CN1832929A - 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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- CN1832929A CN1832929A CNA2004800227255A CN200480022725A CN1832929A CN 1832929 A CN1832929 A CN 1832929A CN A2004800227255 A CNA2004800227255 A CN A2004800227255A CN 200480022725 A CN200480022725 A CN 200480022725A CN 1832929 A CN1832929 A CN 1832929A
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Abstract
Novel pyrimidine derivatives of formula (I) Wherein R is selected from C16-10 aryl, C5-10heteroaryl, C3-12cycloalkyl and C3-10heterocycloalkyl; 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 production method, they are as the application of medicine and the composition 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 described disease of production for treating, its purposes in the described disease of treatment is provided simultaneously, the using method that also relates to this type of pyrimidine derivatives when the described disease of treatment, and the pharmaceutical composition that contains this type of pyrimidine derivatives that is used for the treatment of described disease.
Described formula (I) compound is:
Wherein:
R is selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl 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
8Cycloalkyl, C
3-C
8Cycloalkyl 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, the unsubstituted or C that replaces
5-C
10Aryl, unsubstituted or replace 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, the unsubstituted or C that replaces
5-C
10Aryl C
1-C
8Heterocyclyloxy base alkoxyl group, replacement or that replace, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group, unsubstituted or the amino, the C that replace
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, the unsubstituted or formamyl that replaces, the unsubstituted or sulfamyl that replaces, cyano group, 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
3-12Cycloalkyl;
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 the formamyl, cyano group or the nitro that replace;
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
8Cycloalkyl, C
3-C
8Cycloalkyl 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, the unsubstituted or C that replaces
5-C
10Aryl, unsubstituted or replace 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, the unsubstituted or amino C that replaces
1-C
8Alkoxyl group, the unsubstituted or C that replaces
5-C
10Aryl C
1-C
8Alkoxyl group, the unsubstituted or heterocyclyloxy base that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkyl, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group, unsubstituted or the amino, the C that replace
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, the unsubstituted or formamyl that replaces, the unsubstituted or sulfamyl that replaces, cyano group, 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 connect 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 that carbon atom forms unsubstituted or replacement with it;
X is key or C
1-6Alkylidene group; And
R
11Independently be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl and C
3-10Heterocyclylalkyl;
And R
11Any aryl, heteroaryl, cycloalkyl 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 C that alkyl replaces
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 may 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 described group can be straight chain or have single or multiple branched side chains; Preferred C
1-C
8Alkyl is butyl (as normal-butyl, sec-butyl, isobutyl-, the tertiary butyl), propyl group (as 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 described group can be straight chain or have single or multiple branched side chains; Preferred C
2-C
8Thiazolinyl is pentenyl (as 3-methyl-2-butene-2-yl), butenyl (as 1-or crotyl or 2-butylene-2-yl), propenyl (as 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 described group can be that straight chain also can be a side chain; Preferred C
2-C
8Alkynyl is proyl (as 1-proyl or propargyl) or ethynyl.
C
3-C
8The cycloalkyl representative has the group of naphthene base of 3-8 carbon atom, as 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 the formamyl that replaces is for to be selected from the following formamyl that substituting group replaced by one or two: hydrogen, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkyl 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, the unsubstituted or C that replaces
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 the sulfamyl that replaces is for to be selected from the following sulfamyl that substituting group replaced by one or two: hydrogen, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkyl 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, the unsubstituted or C that replaces
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 the amino that replaces is for to be selected from the amino that following substituting group replaces by one or two: hydrogen, C
1-C
8Alkyl, C
2-C
8Thiazolinyl, C
2-C
8Alkynyl, C
3-C
8Cycloalkyl, C
3-C
8Cycloalkyl 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, the unsubstituted or C that replaces
5-C
10Aryl, amino C
1-C
8Alkyl, acyl group (as 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 replace C
5-C
10Aryl is, 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
8The amino of alkoxyl group, methylene-dioxy, amino, replacement, halogen, carboxyl, C
1-C
8Alkoxy carbonyl, formamyl, sulfamyl, cyano group 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 group or methoxyl group phenoxy group, as right-methoxyl group phenoxy group.
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.
Unsubstituted or replace contain 1,2 or 3 are selected from N, heteroatomic 5 or 6 yuan of heterocycles of O and S can be undersaturated, fractional saturation or saturated, and can by heteroatoms or carbon atom further with phenyl ring or 5 or 6 yuan of heterocyclic radicals are thick and, for example, pyrryl, indyl, pyrrolidyl, imidazolyl, benzimidazolyl-, pyrazolyl, triazolyl, the benzotriazole base, tetrazyl, pyridyl, quinolyl, isoquinolyl, 1,2,3, the 4-tetrahydric quinoline group, piperidyl, pyrimidyl, pyrazinyl, piperazinyl, purine radicals, tetrazine base oxazolyl isoxazolyl (isoxalyl), morpholinyl, thiazolyl, benzothiazolyl oxadiazole base and Ben Bing oxadiazole base.Described 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
8The amino of alkyl, hydroxyl, amino, replacement, 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, cyano group, oxo, this section defined unsubstituted or replace 5 or 6 yuan of heterocyclic radicals.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-cyano group (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 the heterocyclyloxy base of unsubstituted or replacement, heterocyclic radical is preferably N-methyl-4-piperidyl oxygen base as defined above.At heterocyclic radical C unsubstituted or that replace
1-C
8In the alkoxyl group, heterocyclic radical 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) as defined above] propoxy-or 2-(1-imidazolyl) oxyethyl group.
In containing in 0,1,2 or 3 heteroatomic 5 or 6 yuan of carbocyclic ring or heterocycle that are selected from N, O and S of being formed with phenyl ring by two adjacent substituting groups, this ring can further be replaced by following groups: as C
1-C
8Alkyl, C
1-C
8Alkoxyl group, halo C
1-C
8The amino of alkyl, hydroxyl, amino, replacement, C
1-C
8Alkoxyl group, halogen, carboxyl, C
1-C
8Alkoxy carbonyl, formamyl, cyano group 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 derivative 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 is, for example, and haloid acid (example hydrochloric acid), sulfuric acid or phosphoric acid.Suitable organic acid is, for example, carboxylic acid, phosphoric acid, sulfonic acid or thionamic acid, acetate for example, 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, citric acid, amino acid (as L-glutamic acid or aspartic acid), toxilic acid, hydroxymaleic acid, methyl-maleic acid, naphthenic acid, adamantanecarboxylic acid (adamantanecarboxylic acid), phenylformic acid, Whitfield's ointment, the 4-aminosallcylic acid, phthalic acid, toluylic acid, amygdalic acid, styracin, methylsulfonic acid or ethyl sulfonic acid, the 2-ethylenehydrinsulfonic acid, ethane-1, the 2-disulfonic acid, Phenylsulfonic acid, the 2-naphthene sulfonic acid, 1, the 5-naphthalene disulfonic acid, 2-, 3-or 4-toluene sulfonic acide, methylsulfuric acid, ethylsulfuric acid, dodecyl sulphate, N-cyclohexyl thionamic acid, the N-methyl-, the N-ethyl-or N-propyl group-thionamic acid, or other organic protonic acid (as xitix).
When carrying out isolated or purified, also can use pharmaceutically unacceptable salt, for example picrate or perchlorate.But when being used for the treatment of, can only use pharmacy acceptable salt or free cpds (form with pharmaceutical preparation is used), and these forms all are preferred.
Consider being closely connected between the form (for example comprise or be used as the salt of intermediate in differentiating) of free form and its salt of new compound, be understandable that, also refer to its corresponding salt when mentioning new compound herein at the purifying of new compound.
As described herein, formula I compound has the valuable pharmacological characteristic.
