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CN106928200A - For the pyrrolotriazine derivatives for the treatment of cancer - Google Patents

For the pyrrolotriazine derivatives for the treatment of cancer Download PDF

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Publication number
CN106928200A
CN106928200A CN201511022453.5A CN201511022453A CN106928200A CN 106928200 A CN106928200 A CN 106928200A CN 201511022453 A CN201511022453 A CN 201511022453A CN 106928200 A CN106928200 A CN 106928200A
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compound
methyl
bases
amino
formula
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徐良亮
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Hunan Fuwo Pharmaceutical Co Ltd
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Hunan Fuwo Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Pyrrolotriazine derivatives the present invention relates to be used for treating cancer.Specifically, the present invention relates to the anilino--triaizine compounds and its pharmaceutically acceptable salt shown in formula (I), the compound or its salt can be used for treatment or prevention disease or illness by adjusting the EGF-R ELISA of some mutant forms.The invention further relates to the pharmaceutical composition comprising the compound or its salt, and the various diseases mediated by EGFR using the compound and its salts for treating method.

Description

For the pyrrolotriazine derivatives for the treatment of cancer
Technical field
There is regulation EGF-R ELISA (EGFR) kinase activity the invention provides one kind Pyrrolotriazine derivatives.Specifically, the present invention relates to anilino--triaizine compounds and its pharmaceutically acceptable Salt, the compound or its salt can by adjusting the EGF-R ELISA of some mutant forms and For treatment or prevention disease or illness.The invention further relates to the medicine comprising the compound or its salt Composition, and be situated between by the EGFR of various multi-forms using the compound and its salts for treating The method of the various diseases led, including non-small cell lung cancer.
Background technology
In cancer therapy drug field, for the new anticancer compound one with more preferable activity/selectivity Directly there is demand.Known EGFR is the transmembrane protein tyrosine kinase members of erbB receptor families. Some tyrosine are residual during the homodimerization and/or Heterodimerization of erbB acceptors cause intracellular domain The phosphorylation of base, and activate signal transduction pathway in the various kinds of cell for participating in cell propagation and existence. The imbalance of erbB families signal transduction can cause cell to be bred, invades, shift and angiogenesis, and Had been reported that in the cancers such as lung cancer, incidence cancer and breast cancer.Accordingly, as cancer therapy drug exploitation Target spot, many medicines for targeting EGFR or erbB2 have clinically been applied at present. For example, in New England Journal of Medicine (New England Journal of medicine), 2008 358 phases, 1160-1174 pages and biochemistry and biophysical research communication (Biochemical and Biophysical Research Communications), 2004 volume 319, be given in 1-11 pages Tumorigenic summary is conducted and its participated in erbB receptor signals.
But, exist in actual treatment of cancer EGFR activated mutants (such as L858R and DelE746_A750), for example, with reference to science (Science), the 304th phase in 2004,1497-500 Page and New England Journal of Medicine, the 350th phase in 2004,2129-39 pages.These most common EGFR Activated mutant (L858R and delE746_A750) is right for wild type (WT) EGFR The affinity of small molecule tyrosine kinase inhibitors (such as Gefitinib and Tarceva) increases, same When the affinity of atriphos (ATP) is declined.Finally, produce and Gefitinib or Lip river in distress are replaced The acquired resistance of Buddhist nun's treatment, such as due to the mutation of the residue T790M that guards the gate.Due to this mutation Cause the resistance of the existing medicine to targeting EGFR, there is still a need for can suppress to include seeing in this area The noval chemical compound of the EGFR of door gene mutation.Described noval chemical compound should be relative to activated mutant Body form EGFR (such as L858R EGFR mutant or delE746_A750 mutant or Exon19 missings EGFR mutant) and/or resistant mutant forms EGFR (such as T790M EGFR mutant) for, with favorable activity and/or selectivity to Wild type EGFR.Change speech It, this area need to some activation or resistant mutant forms EGFR show suppression higher, The compound of relatively low suppression is shown to Wild type EGFR simultaneously, so as to can not only play Anticancer efficacy, and adverse reaction and the toxicology (example related to Wild type EGFR is suppressed can be reduced Such as fash and/or diarrhoea).
In order to solve this problem, inventor is by after research, in fact it has surprisingly been found that a class aniline Base-triaizine compounds, its mutant forms for EGFR have suppression effect higher, while There is the suppression relatively low to Wild type EGFR again.Additionally, these compounds have preferably Pharmacological effect, acceptable toxicological action and favourable pharmacokinetic property.
The content of the invention
On the one hand, the invention provides the compound or its pharmaceutically acceptable salt of formula (I)：
Wherein
G is selected from aryl, heteroaryl or heterocyclic radical, preferably C6-10Aryl, C5-10Heteroaryl or C4-10 Heterocyclic radical, the aryl, heteroaryl or heterocyclic radical are optionally independently selected by one or more from C1-6 Alkyl, C1-6Alkoxy, oxo, halogen or C1-6The substitution base of haloalkyl is replaced；
R1Selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, halogen and C1-6Haloalkyl；
R2Selected from C1-6Alkyl, C1-6Miscellaneous alkyl, C6-10Aryl, C5-10Heteroaryl, C4-10Heterocyclic radical, C6-10Aryl-C1-6Alkylidene, C5-10Heteroaryl-C1-6Alkylidene or C4-10Heterocyclic radical-C1-6Alkylene Base, wherein the alkyl, aryl, heteroaryl or heterocyclic radical are optionally independently selected by one or more From C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two-C1-6Alkyl amino, oxo, halogen, C1-6Haloalkyl, aminoacyl, C1-6Alkylaminoacyl or two-C1-6The substitution of alkylaminoacyl Base is replaced；
R3Selected from hydrogen or C1-6Alkyl；
Or R2And R3Heteroaryl or heterocyclic radical are formed together with the nitrogen-atoms being connected with them, preferably C5-10Heteroaryl or C4-10Heterocyclic radical, wherein the heteroaryl or heterocyclic radical are optionally by one or more Independently selected from C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two-C1-6Alkyl amino, oxo, Halogen, C1-6Haloalkyl, aminoacyl, C1-6Alkylaminoacyl or two-C1-6Alkylaminoacyl Substitution base replaced；
R4Selected from hydrogen or C1-6Alkyl；
R5Selected from following group：
On the other hand, the invention provides pharmaceutical composition, its chemical combination for including formula as described above (I) Thing or its pharmaceutically acceptable salt and pharmaceutically acceptable diluent or carrier.
On the other hand, the invention provides the compound of formula as described above (I) or its can pharmaceutically connect The salt received, it is used as medicine.
On the other hand, present invention also offers the compound of formula as described above (I) or its can pharmaceutically connect Purposes of the salt received in the medicine for treating cancer is prepared.
On the other hand, produced present invention also offers in the warm-blooded animal such as people for needing this treatment The method of antitumaous effect, it includes：The change of the formula as described above (I) of effective dose is applied to the animal Compound or its pharmaceutically acceptable salt.
On the other hand, present invention also offers the compound of formula as described above (I) or its can pharmaceutically connect The salt and the purposes of other antitumorigenic substance received, while for cancer, independence or sequential therapy.
Definition
In the present invention, following term has implication as described below：
The term " alkyl " for combining individually or with other groups represents the straight chain being made up of carbon and hydrogen atom Or the monovalent saturated hydrocarbon group of side chain.“C1-6Alkyl " represents the side chain with 1 to 6 carbon atom Or straight chained alkyl, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, tertiary fourth Base, n-hexyl.
Individually or combine with other groups term " alkylidene " expression by carbon and hydrogen atom constitute it is straight The divalent saturated hydrocarbon group of chain or side chain.“C1-6Alkylidene " is represented has 1 to 6 carbon atom Branched-chain or straight-chain alkyl, such as methylene, ethylidene, propylidene etc..
The term " alkoxy " for combining individually or with other groups represents that group R '-O-, wherein R ' are Alkyl as described above.“C1-6Alkoxy " represents that group R '-O-, wherein R ' are as described above C1-6Alkyl.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" haloalkyl " represents the alkyl as defined above replaced by one or more halogens, for example C1-6Haloalkyl.The non-limiting example of haloalkyl includes methyl fluoride, difluoromethyl, fluoroform Base, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl group, heptafluoropropyl, difluorochloromethyl, Dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl and two chloropropyls.Whole haloalkyl is Refer to the alkyl that whole hydrogen atoms are all replaced by halogen atom, such as trifluoromethyl.
Term " cycloalkyl " refers to 4-7 unit monocycle saturated hydrocarbons ring systems.Group of naphthene base can optionally by One or more substitution base substitutions defined herein.Cycloalkyl includes cyclobutyl, cyclopenta, hexamethylene Base and suberyl.
