CN108570053A - Five yuan and 6-membered heterocyclic compound, preparation method, intermediate, combination and application - Google Patents
Five yuan and 6-membered heterocyclic compound, preparation method, intermediate, combination and application Download PDFInfo
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- CN108570053A CN108570053A CN201710158943.0A CN201710158943A CN108570053A CN 108570053 A CN108570053 A CN 108570053A CN 201710158943 A CN201710158943 A CN 201710158943A CN 108570053 A CN108570053 A CN 108570053A
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- 0 C1*CN*C1 Chemical compound C1*CN*C1 0.000 description 2
- VZCKAHQOGDXCSH-ZTOZKROFSA-N C[n]1ncc(/C(/N)=C/N=C(/C=CN2CCS(c3cccc(N=O)c3)=C)\C2=C)c1 Chemical compound C[n]1ncc(/C(/N)=C/N=C(/C=CN2CCS(c3cccc(N=O)c3)=C)\C2=C)c1 VZCKAHQOGDXCSH-ZTOZKROFSA-N 0.000 description 1
- ITQTTZVARXURQS-UHFFFAOYSA-N Cc1cccnc1 Chemical compound Cc1cccnc1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N c1ccncc1 Chemical compound c1ccncc1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The invention discloses a kind of five yuan and 6-membered heterocyclic compound, preparation method, intermediate, combination and applications.Five yuan in the present invention and 6-membered heterocyclic compound have excellent FGFR and/or RET inhibitory activity.
Description
Technical field
The present invention relates to a kind of five yuan and 6-membered heterocyclic compound, preparation method, intermediate, combination and applications.
Background technology
Fibroblast growth factor acceptor (Fibroblast growth factor receptors, FGFRs) be by
Important a member in the protein tyrosine kinase superfamily of build.Have now been found that 4 kinds of FGFR hypotypes, including FGFR1, FGFR2,
FGFR3 and FGFR4, they are mostly single-stranded glycoprotein molecule, and molecular mass is 110~150ku, by extracellular immune globulin
White spline structure domain, transmembrane region and intracellular tyrosine kinase receptor domain composition.In heparin sulfated proteoglycans (HSPG)
In the presence of, fibroblast growth factor (Fibroblast growth factor, FGF) and FGFRs combine rear receptor dimerization
Change, the tyrosine kinase of intracellular section is activated, and to enabling signal cascade reaction, participates in the adjusting of physiological activity, such as promotes blood
Pipe generation, wound healing and tissue damage reparation etc..Studies have shown that the variation of the gene variation and expression quantity of FGFRs with it is swollen
The occurrence and development of oncocyte are closely related.It has been reported that can detect 20% in non-small cell lung cancer and breast cancer
Gene magnification with 10% FGFR1, the FGFR2 gene magnifications for having 10% in stomach cancer cell have in non-wettability carcinoma of urinary bladder
The rite-directed mutagenesis etc. of the FGFR3 of 50%-60%.Therefore, FGFR is a kind of important target during antitumor drug is developed, special at present
Anisotropic small molecule FGFR inhibitor is still in clinical investigation phase, faces as LY-2874455, BGJ-398, AZD-4547 are in
II phase of bed, JNJ-42756493 is in clinicalⅰstage, therefore the FGFR inhibitor of exploration discovery structure novel has great importance.
Invention content
The technical problem to be solved by the present invention is in order to seek the kinase inhibitor of structure novel, and provide one kind five
Member and 6-membered heterocyclic compound, preparation method, intermediate, combination and application.Five yuan in the present invention and 6-membered heterocyclic compound
With excellent FGFR and/or RET inhibitory activity.
The present invention provides one kind such as general formula I shown in five yuan simultaneously 6-membered heterocyclic compound, its pharmaceutically acceptable salt
Or pharmaceutically acceptable solvate,
Wherein, Z is C or N；W is C, N, O or S；Y is C, N, O or S；
L is-S (O)2-、-S(O)-、-C(O)-、-CH2-、-CH(CH3)-、-(CH2)2-、-(CH2)3-、-S(O)2CH2-、-S
(O)CH2-、-C(O)CH2-、-CH2C(O)-、-CH2S(O)2Or-CH2S(O)-；
R1For hydrogen, substituted or unsubstituted C1-C6Alkyl ,-ORb1、-SRb2、-NRb3Rb4、-C(O)Rb5、-S(O)2Rb6、-S
(O)Rb7、-C(O)ORb8、-C(O)SRb9、-C(O)(NRb10Rb11)、-S(O)2NRb12Rb13、-S(O)NRb14Rb15、-NRb16C(O)
Rb17、-NRb18S(O)2Rb19、-NRb20S(O)Rb21、-NRb22C(O)NRb23Rb24、-NRb25S(O)NRb25Rb27, substitution or it is unsubstituted
" containing heteroatomic 3~10 circle heterocyclic ring bases of the 1-5 in N, O and S " or substituted or unsubstituted 3~6 yuan of cycloalkanes
Base；It is described substituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S " and substituted 3~6 yuan described
Substitution in naphthenic base is each independently by one or more (such as 2,3 or 4) R4Substitution, when there is multiple R4When, substituent group phase
It is same or different；
Rb1~Rb27It is each independently hydrogen, the unsubstituted or C that is replaced by 1~3 halogen1-C4Alkyl or 3~6 yuan
Naphthenic base；R4For halogen or C1-C4Alkyl；
R2For substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene, substitution
Or unsubstituted " containing heteroatomic 5~10 unit's heteroaryls of the 1-5 in N, O and S ", substituted or unsubstituted " contain
Heteroatomic 3~10 circle heterocyclic ring bases of the 1-5 in N, O and S ", substituted or unsubstituted 3~6 yuan of naphthenic base or substitution or
Unsubstituted 3~6 member cycloalkenyl；Wherein, the substituted C1-C6Substituent group in alkyl one in following radicals or
It is multiple：-ORa1、-SRa2Or-NRa3Ra4, when there is multiple substituent groups, substituent group is identical or different；Ra1、Ra2、Ra3And Ra4Respectively
From independently being hydrogen or C1-C4Alkyl；The substituted phenyl, described substituted " is selected from the substituted naphthalene containing 1-5
N, heteroatomic 5~10 unit's heteroaryl in O and S ", it is described it is substituted " containing 1-5 in N, O and S heteroatomic 3
Substitution in~10 circle heterocyclic ring bases ", 3~6 yuan of substituted naphthenic base and 3~6 substituted member cycloalkenyls is respectively independent
Ground is by 1-3 (such as 2) RmReplaced, when there are multiple RmWhen substitution, substituent group is identical or different；
RmFor halogen, nitro, cyano ,-ORc1、-SRc2、-NRc3Rc4、-C(O)Rc5、-S(O)2Rc6、-S(O)Rc7、-C(O)
ORc8、-C(O)SRc9、-C(O)NRc10Rc1、-S(O)2NRc12Rc13、-S(O)NRc14Rc15、-NRc16C(O)Rc17、-NRc18S(O)2Rc19、-NRc20S(O)Rc21、-NRc22C(O)NRc23Rc24、-NRc25S(O)NRc26Rc27, substituted or unsubstituted C1-C6Alkyl takes
Generation or unsubstituted phenyl substituted or unsubstituted " contain heteroatomic 5~10 yuan heteroaryls of the 1-5 in N, O and S
Base ", substituted or unsubstituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S " or substitution do not take
3~6 yuan of naphthenic base in generation；Wherein, the substituted C1-C6Being substituted by by 1-3 (such as 2) R in alkyl3Replaced, when
There are multiple R3When substitution, substituent group is identical or different；The substituted phenyl described substituted " is selected from N, O containing 1-5
With heteroatomic 5~10 unit's heteroaryl in S ", it is described it is substituted " containing 1-5 in N, O and S heteroatomic 3~10
Substitution in circle heterocyclic ring base " and 3~6 yuan of substituted naphthenic base is each independently by 1-3 (such as 2) RnIt is taken
Generation, when there is multiple RnWhen substitution, substituent group is identical or different；
Rc1~Rc27It is each independently hydrogen, C2-C6It is alkenyl, unsubstituted or C is replaced by 1~3 (such as 2) halogen1
~C4Alkyl or 3~6 yuan of naphthenic base；
R3For halogen ,-ORd1、-SRd2、-NRd3Rd4、-C(O)(NRd5Rd6)、-C(O)Rd7、-C(O)ORd8、-S(O)2Rd9、-S
(O)Rd10、-N(Rd11)C(O)Rd12, it is substituted or unsubstituted " miscellaneous containing 1~3 heteroatomic 3~6 yuan in N, O and S
Ring group " or substituted or unsubstituted 3~6 yuan of naphthenic base；It is described substituted " to contain 1~3 hetero atom in N, O and S
3~6 circle heterocyclic ring bases " and 3~6 yuan of substituted naphthenic base in substitution be each independently by 1~3 (such as 2) a R5
Substitution, when there is multiple substituent groups, substituent group is identical or different；
Rd1~Rd12It is each independently hydrogen or C1-C4Alkyl；R5Halogen or C1-C4Alkyl；
RnFor halogen, nitro, cyano, the unsubstituted or C that is replaced by 1~3 halogen1-C6Alkyl ,-ORf1、-SRf2、-
NRf3Rf4、-C(O)Rf5、-S(O)2Rf6、-S(O)Rf7、-C(O)ORf8、-C(O)SRf9、-C(O)(NRf10Rf11)、-S(O)2NRf12Rf13、-S(O)NRf14Rf15、-NRf16C(O)Rf17、-NRf18S(O)2Rf19、-NRf20S(O)Rf21、-NRf22C(O)
NRf23Rf24Or-NRf25S(O)NRf25Rf27；Rf1~Rf27It is each independently hydrogen or C1-C4Alkyl.
