyl or sec.-propyl), ethyl or methyl; Special preferable methyl, propyl group or the tertiary butyl.
C
2-C
8Thiazolinyl has the alkenyl group of 2-8 (preferred maximum 5) carbon atom, and said group can be straight chain or have single or a plurality of branched side chains; Preferred C
2-C
8Thiazolinyl is pentenyl (like 3-methyl-2-butene-2-yl), crotonyl (like 1-or crotyl or 2-butylene-2-yl), propenyl (like 1-propenyl or allyl group) or vinyl.
C
2-C
8The alkynyl representative has the alkynyl group of 2-8 (preferred maximum 5) carbon atom, and said group can be that straight chain also can be a side chain; Preferred C
2-C
8Alkynyl is proyl (like 1-proyl or propargyl) or ethynyl.
C
3-C
8The naphthenic base representative has the group of naphthene base of 3-8 carbon atom, like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group, preferred cyclopropyl, cyclopentyl or cyclohexyl.
C-C
8Alkoxyl group is preferably methoxyl group, oxyethyl group, isopropoxy or tert.-butoxy.
Hydroxyl C
1-C
8Alkyl is preferably hydroxymethyl, 2-hydroxyethyl or 2-hydroxyl-2-propyl group.
Hydroxyl C
1-C6 alkoxyl group is preferably 2-hydroxyl-oxethyl or 3-hydroxyl propoxy-.
C
1-C
8Alkoxy C
1-C
8Alkoxyl group is preferably the 2-methoxy ethoxy.
C
1-C
8Alkoxy C
1-C
8Alkyl is preferably methoxymethyl, 2-methoxy ethyl or or 2-ethoxyethyl group.
Halogen is preferably fluorine, chlorine, bromine or iodine, is preferably fluorine, chlorine or bromine especially.
Halo C
1-C
8Alkyl is preferably chloro C
1-C
8Alkyl or fluoro C
1-C
8Alkyl is preferably trifluoromethyl or pentafluoroethyl group especially.
Halo C
1-C
8Alkoxyl group is preferably chloro C
1-C
8Alkoxyl group or fluoro C
1-C
8Alkoxyl group is preferably trifluoromethoxy especially.
C
1-C
8Alkoxy carbonyl is preferably tert-butoxycarbonyl, isopropoxy carbonyl, methoxycarbonyl or ethoxy carbonyl.
Unsubstituted or substituted formamyl is for to be selected from the following substituted formamyl of substituting group by one or two: hydrogen, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Naphthenic base, C
3-C
8Naphthenic base C
1-C
8Alkyl, C
5-C
10Aryl C
1-C
8Alkyl, hydroxyl C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, halo C
1-C
8Alkyl, unsubstituted or substituted C
5-C
10Aryl or amino C
1-C
8Alkyl, perhaps as the formamyl of giving a definition, wherein substituting group on the formamyl group and nitrogen-atoms are represented together and are comprised 0,1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from N, O and S in addition; And be preferably formamyl, methylamino formyl radical, formyl-dimethylamino, propyl group formamyl, hydroxyethyl-methyl-formamyl, two (hydroxyethyl) formamyl, dimethyl aminoethyl formamyl and tetramethyleneimine-1-base carbonyl, piperidines-1-base carbonyl, N methyl piperazine-1-base carbonyl or morpholine-4-base carbonyl, preferred especially formamyl or formyl-dimethylamino.
Unsubstituted or substituted sulfamyl is for to be selected from the following substituted sulfamyl of substituting group by one or two: hydrogen, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Naphthenic base, C
3-C
8Naphthenic base C
1-C
8Alkyl, C
5-C
10Aryl C
1-C
8Alkyl, hydroxyl C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, halo C
1-C
8Alkyl, unsubstituted or substituted C
5-C
10Aryl or amino C
1-C
8Alkyl, perhaps as the sulfamyl of giving a definition, wherein substituting group on the sulfamyl and nitrogen-atoms are represented together and are comprised 0,1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from N, O and S in addition; And be preferably sulfamyl, methyl sulfamyl, propyl group sulfamyl, cyclopropyl methyl-sulfamyl, 2; 2; 2-trifluoroethyl sulfamyl, dimethyl aminoethyl sulfamyl, dimethylamino alkylsulfonyl, hydroxyethyl-methyl-sulfamyl, two (hydroxyethyl) sulfamyl or tetramethyleneimine-1-base alkylsulfonyl, piperidines-1-base alkylsulfonyl, N methyl piperazine-1-base alkylsulfonyl or morpholine-4-base alkylsulfonyl are preferably sulfamyl or methyl sulfamyl especially.
Unsubstituted or substituted amino is for to be selected from the substituted amino of following substituting group by one or two: hydrogen, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Naphthenic base, C
3-C
8Naphthenic base C
1-C
8Alkyl, C
5-C
10Aryl C
1-C
8Alkyl, hydroxyl C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, halo C
1-C
8Alkyl, unsubstituted or substituted C
5-C
10Aryl, amino C
1-C
8Alkyl, acyl group (like formyl radical), C
1-C
8Alkyl-carbonyl, C
5-C
10Aryl carbonyl, C
1-C
8Alkyl sulphonyl or C
5-C
10Aryl sulfonyl; And be preferably that amino, methylamino, dimethylamino, propyl group amino, benzylamino, hydroxyethyl-methyl-amino, two (hydroxyethyl) are amino, dimethyl aminoethyl is amino, acetylamino, ethanoyl-methyl-amino, benzoyl-amido, methyl sulphonyl amino or phenyl sulfonyl amino, be preferably amino or dimethylamino especially.
Amino C
1-C
8Alkyl is preferably amino-ethyl, methylamino ethyl, dimethyl aminoethyl or dimethylaminopropyl.
Unsubstituted or substituted C
5-C
10Aryl does, for example, phenyl, indenyl, indanyl, naphthyl or 1,2,3, the 4-tetralyl is optionally replaced by following groups: C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, halo C
1-C
8Alkyl, hydroxyl, C
1-C
8Alkoxyl group, methylene-dioxy, amino, substituted amino, halogen, carboxyl, C
1-C
8Alkoxy carbonyl, formamyl, sulfamyl, cyanic acid or nitro; Be preferably phenyl, tolyl, trifluoromethyl, p-methoxy-phenyl, Dimethoxyphenyl, methylenedioxyphenyl, chlorophenyl or bromo phenyl, wherein substituting group can be at the ortho position, a position or contraposition, position or contraposition between being preferably.
C
5-C
10Aryloxy is preferably phenoxy or methoxyl group phenoxy, like right-methoxyl group phenoxy.
C
5-C
10Aryl C
1-C
8Alkyl is preferably benzyl or 2-phenylethyl.
C
5-C
10Aryl C
1-C
8Alkoxyl group is preferably benzyl oxygen base or 2-phenyl ethoxy.
It is unsubstituted or substituted that to contain 1,2 or 3 heteroatomic 5 or 6 yuan of heterocycle that are selected from N, O and S can be undersaturated, fractional saturation or saturated; And can through heteroatoms or carbon atom further with phenyl ring or 5 or 6 yuan of heterocyclic radicals thick with; For example; Pyrryl, indyl, pyrrolidyl, imidazolyl, benzimidazolyl-, pyrazolyl, triazolyl, benzotriazole base, tetrazyl, pyridyl, quinolyl, isoquinolyl, 1; 2; 3,4-tetrahydric quinoline group, piperidyl, pyrimidyl, pyrazinyl, piperazinyl, purine radicals, tetrazine Ji 、 oxazolyl 、 isoxazolyl (isoxalyl), morpholinyl, thiazolyl, benzothiazolyl 、 oxadiazole base and Ben Bing oxadiazole base.Said substituting group is C
1-C
8Alkyl, hydroxyl C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkyl, C
1-C
8Alkoxy C
1-C
8Alkoxyl group, halo C
1-C
8Alkyl, hydroxyl, amino, substituted amino, C
1-C
8Alkoxyl group, halogen, carboxyl, C
1-C
8Alkyl-carbonyl, C
1-C
8Alkoxy carbonyl, formamyl, C
1-C
8Alkoxy amino formyl radical, cyanic acid, oxo, defined 5 or 6 yuan of unsubstituted or substituted heterocyclic radicals of this section.5 and 6 yuan of heterocyclic radicals preferably contain 1 or 2 heteroatoms that is selected from N, O and S; And be preferably indyl, pyrrolidyl, pyrroles's ketone group, imidazolyl, N-methylimidazolyl, benzimidazolyl-, S; S-dioxo isothiazole alkyl, piperidyl, 4-acetylamino piperidyl, 4-methylamino formyl piperidine base, 4-(piperidines-1-yl) piperidyl, 4-cyanic acid (piperidines-1-yl) piperazinyl, N methyl piperazine base, N-(2-hydroxyethyl) piperazinyl, morpholinyl, 1-azepine-2,2-dioxo-thia cyclohexyl or tetramethylene sulfone base.
In unsubstituted or substituted heterocyclyloxy base, heterocyclic radical as above defines, and is preferably N-methyl-4-piperidyl oxygen base.At unsubstituted or substituted heterocyclic radical C
1-C
8In the alkoxyl group; Heterocyclic radical as above defines, and is preferably 2-(tetramethyleneimine-1-yl) oxyethyl group, 2-(morpholine-4-yl) oxyethyl group, 3-(morpholine-4-yl) propoxy-, 1-methyl-piperidines-3-ylmethoxy, 3-[N-methyl (piperazine-1-yl)] propoxy-or 2-(1-imidazolyl) oxyethyl group.
Contain in 0,1,2 or 3 heteroatomic 5 or 6 yuan of carbocyclic ring or heterocycle that are selected from N, O and S what formed with phenyl ring by two adjacent substituting groups, this ring can further be replaced by following groups: like C
1-C
8Alkyl, C
1-C
8Alkoxyl group, halo C
1-C
8Alkyl, hydroxyl, amino, substituted amino, C
1-C
8Alkoxyl group, halogen, carboxyl, C
1-C
8Alkoxy carbonyl, formamyl, cyanic acid or oxo.Two adjacent substituting groups that form this ring are preferably propylidene, butylidene, 1-azepine-2-propylidene (propylidene), 3-azepine-1-propylidene, 1; 2-diaza-2-propylidene, 2; 3-diaza-1-propylidene, 1-oxa-propylidene, 1-oxa-propylidene, methylene-dioxy, difluoro methylene-dioxy, 2-azepine-2-oxo propylidene, 2-azepine-2-methyl isophthalic acid-oxo propylidene, 1-azepine-2-oxo propylidene, 2-azepine-1,1-dioxo-1-thia propylidene or form the corresponding butylidene verivate of 6 yuan of rings.
Salt is preferably the pharmacy acceptable salt of formula I compound.
Can be by formula I compound formation salt with basic nitrogen atom, for example acid salt preferably forms this type of salt with organic or inorganic acid, is preferably pharmacy acceptable salt.Suitable mineral acid does, for example, and haloid acid (example hydrochloric acid), sulfuric acid or phosphoric acid.Suitable organic acid does; For example; Carboxylic acid, phosphoric acid, sulfonic acid or thionamic acid; For example acetate, propionic acid, sad, capric acid, dodecylic acid, oxyacetic acid, lactic acid, fumaric acid, succsinic acid, hexanodioic acid, pimelic acid, suberic acid, nonane diacid, oxysuccinic acid, tartrate, Hydrocerol A, amino acid (like L-glutamic acid or aspartic acid), toxilic acid, hydroxymaleic acid, methyl-maleic acid, naphthenic acid, adamantanecarboxylic acid (adamantanecarboxylic acid), phenylformic acid, Whitfield's ointment, 4-aminosallcylic acid, phthalic acid, toluylic acid, racemic melic acid, styracin, methylsulfonic acid or ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, ethane-1; 2-disulfonic acid, Phenylsulfonic acid, 2-naphthene sulfonic acid, 1,5-naphthalene disulfonic acid, 2-, 3-or 4-toluene sulfonic acide, methylsulfuric acid, ethylsulfuric acid, dodecyl sulphate, N-cyclohexyl thionamic acid, N-methyl-, N-ethyl-or N-propyl group-thionamic acid or other organic protonic acid (like xitix).
When carrying out isolated or purified, also can use pharmaceutically unacceptable salt, for example picrate or perchlorate.But when being used to treat, can only use pharmacy acceptable salt or free cpds (form with pharmaceutical prepn is used), and these forms all are preferred.
Consider being closely connected between the form (for example comprising the salt that is used as midbody at the purifying of new compound or in differentiating) of free form and its salt of new compound, it is understandable that, also refer to its corresponding salt when mentioning new compound among this paper.
As described herein, formula I compound has the valuable pharmacological characteristic.
In formula I, preferred following definition is independent to be used, uses jointly or use with any array configuration or inferior array configuration.R is C
6-10Aryl, C
5-10Heteroaryl, C
3-12Naphthenic base or C
3-10Heterocyclylalkyl; Preferred R does
R wherein
7, R
8, R
9, R
10Or R '
10As above define;
Hereinafter, A, D or E are C or N, but A, D and E can not be N simultaneously, and preferred A, D or E are C:
(a) R
0Or R
2Independent is hydrogen, C
1-C
8Alkyl (for example methyl, ethyl or sec.-propyl), hydroxyl C
1-C
8Alkyl (for example hydroxyethyl or hydroxybutyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstituted or substituted C
5-C
10Aryl (like phenyl or p-methoxy-phenyl), unsubstituted or substituted 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from N, O and S (like morpholine-1-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), the C of containing
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (like trifluoromethoxy), C
5-C
10Aryloxy (like phenoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or substituted amino (like methylamino, dimethylamino or acetylamino), C
1-C
8Alkyl sulphonyl (like methyl sulphonyl), halogen (like fluorine or chlorine), unsubstituted or substituted formamyl (like cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl), unsubstituted or substituted sulfamyl (like sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl); Be preferably hydrogen, piperazine-1-base, N-methyl (piperazine-1-yl) or 1-methyl-4-piperidyl oxygen base ,-S (O)
0-2NR
12R
13,-S (O)
0-2R
13,-NR
12S (O)
0-2R
13,-C (O) NR
12R
13With-C (O) OR
13, preferred especially hydrogen;
(b) R
1Be hydrogen, C
1-C
8Alkyl (for example methyl, ethyl or sec.-propyl), hydroxyl C
1-C
8Alkyl (for example hydroxyethyl or hydroxybutyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstituted or substituted C
5-C
10Aryl (like phenyl or p-methoxy-phenyl), unsubstituted or substituted 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (like morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), the C of containing
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (like trifluoromethoxy), C
5-C
10Aryloxy (like phenoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or substituted amino (like methylamino, dimethylamino or acetylamino), C
1-C
8Alkyl sulphonyl (like methyl sulphonyl), halogen (like fluorine or chlorine), unsubstituted or substituted formamyl (like cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl), unsubstituted or substituted sulfamyl (like sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl); Be preferably hydrogen, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, 1-methyl-4-piperidyl oxygen base, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group, preferred especially hydrogen;
(c) R
3Be hydrogen, C
1-C
8Alkyl (for example methyl or ethyl), hydroxyl C
1-C
8Alkyl (for example hydroxyethyl or hydroxybutyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstitutedly or substituted contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (like 2-pyrroles's ketone group or S, S-dioxo isothiazole alkyl), C that is selected from N, O and S
1-C
8Alkoxyl group (like methoxyl group), substituted amino (like acetylamino, ethanoyl-methyl-amino, benzoyl-amido, methyl sulphonyl amino or phenyl sulfonyl amino), C
1-C
8Alkyl sulphonyl (like methyl sulphonyl, propyl group-alkylsulfonyl, cyclohexyl-alkylsulfonyl, sec.-propyl-alkylsulfonyl), C
5-C
10Aryl sulfonyl (like phenyl sulfonyl), halogen (like fluorine or chlorine), carboxyl, substituted or unsubstituted formamyl (like formamyl, methylamino formyl radical, ethyl-amino-carbonyl or formyl-dimethylamino), unsubstituted or substituted sulfamyl are (like sulfamyl, methyl sulfamyl, propyl group sulfamyl, sec.-propyl sulfamyl, isobutyl-sulfamyl, cyclopropyl methyl-sulfamyl, 2; 2,2-trifluoroethyl sulfamyl, dimethylamino alkylsulfonyl or (morpholine-4-yl) alkylsulfonyl dimethyl--sulfamyl, ethyl-sulfamyl, 1-ethyl-propyl group-sulfamyl, cyclopentyl-sulfamyl, cyclobutyl-sulfamyl); Preferred sulfamyl, methyl sulfamyl or propyl group sulfamyl;
(d) adjacent substituting group is to R
0And R
1, R
1And R
2, or R
2And R
3For-CH
2-NH-CO-,-CH
2-CH
2-NH-CO-,-CH
2-CO-NH-,-CH
2-CH
2-CO-NH-,-CH
2-NH-SO
2-,-CH
2-CH
2-NH-SO
2-,-CH
2-SO
2-NH-,-CH
2-CH
2-SO
2-NH-,-CH
2-CH
2-SO
2-,-CH
2-CH
2-CH
2-SO
2-,-O-CH
2-O-or-O-CF
2-O-, and such substituting group is right, promptly the hydrogen on the NH is by C
1-C
8Alkyl replaces; Preferred adjacent substituting group is to R
0And R
1, or R
1And R
2For-O-CH
2-O-, adjacent substituting group is to R
2And R
3For-CH
2-NH-CO-or-CH
2-NH-SO
2-.