Term " cycloalkenyl group " refers to 5-7 unit monocycles unsaturation (but nonaro-maticity) hydrocarbon ring system.Cycloalkenyl group Group can optionally by one or more substitution base substitutions defined herein.Cycloalkenyl group includes ring penta Alkenyl, cyclohexenyl group and cycloheptenyl.
Term " aryl " refers to monocyclic or condensed-bicyclic the aromatic rings containing carbon atom.“C6-10Virtue Base " refers to contain the 6-10 aryl of carbon atom.For example, C6-10Aryl can be phenyl or naphthyl.
As used herein, term " hetero atom " refers to nitrogen (N), oxygen (O) and sulphur (S) atom.
Term " miscellaneous alkyl " and " miscellaneous alkylidene " refer to alkyl as described above and alkylidene, wherein One or more carbon atoms substituted by hetero atom.
As used herein, except as otherwise noted, term " heteroaryl " refers to the mono-cyclic aromatic ring of 5-10 units System or Bicyclic-fused aromatic ring, it has 1-4 hetero atom.Heteroaryl can also refer to 8-10 yuan of rings System, wherein hetero-aromatic ring is condensed with phenyl, cycloalkyl, cycloalkenyl group or a heterocyclic ring, wherein connecting Base or tie point are on hetero-aromatic ring.The non-limiting example of heteroaryl includes 2- or 3- thienyls；2- Or 3- furyls；2- or 3- pyrrole radicals；2-, 4- or 5- imidazole radicals；3-, 4- or 5- pyrazolyl；2-、 4- or 5- thiazolyls；3-, 4- or 5- isothiazolyl；2-, 4- or 5- oxazolyl；3-, 4- or 5- Yi Evil Oxazolyl；3- or 5-1,2,4- triazolyls；4- or 5-1,2,3- triazolyls；Furazanyl；Thiadiazolyl group；Tetrazolium Base；2-, 3- or 4- pyridine radicals；3- or 4- pyridazinyls；3-, 4- or 5- pyrazinyl；2- pyrazinyls and 2-, 4- or 5- pyrimidine radicals；1-, 2-, 3-, 5-, 6-, 7- or 8- indolizine base；1-, 3-, 4-, 5-, 6- or 7- isoindolyls；2-, 3-, 4-, 5-, 6- or 7- indyl；2-, 3-, 4-, 5-, 6- or 7- indazole Base；2-, 4-, 5-, 6-, 7- or 8- purine radicals；1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- quinolizine Base；2-, 3-, 4-, 5-, 6-, 7- or 8- quinolyl；1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinoline Quinoline base；1-, 4-, 5-, 6-, 7- or 8- phthalazinyl；2-, 3-, 4-, 5- or 6- naphthyridines base；2-、3-、 5-, 6-, 7- or 8- quinazolyl；3-, 4-, 5-, 6-, 7- or 8- cinnolines base；2-, 4-, 6- or 7- pteridyls；1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazyl；1-、2-、3-、4-、 5-, 6-, 7- or 8- carbazyl；1-, 3-, 4-, 5-, 6-, 7-, 8- or 9- carboline base；1-、2-、 3-, 4-, 6-, 7-, 8-, 9- or 10- phenanthridinyl；1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9- Acridinyl；1-, 2-, 4-, 5-, 6-, 7-, 8- or 9- perimidinyl；2-、3-、4-、 5-, 6-, 8-, 9- or 10- phenanthroline；1-, 2-, 3-, 4-, 6-, 7-, 8- or 9- phenol piperazine base； 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or lysivane base；1-、2-、3-、4-、6-、7-、 8-, 9- or 10- phenoxazine group；2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- benzisoquinoline bases；2-, 3-, 4- or thieno [2,3-b] furyl；2-、3-、5-、6-、 7-, 8-, 9-, 10- or 11-7H- pyrazine simultaneously [2,3-c] carbazyl；2-, 3-, 5-, 6- or 7-2H- furan Mutter simultaneously [3,2-b]-pyranose；2-, 3-, 4-, 5-, 7- or 8-5H- pyrido [2,3-d]-o- oxazinyls； The oxazolyl of 1-, 3- or 5-1H- pyrazolo [4,3-d]-；2-, 4- or 54H- imidazo [4,5-d] thiazolyl； 3-, 5- or 8- pyrazine simultaneously [2,3-d] pyridazinyl；2-, 3-, 5- or 6- imidazo [2,1-b] thiazolyl；1-、 3-, 6-, 7-, 8- or 9- furans simultaneously [3,4-c] cinnolines base；1-、2-、3-、4-、5-、6-、8-、9-、 10 or 11-4H- pyrido [2,3-c] carbazyl；2-, 3-, 6- or 7- imidazo [1,2-b] [1,2,4] triazine Base；7- benzos [b] thienyl；2-, 4-, 5-, 6- or 7- benzoxazolyl；2-, 4-, 5-, 6- or 7- benzimidazolyls；2-, 4-, 4-, 5-, 6- or 7- benzothiazolyl；2-、4-、5-、6-、7- Or 8- benzoxazinyls.The heteroaryl groups for generally condensing also include but is not limited to 2-, 3-, 4-, 5-, 6-, 7- or 8- quinolyl；1-, 3-, 4-, 5-, 6-, 7- or 8- isoquinolyl；2-、3-、4-、5-、 6- or 7- indyls；2-, 3-, 4-, 5-, 6- or 7- benzo [b] thienyl；2-, 4-, 5-, 6- or 7- benzoxazolyls；2-, 4-, 5-, 6- or 7- benzimidazolyl；2-, 4-, 5-, 6- or 7- benzo Thiazolyl；Cycloheptadiene simultaneously [d] imidazole radicals；7,8- dihydro -5H- pyrans simultaneously [4,3-d] pyrimidine radicals；1H- pyrroles Azoles simultaneously [3,4-d] pyrimidine radicals；Thieno [3,2-d] pyrimidine radicals；6,7- dihydro -5H- cyclopentapyrimidin bases； 5,6- dihydro-thiazols simultaneously [2,3-c] [1,2,4] triazolyl；[1,2,4] triazol [4,3-a] pyridine radicals；7,8- dihydros - 5H- pyrans simultaneously [3,4-d] pyridazinyl；He isoxazoles simultaneously [5,4-b] pyridine radicals.
Except as otherwise noted, comprising more than a heteroatomic heteroaryl groups can be comprising different miscellaneous Atom.Heteroaryl groups can optionally by one or more substitution base substitutions defined herein.
" heterocyclic radical " refers to contain 1-4 heteroatomic 4-10 unit monocycle or two as the term is employed herein Ring filling or unsaturation ring, including bridging heterocycle or volution.Heterocyclic ring is not armaticity. Comprising more than a heteroatomic heterocyclic radical can be comprising different hetero atom.Heterocyclyl groups can appoint Selection of land is by one or more substitution base substitutions defined herein.The example of heterocyclic radical include tetrahydrofuran, Dihydrofuran, 1,4- dioxs, morpholine, 1,4- dithiane, piperazine, piperidines, 1,3- dioxanes penta Alkane, imidazolidine, imidazoline, pyrrolin, pyrrolidines, oxinane, dihydropyran, azetidin Alkane, oxathiolanes, dithiolane, 1,3- dioxs, 1,3- dithiane, oxa- thia Thiacyclohexane, thiomorpholine etc..Heterocyclic radical can be directly connected to the other parts of molecule, it is also possible to pass through C1-6Alkylidene or C1-6Miscellaneous alkylidene chain is attached.
When any group or part (such as alkyl, aryl, heteroaryl or heterocyclic radical) are defined herein as When " being optionally independently selected by one or more from following substitution base substitution ", it will be appreciated that described Group or part are unsubstituted or are taken by one, one or two or one to three substitution base The group of generation, wherein each substitution base independently selected from the substitution base.
Herein, the example of described optionally substituted heteroaryl or heterocyclic radical is included but is not limited to 4,5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridin-3-yl, 1H- indol-3-yls, 1- Methyl-1H-indole -3- bases With pyrazolo [1,5-a] pyridin-3-yl, (3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (diformazan ammonia Base) pyrrolidin-1-yl, 3- (dimethylamino) azetidine -1- bases, 5- methyl -2,5- diazaspiracyclics [3.4] Octyl- 2- bases, (3aR, 6aR) -5- methyl hexahydro-pyrrolo- [3,4-b] pyrroles -1 (2H)-base, 1- methyl - 1,2,3,6- tetrahydropyridine -4- bases, 4- methylpiperazine-1-yls, 4- [2- (dimethylamino) -2- oxoethyls] piperazine Piperazine -1- bases, methyl [2- (4- methylpiperazine-1-yls) ethyl] amino, methyl [2- (morpholine -4- bases) ethyl] ammonia Base, 1- amino -1,2,3,6- tetrahydropyridine -4- bases or 4- [(2S) -2- aminopropionyls] piperazine -1- bases.
Term " acyl group " refers to group-CO-R, and wherein R is alkyl as described above, aryl, miscellaneous Aryl or heterocyclic radical.