The L preferably-S (O)2-、-C(O)-、-CH2-、-(CH2)2-、-(CH2)3Or-CH2C (O)-, more preferable-S
(O)2-。
In the general formula I, it will be appreciated that on the basis of without prejudice to organic field basic principle, Z, W, Y and and they
Connected carbon atom forms 5-membered aromatic ring, the preferred N of Z together；W is preferably C or N；Y preferred C or N；It is preferred that
For
The R1Or R2In, the substituted or unsubstituted C1-C6C in alkyl1-C6The preferred methyl of alkyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group or tertiary butyl.
The R1Or R2In, it is described substituted or unsubstituted " to contain heteroatomic 3~10 yuan of 1-5 in N, O and S
" contain 1-5 heteroatomic 3~10 yuan (such as 5 or 6 yuan) of (such as 1,2 or 3) in N, O and S in heterocycle "
Heterocycle " is preferred
The R1Or R2In, 3~6 yuan of preferred hexamethylenes of naphthenic base in " substituted or unsubstituted 3~6 yuan of naphthenic base "
Base or cyclopenta.
The R2In, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 5~10 yuan of 1-5 in N, O and S
In aryl " " containing 1-5 (such as 1,2,3 or 4) in N, O and S heteroatomic 5~10 yuan (such as 5,6,7,8,
9,10 yuan) heteroaryl " it is preferably following any group：
The R2In, 3~6 member cycloalkenyls such as cyclohexenyl group in substituted or unsubstituted 3~6 member cycloalkenyl or
Cyclopentenyl.
The R2In, in the substituted or unsubstituted phenyl, substituent group in substituted phenyl can positioned at the ortho position of L,
Meta position and at one in contraposition or a few places.
The Rb1~Rb27In, " the unsubstituted or C that is replaced by 1~3 halogen1-C4C in alkyl "1~C4Alkane
Base is preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl each independently；1~3 halogen
The C of element substitution1-C4Alkyl preferred trifluoromethyl each independently.3~6 yuan of naphthenic base each independently preferred cyclopropyl,
Cyclopenta or cyclohexyl.The Rb1More preferably hydrogen.The Rb5The more preferably described unsubstituted C1-C4Alkyl (such as methyl,
Ethyl or tertiary butyl).The Rb6The more preferably described unsubstituted C1-C4Alkyl (such as methyl) or 3~6 yuan of naphthenic base
(such as cyclopropyl).The Rb8The more preferably described unsubstituted C1-C4Alkyl (such as methyl or ethyl).The Rb10It is more excellent
It is selected as hydrogen or the unsubstituted C1-C4Alkyl (such as methyl)；The Rb11The more preferably described unsubstituted C1-C4Alkyl
(such as methyl).
The R4In, the preferred fluorine of the halogen, chlorine, bromine or iodine；The C1-C4It is the preferred methyl of alkyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group or tertiary butyl.
The Ra1、Ra2、Ra3Or Ra4In, the C1-C4The preferred methyl of alkyl, ethyl, n-propyl, isopropyl, normal-butyl,
Isobutyl group or tertiary butyl.
The RmIn, the preferred fluorine of the halogen, chlorine, bromine or iodine.
The RmIn, the substituted or unsubstituted C1-C6C in alkyl1-C6The preferred methyl of alkyl, ethyl, n-propyl,
Isopropyl, normal-butyl, isobutyl group or tertiary butyl.
The RmIn, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 5~10 yuan of 1-5 in N, O and S
In aryl " " containing 1-5 (such as 1,2 or 3) in N, O and S heteroatomic 5~10 yuan (such as 5,6,7,8,
9,10 yuan) heteroaryl " preferably pyrazolyl (such as), pyridyl group (such as) or pyrimidine
Base (such as)。
The RmIn, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 3~10 yuan of 1-5 in N, O and S
It is " miscellaneous containing 1-5 heteroatomic 3~10 yuan (such as 5 or 6 yuan) of (such as 1,2 or 3) in N, O and S in ring group "
Ring group " is preferred
The RmIn, the preferred cyclohexyl of 3~6 yuan of naphthenic base in " substituted or unsubstituted 3~6 yuan of naphthenic base " or
Cyclopenta.
The Rc1~Rc27In, it is described unsubstituted or C is replaced by 1~3 halogen1~C4C in alkyl1~C4Alkyl is each
From independently be preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；It is described by 1~3 halogen
Replace C1~C4Alkyl preferred trifluoromethyl each independently；3~6 yuan of naphthenic base preferred cyclopropyl, ring penta each independently
Base or cyclohexyl；The C2-C6Alkenyl preferred vinyl each independently.
The Rc1More preferable hydrogen or the unsubstituted C1~C4Alkyl (such as methyl).The Rc3And Rc4More preferable hydrogen.
Rc6The more preferably described unsubstituted C1~C4Alkyl (such as methyl).The Rc16More preferable hydrogen.The Rc17More preferably institute
State unsubstituted C1~C4Alkyl (such as methyl or ethyl).
The R3In, the preferred fluorine of the halogen, chlorine, bromine or iodine.Work as R3For halogen, RmFor substituted or unsubstituted C1-C6Alkane
When base, the substituted or unsubstituted C1-C6C in alkyl1-C6The more preferable ethyl of alkyl；The substituted C1-C6Alkyl is more
Preferably-CH2CH2F。
The R3In, it is described substituted or unsubstituted " miscellaneous containing 1~3 heteroatomic 3~6 yuan in N, O and S
" contain heteroatomic 3~6 yuan (such as the 5 yuan or 6 yuan) heterocycles of 1~3 (such as 2) in N, O and S in ring group "
Base " is
The R3In, the preferred cyclopenta of 3~6 yuan of naphthenic base in substituted or unsubstituted 3~6 yuan of naphthenic base or hexamethylene
Base.
The R5In, the halogen is preferably fluorine, chlorine, bromine or iodine.
The R5In, the C1-C4Alkyl is preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or uncle
Butyl.
The Rd1~Rd12In, the C1~C4Alkyl each independently be preferably methyl, ethyl, n-propyl, isopropyl,
Normal-butyl, isobutyl group or tertiary butyl.
The RnIn, the preferred fluorine of the halogen, chlorine, bromine or iodine." the unsubstituted or C that is replaced by 1~3 halogen1-
C6C in alkyl "1-C6The preferred methyl of alkyl or ethyl；The C replaced by 1~3 halogen1-C6The preferred trifluoromethyl of alkyl.