(e) R
4Be hydrogen or C
1-C
8Alkyl (like methyl); Be preferably hydrogen;
(f) R
5Be hydrogen; C
1-C
8Alkyl (like methyl or ethyl), halogen (like chlorine or bromine), halo C
1-C
8Alkyl (like trifluoromethyl), cyanic acid or nitro; Be preferably hydrogen, methyl, ethyl, chlorine, bromine, trifluoromethyl or nitro; Be preferably chlorine or bromine especially;
(g) R
6Be hydrogen;
(h) R
7And R
9Independent is hydrogen, C
1-C
8Alkyl (like methyl, ethyl or sec.-propyl), hydroxyl C
1-C
6Alkyl (like hydroxyethyl or hydroxybutyl), C
1-C
8Alkyl-carbonyl (methyl carbonyl), aminoalkoxy (like the diethyl amino base oxethyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstituted or substituted C
5-C
10Aryl (like phenyl or p-methoxy-phenyl), unsubstitutedly or substituted contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (like morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl), C
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (like trifluoromethoxy), C
5-C
10Aryloxy (like phenoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or substituted amino (like methylamino, dimethylamino or acetylamino), C
1-C
8Alkyl sulphonyl (like methyl sulphonyl), heterocycle alkylsulfonyl (like the piperazinyl alkylsulfonyl), heterocycle carbonyl (like N-METHYL PIPERAZINE base carbonyl), cyanic acid, halogen (like fluorine or chlorine), unsubstituted or substituted formamyl (like cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl), unsubstituted or substituted sulfamyl (like sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl); Be preferably hydrogen, methyl, sec.-propyl, trifluoromethyl, phenyl, p-methoxy-phenyl, piperidines-1-base, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, methoxyl group, oxyethyl group, isopropoxy, phenoxy, 3-(morpholine-4-yl) propoxy-, 2-(morpholine-4-yl) oxyethyl group, 2-(1-imidazolyl) oxyethyl group, dimethylamino, fluorine, (morpholine-4-yl) carbonyl, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl or cyclohexyl carboxyamide base;
(i) R
8Be hydrogen, C
1-C
8Alkyl (like methyl, ethyl or sec.-propyl), hydroxyl C
1-C
8Alkyl (like hydroxyethyl or hydroxybutyl), halo C
1-C
8Alkyl (like trifluoromethyl), C
5-C
10Aryl (like phenyl or p-methoxy-phenyl), unsubstituted or substituted 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (like morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), heterocyclic radical alkyl (like methyl (piperazine-1-yl) ethyl), heterocyclic radical carbonyl (like (piperazine-1-yl) carbonyl), the heterocyclic radical C of containing
1-C
8Alkylamino (like pyridyl ethyl (methyl) amino), C
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (like trifluoromethoxy), C
5-C
10Aryloxy (like phenoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or substituted amino (like methylamino or dimethylamino), C
1-C
8Alkylamino-C
1-C
8Alkylamino (amino), C like dimethylamino-propyl group
1-C
8Alkyl sulphonyl (like methyl sulphonyl), halogen (like fluorine or chlorine), unsubstituted or substituted formamyl (like cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl), unsubstituted or substituted sulfamyl (like sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl), cyanic acid or nitro; Preferred hydrogen, methyl, piperidines-1-base, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, methoxyl group, oxyethyl group, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyl oxygen base, 3-(morpholine-4-yl) propoxy-, 2-(morpholine-4-yl) oxyethyl group, 3-(N-methyl (piperazine-1-yl))-propoxy-, methylamino, fluorine, chlorine, sulfamyl or nitro;
(j) R
10Be hydrogen, C
1-C
8Alkyl (like methyl, ethyl or butyl), hydroxyl, cyanic acid, hydroxyl C
1-C
8Alkyl (like hydroxyethyl or hydroxybutyl), halo C
1-C
8Alkyl (like trifluoromethyl), C
1-C
8Alkoxyl group (like methoxy or ethoxy), cycloalkyl alkoxy, aryloxy, halo C
1-C
8Alkoxyl group, unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, unsubstituted or substituted amino (like methylamino or dimethylamino), halogen (like fluorine or chlorine), carboxyl, formamyl is unsubstituted or substituted sulfamyl (like sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl); Preferable methyl, butyl, methoxyl group, oxyethyl group, 2-(1-imidazolyl) oxyethyl group, methylamino, dimethylamino or fluorine; And
(k) adjacent substituting group is to R
7And R
8, or R
8And R
9Or R
9And R
10For-NH-CH=CH-,-CH=CH-NH-,-NH-N=CH-,-CH=N-NH-,-CH
2-CH
2-CH
2-,-CH
2-CH
2-CH
2-CH
2-,-CH
2-CH
2-O-,-CH
2C (CH
3)
2O-,-CH=C (CH
3) O-,-OCH
2CH
2O-,-((morpholine-4-yl) propyl group) N-CH=CH-,-CH=CH-O-,-O-CH
2-O-or-O-CF
2-O-; Preferred adjacent substituting group is to R
7And R
8Or R
8And R
9For-O-CH
2-O-or adjacent substituting group are to R
9And R
10For-NH-CH=CH-,-CH=N-NH-,-CH
2-CH
2-CH
2-,-CH
2-CH
2-CH
2-CH
2-or-O-CF
2-O-.
(l) or R
7, R
8, R
9, R
10And R
' 10Be oxyethyl group, ethyl, propyl group, methyl, the tertiary butyl, trifluoromethyl, itrile group, cyclobutyl oxygen base, 2; 2,2-trifluoro ethoxy, methoxyl group, isobutoxy, tertiary butyl oxygen base, sec.-propyl oxygen base, methyl-amino-carbonyl, cyclopropyl-methoxyl group, dimethylamino-propyl group-amino, methoxyl group-oxyethyl group ,-XR
11,-C (O) R
11With-OXR
11Wherein X is key, methylene radical, ethylidene; R
11Be selected from piperazinyl, piperidyl, pyrrolidyl, morpholine-4-base, azepan base and 1,4-dioxa-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-base; R wherein
11Can choose wantonly and independently be selected from 1-3 following group and replace: methyl, sec.-propyl, ethanoyl, ethanoyl-methyl-amino, 3-dimethylamino-2,2-dimethyl--propyl group amino, ethyl-methyl-amino-oxyethyl group, diethylammonium-amino-oxyethyl group, amino-carbonyl, ethyl, 2-oxo-tetramethyleneimine-1-base, pyrrolidyl, pyrrolidyl-methyl, optional by methyl or the substituted piperidyl of ethyl, morpholine-4-base, dimethylamino, dimethylamino-propyl group-amino, methyl-amino and ethyl-amino.
More preferably following definition is independent to be used, uses jointly or its any combination or the use of inferior array configuration:
(a ') R
0Or R
2Independent is hydrogen, C
1-C
8Alkyl (like methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstituted or substituted 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (like morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), the C of containing
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or substituted amino (like methylamino, dimethylamino or acetylamino), halogen (like fluorine or chlorine); Preferred hydrogen, piperazine-1-base, N-methyl (piperazine-1-yl) or 1-methyl-4-piperazinyl oxygen base are preferably hydrogen especially;
(b ') R
1Be hydrogen, C
1-C
8Alkyl (like methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstituted or substituted 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (like morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), the C of containing
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or substituted amino (like methylamino, dimethylamino or acetylamino), halogen (like fluorine or chlorine); Preferred hydrogen, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, 1-methyl-4-piperazinyl oxygen base, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group are preferably hydrogen especially;
(c ') R
3Be hydrogen, C
1-C
8Alkyl (like methyl or ethyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstitutedly or substituted contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (like 2-pyrroles's ketone group or S, S-dioxo isothiazole alkyl), C that is selected from N, O and S
1-C
8Alkoxyl group (like methoxyl group), substituted amino (like acetylamino, ethanoyl-methyl-amino, benzoyl-amido, methyl sulphonyl amino or phenyl sulfonyl amino), C
1-C
8Alkyl sulphonyl (like methyl sulphonyl), C
5-C
10Aryl sulfonyl (phenyl sulfonyl), halogen (like fluorine or chlorine), carboxyl, substituted or unsubstituted formamyl (like formamyl, methylamino formyl radical or formyl-dimethylamino), unsubstituted or substituted sulfamyl are (like sulfamyl, methyl sulfamyl, propyl group sulfamyl, sec.-propyl sulfamyl, isobutyl-sulfamyl, cyclopropyl methyl-sulfamyl, 2; 2,2-trifluoroethyl sulfamyl, dimethylamino alkylsulfonyl or (morpholine-4-yl) alkylsulfonyl); Preferred sulfamyl, methyl sulfamyl or propyl group sulfamyl;
(d ') adjacent substituting group is to R
0And R
1, or R
1And R
2, or R
2And R
3For-CH
2-NH-CO-,-CH
2-NH-SO
2-,-CH
2-CH
2-SO
2-,-O-CH
2-O-or-O-CF
2-O-, and so adjacent substituting group is right, promptly the hydrogen on the NH is by C
1-C
8Alkyl replaces; Preferred adjacent substituting group is to R
0And R
1, or R
1And R
2For-O-CH
2-O-, adjacent substituting group is to R
2And R
3For-CH
2-NH-CO-or-CH
2-NH-SO
2-.
(e ') R
4Be hydrogen;
(f ') R
5Be hydrogen, halogen (like chlorine or bromine), halo C
1-C
8Alkyl (like trifluoromethyl) or nitro; Be preferably hydrogen, chlorine, bromine, trifluoromethyl or nitro; Be preferably chlorine or bromine especially;
(g ') R
6Be hydrogen;
(h ') R
7And R
9Independent is hydrogen, C
1-C
8Alkyl (like methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (like trifluoromethyl), unsubstituted or substituted C
5-C
10Aryl (like phenyl or p-methoxy-phenyl), unsubstituted or substituted 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (like morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), the C of containing
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group is (like 2-(1-imidazolyl) oxyethyl group; 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group); Unsubstituted or substituted amino is (like methylamino; Dimethylamino or acetylamino); Halogen (like fluorine or chlorine); Unsubstituted or substituted formamyl is (like the cyclohexyl carboxyamide base; (piperidines-1-yl) carbonyl; (piperazine-1-yl) carbonyl; N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl); Unsubstituted or substituted sulfamyl is (like sulfamyl; Methyl sulfamyl or dimethylamino alkylsulfonyl); Preferred hydrogen, methyl, sec.-propyl, trifluoromethyl, phenyl, neighbour-,-or right-p-methoxy-phenyl, piperidines-1-base, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, methoxyl group, oxyethyl group, isopropoxy, phenoxy, 3-(morpholine-4-yl) propoxy-, 2-(morpholine-4-yl) oxyethyl group, 2-(1-imidazolyl) oxyethyl group, dimethylamino, fluorine, (morpholine-4-yl) carbonyl, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl or cyclohexyl carboxyamide base;
(i ') R
8Be hydrogen, C
1-C
8Alkyl (like methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (like trifluoromethyl), C
5-C
10Aryl (like phenyl or p-methoxy-phenyl), unsubstituted or substituted C
5-C
10Aryl (like phenyl or p-methoxy-phenyl), unsubstituted or substituted 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (like morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), the C of containing
1-C
8Alkoxyl group (like methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (like trifluoromethoxy), C
5-C
10Aryloxy (like phenoxy), unsubstituted or substituted heterocyclyloxy base (like 1-methyl-4-piperidyl oxygen base), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or substituted amino (like methylamino or dimethylamino), halogen (like fluorine or chlorine), unsubstituted or substituted sulfamyl (like sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl) or nitro; Preferred hydrogen, methyl, piperidines-1-base, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, methoxyl group, oxyethyl group, trifluoromethoxy, phenoxy, 1-methyl-4-piperidyl oxygen base, 3-(morpholine-4-yl) propoxy-, 2-(morpholine-4-yl) oxyethyl group, 3-(N-methyl (piperazine-1-yl))-propoxy-, methylamino, fluorine, chlorine, sulfamyl or nitro;
(j ') R
10Be C
1-C
8Alkyl (like methyl, ethyl or butyl), halo C
1-C
8Alkyl (like trifluoromethyl), C
1-C
8Alkoxyl group (like methoxy or ethoxy), unsubstituted or substituted heterocyclic radical C
1-C
8Alkoxyl group (like 2-(1-imidazolyl) oxyethyl group), unsubstituted or substituted amino (like methylamino or dimethylamino), halogen (like fluorine or chlorine); Preferable methyl, butyl, methoxyl group, oxyethyl group, 2-(1-imidazolyl) oxyethyl group, methylamino, dimethylamino or fluorine; And
(k ') adjacent substituting group is to R
7And R
8, or R
8And R
9Or R
9And R
10For-NH-CH=CH-,-CH=CH-NH-,-NH-N=CH-,-CH=N-NH-,-CH
2-CH
2-CH
2-,-CH
2-CH
2-CH
2-CH
2-,-O-CH
2-O-or-O-CF
2-O-; Preferred adjacent substituting group is to R
7And R
8Or R
8And R
9For-O-CH
2-O-, or adjacent substituting group is to R
9And R
10For-NH-CH=CH-,-CH=N-NH-,-CH
2-CH
2-CH
2-,-CH
2-CH
2-CH
2-CH
2-or-O-CF
2-O-.
Most preferred formula I compound be those wherein substituting group have the compound of the given definition of embodiment.
In another embodiment of the invention, the invention provides formula I ' compound and pharmacy acceptable salt thereof, hydrate, solvolyte, isomer and prodrug, but being them, prerequisite do not comprise any compound that embodiment 1-52 is comprised.
Wherein:
N ' is selected from 1,2 and 3;
R '
1Be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Naphthenic base and C
5-12Heterocyclylalkyl;
R ' wherein
1Arbitrary aryl, heteroaryl, naphthenic base or Heterocyclylalkyl can choose wantonly and independently be selected from following group by 1-3 and replace: C
1-6Alkyl, C
1-6Alkoxyl group, alkoxyl group-substituted-C
1-6Alkyl, halogen-substituted-C
1-6Alkyl, halogen-substituted-C
1-6Alkoxyl group, C (O) NR '
5R '
6,-S (O)
0-2NR '
5R '
6,-S (O)
0-2R '
5,-C (O) R '
4,-OXR '
4,-NR '
5XNR '
5R ' ,-OXNR '
5R '
6,-OXOR '
5With-XR '
4
Wherein X ' is key or C
1-6Alkylidene group; R '
5Be selected from hydrogen or C
1-6Alkyl; R '
6Be selected from hydrogen, C
1-6Alkyl and C
3-12Naphthenic base-C
1-4Alkyl; And R '
4Be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Naphthenic base and C
3-10Heterocyclylalkyl;
R '
4Arbitrary aryl, heteroaryl, naphthenic base or Heterocyclylalkyl can choose wantonly and independently be selected from following group by 1-3 and replace: C
1-6Alkyl, optional by C
1-6The substituted C of alkyl
3-10Heterocyclylalkyl-C
0-4Alkyl ,-C (O) NR '
5R '
6,-XNR '
5R '
6,-NR '
5XNR '
5R '
6With-NR '
5C (O) R '
6Wherein X is key or C
1-6Alkylidene group; R '
5And R '
6Independently be selected from hydrogen and C
1-6Alkyl;
R '
2Be selected from hydrogen and halogen, cyanic acid, C
1-6Alkyl, halogen-substituted-C
1-6Alkyl;
R '
3Be selected from halogen ,-S (O)
0-2NR '
5R '
6,-S (O)
0-2R '
6,-NR '
5(O)
0-2R '
6,-C (O) NR '
5R '
6,-C (O) R '
6With-C (O) OR '
6R ' wherein
5Be selected from hydrogen and C
1-C
6Alkyl; And R '
6Be selected from hydrogen, C
1-6Alkyl and C
3-C
12Naphthenic base.
Preferred formula I ' compound, wherein:
N ' is selected from 1 and 2;
R '
1Be selected from C
6-10Aryl and C
5-10Heteroaryl, wherein R '
1Arbitrary aryl or heteroaryl can choose wantonly and independently be selected from following group by 1-3 and replace: C
1-6Alkyl, C
1-6Alkoxyl group ,-C (O) NR '
5R '
6,-OX ' R '
4,-C (O) R '
4,-NR '
5X ' NR '
5R '
6,-OX ' NR '
5R '
6,-OX ' OR '
5With-X ' R '
4Wherein X is key or C
1-6Alkylidene group; R '
5Be selected from hydrogen and C
1-C
6Alkyl; R '
6Be selected from hydrogen, C
1-6Alkyl and C
3-C
12Naphthenic base C
1-
4Alkyl; R '
4Be C
3-10The heterocyclic radical alkyl, it can be chosen wantonly and independently is selected from following group by 1-3 and replace: C
1-6Alkyl, halogen-substituted-C
1-6Alkyl, optional by C
1-6The substituted C of alkyl
3-10Heterocyclic radical alkyl-C
0-4Alkyl ,-C (O) NR '
5R '
6,-X ' NR '
5R '
6,-NR '
5X ' NR '
5R '
6With-NR '
5C (O) R '
6Wherein X ' is key or C
1-6Alkylidene group; R '
5And R '
6Independently be selected from hydrogen and C
1-6Alkyl;
R '
2Be selected from hydrogen and halogen;
R '
3Be selected from halogen ,-S (O)
0-2NR '
5R '
6,-S (O)
0-2R '
6,-NR '
5S (O)
0-2R '
6,-C (O) NR '
5R '
6With-C (O) OR '
6R ' wherein
5Be selected from hydrogen and C
1-C
6Alkyl; R '
6Be selected from hydrogen, C
1-6Alkyl and C
3-C
12Naphthenic base.
More preferably formula I ' compound, wherein R '
1Be selected from phenyl, pyridyl, pyrazolyl and pyrimidyl; R ' wherein
1Arbitrary aryl or heteroaryl can choose wantonly and independently be selected from following group by 1-3 and replace: oxyethyl group, ethyl, propyl group, methyl, the tertiary butyl, trifluoromethyl, itrile group, cyclobutoxy group, 2; 2,2-trifluoro ethoxy, methoxyl group, isobutoxy, tert.-butoxy, sec.-propyl oxygen base, methyl-amino-carbonyl, cyclopropyl-methoxyl group, dimethylamino-propyl group-amino, methoxyl group-oxyethyl group ,-X ' R '
4,-C (O) R '
4With-OX ' R '
4Wherein X ' is key, methylene radical or ethylidene; R '
4Be selected from piperazinyl, piperidyl, pyrrolidyl, morpholine-4-base, azepan base and 1,4-dioxa-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-base; R ' wherein
4Can choose wantonly and independently be selected from following group by 1-3 and replace: methyl, sec.-propyl, ethanoyl, ethanoyl-methyl-amino, 3-dimethylamino-2,2-dimethyl--propyl group amino, ethyl-methyl-amino-oxyethyl group, diethylammonium-amino-oxyethyl group, amino-carbonyl, ethyl, 2-oxo-tetramethyleneimine-1-base, pyrrolidyl, pyrrolidyl-methyl, optional by methyl or the substituted piperidyl of ethyl, morpholine-4-base, dimethylamino, dimethylamino-propyl group-amino, methyl-amino and ethyl-amino.
More preferably formula I ' compound, wherein R '
2Be selected from hydrogen and halogen; R '
3Be selected from halogen, dimethyl--sulfamyl, isobutyl--sulfamyl, methyl-sulfamyl, ethyl-sulfamyl, propyl group-alkylsulfonyl, ethyl-amino-carbonyl, 1-ethyl-propyl group-sulfamyl, cyclopentyl-sulfamyl, sec.-propyl-sulfamyl, cyclohexyl-alkylsulfonyl, cyclopropyl-methyl-sulfamyl, cyclobutyl-sulfamyl, sec.-propyl-alkylsulfonyl.
The compound of most preferred embodiment 53.
In another embodiment of the invention, the present invention also provides the method for preparation I compound, and this method comprises makes formula II compound
R wherein
0, R
1, R
2, R
3, R
4, R
5And R
6As above define, and Y is leavings group, is preferably halogen such as bromine, iodine, particularly chlorine;
React with the formula III compound
R wherein
7, R
8, R
9And R
10As above define, if desired, can formula I compound (wherein substituting group as above defines) be converted into as above other formula I compound of definition;
And the target compound of recovery free form or salt form, and, if desired, can the formula I compound of the free form that obtains be converted into the salt that needs, perhaps the salt that obtains is converted into free form.
Reaction can be carried out through known method; Reaction conditions depends primarily on the reactive behavior of the amino group on the aniline of reactive behavior and formula III compound of leavings group Y, in the presence of appropriate solvent or thinner or its mixture, carries out usually, if desired; Also can in the presence of acid or alkali, carry out; Through cooling off or preferably reacting through heating, for example TR generally is about 0 ℃ to+100 ℃ greatly about-30 ℃ to+150 ℃; Be preferably room temperature (approximately+20 ℃) to+80 ℃, reaction is usually in open or airtight container and/or under rare gas element (for example nitrogen) environment, carry out.Perhaps, reaction can be carried out in the presence of suitable catalyzer (like two-benzyl-acetone palladium), in the presence of alkali (like cesium carbonate), carries out, and in the presence of suitable reaction promotor (like xanthphos), carries out.
If one or more other functional groups (like carboxyl, hydroxyl or amino) are protected or need be protected in formula II or the III compound; Because they should not participate in reaction, so said blocking group is to be generally used in peptides, cynnematin and penicillium mould and nucleic acid derivative and carbohydrate synthetic those.
Already in the precursor, it can protect relevant functional group to avoid unwanted second order reaction, like replacement(metathesis)reaction or solvolysis reaction to blocking group.Blocking group is characterised in that they self can be easier to remove; That is to say and need not the second order reaction that takes place not expect; Generally remove: solvolysis reaction, reduction reaction, photolysis or through enzyme catalysis through following method; For example under the condition similar, so they can not be present in the end product with physiological condition.Brainstrust is known or can be confirmed more easily that which blocking group is applicable to above-mentioned reaction.
The salt that can prepare formula I compound through known method with salt forming group.Therefore, through can obtain the acid salt of formula I compound with acid or suitable anionresin agent treated.