Term " oxo " refers to group (=O).
In the context of the present specification, unless the contrary indication, term " treatment " is also comprising " pre- It is anti-".Term " treatment " used herein is intended to have its following its ordinary meaning：Treatment disease is with complete Alleviate entirely or partly a kind of, part or all of in its symptom, or correct or compensation is potential Pathology.Term " prevention " used herein is intended to have its normal daily implication, and including preventing The primary prevention of disease development and the secondary prevention for preventing from disease, temporarily or continuously prevent from suffering from The aggravation or deterioration of person's disease or the generation of the new symptom related to disease.
Compound of the invention
The invention provides the compound or its pharmaceutically acceptable salt of formula (I)：
Wherein
G is selected from aryl, heteroaryl or heterocyclic radical, preferably C6-10Aryl, C5-10Heteroaryl or C4-10 Heterocyclic radical, the aryl, heteroaryl or heterocyclic radical are optionally independently selected by one or more from C1-6 Alkyl, C1-6Alkoxy, oxo, halogen or C1-6The substitution base of haloalkyl is replaced；
R1Selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, halogen and C1-6Haloalkyl；
R2Selected from C1-6Alkyl, C1-6Miscellaneous alkyl, C6-10Aryl, C5-10Heteroaryl, C4-10Heterocyclic radical, C6-10Aryl-C1-6Alkylidene, C5-10Heteroaryl-C1-6Alkylidene or C4-10Heterocyclic radical-C1-6Alkylene Base, wherein the alkyl, aryl, heteroaryl or heterocyclic radical are optionally independently selected by one or more From C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two-C1-6Alkyl amino, oxo, halogen, C1-6Haloalkyl, aminoacyl, C1-6Alkylaminoacyl or two-C1-6The substitution of alkylaminoacyl Base is replaced；
R3Selected from hydrogen or C1-6Alkyl；
Or R2And R3Heteroaryl or heterocyclic radical are formed together with the nitrogen-atoms being connected with them, preferably C5-10Heteroaryl or C4-10Heterocyclic radical, wherein the heteroaryl or heterocyclic radical are optionally by one or more Independently selected from C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two-C1-6Alkyl amino, oxo, Halogen, C1-6Haloalkyl, aminoacyl, C1-6Alkylaminoacyl or two-C1-6Alkylaminoacyl Substitution base replaced；
R4Selected from hydrogen or C1-6Alkyl；
R5Selected from following group：
In a preferred embodiment, R2And R3Formed together with the nitrogen-atoms being connected with them Selected from following groups：(3R) -3- (dimethylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidines - 1- bases, 3- (dimethylamino) azetidine -1- bases, [2- (dimethylamino) ethyl]-(methyl) amino, [2- (first Amino) ethyl] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- bases, (3aR, 6aR) -5- Methyl hexahydro-pyrrolo- [3,4-b] pyrroles -1 (2H)-base, 1- methyl isophthalic acids, 2,3,6- tetrahydropyridine -4- bases, 4- Methylpiperazine-1-yl, 4- [2- (dimethylamino) -2- oxoethyls] piperazine -1- bases, methyl [2- (4- methyl piperazines Piperazine -1- bases) ethyl] amino, methyl [2- (morpholine -4- bases) ethyl] amino, 1- amino -1,2,3,6- tetrahydropyridines - 4- bases or 4- [(2S) -2- aminopropionyls] piperazine -1- bases.
In a further preferred embodiment, the invention provides the compound of formula (I) or its pharmaceutically Acceptable salt：
Wherein
G is selected from 4,5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridin-3-yl, 1H- indol-3-yls, 1- methyl isophthalic acids H- Indol-3-yl and pyrazolo [1,5-a] pyridin-3-yl；
R1Selected from methoxyl group, methyl, chlorine, fluorine and trifluoromethyl；
R4It is hydrogen；
R5It is following group：
R2And R3Formed together with the nitrogen-atoms being connected with them selected from following groups：(3R) -3- (two Methylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azacyclo- Butane -1- bases, [2- (dimethylamino) ethyl]-(methyl) amino, [2- (methylamino) ethyl] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- bases, (3aR, 6aR) -5- methyl hexahydro-pyrrolo- [3,4-b] (the 2H)-CN of pyrroles -1 bases, 1- methyl isophthalic acids, 2,3,6- tetrahydropyridine -4- bases, 4- methylpiperazine-1-yls, 4- [2- (two Methylamino) -2- oxoethyls] piperazine -1- bases, methyl [2- (4- methylpiperazine-1-yls) ethyl] amino, methyl [2- (morpholine -4- bases) ethyl] amino, 1- amino -1,2,3,6- tetrahydropyridine -4- bases or 4- [(2S) -2- amino Propiono] piperazine -1- bases.
In a further preferred embodiment, G is 1H- indol-3-yls, 1- Methyl-1H-indoles -3- Base or pyrazolo [1,5-a] pyridin-3-yl.
In another preferred embodiment, R1It is methoxyl group.
In another preferred embodiment, G is 1- Methyl-1H-indole -3- bases.
In another preferred embodiment, R2And R3Shape together with the nitrogen-atoms being connected with them Into [2- (dimethylamino) ethyl] (methyl) amino.
In particularly preferred embodiments, the compound or its pharmaceutically acceptable salt of formula (I) are N- (2- { 2- (dimethylamino) ethyl-(methyl) amino } -4- methoxyl groups -5- { [4- (1- methyl indols -3- Base) -1,3,5- triazine -2- bases] amino } phenyl) propyl- 2- acrylamides or its pharmaceutically acceptable salt
In another preferred embodiment, the compound or its pharmaceutically acceptable salt of formula (I) are N- (4- methoxyl groups -5- { [4- (1- methyl indol -3- bases) -1,3,5- triazine -2- bases] amino } -2- [methyl-(2- first Amino-ethyl) amino] phenyl) propyl- 2- acrylamides or its pharmaceutically acceptable salt.
It will be appreciated by those skilled in the art that the salt of formula (I) compound can be prepared, including pharmaceutically may be used The salt of receiving.These salts can be finally recovered in the compound and prepared by purge process situ, Or by independently respectively by with its free acid or the compound of the purifying of free alkali form with it is suitable It is prepared by alkali or acid reaction.
Pharmaceutically acceptable acid-addition salts can be formed with inorganic acid and organic acid, for example, acetate, Aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, Disulfate/sulfate, camsilate, chloride/hydrochloride, citrate, ethanedisulphonate, Fumarate, gluceptate, gluconate, glucuronate, hippurate, hydriodide/ Iodide, isethionate, lactate, Lactobionate, lauryl sulfate, malate, Maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene Sulfonate, nicotinate, nitrate, stearate, oleate, oxalates, palmitate, double hydroxyls Naphthoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, Polygalacturonate, propionate, tristearin Hydrochlorate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetate.
The inorganic acid that salt can be generated includes, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc..
The organic acid that salt can be generated includes, for example, acetic acid, propionic acid, glycolic, oxalic acid, Malaysia Acid, malonic acid, butanedioic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, first sulphur Acid, ethyl sulfonic acid, toluenesulfonic acid, sulfosalicylic acid etc..Pharmaceutically acceptable base addition salts can be with Inorganic or organic base is formed.
The inorganic base that salt can be generated includes, the gold of I to the XII races of such as ammonium salt and the periodic table of elements Category.In certain embodiments, the salt be derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, Zinc and copper；Particularly suitable salt includes ammonium salt, sylvite, sodium salt, calcium salt and magnesium salts.
The organic base that salt can be generated includes, for example, primary amine, secondary amine and tertiary amine, substituted amine includes Naturally-produced substitutional amine-group, cyclammonium, basic ion-exchange resins etc..Some organic amines include isopropyl Amine, diethanol amine, diethylamine, lysine, meglumine, piperazine and tromethamine.
Pharmaceutically acceptable salt of the invention can be by conventional chemical method by alkalescence or acidity portion Division into.Generally, these salt can be by by the free acid form and chemical quantity of these compounds Suitable alkali (hydroxide, carbonate, bicarbonate of Na, Ca, Mg or K etc.) reaction, Or made with the suitable acid reaction of chemical quantity by by the free alkali form of these compounds It is standby.These reactions are generally carried out in water or in organic solvent or in both mixtures.It is logical Often, it is necessary to use non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol when suitable Or acetonitrile.The list of other suitable salt can at " Remington's Pharmaceutical Sciences ", 20th edition, Mack Publishing Company, Easton, Pa., (1985)；And Stahl and " the Handbook of Pharmaceutical Salts of Wermuth：Properties,Selection,and Found in Use " (Wiley-VCH, Weinheim, Germany, 2002).