The Rf1~Rf27In, the C1-C4Alkyl preferred methyl, ethyl, n-propyl, isopropyl, positive fourth each independently
Base, isobutyl group or tertiary butyl.
Preferably, five yuan and 6-membered heterocyclic compound shown in the general formula I are following general formula II, general formula III or general formula
Five-ring heterocycles shown in IV and 6-membered heterocyclic compound,
Wherein, R1And R2It is defined as above described.
Preferably, five yuan and 6-membered heterocyclic compound shown in the general formula I be five-ring heterocycles shown in following general formula V simultaneously
6-membered heterocyclic compound,
Wherein, R2It is defined as above described.
It is highly preferred that simultaneously 6-membered heterocyclic compound is five yuan shown in general formula VI to five-ring heterocycles shown in the general formula V
Heterocycle and 6-membered heterocyclic compound,
Wherein, RmIt is defined as above described.
In five-ring heterocycles shown in the general formula VI and 6-membered heterocyclic compound, the RmMore preferably it is described substitution or not
Substituted C1-C6Alkyl.
Most preferably, five yuan and 6-membered heterocyclic compound shown in the general formula I are following any compound：
The pharmaceutically acceptable salt of five yuan and 6-membered heterocyclic compound shown in heretofore described general formula I can be by logical
Compound of formula I and inorganic acid or organic acid reaction are made, and the inorganic acid includes hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid etc., described
Organic acid include ascorbic acid, niacin, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, oxalic acid, malic acid,
Glycolic, succinic acid, propionic acid, acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid etc..
Preferably, the pharmaceutically acceptable salt of five yuan and 6-membered heterocyclic compound shown in the general formula I can pass through
Compound of Formula I is dissolved in being reacted in the alcoholic solution of corresponding acid saturation and is prepared, such as：By compound of Formula I institute
Five yuan shown and 6-membered heterocyclic compound are dissolved in the dioxane solution of HCl saturations, are stirred at room temperature 30 minutes, filter, obtain
Corresponding hydrochloride.
The pharmaceutically acceptable solvate of five yuan and 6-membered heterocyclic compound shown in heretofore described general formula I is
Refer to the combination of the compound of Formula I of the present invention and solvent molecule that are formed by solvation.For example, when solvent molecule is moisture
The period of the day from 11 p.m. to 1 a.m, solvate refer to hydrate.
Those skilled in the art are according to the synthetic method of the application specific embodiment disclosure combination this field routine
Five yuan and 6-membered heterocyclic compound shown in the general formula I is prepared.
The present invention also provides the preparation method of five yuan shown in a kind of general formula I as mentioned and 6-membered heterocyclic compound,
It can be prepared by method A or method B；
Method A, includes the following steps：In the presence of alkali, by Formula II compound and R2- L-LG carries out nucleophilic as follows and takes
Generation reaction, obtains shown compound of formula I；
Wherein, R1、R2, Y and W be defined as above described, LG is leaving group；
Method B, includes the following steps：- 1 compound of formula III and -2 compound of Formula II are subjected to coupling reaction as follows,
Obtain shown compound of formula I；
Wherein, R1、R2, Z, Y and W be defined as above described, RaAnd RbIt is each independently C1-C4Alkyl；Or Ra、RbWith with
Its connected oxygen atom forms substituted or unsubstituted 5-6 membered rings together, and the substituent group in substituted 5-6 membered rings is C1-C4Alkane
Base.
In the method A, the condition of the nucleophilic substitution is referred to such routine reacted of this field and is selected
It selects.The LG can be such nucleophilic substitution of this field in conventional use of leaving group, preferably halogen (such as chlorine, bromine or
Iodine).The alkali is conventional use of alkali in art technology such reaction, such as sodium hydroxide, potassium hydroxide, the tert-butyl alcohol
Potassium, sodium tert-butoxide, sodium hydrogen etc..The nucleophilic substitution preferably carries out in organic solvent, and the organic solvent is preferred
For this field, such reacts conventional use of solvent, such as tetrahydrofuran or DMF etc..
In the method B, the condition of the coupling reaction is referred to such routine reacted of this field and is selected.
The RaOr RbIn, C1-C4Alkyl such as methyl or ethyl.In substituent group in 5-6 membered rings, C1-C4Alkyl such as methyl or second
Base.Work as Ra、RbWhen forming substituted or unsubstituted 5-6 membered rings together with coupled oxygen atom, the formula III -1 is for example
The present invention also provides a kind of such as Formula Il -1 and II-2 compounds represented,
Wherein, Z, W, Y, L, R1And R2It is as defined above described.
The preferably following any structure of -1 compound of Formula II：
Wherein, R1(the R as defined above1It is preferred that hydrogen).
The preferably following any structure of -2 compound of Formula II：
Wherein, R2(the R as defined above2It is preferred thatRmIt is as defined above described).
The present invention provides one kind such as general formula I shown in five yuan simultaneously 6-membered heterocyclic compound, its pharmaceutically acceptable salt
Or application of the pharmaceutically acceptable solvate in being used to prepare FGFR inhibitor and/or RET inhibitor.
The present invention also provides one kind such as general formula I shown in five yuan simultaneously 6-membered heterocyclic compound, its is pharmaceutically acceptable
Salt or pharmaceutically acceptable solvate are preparing treatment and/or are preventing the " expression with tyrosine kinase FGFR and/or RET
Or the relevant disease of activity " drug in application.
In the present invention, described " expression or the relevant disease of activity with tyrosine kinase FGFR " can be conventional in this field
The variation by tyrosine kinase FGFR caused by disease, such as tumour or cancer caused by variation by tyrosine kinase FGFR
Disease.The cancer for example lung cancer, gastric cancer, liver cancer, breast cancer, colon cancer, prostate cancer, cancer of pancreas, the cancer of the esophagus, oophoroma,
Kidney or thyroid cancer etc.；The tumour such as glioma or melanoma.
In the present invention, described " expression or the relevant disease of activity with tyrosine kinase RET " can be conventional in this field
The variation by tyrosine kinase RET caused by disease, such as tumour or cancer caused by variation by tyrosine kinase RET
Disease.The cancer for example lung cancer, gastric cancer, liver cancer, breast cancer, colon cancer, prostate cancer, cancer of pancreas, the cancer of the esophagus, oophoroma,
Kidney or thyroid cancer etc.；The tumour such as glioma or melanoma.
The present invention also provides a kind of pharmaceutical composition, it includes therapeutically effective amounts as shown in general formula I five yuan and hexa-atomic
Heterocyclic compound, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate and one or more pharmaceutic adjuvants.
The pharmaceutical composition can be prepared by the method for this field routine.The pharmaceutic adjuvant is ability
Conventional pharmaceutical adjuvants in domain, selection is different because of administration method and action character, preferably includes filler, diluent, bonding
Agent, wetting agent, disintegrant, lubricant, emulsifier, suspending agent.The pharmaceutical composition can take orally, inject (vein, flesh
In meat, subcutaneous and coronary artery), sublingual, buccal, per rectum, per urethra, Via vagina, intranasal, sucking or topic route application.
In the present invention, unless otherwise specified, halogen refers generally to fluorine, chlorine, bromine or iodine.
Term " heterocycle " indicates to include specified heteroatomic one or more cyclic groups (including loop coil, bridged ring and condensed ring),
Wherein each ring can contain one or more double bonds, but at least one ring does not have the pi-electron system of total conjugated；N is former
Son can be quaternized.Heterocycle is attached by the ring of " the pi-electron system for not having total conjugated " with other groups；Heterocycle
Base can be attached through carbon atom therein or hetero atom with other groups.One or more hydrogen atoms on " heterocycle "
(can be by the hydrogen on carbon atom or nitrogen-atoms) be replaced by one or more substituent groups described in the invention individually optionally.