In formula I, preferred following definition is independent use, use jointly or in any combination or the subgroup form of closing use.R is C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl or C
3-10Heterocyclylalkyl; Preferred R is
R wherein
7, R
8, R
9, R
10Or R '
10As defined above;
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 (as trifluoromethyl), the unsubstituted or C that replaces
5-C
10Aryl (as phenyl or p-methoxy-phenyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocycles (as morpholine-1-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (as trifluoromethoxy), C
5-C
10Aryloxy (as phenoxy group), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or the amino (as methylamino, dimethylamino or acetylamino), the C that replace
1-C
8Alkyl sulphonyl (as methyl sulphonyl), halogen (as fluorine or chlorine), the unsubstituted or formamyl (as cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl) that replaces, the unsubstituted or sulfamyl (as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl) that replaces; 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 (as trifluoromethyl), the unsubstituted or C that replaces
5-C
10Aryl (as phenyl or p-methoxy-phenyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (as trifluoromethoxy), C
5-C
10Aryloxy (as phenoxy group), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or the amino (as methylamino, dimethylamino or acetylamino), the C that replace
1-C
8Alkyl sulphonyl (as methyl sulphonyl), halogen (as fluorine or chlorine), the unsubstituted or formamyl (as cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl) that replaces, the unsubstituted or sulfamyl (as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl) that replaces; 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 (as trifluoromethyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as 2-pyrroles's ketone group or S, S-dioxo isothiazole alkyl), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group), the amino (as acetylamino, ethanoyl-methyl-amino, benzoyl-amido, methyl sulphonyl amino or phenyl sulfonyl amino), the C that replace
1-C
8Alkyl sulphonyl (as methyl sulphonyl, propyl group-alkylsulfonyl, cyclohexyl-alkylsulfonyl, sec.-propyl-alkylsulfonyl), C
5-C
10Aryl sulfonyl (as phenyl sulfonyl), halogen (as fluorine or chlorine), carboxyl, that replace or unsubstituted formamyl is (as formamyl, the methylamino formyl radical, ethyl-amino-carbonyl or formyl-dimethylamino), unsubstituted or the sulfamyl that replaces is (as sulfamyl, the methyl sulfamyl, the propyl group sulfamyl, the sec.-propyl sulfamyl, the 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 (as methyl); Be preferably hydrogen;
(f) R
5Be hydrogen; C
1-C
8Alkyl (as methyl or ethyl), halogen (as chlorine or bromine), halo C
1-C
8Alkyl (as trifluoromethyl), cyano group 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 (as methyl, ethyl or sec.-propyl), hydroxyl C
1-C
6Alkyl (as hydroxyethyl or hydroxybutyl), C
1-C
8Alkyl-carbonyl (methyl carbonyl), aminoalkoxy (as the diethyl amino base oxethyl), halo C
1-C
8Alkyl (as trifluoromethyl), the unsubstituted or C that replaces
5-C
10Aryl (as phenyl or p-methoxy-phenyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S (as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl), C
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (as trifluoromethoxy), C
5-C
10Aryloxy (as phenoxy group), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or the amino (as methylamino, dimethylamino or acetylamino), the C that replace
1-C
8Alkyl sulphonyl (as methyl sulphonyl), heterocycle alkylsulfonyl (as the piperazinyl alkylsulfonyl), heterocycle carbonyl (as methylpiperazine base carbonyl), cyano group, halogen (as fluorine or chlorine), unsubstituted or the formamyl that replaces is (as 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 the sulfamyl that replaces is (as 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 group, 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 (as methyl, ethyl or sec.-propyl), hydroxyl C
1-C
8Alkyl (as hydroxyethyl or hydroxybutyl), halo C
1-C
8Alkyl (as trifluoromethyl), C
5-C
10Aryl (as phenyl or p-methoxy-phenyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), heterocyclic radical alkyl (as methyl (piperazine-1-yl) ethyl), heterocyclic radical carbonyl (as (piperazine-1-yl) carbonyl), heterocyclic radical C that is selected from N, O and S
1-C
8Alkylamino (as pyridyl ethyl (methyl) amino), C
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (as trifluoromethoxy), C
5-C
10Aryloxy (as phenoxy group), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or the amino (as methylamino or dimethylamino), the C that replace
1-C
8Alkylamino-C
1-C
8Alkylamino (as dimethylamino-propyl group amino), C
1-C
8Alkyl sulphonyl (as methyl sulphonyl), halogen (as fluorine or chlorine), the unsubstituted or formamyl (as cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl) that replaces, unsubstituted or the sulfamyl (as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl), cyano group or the nitro that replace; Preferred hydrogen, methyl, piperidines-1-base, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, methoxyl group, oxyethyl group, trifluoromethoxy, phenoxy group, 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 (as methyl, ethyl or butyl), hydroxyl, cyano group, hydroxyl C
1-C
8Alkyl (as hydroxyethyl or hydroxybutyl), halo C
1-C
8Alkyl (as trifluoromethyl), C
1-C
8Alkoxyl group (as methoxy or ethoxy), cycloalkyl alkoxy, aryloxy, halo C
1-C
8Alkoxyl group, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group is (as 2-(1-imidazolyl) oxyethyl group, unsubstituted or the amino (as methylamino or dimethylamino), halogen (as fluorine or chlorine), carboxyl, formamyl or the sulfamyl (as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl) unsubstituted or that replace that replace; 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-two oxa-s-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, diethyl-amino-oxyethyl group, amino-carbonyl, ethyl, 2-oxo-tetramethyleneimine-1-base, pyrrolidyl, pyrrolidyl-methyl, optional piperidyl, morpholine-4-base, dimethylamino, dimethylamino-propyl group-amino, methyl-amino and the ethyl-amino that is replaced by methyl or ethyl.
More preferably following definition is independent to be used, uses jointly or its any combination or the subgroup form of closing are used:
(a ') R
0Or R
2Independent is hydrogen, C
1-C
8Alkyl (as methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (as trifluoromethyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or the amino (as methylamino, dimethylamino or acetylamino), the halogen (as fluorine or chlorine) that replace; 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 (as methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (as trifluoromethyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or the amino (as methylamino, dimethylamino or acetylamino), the halogen (as fluorine or chlorine) that replace; 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 (as methyl or ethyl), halo C
1-C
8Alkyl (as trifluoromethyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as 2-pyrroles's ketone group or S, S-dioxo isothiazole alkyl), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group), the amino (as acetylamino, ethanoyl-methyl-amino, benzoyl-amido, methyl sulphonyl amino or phenyl sulfonyl amino), the C that replace
1-C
8Alkyl sulphonyl (as methyl sulphonyl), C
5-C
10Aryl sulfonyl (phenyl sulfonyl), halogen (as fluorine or chlorine), carboxyl, replacement or unsubstituted formamyl (as formamyl, methylamino formyl radical or formyl-dimethylamino), the unsubstituted or sulfamyl that replaces (as 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 (as chlorine or bromine), halo C
1-C
8Alkyl (as 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 (as methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (as trifluoromethyl), the unsubstituted or C that replaces
5-C
10Aryl (as phenyl or p-methoxy-phenyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group is (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), unsubstituted or the amino that replaces is (as methylamino, dimethylamino or acetylamino), halogen (as fluorine or chlorine), unsubstituted or the formamyl that replaces is (as 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 the sulfamyl that replaces is (as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl); Preferred hydrogen, methyl, sec.-propyl, trifluoromethyl, phenyl, adjacent-, between-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 group, 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 (as methyl, ethyl or sec.-propyl), halo C
1-C
8Alkyl (as trifluoromethyl), C
5-C
10Aryl (as phenyl or p-methoxy-phenyl), the unsubstituted or C that replaces
5-C
10Aryl (as phenyl or p-methoxy-phenyl), unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radicals (as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl)), C that is selected from N, O and S
1-C
8Alkoxyl group (as methoxyl group, oxyethyl group or isopropoxy), halo C
1-C
8Alkoxyl group (as trifluoromethoxy), C
5-C
10Aryloxy (as phenoxy group), the unsubstituted or heterocyclyloxy base (as 1-methyl-4-piperidyl oxygen base) that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group), the unsubstituted or amino (as methylamino or dimethylamino) that replaces, halogen (as fluorine or chlorine), unsubstituted or the sulfamyl (as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl) or the nitro that replace; Preferred hydrogen, methyl, piperidines-1-base, piperazine-1-base, N-methyl (piperazine-1-yl), morpholine-4-base, methoxyl group, oxyethyl group, trifluoromethoxy, phenoxy group, 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 (as methyl, ethyl or butyl), halo C
1-C
8Alkyl (as trifluoromethyl), C
1-C
8Alkoxyl group (as methoxy or ethoxy), the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group (as 2-(1-imidazolyl) oxyethyl group), unsubstituted or the amino (as methylamino or dimethylamino), the halogen (as fluorine or chlorine) that replace; 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, solvate, 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
3-12Cycloalkyl and C
5-12Heterocyclylalkyl;
R ' wherein
1Arbitrary aryl, heteroaryl, cycloalkyl 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-replacement-C
1-6Alkyl, halogen-replacement-C
1-6Alkyl, halogen-replacement-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
3-12Cycloalkyl-C
1-4Alkyl; And R '
4Be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl and C
3-10Heterocyclylalkyl;
R '
4Arbitrary aryl, heteroaryl, cycloalkyl 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 C that alkyl replaces
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, cyano group, C
1-6Alkyl, halogen-replacement-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
12Cycloalkyl.
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
12Cycloalkyl 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-replacement-C
1-6Alkyl, optional by C
1-6The C that alkyl replaces
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
12Cycloalkyl.
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-two oxa-s-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, diethyl-amino-oxyethyl group, amino-carbonyl, ethyl, 2-oxo-tetramethyleneimine-1-base, pyrrolidyl, pyrrolidyl-methyl, optional piperidyl, morpholine-4-base, dimethylamino, dimethylamino-propyl group-amino, methyl-amino and the ethyl-amino that is replaced by methyl or ethyl.
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 defined above, 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 defined above, if desired, formula I compound (wherein substituting group as defined above) can be converted into other formula I compound as defined above;
And reclaim the target compound of free form or salt form, and, if desired, the formula I compound of the free form that obtains can be converted into the salt that needs, perhaps the salt that obtains is converted into free form.
Reaction can be undertaken by known method, reaction conditions depends primarily on the reactive behavior of the amino group on the aniline of the reactive behavior of leavings group Y and formula III compound, usually in the presence of appropriate solvent or thinner or its mixture, carry out, if desired, also can in the presence of acid or alkali, carry out, by cooling off or preferably reacting by heating, for example temperature range is greatly about-30 ℃ to+150 ℃, generally be about 0 ℃ to+100 ℃, be preferably room temperature (approximately+20 ℃) to+80 ℃, reaction is usually in open or airtight container and/or carry out under rare gas element (for example nitrogen) environment.Perhaps, reaction can be carried out in the presence of suitable catalyzer (as two-benzyl-acetone palladium), carries out in the presence of alkali (as cesium carbonate), carries out in the presence of suitable reaction promotor (as xanthphos).
If one or more other functional groups (as carboxyl, hydroxyl or amino) are protected or need protected in formula II or the III compound; because they should not participate in reaction, so described blocking group is to be generally used in peptides, cynnematin and penicillin and nucleic acid derivative and carbohydrate synthetic those.
Already in the precursor, it can protect relevant functional group to avoid unwanted second order reaction, as 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 by enzyme catalysis by following method; for example under the condition similar, so they can not be present in the end product to physiological condition.Brainstrust is known or can be determined more easily which blocking group is applicable to above-mentioned reaction.
The salt that can prepare formula I compound by known method with salt forming group.Therefore, by 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 by handling with suitable alkaline reagents, as adopting alkaline carbonate, alkali metal hydrocarbonate or alkali metal hydroxide, adopts salt of wormwood or sodium hydroxide usually.
By known suitable for separation, three-dimensional heterogeneous mixture (as non-enantiomer mixture) can be separated into its corresponding isomer.
Distribute and similar methods by fractional crystallization, chromatogram, solvent, non-enantiomer mixture can 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 by diastereomeric salt can separate enantiomer, for example adopts the chiral acid of enantiomer-pure to form salt, perhaps by the stratographic method, for example by HPLC, adopts the chromatogram substrate with chiral ligand.