The solvate of formula (I) compound, including pharmaceutically acceptable solvate can also be prepared. " solvate " refers to the compound of the varying chemical amount formed by solute and solvent.For mesh of the present invention Such solvent do not influence the bioactivity of the solute.The example for being adapted to solvent is included but is not limited to Water, MeOH, EtOH and AcOH.Its reclaimed water is that the solvate of solvent molecule typically refers to water Compound.The component of water of the hydrate including the amount comprising stoichiometry, and the water comprising variable Component.
As used herein, term " pharmaceutically acceptable " is meant that the chemical combination suitable for medicinal usage Thing.Suitable for the salt and solvate (such as the hydrate of hydrate and salt) of the compounds of this invention of medicine Be wherein ion balance or with reference to solvent be it is pharmaceutically acceptable those.But, with non-pharmaceutical Acceptable ion balance or salt and solvate with reference to solvent are also included in the scope of the present invention, example Such as, as the centre for preparing other the compounds of this invention and its pharmaceutically acceptable salt and solvate Body.
Formula (I) compound (including its salt and solvate) can in crystalline form, non-crystalline forms or its Mixture is present.The compound or its salt or solvate can also show polymorphism, i.e., with The ability that different crystal forms occur.These different crystal forms are commonly known as " polymorphic ".It is many Crystal formation has identical chemical composition, but the accumulation of crystalline solid state, geometry are arranged and other are retouched State characteristic different.Therefore, polymorphic can have different physical properties, for example shape, density, Hardness, morphotropism, stability and solubility properties.Polymorphic typically exhibits different fusing points, IR Spectrum and X-ray powder diffraction collection, its whole may be used to differentiate.Those skilled in the art's energy Solution much of that, for example, by the way that the bar used in the crystallization/recrystallization of formula (I) compound is altered or modified Part and there may be different polymorphics.
The present invention also different isomer comprising formula (I) compound." isomers " refers to identical composition And molecular weight, but the physically and/or chemically different compound of property.The difference of structure can be in knot In structure (geometric isomer) or in the ability of Plane of rotation polarised light (stereoisomer).On solid Isomers, formula (I) compound can have one or more asymmetric carbon atoms, it is possible to racemic Body, racemic mixture and occur with single enantiomter or diastereoisomer.It is all such Isomeric forms are intended to be included within the scope of the present invention, including its mixture.If the compound contains Double bond, substitution base can be E or Z configurations.If the compound includes dibasic cycloalkyl, The substitution base of the cycloalkyl can have cis-or trans-configuration.It is also desirable that comprising whole mutual variations Structure body form.
Any asymmetric atom (such as carbon etc.) of formula (I) compound can be with racemic or enantiomerism Body enrichment exist, for example (R)-, (S)-or (R, S)-configuration.In certain embodiments, each is not Symmetry Atoms have at least 50% enantiomter excess, at least 60% mapping in (R)-or (S)-configuration Isomers excess, at least 70% enantiomter excess, at least 80% enantiomter are excessively, at least 90% enantiomter is excessive, at least 95% enantiomter is excessive or at least 99% enantiomter It is excessive.If possible, the substitution base on the atom with unsaturated double-bond with cis-(Z)-or trans- (E)-form is present.
Therefore, as used herein, formula (I) compound can be possible isomers, rotational isomer, The form of one of atropisomer, dynamic isomer or its mixture, such as substantially pure several What isomers (cis or trans), diastereoisomer, optical isomer (enantiomter), racemic Body or its mixture.
The physical chemical differences that the mixture of the isomers of any gained can be based on component are separated into Pure or substantially pure geometry or optical isomer, diastereoisomer, racemic modification, for example, lead to Cross chromatography and/or fractional crystallization.
The end-product of any gained or the racemic modification of intermediate (can for example be led to by known method Cross the separation of its diastereoisomeric salt) be split into enantiomers, its with have it is optically active acid or Alkali is obtained, and has discharged optically active acid or alkali compounds.Especially, basic moiety Therefore can be used for for compound of the invention splitting into its enantiomers, for example by with have Optically active acid (such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, two-O, O'- couples Toluoyl tartaric acid, mandelic acid, malic acid or camphor -10- sulfonic acid) formed salt fractional crystallization.Outward Racemic product can also be split by chiral chromatography, for example, use the high pressure liquid of chiral sorbent Phase chromatography (HPLC).
The form of unlabelled form and isotope marks of the present invention including formula (I) compound.Same position The compound of element mark has the structure described by chemical formula given in this article, except one or more Atom is replaced by the atom with selected atomic weight or mass number.Chemical combination of the present invention can be impregnated in The example of the isotope of thing includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively for example2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I.Present invention bag The compound of various isotope marks as herein defined is included, for example, radio isotope wherein occurs (for example3H and14C) those or wherein there is non radioactive isotope (for example2H and13C) those. The compound of these isotope marks can be used for metabolism research and (for example use14C), Reaction kinetics research (for example use2H or3H), detection or imaging technique, such as positron emission tomography (PET) Or single photon emission computed tomography art (SPECT), including drug substrate tissue distribution assays, or Person is used for the radiotherapy of patient.Especially, may especially be needed for PET or SPECT researchs18The compound of F or mark.Formula (I) compound of isotope marks usually can be by the skill of this area Routine techniques known to art personnel or by similar with method described in appended embodiment and preparation example Method, using the reagent of suitable isotope marks instead of previously used unlabelled reagent system It is standby.
Additionally, with heavier isotope, particularly deuterium (i.e.2H or D) substitution may band come by stronger Metabolic stability caused by some treatment advantages, such as dosage of increased Half-life in vivo or reduction The improvement of demand or therapeutic index.It is appreciated that deuterium is considered as taking for the compound of formula (I) herein Dai Ji.The higher isotope, the concentration of particularly deuterium may be determined by isotope enrichment factor.Such as this Term " isotope enrichment factor " used by text refers to the isotope abundance and natural abundance of specific isotope Between ratio.If the substitution base in the compounds of this invention is denoted as deuterium, then for each mark The D-atom for going out, the compound has at least 3500 (at the D-atom that each is marked 52.5% deuteriums Mix), at least 4000 (incorporations of 60% deuterium), at least 4500 (incorporations of 67.5% deuterium), at least 5000 (75% Deuterium mix), at least 5500 (incorporations of 82.5% deuterium), at least 6000 (incorporations of 90% deuterium), at least 6333.3 (incorporation of 95% deuterium), at least 6466.7 (incorporations of 97% deuterium), at least 6600 (incorporations of 99% deuterium) or extremely The isotope enrichment factor of few 6633.3 (incorporations of 99.5% deuterium).
Pharmaceutical composition
The invention provides pharmaceutical composition, its compound or its pharmacy for including formula as described above (I) Upper acceptable salt and pharmaceutically acceptable diluent or carrier.
Pharmaceutical composition can be prepared for specific method of administration, for example oral administration, stomach External administration and rectally etc..Additionally, pharmaceutical composition of the invention can be (unrestricted in solid form Property ground include capsule, tablet, pill, granule, powder agent or suppository) or (non-limit in liquid form Property ground processed includes solution, supensoid agent or emulsion) it is made.Pharmaceutical composition can experience conventional pharmacy Operate (for example sterilize) and/or conventional inert diluent, lubricant or buffer can be contained and auxiliary Material, such as preservative, stabilizer, wetting agent, emulsifying agent and buffer etc..
Generally, pharmaceutical composition is tablet or gelatine capsule, its include active component and
A) diluent, such as lactose, dextrose, sucrose, mannitol, sorbierite, cellulose and/or Glycine；
B) lubricant, such as silica, talcum powder, stearic acid, its magnesium or calcium salt and/or poly- second two Alcohol；Also included for tablet
C) adhesive, such as aluminium-magnesium silicate, gelatinized corn starch, gelatin, bassora gum, methylcellulose, carboxylic Sodium carboxymethylcellulose pyce and/or polyvinylpyrrolidone；If desired, also having
D) disintegrant, such as starch, agar, alginic acid or its sodium salt or effervescent mixture；With/ Or
E) absorbent, colouring agent, flavor enhancement and sweetener.
According to procedures known in the art, tablet can be film coating or enteric coating.
For formula (I) compound of suitable composition including effective dose being administered orally or its pharmaceutically Acceptable salt, it is tablet, lozenge, water or oil suspension, dispersible powder or particle, breast Agent, the form of hard or soft capsule or syrup or elixir.According to as known in the art for preparing medicine Any means of compositions prepare composition for oral use, and refined and suitable in order to provide The preparation said composition of mouth can be containing one or more are selected from sweetener, flavor enhancement, colouring agent and prevent The reagent of rotten agent.Tablet can contain and the nontoxic pharmaceutically acceptable tax for being suitable for preparing tablet The active component that shape agent is mixed.These excipient are for example inert diluent (such as carbonic acid Calcium, sodium carbonate, lactose, calcium phosphate or sodium phosphate)；Granulating agent and disintegrant (such as cornstarch, Or alginic acid)；Adhesive (such as starch, gelatin or Arabic gum)；With lubricant (such as magnesium stearate, Stearic acid or talcum powder).Tablet is not coated or is coated so as to prolong by known technology Delay the disintegration and absorption in intestines and stomach, so as to provide lasting effect in the period of more long.For example, Time delay material, such as glycerin monostearate or distearin can be used.For oral Preparation can be presented with hard gelatin capsule, wherein active component and inert solid diluent (such as carbonic acid Calcium, calcium phosphate or kaolin) mixing, or presented with Perle, wherein active component and water or Oil medium (such as peanut oil, atoleine or olive oil) mixes.