Term " heteroaryl " indicate comprising specify heteroatomic monocycle or polycyclic aroma system (for example, hetero-aromatic ring and aromatic ring,
Bicyclic heteroaromatic rings), heteroaryl can be attached through carbon atom therein or hetero atom with other groups.On " heteroaryl "
One or more hydrogen atoms are replaced by one or more substituent groups described in the invention individually optionally.Some embodiments
In, the N atoms in nitrogenous heterocycle are aoxidized, and nitrogen oxides is formed.
Term " naphthenic base " is indicated comprising the full carbon one or more cyclic groups of saturation of ring carbons specified number, on ring
One or more ring hydrogen atoms are replaced by one or more substituent groups described in the invention individually optionally.
Term " alkenyl " refers to containing the linear chain or branched chain alkenyl for specifying number carbon atom and at least one carbon-carbon double bond.Such as
“C2-6Alkenyl " refers to the alkenyl for having 2-6 carbon atom, such as vinyl, acrylic, cyclobutenyl or 2- methyl butene bases.Alkene
Base is attached by ethylene linkage carbon atom with other groups.
Term " cycloalkenyl group " refers to containing specifying number the cyclic annular non-aromatic alkyl of carbon atom and at least one carbon-carbon double bond, ring
Upper one or more ring hydrogen atom is replaced by one or more substituent groups described in the invention individually optionally.Cyclenes
Base can be attached by ethylene linkage carbon atom or non-ethylene linkage carbon atom and other groups (such as)。
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined arbitrarily each preferably to get the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that：This application provides a kind of structure completely new five yuan and hexa-member heterocycle chemical combination
Object.Five yuan in the present invention and 6-membered heterocyclic compound have excellent FGFR and/or RET inhibitory activity.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
Product specification selects.
Nuclear magnetic resonance spectroscopy BrukerAMX-300 or 400 types.All reaction dissolvents conventionally carry out pure
Change.Column chromatography silica gel (200-300 mesh or 300-400 mesh) produces for Qingdao Haiyang chemical industry subsidiary factory.Combiflash companion is used
Parallel Frac FR-260 types produce for YAMAZEN companies of Japan.Thin layer chromatography board used is HSGF-254 with plate is prepared
Type produces for Yantai Jiang You silica gel development corporation, Ltd..All solvents are analysis pure solvent, and agents useful for same is purchased from traditional Chinese medicines collection
Chemical reagent Co., Ltd of group.It is developed the color using the methods of iodine, Ultraluminescence.Remove under reduced pressure organic solvent in Rotary Evaporators into
Row.
Embodiment 1：(1- methyl-1 H- pyrazoles -4- bases) -5- (phenyl sulfonyl) -5H- pyrrolo-es [2,3-b] pyrazine (is changed
Close object 1) preparation
Step 1：The preparation of compound Ia
By compound a (1.5g, 1.0eq), b (1.15g, 1.2eq), potassium carbonate (3.15g, 3.0eq), the bis- (hexichol of 1,1'-
Phosphino-) ferrocene palladium chloride (II) chloride dichloromethane complex (II) (310mg, 0.05eq) is placed in a reaction flask, 15mL is added
Dioxane, 5ml water (dioxane：Water=3:1), with nitrogen displaced air 3 times, 90 DEG C of reaction 6h add water after completion of the reaction
200mL, dichloromethane extract three times, and organic layer concentrates after being dried with anhydrous sodium sulfate, and target is detached to obtain with combiflash companion
Compound Ia (1.05g, yield：69%).
1H NMR(400MHz,Chloroform-d)δ9.30(s,1H),8.71(s,1H),8.09(s,1H),7.97(s,
1H), 7.54 (dd, J=3.67,2.67Hz, 1H), 6.73 (dd, J=3.68,1.92Hz, 1H), 4.02 (s, 3H)
ESI(m/z):200.1[M+H]+
Step 2：The preparation of compound 1
Hydrogen sodium (24mg, 1.5eq) is dissolved in 5mL anhydrous tetrahydro furans, by chemical compounds I a (80mg, 1.0eq) under stirring
It is added portionwise, after stirring at normal temperature 30min, benzene sulfonyl chloride (56.2 μ L, 1.1eq) is added dropwise in reaction solution, 5h is stirred at room temperature, waits for
After the reaction was complete, tetrahydrofuran being concentrated away, 20mL water being added, PH nearly 7, ethyl acetate is adjusted to extract three times, organic layer is with anhydrous
It is concentrated after sodium sulphate drying, target compound 1 (42mg, yield is detached to obtain with combiflash companion：52%).
1H NMR(400MHz,Chloroform-d)δ8.71(s,1H),8.28–8.19(m,2H),8.09(s,1H),
8.03 (s, 1H), 7.94 (d, J=4.1Hz, 1H), 7.62 (d, J=7.4Hz, 1H), 7.54 (t, J=7.7Hz, 2H), 6.80
(d, J=4.1Hz, 1H), 4.04 (s, 3H)
ESI(m/z):340.0[M+H]+
Reaction substrate only need to be correspondingly replaced, compound is corresponding by the preparation route of following compound with embodiment 1
Characterize data it is as follows：
Embodiment 2：3- ((3- (1- methyl-1 H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine -5- bases) sulfonyl)
The preparation of aniline (compound 9)
Compound 17 (60mg, 1eq) is dissolved in 10mL ethyl alcohol, 50 DEG C sequentially add iron powder (31mg, 5eq) and ammonium chloride
Water (2mL) solution of (30mg, 5eq), heating reaction 2h, after the reaction was complete, is evaporated under reduced pressure away ethyl alcohol, uses saturated sodium bicarbonate
Aqueous solution tune PH is 7~8, and ethyl acetate extracts three times, and target compound 9 (40mg, yield are detached to obtain with combiflash companion：
67%).
1H NMR (600MHz, Chloroform-d) δ 9.05 (d, J=1.9Hz, 1H), 8.67 (s, 1H), 8.17-8.14
(m, 2H), 8.06 (dd, J=8.5,0.8Hz, 1H), 8.04 (d, J=0.8Hz, 1H), 7.98 (d, J=4.1Hz, 1H), 7.42
(d, J=8.4Hz, 1H), 6.80 (d, J=4.1Hz, 1H), 4.05 (s, 3H)
ESI(m/z):355.4[M+H]+
Reaction substrate only need to be correspondingly replaced, compound is corresponding by the preparation route of following compound with embodiment 2
Characterize data it is as follows：
Embodiment 3：N- (3- ((3- (1- methyl-1 H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine -5- bases) sulphonyl
Base) phenyl) acetamide (compound 14) preparation
By compound 9 (50mg, 1eq), chloroacetic chloride (18mg, 2eq) is dissolved in anhydrous methylene chloride, and the 4- of catalytic amount is added
3h is stirred at room temperature in dimethylamino naphthyridine, and after the reaction was complete, target compound 5 (28mg, yield are detached to obtain with combiflash companion：
50%).
1H NMR(400MHz,Chloroform-d)δ8.79(s,1H),8.61(s,1H),8.30(s,1H),8.07(s,
1H), 7.71 (t, J=6.2,6.2Hz, 2H), 7.61 (d, J=8.1Hz, 1H), 7.47 (d, J=8.1Hz, 1H), 7.28 (m,
1H), 6.81 (d, J=4.1Hz, 1H), 3.95 (s, 3H), 2.04 (s, 3H)
ESI(m/z):397.4[M+H]+
Reaction substrate only need to be correspondingly replaced, compound is corresponding by the preparation route of following compound with embodiment 3
Characterize data it is as follows：
Embodiment 4：5- ((1- methyl-1 H- imidazol-4 yls) sulfonyl) -3- (1- (tetrahydrochysene -2H- pyrans -2- bases) -1H-
Pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine (compound 26) preparation
Step 1：The preparation of compound Ib
Hydrogen sodium (100mg, 1.5eq) is dissolved in 5mL anhydrous tetrahydro furans, by compound a (328mg, 1.2eq) under stirring
It is added portionwise, after stirring at normal temperature 30min, methylimidazole sulfonic acid chloride (360mg, 1.2eq) is slowly added in reaction solution, room temperature is stirred
5h is mixed, after complete reaction, tetrahydrofuran is concentrated away, 20mL water is added, adjusts PH nearly 7, ethyl acetate to extract three times, organic layer
It is concentrated after being dried with anhydrous sodium sulfate, I b of target compound is detached to obtain with combiflash companion.