It is emphasized that the reaction similar to the described 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 by formula IV compound is reacted with formula V compound as the formula II compound of initial substance:
R wherein
1, R
2, R
3, R
4, R
5And R
6As defined above, 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 by 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 inhibitor of focal adhesion kinase, and medicine is used for the treatment of because the described tumour of disease, particularly back that focal adhesion kinase coherent signal cascade fault is caused 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 by 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, by 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 overexpression.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 T lymphocyte, bone-marrow-derived lymphocyte, the disease or the illness of 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 amyotrophic lateral sclerosis, 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, as rheumatic arthritis, osteoarthritis, systemic lupus erythematous, this (thyroiditis of Hashimoto ' s) of bridge, multiple sclerosis, myasthenia gravis, diabetes (I type and II type) and associated disease, respiratory tract disease such as asthma or inflammatory liver injury, the inflammatory glomerular injury, the skin table picture of immune-mediated discomfort or disease, inflammatory and high hyperplasia dermatosis are (as psoriatic, atopic dermatitis, supersensitivity contact dermatitis, pungency contact dermatitis and other eczematoid dermatitis, seborrheic dermatitis), the inflammatory eye disease is (as Sjoegren ' s syndrome, keratoconjunctivitis or uveitis), inflammatory enteritis, regional ileitis or ulcerative colitis.
Described in example, 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 associated protein 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 as LAT-11 (T cell activation linking agent) phosphorylation by people ZAP-70 protein tyrosine kinase in its prevention aqueous solution.So The compounds of this invention also can prevent or treat discomfort or illness that wherein ZAP-70 inhibition is worked.
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, as described in following embodiment 2 and 3-2.
The compounds of this invention also is the good inhibitor of IGF-IR (IGF-1 1), so can be used for treating the disease of IGF-IR mediation, as proliferative disease, tumour for example is as breast, kidney, prostate gland, knot rectum, Tiroidina, ovary, pancreas, neurone, lung, uterus and gastroenteric tumor and osteosarcoma and melanoma.Can by cell " catch the ELISA method " (CaptureELISA) the proof The compounds of this invention as the usefulness of IGF-IR tyrosine kinase activity inhibitor.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 inhibitor of modification lymphoma kinases (ALK), be used for the treatment of the described tumour of disease, particularly back that is caused with a signal cascade fault that modification lymphoma kinases is relevant so can be used as medicine.
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 sample 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, in neuroblastoma be derived from the overexpression of having found ALK in several 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).
By adopting known method can determine 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 by suppressing percentile linear regression analysis
50Value.Compare with the contrast that does not have inhibitor, 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 overexpression mouse BaF3 cell growth (DSMZ Deutsche Sammlung von Mikroorganismen und ZellkulturenGmbH, Braunschweig, Germany).By 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 by the NPM-ALK kinases.So the kinase whose supposition inhibitor of NPM-ALK can be eliminated growth signals and produce antiproliferative activity.Yet can eliminate the antiproliferative activity of the kinase whose supposition inhibitor of NPM-ALK by adding IL-3, IL-3 can by 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 by 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).Add finish after, with above-mentioned plate incubation two days, do not have the control cultures of test-compound can experience two cell fission circulations during this period.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.Finish 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 instrument (PerSeptive Biosystems) and measure the Yopro sum that is attached on the DNA.
By computer aided system, adopt following formula to calculate 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 inhibitor.Formula I compound has IC
50The inhibition activity that is about 0.01-1 μ M.
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 by 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, 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzamide is a strong especially ALK inhibitor, 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) is back embodiment 7A and 7B and the described compound of 7-2,7-15,19-5,21-1,26-3 and 28-5 between particularly preferred in addition 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 by any conventional route administration, particularly administration (preferred oral administration in the parenteral admin form of injection liquid or suspension (for example with), the enteron aisle, as with tablet or capsular form), topical (as form), perhaps intranasal administration or suppository with lotion, gel, ointment or creme.With ordinary method, by 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 is, for example, and percutaneous drug delivery.Other form of topical is a dosing eyes.
Can prepare pharmaceutical composition of the present invention by well-known method, for example, by routine mixing, granulation, dressing, dissolving or freeze dried method.
The solution of preferred activeconstituents also can be suspension or dispersion liquid, particularly isotonic aqueous solution, suspension or dispersion liquid, for example, for only containing activeconstituents or also comprising under the situation of lyophilised compositions of carrier (as N.F,USP MANNITOL), can prepare before use, for example.Pharmaceutical composition can be sterilized and/or be contained vehicle, 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 by well-known method preparation, for example by conventional dissolving and freeze drying process.Described solution or suspension comprise thickening material, and Xylo-Mucine commonly used, carboxymethyl cellulose, dextran, polyvinylpyrrolidone or gelatin also can comprise solubilizing agent, as Tween 80
(polyoxyethylene (20) dehydrated sorbitol mono-fatty acid ester).
Suspension 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, tridecylic acid, tetradecanoic acid, pentadecanoic acid, palmitinic acid, margaric acid, 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 acid esters is up to 6 carbon atoms and can be unit price or polyvalent, for example monovalence, divalence or trivalent alcohol, and as methyl alcohol, ethanol, propyl alcohol, butanols or amylalcohol or its isomer, but preferred ethylene glycol and glycerol.So, following is the fatty acid ester of mentioning: ethyl oleate, Isopropyl myristate, Wickenol 111, " Labrafil M 2375 " (polyoxyethylene glyceryl ester), " Labrafil M 1944CS " are (by the undersaturated polyglycolic acid glyceryl ester of Prunus amygdalus oil alcoholysis preparation, contain glyceryl ester and polyethylene glycol ester), " Labrasol " (by the saturated polyglycolic acid 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 saturated fatty acid, available from H ü ls AG, Germany), but special preferably vegetable oil such as Oleum Gossypii semen, Prunus amygdalus oil, sweet oil, Viscotrol C, soybean oil, more preferably peanut oil.
The production of injection is carried out under aseptic condition usually, as can in ampoule or bottle and with container closure.
Can pass through, for example, activeconstituents be mixed obtaining being used for pharmaceutical composition for oral administration with one or more solid carriers, if desired, the gained mixture is made 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, as carbohydrate (as lactose, sucrose, N.F,USP MANNITOL or sorbyl alcohol), cellulosics and/or calcium phosphate (as tricalcium phosphate or secondary calcium phosphate), also can comprise tackiness agent, as starch (as corn, wheat, rice or yam starch), methylcellulose gum, Vltra tears, Xylo-Mucine and/or polyvinylpyrrolidone, and/or, if desired, comprise disintegrating agent, starch as described above, also have carboxymethyl starch, cross-linked polyvinylpyrrolidone, alginic acid or its salt (as sodiun alginate).
Other vehicle is particularly including glidant and lubricant, for example silicic acid, talcum powder, stearic acid or its salt (as Magnesium Stearate or calcium) and/or polyoxyethylene glycol or derivatives thereof.
Label can obtain by suitable enteric coating; by using the priming dressing; comprise gum arabic, talcum powder, polyvinylpyrrolidone, polyoxyethylene glycol and/or titanium dioxide; 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, as 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 (as glycerine or sorbyl alcohol).Hard capsule can contain the activeconstituents of particle form, for example with the mixture of weighting agent (as W-Gum), tackiness agent and/or glidant (as talcum powder or Magnesium Stearate) and optional stabilizer.In soft capsule, activeconstituents preferably is dissolved in or is suspended in the suitable liquid excipient, as the fatty acid ester of fatty oil, paraffin oil or liquid macrogol or ethylene glycol or propylene glycol, 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 is, 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 (as water-soluble salt) or contain thickening thing (as Xylo-Mucine, sorbyl alcohol and/or dextran), can comprise that also the water injection solution of stablizer or suspension are suitable if desired.Activeconstituents, and optional vehicle also can be made freeze dried form, make solution by adding appropriate solvent before parenteral admin.
This type of solution for example is used for parenteral admin, also can be used for transfusion.
Preferably sanitas is, 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 for the treatment of 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), Etoposide, Rinotecan, taxol, Docetaxel, Mabthera (rituxan), Dx, Gefitinib or imatinib, also can with following medication combined use: Cyclosporin A, rapamycin, ascosin or its similar immunosuppressor are as cyclosporin A, Cyclosporin A G, FK-560, sirolimus or everolimus, cortical steroid is (as prednisone, endoxan, azathioprine (azathioprene), Rheumatrex, gold salt, sulfasalazine, antimalarial drug, brequinar, leflunomide, mizoribine, mycophenolic acid, mycophenolic acid morpholine ester, Gusperimus, the immunosuppression monoclonal antibody is (as 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 (as 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 described pharmaceutical composition contains as the The compounds of this invention of activeconstituents and one or more pharmaceutically acceptable diluent or carriers;
(4) be used for the treatment of the method for described any indication, this method comprises The compounds of this invention that gives described 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 described medicine is used for the treatment of 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 Combined Preparation, for example, will treat The compounds of this invention and the administration simultaneously of one or more other medicines or the sequential administration of significant quantity, described other medicines can be used for treating above-mentioned any indication;
(7) joint product, this joint product comprise The compounds of this invention and one or more other medicines for the treatment of significant quantity, and described 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 for the treatment of or prevents 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-benzamide 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, described method comprises the The compounds of this invention that gives significant quantity, and particularly 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzamide 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.
Particularly preferred in addition as the FAK inhibitor or as ALK inhibitor or the two common inhibitor and usually can be as follows according to the compound of the present invention of foregoing method preparation: 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base be amino]-N-methyl-benzamide, N
2-(4-[1,4 '] connection piperidyl-1 '-Ji-2-methoxyl group-phenyl)-5-chloro-N
4-[2-(propane-1-alkylsulfonyl)-phenyl]-pyrimidine-2; the 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 is 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, the 4-diamines, (2-methoxyl group-4-piperazine-1-base phenyl amino)-pyrimidine-4-base is amino for 2-[5-chloro-2-]-N-methyl-benzsulfamide, 2-[5-bromo-2-(5-fluoro-2-methoxyl group-phenyl amino)-pyrimidine-4-base is 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 is 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 is 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, limit the scope of the invention but be not used in.