The composition of some injectables is isotonic aqueous solution or suspension, suppository advantageously by Fat Emulsion or Suspension is obtained.Described composition can be sterilized and/or be contained auxiliary material, for example anti-corrosion, stabilization, Wetting or emulsifying agent, dissolution accelerator, salt and/or buffer for adjusting osmotic pressure.Additionally, its The upper valuable material of other treatments can also be contained.Described composition is mixed according to conventional respectively Close, granulation or coating method are prepared, and containing about 0.1-75% or contain about 1-50%'s Active component.
The degraded of some compounds may be promoted due to water, the present invention also provides anhydrous pharmaceutical composition And formulation, it is included as the compounds of this invention of active component.
This hair can be prepared using the condition of anhydrous or low water content composition and low water content or low humidity Bright anhydrous pharmaceutical composition and dosage form.Anhydrous pharmaceutical composition can be prepared and stored to protect Hold its anhydrous property.Therefore, prevent the material contacted with water from packing anhydrous composition using known So that it can be contained in suitable formula medicine box.The example of suitable packaging includes without limitation Airtight paper tinsel, plastics, unit-dose container (such as phial), blister package and strip package.
The present invention further provides pharmaceutical composition and dosage form, it includes one or more and reduces as living The reagent of the decomposition rate of the compounds of this invention of property composition.(it is herein referred to as " stabilization to the reagent Agent ") without limitation including antioxidant (such as ascorbic acid), pH buffer or salt buffer agent etc..
For the individuality of about 50-70kg, pharmaceutical composition of the invention or combination product can be big The UD of about 1-1000mg active components, or about 1-500mg or about 1-250mg Or about 1-150mg or about 0.5-100mg or about 1-50mg active components.Compound, The treatment effective dose of pharmaceutical composition or its combination product depends on individual species, body weight, the age With individual instances, its illness or disease or its order of severity for receiving treatment.Ordinary skill it is interior Section doctor, clinician or animal doctor can be readily determined to prevent, treating or suppress illness or disease The effective dose of each active component needed for the development of disease.
Therapeutical uses
On the other hand, the invention provides the compound or its pharmaceutically acceptable salt of formula (I), its use Make medicine.On the other hand, present invention also offers the compound of formula (I) or its is pharmaceutically acceptable Purposes of the salt in the medicine for treating cancer is prepared.
On the other hand, produced present invention also offers in the warm-blooded animal such as people for needing this treatment The method of antitumaous effect, it includes：Obtained as in claim 1 to 8 to the animal effective dosage The compound or its pharmaceutically acceptable salt of the formula (I) described in any one.
On the other hand, present invention also offers the compound or its pharmaceutically acceptable salt of formula (I) and another The purposes of outer antitumorigenic substance, while for cancer, independence or sequential therapy.
In either side mentioned above or embodiment, the cancer can be selected from oophoroma, palace Neck cancer, colorectal cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, melanoma, Prostate cancer, leukaemia, lymthoma, NHL, stomach cancer, lung cancer, hepatocellular carcinoma, Stomach cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, carcinoma of endometrium, kidney, Denaturation large celllymphoma, acute myelocytic leukemia (AML), Huppert's disease, melanoma, Celiothelioma.
In a preferred embodiment, the cancer is non-small cell lung cancer.
The compound or its pharmaceutically acceptable salt of above-mentioned formula (I) can be applied as monotherapy, or Person also relates to conventional operation or radiotherapy or chemotherapy or exempts from addition to the compounds of this invention Epidemic disease therapy.This chemotherapy and the compounds of this invention can side by side, simultaneously, sequentially or Respectively it is administered, and can includes one or more of following kind of antitumor agent：
Antiproliferative/antineoplastic used in (i) Medical oncology and combinations thereof, such as alkylating agent (such as cis-platinum, oxaliplatin, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, white Disappear peace, Temozolomide, nitrosoureas)；Antimetabolite (such as gemcitabine and antifol, example Such as fluoropyrimidine (such as 5 FU 5 fluorouracil and Tegafur), Raltitrexed, methopterin, cytarabine, hydroxyl Base urea)；Antitumor antibiotics (such as anthracycline, such as adriamycin, bleomycin, Doxorubicin, road Promise mycin, epirubicin, idarubicin, mitomycin C, D actinomycin D, mithramycin)；It is anti-to have (such as vinca alkaloids, such as vincristine, vincaleukoblastinum, eldisine, Changchun are auspicious for silk division medicament Shore；And taxanes, such as taxol, taxotere)；Topoisomerase enzyme inhibitor (such as table Podophyllum emodi var chinense Toxin (such as Etoposide, Teniposide), amsacrine, Hycamtin, camptothecine)；
(ii) cytostatic agent, such as antiestrogen (such as TAM, fulvestrant, support Rui meter Fen, Raloxifene, Droloxifene, antiandrogen (such as Bicalutamide, Flutamide, Ni Lu Meter Te, cyproterone acetate), lhrh antagonist or LHRH activators (such as Goserelin, Leuprorelin and Buserelin), progestogens (such as megestrol acetate), aromatase inhibitor (example Such as Anastrozole, Letrozole, exemestane), 5α-reductase inhibitor (such as Finasteride)；
(iii) anti-invasion agent, such as c-Src kinase families inhibitor, such as Dasatinib and Bo Shu are replaced Buddhist nun (SKI-606), and metal protease inhibitors (such as Marimastat), urokinase plasminogen swash The inhibitor of being function of receptors or the antibody of heparanase；
(iv) inhibitor of growth factor function：Such as this inhibitor includes growth factor antibodies and life Growth factor receptor body antibody (for example anti-erbB 2 antibody trastuzumab, anti-egfr antibodies Victibix, Anti- erbB1 antibody cetuximabs and any growth factor or growth factor receptor antibody)；This suppression Preparation also includes：The inhibitor of tyrosine kinase inhibitor, such as epidermal growth factor family is (for example EGFR families tyrosine kinase inhibitor, such as N- (the chloro- 4- fluorophenyls of 3-) -7- methoxyl group -6- (morpholinyls Propoxyl group)-quinazoline -4- amine (Gefitinib, ZD1839), double (the 2- methoxies of N- (3- ethynyl phenyls) -6,7- Base oxethyl) quinazoline -4- amine (Tarceva, OSI-774), 6- acrylamidos-N- (the chloro- 4- fluorobenzene of 3- Base) -7- (morpholinyl propoxyl group)-quinazoline -4- amine (CI 1033), erbB2 tyrosine kinase inhibitors (such as Lapatinib)；The inhibitor of HGF family；Insulin-like growth factor family Inhibitor；The inhibitor of platelet-derived growth factor family, such as Imatinib and/or Buddhist nun Lip river are replaced Buddhist nun (AMN107)；Serine/threonine kinase inhibitor (such as Ras/Raf signal transduction inhibitors, Such as farnesyl tranfering enzyme inhibitor, such as Sorafenib (BAY43-9006), Zarnestra (R115777), chlorine Na Fani (SCH66336)), believed by the cell of mEK and/or AKT kinases Number conduction depressant drug, c-kit inhibitor, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 swash Enzyme inhibitor, CSF-1R kinase inhibitors, IGF acceptors (IGF) kinase inhibition Agent；Aurora kinase (aurora kinase) inhibitor (such as AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528, AX39459), cyclin Dependant kinase inhibitors, such as CDK2 and/or CDK4 inhibitor；
V () anti-angiogenic agent, for example, suppress the medicament of VEGF effect, for example, resist Human vascular endothelial growth factor antibody Avastin and such as vegf receptor tyrosine-kinase Enzyme inhibitor, such as ZD6474 (ZD6474), vatalanib (PTK787), Sutent (SU11248), Axitinib (AG-013736), pazopanib (GW786034), 4- (the fluoro- 2- methyl of 4- Indoles -5- bases epoxide) -6- methoxyl groups -7- (3- pyrrolidin-1-yls propoxyl group) quinazoline (AZD2171；WO Embodiment 240 in 00/47212), such as WO 97/22596, WO 97/30035, WO Those disclosed in 97/32856 and WO 98/13354；
(vi) injury of blood vessel agent, such as Combretastatin A-4 4 and WO 99/02166, WO 00/40529, Change disclosed in WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 Compound；
(vii) endothelin-receptor antagonists, such as Zibotentan (ZD4054) or atrasentan；
(viii) gene therapy method, including for example replace aberrant gene (such as exception p53 or exception BRCA1 or BRCA2) method；GDEPT (enzyme prodrug treatment of gene orientation) method, for example, make With cytosine deaminase, thymidine kinase or bacterium nitroreductase those；Patient is improved to chemistry The treatment of the method for the tolerance for the treatment of or radiotherapy, such as Multiresistant genes；With
(ix) immunotherapy method, including for example improve patient tumors cell immunogenicity external and Vivo approaches, such as with cell factor (such as interleukin 2, interleukin-4 or granulocyte Macrophage colony stimulatory factor) transfected；Reduce the powerless method of T cell；Use transfection The method of immunocyte (BMDC of such as cytokine transfection)；Use cytokine transfection The method of tumor cell line；Use the method for anti-idiotype；Reduce inhibitive ability of immunity cell (for example Regulatory T cells, marrow source property suppress the dendron of cell or expression IDO (indoleamine 2,3- deoxygenases) Shape cell) function method；And using derived from tumor associated antigen (such as NY-ESO-1, MAGE-3, WT1 or Her2/neu) protein-based or peptides composition cancer vaccine method.