1H NMR(400MHz,CDCl3) δ 8.58 (s, 1H), 8.07 (d, J=4.1Hz, 1H), 7.99 (d, J=1.4Hz,
1H), 7.43 (d, J=1.1Hz, 1H), 6.82 (d, J=4.1Hz, 1H), 3.79 (s, 3H)
Step 2：The preparation of compound 26
By chemical compounds I b (50mg, 1.0eq), 1-THP-4- pyrazoles pinacol borate (49m g, 1.2eq), potassium carbonate
(60m g, 3.0eq), bis- (diphenyl phosphine) ferrocene palladium chloride (II) chloride dichloromethane complex (II) of 1,1'- (6mg,
It 0.05eq) is placed in a reaction flask, 1.5mL dioxane, 0.5ml water (dioxane is added：Water=3:1) it, is replaced with nitrogen empty
Gas 3 times, 80 DEG C of reaction 5h add water 5mL, dichloromethane to extract three times, after organic layer is dried with anhydrous sodium sulfate after completion of the reaction
Concentration, target compound 26 is detached to obtain with combiflash companion.
1H NMR(400MHz,CDCl3) δ 8.71 (s, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 8.02 (d, J=4.1Hz,
1H), 7.90 (d, J=1.3Hz, 1H), 7.40 (d, J=1.2Hz, 1H), 6.80 (d, J=4.1Hz, 1H), 5.47-5.43 (m,
1H),4.15–4.10(m,1H),3.80–3.76(m,1H),3.73(s,3H),2.19–2.15(m,2H),2.12–2.06(m,
1H),1.78–1.68(m,3H).
ESI(m/z):414.1[M+H]+
Reaction substrate only need to be correspondingly replaced, compound is corresponding by the preparation route of following compound with embodiment 4
Characterize data it is as follows：
Embodiment 5：5- ((1- (2- fluoro ethyls) -1H- imidazol-4 yls) sulfonyl) -3- (1H- pyrazoles -4- bases) -5H- pyrroles
Cough up the preparation of simultaneously [2,3-b] pyrazine compound (52)
Step 1：The preparation of compound Ic
Hydrogen sodium (60mg, 1.1eq) is dissolved in 5mL anhydrous tetrahydro furans, by compound a (450mg, 1.0eq) under stirring
It is added portionwise, after stirring at normal temperature 30min, imidazoles sulfonic acid chloride (380mg, 1.1eq) is slowly added in reaction solution, is stirred at room temperature
3h concentrates away tetrahydrofuran after complete reaction, and 5mL water is added, and adjusts PH nearly 7, ethyl acetate to extract three times, organic layer is used
It is concentrated after anhydrous sodium sulfate drying, I c of target compound is detached to obtain with combiflash companion.
1H NMR(400MHz,CDCl3) δ 8.68 (s, 1H), 8.12 (d, J=4.1Hz, 1H), 7.85 (d, J=1.3Hz,
1H), 7.41 (d, J=1.4Hz, 1H), 6.45 (d, J=4.1Hz, 1H)
Step 2：The preparation of compound Id
Compound Ic (160mg, 1.0eq) is dissolved in DMF, the fluoro- 2- iodoethane (102mg, 1.2eq) of 1-, carbon are added
Sour caesium (635mg, 4eq) is warming up to 60 DEG C of stirring 4h, after the reaction was complete, water 5ml is added, ethyl acetate extracts three times, organic
Layer concentrates after being dried with anhydrous sodium sulfate, and I d of target compound is detached to obtain with combiflash companion.
1H NMR(400MHz,CDCl3) δ 8.58 (s, 1H), 8.14 (s, 1H), 8.07 (d, J=4.1Hz, 1H), 7.54 (s,
1H), 6.83 (d, J=4.1Hz, 1H), 4.80-4.76 (m, 1H), 4.69-4.64 (m, 1H), 4.39-4.35 (m, 1H), 4.32-
4.29(m,1H).
Step 3：The preparation of compound 52
By chemical compounds I d (300mg, 1.0eq), 1-Boc- pyrazoles -4- pinacol borates (284m g, 1.2eq), carbonic acid
Potassium (333m g, 3.0eq), bis- (diphenyl phosphine) ferrocene palladium chloride (II) chloride dichloromethane complex (II) of 1,1'- (32mg,
It 0.05eq) is placed in a reaction flask, 3mL dioxane, 1ml water (dioxane is added：Water=3:1), with nitrogen displaced air 3
Secondary, 80 DEG C of reaction 5h add water 5mL, dichloromethane to extract three times, organic layer is dense after being dried with anhydrous sodium sulfate after completion of the reaction
Contracting, target compound 52 is detached to obtain with combiflash companion.
1H NMR(400MHz,DMSO)δ13.23(s,1H),8.97(s,1H),8.67(s,1H),8.48(s,1H),8.19
(s, 1H), 8.10 (d, J=4.1Hz, 1H), 7.86 (s, 1H), 6.93 (d, J=4.1Hz, 1H), 4.75 (t, J=4.7Hz,
1H), 4.64 (t, J=4.6Hz, 1H), 4.43 (t, J=4.6Hz, 1H), 4.36 (t, J=4.7Hz, 1H)
Reaction substrate only need to be correspondingly replaced, compound is corresponding by the preparation route of following compound with embodiment 5
Characterize data it is as follows：
Embodiment 6：Ethyl 2- (4- (5-((2- (2- fluoro ethyls)-1H- imidazol-4 yls) sulfonyl)-5H- pyrrolo-es [2,
3-b] pyrazine -3- bases) -1- bases) and ethyl acetate (compound 33) preparation
Step 1：The preparation of compound 33
52 (30mg, 1.0eq) are dissolved in DMF, add bromoacetate (15mg, 1.2eq), potassium carbonate (34mg,
3eq), 60 DEG C of stirring 5h are warming up to, after the reaction was complete, water 5ml are added, ethyl acetate extracts three times, the anhydrous sulphur of organic layer
It is concentrated after sour sodium drying, target compound 33 is detached to obtain with combiflash companion.
1H NMR (400MHz, DMSO) δ 8.96 (s, 1H), 8.64 (d, J=1.3Hz, 1H), 8.50 (s, 1H), 8.21 (s,
1H), 8.13 (d, J=4.1Hz, 1H), 7.86 (s, 1H), 6.95 (d, J=4.1Hz, 1H), 5.16 (s, 2H), 4.75 (t, J=
4.2Hz, 1H), 4.64 (t, J=4.2Hz 1H), 4.43 (t, J=4.2Hz 1H), 4.36 (t, J=4.7Hz, 1H), 4.20 (q,
J=7.1Hz, 2H), 1.24 (t, J=7.1Hz, 3H)
ESI(m/z):448.2[M+H]+
Reaction substrate only need to be correspondingly replaced, compound is corresponding by the preparation route of following compound with embodiment 6
Characterize data it is as follows：
Effect example 1：Compound influences different types of tyrosinase activity in molecular level
1, experimental method (enzyme linked immunosorbent assay (ELISA), ELISA)
(1) enzyme reaction substrate Poly (Glu, Tyr) 4:1 with PBS (10mM sodium phosphate buffers, the 150mM of no potassium ion
NaCl, pH7.2-7.4) 20 μ g/mL are diluted to, 125 holes μ L/ coated elisa plates are set 37 DEG C and are reacted 12-16 hours.It discards in hole
Liquid.Board-washing, three times with T-PBS (PBS without potassium ion containing the 0.1%Tween-20) board-washing in 200 holes μ L/, 5 points every time
Clock.Dry ELISA Plate 1-2 hours in 37 DEG C of baking ovens.
(2) it is added per hole and uses reaction buffer (50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM
Na3VO4, 1mM DTT) diluted 50 μ L of ATP solution, per hole in 1 μ L compounds to be tested are added, it is slow with reaction to add 50 μ L
The diluted different kinase domain recombinant proteins of fliud flushing start reaction, and experiment every time need to set no ATP control wells holes.Set 37 DEG C of shaking tables
(100rpm) reacts 1 hour.Liquid in hole is discarded, T-PBS board-washings are three times.