Salt can be converted into the compound of free form usually, for example through handling with suitable alkaline reagents, as adopting alkaline carbonate, alkali metal hydrocarbonate or alkali metal hydroxide, adopts salt of wormwood or sodium hydroxide usually.
Through known suitable for separation, can three-dimensional heterogeneous mixture (like non-enantiomer mixture) be separated into its corresponding isomer.
Distribute and similar methods through fractional crystallization, chromatogram, solvent, can non-enantiomer mixture be separated into its single diastereomer.This separation can be carried out in the initial compounds stage, also can carry out with regard to formula I compound itself.Formation through diastereomeric salt can separate enantiomer, for example adopts the chiral acid of enantiomer-pure to form salt, perhaps through the stratographic method, for example through HPLC, adopts the chromatogram substrate with chiral ligand.
It is emphasized that the reaction similar with the said conversion reaction of this paragraph also can carry out in the suitable intermediate product stage.
Formula I compound (comprising its salt) also can obtain with the form of hydrate, and perhaps its crystallization can comprise and for example is used for crystalline solvent (existing with solvate forms).
Can obtain through formula IV compound is reacted with formula V compound as the formula II compound of starting substance:
R wherein
1, R
2, R
3, R
4, R
5And R
6As above define, and Y
1And Y
2For as the defined identical or different leavings group of above-mentioned Y.Mentioned identical in reaction conditions and above-mentioned formula II compound and the reaction of formula III compound.
Formula IV and V compound are known, perhaps can be through known method production.
When external when carrying out the experiment of not celliferous kinase activity assay and cell analysis, formula I compound and pharmacy acceptable salt thereof present valuable pharmacological activity, so they can be used as medicine.Specifically, The compounds of this invention is the suppressor factor of focal adhesion kinase, and medicine is used to treat because the disease that focal adhesion kinase coherent signal cascade fault is caused, the particularly described tumour in back so can be used as.
In the signal transduction of 6 integrin-mediated ecto-entad, focal adhesion kinase (FAK) be key enzyme (D.Schlaepfer etc., Prog Biophys Mol Biol 1999,71,435-478).As intracellular signal transduction, this growth for cell, existence and migration are moving extremely important through the cell surface receptor integrin in interaction between cell and extracellular matrix (ECM) albumen.FAK has played significant feature in the signal cascade of 6 integrin-mediated ecto-entad.The triggering of signal transduction cascade is the automatic phosphorylation of Y397.The Y397 of phosphorylation is the SH2 target position of Src family Tyrosylprotein kinase.Bonded c-Src Tyrosylprotein kinase makes the tyrosine residues phosphorylation among other FAK.
Wherein, the Y925 of phosphorylation becomes the binding site at the little adaptive proteic SH2 of Grb2 position.This Grb2 is one of downstream target spot such as Ras-ERK2/MAP kinase cascade activated important step with direct combination of FAK.
The inhibition of endogenous FAK signal causes mobility to reduce, and causes necrocytosis in some cases.On the other hand, through the exogenous expression, strengthen that the FAK signal can increase cell mobility and from ECM transfer cell existence signal.In addition, in epithelium, mesenchymal cell, Tiroidina and the carcinoma of prostate of invading and shifting, FAK is by over-expresses.Therefore, FAK might become the medicine that is used for neoplasm growth and transfer.So The compounds of this invention is suitable for; For example; Prevention and/treatment vertebrates especially mammiferous ND, particularly mammary tumor, intestinal cancer (colon and rectum), cancer of the stomach and ovary and prostate cancer, non-leaflet cell lung cancer, leaflet cell lung cancer, liver cancer, melanoma, bladder tumor and brain and neck cancer.
FAK suppress and immune relation referring to, for example, G.A.van Seventer etc., Eur.J.Immunol.2001,31,1417-1427.So The compounds of this invention can be used for, for example, prevent and/or treat the especially mammiferous disease of immune system of vertebrates; The disease or the illness of T lymphocyte, bone-marrow-derived lymphocyte, mastocyte and/or eosinophil mediation, for example organ or tissue's acute or chronic rejection of the same race or heteroplastic, arteriosclerosis is because the angiemphraxis that vascular injury such as angioplasty cause; Restenosis, hypertension, heart trouble; Chronic obstructive disease of lung, CNS disease such as Alzheimer or ALS, cancer; Communicable disease such as AIDS, septic shock or adult respiratory distress syndrome, local asphyxia/reperfusion injury such as myocardial infarction; Apoplexy, enteron aisle ischemic, renal failure or hemorrhagic shock or traumatic shock.The compounds of this invention also can be used for treating and/or preventing acute or chronic inflammatory diseases or illness or autoimmune disorder, like rheumatic arthritis, osteo-arthritis, systemic lupus erythematous, bridge this (skin table picture, inflammatory and the high hyperplasia dermatosis of Hashimoto ' s) thyroiditis, multiple sclerosis, myasthenia gravis, mellitus (I type and II type) and disease, respiratory tract disease such as the asthma of being correlated with it or inflammatory liver injury, inflammatory glomerular injury, immune-mediated discomfort or disease (contact dermatitis, pungency like psoriatic, atopic dermatitis, supersensitivity and contact dermatitis and other eczematoid dermatitis, seborrheic dermatitis), inflammatory eye disease (like Sjoegren ' s syndrome, keratoconjunctivitis or uveitis), inflammatory enteritis, segmental enteritis or ulcerative colitis.
Described in instance, The compounds of this invention shows active in the FAK detection system, and its IC
50Scope be 1nM-100nM.Activated especially compound is the compound of embodiment 3-12 and 3-17, its IC
50Scope be the scope of 1-5mM.
Some compound of the present invention also has ZAP-70 (the ξ chain GAP-associated protein GAP of 70kD) protein tyrosine kinase and suppresses active.As be shown in the examples, the ZAP-70 protein tyrosine kinase of The compounds of this invention interacts can be proved the ability like LAT-11 (T cell activation linking agent) phosphorylation through people ZAP-70 protein tyrosine kinase in its prevention aqueous solution.ZAP-70 suppresses acting discomfort or illness so The compounds of this invention also can prevent or treat wherein.
As be shown in the examples, The compounds of this invention shows active in the ZAP-70 detection system, its IC
50Scope be 1 μ M-10 μ M, of following embodiment 2 and 3-2.
The compounds of this invention also is the good suppressor factor of IGF-IR (IGF-1 1); So can be used for treating the disease of IGF-IR mediation; Like proliferative disease; Tumour for example is like breast, kidney, prostate gland, knot rectum, Tiroidina, ovary, pancreas, neurone, lung, uterus and gastroenteric tumor and osteosarcoma and melanoma.Can through cell " catch the ELISA method " (CaptureELISA) the proof The compounds of this invention as the usefulness of IGF-IR tyrosine kinase activity suppressor factor.In this is measured, proved the activity of the IGF-IR autophosphorylation that The compounds of this invention antagonism type-1 insulin like growth factor (IGF-I) is mediated.
When external when carrying out the experiment of not celliferous kinase activity assay and cell analysis, formula I compound and pharmacy acceptable salt thereof present valuable pharmacological activity, so they can be used as medicine.Particularly, The compounds of this invention be between the suppressor factor of modification lymphoma kinases (ALK), be used to treat and a disease that the signal cascade fault that modification lymphoma kinases is relevant is caused so can be used as medicine, particularly the described tumour in back.
The signal of ALK-mediation has effect (Pulford, K etc., J.Cell.Physiol.2004 June in the growth of many common solid tumors and/or evolution; 199 (3): 330-58).The compounds of this invention has very strong restraining effect to the tyrosine kinase activity of a modification lymphoma kinases and fusion rotein thereof, particularly the NPM-ALK fusion rotein.Protein tyrosine kinase is formed by the gene fusion of a kernel phosphoric acid albumen (NPM) and a modification lymphoma kinases (ALK), thus make the protein tyrosine kinase activity of ALK be part independently.NPM-ALK plays an important role in the many hematopoietic cells that cause hematologic disease and ND and other human cell's signal transmission; Above-mentioned disease comprise as a modification large celllymphoma (ALCL) and non_hodgkin lymphoma (NHL), particularly ALK+NHL or Alkomas, inflammatory myofibroblastic tumor (IMT) and neuroblastoma (.2001Oncogene 20 such as Duyster J, 5623-5637).Proved NPM-ALK external be a kind of very strong oncogene, can transform various clones and elementary hematopoietic cell.In addition, when being transplanted to the acceptor mouse of shining, the medullary cell of NPM-ALK conversion can be induced lymphoma appearance disease.NPM-ALK activated signalling channel comprises ras, PLC and PI3K passage, in addition, has proved that STAT5 can be by the NPM-ALK phosphorylation.Except NPM-ALK, in human blood and ND, also confirmed to exist other gene fusion; Mainly be TPM3-ALK (tropomyosin 3 of non-flesh and the fusion of ALK).In addition, ALK fusion rotein CLTC-ALK with comprise conventional T cell and naked ALCL, ALK
+The disease of DLBCL and inflammatory myofibroblastic tumor is relevant.CLTCL-ALK also has effect in the pathogeny of large B cell lymphoid tumor.
In addition, ALK fusion rotein CLTC-ALK is with to comprise typical T cell (classical T cell) relevant with the disease of null cell type ALCL, ALK+DLBCL and inflammatory myofibroblastic tumor.CLTCL-ALK also has effect in the pathogeny of loose B-cell lymphoma.
The abnormal activity of ALK is relevant with the growth of brain tumor, neuroblastoma be derived from the over-expresses of having found ALK in several kinds of clones of nervous tissue.The signal of ALK mediation has effect (Pulford, K. etc., J.Cell.Physiol.2004 June in the growth of many common solid tumors and/or evolution; 199 (3): 330-58).
Through adopting known method can confirm the active inhibition of alk tyrosine kinase, for example adopt with J.Wood etc. at Cancer Res.60, the ALK reorganization kinases territory method that VEGF-R kinase assay described in the 2178-2189 (2000) is similar.External, at 20mM Tris-HCI, pH=7.5,3mM MgCl
2, 10mM MnCl
2, 1mM DTT, the every mensuration of 0.1 μ Ci/ (=30 μ l) [γ-
33P]-ATP, 2 μ M ATP, 3 μ g/ml poly (Glu, Tyr 4: 1) Poly-EY (Sigma P-0275), 1%DMSO, 25ng ALK enzyme in, on 96 orifice plates, carry out the enzyme analysis of GST-ALK protein tyrosine kinase, as the filter binding analysis.With above-mentioned analytic liquid incubation 10 minutes at room temperature.The 125mM EDTA termination reaction that adds 50 μ l, with reaction mixture transfer to the many sieve plates of MAIP (Millipore, Bedford, MA, USA) on, this plate had before been used wetted with methanol, used water hydratable again 5 minutes.Wash (0.5% H then
3PO
4), in liquid scintillation counter, plate is counted.Calculate IC through suppressing percentile linear regression analysis
50Value.Compare with the contrast that does not have suppressor factor, formula I compound suppresses 50% enzymic activity (IC
50) concentration range for example between 0.001-0.5 μ M, especially between 0.01-0.1 μ M.
Formula I compound suppress effectively human NPM-ALK over-expresses mouse BaF3 cell growth (DSMZ Deutsche Sammlung von Mikroorganismen und ZellkulturenGmbH, Braunschweig, Germany).Through expression vector pClneoT with coding NPM-ALK
M(USA) transfection BaF3 clone also selects the G418 resistant cell to obtain the expression of NPM-ALK subsequently for Promega Corp, MadisonWI.The BaF3 cell of untransfected relies on the IL-3 survival.On the contrary, express the BaF3 cell (after this being called BaF3-NPM-ALK) of NPM-ALK and can breed under the condition of IL-3 not having, because the signal that they obtain breeding through the NPM-ALK kinases.So the kinase whose supposition suppressor factor of NPM-ALK can be eliminated growth signals and produce antiproliferative activity.Yet can eliminate the antiproliferative activity of the kinase whose supposition suppressor factor of NPM-ALK through adding IL-3, IL-3 can through the NPM-ALK independent mechanism provide growth signals [can be referring to E Weisberg etc. for the similar cell system that uses FLT3, Cancer Cell; 1,433-443 (2002)].The inhibition activity of formula I compound can be measured through following method.In brief, with the BaF3-NPM-ALK cell transfer to 96 hole droplet plates (15,000 μ l/ hole).Add test-compound (being dissolved in methyl-sulphoxide (DMSO)) but the concentration of final DMSO is no more than 1% (v/v) with series concentration (serial dilution).After add accomplishing,, there is not the control cultures of test-compound can experience two cell fission circulations during this period with above-mentioned plate incubation two days.Pass through Yopro
TMDyeing process is measured the growth [J.Immunol.Methods such as T Idziorek of BaF3-NPM-ALK cell; 185:249-258 (1995)]: in each hole, add the 25 μ l lysis buffers that contain 20mM Trisodium Citrate (pH 4.0), 26.8mM sodium-chlor, 0.4%NP40,20mM EDTA and 20mM.Accomplish lysis in room temperature in following 60 minutes, adopt following setup parameter: excite (nm) 485/20 and emission (nm) 530/25, use Cytofluor II 96 holes to read plate appearance (PerSeptive Biosystems) and measure the Yopro sum that is attached on the DNA.
Through computer aided system, adopt computes IC
50Value:
IC
50=[(ABS
Experiment-ABS
Initial)/(ABS
Contrast-ABS
Initial)] * 100. (ABS=optical densitys).
IC in these experiments
50Value makes the concentration of the test-compound of cell counting minimizing 50% with respect to the contrast that does not have suppressor factor.Formula I compound has IC
50The inhibition that is about 0.01-1 μ M is active.
Also can adopt above-mentioned about the identical method of BaF3-NPM-ALK clone; At people KARPAS-299 lymphoma cell line (DSMZ Deutsche Sammlung vonMikroorganismen und Zellkulturen GmbH; Braunschweig; Germany) antiproliferative effect [referring to Int.J.Cancer 100 such as WG Dirks, 49-56 (2002)] of mensuration formula I compound in.
Formula I compound has the activity of inhibition, its anti-IC
50Be about 0.01-1 μ M.
Equal Int.J.Cancer 100 through WG Dirks, the immunoblotting described in the 49-56 (2002) in people KARPAS-299 lymphoma cell line, can be measured the effect of formula I compound to the ALK autophosphorylation.In this experiment, the IC of formula I compound
50Value is about 0.001-1 μ M.
In formula I compound, [5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-BM is a strong especially ALK suppressor factor to 2-, and this compound can suppress the growth of BaF3-NPM-ALK cell, its IC
50Be 97nM.The compound of the tyrosine kinase activity of modification lymphoma kinases (ALK) be embodiment 7A and 7B and the described compound of 7-2,7-15,19-5,21-1,26-3 and 28-5 at the back between preferred especially in addition the inhibition, all these compounds all have＜and the IC of 0.5-200nM
50Value.
When being used for above-mentioned treatment ND and disease of immune system, the dosage that needs depends on the pattern of administration, individual instances and desired effects to be treated certainly.Usually, if will obtain whole satisfied result, per daily dose should be per kilogram of body weight about 0.1 to about 100mg.For the large mammal such as the mankind, the scope of suggestion per daily dose is about 0.5mg to 2000mg, can, for example, single-dose to a day four administrations or employing slow release formulation.
The compounds of this invention can be through any conventional route administration; Particularly administration (preferred oral administration in the parenteral admin form of injection liquid or suspension-s (for example with), the enteron aisle; As with tablet or capsular form), topical (like form), perhaps intranasal administration or suppository with lotion, gel, ointment or creme.With ordinary method, through with pharmaceutically acceptable carrier or mixing diluents, can produce the pharmaceutical composition that contains The compounds of this invention and at least a pharmaceutically acceptable carrier or thinner.The unit dosage of oral administration contains, and for example, about 0.1mg is to the active substance of about 500mg.Topical does, for example, and percutaneous drug delivery.Other form of topical is a dosing eyes.
Can prepare pharmaceutical composition of the present invention through well-known method, for example, through routine mixing, granulation, dressing, dissolving or freeze dried method.
The solution of preferred activeconstituents also can be suspension-s or dispersion liquid, particularly isotonic aqueous solution, suspension-s or dispersion liquid; For example; For only containing activeconstituents or also comprising under the situation of lyophilised compsns of carrier (like N.F,USP MANNITOL), can prepare before use, for example.Pharmaceutical composition can and/or contain vehicle by sterilization; For example; Sanitas, stablizer, wetting agent and/or emulsifying agent, solubilizing agent, be used to regulate the salt and/or the damping fluid of osmotic pressure, can be through well-known method preparation, for example through conventional dissolving and freeze drying process.Said solution or suspension-s comprise thickening material; Xylo-Mucine commonly used, CMC 99.5, Expex, Vinylpyrrolidone polymer or gelatin; Also can comprise solubilizing agent, like Tween 80
(T 46155 (20) dehydrated sorbitol mono-fatty acid ester).
Suspension-s in oil contains plant that routine is used to inject, synthetic or semi-synthetic oil as oil component.Thus; Be to be noted that the liquid aliphatic acid esters, it contains the longer chain fatty acid with the individual carbon atom of 8-22 (preferred 12-22) as acidic component, for example LAURIC ACID 99 MIN, tridecylic acid, tetradecanoic acid, pentadecanoic acid, palmitinic acid, margaric acid, Triple Pressed Stearic Acid, eicosanoic acid, docosoic or corresponding unsaturated acid; For example; Oleic acid, elaidic acid, erucic acid, brassidic acid or linolic acid if desired, can add oxidation inhibitor; For example vitamin E, β-Hu Luobusu or 3,5-two-tertiary butyl-4-hydroxy toluene.The pure composition of these fatty esters is up to 6 carbon atoms and can be unit price or polyvalent, for example monovalence, divalence or trivalent alcohol, and like methyl alcohol, ethanol, propyl alcohol, butanols or amylalcohol or its isomer, but preferred terepthaloyl moietie and USP Kosher.So; Following is the fatty ester of mentioning: OE, Isopropyl myristate, Wickenol 111, " Labrafil M 2375 " (polyoxyethylene glyceryl ester), " Labrafil M 1944CS " are (by the undersaturated Hydroxyacetic acid polymer glyceryl ester of Prunus amygdalus oil alcoholysis preparation; Contain glyceryl ester and polyethylene glycol ester), " Labrasol " (by the saturated Hydroxyacetic acid polymer glyceryl ester of TCM alcoholysis preparation; Contain glyceryl ester and polyethylene glycol ester; All can be available from Gattefoss é, France) and/or " Miglyol812 " (chain length is C
8To C
12The triglyceride level of sfas, available from H ü ls AG, Germany), but special preferably vegetable oil such as Oleum Gossypii semen, Prunus amygdalus oil, sweet oil, Viscotrol C, VT 18, more preferably peanut oil.
The production of injection is carried out under aseptic condition usually, like can in ampoule or bottle and with container closure.
Can pass through, for example, activeconstituents mixed obtaining being used for pharmaceutical composition for oral administration with one or more solid carriers; If desired; The gained mixture is processed particle, if desired or necessary, can be with other vehicle process mixture or particle to obtain tablet or label.
Appropriate carriers is particularly including weighting agent; Like carbohydrate (like lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol), cellulosis and/or calcium phosphate (like tricalcium phosphate or secondary calcium phosphate); Also can comprise tackiness agent; Like starch (like corn, wheat, rice or yam starch), methylcellulose gum, Vltra tears, Xylo-Mucine and/or Vinylpyrrolidone polymer, and/or, if desired; Comprise disintegrating agent, starch as described above, also have CMS, cross-linked polyvinylpyrrolidone, alginic acid or its salt (like sodiun alginate).