Herein, if term " therapeutic alliance " is for describing combined therapy, it should be understood that this can be with Expression is administered simultaneously, separate administrable or sequential administration.Should similarly understand on " administering drug combinations ". One aspect of the present invention, " therapeutic alliance " refers to be administered simultaneously.In another aspect of this invention, " connection Close treatment " refer to separate administrable.In another aspect of this invention, " therapeutic alliance " refers to sequential administration. When sequential administration or separate administrable, the delay of the second component of administration should not for example lose is produced using combination The interests of raw effect.
Universal synthesis method
The compounds of this invention can be prepared by many kinds of methods, including standard chemical method.Under Text lists illustrative general synthetic method, and the prepared present invention is provided in embodiment Particular compound.
Formula (I) compound can be prepared by known method in organic synthesis field.With reference to hereafter institute During the method for the embodiment stated, it will be appreciated that moiety substituent can be carried out well known in the art Group is replaced, so as to obtain similar derivative in the case of without departing from purport of the invention.If Necessity, blocking group is used according to General Principle or chemical method to sensitiveness or reactive group.Protect Shield group is to be operated (T.W.Greene and P.G.M. according to the standard method of organic synthesis Wuts, " Protective Groups in Organic Synthesis ", the third edition, Wiley, New York 1999).These groups use those skilled in the art very clear in the stage that facilitates of compound synthesis The method of Chu is removed.System of selection and reaction condition and its processing order, should be with formula (I) compound Preparation be consistent.
Those skilled in the art are possible to identification and whether there is Stereocenter in formula (I) compound.Cause This, the present invention includes possible stereoisomer, and not only including racemic compound but also including single Enantiomter.When required compound is single enantiomter, it can be by stereospecificity Synthesis is split and is obtained by end-product or any convenient intermediate.End-product, intermediate or starting The fractionation of raw material can be realized by any suitable method known in the art.See, e.g. E.L. " the Stereochemistry of Organic of Eliel, S.H.Wilen and L.N.Mander Compounds”(Wiley-interscience,1994)。
Compound as herein described can be prepared from commercially available initiation material or using it is known it is organic, Inorganic and/or enzymatic method synthesis.For example, compound of the invention can according to PCT application The method that synthetic method described in PCT/GB2012/051783 is similar to, using suitable raw materials of compound It is prepared.
For example, compound of the invention can be synthesized according to the method for scheme 1 below：
Flow 1
In flow 1, by initiation material 2, the chloro-1,3,5-triazines of 4- bis- are anti-with the amino benzenes compounds of substitution Intermediate B should be obtained, by the reaction and suitable jeterocyclic chemistry of the coupling reaction or correlation of metal catalytic Compound coupling obtains intermediate C, then intermediate D is obtained by amino substitution reaction, by reducing nitro Intermediate E is obtained, then final formula (I) compound is obtained with suitable acyl chlorides or carboxylic acid compound reaction. Wherein, R1、R2、R3、R4、R5With G as hereinbefore defined.
Specific embodiment
The method of the present invention is further detailed by following examples.It should be understood that, there is provided The purpose of following examples is used for the purpose of that the present invention can be better understood from, rather than by any way Limit the scope of the present invention.
The abbreviation for using in this application has following implication.
Abbreviation：
Boc tert-butoxycarbonyls
DCM dichloromethane
DEAD diethyl azodiformates
DIPEA diisopropylethylamine
EtOAc ethyl acetate
HATU O- (7- azepine benzos triazol-1-yl)-N, N, N', N'- tetramethylurea hexafluoro phosphorus Hydrochlorate
TBAF tetrabutyl ammonium fluorides
THF tetrahydrofurans
Embodiment 1：
N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4- methoxyl groups -5- ((4- (1- methyl isophthalic acid H- Yin Diindyl -3- bases) -1,3,5- triazine -2- bases) amino) phenyl) propyl- 2- acrylamides
Acrylic acid (1.62g, 22.3mmol, 1.06 equivalent) is dissolved in dichloromethane (100mL), Ran Houyong Frozen water is down to 0 degree, sequentially adds DIPEA (4.14g, 31.95mmol, 1.5 equivalent) and HATU (12.2g, 31.95mol, 1.5 equivalent) stir 10 minutes, be dividedly in some parts compound 2 (9.5g, 21.3mmol, 1 equivalent) finish after, stir 4 hours at this temperature, reaction is complete.By reaction solution Dichloromethane (200ml) and water (200ml) are poured into, are layered, organic layer is washed twice, dry with sodium sulphate Dry, concentration adds silica gel mixed sample, crosses post purifying (MeOH/DCM：1%-5% gradients) obtain yellow Solid.The solid dichloromethane of 50ml dissolves, and adds the saturated sodium bicarbonate of 20ml, stirring two Ten minutes, layering.Organic phase is washed, and drying is concentrated to dryness, and obtains flaxen title compound 1 (3 g).MS (ESI) m/z=501.3 [M+H]+；1H NMR(400MHz,CDCl3)δ10.15(s, 1H), 9.92 (s, 1H), 9.38 (s, 1H), 8.74 (s, 1H), 8.65 (dd, J=6.1,2.9Hz, 1H), 7.80 (s, 1H), 7.41 (dd, J=6.3,2.8Hz, 1H), 7.37-7.22 (m, 2H), 6.83 (s, 1H), 6.57-6.46 (m, 1H), 6.41 (dd, J=16.8,9.8Hz, 1H), 5.77 (dd, J=9.8,1.9Hz, 1H), 4.02 (s, 3H), 3.93 (s, 3H), 2.37 (s, 2H), 2.36 (d, J=8.7Hz, 6H).
Biological examples
Test 1：L858R (activation single mutant) cells phosphorylation is test
Human pneumonocyte system NCI-H3255 (L858R single mutation EGFR) is from American Type culture Collection is obtained.NCI-H3255 cell culture is being contained into 10% hyclone and 2mM paddy In the BEGM culture mediums of glutamine (LONZA).Cell is set to have 5%CO2Humidification culture In 37 DEG C of growths in case.
According to the DuoSet IC Human Phospho-EGFR ELISA of R＆D Systems companies Scheme described in (R＆D Systems catalog number (Cat.No.) #DYC1095) carries out cell pyrolysis liquid The detection of middle endogenous cell phosphorylation p-EGFR.By the culture of 90 μ l cells (8000 cells/well) In growth medium in the orifice plate of Corning black transparents bottom 96, and at 37 DEG C in 5%CO2 Overnight incubation in humidified incubator.Using pipettor by the compound of serial dilution in 100%DMSO Cell is added to, after soft mixed culture medium, and cell is further cultured for 2 hours.By 100 μ l 1X Lysis buffer is added in each hole.The orifice plate of Greiner high-bonds 96 is covered with capture antibody, Then closed with 3%BSA.After removal confining liquid, 100 μ l lysates are transferred to In the orifice plate of Greiner high-bonds 96, it is incubated 2 hours.Soft mixing simultaneously uses PBS culture plate Afterwards, 100 μ l detection antibodies are added, and is incubated 2 hours.Soft mixing simultaneously uses PBS culture After plate, 100 μ l tmb substrates (Cell Signaling Technology catalog number (Cat.No.)s 7004) are added, It is incubated 1 hour.100 μ l stop baths are added in culture plate, and detect each hole to 450nm The absorbance of wavelength.Suitable software kit (such as Prism) is finally entered data into carry out curve Fitting Analysis.Based on this data and by calculate obtain 50% inhibition needed for compound concentration come Determine IC50Value.