(3) 100 holes the μ L/ (T-PBS 1 of antibody 5mg/mL containing BSA of antibody PY99 are added:500 dilutions), 37 DEG C are shaken
Bed reaction 0.5 hour.Liquid in hole is discarded, T-PBS board-washings are three times.
(4) 100 holes the μ L/ (T- of antibody 5mg/ml containing BSA of sheep anti mouse secondary antibody of horseradish peroxidase-labeled is added
PBS 1:2000 dilutions), 37 DEG C of shaking tables react 0.5 hour.Liquid in hole is discarded, T-PBS board-washings are three times.
(5) 100 holes μ L/ of OPD developing solutions of 2mg/ml are added (with containing 0.03%H2O20.1M citric acids-citric acid
Sodium buffer solution (pH=5.4) dilutes), 25 DEG C are protected from light 1-10 minutes.
(6) 2M H are added2SO450 holes μ L/ stopped reactions are declined orifice plate microplate reader VERSAmax reading with wavelengthtunable,
Wavelength is 490nm.
(7) inhibiting rate of sample is acquired by following equation：
2, experimental result
The enzymatic activity test of molecular level shows that the compound of the present invention can obviously inhibit FGFR tyrosine-kinase enzyme activity
Property.
Compound of the embodiment of the present invention inhibits the bioactivity of tyrosine kinase enzyme
(2) it notes：(1)+indicate that compound is more than 50% at 1 μM to FGFR1 or FGFR2 enzymes or RET inhibition of enzyme activity rates.
(3) ++ indicate that compound is more than 50% at 0.1 μM to FGFR1 or FGFR2 enzymes or RET inhibition of enzyme activity rates.
(4) +++ indicate that compound is more than 50% at 0.01 μM to FGFR1 or FGFR2 enzymes or RET inhibition of enzyme activity rates.
(4)aIndicate compound to FGFR1 inhibition of enzyme activity rates.
(5)bIndicate compound to FGFR2 inhibition of enzyme activity rates.
(6)cIndicate compound to RET inhibition of enzyme activity rates.
2 compound of effect example is to the relevant cellular level bioactivity of FGFR
1, compound is prepared
Compound 12000g centrifuges 5min, and DMSO is added and is configured to 10-2M liquid storages, ultrasound 10min is for use after shaking uniformly ,-
40 DEG C preserve and (have the compound that special storage requires to be changed according to concrete condition).By compound physiological saline from storage when test
Liquid is diluted to 10 times (concentration of physiological saline is no more than 10% in system) of institute's test concentrations.
2, test method
Compound to the inhibited proliferations of SNU16 cells with tetrazolium (microculture tetrozolium,
MTT) decoration method detects.It is as follows：SNU16 cells in exponential phase are seeded to the culture of 96 holes by proper density
In plate, per 90 μ L of hole, after overnight incubation, compound (DMSO concentration is less than 0.5%) effect 72hr of various concentration is added, each
Concentration sets three wells, and setting solvent control group (negative control).It is added 20 μ L MTT (5mg/mL) after drug-treated, 37
Be added 100 μ L, tri- liquid (10%SDS-5% isobutanol -0.01M HCl) after DEG C culture 4hr, 37 DEG C overnight after use all-wave length
The orifice plate microplate reader that declines SpectraMax 190 is read, and OD values are measured under 570nm wavelength.
Use the inhibiting rate (%) that compound on tumor cell growth is calculated with following equation：
Inhibiting rate (%)=(OD control wells-OD dosing holes)/OD control wells × 100%
IC50Value uses the random bundled software of microplate reader to be acquired with the recurrence of four parametric methods.
3, experimental result
(1) the batch compound is as shown in the table to SNU16 cell proliferation inhibition rates；
(2) positive compound activity is close with reported in literature.
Compound of the embodiment of the present invention is to SNU16 cell inhibitory effects
| Compound number | Bioactivity | Compound number | Bioactivity |
| 1 | ++ | 17 | ++ |
| 24 | ++ | 44 | ++ |
| 45 | +++ | 50 | ++ |
| 52 | +++ | 54 | ++ |
Note：(1)+indicate that compound is more than 50% at 10 μM to SUN16 cell-proliferation activity inhibiting rates.
(2) ++ indicate that compound is more than 50% at 1 μM to SUN16 cell-proliferation activity inhibiting rates.
(3) +++ indicate that compound is more than 50% at 0.2 μM to SUN16 cell-proliferation activity inhibiting rates.
Selectivity of 3 compound 52 of effect example to different tyrosine kinase
1, experimental method (enzyme linked immunosorbent assay (ELISA), ELISA)
(1) enzyme reaction substrate Poly (Glu, Tyr) 4:1 with PBS (10mM sodium phosphate buffers, the 150mM of no potassium ion
NaCl, pH7.2-7.4) 20 μ g/mL are diluted to, 125 holes μ L/ coated elisa plates are set 37 DEG C and are reacted 12-16 hours.It discards in hole
Liquid.Board-washing, three times with T-PBS (PBS without potassium ion containing the 0.1%Tween-20) board-washing in 200 holes μ L/, 5 points every time
Clock.Dry ELISA Plate 1-2 hours in 37 DEG C of baking ovens.
(2) it is added per hole and uses reaction buffer (50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM
Na3VO4, 1mM DTT) diluted 50 μ L of ATP solution, per hole in 1 μ L compounds to be tested are added, it is slow with reaction to add 50 μ L
The kinase domain recombinant protein of the diluted different protein kinases of fliud flushing starts reaction, and experiment every time need to set no ATP control wells holes.It sets
37 DEG C of shaking tables (100rpm) are reacted 1 hour.Liquid in hole is discarded, T-PBS board-washings are three times.
(3) 100 holes the μ L/ (T-PBS 1 of antibody 5mg/mL containing BSA of antibody PY99 are added:500 dilutions), 37 DEG C are shaken
Bed reaction 0.5 hour.Liquid in hole is discarded, T-PBS board-washings are three times.
(4) 100 holes the μ L/ (T- of antibody 5mg/ml containing BSA of sheep anti mouse secondary antibody of horseradish peroxidase-labeled is added
PBS 1:2000 dilutions), 37 DEG C of shaking tables react 0.5 hour.Liquid in hole is discarded, T-PBS board-washings are three times.
(5) 100 holes μ L/ of OPD developing solutions of 2mg/ml are added (with containing 0.03%H2O20.1M citric acids-citric acid
Sodium buffer solution (pH=5.4) dilutes), 25 DEG C are protected from light 1-10 minutes.
(6) 2M H are added2SO450 holes μ L/ stopped reactions are declined orifice plate microplate reader VERSAmax reading with wavelengthtunable,
Wavelength is 490nm.
(7) inhibiting rate of sample is acquired by following equation：
2, experimental result
Show that the compound of the present invention 52 can obviously inhibit FGFR and RET junket ammonia by the enzymatic activity test of molecular level
Kinase activity, but to c-Met kinases almost without inhibitory activity.It is found through applicant's analysis, in the application compound of Formula I
InPyridine ring on the N atoms that mark at 1 be FGFR and/or RET kinase activities necessary position, when will herein
Nitrogen-atoms remove after can influence FGFR and/or RET kinase inhibiting activities.