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=ethylenediamine tetraacetic acid (EDTA), Et=ethyl, EtOAc=ethyl acetate, EtOH=ethanol, Eu-PT66=LANCE
TMThe anti-phosphorylated tyrosine antibody (Perkin Elmer) of europium-W1024-mark, FAK=focal adhesion kinase, FRET=FRET (fluorescence resonance energy transfer), 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
TMThat the conjugated Streptavidin of allophycocyanin (Perkin Elmer), subst.=replace, TBTU=O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-ammonium tetrafluoroborate, THF=tetrahydrofuran (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: ethyl 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: ethyl 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
To 2-(5-bromo-2-chloro-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).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: ethyl 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: ethyl 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) will to contain salt of wormwood under room temperature.Add saturated aqueous ammonium chloride solution, reaction mixture is poured in the water, use the ethyl acetate extraction secondary.With salt water washing 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-ethyl 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: ethyl acetate=10: 3): 0.33.
Embodiment 3: according to the method for embodiment 2, it is amino to prepare following 2-[5-bromo-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide and corresponding aniline]-N-methyl-benzene-sulphonamide:
Embodiment 4:2-[5-bromo-2-(phenyl amino of replacement)-pyrimidine-4-base is amino]-N-propyl group-benzene-sulphonamide
Can by with embodiment 2 similar methods, adopt 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-propyl group-benzsulfamide and corresponding aniline to prepare these compounds, 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 poured in the water and with ethyl acetate extraction 3 times.Wash organic phase with water, use the salt water washing then, through dried over sodium sulfate and vacuum-evaporation.Residue is through silica gel chromatography (normal hexane: ethyl 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: ethyl acetate=1: 1): 0.64.
Embodiment 5:2-[5-trifluoromethyl-2-(phenyl amino of replacement)-pyrimidine-4-base is amino]-N-methyl-benzsulfamide
Can by with embodiment 2 similar methods, employing-2-(2-chloro-5-trifluoromethyl-pyrimidine-4-base is amino)-N-methyl benzenesulfonamide and corresponding aniline prepare these compounds, 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: ethyl 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: ethyl 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 poured in the sodium bicarbonate aqueous solution and with ethyl acetate extraction 3 times.Wash organic layer with water, through dried over sodium sulfate and vacuum-drying.Residue is through column chromatography purifying (hexane: ethyl acetate=2: 1) obtain target compound.
Rf (hexane: ethyl 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-benzamide
To 2-(2,5-two chloro-pyrimidine-4-base-amino)-N-methyl-benzamide (5.05g, 17.0mmol) the 2-methyl cellosolve suspension of 90mL in add 2-methoxyl group-4-morpholinyl aniline dihydrochloride (4.56g, 16.2mmol) and 1N hydrogenchloride (17.0mmol) the ethanol liquid of 17.0mL.
Reaction mixture after 4 hours, is cooled to room temperature in 110 ℃ of stirrings, with 1N NaOH aqueous solution neutralization reactant, with EtOAc (100mL * 3) extraction.With salt water washing 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: it is amino 2) to obtain 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine of faint yellow solid-4-base]-N-methyl-benzamide.
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, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(2,5-two chloro-pyrimidine-4-base is amino)-N-methyl-benzamide and corresponding aniline]-N-methyl-benzamide.
| The embodiment numbering | Rx | Rf (solvent) or MS | NMR(400MHz)，δ(ppm) |
According to the method for embodiment 7A, it is amino to prepare following 2-[5-bromo-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(5-bromo-2-chloro-pyrimidine-4-base is amino)-N-ethyl-benzamide and corresponding aniline]-N-ethyl-benzamide.
According to the method for embodiment 7A, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(2,5-two chloro-pyrimidine-4-base is amino)-N-ethyl-benzamide and corresponding aniline]-N-ethyl-benzamide.
According to the method for embodiment 7A, from 2-(2,5-two chloro-pyrimidine-4-base is amino)-6, it is amino that N-dimethyl-benzamide and corresponding aniline prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base]-6, N-dimethyl-benzamide.
According to the method for embodiment 7A, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(2,5-two chloro-pyrimidine-4-base is amino)-5-fluoro-N-methyl-benzamide and corresponding aniline]-5-fluoro-N-methyl-benzamide.
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, 4.63mmol) THF (13mL) solution 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-2,3-xylylenimine-1-ketone (561.0mg, EtOAc 2.92mmol) (8.4mL) solution SnCl
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 mixture 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, it is amino that 3-dihydro-isoindole-1-ketone and corresponding aniline prepare following 7-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base]-2-methyl-2,3-dihydro-isoindole-1-ketone.
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 and corresponding aniline prepare following 7-(5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base is amino)-2-methyl-2,3-dihydro-isoindole-1-ketone.
Method according to embodiment 2, from 7-(2,5-two chloro-pyrimidine-4-base is amino)-2-ethyl-2,3-dihydro-isoindole-1-ketone and corresponding aniline prepare following 7-(5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base is amino)-2-ethyl-2,3-xylylenimine-1-ketone:
Embodiment 7B:2-5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzamide (the selectable synthetic method of embodiment 7A)
In-5 ℃, amino to 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base]-(5.5g adds Et in 100mL THF suspension 12.1mmol) to phenylformic acid
3N (2.06mL, 14.8mmol) and 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 precipitation, and wash with water, drying under reduced pressure obtains the intermediate (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 intermediate 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.With salt water washing 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 are as described in the embodiment 7A.
Adopt suitable initial substance and condition,, obtain following compounds by repeating aforesaid method.
According to the method for embodiment 2, prepare following 2-(5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base is amino)-N-methyl-5-tetramethyleneimine-1-base-benzamide from 2-(5-chloro-2-methyl-pyrimidine-4-base is amino)-N-methyl-5-tetramethyleneimine-1-base-benzamide and corresponding aniline.
According to the method for embodiment 2, it is amino to prepare following 2-[5-chloro-2-(4-fluoro-2-methoxyl group-phenyl amino)-pyrimidine-4-base from corresponding aniline]-5-substituting group-N-methyl-benzamide.
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-(phenyl amino of replacement)-pyrimidine-4-base is amino)-5-fluoro-N-methyl-benzamide from 2-(2,5-two chloro-pyrimidine-4-base is amino)-5-fluoro-N-methyl-benzamide and corresponding aniline.
According to the method for embodiment 7A, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-sec.-propyl-benzsulfamide and corresponding aniline]-N-sec.-propyl-benzsulfamide.
According to the method for embodiment 7A, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-methyl-benzsulfamide and corresponding aniline]-N-methyl-benzsulfamide.
| 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-(phenyl amino of replacement)-pyrimidine-4-base amino ready from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-sec-butyl-benzsulfamide and corresponding aniline self-control]-N-sec-butyl-benzsulfamide.
According to the method for embodiment 7A, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-isobutyl--benzsulfamide and corresponding aniline]-N-isobutyl--benzsulfamide.
According to the method for embodiment 7A, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-(1-ethyl-propyl group)-benzsulfamide and corresponding aniline]-N-(1-ethyl-propyl group)-benzsulfamide.
According to the method for embodiment 7A, it is amino to prepare following 2-[5-chloro-2-(phenyl amino of replacement)-pyrimidine-4-base from 2-(5-chloro-2-chloro-pyrimidine-4-base is amino)-N-cyclobutyl-benzsulfamide and corresponding aniline]-N-isobutyl--benzsulfamide.
| 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-(phenyl of replacement)-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-(phenyl of replacement)-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-(phenyl of replacement)-N
4-[2-(propane-2-alkylsulfonyl)-phenyl]-pyrimidine-2, the 4-diamines.
| Embodiment compiles | MS | NMR(400MHz)，CDCl 3，δppm |
Embodiment 36 (intermediate of the aniline on the left side)
The preparation of 36-1:2-amino-N-methyl-benzamide
Under room temperature, gradation adds 2N methylamine-tetrahydrofuran (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 salt water washing, Na
2SO
4Dry also concentrating under reduced pressure obtains the 2-amino-N-methyl-benzamide (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-benzamide
In the DMF (300mL) of the 2-of 15.0g (99.8mmol) amino-N-methyl-benzamide 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 precipitation, 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-benzamide (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-benzamide
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-benzamide
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 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 ethyl acetate.With salt water washing 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-ethyl 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: ethyl 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, use ethyl acetate extraction mixture 3 times.With salt water washing 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: ethyl 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 dimethyl formamide (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 salt water washing concentrates through dried over sodium sulfate and vacuum-evaporation.Residue obtains the target compound into colorless solid through silica gel chromatography (normal hexane-ethyl 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: ethyl acetate=3: 1): 0.63.
According to aforesaid method, the preparation following compounds.
Embodiment 36-16
The amine of non-replacement available from commercial sources synthetic:
3-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 poured in the water and with ethyl acetate extraction 2 times.Organic layer washes with water, uses the salt water washing then, and dried over mgso and vacuum-evaporation concentrate.Residue through silica gel chromatography (normal hexane: ethyl 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: ethyl acetate=3: 1): 0.40.
In hydrogen, with 4 '-methoxyl group-4-methyl-3-nitro biphenyl (630mg, 2.95mmol) and 10% palladium charcoal (63mg, methyl alcohol 0.059mmol) (6mL) suspension stirred 12 hours.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: ethyl 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 poured in the water and with ethyl acetate extraction 2 times.Organic layer washes with water, uses the salt water washing then, and dried over mgso and vacuum-evaporation concentrate.Residue is through silica gel chromatography (normal hexane: ethyl 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: ethyl acetate=10: 1): 0.13.
In methanol solution, obtain target compound by 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, 1.46mmol) toluene solution in add palladium diacetate (31.2mg, 0.139mmol) and 2-(two-tertiary butyl phosphino-) biphenyl (125mg, 0.403mmol), stirred 5 hours in 100 ℃.After the cooling, reactant is removed insolubles after filtration.Filtrate poured in the water and with ethyl acetate extraction 2 times.Organic layer washes with water, uses the salt water washing then, and dried over mgso and vacuum-evaporation concentrate.Residue is through silica gel chromatography (normal hexane: ethyl 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: ethyl acetate=5: 1): 0.20.
In methanol solution,, obtain target compound by in the presence of 10% palladium charcoal, carrying out with hydrogen reduction.