Test 2：Exon19 missing EGFR (activation single mutant) cells phosphorylation tests
Human pneumonocyte system PC-9 (Exon19 lacks EGFR) is from American Type Tissue Culture The heart is obtained.By PC-9 cell culture containing 10% hyclone and 2mM glutamine In RPMI1640 culture mediums.Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.
According to the DuoSet IC Human Phospho-EGFR ELISA of R＆D Systems companies Scheme described in (R＆D Systems catalog number (Cat.No.) #DYC1095) carries out cell pyrolysis liquid The detection of middle endogenous cell phosphorylation p-EGFR.By the culture of 90 μ l cells (8000 cells/well) In growth medium in the orifice plate of Corning black transparents bottom 96, and at 37 DEG C in 5%CO2 Overnight incubation in humidified incubator.Using pipettor by the compound of serial dilution in 100%DMSO Cell is added to, after soft mixed culture medium, and cell is further cultured for 2 hours.By 100 μ l 1X Lysis buffer is added in each hole.The orifice plate of Greiner high-bonds 96 is covered with capture antibody, Then closed with 3%BSA.After removal confining liquid, 100 μ l lysates are transferred to In the orifice plate of Greiner high-bonds 96, it is incubated 2 hours.Soft mixing simultaneously uses PBS culture plate Afterwards, 100 μ l detection antibodies are added, and is incubated 2 hours.Soft mixing simultaneously uses PBS culture After plate, 100 μ l tmb substrates (Cell Signaling Technology catalog number (Cat.No.)s 7004) are added, It is incubated 1 hour.100 μ l stop baths are added in culture plate, and detect each hole to 450nm The absorbance of wavelength.Suitable software kit (such as Prism) is finally entered data into carry out curve Fitting Analysis.Based on this data and by calculate obtain 50% inhibition needed for compound concentration come Determine IC50Value.
Test 3：L858R/T790M EGFR (double-mutant) cells phosphorylation is test
Human pneumonocyte system NCI-H1975 (the double mutation EGFR of L858R/T790M) is from U.S.'s allusion quotation Type culture collection is obtained.NCI-H1975 cell culture is being contained into 10% hyclone and 2 In the RPMI1640 culture mediums of mM glutamine.Cell is set to have 5%CO2Humidified incubator In in 37 DEG C growth.
According to the DuoSet IC Human Phospho-EGFR ELISA of R＆D Systems companies Scheme described in (R＆D Systems catalog number (Cat.No.) #DYC1095) carries out cell pyrolysis liquid The detection of middle endogenous cell phosphorylation p-EGFR.By the culture of 90 μ l cells (8000 cells/well) In growth medium in the orifice plate of Corning black transparents bottom 96, and at 37 DEG C in 5%CO2 In humidified incubator after overnight incubation, cell culture fluid is changed into and contains 1% hyclone and 2mM The RPMI1640 culture mediums of glutamine continue to cultivate.To be connected in 100%DMSO using pipettor The compound of continuous dilution adds to cell, after soft mixed culture medium, and cell is further cultured for 2 hours. 100 μ l 1X lysis buffers are added in each hole.By the orifice plate of Greiner high-bonds 96 with catching Antibody covering is obtained, is then closed with 3%BSA.After removal confining liquid, by 100 μ l cracking Liquid is transferred in the orifice plate of Greiner high-bonds 96, is incubated 2 hours.Softly mix and use PBS After cleaning culture plate, 100 μ l detection antibodies are added, and be incubated 2 hours.Softly mix and use PBS After cleaning culture plate, 100 μ l tmb substrates (Cell Signaling Technology catalogues are added Number 7004), it is incubated 1 hour.100 μ l stop baths are added in culture plate, and detect each hole To the absorbance of 450nm wavelength.Finally enter data into suitable software kit (such as Prism) with Carry out curve fitting analysis.Based on this data and by calculating the chemical combination needed for obtaining 50% inhibition Thing concentration determines IC50Value.
Test 4：Wild type EGFR cells phosphorylation is test
Human pneumonocyte system NCI-H838 (Wild type EGFR) is from American Type Tissue Culture The heart is obtained.By NCI-H838 cell culture containing 10% hyclone and 2mM glutamine In RPMI1640 culture mediums.Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.
According to the DuoSet IC Human Phospho-EGFR ELISA of R＆D Systems companies Scheme described in (R＆D Systems catalog number (Cat.No.) #DYC1095) carries out cell pyrolysis liquid The detection of middle endogenous cell phosphorylation p-EGFR.By the culture of 90 μ l cells (8000 cells/well) In growth medium in the orifice plate of Corning black transparents bottom 96, and at 37 DEG C in 5%CO2 Overnight incubation in humidified incubator.Using pipettor by the compound of serial dilution in 100%DMSO Cell is added to, after soft mixed culture medium, and cell is further cultured for 2 hours.By 100 μ l 1X Lysis buffer is added in each hole.The orifice plate of Greiner high-bonds 96 is covered with capture antibody, Then closed with 3%BSA.After removal confining liquid, 100 μ l lysates are transferred to In the orifice plate of Greiner high-bonds 96, it is incubated 2 hours.Soft mixing simultaneously uses PBS culture plate Afterwards, 100 μ l detection antibodies are added, and is incubated 2 hours.Soft mixing simultaneously uses PBS culture After plate, 100 μ l tmb substrates (Cell Signaling Technology catalog number (Cat.No.)s 7004) are added, It is incubated 1 hour.100 μ l stop baths are added in culture plate, and detect each hole to 450nm The absorbance of wavelength.Suitable software kit (such as Prism) is finally entered data into carry out curve Fitting Analysis.Based on this data and by calculate obtain 50% inhibition needed for compound concentration come Determine IC50Value.
Following table shows representative compound of the invention, i.e., the compound of embodiment 1 is in above-mentioned life IC in thing experiment50Value (μM), wherein with the compound Osimertinib (AZD9291) for comparing It is to synthesize according to the method described in documents below： Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of Both Se nsitizing and T790M Resistance Mutations That Spares the Wild Type For M of the Receptor, J.Med.Chem., 2014,57 (20), pp 8249-8267.
Test 5：L858R EGFR (activation single mutant) cell proliferation assay
Human pneumonocyte system H3255 (L858R single mutation EGFR) is from American Type Tissue Culture Center obtains.By H3255 cell culture containing 10% hyclone and 2mM glutamine In BEGM culture mediums (LONZA).Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.
According to the Cell Titer-Glo Luminescent cell Viability Assay of Promega companies Scheme described in (Promega catalog number (Cat.No.) #G7570) carries out living cells in detection culture Number.By the culture of 90 μ l cells (8000 cells/well) in the hole of Corning black transparents bottom 96 In growth medium in plate, and at 37 DEG C in 5%CO2Overnight incubation in humidified incubator.Make The compound of serial dilution in 100%DMSO is added into cell with pipettor, and cell is further cultured for 72 hours.The Cell Titer-Glo reagents that 100 μ l are mixed are added to thin in 96 well culture plates Cell lysis in born of the same parents, and softly mix.Then, carried out on Envision micropore board detectors spontaneous The detection of fluorescence, obtains the data of each compound.Finally enter data into suitable software kit (example Such as Prism) with the analysis that carries out curve fitting.50% suppression effect is obtained based on this data and by calculating Compound concentration needed for fruit determines IC50Value.
Test 6：Exon19 lacks EGFR (activation single mutant) cell proliferation assay
Human pneumonocyte system PC9 (Exon19 lacks EGFR) is from American type culture collection Obtain.By PC9 cell culture containing 10% hyclone and 2mM glutamine In RPMI1640 culture mediums.Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.
According to the Cell Titer-Glo Luminescent cell Viability Assay of Promega companies Scheme described in (Promega catalog number (Cat.No.) #G7570) carries out living cells in detection culture Number.By the culture of 90 μ l cells (8000 cells/well) in the hole of Corning black transparents bottom 96 In growth medium in plate, and at 37 DEG C in 5%CO2Overnight incubation in humidified incubator.Make The compound of serial dilution in 100%DMSO is added into cell with pipettor, and cell is further cultured for 72 hours.The Cell Titer-Glo reagents that 100 μ l are mixed are added to thin in 96 well culture plates Cell lysis in born of the same parents, and softly mix.Then, carried out on Envision micropore board detectors spontaneous The detection of fluorescence, obtains the data of each compound.Finally enter data into suitable software kit (example Such as Prism) with the analysis that carries out curve fitting.50% suppression effect is obtained based on this data and by calculating Compound concentration needed for fruit determines IC50Value.
Test 7：L858R/T790M EGFR (double-mutant) cell proliferation assay
Human pneumonocyte system NCI-H1975 (the double mutation EGFR of L858R/T790M) is from U.S.'s allusion quotation Type culture collection is obtained.NCI-H1975 cell culture is being contained into 10% hyclone and 2 In the RPMI1640 culture mediums of mM glutamine.Cell is set to have 5%CO2Humidified incubator In in 37 DEG C growth.