Claims (11)
1. one kind five yuan and 6-membered heterocyclic compound, its pharmaceutically acceptable salt or pharmaceutically acceptable as shown in general formula I
Solvate,
Wherein, Z is C or N；W is C, N, O or S；Y is C, N, O or S；
L is-S (O)2-、-S(O)-、-C(O)-、-CH2-、-CH(CH3)-、-(CH2)2-、-(CH2)3-、-S(O)2CH2-、-S(O)
CH2-、-C(O)CH2-、-CH2C(O)-、-CH2S(O)2Or-CH2S(O)-；
R1For hydrogen, substituted or unsubstituted C1-C6Alkyl ,-ORb1、-SRb2、-NRb3Rb4、-C(O)Rb5、-S(O)2Rb6、-S(O)
Rb7、-C(O)ORb8、-C(O)SRb9、-C(O)(NRb10Rb11)、-S(O)2NRb12Rb13、-S(O)NRb14Rb15、-NRb16C(O)
Rb17、-NRb18S(O)2Rb19、-NRb20S(O)Rb21、-NRb22C(O)NRb23Rb24、-NRb25S(O)NRb25Rb27, substitution or it is unsubstituted
" containing heteroatomic 3~10 circle heterocyclic ring bases of the 1-5 in N, O and S " or substituted or unsubstituted 3~6 yuan of cycloalkanes
Base；It is described substituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S " and substituted 3~6 yuan described
Substitution in naphthenic base is each independently by one or more (such as 2,3 or 4) R4Substitution, when there is multiple R4When, substituent group phase
It is same or different；
Rb1~Rb27It is each independently hydrogen, the unsubstituted or C that is replaced by 1~3 halogen1-C4Alkyl or 3~6 yuan of cycloalkanes
Base；R4For halogen or C1-C4Alkyl；
R2For substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthalene, substitution or not
It is " the containing heteroatomic 5~10 unit's heteroaryls of the 1-5 in N, O and S " of substitution, substituted or unsubstituted " a containing 1-5
Heteroatomic 3~10 circle heterocyclic ring base in N, O and S ", substituted or unsubstituted 3~6 yuan of naphthenic base or substitution do not take
3~6 member cycloalkenyls in generation；Wherein, the substituted C1-C6One or more in following radicals of substituent group in alkyl
It is a：-ORa1、-SRa2Or-NRa3Ra4, when there is multiple substituent groups, substituent group is identical or different；Ra1、Ra2、Ra3And Ra4Respectively
It independently is hydrogen or C1-C4Alkyl；The substituted phenyl, the substituted naphthalene, it is described it is substituted " containing 1-5 selected from N,
Heteroatomic 5~10 unit's heteroaryl in O and S ", it is described it is substituted " containing 1-5 in N, O and S heteroatomic 3~
Substitution in 10 circle heterocyclic ring bases ", 3~6 yuan of substituted naphthenic base and 3~6 substituted member cycloalkenyls is each independently
For by 1-3 RmReplaced, when there are multiple RmWhen substitution, substituent group is identical or different；
RmFor halogen, nitro, cyano ,-ORc1、-SRc2、-NRc3Rc4、-C(O)Rc5、-S(O)2Rc6、-S(O)Rc7、-C(O)ORc8、-
C(O)SRc9、-C(O)NRc10Rc1、-S(O)2NRc12Rc13、-S(O)NRc14Rc15、-NRc16C(O)Rc17、-NRc18S(O)2Rc19、-
NRc20S(O)Rc21、-NRc22C(O)NRc23Rc24、-NRc25S(O)NRc26Rc27, substituted or unsubstituted C1-C6Alkyl, substitution or not
Substituted phenyl, substituted or unsubstituted " containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S ", substitution
Or unsubstituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S " or substituted or unsubstituted 3~6
First naphthenic base；Wherein, the substituted C1-C6Being substituted by by 1-3 R in alkyl3Replaced, when there are multiple R3When substitution, take
It is identical or different for base；The substituted phenyl, it is described it is substituted " containing 1-5 in N, O and S heteroatomic 5~
Substitution in 10 unit's heteroaryls " and substituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S "
It is each independently by 1-3 RnReplaced, when there are multiple RnWhen substitution, substituent group is identical or different；
Rc1~Rc27It is each independently hydrogen, C2-C6It is alkenyl, unsubstituted or C is replaced by 1~3 halogen1~C4Alkyl or 3~
6 yuan of naphthenic base；
R3For halogen ,-ORd1、-SRd2、-NRd3Rd4、-C(O)(NRd5Rd6)、-C(O)Rd7、-C(O)ORd8、-S(O)2Rd9、-S(O)
Rd10、-N(Rd11)C(O)Rd12, substituted or unsubstituted " contain 1~3 heteroatomic 3~6 circle heterocyclic ring in N, O and S
Base " or substituted or unsubstituted 3~6 yuan of naphthenic base；It is described it is substituted " containing 1~3 in N, O and S heteroatomic 3
Substitution in~6 circle heterocyclic ring bases " and 3~6 yuan of substituted naphthenic base is each independently by 1~3 (such as 2) a R5It takes
In generation, when there is multiple substituent groups, substituent group is identical or different；
Rd1~Rd12It is each independently hydrogen or C1-C4Alkyl；R5For halogen or C1-C4Alkyl；
RnFor halogen, nitro, cyano, the unsubstituted or C that is replaced by 1~3 halogen1-C6Alkyl ,-ORf1、-SRf2、-
NRf3Rf4、-C(O)Rf5、-S(O)2Rf6、-S(O)Rf7、-C(O)ORf8、-C(O)SRf9、-C(O)(NRf10Rf11)、-S(O)2NRf12Rf13、-S(O)NRf14Rf15、-NRf16C(O)Rf17、-NRf18S(O)2Rf19、-NRf20S(O)Rf21、-NRf22C(O)
NRf23Rf24Or-NRf25S(O)NRf25Rf27；Rf1~Rf27It is each independently hydrogen or C1-C4Alkyl.
2. as described in claim 1 such as general formula I shown in five yuan simultaneously 6-membered heterocyclic compound, its pharmaceutically acceptable salt or
Pharmaceutically acceptable solvate, which is characterized in that
The L is-S (O)2-、-C(O)-、-CH2-、-(CH2)2-、-(CH2)3Or-CH2C(O)-；
And/or Z N；
And/or W is C or N；
And/or Y is C or N；
And/or the R1Or R2In, the substituted or unsubstituted C1-C6C in alkyl1-C6Alkyl is methyl, ethyl, positive third
Base, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or the R1Or R2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 3~10
In circle heterocyclic ring base " " is to be selected from N, O containing 1-3 containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S
With heteroatomic 5~6 circle heterocyclic ring base in S；
And/or the R1Or R2In, 3~6 yuan of naphthenic base in " substituted or unsubstituted 3~6 yuan of naphthenic base " are hexamethylene
Base or cyclopenta；
And/or the R2In, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 5~10 yuan of 1-5 in N, O and S
In aryl " is to be selected from N, O and S containing 1-3 " containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S "
In the unit's heteroaryl of heteroatomic 5,6,7,8,9 or 10；
And/or the R2In, 3~6 member cycloalkenyls in substituted or unsubstituted 3~6 member cycloalkenyl be cyclohexenyl group or
Cyclopentenyl；
And/or the R2In, in the substituted or unsubstituted phenyl, the substituent group in substituted phenyl be located at L ortho position,
Position and at one in contraposition or a few places；
And/or the Rb1~Rb27In, " the unsubstituted or C that is replaced by 1~3 halogen1-C4C in alkyl "1~C4
Alkyl is each independently methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or the Rb1~Rb27In, 3~6 yuan of naphthenic base are each independently cyclopropyl, cyclopenta or cyclohexyl；
And/or the R4In, the halogen is fluorine, chlorine, bromine or iodine；
And/or the R4In, the C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary fourth
Base；
And/or the Ra1、Ra2、Ra3Or Ra4In, the C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, different
Butyl or tertiary butyl；
And/or the RmIn, the halogen is fluorine, chlorine, bromine or iodine；
And/or the RmIn, the substituted or unsubstituted C1-C6C in alkyl1-C6Alkyl be methyl, ethyl, n-propyl,
Isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or the RmIn, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 5~10 yuan of 1-5 in N, O and S
In aryl " " is a in N, O and S containing 1-3 containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S
The unit's heteroaryl of heteroatomic 5,6,7,8,9 or 10；
And/or the RmIn, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 3~10 yuan of 1-5 in N, O and S
In ring group " is to be selected from N, O and S containing 1-3 " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S "
In heteroatomic 5~6 circle heterocyclic ring base；
And/or the RmIn, 3~6 yuan of naphthenic base in " substituted or unsubstituted 3~6 yuan of naphthenic base " be cyclohexyl or
Cyclopenta；
And/or the Rc1~Rc27In, it is described unsubstituted or C is replaced by 1~3 halogen1~C4C in alkyl1~C4Alkyl
It is each independently methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or the Rc1~Rc27In, 3~6 yuan of naphthenic base are each independently cyclopropyl, cyclopenta or cyclohexyl；
And/or the Rc1~Rc27In, the C2-C6Alkenyl is each independently vinyl；
And/or the R3In, the halogen is fluorine, chlorine, bromine or iodine；
And/or the R3In, it is described substituted or unsubstituted " miscellaneous containing 1~3 heteroatomic 3~6 yuan in N, O and S
" containing 1~2 heteroatomic 5 yuan or 6 circle heterocyclic ring bases in N, O and S " in ring group "；
And/or the R3In, it is 3~6 yuan of cycloalkyl cyclopropyls, ring penta in substituted or unsubstituted 3~6 yuan of naphthenic base
Base or cyclohexyl；
And/or the Rd1~Rd12In, the C1~C4Alkyl is each independently methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, isobutyl group or tertiary butyl；
And/or the R5In, the halogen is fluorine, chlorine, bromine or iodine；
And/or the R5In, the C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary fourth
Base；
And/or the RnIn, the halogen is fluorine, chlorine, bromine or iodine；
And/or the RnIn, " the unsubstituted or C that is replaced by 1~3 halogen1-C6C in alkyl "1-C6Alkyl is first
Base or ethyl；
And/or the Rf1~Rf27In, the C1-C4Alkyl is each independently methyl, ethyl, n-propyl, isopropyl, positive fourth
Base, isobutyl group or tertiary butyl.