Embodiment 37: the amine of non-replacement available from commercial sources synthetic:
37-1:1-(3-methoxyl group-4-nitro-phenyl)-piperidines-4-alcohol
To piperidines-4-alcohol (2.79g, 28mmol) and salt of wormwood ((4.0g 23mmol), and stirred 24 hours under room temperature to add 4-fluoro-2-methoxyl group-1-nitro-benzene in dinethylformamide (40mL) suspension for 3.88g, N 28mmol).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 initial substance and condition,, obtain following compounds by repeating aforesaid method.
| The embodiment numbering | Rx | Appraising datum |
38:1-[4-(4-methoxyl group-3-nitro-phenyl)-piperazine-1-yl]-preparation of 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.Filtrate poured in the water and with ethyl acetate extraction 2 times.Organic layer washes with water, uses the salt water washing then, and dried over mgso and vacuum-evaporation concentrate.Residue through silica gel chromatography (normal hexane: the ethyl acetate gradient), obtain 1-[4-(4-methoxyl group-3-nitro-phenyl)-piperazine-1-yl into yellow solid]-ethyl ketone (319mg, 44%).
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 (ethyl 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) and salt of wormwood (20.2g), and under 70 ℃ with said mixture stirring 20 hours.After the filtration, filtrate is poured in the water (about 300mL), filter and collect the gained precipitation, wash with water then several times, obtain target compound (8.98g), yield 61% into orange solids.
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)。
40:1-[1-(3-methoxyl group-4-nitro-phenyl)-piperidin-4-yl]-preparation of 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 and use 1N sodium-chlor extraction 3 times.With 2N sodium hydroxide alkalization water layer, and with dichloromethane extraction 3 times.With salt water washing organic layer, through dried over sodium sulfate and vacuum-evaporation, obtain 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, used ethyl acetate extraction 2 times.Organic layer washes with water, uses the salt water washing then, and dried over mgso and vacuum-evaporation concentrate.Residue through silica gel chromatography (normal hexane: ethyl 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: ethyl 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 poured in the water and with ethyl acetate extraction 2 times.With salt water washing 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-ethyl 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 group)-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) and 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 usefulness ethyl acetate extraction 2 times into.Use dil. hydrochloric acid and salt water washing organic layer successively, concentrate, obtain the crude product 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 group)-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.Ethyl acetate extraction 2 times of gained mixture, then with organic layer water successively and salt water washing, through dried over sodium sulfate, filtration and vacuum-evaporation concentrate, and obtain crude product 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 uses the cooling of the 1N HCl aqueous solution at leisure in 0 ℃.Ethyl acetate extraction 2 times of gained mixture are used the salt water washing continuously with organic layer then, and through dried over sodium sulfate, filtration and vacuum-evaporation concentrate, and obtain crude product 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 crude product 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 salt water washing successively, and through dried over sodium sulfate, filtration and vacuum-evaporation concentrate, and obtain the crude product 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 group)-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 ethyl acetate extraction 2 times, organic layer water and salt solution wash successively then, and through dried over sodium sulfate, filtration and vacuum-evaporation concentrate, and obtain the crude product 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 group)-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.The reactant stirring is spent the night.Reaction mixture is filtered by Celite pad, use methanol wash.With the filtrate vacuum concentration, obtain 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 initial substance and condition,, obtain following compounds by 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, use 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: ethyl 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: ethyl 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, 1.46mmol) toluene suspension in add 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.Filtrate is inclined to water, used 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: ethyl 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: ethyl 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
To 1.0g (3.37mmol) 2-(2,5-two chloro-pyrimidine-4-base is amino)-add in the 15ml acetic acid solution of N-methyl-benzamide 2-methoxyl group-4-morpholinyl aniline dihydrochloride (1.9g, 6.73mmol) and 6.0ml 1N hydrogenchloride (6.0mmol) ethanolic soln.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 precipitation 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 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 poured in the frozen water and with extracted with diethyl ether 3 times.Organic layer washes with water, uses the salt water washing 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)。
The SULPHURYL CHLORIDE of this replacement and the reaction of suitable amine.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
Amino to 2-[5-bromo-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base]-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 was stirred 1 hour in 50 ℃.In reaction mixture, add entry, and with ethyl acetate extraction 3 times.Organic layer washes with water, 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 ℃ to add aluminum chloride in 0 ℃ in solution.After being cooled to room temperature, adding entry and use ethyl acetate extraction 2 times.Organic layer salt water washing is through dried over sodium sulfate and concentrating under reduced pressure.The gained solid is collected after filtration and with the ether washing, is obtained 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, washes with water and obtains lavender solid (3.96g, 65%).
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 described 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, the aniline that replaces 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:
| Compound number | Structure | Physical data 1H NMR 400MHz(DMSO-d 6) and/or MS (m/z) |
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 polypropylene 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 inhibitor 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 inhibitor 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 obtains under the situation that does not have given the test agent 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 by 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.Determine the verity of ZAP-70cDNA insert by 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 by plaque purification technique (plaque-purification) then, amplification in a small amount, adopt subsequently and derive from commercial anti--ZAP-70 antibody (Clone 2F3.1, Upstate Biotechnology, Lake Placid, NY, USA) expression by 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).By 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): by synthesizing similar methods with known peptide, preparation is used as the biotinylated peptide LAT-11 (Biotin-EEGAPDYENLQELN) of substrate in the analysis of ZAP-70 kinases.Adopt 20% DMF solution of piperidines, with Fmoc-Asn (Trt)-oxygen ylmethyl-4-phenoxymethyl-the N-α Fmoc group of (polystyrene-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 protecting [Asp (OtBu), Glu (OtBu), Asn (Trt), Gin (Trt) and Tyr (tBu)] is carried out coupling on its side chain.After the peptide chain assembling is finished; 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 filtrate that merges, with ether washing and dry.On C-18 macroporous silica gel post, adopt 2% phosphate aqueous solution gradient elution of acetonitrile, pass through chromatogram purified product.Collection contains the fraction of the thing that isozygotys, and filters by 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 inhibitor 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.By at Forene
Anesthesia (Abbott Japan Co., 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.By 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 mean value that anti-tumor activity increases with the animal subject gross tumor volume represents divided by the mean value that the gross tumor volume of untreated animal increases, multiply by 100 after, with Δ T/C[%] expression.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 described 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 as 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 made paste with the water of 5 times of amounts, pulverulent mixture is kneaded together until obtaining the slightly agglomerate of plasticity with paste.