Other vehicle is particularly including glidant and lubricant, for example silicic acid, talcum powder, Triple Pressed Stearic Acid or its salt (like Magnesium Stearate or calcium) and/or polyoxyethylene glycol or derivatives thereof.
Label can obtain through suitable enteric coating; Through using the priming dressing; Comprise gum arabic, talcum powder, Vinylpyrrolidone polymer, polyoxyethylene glycol and/or titanium oxide; Perhaps use at suitable organic solvent or the dressing solution dressing in the solvent mixture, perhaps adopt the formulations prepared from solutions enteric coating liquid of suitable cellulose prods, like phthalic acid ethanoyl Mierocrystalline cellulose or Hydroxypropyl Methylcellulose Phathalate.Can in tablet or tablet coating, add dyestuff or pigment, as, be the purpose of identification or the various dose of difference activeconstituents.
Pharmaceutical composition for oral administration also can be the soft seal capsule of snap fit capsule and gelatin and softening agent (like glycerine or sorbyl alcohol).Hard capsule can contain the activeconstituents of particle form, for example with the mixture of weighting agent (like W-Gum), tackiness agent and/or glidant (like talcum powder or Magnesium Stearate) and optional stabilizer.In soft capsule; Activeconstituents preferably is dissolved in or is suspended in the suitable liquid excipient; Like the fatty ester of wax, Yellow Protopet 2A or liquid macrogol or terepthaloyl moietie or Ucar 35, also can be to wherein adding stablizer and sanitising agent, polyoxyethylene sorbitan fatty acid esters class for example.
The pharmaceutical composition that is applicable to rectal administration is that for example, suppository comprises activeconstituents and suppository base.Suitable suppository base does, for example, and natural and synthetic triglyceride level, paraffinic hydrocarbon, polyoxyethylene glycol or high triacontanol.
For parenteral admin, the aqueous solution of water-soluble active ingredient (like water-soluble salt) or contain thickening thing (like Xylo-Mucine, sorbyl alcohol and/or Expex), can comprise that also the water injection solution of stablizer or suspension-s are suitable if desired.Activeconstituents, and optional vehicle also can be processed freeze dried form, before parenteral admin, process solution through adding appropriate solvent.
This type of solution for example is used for parenteral admin, also can be used for transfusion.
Preferably sanitas does, for example, and oxidation inhibitor such as xitix or sterilant such as Sorbic Acid or phenylformic acid.
The compounds of this invention can be used as independent delivery of active ingredients, perhaps is used to treat the medicine of ND or is used for immunoregulatory medicine administration with other.
For example; The compounds of this invention can with above-mentioned various diseases drug composition effective is united use; As with following medication combined use: endoxan, 5 FU 5 fluorouracil, fludarabine, gemcitabine, cis-platinum, carboplatin, vincristine(VCR), vinealeucoblastine(VLB), VP, Rinotecan, taxol, Docetaxel, Mabthera (rituxan), Dx, ZD1939 or imatinib; Also can with following medication combined use: Cyclosporin A, rapamycin, WS7238A or its similar immunosuppressor, like cyclosporin A, Cyclosporin A G, FK-560, sirolimus or SDZ-RAD, cortical steroid (like prednisone, endoxan, azathioprine (azathioprene), Rheumatrex, golden salt, sulfasalazine, antimalarial drug, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolic acid morpholine ester, Gusperimus, immunosuppression monoclonal antibody (like leukocyte receptors monoclonal antibody such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4 or its part) or other immunomodulatory compounds (like CTLA4Ig).
According to noted earlier, the present invention also provides:
(1) compound of the present invention is as medicine;
(2) The compounds of this invention such as 5-chloro-N
*2
*-{ 2-methoxyl group-4-[4-(4-methyl-piperazine-1-yl)-piperidines-1-yl]-phenyl }-N
*4
*-[2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-2, the 4-diamines for example is used for foregoing any indication;
(3) pharmaceutical composition for example is used for foregoing any indication, and said pharmaceutical composition contains as the The compounds of this invention of activeconstituents and one or more pharmaceutically acceptable diluent or carriers;
(4) be used to treat the method for described any indication, this method comprises The compounds of this invention that gives said patient person's significant quantity that needs are arranged or the pharmaceutical composition that contains them;
(5) The compounds of this invention is used to prepare the purposes of medication medication, and said medicine is used to treat or prevents the activation of FAK wherein and/or ALK and/or ZAP-70 and/or IGF-IR, preferred ALK to play a role or diseases associated or illness;
(6) defined method under (4) item above, this method comprises administation of combination, for example, with The compounds of this invention and the administration simultaneously of one or more other medicines or the sequential administration of treatment significant quantity, said other medicines can be used for treating above-mentioned any indication;
(7) joint product, this joint product comprise the The compounds of this invention and one or more other medicines of treating significant quantity, and said other medicines can be used for treating above-mentioned any indication;
(8) The compounds of this invention is used to prepare the purposes of medicine, and this medicine is used to treat or prevent a kinase whose inhibition of modification lymphoma is had the disease of response;
(9) according to the purposes of (8), disease wherein to be treated is selected from lymphoma, primary cutaneous type, non_hodgkin lymphoma, inflammatory myofibroblastic tumor and neuroblastoma;
(10) according to the purposes of (8) or (9), wherein said compound is 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base-amino]-N-methyl-BM or 5-chloro-N
*2
*-{ 2-methoxyl group-4-[4-(4-methyl-piperazine-1-yl)-piperidines-1-yl]-phenyl }-N
*4
*-[2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-2,4-diamines or its pharmacy acceptable salt perhaps are the pharmacy acceptable salt of any compound described in the embodiment in the back or its arbitrary compound;
(11) treatment has the method for the disease of response to a kinase whose inhibition of modification lymphoma; Particularly be selected from following disease: primary cutaneous type, non_hodgkin lymphoma, inflammatory myofibroblastic tumor and neuroblastoma; Said method comprises the The compounds of this invention that gives significant quantity, particularly 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-BM or 5-chloro-N
*2
*-{ 2-methoxyl group-4-[4-(4-methyl-piperazine-1-yl)-piperidines-1-yl]-phenyl }-N
*4
*-(2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-2,4-diamines or its pharmacy acceptable salt.
The compound of the present invention that preferably is used for foregoing method, purposes and disease in addition is the compound that embodiment mentioned especially.
Special in addition preferred for use FAK suppressor factor or as ALK suppressor factor or the two common suppressor factor and usually can be following: 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-BM, N according to the compound of the present invention of foregoing method preparation
2-(4-[1,4 '] couplet piperidyl-1 '-Ji-2-methoxyl group-phenyl)-5-chloro-N
4-[2-(propane-1-alkylsulfonyl)-phenyl]-pyrimidine-2; 4-diamines, 2-{5-chloro-2-[2-methoxyl group-4-(4-methyl-piperazine-1-yl)-phenyl amino]-pyrimidine-4-base is amino }-N-sec.-propyl-benzsulfamide, 2-[5-bromo-2-(2-methoxyl group-5-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzsulfamide, 2-{2-[5-(1-ethanoyl-piperidin-4-yl oxygen base)-2-methoxyl group-phenyl amino]-5-bromo-pyrimidine-4-base are amino }-N-methyl-benzsulfamide, N-[5-bromo-2-(2,5-dimethoxy-phenyl amino)-pyrimidine-4-base is amino]-N-(4-morpholine-4-base phenyl) Toluidrin, 5-bromo-N-4-(4-fluorophenyl)-N
*2
*-(2-methoxyl group-4-morpholine-4-base phenyl)-pyrimidine-2; 4-diamines, 2-[(2-methoxyl group-4-piperazine-1-base phenyl amino)-pyrimidine-4-base is amino for 5-chloro-2-]-N-methyl-benzsulfamide, 2-[5-bromo-2-(5-fluoro-2-methoxyl group-phenyl amino)-pyrimidine-4-is basic amino]-N-methyl-benzsulfamide, 2-[5-chloro-2-(5-fluoro-2-methoxyl group-phenyl amino)-pyrimidine-4-base is amino]-N-isobutyl--benzsulfamide, 2-{5-chloro-2-[2-methoxyl group-5-(4-methyl-piperazine-1-ylmethyl) phenyl amino]-pyrimidine-4-base amino]-N-methyl-benzsulfamide and 5-chloro-N
*2
*-{ 2-methoxyl group-4-[4-(4-methyl-piperazine-1-yl) piperidines-1-yl] phenyl }-N
*4
*-[2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-2, the 4-diamines.
The present invention also provides 2-{5-chloro-2-[4-(3-methylamino-tetramethyleneimine-1-yl) phenyl amino]-pyrimidine-4-base amino }-N-sec.-propyl-benzsulfamide.
The present invention also provides 5-chloro-N
*2
*-{ 2-methoxyl group-4-[4-(4-methyl-piperazine-1-yl) piperidines-1-yl] phenyl }-N
*4
*-[2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-2, the 4-diamines.
Further specify the present invention with the following example, but be not used in restriction scope of the present invention.
Embodiment
Abbreviation: modification lymphoma kinases, ATP=5 '-Triphosaden, salt solution=saturated nacl aqueous solution, BSA=bovine serum albumin, DIAD=diisopropyl azo-2-carboxylic acid, DIPCDI=N between AcOH=acetate, ALK=; N '-DIC, DMAP=4-dimethyl aminopyridine, DMF=N; Dinethylformamide, DTT=1; 4-two sulphur-D, L-threitol, EDTA=YD 30, Et=ethyl, EtOAc=ETHYLE ACETATE, EtOH=ethanol, Eu-PT66=LANCE
TMThe anti-phosphorylated tyrosine antibody (Perkin Elmer) of europium-W1024-mark, FAK=focal adhesion kinase, FRET=FRET, HEPES=N-2-hydroxyethyl-piperazine-N '-2-ethanesulfonic acid, HOAt=1-hydroxyl-7-azepine benzotriazole, Me=methyl, RT-PCR=RT-polymerase chain reaction, SA-(SL) APC=and SuperLight
TMThe conjugated Streptavidin of allophycocyanin (Perkin Elmer), substituted, the TBTU=O-(benzotriazole-1-yl)-N of subst.=, N, N ', N '-tetramethyl-ammonium tetrafluoroborate, THF=THF.
Embodiment 1:2-[2-(2,5-dimethoxy-phenyl amino)-5-nitro-pyrimidine-4-base is amino]-N-methyl-benzsulfamide
Under room temperature to 2-(2-chloro-5-nitro-pyrimidine-4-base amino)-N-methyl-benzsulfamide (100mg adds 2 in EtOH 0.29mmol) (3mL) solution, the 5-dimethoxyaniline (49mg, 0.32mmol).Mixture was heated 5 hours in 78 ℃.Evaporating solvent, mixture obtains target compound through the reversed-phase HPLC purifying.
Rf=0.47 (normal hexane: ETHYLE ACETATE=1: 1).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：2.36(d，3H)，3.57(s，3H)，3.73(s，3H)，6.72(d，1H)，6.99(d，1H)，7.17(s，1H)，7.35(t，1H)，7.4-7.6(m，1H)，7.63(d，1H)，7.81(d，1H)，8.0-8.2(m，1H)，9.13(s，1H)，9.41(br.s，1H)，11.0(s，1H)。
The preparation of 2-(2-chloro-5-nitro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide:
With 2, (1.94g, 10mmol) (1.86g 10mmol) is dissolved in CHCl to 4-two chloro-5-nitro-pyrimidines with 2-amino-N-methyl-benzsulfamide
3(30mL).Reaction mixture was heated 2 hours in 61 ℃.Evaporating solvent also obtains target compound with residue with ether washing.
Rf=0.5 (normal hexane: ETHYLE ACETATE=1: 1).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：2.67(d，3H)，4.6-4.7(m，2H)，7.41(dd，1H)，7.7(dd，1H)，8.04(d，1H)，8.15(d，1H)，9.21(s，1H)，11.2(s，1H)。
Embodiment 2:2-[5-bromo-2-(2,4-dimethoxy-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzsulfamide
(300mg, 0.79mmol), 2, the 4-dimethoxyaniline (adds 1N hydrochloric acid (0.03mL), and stirred 5 hours down in reflux conditions among the 181.5mg, ethanolic soln 1.18mmol) (3mL) to 2-(5-bromo-2-chloro-pyrimidine-4-base amino)-N-methyl-benzsulfamide.Reaction mixture is cooled to room temperature, also uses the ethyl acetate extraction secondary in the impouring water.Water and salt solution wash organic phase successively, dried over mgso and vacuum-evaporation.Residue is through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1 to 1: 1) obtain target compound.
1H-NMR(CDCl
3)，δ(ppm)：8.95(s，1H)，8.44(d，1H)，8.20(s，1H)，7.98(dd，1H)，7.58(ddd，1H)，7.22-7.32(m，1H)，6.51(d，1H)，6.40(d，1H)，4.56-4.48(m，1H)，3.86(s，3H)，3.81(s，3H)，2.64(d，3H)。Rf (normal hexane: ETHYLE ACETATE=1: 1): 0.31.
The preparation of 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide:
((684mg is 3.0mmol) with 2-amino-N-methyl benzenesulfonamide (559mg, N 3.0mmol), dinethylformamide (10mL) solution stirring 23 hours for the 4-dichloro pyrimidine for 830mg, 5-bromo-2 6.0mmol) under room temperature, will to contain salt of wormwood.Add saturated aqueous ammonium chloride solution, reaction mixture is poured in the water, use the ethyl acetate extraction secondary.Use the brine wash organic layer, through dried over sodium sulfate and vacuum-evaporation.Residue obtains the target compound of faint yellow solid through silica gel chromatography (normal hexane-ETHYLE ACETATE gradient elution).
1H-NMR(CDCl
3)：δ(ppm)：2.67(d，3H)，4.79(q，1H)，7.26(s，1H)，7.29(ddd，1H)，7.66(ddd，1H)，7.95(dd，1H)，8.37(s，1H)，8.48(d，1H)，9.52(s，1H)。Rf (normal hexane: ETHYLE ACETATE=10: 3): 0.33.
Embodiment 3: according to the method for embodiment 2, prepare following 2-[5-bromo-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzene-sulphonamide from 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide and corresponding aniline:
Embodiment 4:2-[5-bromo-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-propyl group-benzene-sulphonamide
Can through with embodiment 2 similar methods; Adopt 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-propyl group-benzsulfamide and corresponding these compounds of aniline preparation; Obtain the No.4-1 compound to the 4-31 compound, its substituent R x and the No.3-1 compound of listing in embodiment 3 are identical to the 3-31 compound.
The preparation of 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-propyl group-benzsulfamide
To 5-bromo-2, (90 μ L, 0.70mmol) (100mg, (54.2mg, DMSO 0.56mmol) (1.0mL) liquid stir gained solution 3.0 hours in 80 ℃ the 4-dichloro pyrimidine to add sodium hydride in solution 0.47mmol) with 2-amino-N-propyl group-benzsulfamide.Mixture is poured in the water and with ethyl acetate extraction 3 times.Use the water washing organic phase, use brine wash then, through dried over sodium sulfate and vacuum-evaporation.Residue is through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1), obtain the target compound of faint yellow solid.
1H-NMR(δ，ppm)：0.89(t，3H)，1.41(q，2H)，3.56(t，2H)，4.92(br.s，2H)，6.71(dd，1H)，6.77(dd，1H)，7.33(dd，1H)，7.54(dd，1H)，8.79(s，1H)。
Rf (hexane: ETHYLE ACETATE=1: 1): 0.64.
Embodiment 5:2-[5-trifluoromethyl-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzsulfamide
Can through with embodiment 2 similar methods; Employing-2-(2-chloro-5-trifluoromethyl-pyrimidine-4-base is amino)-N-methyl benzenesulfonamide and corresponding these compounds of aniline preparation; Obtain the No.5-1 compound to the 5-31 compound, its substituent R x and the No.3-1 compound of listing in embodiment 3 are identical to the 3-31 compound.
The preparation of 2-(2-chloro-5-trifluoromethyl-pyrimidine-4-base is amino)-N-methyl-benzsulfamide
Under room temperature, to 2,4-two chloro-5-trifluoromethyl-pyrimidine (386mg; 1.79mmol) acetonitrile (10mL) solution in add 2-amino-N-methyl-benzsulfamide (333mg successively; 1.79mmol) and 1,8-diaza [5.4.0]-dicyclo-7-undecylene (280 μ L, 1.88mmol).After stirring 15 hours under the room temperature, in mixture, add methylene dichloride (30mL), wash above-mentioned solution with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution, dried over mgso and vacuum-evaporation.The gained solid is through purification by flash chromatography.
1H NMR(CDCl
3)δ3.73(s，3H)，6.67-6.69(m，1H)，6.72-6.73(m，1H)，7.27-7.31(m，1H)，7.78(dd，1H)，8.60(s，1H)。Rf (hexane: ETHYLE ACETATE=1: 1): 0.28.
Embodiment 6:2-[5-bromo-2-(2,3-[difluoro methylene-dioxy] phenyl amino)-pyrimidine-4-base is amino]-benzsulfamide
According to the method for embodiment 2, by 2-(5-bromo-2-chloropyrimide-4-base amino)-N-methyl-benzsulfamide and 2,3-(difluoro methylene-dioxy base) aniline reaction forms the target compound of by product through the N-demethylation.Also can pass through 2-(5-bromo-2-chloropyrimide-4-base is amino) benzsulfamide and 2,3-(difluoro methylene-dioxy)-aniline reaction preparation.
Rf (normal hexane: ETHYLE ACETATE=1: 1): 0.46.
1H-NMR：(CDCl
3)δ4.83(bs，2H)，6.77(dd，1H)，6.86(s，1H)，6.97(dd，1H)，7.31-7.24(m，1H)，7.57(dd，1H)，7.81(d，1H)，8.02(dd，1H)，8.28(d，1H)，8.29(s，1H)，8.88(s，1H)。
The preparation of 2-(5-bromo-2-chloropyrimide-4-base is amino) benzsulfamide:
To 5-bromo-2, (300mg, 1.32mmol) (340mg adds concentrated hydrochloric acid (0.06mL) in 2-propyl alcohol (3mL) solution 1.97mmol) to the 4-dichloro pyrimidine, and said mixture was stirred 4.5 hours in 90 ℃ with 2-amino-benzsulfamide.Mixture is poured in the sodium bicarbonate aqueous solution and with ethyl acetate extraction 3 times.Use the water washing organic layer, through dried over sodium sulfate and vacuum-drying.Residue is through purified (hexane: ETHYLE ACETATE=2: 1) obtain target compound.
Rf (hexane: ETHYLE ACETATE=1: 1): 0.55.
1H-NMR(400MHz，CDCl
3)δ：4.78(br.s，2H)，7.22(dd，1H)，7.61(ddd，1H)，7.95(dd，1H)，8.35(s，1H)，8.35(d，1H)，9.18(s，1H)。
Embodiment 7A:2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-BM
To 2-(2; 5-two chloro-pyrimidine-4-base-amino)-N-methyl-BM (5.05g; 17.0mmol) the 2-methyl cellosolve suspension-s of 90mL in add 2-methoxyl group-4-morpholinyl aniline dihydrochloride (4.56g be 16.2mmol) with 1N hydrogenchloride (17.0mmol) the ethanol liquid of 17.0mL.
Reaction mixture after 4 hours, is cooled to room temperature in 110 ℃ of stirrings,, extracts with EtOAc (100mL * 3) with 1N NaOH aqueous solution neutralization reactant.Use the brine wash organic layer, through dried over sodium sulfate and concentrating under reduced pressure.The gained black solid is with EtOH (90mL) washing, then through silica gel chromatography (CH
2Cl
2-CH
2Cl
2: AcOEt=1: 2) obtain 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base amino]-N-methyl-BM of faint yellow solid.