According to the Cell Titer-Glo Luminescent cell Viability Assay of Promega companies Scheme described in (Promega catalog number (Cat.No.) #G7570) carries out living cells in detection culture Number.By the culture of 90 μ l cells (8000 cells/well) in the hole of Corning black transparents bottom 96 In growth medium in plate, and at 37 DEG C in 5%CO2Overnight incubation in humidified incubator.Make The compound of serial dilution in 100%DMSO is added into cell with pipettor, and cell is further cultured for 72 hours.The Cell Titer-Glo reagents that 100 μ l are mixed are added to thin in 96 well culture plates Cell lysis in born of the same parents, and softly mix.Then, carried out on Envision micropore board detectors spontaneous The detection of fluorescence, obtains the data of each compound.Finally enter data into suitable software kit (example Such as Prism) with the analysis that carries out curve fitting.50% suppression effect is obtained based on this data and by calculating Compound concentration needed for fruit determines IC50Value.
Test 8：Wild type EGFR cell proliferation assay
Human pneumonocyte system NCI-H838 (Wild type EGFR) is from American Type Tissue Culture The heart is obtained.By NCI-H838 cell culture containing 10% hyclone and 2mM glutamine In RPMI1640 culture mediums.Cell is set to have 5%CO2Humidified incubator in 37 DEG C growth.
According to the Cell Titer-Glo Luminescent cell Viability Assay of Promega companies Scheme described in (Promega catalog number (Cat.No.) #G7570) carries out living cells in detection culture Number.By the culture of 90 μ l cells (8000 cells/well) in the hole of Corning black transparents bottom 96 In growth medium in plate, and at 37 DEG C in 5%CO2 humidified incubators overnight incubation.Make The compound of serial dilution in 100%DMSO is added into cell with pipettor, and cell is further cultured for 72 hours.The Cell Titer-Glo reagents that 100 μ l are mixed are added to thin in 96 well culture plates Cell lysis in born of the same parents, and softly mix.Then, carried out on Envision micropore board detectors spontaneous The detection of fluorescence, obtains the data of each compound.Finally enter data into suitable software kit (example Such as Prism) with the analysis that carries out curve fitting.50% suppression effect is obtained based on this data and by calculating Compound concentration needed for fruit determines IC50Value.
Following table shows representative compound of the invention, i.e., the compound of embodiment 1 is in above-mentioned life IC in thing experiment50Value (μM), wherein with the compound Osimertinib (AZD9291) for comparing It is to synthesize according to the method described in documents below： Discovery of a Potent and Selective EGFR Inhibitor(AZD9291)of Both Se nsitizing and T790M Resistance Mutations That Spares the Wild Type For M of the Receptor, J.Med.Chem., 2014,57 (20), pp 8249-8267.

Claims (14)

1. the compound or its pharmaceutically acceptable salt of formula (I)：
Wherein
G is selected from aryl, heteroaryl or heterocyclic radical, preferably C6-10Aryl, C5-10Heteroaryl or C4-10 Heterocyclic radical, the aryl, heteroaryl or heterocyclic radical are optionally independently selected by one or more from C1-6 Alkyl, C1-6Alkoxy, oxo, halogen or C1-6The substitution base of haloalkyl is replaced；
R1Selected from hydrogen, C1-6Alkyl, C1-6Alkoxy, halogen and C1-6Haloalkyl；
R2Selected from C1-6Alkyl, C1-6Miscellaneous alkyl, C6-10Aryl, C5-10Heteroaryl, C4-10Heterocyclic radical, C6-10Aryl-C1-6Alkylidene, C5-10Heteroaryl-C1-6Alkylidene or C4-10Heterocyclic radical-C1-6Alkylene Base, wherein the alkyl, aryl, heteroaryl or heterocyclic radical are optionally independently selected by one or more From C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two-C1-6Alkyl amino, oxo, halogen, C1-6Haloalkyl, aminoacyl, C1-6Alkylaminoacyl or two-C1-6The substitution of alkylaminoacyl Base is replaced；
R3Selected from hydrogen or C1-6Alkyl；
Or R2And R3Heteroaryl or heterocyclic radical are formed together with the nitrogen-atoms being connected with them, preferably C5-10Heteroaryl or C4-10Heterocyclic radical, wherein the heteroaryl or heterocyclic radical are optionally by one or more Independently selected from C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, two-C1-6Alkyl amino, oxo, Halogen, C1-6Haloalkyl, aminoacyl, C1-6Alkylaminoacyl or two-C1-6Alkylaminoacyl Substitution base replaced；
R4Selected from hydrogen or C1-6Alkyl；
R5Selected from following group：
2. the compound or its pharmaceutically acceptable salt of formula (I) as claimed in claim 1, wherein：
G is selected from 4,5,6,7- tetrahydro-pyrazoles simultaneously [1,5-a] pyridin-3-yl, 1H- indol-3-yls, 1- methyl isophthalic acids H- Indol-3-yl and pyrazolo [1,5-a] pyridin-3-yl；
R1Selected from methoxyl group, methyl, chlorine, fluorine and trifluoromethyl；
R4It is hydrogen；
R5It is following group：
R2And R3Formed together with the nitrogen-atoms being connected with them selected from following groups：(3R) -3- (two Methylamino) pyrrolidin-1-yl, (3S) -3- (dimethylamino) pyrrolidin-1-yl, 3- (dimethylamino) azacyclo- Butane -1- bases, [2- (dimethylamino) ethyl]-(methyl) amino, [2- (methylamino) ethyl] (methyl) amino, 5- methyl -2,5- diazaspiracyclic [3.4] octyl- 2- bases, (3aR, 6aR) -5- methyl hexahydro-pyrrolo- [3,4-b] Pyrroles -1 (2H)-base, 1- methyl isophthalic acids, 2,3,6- tetrahydropyridine -4- bases, 4- methylpiperazine-1-yls, 4- [2- (two Methylamino) -2- oxoethyls] piperazine -1- bases, methyl [2- (4- methylpiperazine-1-yls) ethyl] amino, methyl [2- (morpholine -4- bases) ethyl] amino, 1- amino -1,2,3,6- tetrahydropyridine -4- bases or 4- [(2S) -2- amino Propiono] piperazine -1- bases.
3. the compound or its pharmaceutically acceptable salt of formula (I) as claimed in claim 2, wherein G It is 1H- indol-3-yls, 1- Methyl-1H-indole -3- bases or pyrazolo [1,5-a] pyridin-3-yl.
4. the compound of formula (I) as described in any one of claims 1 to 3 or its is pharmaceutically acceptable Salt, wherein R1It is methoxyl group.
5. the compound of formula (I) as described in any one of Claims 1-4 or its is pharmaceutically acceptable Salt, wherein G are 1- Methyl-1H-indole -3- bases.
6. the compound of formula (I) as described in any one of claim 1 to 5 or its is pharmaceutically acceptable Salt, wherein R2And R3Formed together with the nitrogen-atoms being connected with them [2- (dimethylamino) ethyl] (methyl) Amino.
7. the compound of formula (I) as described in any one of claim 1 to 6 or its is pharmaceutically acceptable Salt, wherein the compound is：N- (2- { 2- (dimethylamino) ethyl-(methyl) amino } -4- methoxyl groups - 5- { [4- (1- methyl indol -3- bases) -1,3,5- triazine -2- bases] amino } phenyl) propyl- 2- acrylamides
8. the compound or its pharmaceutically acceptable salt of formula (I) as described in claim 1 to 6, its Described in compound be N- (4- methoxyl groups -5- { [4- (1- methyl indol -3- bases) -1,3,5- triazine -2- bases] ammonia Base } -2- [methyl-(2- methylaminoethyls) amino] phenyl) propyl- 2- acrylamides.
9. pharmaceutical composition, its chemical combination for including the formula (I) as any one of claim 1 to 8 Thing or its pharmaceutically acceptable salt and pharmaceutically acceptable diluent or carrier.
10. the compound of formula (I) as any one of claim 1 to 8 or its can pharmaceutically connect The salt received, it is used as medicine.
The compound of 11. formula (I) as any one of claim 1 to 8 or its can pharmaceutically connect Purposes of the salt received in the medicine for treating cancer is prepared.
The compound of 12. formulas (I) as described in claim 11 or its pharmaceutically acceptable salt Purposes, wherein the cancer is non-small cell lung cancer.
13. methods that antitumaous effect is produced in the warm-blooded animal such as people for needing this treatment, its bag Include：The change of the formula (I) as any one of claim 1 to 8 is obtained to the animal effective dosage Compound or its pharmaceutically acceptable salt.
The compound of 14. formula (I) as any one of claim 1 to 8 or its can pharmaceutically connect The salt and the purposes of other antitumorigenic substance received, while for cancer, independence or sequential therapy.
CN201511022453.5A 2015-12-30 2015-12-30 For the pyrrolotriazine derivatives for the treatment of cancer Pending CN106928200A (en)

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