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, for example a kind of in the formula of describing in embodiment 1-131 (I) compound:
Form:
Activeconstituents 250g
2 liters of lauroglykol
Preparation 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 | FAKIC50 (nM) | Phos IC 50 (μM) | Growth IC 50 (μM) | T cell migration IC 50(μM) | IGF-1R IC 50 (μM) |
| 1.00 2.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 | 140 13 44 36 9.1 32 21 13 16 74 48 52 9 5.4 58 54 7 48 2.8 | 0.7 1.2 0.34 0.85 0.14 0.53 0.17 0.11 0.45 0.3 0.5 0.95 0.04 0.01 1.7 0.4 0.02 1.1 0.03 | ＞10 ＞10 4 0.8 2 2 2 2 6 0.7 ＞10 0.3 1 0.6 5 0.8 3 0.2 | ＞10 0.2 0.74 0.94 ＜0.08 |
| 3.18 3.19 3.20 3.22 3.23 3.24 3.25 3.26 3.28 3.29 3.30 3.31 3.32 3.33 3.34 3.35 3.36 3.37 3.38 3.39 3.40 3.41 3.42 3.43 3.44 3.45 3.46 3.47 3.48 3.49 3.50 3.51 3.52 3.53 3.54 3.55 3.56 3.57 3.58 3.59 3.60 3.61 3.62 3.63 3.64 3.65 3.66 3.67 3.68 3.69 3.70 | 130 6.8 16 120 38 64 22 50 43 89 69 13 14 2.9 7 13 43 39 64 2 9 22 29 5.6 11 0.9 4 1 7 39 13 29 29 6 0.9 34 28 28 21 95 90 12 63 27 5 8 1 6 5.5 4 3.5 | 1.5 0.35 0.22 0.9 0.39 3.5 0.3 0.79 0.71 0.6 0.6 1.1 0.18 0.03 0.1 0.02 1.8 1.1 1.7 0.02 ＞10 ＞10 0.35 0.2 0.05 0.02 0.1 0.1 0.07 10 0.12 0.2 0.42 0.07 0.01 ＞10 0.53 0.61 0.08 1.2 0.93 10 ＞10 ＞10 0.13 0.08 0.08 0.38 0.2 0.2 0.02 | 9 0.8 0.3 2 0.5 5 0.3 2 0.7 ＞10 3 5 0.49 0.05 0.24 0.17 2.8 2.6 3.8 0.03 0.9 0.43 0.3 0.11 0.09 0.02 0.18 0.06 0.3 0.39 1 0.4 2 0.21 0.07 3 0.15 3 0.3 ＞10 2 ＞10 ＞10 ＞10 0.7 0.1 0.07 0.39 0.63 0.11 0.13 | 0.28 0.09 0.13 0.8 1 0.3 0.21 1 0.58 | 0.1 0.81 0.12 0.13 ＜0.08 3.55 0.09 0.27 0.09 0.21 1.19 0.41 ＜0.08 0.14 0.15 0.25 |
| 3.71 3.72 3.73 3.74 3.75 3.76 3.77 3.78 3.79 3.80 3.81 3.82 3.83 3.84 6.00 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 7.19 7.20 7.21 7.22 7.23 7.24 7.25 7.25 7.26 7.27 7.28 7.29 7.30 8.01 8.02 8.03 8.04 | 11 2.1 11 15 72 15 65 10 5 12 21 4.8 20 10 110 5.3 4.7 7.5 2.9 5.2 6.2 17 4.1 8.7 8.2 6.6 2.5 1.9 5.5 7.6 4.5 6.4 4.3 6.2 13 2.5 3.3 25 1.4 5.1 13 2 4.1 21 34 57 2.1 6.6 2.4 13 8 | 0.05 0.11 0.03 0.1 0.5 0.29 ＞10 ＞10 1.3 0.22 0.52 0.2 0.08 1 0.35 0.21 0.6 0.1 0.3 1 0.3 0.8 0.9 0.8 1 1 0.6 0.9 0.8 0.3 0.06 0.2 0.7 0.5 ＞10 ＞10 0.2 ＞10 0.5 1 2 0.6 0.5 0.22 ＞10 | 0.08 0.06 0.29 0.15 1.3 1.3 3 0.22 0.12 0.45 0.98 0.07 0.32 0.08 5 0.47 0.54 0.36 0.39 0.29 0.2 1.09 0.18 1 0.85 0.98 1.2 1 1.22 0.36 0.19 0.42 0.69 0.7 0.33 0.11 0.46 0.48 0.25 0.09 0.73 0.57 0.15 0.22 0.15 0.48 0.3 0.33 0.99 1 1.1 | 0.7 0.04 0.25 0.31 1 | 1.63 5 ＞10 0.68 0.19 0.19 0.77 0.27 0.25 0.77 0.62 0.33 0.26 ＞10 |
| 9.01 9.02 9.03 9.04 9.05 9.06 9.07 10.01 10.02 10.03 11.01 11.02 11.03 11.04 12.01 12.02 12.03 12.04 12.06 13.01 14.01 14.02 14.03 14.04 14.05 14.06 14.07 15.01 15.02 15.03 16.01 16.02 16.03 16.04 16B 16.C 18.01 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 | 22 15 18 13 22 23 17 39 26 23 9 4.1 26 4.3 2.5 1.6 2.3 1.1 2.6 65 19 190 30 18 37 63 7.5 15 21 44 44 6 21 9.5 11 28 19 ＜1 1.6 ＜1 1.6 1.8 5 2.1 3.2 1.3 1.3 38 9 2.5 2.6 | 0.36 0.5 0.1 0.2 0.36 3 ＞10 1 0.9 0.9 0.7 0.8 0.41 ＞10 0.09 0.2 2 10 ＞10 10 0.2 10 ＞10 2 ＞10 ＞10 3 ＞10 3 0.9 ＞10 0.2 0.13 0.3 0.2 0.2 1 0.3 0.03 0.17 0.06 ＞10 ＞10 0.3 0.4 | 1 0.81 0.37 0.73 1.6 0.4 0.26 0.44 1.06 2.4 0.85 0.69 0.1 3.2 0.4 0.05 0.25 0.14 0.81 1.47 1.1 1.01 0.54 1 1.11 1.4 0.47 0.66 1.67 4 0.6 ＞10 0.92 7 ＞10 1.29 0.3 0.38 0.09 0.34 0.67 0.7 0.11 0.4 0.39 0.56 2 0.7 1.1 1.13 | 0.6 0.3 0.22 0.28 1 0.29 0.07 0.29 0.3 | 0.6 1.41 0.91 0.64 0.14 0.47 0.13 0.48 1.02 0.63 0.44 |
| 19.15 19.16 19.17 19.18 19.19 19.20 19.21 19.22 19.23 19.24 19.25 19.26 19.27 19.28 19.29 19.30 19.31 19.32 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 20.10 20.11 20.12 20.13 20.14 20.15 20.16 20.17 20.18 20.19 20.20 20.21 20.22 20.23 20.24 20.25 20.26 20.27 20.28 20.29 20.30 20.31 20.32 20.33 | 3.1 2.3 1 7 5.7 1.6 84 3.4 6.4 1.8 7.2 6.1 1.5 4.8 1.9 ＜1 1.8 1.4 10 9 42 23 6.8 5 3 6.8 2 2 26 9.5 6.3 33 14 7.5 2 15 28 3.12 26 8 30 19 6.2 5.3 12 9.2 6.1 7.6 39 13 2.5 | 0.5 0.7 ＞10 0.13 0.03 ＞10 0.12 0.7 0.05 1 0.1 0.3 0.1 0.06 0.4 0.2 0.3 0.12 0.4 0.58 0.87 0.36 0.1 0.17 0.3 0.1 2 0.4 3 ＞10 0.49 0.48 0.21 0.76 0.85 0.17 0.2 0.3 | 0.36 1.1 0.17 0.87 0.4 0.07 1.71 0.51 0.71 0.12 0.49 0.3 0.4 0.12 0.1 0.38 0.31 0.18 0.17 2.5 1.9 1.46 0.14 0.05 0.05 0.01 0.02 0.4 0.04 0.32 0.97 0.06 0.14 0.81 0.21 0.68 0.19 3 2 0.06 0.27 0.05 0.08 0.05 0.08 0.5 0.11 0.38 | 0.3 0.25 0.75 49 0.29 0.3 | 0.23 0.24 0.46 0.7 0.52 2.78 0.38 0.1 0.29 0.42 0.31 0.67 |
| 20.34 20.35 21.01 21.02 21.03 21.04 22.01 22.02 22.03 23.01 23.02 23.03 23.04 23.05 23.06 23.07 23.08 23.09 24.01 24.02 24.03 25.01 25.02 26.01 26.02 26.03 26.04 26.05 26.06 26.07 26.08 26.09 26.10 26.11 26.12 26.13 26.14 26.15 26.16 26.17 26.18 26.19 26.20 26.21 26.22 26.23 26.24 26.25 26.26 26.27 26.28 | 13 8.7 1 8.5 1.7 1.8 43 26 6.6 3.4 1.5 1.7 1.2 1.9 16 2.1 6.7 2.1 3.6 2.1 1 8.5 3 4.4 1.9 1.4 4.9 2.1 4.4 11 2.9 2.3 2 4.4 3.7 1.6 5 6.9 9 17 1.3 9.2 10 1.1 ＜1 1.4 1 ＜1 1.9 4.8 2.1 | 1 0.09 0.07 0.33 0.3 0.05 ＞10 1 0.09 0.6 0.2 1 0.9 ＞10 1 3 0.3 0.2 0.11 0.5 0.3 3 0.4 0.05 0.03 0.1 0.05 0.09 0.1 0.5 0.01 0.04 0.01 0.4 0.2 0.2 1.2 0.32 0.3 6 0.43 0.14 0.1 0.1 0.3 0.5 0.6 0.2 0.6 0.5 | 0.12 0.09 0.19 ＞10 0.3 0.3 ＞10 3 0.15 0.2 0.4 1.12 1.07 0.59 0.57 0.84 0.49 0.28 0.44 0.11 1.08 1 0.13 0.35 0.12 0.13 0.43 0.23 0.35 0.95 0.18 0.22 0.14 0.78 0.19 0.44 0.19 0.08 2 0.1 1.17 0.79 0.22 0.49 0.28 0.09 0.48 0.73 0.07 1.49 1.52 | 0.63 0.09 0.29 0.5 0.26 0.6 0.3 0.9 0.3 | 0.15 0.47 0.26 0.53 0.8 0.82 0.6 0.05 0.39 0.64 0.29 0.39 0.23 1.16 1.5 0.07 0.49 0.18 0.34 |
| 26.29 26.30 26.31 26.32 26.33 26.34 26.35 26.36 26.37 26.38 26.39 27.01 27.02 27.03 27.04 27.05 27.06 27.07 27.08 27.09 28.01 28.02 28.03 28.04 28.05 28.06 28.07 28.08 28.09 28.10 28.11 28.12 28.13 28.14 28.15 28.16 28.17 28.18 28.19 28.20 28.21 28.22 28.23 28.24 28.25 28.26 28.27 28.28 28.29 28.30 28.31 | ＜1 4.4 2 1.6 4 7 4.5 1.9 ＜1 ＜1 3.1 14 5.1 6.3 11 8.2 1 5.5 9.3 4.2 12 1.9 7.4 7.5 6.7 17 47 4.6 3.1 20 4.2 3.2 7.8 3 10 11 15 9.1 3.7 4.4 1.3 1.3 5.9 2.9 3.9 6.6 2.4 5.2 11 2.3 7.4 | 0.31 1 0.3 0.06 0.5 ＞10 0.1 0.04 0.08 2 0.6 0.5 0.3 0.08 0.07 0.3 0.1 0.6 3 0.4 0.5 3 0.5 0.3 0.1 0.1 0.5 0.11 0.16 ＞10 0.5 2 0.1 0.1 0.5 0.2 0.04 0.2 0.3 0.4 0.4 0.9 0.06 | 0.26 0.76 0.16 0.05 0.06 0.1 0.05 0.07 0.47 1.1 0.56 0.27 0.3 0.31 0.57 0.75 0.36 0.46 0.44 0.29 0.3 0.12 0.56 ＞10 0.37 0.36 1.85 0.63 0.43 0.55 1.44 0.69 1 1.9 2.03 0.14 0.4 0.23 0.3 0.28 0.09 0.13 0.57 0.42 0.52 0.36 0.11 1.06 | 0.6 0.23 0.25 0.3 0.09 0.29 0.6 0.5 1 | 0.3 3.71 1.39 0.1 2.57 |
| 29.01 29.02 29.03 30.01 30.02 30.03 30.04 30.05 30.06 30.07 31.01 31.02 32.01 32.02 33.01 33.02 34.01 34.02 34.03 34.04 34.05 34.06 34.07 34.08 35.01 35.02 51.00 52.00 | 13 3.3 5.6 22 12 19 25 8.5 15 8.8 30 31 4.1 5.9 2.5 5.2 8 11 33 13 51 14 27 8.7 6.8 6.1 8.1 13 | 0.7 0.7 0.1 0.2 0.2 0.5 0.3 2 1 0.6 ＞10 0.28 0.1 0.05 0.08 0.06 0.1 0.08 0.19 ＞10 0.36 ＞10 ＞10 ＞10 ＞10 0.7 0.013 0.2 | 2.2 1.1 0.99 0.89 0.47 0.68 0.99 0.29 1.03 0.47 1.6 0.29 0.29 0.37 0.25 0.25 0.37 1.17 2.25 1.22 5.1 3 2.7 1.9 1.43 0.23 0.19 0.41 | 0.09 0.42 0.12 0.1 0.28 0.2 ＜0.08 |
Claims (22)
1. be used for the treatment of and the tyrosine kinase activity diseases associated of a modification lymphoma kinases (ALK) in formula (I) compound and salt thereof:
Wherein:
R is selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl 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
8Cycloalkyl, C
3-C
8Cycloalkyl 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, the unsubstituted or C that replaces
5-C
10Aryl, unsubstituted or replace 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, the unsubstituted or C that replaces
5-C
10Aryl C
1-C
8Heterocyclyloxy base alkoxyl group, replacement or that replace, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group, unsubstituted or the amino, the C that replace
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, the unsubstituted or formamyl that replaces, the unsubstituted or sulfamyl that replaces, cyano group, 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
3-12Cycloalkyl;
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 the formamyl, cyano group or the nitro that replace;
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
8Cycloalkyl, C
3-C
8Cycloalkyl 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, the unsubstituted or C that replaces
5-C
10Aryl, unsubstituted or replace 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, the unsubstituted or amino C that replaces
1-C
8Alkoxyl group, the unsubstituted or C that replaces
5-C
10Aryl C
1-C
8Alkoxyl group, the unsubstituted or heterocyclyloxy base that replaces, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkyl, the unsubstituted or heterocyclic radical C that replaces
1-C
8Alkoxyl group, unsubstituted or the amino, the C that replace
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, the unsubstituted or formamyl that replaces, the unsubstituted or sulfamyl that replaces, cyano group, 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 the carbon atom that it connected form unsubstituted or replace contain 0,1,2 or 3 heteroatomic 5 or 6 yuan of carbocyclic rings or heterocycle that is selected from N, O and S;
X is key or C
1-6Alkylidene group; And
R
11Independently be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl and C
3-10Heterocyclylalkyl;
And R
11Any aryl, heteroaryl, cycloalkyl 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 C that alkyl replaces
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.