1H-NMR(400MHz，DMSO-d6，δ)：2.80(d，3H，J＝4.52Hz)，3.10-3.20(m，4H)，3.78(s，3H)，3.70-3.80(m，4H)，6.49(dd，1H，J＝8.56，2.52Hz)，6.66(d，1H，J＝2.52Hz)，7.08(dd，1H，J＝8.04，8.04Hz)，7.44(d，1H，J＝8.56Hz)，7.71(dd，1H，J＝8.04，1.48Hz)，8.10(s，1H)，8.13(s，1H)，8.59(d，1H，J＝8.04Hz)，8.68-8.75(m，1H)，11.59(S，1H)。MS m/z 469，471(M+1)
+。
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-methyl-BM from 2-(2,5-two chloro-pyrimidine-4-base is amino)-N-methyl-BM and corresponding aniline.
| The embodiment numbering | Rx | Rf (solvent) or MS | NMR(400MHz)，δ(ppm) |
According to the method for embodiment 7A, prepare following 2-[5-bromo-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-ethyl-BM from 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-ethyl-BM and corresponding aniline.
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-ethyl-BM from 2-(2,5-two chloro-pyrimidine-4-base is amino)-N-ethyl-BM and corresponding aniline.
According to the method for embodiment 7A, from 2-(2,5-two chloro-pyrimidine-4-base is amino)-6, N-dimethyl--BM prepares following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-6, N-dimethyl--BM with corresponding aniline.
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-5-fluoro-N-methyl-BM from 2-(2,5-two chloro-pyrimidine-4-base is amino)-5-fluoro-N-methyl-BM and corresponding aniline.
12-1:7-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-2-methyl-2, the preparation of 3-xylylenimine-1-ketone
Preparation 7-(2,5-two chloro-pyrimidine-4-base is amino)-2-methyl-2,3-xylylenimine-1-ketone
N-methyl-7-nitro-2; 3-xylylenimine-1-ketone: under room temperature, with 2-brooethyl-6-nitrobenzoic acid methyl esters (1.26g, THF 4.63mmol) (13mL) solution is with THF (14mL) solution-treated of 2M methylamine; Stirred 5 hours; With EtOAc (100mL) dilution, with saturated aqueous solution of sodium bicarbonate (15mL) and salt solution (15mL) washing, dry (MgSO
4) and evaporation concentration.Through flash chromatography (30g silica gel; CH
2Cl
2/ EtOAc 1: 1) obtain N-methyl-7-nitro-2, (0.561g, 2.92mmol), yield is 63% to 3-xylylenimine-1-ketone.Be yellow solid.R
f(CH
2Cl
2/EtOAc 1∶1)0.46。
1H-NMR(400MHz，CDCl
3)3.21(s)，4.44(s)，7.63-7.69(m，2H)，7.70-7.75(m，1H)。
7-amino-N-methyl-2,3-xylylenimine-1-ketone
Under room temperature, with N-methyl-7-nitro-2, (561.0mg, EtOAc 2.92mmol) (8.4mL) solution is used SnCl to 3-xylylenimine-1-ketone
22H
2O (2.68g) handles, and stirs 5 hours down in 80 ℃ of backflows, and handles in 0 ℃ of 5N NaOH with 30mL.After the separates two, (2 * 8mL) extractions, the extraction liquid of merging washs with salt solution (5mL) water layer, dry (MgSO with EtOAc
4) and evaporation concentration, obtaining 7-amino-N-methyl-2 into yellow solid, (455.9g, 2.81mmol), yield is 96% to 3-xylylenimine-1-ketone.
R
f(CH
2Cl
2/EtOAc 1∶1)0.53
1H-NMR(400MHz，CDCl
3)3.12(s)，4.28(s)，5.20(br.s)，6.56(d，J＝8.0)，6.68(d，J＝8.0)，7.21(dd，J＝8.0，8.0)。
7-(4-amino-2,5-dichloro pyrimidine-4-yl) amino-N-methyl-2,3-xylylenimine-1-ketone
In 0 ℃, with 7-amino-N-methyl-2,3-xylylenimine-1-ketone (232.6mg; 1.43mmol) DMF (2.0mL) solution handle with 60%NaH (89.8mg), under same temperature, stirred 1.5 hours, with 2; 4; DMF (3.5mL) solution-treated of 5-trichloropyrimidine (0.557g) stirred 1 hour, was warmed to room temperature.Continue to stir after 13 hours, use NH
4Cl (6mL) aqueous solution treating mixt is filtered and is collected gained brown precipitate, water, hexane and CH then
3The CN washing obtains 7-(4-amino-2, the 5-dichloro pyrimidine-4-yl) amino-N-methyl-2 into brown solid, and (130.2g, O.416mmol), yield is 26% to 3-xylylenimine-1-ketone.R
f(CH
2Cl
2/EtOAc 1∶1)0.50。
1H-NMR(400MHz，CDCl
3)：3.22(s)，4.43(s)，7.15(d，J＝8.0)，7.59(dd，J＝8.O，8.0)，8.24(s)，8.71(d，J＝8.0)，11.05(br.s)。
Method according to embodiment 7A; From 7-(2; 5-two chloro-pyrimidine-4-base is amino)-2-methyl-2,3-dihydro-isoindole-1-ketone prepares following 7-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-2-methyl-2,3-dihydro-isoindole-1-ketone with corresponding aniline.
7-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-2-methyl-2,3-dihydro-isoindole-1-ketone
1H-NMR(400MHz，DMSO-d6，δ)：3.07(s，3H)，3.13-3.17(m，4H)，3.75(s，3H)，3.34-3.78(m，4H)，4.46(s，2H)，6.54(dd，1H，J＝8.6，2.5Hz)，6.67(d，1H，J＝2.5Hz)，7.15(d，1H，J＝7.6Hz)，7.25-7.34(m，1H)7.36(d，1H，J＝8.6Hz)，8.13(s，1H)，8.36(s，1H)，8.37-8.50(m，1H)，10.57(s，1H)。MS(ESI)m/z 481，483(M+1)
+。
Method according to embodiment 2; From 7-(2; 5-two chloro-pyrimidine-4-base is amino)-2-methyl-2,3-dihydro-isoindole-1-ketone prepares following 7-(5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino)-2-methyl-2,3-dihydro-isoindole-1-ketone with corresponding aniline.
Method according to embodiment 2; From 7-(2; 5-two chloro-pyrimidine-4-base is amino)-2-ethyl-2,3-dihydro-isoindole-1-ketone prepares following 7-(5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino)-2-ethyl-2,3-xylylenimine-1-ketone with corresponding aniline:
Embodiment 7B:2-5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-BM (the selectable compound method of embodiment 7A)
In-5 ℃, [5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-(5.5g adds Et in 100mL THF suspension-s 12.1mmol) to phenylformic acid to 2-
3N (2.06mL, 14.8mmol) with the carbonochloridic acid isobutyl (1.7mL, 12.8mmol).After same temperature stirs 30 minutes, reaction mixture is continued to stir 1 hour under room temperature, in reaction mixture, add entry then.Filter and collect the gained deposition, and use water washing, drying under reduced pressure to obtain midbody (4.80g) (10.96mmol, 91%) into yellow solid.
1H NMR(400MHz，DMSO-d6，δ)：3.10-3.20(m，4H)，3.70-3.80(m，4H)，3.93(s，3H)，6.53(dd，1H，J＝9.08，2.0Hz)，6.70(d，1H，J＝2.0Hz)，7.49-7.4(m，1H)，7.67(d，1H，J＝8.56Hz)，7.89(s，1H)，7.85-7.95(m，1H)，8.23(d，1H，J＝9.08Hz)，8.26(d，1H，J＝8.56Hz)，12.60(s，1H)。
To the THF of 1M methylamine (560 μ l add the above-mentioned gained midbody of 82mg (0.187mmol) in solution 0.56mmol), drip then 1M NaHMDS THF (560 μ l, 0.56mmol) solution, reaction mixture stirred 10 minutes after, add the H of 5mL
2O also extracts with AcOEt.Use the brine wash organic layer, through dried over sodium sulfate, concentrating under reduced pressure, silica gel chromatography (hexane: AcOEt=1: 1-AcOEt), obtain target compound into faint yellow solid.Data such as embodiment 7A are said.
Adopt suitable starting substance and condition,, obtain following compounds through repeating aforesaid method.
According to the method for embodiment 2, prepare following 2-(5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino)-N-methyl-5-tetramethyleneimine-1-base-BM from 2-(5-chloro-2-methyl-pyrimidine-4-base is amino)-N-methyl-5-tetramethyleneimine-1-base-BM and corresponding aniline.
According to the method for embodiment 2, prepare following 2-[5-chloro-2-(4-fluoro-2-methoxyl group-phenyl amino)-pyrimidine-4-base is amino]-5-substituting group-N-methyl-BM from corresponding aniline.
Embodiment 16B
CDCl
3：3.01-3.10(m，4H)，3.63-3.68(m，4H)，3.89(s，3H)，6.59(ddd，1H)，6.66(dd，1H)，7.20-7.26(m，1H)，7.36(s，1H)，7.57-7.63(m，1H)，7.84(dd，1H)，8.09-8.14(m，1H)，8.14(s，1H)，8.53(d，1H)，9.30(s，1H)。
Embodiment 16C
CDCl
3：3.56-3.65(m，2H)，3.88(s，3H)，5.11-5.19(m，1H)，6.50-6.56(m，1H)，6.61-6.66(m，1H)，7.25-7.29(m，1H)，7.38(brs，1H)，7.58-7.62(m，1H)，7.97(dd，1H)，8.02-8.10(m，1H)，8.15(s，1H)，8.41(dd，1H)，8.81(s，1H)。
According to the method for embodiment 2, prepare following 2-(5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino)-5-fluoro-N-methyl-BM from 2-(2,5-two chloro-pyrimidine-4-base is amino)-5-fluoro-N-methyl-BM and corresponding aniline.
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-sec.-propyl-benzsulfamide from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-sec.-propyl-benzsulfamide and corresponding aniline.
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzsulfamide from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide and corresponding aniline.
| The embodiment numbering | Rx | Rf (solvent) or MS | NMR(400MHz)，δ(ppm) |
According to the method for embodiment 7A, get row 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-sec.-butyl-benzsulfamide ready from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-sec.-butyl-benzsulfamide and corresponding aniline self-control.
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-isobutyl--benzsulfamide from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-isobutyl--benzsulfamide and corresponding aniline.
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-(1-ethyl-propyl group)-benzsulfamide from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-(1-ethyl-propyl group)-benzsulfamide and corresponding aniline.
According to the method for embodiment 7A, prepare following 2-[5-chloro-2-(substituted phenyl amino)-pyrimidine-4-base is amino]-N-isobutyl--benzsulfamide from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-cyclobutyl-benzsulfamide and corresponding aniline.
| The embodiment numbering | Rx | Rf (solvent) or MS | NMR(400MHz)，δ(ppm) |
According to the method for embodiment 7A, prepare following 5-chloro-N from (2,5-two chloro-pyrimidine-4-yl)-[2-(propane-1-alkylsulfonyl)-phenyl]-amine and corresponding aniline
2-(substituted phenyl)-N
4-[2-(propane-1-alkylsulfonyl)-phenyl]-pyrimidine-2, the 4-diamines.
According to the method for embodiment 7A, prepare following 5-chloro-N from (2,5-two chloro-pyrimidine-4-yl)-[2-ethylsulfonyl-phenyl]-amine and corresponding aniline
2-(substituted phenyl)-N
4-[2-ethylsulfonyl-phenyl]-pyrimidine-2, the 4-diamines.
The HPLC condition
Post: YMC CombiScreen ODS-A (5um, 12nm), 50 * 4.6mm I.D.
Flow velocity: 2.0ml/min,
Elutriant: A) TFA/ water (0.1/100), B) TFA/ acetonitrile (0.1/100)
Gradient: 5-100%B (0-5min)
Detector: UV, 215nm
According to the method for embodiment 7A, prepare following 5-chloro-N from (2,5-two chloro-pyrimidine-4-yl)-[2-(propane-2-alkylsulfonyl)-phenyl]-amine and corresponding aniline
2-(substituted phenyl)-N
4-[2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-2, the 4-diamines.
| Embodiment compiles | MS | NMR(400MHz)，CDCl 3，δppm |
Embodiment 36 (midbody of the aniline on the left side)
The preparation of 36-1:2-amino-N-methyl-BM
Under room temperature, gradation adds 2N methylamine-THF (200mmol) of 100mL in 16.3g (100mmol) isatoic anhydride 100mL water.Reaction mixture was stirred 1 hour, extract with AcOEt then.Organic layer water and brine wash, Na
2SO
4Dry also concentrating under reduced pressure obtains the 2-amino-N-methyl-BM (92mmol, 92%) into the 13.79g expectation of colorless solid.
1H NMR(400MHz，CDCl
3，δ)：2.97(d，3H，J＝4.52Hz)，5.49(bs，1H)，6.07(bs，1H)，6.64(ddd，1H，J＝8.04，7.56，1.0Hz)，6.68(dd，1H，J＝8.32，1.0Hz)，7.20(ddd，1H，J＝8.32，7.56，1.52Hz)，7.29(dd，1H，J＝8.04，1.52Hz)。
36-2:2-(2,5-two chloro-pyrimidine-4-base is amino)-N-methyl-BM
In the DMF (300mL) of the 2-of 15.0g (99.8mmol) amino-N-methyl-BM solution, add 2,4, the 5-trichloropyrimidine (23.8g, 130mmol) and salt of wormwood (17.9g, 130mmol).Reaction mixture in 75 ℃ of stirrings 5 hours, is cooled to room temperature, and pours in the water (600mL).Filter and collect the gained deposition, use 50% CH then
3CN (200mL) solution washing, drying under reduced pressure (40 ℃, 10 hours) obtains being ivory white solid target compound 2-(2,5-two chloro-pyrimidine-4-base-amino)-N-methyl-BM (26.4g, 88.9mmol, 89%).
1H NMR(400MHz，DMSO-d6，δ)：2.81(d，3H，J＝4.52Hz)，7.22(dd，1H，J＝8.56，8.04Hz)，7.60(ddd，1H，J＝8.56，8.56，1.0Hz)，7.81(dd，1H，J＝8.04，1.0Hz)，8.48(s，1H)，8.52(d，1H，J＝8.56Hz)8.80-8.90(m，1H)，12.18(s，1H)。
According to aforesaid method, the preparation following compounds.
36-3:2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-methyl-BM
NMR(400MHz，DMSO-d6，δ)：2.81(d，3H)，7.23(ddd，1H，J＝7.54，7.54，1.0Hz)，7.59(ddd，1H，J＝7.93，8.06，1.52Hz)，7.79(dd，1H，J＝7.8，1.52Hz)，8.47(dd，1H J＝8.06，1.0Hz)，8.55(s，1H)，8.81-8.87(m，1H)，12.0(brs，1H)。Rf:0.46 (normal hexane: AcOEt=7: 3).
36-4:2-(2,5-two chloro-pyrimidine-4-base is amino)-N-ethyl-BM
NMR(400MHz，CDCl
3，δ)：1.28(t，d＝7.04，3H)，3.48-3.57(m，2H)，6.22(br.s，1H)，7.11-7.17(m，1H)，7.51(dd，J＝1.0，8.04，1H)，7.53-7.61(m，1H)，8.22(s，1H)，8.69-8.74(m，1H)，11.66(br.s，1H)。Rf:0.60 (hexane: AcOEt=1: 1).
The preparation of 36-5:2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide
((684mg, 3.0mmol) (dinethylformamide (10mL) suspension-s stirred under room temperature 23 hours the 4-dichloro pyrimidine for 559mg, N 3.0mmol) with 2-amino-N-methyl-benzsulfamide for 830mg, 5-bromo-2 6.0mmol) will to contain salt of wormwood.Add saturated aqueous ammonium chloride solution, mixture is poured in the water, wash secondary with ETHYLE ACETATE.Use the brine wash organic layer, concentrate through dried over sodium sulfate and vacuum-evaporation.Residue obtains the target compound into faint yellow solid through silica gel chromatography (normal hexane-ETHYLE ACETATE gradient elution).
1H-NMR (CDCl
3), δ (ppm): 2.67 (d, 3H), 4.79 (q, 1H), 7.26 (s, 1H), 7.29 (ddd, 1H), 7.66 (ddd, 1H), 7.95 (dd, 1H), 8.37 (s, 1H), 8.48 (d, 1H), 9.52 (s, 1H) .Rf (normal hexanes: ETHYLE ACETATE=10: 3): 0.33.
According to aforesaid method, the preparation following compounds.
36-6:2-(2,5-two chloro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide
1H-NMR(400MHz，CDCl
3，δ)；2.67(d，3H)，4.97-5.04(m，1H)，7.29(ddd，1H，J＝7.54，7.54，1.0Hz)，7.66(ddd，1H，J＝7.93，8.08，1.48Hz)，7.94(dd，1H，J＝8.04，1.52Hz)，8.24(s，1H)，8.51(dd，1H J＝8.06，1.0Hz)，9.64(brs，1H)。Rf:0.45 (normal hexane: AcOEt=4: 1).
36-7:2-(2,5-two chloro-pyrimidine-4-base is amino)-N-sec.-propyl-benzsulfamide
In 0 ℃, to 2-amino-N-sec.-propyl-benzsulfamide (16.1g, in DMI 75.1mmol) (150mL) solution gradation add sodium hydride (6.6g, 165.3mmol).After under the room temperature mixture being stirred 1 hour, add 2,4 in 0 ℃, the 5-trichloropyrimidine (20.7g, 112.7mmol).After further stirring 5 hours under the room temperature, with ethyl acetate extraction mixture 3 times.Use the brine wash organic layer, concentrate through dried over sodium sulfate and reduction vaporization.Residue is through silica gel chromatography (hexane-hexane: AcOEt=4: 1) be light brown solid target compound (10.2g, 38%).
1H-NMR(400MHz，CDCl
3，δ)；1.06(d，6H)，3.43-3.53(m，1H)，4.38(d，1H)，7.29(dd，1H)，7.66(dd，1H)，7.98(d，1H)，8.29(s，1H)，8.51(d，1H)，9.51(brs，1H)。Rf:0.45 (normal hexane: AcOEt=4: 1).
Prepare following compounds according to above-mentioned same method.
The preparation of 36-10:2-(2-chloro-5-nitro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide:
With 2, (1.94g, 10mmol) (1.86g 10mmol) is dissolved in CHCl to 4-two chloro-5-nitro-pyrimidines with 2-amino-N-methyl-benzsulfamide
3(30mL).Reaction mixture was heated 2 hours in 61 ℃.Evaporating solvent, residue obtains target compound through the ether washing.
Rf=0.5 (normal hexane: ETHYLE ACETATE=1: 1).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：2.67(d，3H)，4.6-4.7(m，2H)，7.41(t，1H)，7.7(t，1H)，8.04(d，1H)，8.15(d，1H)，9.21(s，1H)，11.2(s，1H)。
36-11: (2.5-two chloro-pyrimidine-4-yl)-[2-(propane-1-alkylsulfonyl)-phenyl]-amine
In 0 ℃, to 2-(propane-1-alkylsulfonyl)-phenyl amine (3.69g, N 18.5mmol), in N N (40mL) solution gradation add sodium hydride (1.48g, 37mmol).Stir the back and add 2,4, and the 5-trichloropyrimidine (2.1mL, 18.5mmol).Mixture, was further stirred 7 hours under room temperature after 30 minutes in 0 ℃ of stirring.After adding saturated aqueous ammonium chloride solution, mixture is poured in the water, and with ethyl acetate extraction 2 times.Organic layer is used brine wash, concentrates through dried over sodium sulfate and vacuum-evaporation.Residue obtains the target compound into colorless solid through silica gel chromatography (normal hexane-ETHYLE ACETATE gradient elution).