3. as claimed in claim 2 such as general formula I shown in five yuan simultaneously 6-membered heterocyclic compound, its pharmaceutically acceptable salt or
Pharmaceutically acceptable solvate, which is characterized in that
The L is-S (O)2-；
And/or in the general formula I,For
And/or the R1Or R2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 3~10
" containing a heteroatomic 3~10 circle heterocyclic ring bases in N, O and S of 1-5 " in circle heterocyclic ring base " is
And/or the R2In, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 5~10 yuan of 1-5 in N, O and S
In aryl " is following any group " containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S "：
And/or the Rb1~Rb27In, the C of 1~3 halogen substitution1-C4Alkyl is each independently trifluoromethyl；
And/or the RmIn, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 5~10 yuan of 1-5 in N, O and S
In aryl " " is pyrazolyl, pyridyl group or pyrimidine containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S
Base；The pyrazolyl is preferredThe pyridyl group is preferredThe pyrimidine radicals is preferred
And/or the RmIn, it is described substituted or unsubstituted " miscellaneous containing heteroatomic 3~10 yuan of 1-5 in N, O and S
" containing a heteroatomic 3~10 circle heterocyclic ring bases in N, O and S of 1-5 " in ring group " is
And/or the Rc1~Rc27In, it is described that C is replaced by 1~3 halogen1~C4Alkyl is each independently trifluoromethyl；
And/or work as R3For halogen, RmFor substituted or unsubstituted C1-C6When alkyl, the substituted or unsubstituted C1-C6Alkane
C in base1-C6Alkyl is ethyl；The substituted C1-C6Alkyl is preferably-CH2CH2F；
And/or the R3In, it is described substituted or unsubstituted " miscellaneous containing 1~3 heteroatomic 3~6 yuan in N, O and S
In ring group " is " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S "
And/or the RnIn, the C replaced by 1~3 halogen1-C6Alkyl is trifluoromethyl.
4. five yuan and 6-membered heterocyclic compound as described in any one of claims 1-3 as shown in general formula I, it can pharmaceutically connect
The salt or pharmaceutically acceptable solvate received, which is characterized in that five yuan and 6-membered heterocyclic compound shown in the general formula I
For five-ring heterocycles shown in following general formula II, general formula III or general formulae IV and 6-membered heterocyclic compound,
Wherein, R1And R2Definition as described in claim any one of 1-3.
5. five yuan and 6-membered heterocyclic compound as described in any one of claims 1-3 as shown in general formula I, it can pharmaceutically connect
The salt or pharmaceutically acceptable solvate received, which is characterized in that five yuan and 6-membered heterocyclic compound shown in the general formula I
For five-ring heterocycles shown in following general formula V and 6-membered heterocyclic compound,
Wherein, R2Definition as described in claim any one of 1-3；
Five-ring heterocycles shown in the general formula V and 6-membered heterocyclic compound are preferably five-ring heterocycles shown in general formula VI and hexa-atomic
Heterocyclic compound,
Wherein, RmDefinition as described in claim any one of 1-3.
6. as described in claim 1 such as general formula I shown in five yuan simultaneously 6-membered heterocyclic compound, its pharmaceutically acceptable salt or
Pharmaceutically acceptable solvate, which is characterized in that five yuan and 6-membered heterocyclic compound shown in the general formula I are following appoint
One compound：
7. a kind of preparation side of five yuan and 6-membered heterocyclic compound as claimed in any one of claims 1 to 6 as shown in general formula I
Method is prepared by method A or method B；
Method A, includes the following steps：In the presence of alkali, by Formula II compound and R2It is anti-that-L-LG carries out nucleophilic displacement of fluorine as follows
It answers, obtains shown compound of formula I；
Wherein, R1、R2, Y and W definition as described in claim any one of 1-6, LG is leaving group；
Method B, includes the following steps：- 1 compound of formula III and -2 compound of Formula II are subjected to coupling reaction as follows, obtained
Shown compound of formula I；
Wherein, R1、R2, Z, Y and W definition as described in claim any one of 1-6, RaAnd RbIt is each independently C1-C4Alkyl；
Or Ra、RbSubstituted or unsubstituted 5-6 membered rings, the substituent group in substituted 5-6 membered rings are formed together with coupled oxygen atom
For C1-C4Alkyl.
8. a kind of such as Formula Il -1 and II-2 compounds represented,
Wherein, Z, W, Y, L, R1And R2As described in claim any one of 1-6；
The preferably following any structure of -1 compound of Formula II：
Wherein, R1Definition such as claim 1-6 appoint
Described in one；
The preferably following any structure of -2 compound of Formula II：
Wherein, R2Any one of definition such as claim 1-6 institute
It states.
9. such as claim 1~6 any one of them five yuan and 6-membered heterocyclic compound as shown in general formula I, it pharmaceutically may be used
The application of the salt of receiving or pharmaceutically acceptable solvate in being used to prepare FGFR inhibitor and/or RET inhibitor.
10. such as claim 1~6 any one of them five yuan and 6-membered heterocyclic compound as shown in general formula I, it pharmaceutically may be used
The salt of receiving or pharmaceutically acceptable solvate are preparing treatment and/or are preventing and tyrosine kinase FGFR and/or RET
Application in the drug of expression or the relevant disease of activity；
" expression with tyrosine kinase FGFR or the relevant disease of activity " is preferably by the change of tyrosine kinase FGFR
Tumour or cancer caused by changing；The preferred lung cancer of the cancer, gastric cancer, liver cancer, breast cancer, colon cancer, prostate cancer, pancreas
Cancer, the cancer of the esophagus, oophoroma, kidney or thyroid cancer；The preferred glioma of the tumour or melanoma；
" expression with tyrosine kinase RET or the relevant disease of activity " is preferably by the variation of tyrosine kinase RET
Caused tumour or cancer；The preferred lung cancer of the cancer, gastric cancer, liver cancer, breast cancer, colon cancer, prostate cancer, cancer of pancreas,
The cancer of the esophagus, oophoroma, kidney or thyroid cancer；The preferred glioma of the tumour or melanoma.
11. a kind of pharmaceutical composition, it includes therapeutically effective amount such as claim 1~6 any one of them as shown in general formula I
Five yuan and 6-membered heterocyclic compound, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, and it is a kind of or
A variety of pharmaceutic adjuvants.
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