2. according to the purposes of formula (I) compound of claim 1, wherein
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 is as trifluoromethyl; Unsubstituted or replace C
5-C
10Aryl is as phenyl or p-methoxy-phenyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocycle that are selected from N, O and S, as morpholine-1-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Halo C
1-C
8Alkoxyl group is as trifluoromethoxy; C
5-C
10Aryloxy is as phenoxy group); Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group); Unsubstituted or replace amino is as methylamino, dimethylamino or acetylamino; C
1-C
8Alkyl sulphonyl is as methyl sulphonyl; Halogen is as fluorine or chlorine; Unsubstituted or replace formamyl, as 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 replace sulfamyl is as 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;
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 is as trifluoromethyl; Unsubstituted or replace C
5-C
10Aryl is as phenyl or p-methoxy-phenyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Halo C
1-C
8Alkoxyl group is as trifluoromethoxy; C
5-C
10Aryloxy is as phenoxy group; Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group; Unsubstituted or replace amino is as methylamino, dimethylamino or acetylamino; C
1-C
8Alkyl sulphonyl is as methyl sulphonyl; Halogen is as fluorine or chlorine; Unsubstituted or replace formamyl is as cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl; Unsubstituted or replace sulfamyl is as 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;
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 is as trifluoromethyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as 2-pyrroles's ketone group or S, S-dioxo isothiazole alkyl; C
1-C
8Alkoxyl group is as methoxyl group; The amino that replaces is as acetylamino, ethanoyl-methyl-amino, benzoyl-amido, methyl sulphonyl amino or phenyl sulfonyl amino; C
1-C
8Alkyl sulphonyl is as methyl sulphonyl, propyl group-alkylsulfonyl, cyclohexyl-alkylsulfonyl, sec.-propyl-alkylsulfonyl; C
5-C
10Aryl sulfonyl is as phenyl sulfonyl; Halogen is as fluorine or chlorine; Carboxyl; That replace or unsubstituted formamyl is as formamyl, methylamino formyl radical, ethyl-amino-carbonyl or formyl-dimethylamino; Unsubstituted or replace sulfamyl, as 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;
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, wherein 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-;
R
4Be hydrogen or C
1-C
8Alkyl is as methyl; Be preferably hydrogen;
R
5Be hydrogen; C
1-C
8Alkyl is as methyl or ethyl; Halogen is as chlorine or bromine; Halo C
1-C
8Alkyl is as trifluoromethyl; Cyano group or nitro; Be preferably hydrogen, methyl, ethyl, chlorine, bromine, trifluoromethyl or nitro; Be preferably chlorine or bromine especially;
R
6Be hydrogen;
R
7And R
9Independent is hydrogen; C
1-C
8Alkyl is as methyl, ethyl or sec.-propyl; Hydroxyl C
1-C
6Alkyl is as hydroxyethyl or hydroxybutyl; C
1-C
8Alkyl-carbonyl is as the methyl carbonyl; Aminoalkoxy is as the diethyl amino base oxethyl; Halo C
1-C
8Alkyl is as trifluoromethyl; Unsubstituted or replace C
5-C
10Aryl is as phenyl or p-methoxy-phenyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Halo C
1-C
8Alkoxyl group is as trifluoromethoxy; C
5-C
10Aryloxy is as phenoxy group; Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group; Unsubstituted or replace amino is as methylamino, dimethylamino or acetylamino; C
1-C
8Alkyl sulphonyl is as methyl sulphonyl; The heterocycle alkylsulfonyl is as the piperazinyl alkylsulfonyl; The heterocycle carbonyl is as methylpiperazine base carbonyl; Cyano group; Halogen is as fluorine or chlorine; Unsubstituted or replace formamyl is as cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl; Unsubstituted or replace sulfamyl is as 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 group, 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;
R
8Be hydrogen; C
1-C
8Alkyl is as methyl, ethyl or sec.-propyl; Hydroxyl C
1-C
8Alkyl is as hydroxyethyl or hydroxybutyl; Halo C
1-C
8Alkyl is as trifluoromethyl; C
5-C
10Aryl is as phenyl or p-methoxy-phenyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); The heterocyclic radical alkyl is as methyl (piperazine-1-yl) ethyl; The heterocyclic radical carbonyl is as (piperazine-1-yl) carbonyl; Heterocyclic radical C
1-C
8Alkylamino is as pyridyl ethyl (methyl) amino; C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Halo C
1-C
8Alkoxyl group is as trifluoromethoxy; C
5-C
10Aryloxy is as phenoxy group; Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group; Unsubstituted or replace amino is as methylamino or dimethylamino; C
1-C
8Alkylamino-C
1-C
8Alkylamino is as dimethylamino-propyl group amino; C
1-C
8Alkyl sulphonyl is as methyl sulphonyl; Halogen is as fluorine or chlorine; Unsubstituted or replace formamyl is as cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl; Unsubstituted or replace sulfamyl is as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl; Cyano group 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 group, 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;
R
10Be hydrogen; C
1-C
8Alkyl is as methyl, ethyl or butyl; Hydroxyl; Cyano group; Hydroxyl C
1-C
8Alkyl is as hydroxyethyl or hydroxybutyl; Halo C
1-C
8Alkyl is as trifluoromethyl; C
1-C
8Alkoxyl group is as methoxy or ethoxy; Cycloalkyl alkoxy; Aryloxy; Halo C
1-C
8Alkoxyl group; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group; Unsubstituted or replace amino is as methylamino or dimethylamino; Halogen is as fluorine or chlorine; Carboxyl; Formamyl; Or sulfamyl unsubstituted or that replace, as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl; Preferable methyl, butyl, methoxyl group, oxyethyl group, 2-(1-imidazolyl) oxyethyl group, methylamino, dimethylamino or fluorine; And
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-.
3. according to the purposes of formula (I) compound of claim 1 or 2, wherein
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-two oxa-s-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, diethyl-amino-oxyethyl group, amino-carbonyl, ethyl, 2-oxo-tetramethyleneimine-1-base, pyrrolidyl, pyrrolidyl-methyl, optional piperidyl, morpholine-4-base, dimethylamino, dimethylamino-propyl group-amino, methyl-amino and the ethyl-amino that is replaced by methyl or ethyl.
4. according to the purposes of formula (I) compound of claim, wherein
R
0Or R
2Independent is hydrogen; C
1-C
8Alkyl is as methyl, ethyl or sec.-propyl; Halo C
1-C
8Alkyl is as trifluoromethyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group; Unsubstituted or replace amino is as methylamino, dimethylamino or acetylamino; Halogen is as fluorine or chlorine; Preferred hydrogen, piperazine-1-base, N-methyl (piperazine-1-yl) or 1-methyl-4-piperazinyl oxygen base are preferably hydrogen especially;
R
1Be hydrogen; C
1-C
8Alkyl is as methyl, ethyl or sec.-propyl; Halo C
1-C
8Alkyl is as trifluoromethyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group; Unsubstituted or replace amino is as methylamino, dimethylamino or acetylamino; Halogen is as 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;
R
3Be hydrogen; C
1-C
8Alkyl is as methyl or ethyl; Halo C
1-C
8Alkyl is as trifluoromethyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as 2-pyrroles's ketone group or S, S-dioxo isothiazole alkyl; C
1-C
8Alkoxyl group is as methoxyl group; The amino that replaces is as acetylamino, ethanoyl-methyl-amino, benzoyl-amido, methyl sulphonyl amino or phenyl sulfonyl amino; C
1-C
8Alkyl sulphonyl is as methyl sulphonyl; C
5-C
10Aryl sulfonyl is as phenyl sulfonyl; Halogen is as fluorine or chlorine; Carboxyl; That replace or unsubstituted formamyl is as formamyl, methylamino formyl radical or formyl-dimethylamino; Unsubstituted or replace sulfamyl, as 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;
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, wherein 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-;
R
4Be hydrogen;
R
5Be hydrogen; Halogen is as chlorine or bromine; Halo C
1-C
8Alkyl is as trifluoromethyl; Or nitro; Be preferably hydrogen, chlorine, bromine, trifluoromethyl or nitro; Be preferably chlorine or bromine especially;
R
6Be hydrogen;
R
7And R
9Independent is hydrogen; C
1-C
8Alkyl is as methyl, ethyl or sec.-propyl; Halo C
1-C
8Alkyl is as trifluoromethyl; Unsubstituted or replace C
5-C
10Aryl is as phenyl or p-methoxy-phenyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group; Unsubstituted or replace amino is as methylamino, dimethylamino or acetylamino; Halogen is as fluorine or chlorine; Unsubstituted or replace formamyl is as cyclohexyl carboxyamide base, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl, N-methyl (piperazine-1-yl) carbonyl or (morpholine-4-yl) carbonyl; Unsubstituted or replace sulfamyl is as sulfamyl, methyl sulfamyl or dimethylamino alkylsulfonyl; Preferred hydrogen, methyl, sec.-propyl, trifluoromethyl, phenyl, adjacent-, between-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 group, 3-(morpholine-4-yl) propoxy-, 2-(morpholine-4-yl) oxyethyl group, 2-(l-imidazolyl) oxyethyl group, dimethylamino, fluorine, (morpholine-4-yl) carbonyl, (piperidines-1-yl) carbonyl, (piperazine-1-yl) carbonyl or cyclohexyl carboxyamide base;
R
8Be hydrogen; C
1-C
8Alkyl is as methyl, ethyl or sec.-propyl; Halo C
1-C
8Alkyl is as trifluoromethyl; C
5-C
10Aryl is as phenyl or p-methoxy-phenyl; Unsubstituted or replace C
5-C
10Aryl is as phenyl or p-methoxy-phenyl; Unsubstituted or replace contain 1 or 2 heteroatomic 5 or 6 yuan of heterocyclic radical that are selected from N, O and S, as morpholine-4-base, piperidines-1-base, piperazine-1-base or N-methyl (piperazine-1-yl); C
1-C
8Alkoxyl group is as methoxyl group, oxyethyl group or isopropoxy; Halo C
1-C
8Alkoxyl group is as trifluoromethoxy; C
5-C
10Aryloxy is as phenoxy group; Unsubstituted or replace heterocyclyloxy base is as 1-methyl-4-piperidyl oxygen base; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group, 3-(morpholine-4-yl) propoxy-or 2-(morpholine-4-yl) oxyethyl group; Unsubstituted or replace amino is as methylamino or dimethylamino; Halogen is as fluorine or chlorine; Unsubstituted or replace sulfamyl is as 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 group, 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;
R
10Be C
1-C
8Alkyl is as methyl, ethyl or butyl; Halo C
1-C
8Alkyl is as trifluoromethyl; C
1-C
8Alkoxyl group is as methoxy or ethoxy; Unsubstituted or replace heterocyclic radical C
1-C
8Alkoxyl group is as 2-(1-imidazolyl) oxyethyl group; Unsubstituted or replace amino is as methylamino or dimethylamino; Halogen is as fluorine or chlorine; Preferable methyl, butyl, methoxyl group, oxyethyl group, 2-(1-imidazolyl) oxyethyl group, methylamino, dimethylamino or fluorine; And
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-.