1H-NMR(CDCl
3)，δ(ppm)：0.99(t，3H)，1.77(d，2H)，3.07-3.11(m，2H)，7.26(s，1H)，7.32(ddd，1H)，7.73(ddd，1H)，7.95(dd，1H)，8.31(s，1H)，8.61(dd，1H)，9.94(bs，1H)。Rf (normal hexane: ETHYLE ACETATE=3: 1): 0.63.
According to aforesaid method, the preparation following compounds.
Embodiment 36-16
Non-substituted amine available from commercial sources synthetic:
3-is amino-4 '-preparation of methoxyl group-4-methyl diphenyl
To 4-p-methoxy-phenyl-boric acid (500mg; 3.29mmol) toluene (5.2mL) and ethanol (1.3mL) solution in add salt of wormwood (910mg; 6.58mmol), four (triphenyl phosphorus)-palladium (228.1mg; 0.099mmol) and 4-bromo-1-methyl-2-oil of mirbane (711mg, 3.29mmol), and in 100 ℃ of stirrings 7 hours.Mixture is poured in the water and with ethyl acetate extraction 2 times.Organic layer is used water washing, uses brine wash then, and dried over mgso and vacuum-evaporation concentrate.Residue through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1), obtain into 4 of yellow solid '-methoxyl group-4-methyl-3-nitro-biphenyl.
1H-NMR(δ，ppm)：2.62(s，3H)，3.86(s，3H)，7.02-6.98(m，2H)，7.37(d，1H)，7.54(dd，2H)，7.68(dd，1H)，8.18(d，1H)。Rf (hexane: ETHYLE ACETATE=3: 1): 0.40.
In hydrogen, with 4 '-(630mg, 2.95mmol) (63mg, methyl alcohol 0.059mmol) (6mL) suspension-s stirred 12 hours methoxyl group-4-methyl-3-nitro biphenyl with 10% palladium charcoal.Remove by filter palladium catalyst,, obtain target compound the evaporation of gained solution for vacuum.
1H-NMR(δ，ppm)：2.20(s，3H)，3.84(s，3H)，6.87(d，1H)，6.89(dd，1H)，6.95(d，2H)，7.09(d，1H)，7.48(d，2H)。Rf (normal hexane: ETHYLE ACETATE=1: 1): 0.50.
The preparation of 4-(3-amino-4-methyl benzoyl)-piperazine-l-t-butyl formate
To 4-methyl-3-nitro-phenylformic acid (300mg; 2.76mmol), N-butoxy carbonyl-piperazine (340mg; 1.83mmol) DMF (3.0mL) solution in add triethylamine (300 μ L, 3.59mmol), TBTU (800mg, 2.49mmol) and HOAt (270.5mg; 1.99mmol), and under room temperature, stirred 24 hours.Mixture is poured in the water and with ethyl acetate extraction 2 times.Organic layer is used water washing, uses brine wash then, and dried over mgso and vacuum-evaporation concentrate.Residue is through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1), obtain 4-(the 4-methyl-3-nitro benzoyl-)-piperazine-1-t-butyl formate into colorless solid.
1H-NMR(δ，ppm)：1.47(s，9H)，2.64(s，3H)，3.28-3.88(m，8H)，7.42(d，1H)，7.56(dd，1H)，8.03(d，1H)。Rf (hexane: ETHYLE ACETATE=10: 1): 0.13.
In methanol solution, obtain target compound through hydrogen reduction in the presence of 10% palladium charcoal.
The preparation of 4-(3-amino-4-aminomethyl phenyl)-morpholine
To 4-bromo-1-methyl-2-oil of mirbane (225mg; 1.04mmol), morpholine (125 μ L; 1.25mmol) and cesium carbonate (474.4mg, add in toluene solution 1.46mmol) palladium diacetate (31.2mg, 0.139mmol) and 2-(two-tertiary butyl phosphino-) biphenyl (125mg; 0.403mmol), stirred 5 hours in 100 ℃.After the cooling, remove insolubles through filtering reactant.Filtrating is poured in the water and with ethyl acetate extraction 2 times.Organic layer is used water washing, uses brine wash then, and dried over mgso and vacuum-evaporation concentrate.Residue is through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1), obtain 4-(4-methyl-3-nitro the phenyl)-morpholine into yellow solid.
1H-NMR(δ，ppm)：2.50(s，3H)，3.17-3.19(m，4H)，3.86-3.88(m，4H)，7.04(dd，1H)，7.21(d，1H)，7.47(d，1H)。Rf (hexane: ETHYLE ACETATE=5: 1): 0.20.
In methanol solution,, obtain target compound through in the presence of 10% palladium charcoal, carrying out with hydrogen reduction.
Embodiment 37: non-substituted amine available from commercial sources synthetic:
37-1:1-(3-methoxyl group-4-nitro-phenyl)-piperidines-4-alcohol
To piperidines-4-alcohol (2.79g, 28mmol) with salt of wormwood (3.88g, N 28mmol), add in dinethylformamide (40mL) suspension-s 4-fluoro-2-methoxyl group-1-nitro-benzene (4.0g, 23mmol), and stirring 24 hours under room temperature.Mixture is poured in the water, filtered collecting precipitation.The gained solid obtains 1-(3-methoxyl group-4-nitro-phenyl)-piperidines-4-alcohol (5.23g) into yellow solid in 50 ℃ of vacuum-dryings, and yield is 89%.
1H-NMR(400MHz，CDCl
3，δppm)：1.54(d，1H)，1.62-1.71(m，2H)，1.98-2.04(m，2H)，3.22(ddd，4H)，3.73-3.80(m，2H)，3.95(s，3H)，3.98-4.02(m，1H)，6.33(d，1H)，6.43(dd，1H)，8.00(d，1H)。
Adopt suitable starting substance and condition,, obtain following compounds through repeating aforesaid method.
| The embodiment numbering | Rx | Appraising datum |
The preparation of 38:1-[4-(4-methoxyl group-3-nitro-phenyl)-piperazine-1-yl]-ethyl ketone
To 5-bromo-1-methoxyl group-2-oil of mirbane (300mg; 1.29mmol) dioxane solution in add 1-ethanoyl piperazine (400mg; 3.12mmol), cesium carbonate (1.0g, 3.07mmol), palladium diacetate (29.0mg, 0.129mmol) and 2-(di-t-butyl phosphorus base) biphenyl (77mg; 0.258mmol), and in 100 ℃ of stirrings 8 hours.After the cooling, filtering mixt is removed insolubles.Filtrating is poured in the water and with ethyl acetate extraction 2 times.Organic layer is used water washing, uses brine wash then, and dried over mgso and vacuum-evaporation concentrate.Residue is through silica gel chromatography (normal hexane: the ETHYLE ACETATE gradient), obtain 1-[4-(4-methoxyl group-3-nitro-phenyl)-piperazine-1-yl]-ethyl ketone (319mg, 44%) into yellow solid.
1H-NMR(400MHz，CDCl
3，δppm)：2.14(s，3H)，3.63(ddd，4H)，3.63(t，2H)，3.78(t，2H)，3.92(s，3H)，7.03(d，1H)，7.12(d，1H)，7.41(d，1H)。Rf (ETHYLE ACETATE): 0.18
The preparation of 39:1-(3-methoxyl group-4-nitro-phenyl)-piperidin-4-one-
To hydrochloric acid 4-piperidone monohydrate (10.0g, add in DMF 0.065mol) (80mL) solution 4-fluoro-2-methoxyl group-1-nitro-benzene (10.0g, 0.058mol) with salt of wormwood (20.2g), and under 70 ℃ with said mixture stirring 20 hours.After the filtration, filtrating is poured in the water (about 300mL), filter and collect the gained deposition, then several times, obtain target compound (8.98g), yield 61% into orange solids with water washing.
1H-NMR(400MHz，CDCl
3，δ)：2.65-2.62(4H，m)，3.81-3.78(4H，m)，3.98(3H，s)，6.34(1H，d)，6.45(1H，dd)，8.05(1H，d)。
The preparation of 40:1-[1-(3-methoxyl group-4-nitro-phenyl)-piperidin-4-yl]-4-methyl-piperazine
(4.96g, (2.7ml 0.024mol), and stirs said mixture under room temperature to add N methyl piperazine in ethylene dichloride 0.020mol) (50ml) solution to 1-(3-methoxyl group-4-nitro-phenyl)-piperidin-4-one-in 0 ℃.After 4 hours, (5.04g 0.024mol), continued to stir the mixture 24 hours under room temperature then to add sodium triacetoxy borohydride.Behind 0 ℃ of adding 1N sodium hydroxide, with ethylene dichloride extraction 3 times.Merge organic layer also with 1N sodium-chlor extraction 3 times.With 2N sodium hydroxide alkalization water layer, and with dichloromethane extraction 3 times.Use the brine wash organic layer, through dried over sodium sulfate and vacuum-evaporation, obtain the target compound (6.04g) into yellow solid, yield is 91%.
1H-NMR(400MHz，CDCl
3，δ)：1.70-1.57(2H，m)，2.03-1.93(2H，m)，2.29(3H，s)，2.55-2.38(5H，m)，2.70-2.56(4H，m)，2.97(2H，ddd)，3.97-3.92(2H，m)，3.95(3H，s)，6.31(1H，d，)，6.42(1H，dd)，8.00(1H，d)。
The preparation of 41:4 '-methoxyl group-4-methyl-3-nitro-biphenyl
To 4-p-methoxy-phenyl-boric acid (500mg; 3.29mmol) toluene (5.2mL) and ethanol (1.3mL) solution in add salt of wormwood (910mg; 6.58mmol), four (triphenyl phosphorus)-palladium (228.1mg; 0.099mmol) and 4-bromo-1-methyl-2-oil of mirbane (711mg, 3.29mmol), and in 100 ℃ of stirrings 7 hours.Mixture is poured in the water, with ethyl acetate extraction 2 times.Organic layer is used water washing, uses brine wash then, and dried over mgso and vacuum-evaporation concentrate.Residue through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1), obtain into 4 of yellow solid '-methoxyl group-4-methyl-3-nitro-biphenyl (630mg, 79%).
1H-NMR(400MHz，CDCl
3，δppm)：2.62(s，3H)，3.86(s，3H)，7.02-6.98(m，2H)，7.37(d，1H)，7.54(dd，2H)，7.68(dd，1H)，8.18(d，1H)。Rf (hexane: ETHYLE ACETATE=3: 1): 0.40.
42:4-(2-oxyethyl group-oxyethyl group)-1-(3-methoxyl group-4-nitro-phenyl)-piperidines
To 1-(3-methoxyl group-4-nitro-phenyl)-piperidines-4-alcohol (300mg, N 1.2mmol), add in dinethylformamide (3.0mL) solution sodium hydride (1.52g, 3.8mmol).After the stirring, (150 μ l 1.6mmol), and continue mixture down to stir 15 hours in 70 ℃ to add 2-brooethyl methyl ether.After adding saturated ammonium chloride, mixture is poured in the water and with ethyl acetate extraction 2 times.Use the brine wash organic layer, concentrate through dried over sodium sulfate and vacuum-evaporation.Residue obtains 4-(2-methoxyl group-oxyethyl group)-1-(3-methoxyl group-4-nitro-phenyl)-piperidines (111mg, 29%) into yellow oil through silica gel chromatography (normal hexane-ETHYLE ACETATE gradient elution).
1H-NMR(400MHz，CDCl
3，δppm)：1.52(t，3H)，1.95-2.00(m，2H)，1.70-1.79(m，2H)，3.23(ddd，2H)，3.58-3.64(m，2H)，3.65-3.68(m，2H)，3.64-3.72(m，2H)，3.95(s，3H)，6.31(d，1H)，6.42(dd，1H)，8.00(d，1H)。Rf0.53 (normal hexane: AcOEt=1: 1).
According to aforesaid method, adopt suitable alkyl halide, the preparation following compounds.
Embodiment 43
2-methoxyl group-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl amine
4-(3-methoxyl group-4-nitro-phenoxy)-1-methyl-piperidines
Under room temperature to 4-fluoro-2-methoxyl group-1-nitro-benzene (10.3g, add in toluene 60mmol) (50mL) and 25%KOH aq. (50mL) solution 4-hydroxyl-1-methyl piperidine (13.8g, 120mmol) with four-n-butyl brometo de amonio (3.87g, 12mmol).Mixture was heated 1 day in 60 ℃.Reaction mixture is cooled to room temperature and pours in the frozen water, with ethyl acetate extraction 2 times.Use dil. hydrochloric acid and brine wash organic layer successively, concentrate, obtain the bullion compound (13.4g) of quantitative yield through dried over sodium sulfate and vacuum-evaporation.
Rf=0.22 (methyl alcohol: methylene dichloride=1: 4).
1H-NMR(400MHz，CDCl
3，δppm)：1.84-1.92(m，2H)，2.0-2.1(m，2H)，2.3-2.4(m，2H)，2.33(s，3H)，2.65-2.75(m，2H)，3.94(s，3H)，4.39-4.46(m，1H)，6.49(dd，1H)，6.99(d，1H)，6.54(d，1H)，7.99(d，1H)。
Embodiment: 44
2-methoxyl group-4-(2-morpholine-4-base-oxyethyl group)-phenyl amine
3-methoxyl group-4-nitro-phenol
In 0 ℃ to 3-fluoro-4-nitro-phenol (15.7g, add in THF 100mmol) (300mL) solution 30%KOMe methanol solution (49mL, 210mmol).Reaction mixture slowly is heated to backflow 18 hours.
4-[2-(3-methoxyl group-4-nitro-phenoxy)-ethyl]-morpholine
Under room temperature, to 3-methoxyl group-4-nitro-phenol (1.69g, add in DMF 10mmol) (25mL) solution 4-(2-chloroethyl) morpholine hydrochloride (2.05g, 11mmol), K
2CO
3(1.52g, 11mmol), KI (332mg, 2mmol).Mixture slowly is heated to backflow 4 hours.Reaction mixture is cooled to room temperature and water termination reaction.The gained mixture is with ethyl acetate extraction 2 times, then with organic layer water successively and brine wash, through dried over sodium sulfate, filters and vacuum-evaporation concentrates, and obtains bullion compound (2.55g), yield 90%.
Rf=0.11 (only using AcOEt).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：2.56-2.61(m，4H)，2.83(t，
Reaction mixture is cooled to room temperature and cools off with the 1N HCl aqueous solution at leisure in 0 ℃.The gained mixture is used brine wash with organic layer then continuously with ethyl acetate extraction 2 times, through dried over sodium sulfate, filters and vacuum-evaporation concentrates, and obtains bullion compound (15.9g), and yield is 94%.
Rf=0.22 (methyl alcohol: methylene dichloride=1: 4).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：3.95(s，3H)，5.49(s，1H)，6.44(dd，1H，J＝8.8，2.52Hz)，6.54(d，1H，J＝2.52Hz)，7.96(d，1H J＝8.6Hz)。
3.72-3.76(m，4H)，3.94(s，3H)，4.18(t，2H)，6.51(dd，1H，J＝9.08，2.52Hz)，6.56(d，1H，J＝2.48Hz)，8.00(d，1H J＝9.08Hz).
2H)，
Embodiment 45:2-methoxyl group-4-(2-morpholine-4-base-oxyethyl group)-phenyl amine
Acetate 4-methoxyl group-3-nitro-phenylester
(12.4g adds Ac in AcOH 100mmol) (50mL) solution to the 4-methoxyphenol under room temperature
2O (50mL).Mixture slowly is heated to backflow 1.5 hours.Reaction mixture is cooled to room temperature and slowly adds dense HNO in 0 ℃
3(d=1.38,10mL).Mixture was heated 1.5 hours in 55 ℃.Reaction mixture is cooled to room temperature, and in 0 ℃ of water termination reaction.The gained solid filters with B, obtains bullion compound (16.0g), and yield is 76%.
Rf=0.59 (AcOEt: normal hexane=3: 7).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：2.31(s，3H)，3.96(s，3H)，7.08(d，1H，J＝9.04Hz)，7.31(dd，1H，J＝9.04，3.04Hz)，7.96(d，1H J＝3.04Hz)。
4-methoxyl group-3-nitro-phenol
(1.06g adds 1N NaOH aq (5.5mL) in EtOH 5mmol) (20mL) solution to acetate 4-methoxyl group-3-nitro-phenylester in 0 ℃.Mixture was stirred under room temperature 2 hours.With reaction mixture with AcOH cooling and with ethyl acetate extraction 2 times.Organic layer is water and brine wash successively, and through dried over sodium sulfate, filtration and vacuum-evaporation concentrate, and obtain the bullion compound (840mg) of quantitative yield.
Rf=0.59 (AcOEt: normal hexane=3: 7).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：3.91(s，3H)，6.99(d，1H，J＝9.04Hz)，7.17(dd，1H，J＝9.04，3.00Hz)，7.38(d，1H J＝3.04Hz)。
4-[2-(4-methoxyl group-3-nitro-phenoxy)-ethyl]-morpholine
Under room temperature to 4-methoxyl group-3-nitrophenols (1.01g, add in DMF 6mmol) (15mL) solution 4-(2-chloroethyl) morpholine hydrochloride (1.34g, 7.2mmol), K
2CO
3(2.49g, 18mmol), KI (2..9g, 18mmol).Mixture was heated 4 hours in 80 ℃.Reaction mixture is cooled to room temperature, and with saturated NH
4Cl aqueous solution termination reaction.Reaction mixture is with ethyl acetate extraction 2 times, and organic layer water and salt solution wash successively then, through dried over sodium sulfate, filters and vacuum-evaporation concentrates, and obtains the bullion compound (1.70g) of quantitative yield.Rf=0.14 (only using AcOEto).
1H-NMR(400MHz，DMSO，δ，ppm)：2.36-2.51(m，4H)，2.67(t，J＝5.5，2H)，3.52-3.60(m，4H)，3.86(s，3H)，4.11(t，J＝6.0，2H)，7.25-7.29(m，2H)，7.46-7.49(m，1H)。
The preparation of 2-methoxyl group-4-(1-methyl-piperidin-4-yl oxygen base)-phenyl amine:
Under nitrogen environment, (3.0g adds 5% palladium charcoal (300mg) in ethanol 11.3mmol) (50mL) solution to 4-(3-methoxyl group-4-nitro-phenoxy)-1-methyl-piperidines.Reaction vessel is equipped with air bag, connects to charge into hydrogen, finds time to carry out in hydrogen environment up to reacting completely for three times.With the reactant stirred overnight.Reaction mixture is filtered through Celite pad, use methanol wash.The vacuum concentration of will filtrating obtains 2-methoxyl group-4-(1-methyl-piperidin-4-yl oxygen the base)-phenyl amine (2.7g) of quantitative yield.
Rf=0.41 (methyl alcohol: methylene dichloride=1: 1).
1H-NMR(400MHz，CDCl
3)，δ(ppm)：1.75-1.86(m，2H)，1.92-2.05(m，2H)，2.2-2.32(m，2H)，2.30(s，3H)，3.4-3.7(brs，2H)，3.82(s，3H)，4.1-4.2(m，1H)，6.37(dd，1H)，6.46(d，1H)，6.61(d，1H)。
Adopt suitable starting substance and condition,, obtain following compounds through repeating aforesaid method.
The preparation of 47:4-(3-amino-4-methyl-benzyl)-piperazine-1-t-butyl formate
To 4-methyl-3-nitro-phenylformic acid (300mg; 2.76mmol), N-butoxy carbonyl-piperazine (340mg; 1.83mmol) DMF (3.0ml) solution in add triethylamine (300 μ l, 3.59mmol), TBTU (800mg, 2.49mmol) and HOAt (270.5mg; 1.99mmol), under room temperature, stirred 24 hours.Mixture is inclined to water, with twice of ethyl acetate extraction.Water and salt solution wash the organic layer of merging successively, through dried over mgso, and vacuum-evaporation.Residue is through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1), obtain 4-(the 4-methyl-3-nitro benzoyl-)-piperazine-1-t-butyl formate into colorless solid.