5. the purposes of the compound of formula (I), wherein said compound is selected from the compound of embodiment 1-53.
6. the compound of formula (I ') and pharmacy acceptable salt, hydrate, solvate, isomer and prodrug, prerequisite is the compound that does not comprise embodiment 1-52,
Wherein:
N ' is selected from 1,2 and 3;
R '
1Be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl and C
5-12Heterocyclylalkyl;
R ' wherein
1Arbitrary aryl, heteroaryl, cycloalkyl 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-replacement-C
1-6Alkyl, halogen-replacement-C
1-6Alkyl, halogen-replacement-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
3-12Cycloalkyl-C
1-4Alkyl; And R '
4Be selected from C
6-10Aryl, C
5-10Heteroaryl, C
3-12Cycloalkyl and C
3-10Heterocyclylalkyl;
R '
4Arbitrary aryl, heteroaryl, cycloalkyl 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 C that alkyl replaces
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, cyano group, C
1-6Alkyl, halogen-replacement-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
12Cycloalkyl.
7. the formula I ' compound of claim 6, 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
12Cycloalkyl 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-replacement-C
1-6Alkyl, optional by C
1-6The C that alkyl replaces
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
12Cycloalkyl.
8. according to formula (I ') compound of claim 6 or 7, R ' wherein
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-two oxa-s-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, diethyl-amino-oxyethyl group, amino-carbonyl, ethyl, 2-oxo-tetramethyleneimine-1-base, pyrrolidyl, pyrrolidyl-methyl, optional piperidyl, morpholine-4-base, dimethylamino, dimethylamino-propyl group-amino, methyl-amino and the ethyl-amino that is replaced by methyl or ethyl.
9. according to claim 6,7 or 8 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.
10. according to each formula I compound among the claim 6-9, wherein said compound is the compound of embodiment 53.
11. pharmaceutical composition, this pharmaceutical composition comprise among the claim 1-9 that each compound is as activeconstituents and one or more pharmaceutically acceptable diluent or carriers.
12. each compound is used for the treatment of or prevents purposes in the medicine of ND or disease of immune system in preparation among the claim 1-9.
13. joint product, this joint product comprise among the claim 1-9 that treats significant quantity each compound and one or more other medicines, described other medicines can be used for treating ND or disease of immune system.
14. the method for treatment ND or disease of immune system, this method comprise among the claim 1-9 that needs the patient treatment of this treatment significant quantity each compound or contain the pharmaceutical composition of this compound.
15. among the claim 1-9 each compound or its pharmacy acceptable salt preparation be used for the treatment of or the medicine of the disease preventing to suppress in response to FAK and/or ALK and/or ZAP-70 and/or IGF-IR in purposes.
16. the purposes of claim 15, wherein said disease to be treated is selected from proliferative disease.
17. the purposes of claim 16, wherein said proliferative disease is selected from following tumour: breast, kidney, prostate gland, knot rectum, Tiroidina, ovary, pancreas, neurone, lung, uterus and gastroenteric tumor and osteosarcoma and melanoma.
18. the purposes of claim 15, wherein said disease to be treated is an immunological disease.
19. each compound or its pharmacy acceptable salt are used for the treatment of or prevent purposes in the medicine of inflammatory diseases and/or immunological disease in preparation among the claim 1-9.
20. the purposes of claim 19, wherein said inflammatory diseases and/or immunological disease are selected from the autoimmune disorder of graft-rejection, allergy and immunocyte mediation, and described immunocyte is selected from T lymphocyte, bone-marrow-derived lymphocyte, scavenger cell, dendritic cell, mastocyte and eosinophil.
21. each purposes among the claim 14-19, wherein said compound are 2-[5-bromo-2-(2-methoxyl group-5-morpholine-4-base-phenyl amino)-pyrimidine-4-base-amino]-N-methyl-benzsulfamide 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.
22. each purposes among the claim 14-19, wherein said compound is selected from: 2-[5-chloro-2-(2-methoxyl group-4-morpholine-4-base-phenyl amino)-pyrimidine-4-base is amino]-N-methyl-benzamide, N
2-(4-[1,4 '] connection 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 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-2,4-diamines or its pharmacy acceptable salt.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0319227A GB0319227D0 (en) | 2003-08-15 | 2003-08-15 | Organic compounds |
| GB0319227.5 | 2003-08-15 | ||
| 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 |
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| Publication Number | Publication Date |
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| CN1832929A true CN1832929A (en) | 2006-09-13 |
| CN1832929B CN1832929B (en) | 2012-11-07 |
Family
ID=28052593
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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 |
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| CN (1) | CN1832929B (en) |
| AR (2) | AR107965A2 (en) |
| GB (1) | GB0319227D0 (en) |
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| CN104926824A (en) * | 2014-03-17 | 2015-09-23 | 广东东阳光药业有限公司 | Substituted heteroaryl compound as well as composition and uses thereof |
| CN106008503A (en) * | 2015-03-31 | 2016-10-12 | 南京明德新药研发股份有限公司 | Spiro aryl sulfone as protein kinase inhibitor |
| CN106146525A (en) * | 2015-04-10 | 2016-11-23 | 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 |
| EP3133167A1 (en) * | 2009-05-15 | 2017-02-22 | Insight Genetics, Inc. | Methods and compositions relating to fusions of alk for diagnosing and treating cancer |
| CN108997225A (en) * | 2013-03-14 | 2018-12-14 | 特雷罗药物股份有限公司 | JAK2 and ALK2 inhibitor and its application method |
| CN110092759A (en) * | 2018-01-31 | 2019-08-06 | 陆柯潮 | The chloro- 2,4- pyrimidine derivatives of 5- as anti-tumor drug |
| CN114716385A (en) * | 2022-04-08 | 2022-07-08 | 北京师范大学 | Compound of targeting focal adhesion kinase, preparation method and application |
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| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
-
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
-
2019
- 2019-02-04 AR ARP190100267A patent/AR114354A2/en unknown
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| CN103641833A (en) * | 2006-12-08 | 2014-03-19 | Irm责任有限公司 | Compounds and compositions as protein kinase inhibitors |
| EP3133167A1 (en) * | 2009-05-15 | 2017-02-22 | Insight Genetics, Inc. | Methods and compositions relating to fusions of alk for diagnosing and treating cancer |
| CN104854101A (en) * | 2012-11-06 | 2015-08-19 | 上海复尚慧创医药研究有限公司 | Alk kinase inhibitors |
| CN104854101B (en) * | 2012-11-06 | 2018-05-01 | 上海复尚慧创医药研究有限公司 | Alk kinase inhibitors |
| CN108997225A (en) * | 2013-03-14 | 2018-12-14 | 特雷罗药物股份有限公司 | JAK2 and ALK2 inhibitor and its application method |
| CN104926824A (en) * | 2014-03-17 | 2015-09-23 | 广东东阳光药业有限公司 | Substituted heteroaryl compound as well as composition and uses thereof |
| CN104926824B (en) * | 2014-03-17 | 2017-07-07 | 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 |
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| CN106146525A (en) * | 2015-04-10 | 2016-11-23 | 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 |
| CN112004809A (en) * | 2018-01-31 | 2020-11-27 | 陆柯潮 | 5-chloro-2, 4-pyrimidine derivatives as antitumor agents |
| CN114716385A (en) * | 2022-04-08 | 2022-07-08 | 北京师范大学 | Compound of targeting focal adhesion kinase, preparation method and application |
| CN114716385B (en) * | 2022-04-08 | 2024-03-12 | 北京师范大学 | Compound of targeted focal adhesion kinase, preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0319227D0 (en) | 2003-09-17 |
| CN1832929B (en) | 2012-11-07 |
| AR107965A2 (en) | 2018-07-04 |
| AR114354A2 (en) | 2020-08-26 |
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