1H-NMR(δ，ppm)：1.47(s，9H)，2.64(s，3H)，3.88-3.28(m，8H)，7.42(d，1H)，7.56(dd，1H)，8.03(d，1H)。Rf (hexane: ETHYLE ACETATE=10: 1): 0.13.
In methanol solution, in the presence of 10% palladium charcoal, obtain target compound through hydrogen reduction.
The preparation of 48:4-(3-amino-4-aminomethyl phenyl)-morpholine
To 4-bromo-1-methyl-2-oil of mirbane (225mg; 1.04mmol), morpholine (125 μ l; 1.25mmol) and cesium carbonate (474.4mg, add in toluene suspension 1.46mmol) palladium diacetate (31.2mg, 0.139mmol) and 2-(di-t-butyl phosphino-) biphenyl (135mg; 0.403mmol), stirred 5 hours in 100 ℃.After the cooling, filtering mixt is removed insolubles.Filtrating is inclined to water, with twice of ethyl acetate extraction.Water and salt solution wash organic layer successively, through dried over mgso, and vacuum-evaporation.Residue is through silica gel chromatography (normal hexane: ETHYLE ACETATE=5: 1), obtain 4-(4-methyl-3-nitro the phenyl)-morpholine into yellow solid.
1H-NMR(δ，ppm)：2.50(s，3H)，3.19-3.17(m，4H)，3.88-3.86(m，4H)，7.04(dd，1H)，7.21(d，1H)，7.47(d，1H)。Rf (hexane: ETHYLE ACETATE=5: 1): 0.20.
In methanol solution, in the presence of 10% palladium charcoal, obtain target compound through hydrogen reduction.
49:2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-phenylformic acid
(1.9g is 6.73mmol) with 6.0ml 1N hydrogenchloride (6.0mmol) ethanolic soln in the 15ml acetic acid soln of 1.0g (3.37mmol) 2-(2,5-two chloro-pyrimidine-4-base is amino)-N-methyl-BM, to add 2-methoxyl group-4-morpholinyl aniline dihydrochloride.In 120 ℃ of stirred reaction mixtures 16 hours, be cooled to room temperature, add sodium bicarbonate aqueous solution pH is transferred to 5-6.Filter and collect deposition and the drying under reduced pressure that produces, obtain being ivory white solid 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-phenylformic acid (970mg, 2.12mmol, 63%).
NMR(400MHz，DMSO-d6，δ)：3.10-3.20(m，4H)，3.78(s，3H)，3.70-3.80(m，4H)，6.52(dd，1H，J＝8.56，2.52Hz)，6.67(d，1H，J＝2.52Hz)，7.08(dd，1H，J＝8.04，8.04Hz)，7.39(d，1H，J＝8.56Hz)，7.35-7.45(m，1H)，7.99(dd，1H，J＝8.04，1.52Hz)，8.14(s，1H)，8.28(s，1H)，8.70-8.80(m，1H)。
Embodiment 50: the preparation as follows of sulphonamide part:
The preparation of 2-amino-4-chloro-5-methyl-benzene sulfonyl chloride
To 2-amino-5-chloro-4-methyl-Phenylsulfonic acid (3.0g, add in ethylene dichloride 1.35mmol) (10mL) solution SULPHURYL CHLORIDE (4.4mL, 3.83mmol), and in 60 ℃ of stirrings.After 1 hour, add sulphinyl chlorine (1.3mL), continued to stir the mixture 7 hours in 100 ℃.Mixture is poured in the frozen water and with extracted with diethyl ether 3 times.Organic layer is used water washing, uses brine wash then, concentrates through dried over sodium sulfate and vacuum-evaporation.
1H-NMR(δ，ppm)：2.35(s，3H)，6.68(s，1H)，7.75(s，1H)。
This substituted SULPHURYL CHLORIDE and suitable amine reaction.As when reacting, form 2-amino-5-chloro-4, the N-dimethyl benzene sulfonamide with methylamine.
Embodiment 51
2-[5-bromo-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N, the preparation of N-dimethyl--benzsulfamide
To 2-[5-bromo-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzsulfamide (Ex3-19) (1.0g; 1.82mmol) DMF (10mL) solution in add salt of wormwood (300mg; 2.17mmol) and methyl iodide (116 μ l, 1.86mmol).Gained suspension-s was stirred 1 hour in 50 ℃.In reaction mixture, add entry, and with ethyl acetate extraction 3 times.Organic layer is used water washing, through dried over sodium sulfate and vacuum concentration.Residue obtains target compound (728mg, yield 71%) through aluminum oxide column chromatography purifying (AcOEt).
NMR(400MHz，CDCl
3，δ)：2.74((s，6H)，3.05-3.18(m，4H)，3.84-3.93(m，4H)，3.88(s，3H)，6.43(dd，1H)，6.53(d，1H)，7.24(m，1H)，7.31(s，1H)，7.56(m，1H)，7.87(dd，1H)，8.05(d，1H)，8.21(s，1H)，8.49(d，1H)，8.49(d，1H)，9.27(s，1H)。Rf:0.23 (AcOEt: hexane=1: 1).
Embodiment 52
2-[5-bromo-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-5-fluoro-N-methyl-benzsulfamide
7-fluoro-1,1-dioxo-1,4-dihydro-2H-1 λ
6The preparation of-benzo [1,2,4] thiadiazine-3-ketone
(1.2mL, (1.0g 8.97mmol), and stirs reaction mixture 30 minutes to drip the 4-fluoroaniline in nitroethane 13.5mmol) (10mL) solution to chloro sulfonyl isocyanate in 0 ℃.(1.3g 9.87mmol), and stirs reaction mixture 1 hour in 100 ℃ in solution, to add aluminum chloride in 0 ℃.After being cooled to room temperature, add entry and with ethyl acetate extraction 2 times.Organic layer is used brine wash, through dried over sodium sulfate and concentrating under reduced pressure.The gained solid is collected and is washed with ether through filtering, and obtains light gray solid (803.9mg, 41%).
NMR(400MHz，DMSO-d6，δ)：7.22-7.28(m，1H)，7.45-7.57(m，1H)，7.60(m，1H)，11.15-11.30(m，1H)。Rf：0.43(MeOH∶AcOEt＝1∶5)。
7-fluoro-2-methyl isophthalic acid, 1-oxo-1,4-dihydro-2H-1 λ
6The preparation of-benzo [1,2,4] thiadiazine-3-ketone
To 7-fluoro-1,1-dioxy-1,4-dihydro-2H-1-λ
6-benzo [1,2,4] thiadiazine-3-ketone (5.19g, add successively in DMF 24.0mmol) (50mL) solution sodium hydride (1.04g, 26.0mmol) and methyl iodide (1.5mL 24.0mmol), stirs reaction mixture 1 hour in 70 ℃.After being cooled to room temperature, mixture is poured in the water, filtered collecting precipitation and water and hexane and wash successively, obtain light gray solid 5.38g, 94%).
NMR(400MHz，DMSO-d6，δ)：3.32(s，3H)，7.44(dd，1H)，7.75(ddd，1H)，7.94(dd，1H)。Rf (MeOH: AcOEt=1: 5): 0.21.Rf:0.39 (hexane: AcOEt=1: 1).
The preparation of 2-amino-5-fluoro-N-methyl-benzsulfamide
With the 7-fluoro-2-methyl isophthalic acid of 6.79g, 1-dioxo-1,4-dihydro-2H-1 λ
6-benzo [1,2,4] thiadiazine-3-ketone (29.5mmol) is dissolved in 20% aqueous sodium hydroxide solution, and gained solution was stirred 13.5 hours in 100 ℃.Reaction mixture is cooled to room temperature and pours in the water.The 5M HCI aqueous solution that adds 78mL filters collecting precipitation, obtains lavender solid (3.96g, 65%) with water washing.
NMR(400MHz，CDCl
3，δ)：2.60(d，3H)，4.55-4.82(m，3H)，6.74(dd，1H)，7.05-7.12(m，1H)，7.45(dd，1H)。Rf:0.41 (hexane: AcOEt=1: 1).
2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-5-fluoro-N-methyl-benzsulfamide
According to the said method of Embodiment B, carry out the reaction of pyrimidine and 2-amino-5-fluoro-N-methyl-benzsulfamide.
NMR(400MHz，CDCl
3，δ)：2.67(d，3H)，4.56(m，1H)，7.36-7.5(m，1H)，7.68(dd，1H)，8.39(s，1H)，8.42(dd，1H)，9.26(s，1H)。Rf 0.59 (hexane: AcOEt=1: 1).
2-[5-bromo-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-5-fluoro-N-methyl-benzsulfamide
According to the described method of embodiment A, substituted aniline is introduced.
NMR(400MHz，CDCl
3，δ)：2.65(d，3H)，3.09-3.16(m，4H)，3.87(s，3H)，4.50(q，1H)，6.41(dd，1H)，6.52(d，1H)，7.25-7.33(m，2H)，7.69(dd，1H)，7.95(d，1H)，8.20(s，1H)，8.37(dd，1H)，8.70(s，1H)。Rf 0.30 (hexane: AcOEt=1: 1).
Embodiment 53:
Embodiment 54: the assay determination of not celliferous ZAP-70 kinases
Shift (FRET) according to the time resolved fluorescence resonance energy and carry out the analysis of ZAP-70 kinases.Under room temperature, in the Vestolen PP 7052 test tube of silication, with 80nM ZAP-70 with 80nM Lck (lymph T cell protein tyrosine kinase enzyme) and 4 μ M ATP at ZAP-70 kinase buffer liquid (20mMTris, pH7.5,10 μ M Na
3VO
4, 1mM DTT, 1mM MnCl
2, 0.01% BSA, 0.05% polysorbas20) in incubation 1 hour.Then, bringing Selection In property Lck suppressor factor PP2 (the 1-tertiary butyl-3-(4-chloro-phenyl)-1H-pyrazolo [3,4-d] pyrimidine-4-base amine; Alexis Biochemicals) (ultimate density is 1.2 μ M), and continued incubation 10 minutes.The above-mentioned solution of 10 μ L and the serial dilutions of biotinylated peptide LAT-11 of 10 μ L (substrate, 1 μ M) and 20 μ l suppressor factor are mixed, and incubation is 4 hours under room temperature.Make the kinases termination reaction with 10 μ L 10mM EDTA at the solution that detects in the damping fluid (20mM Tris, pH 7.5,0.01%BSA, 0.05% polysorbas20).The anti-phosphotyrosine antibody (Eu-PT66, final concentration are 0.125nM) and the solution of 50 μ l streptavidin-allophycocyanins (SA-APC, final concentration are 40nM) in detecting damping fluid that add 50 μ l europium marks., be in Victor 2Multilabel Counter (Wallae) in 665nm and go up mensuration fluorescence after 1 hour in incubation under the room temperature.Under the situation that does not add given the test agent and ATP, measure background value (low contrast (low control)), and from all values, deduct.The signal that under the situation that does not have given the test agent, obtains is as 100% (high contrast (high control)).Exist the inhibition that obtains under the test-compound situation to represent with respect to the per-cent of height contrast.Obtain to produce the concentration (IC of 50% inhibiting test-compound from dose-response curve
50).In this is measured, the IC of compound of the present invention
50At 10nM-2 μ M, preferred 10nM-100nM.
Obtain reorganization ZAP-70 kinases by following method: increase through in Jurkat cDNA library, will the encode nucleic acid (GenBank#L05148) of total length people ZAP-70 of RT-PCR technology; And clone in pBluescript KS carrier (Stratagene; California, USA) in.Confirm the verity of ZAP-70cDNA insert through the complete sequence analysis.Then this donor plasmid is used to make up the recombinant baculovirus transfer vector, (Pharmingen, California USA), have terminal six Histidines (hexahistidine) mark of N-to this carrier in addition based on plasmid pVL1392.With AcNPV viral DNA cotransfection; Obtain 10 viral coniviums of independence through plaque purification technique (plaque-purification) then, amplification is in a small amount adopted to derive from commercial anti--ZAP-70 antibody (Clone 2F3.1 subsequently; Upstate Biotechnology; Lake Placid, NY, USA) expression through western blot analysis reorganization ZAP-70.Further, prepare titrating viral storing solution then to the amplification of a positive reorganization bacterial plaque, under certain optimal condition, be used for infecting the Sf9 cell that is grown in serum-free SF900II substratum (Life Technologies, Basel, Switzerland).Through affinity chromatography, (Switzerland) lysate of the Sf9 cell of self-infection separates ZAP-70 albumen for Qiagen, Basel on the Ni-NTA post.
The ZAP-70 of the His mark of reorganization also can derive from PanVera LLC, Madison, Wisconsin, USA.
LAT-11 (joint of t cell activation):, be prepared in the biotinylated peptide LAT-11 (Biotin-EEGAPDYENLQELN) that is used as substrate in the analysis of ZAP-70 kinases through synthesizing similar methods with known peptide.Adopt 20% DMF solution of piperidines, with Fmoc-Asn (Trt)-oxygen ylmethyl-4-phenoxymethyl-the N-α Fmoc group of (PS-1%-Vinylstyrene) splits and removes altogether, Ash content is about 0.5mmol/g.With the DMF solution of DIPCDI and HOBt, each amino four normal Fmoc-amino acid of on its side chain, protecting [Asp (OtBu), Glu (OtBu), Asn (Trt), Gin (Trt) and Tyr (tBu)] is carried out coupling.After the peptide chain assembling is accomplished; As previously mentioned, remove terminal Fmoc-blocking group, then in the DMF of DIPCDI and HOBt solution with piperidines DMF solution; Adopt four normal reagent that L (+)-biotinylated-hexosamine is coupled on the terminal amino group group, at room temperature carried out 4 days.On resinous substrates, peptide is separated, in room temperature following 2 hours, adopt the reagent of the TFA that contains 5% dodecyl methyl sulfide and 5% water, all side chain protected groups are removed simultaneously.Remove by filter resin particle, with the TFA washing, the ether that adds the 10-20 volume is precipitated out product in the filtrating that merges, with ether washing and dry.On C-18 macroporous silica gel post, adopt 2% phosphate aqueous solution gradient elution of acetonitrile, through chromatogram purified product.The level branch that collection contains the thing that isozygotys filters through anionite-exchange resin (Biorad, AG4-X4 acetate form), and freeze-drying obtains target compound.
MS：1958.0(M-H)
-1
Embodiment 56: no anchorage dependence growth of tumour cell is analyzed
With mouse breast cancer 4T1 cell (5 * 10
3) the 100 μ l that are tiled in the ultralow adhering sheet in 96 holes (Ultra lowAttachment plates) (#3474, Corning Inc.) contain in the DulbeccoShi improvement eagle substratum of 10% FBS.With cell cultures 2 hours, adding with the final concentration was the suppressor factor of 0.1%DMSO as the various concentration of solvent.After 48 hours, measure the cell growing state with cell counting box-8 (WakoPure Chemical), this mensuration adopts water-soluble tetrazolium WST8 to carry out.In each hole, add 20 μ l reagent, cell was cultivated 2 hours again.Measure optical density(OD) in the 450nm place.Measure and produce 50% inhibiting compound concentrations.
Embodiment 59: to the external activity of bare mouse different species transplantation model
With female or male BALB/c nude mice (age in 5-8 week, Charles River Japan, Inc., Yokohama Japan) raises down in aseptic condition, arbitrarily drinks water and takes food.Through anaesthetizing (Abbott Japan Co. at Forene
; Ltd.; Tokyo, Japan) (human epithelial cell is MIA PaCa-2 to subcutaneous injection of tumor cells under a mouse left side or the right rib; Europe cell culture preservation center (EuropeanCollection of Cell Cultures) (ECACC), Salisbury, Wiltshire, UK, catalog number (Cat.No.) 85062806; Derive from 65 years old male white clone; Undifferentiated human pancreatic cancer cell), thus induced tumor.When the average-volume of tumour reaches about 100mm
3The time, begin tumour to be treated with test-compound.Through measuring two length between the Z-axis, measure tumor growth twice weekly, and the 1st day mensuration after treating the last time once.According to the method for document description (referring to Evans etc., Brit.J.Cancer 45,466-8,1982), calculate tumor size.The MV that anti-tumor activity increases with the animal subject gross tumor volume representes divided by the MV that the gross tumor volume of untreated animal increases, multiply by 100 after, represent with Δ T/C [%].Tumor regression is with the change mean of the gross tumor volume of treatment animal the equal value representation divided by when beginning treatment gross tumor volume, multiply by 100 after, with [%] expression of disappearing.Test-compound can every day oral administration, can be interrupted also can be uninterrupted.
Perhaps; Do not adopt clone MIA PaCa-2, and adopt another clone, measuring method is identical; For example to female BALB/c mouse injection (being injected in mammary fat pad (mammary fatpad)) 4T1 breast cancer cell line (ATCC CRL-2539; Also can be) referring to Cancer.88 (12 supplementary issue), 2979-2988,2000.
In said research, formula of the present invention (I) compound exhibits goes out excellent therapeutic activity, particularly Tyrosylprotein kinase is suppressed the proliferative disease of response.
Embodiment 60: tablet
Prepare every according to conventional methods and contain the 50mg activeconstituents like a kind of tablet in formula (I) compound of in embodiment 1-131, describing:
Form:
Activeconstituents 50mg
Wheat starch 150mg
Lactose 125mg
Colloid silica 12.5mg
Talcum powder 22.5mg
Magnesium Stearate 2.5mg
Total amount 362.5mg
The preparation method: activeconstituents is mixed with part wheat starch, lactose and colloid silica, and mixture sieves.In water-bath, another part wheat starch is processed paste with the water of 5 times of amounts, pulverulent mixture and paste is kneaded together until the agglomerate that obtains to have a little plasticity.
Above-mentioned agglomerate was pressed the sieve in about 3mm mesh screen aperture, dry then, the dried particles that obtains extruded once more sieve.Sneaking into remaining wheat starch, talcum powder and Magnesium Stearate subsequently, heavily is the tablet of 145mg and tool central authorities indenture with the mixture tablet forming.
Embodiment 61: soft capsule
Prepare 5000 soft gelatin capsules according to conventional methods, each capsule contains the 50mg activeconstituents, a kind of in the formula of for example in embodiment 1-131, describing (I) compound:
Form:
Activeconstituents 250g
2 liters of lauroglykol
Preparing method: the atomizing activeconstituents is suspended in Lauroglykol
(Saint Priest France), grinds to form the particle that particle diameter is approximately 1-3 μ m in wet crushing mill for lauric acid propylene glycol ester, Gattefoss é S.A..With capsule filling machine mixture is filled in the soft gelatin capsule then.
Bioassay results:
Embodiment F AK IC50 Phos IC
50Growth IC
50T cell migration IGF-1R IC
50
(nM) (μM) (μM) IC50(μM) (μM)
1.00 140 0.7 ＞10
2.00 13 1.2
3.01 44 0.34 ＞10
3.02 36 0.85 4
3.03 9.1 0.14 0.8
3.04 32 0.53 2
3.05 21 0.17 2 ＞10
3.06 13 0.11 2
3.07 16 0.45 2
3.08 74 0.3 6
3.09 48 0.5 0.7
3.10 52 0.95 ＞10
3.11 9 0.04 0.3 0.2
3.12 5.4 0.01 1
3.13 58 1.7 0.6 0.74
3.14 54 0.4 5
3.15 7 0.02 0.8 0.94
3.16 48 1.1 3
3.17 2.8 1.03 0.2 0.08
3.18 130 1.5 9
3.19 6.8 0.35 0.8 0.1
3.20 16 0.22 0.3
3.22 120 0.9 2
3.23 38 0.39 0.5
3.24 64 3.5 5
3.25 22 0.3 0.3 0.81
3.26 50 0.79 2
3.28 43 0.71 0.7
3.29 89 0.6 ＞10
3.30 69 0.6 3
3.31 13 1.1 5
3.32 14 0.18 0.49 0.28 0.12
3.33 2.9 0.03 0.05 0.09 0.13
3.34 7 0.1 0.24 0.13 ＜0.08
3.35 13 0.02 0.17 0.8 3.55
3.36 43 1.8 2.8
3.37 39 1.1 2.6
3.38 64 1.7 3.8
3.39 2 0.02 0.03 1 0.09
3.40 9 ＞10 0.9
3.41 22 ＞10 0.43
3.42 29 0.35 0.3
3.43 5.6 0.2 0.11 0.27
3.44 11 0.05 0.09 0.09
3.45 0.9 0.02 0.02
3.46 4 0.1 0.18 0.3
3.47 1 0.1 0.06
3.48 7 0.07 0.3 0.21
3.49 39 10 0.39
3.50 13 0.12 1 1.19
3.51 29 0.2 0.4 0.41
3.52 29 0.42 2
3.53 6 0.07 0.21
3.54 0.9 0.01 0.07 ＜0.08
3.55 34 ＞10 3
3.56 28 0.53 0.15
3.57 28 0.61 3
3.58 21 0.08 0.3 0.14
3.59 95 1.2 ＞10
3.60 90 0.93 2
3.61 12 10 ＞10
3.62 63 ＞10 ＞10
3.63 27 ＞10 ＞10
3.64 5 0.13 0.7 0.21
3.65 8 0.08 0.1 0.15
3.66 1 0.08 0.07 0.25
3.67 6 0.38 0.39
3.68 5.5 0.2 0.63 1
3.69 4 0.2 0.11 0.58
3.70 3.5 0.02 0.13
3.71 11 0.05 0.08
3.72 2.1 0.11 0.06
3.73 11 0.03 0.29 1.63
3.74 15 0.1 0.15
3.75 72 0.5 1.3
3.76 15 0.29 1.3 0.7
3.77 65 ＞10 3
3.78 10 ＞10 0.22
3.79 5 1.3 0.12
3.80 12 0.22 0.45 5
3.81 21 0.52 0.98 ＞10
3.82 4.8 0.2 0.07
3.83 20 0.08 0.32 0.68
3.84 10 1 0.08
6.00 110 0.35 5
7.00 5.3 0.21 0.47 0.04 0.19
7.01 4.7 0.6 0.54 0.19
7.02 7.5 0.1 0.36 0.77
7.03 2.9 0.3 0.39 0.27
7.04 5.2 1 0.29
7.05 6.2 0.3 0.2 0.25
7.06 17 0.8 1.09 0.25
7.07 4.1 0.9 0.18
7.08 8.7 0.8 1
7.09 8.2 1 0.85
7.10 6.6 1 0.98
7.11 2.5 0.6 1.2 0.77
7.12 1.9 0.9 1 0.31 0.62
7.13 5.5 0.8 1.22
7.14 7.6 0.3 0.36 0.33
7.15 4.5 0.06 0.19 0.26
7.16 6.4 0.2 0.42
7.17 4.3 0.7 0.69
7.18 6.2 0.5 0.7
7.19 13 0.33
7.20 2.5 ＞10 0.11
7.21 3.3 ＞10 0.46
7.22 25 0.48
7.23 1.4 0.25
7.24 5.1 0.09
7.25 13 0.2 0.73
7.25 2 ＞10 0.57
7.26 4.1 0.15
7.27 21 0.5 0.22
7.28 34 1 0.15
7.29 57 2 0.48
7.30 2.1 0.3 1
8.01 6.6 0.6 0.33
8.02 2.4 0.5 0.99
8.03 13 0.22 1 ＞10
8.04 8 ＞10 1.1
9.01 22 0.36 1 0.6
9.02 15 0.5 0.81
9.03 18 0.1 0.37
9.04 13 0.2 0.73
9.05 22 0.36 1.6 0.6
9.06 23 3 0.4 0.3
9.07 17 ＞10 0.26
10.01 39 1 0.44
10.02 26 0.9 1.06
10.03 23 0.9 2.4
11.01 9 0.7 0.85
11.02 4.1 0.8 0.69
1L03 26 0.41 0.1
11.04 4.3 ＞10 3.2
12.01 2.5 0.09 0.4 0.22
12.02 1.6 0.05
12.03 2.3 0.25
12.04 1.1 0.14
12.06 2.6
13.01 65 0.81
14.01 19 0.2 1.47 0.28
14.02 190 2 1.1 1
14.03 30 10 1.01
14.04 18 0.54
14.05 37 ＞10 1
14.06 63 10 1.11
14.07 7.5 0.2 1.4
15.01 15 10 0.47
15.02 21 ＞10 0.66
15.03 44 2 1.67
16.01 44 ＞10 4
16.02 6 ＞10 0.6
16.03 21 3 ＞10
16.04 9.5 ＞10 0.92
16B 11 3 7
16.C 28 0.9 ＞10
18.01 19 ＞10 1.29
19.01 ＜1 0.2 0.3 0.29 1.41
19.02 1.6 0.13 0.38 0.91
19.03 ＜1 0.3 0.09 0.64
19.04 1.6 0.2 0.34 0.14
19.05 1.8 0.2 0.67 0.07 0.47
19.06 5 1 0.7
19.07 2.1 0.3 0.11
19.08 3.2 0.03 0.4 0.29 0.13
19.09 1.3 0.17 0.39 0.3 0.48
19.10 1.3 0.06 0.56 1.02
19.11 38 ＞10 2
19.12 9 ＞10 0.7 0.63
19.13 2.5 0.3 1.1
19.14 2.6 0.4 1.13 0.44
19.15 3.1 0.5 0.36
19.16 2.3 0.7 1.1
19.17 1 ＞10 0.17
19.18 7 0.13 0.87
19.19 5.7 0.4
19.20 1.6 0.03 0.07 0.23
19.21 84 ＞10 1.71
19.22 3.4 0.12 0.51
19.23 6.4 0.7 0.71
19.24 1.8 0.05 0.12
19.25 7.2 1 0.49 0.24
19.26 6.1 0.1 0.3
19.27 1.5 0.3 0.4
19.28 4.8 0.1 0.12 0.3 0.46
19.29 1.9
19.30 ＜1 0.06 0.1
19.31 1.8 0.4 0.38
19.32 1.4 0.2 0.31
20.01 10 0.3 0.18 0.25 0.7
20.02 9 0.12 0.17 0.75 0.52
20.03 42 0.4 2.5 2.78
20.04 23 0.58 1.9
20.05 6.8 0.87 1.46
20.06 5 0.36 0.14 49
20.07 3 0.1 0.05 0.38
20.08 6.8 0.17 0.05 0.29
20.09 2 0.3 0.01
20.10 2 0.1 0.02
20.11 26 2 0.4
20.12 9.5
20.13 6.3 0.04
20.14 33 0.32
20.15 14 0.4 0.97 0.3
20.16 7.5 0.06
20.17 2 0.14
20.18 15 0.81
20.19 28 0.21
20.20 3.12 0.1
20.21 26 3 0.68
20.22 8 ＞10 0.19
20.23 30 0.49 3
20.24 19 0.48 2
20.25 6.2 0.21 0.06
20.26 5.3 0.76 0.27
20.27 12 0.85 0.05 0.29
20.28 9.2 0.17 0.08 0.42
20.29 6.1 0.2 0.05 0.31
20.30 7.6 0.3 0.08 0.67
20.31 39 0.5
20.32 13 0.11
20.33 2.5 0.38
20.34 13 1 0.12
20.35 8.7 0.09 0.09 0.15
21.01 1 0.07 0.19 0.47
21.02 8.5 0.33 ＞10
21.03 1.7 0.3 0.3
21.04 1.8 0.05 0.3
22.01 43 ＞10 ＞10
22.02 26 1 3
22.03 6.6 0.09 0.15 0.26
23.01 3.4 0.6 0.2 0.63 0.53
23.02 1.5 0.2 0.4 0.8
23.03 1.7 1 1.12 0.82
23.04 1.2 0.9 1.07 0.6
23.05 1.9 ＞10 0.59
23.06 16 1 0.57
23.07 2.1 3 0.84
23.08 6.7 0.3 0.49
23.09 2.1 0.2 0.28
24.01 3.6 0.11 0.44 0.05
24.02 2.1 0.5 0.11 0.39
24.03 1 0.3 1.08
25.01 8.5 3 1
25.02 3 0.4 0.13 0.64
26.01 4.4 0.05 0.35 0.29
26.02 1.9 0.03 0.12 0.09 0.39
26.03 1.4 0.1 0.13 0.23
26.04 4.9 0.05 0.43 0.29 1.16
26.05 2.1 0.09 0.23 1.5
26.06 4.4 0.1 0.35
26.07 11 0.5 0.95
26.08 2.9 0.01 0.18
26.09 2.3 0.04 0.22
26.10 2 0.01 0.14
26.11 4.4 0.4 0.78 0.5
26.12 3.7 0.2 0.19
26.13 1.6 0.2 0.44
26.14 5 0.19
26.15 6.9 1.2 0.08 0.07
26.16 9 0.32 2
26.17 17 0.3 0.1 0.26
26.18 1.3 6 1.17
26.19 9.2 0.43 0.79
26.20 10 0.14 0.22 0.6 0.49
26.21 1.1 0.1 0.49
26.22 ＜1 0.1 0.28
26.23 1.4 0.3 0.09 0.3 0.18
26.24 1 0.5 0.48 0.9
26.25 ＜1 0.6 0.73 0.3
26.26 1.9 0.2 0.07 0.34
26.27 4.8 0.6 1.49
26.28 2.1 0.5 1.52
26.29 ＜1 0.31 0.26
26.30 4.4 1 0.76
26.31 2 0.3 0.16
26.32 1.6 0.05 0.6
26.33 4 0.06 0.23
26.34 7 0.1 0.25
26.35 4.5 0.05 0.3
26.36 1.9 0.07 0.09
26.37 ＜1
26.38 ＜1
26.39 3.1
27.01 14 0.06 0.47
27.02 5.1 0.5 1.1
27.03 6.3 ＞10 0.56
27.04 11 0.1 0.27
27.05 8.2 0.04 0.3
27.06 1 0.08 0.31
27.07 5.5 2 0.57
27.08 9.3 0.6 0.75
27.09 4.2 0.5 0.36
28.01 12 0.3 0.46 0.3
28.02 1.9 0.08 0.44 3.71
28.03 7.4 0.07 0.29
28.04 7.5 0.3 0.3
28.05 6.7 0.1 0.12 1.39
28.06 17 0.6 0.56
28.07 47 3 ＞10
28.08 4.6 0.4 0.37
28.09 3.1 0.5 0.36
28.10 20 3 1.85
28.11 4.2 0.5 0.63
28.12 3.2 0.3 0.43 0.1
28.13 7.8 0.1 0.55 0.29
28.14 3 0.1 1.44
28.15 10 0.5 0.69
28.16 11 0.11 1 0.6
28.17 15 0.16 1.9
28.18 9.1 ＞10 2.03
28.19 3.7 0.5 0.14
28.20 4.4 2 0.4
28.21 1.3 0.1 0.23
28.22 1.3 0.1 0.3
28.23 5.9 0.5 0.28
28.24 2.9 0.2 0.09 2.57
28.25 3.9 0.04 0.13
28.26 6.6 0.2 0.57
28.27 2.4 0.3 0.42 0.5
28.28 5.2 0.4 0.52 1
28.29 11 0.4 0.36
28.30 2.3 0.9 0.11
28.31 7.4 0.06 1.06
29.01 13 0.7 2.2 0.09
29.02 3.3 0.7 1.1
29.03 5.6 0.1 0.99
30.01 22 0.2 0.89
30.02 12 0.2 0.47
30.03 19 0.5 0.68
30.04 25 0.3 0.99
30.05 8.5 2 0.29
30.06 15 1 1.03
30.07 8.8 0.6 0.47
31.01 30 ＞10 1.6
31.02 31 0.28 0.29 0.42
32.01 4.1 0.1 0.29
32.02 5.9 0.05 0.37 0.12
33.01 2.5 0.08 0.25
33.02 5.2 0.06 0.25 0.1
34.01 8 0.1 0.37 0.28
34.02 11 0.08 1.17
34.03 33 0.19 2.25
34.04 13 ＞10 1.22
34.05 51 0.36 5.1
34.06 14 ＞10 3
34.07 27 ＞10 2.7
34.08 8.7 ＞10 1.9
35.01 6.8 ＞10 1.43
35.02 6.1 0.7 0.23
51.00 8.1 0.013 0.19 0.2
52.00 13 0.2 0.41 ＜0.08
Claims (11)
1. the compound of formula (I '),
Wherein:
N ' is selected from 1 and 2;
R '
2Be halogen;
R '
3Be selected from-S (O)
0-2R '
6With-NR '
5(O)
0-2R '
6R ' wherein
5Be selected from hydrogen and C
1-C
6Alkyl; And R '
6Be selected from C
1-6Alkyl and C
3-C
12Naphthenic base;
R '
1Be selected from phenyl, pyridyl, pyrazolyl and pyrimidyl; Wherein arbitrary R '
1Independently being selected from following group by 3 replaces: oxyethyl group, ethyl, propyl group, methyl, the tertiary butyl, trifluoromethyl, itrile group, cyclobutoxy group, 2; 2,2-trifluoro ethoxy, isobutoxy, tert.-butoxy, sec.-propyl oxygen base, methyl-amino-carbonyl, cyclopropyl-methoxyl group, dimethylamino-propyl group-amino, methoxyl group-oxyethyl group ,-X ' R '
4,-C (O) R '
4With-OX ' R '
4Wherein X ' is key, methylene radical or ethylidene;
R '
4Be selected from piperazinyl, piperidyl, pyrrolidyl, morpholine-4-base, azepan base and 1,4-dioxa-8-azepine-spiral shell [4.5] last of the ten Heavenly stems-8-base; R ' wherein
4Can choose wantonly and independently be selected from following group by 1-3 and replace: methyl, sec.-propyl, ethanoyl, ethanoyl-methyl-amino, 3-dimethylamino-2,2-dimethyl--propyl group amino, ethyl-methyl-amino-oxyethyl group, diethylammonium-amino-oxyethyl group, amino-carbonyl, ethyl, 2-oxo-tetramethyleneimine-1-base, pyrrolidyl, pyrrolidyl-methyl, optional by methyl or the substituted piperidyl of ethyl, morpholine-4-base, dimethylamino, dimethylamino-propyl group-amino, methyl-amino and ethyl-amino.
2. according to formula (I ') compound of claim 1, R ' wherein
2Be halogen; R '
3Be selected from propyl group-alkylsulfonyl, cyclohexyl-alkylsulfonyl and sec.-propyl-alkylsulfonyl.
3. pharmaceutical composition, this pharmaceutical composition comprise among the claim 1-2 that each compound is as activeconstituents and one or more pharmaceutically acceptable diluent or carriers.
4. each compound is used for treating or prevent the purposes of the medicine of ND or disease of immune system among the claim 1-2 in preparation.
5. each compound or its pharmacy acceptable salt are used for treating or the purposes of the medicine of the disease preventing to suppress in response to ALK in preparation among the claim 1-2.
6. the purposes of claim 5, disease wherein said to be treated is selected from proliferative disease.
7. the purposes of claim 6, wherein said proliferative disease is selected from following tumour: breast, kidney, prostate gland, Tiroidina, ovary, pancreas, neurone, lung, uterus and gastroenteric tumor and osteosarcoma and melanoma.
8. the purposes of claim 7, wherein said gastroenteric tumor is a colorectal carcinoma.
9. the purposes of claim 5, disease wherein said to be treated is an immunological disease.
10. each compound or its pharmacy acceptable salt are used for treating or prevent the purposes of the medicine of inflammatory diseases and/or immunological disease among the claim 1-2 in preparation.
11. the purposes of claim 10; Wherein said inflammatory diseases and/or immunological disease are selected from the autoimmune disorder of graft-rejection, allergy and immunocyte mediation, and said immunocyte is selected from T lymphocyte, bone-marrow-derived lymphocyte, scavenger cell, dendritic cell, mastocyte and eosinophil.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0319227.5 | 2003-08-15 | ||
| GB0319227A GB0319227D0 (en) | 2003-08-15 | 2003-08-15 | Organic compounds |
| GB0322370.8 | 2003-09-24 | ||
| GB0322370A GB0322370D0 (en) | 2003-09-24 | 2003-09-24 | Organic compounds |
| PCT/EP2004/009099 WO2005016894A1 (en) | 2003-08-15 | 2004-08-13 | 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1832929A CN1832929A (en) | 2006-09-13 |
| CN1832929B true CN1832929B (en) | 2012-11-07 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2004800227255A Active CN1832929B (en) | 2003-08-15 | 2004-08-13 | 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1832929B (en) |
| AR (2) | AR107965A2 (en) |
| GB (1) | GB0319227D0 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628657A (en) * | 2013-11-06 | 2015-05-20 | 韩冰 | Class of compounds for treating ischemic brain damage and purpose thereof |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2671744C (en) * | 2006-12-08 | 2012-08-28 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
| EP2432900A4 (en) * | 2009-05-15 | 2012-11-21 | Insight Genetics Inc | Methods and compositions relating to fusions of alk for diagnosing and treating cancer |
| AU2013344049B2 (en) * | 2012-11-06 | 2017-12-21 | Fochon Pharmaceuticals, Ltd. | ALK kinase inhibitors |
| EP2970205B1 (en) * | 2013-03-14 | 2019-05-08 | Tolero Pharmaceuticals, Inc. | Jak2 and alk2 inhibitors and methods for their use |
| CN104926794B (en) * | 2014-03-17 | 2017-12-05 | 广东东阳光药业有限公司 | Substituted heteroaryl compound and combinations thereof and purposes |
| CN106008503B (en) * | 2015-03-31 | 2020-09-01 | 齐鲁制药有限公司 | Spirocyclic aryl sulfones as protein kinase inhibitors |
| CN106146525B (en) * | 2015-04-10 | 2018-11-02 | 山东轩竹医药科技有限公司 | Three and ring class anaplastic lymphoma kinase inhibitor |
| CN106187915A (en) * | 2015-05-27 | 2016-12-07 | 上海翰森生物医药科技有限公司 | There is inhibitor of ALK Yu EGFR double activity and its preparation method and application |
| CN106349224A (en) * | 2016-08-03 | 2017-01-25 | 山东大学 | JAK kinase inhibitor with 4-amino-(1H)-pyrazole structure and preparation method and application thereof |
| CN110092759A (en) * | 2018-01-31 | 2019-08-06 | 陆柯潮 | The chloro- 2,4- pyrimidine derivatives of 5- as anti-tumor drug |
| CN114716385B (en) * | 2022-04-08 | 2024-03-12 | 北京师范大学 | Compound of targeted focal adhesion kinase, preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003078404A1 (en) * | 2002-03-15 | 2003-09-25 | Novartis Ag | Pyrimidine derivatives |
-
2003
- 2003-08-15 GB GB0319227A patent/GB0319227D0/en not_active Ceased
-
2004
- 2004-08-13 CN CN2004800227255A patent/CN1832929B/en active Active
-
2017
- 2017-03-23 AR ARP170100728A patent/AR107965A2/en unknown
-
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- 2019-02-04 AR ARP190100267A patent/AR114354A2/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003078404A1 (en) * | 2002-03-15 | 2003-09-25 | Novartis Ag | Pyrimidine derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628657A (en) * | 2013-11-06 | 2015-05-20 | 韩冰 | Class of compounds for treating ischemic brain damage and purpose thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0319227D0 (en) | 2003-09-17 |
| AR114354A2 (en) | 2020-08-26 |
| CN1832929A (en) | 2006-09-13 |
| AR107965A2 (en) | 2018-07-04 |
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