CN108570052A - Five-ring heterocycles and pyrazine compound, preparation method, intermediate, combination and application - Google Patents
Five-ring heterocycles and pyrazine compound, preparation method, intermediate, combination and application Download PDFInfo
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- CN108570052A CN108570052A CN201710146224.7A CN201710146224A CN108570052A CN 108570052 A CN108570052 A CN 108570052A CN 201710146224 A CN201710146224 A CN 201710146224A CN 108570052 A CN108570052 A CN 108570052A
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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
- 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-ring heterocycles and pyrazine compound, preparation method, intermediate, combination and applications.Five-ring heterocycles and pyrazine compound in the present invention have excellent FGFR inhibitory activity.
Description
Technical field
The present invention relates to a kind of five-ring heterocycles and pyrazine 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 FGFR inhibitor of structure novel, and provide one kind five
Circle heterocyclic ring and pyrazine compound, preparation method, intermediate, combination and application.Five-ring heterocycles in the present invention and pyrazine compound
With excellent FGFR inhibitory activity.
The present invention provides a kind of five-ring heterocycles as shown in general formula I and pyrazine compound, its pharmaceutically acceptable salts
Or pharmaceutically acceptable solvate,
Wherein, X and Y is each independently C (R ' R "), N (R0), O or S；OrFor-CH=CH-；R0, R ' and
R " is each independently hydrogen or substituted or unsubstituted C1-C4Alkyl；The substituted C1-C4Substituent group in alkyl is selected from down
State one or more of group：-ORa1、-SRa2With-NRa3Ra4, when there is multiple substituent groups, substituent group is identical or different；
Ra1、Ra2、Ra3And Ra4It is each independently hydrogen or C1-C4Alkyl；
R2、R2aAnd R2bIt is each independently hydrogen or halogen；
Z 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)-；
W is N, CH or CR3；R3For halogen, nitro, cyano ,-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
C1-C6Alkyl, substituted or unsubstituted naphthalene, substituted or unsubstituted " is selected from substituted or unsubstituted phenyl containing 1-5
N, heteroatomic 5~10 unit's heteroaryl in O and S " substituted or unsubstituted " contains hetero atoms of the 1-5 in N, O and S
3~10 circle heterocyclic ring bases "；Wherein, the substituted C1-C6Being substituted by by 1-3 (such as 2) R in alkyl4Replaced, when
There are multiple R4When substitution, R4It is identical or different；The substituted phenyl, described substituted " contains 1-5 at the substituted naphthalene
A heteroatomic 5~10 unit's heteroaryl in N, O and S " and described substituted " miscellaneous in N, O and S containing 1-5
Substitution in 3~10 circle heterocyclic ring bases of atom " is each independently by 1-3 (such as 2) Rm1Replaced, when there are multiple Rm1
When substitution, Rm1It is identical 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；
R1For 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：-ORe1、-SRe2Or-NRe3Re4, when there is multiple substituent groups, substituent group is identical or different, Re1、Re2、Re3And Re4Respectively
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) Rm2Replaced, when there are multiple Rm2When substitution, Rm2It is identical or different；
Rm1And Rm2It is each independently 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, substitution or not
Substituted C1-C6Alkyl, substituted or unsubstituted naphthalene, substituted or unsubstituted " contains 1-5 at substituted or unsubstituted phenyl
It is heteroatomic 5~10 unit's heteroaryl in N, O and S ", substituted or unsubstituted " miscellaneous in N, O and S containing 1-5
3~10 circle heterocyclic ring bases of atom ", substituted or unsubstituted 3~6 yuan of naphthenic base or substituted or unsubstituted 3~6 yuan of cyclenes
Base；Wherein, the substituted C1-C6Being substituted by by 1-3 (such as 2) R in alkyl5Replaced, when there are multiple R5Substitution
When, R5It is identical or different；The substituted phenyl, the substituted naphthalene, it is described it is substituted " containing 1-5 selected from N, O and
Heteroatomic 5~10 unit's heteroaryl in S " described substituted " contains 1-5 heteroatomic 3~10 yuan in N, O and S
Substitution in heterocycle ", 3~6 yuan of substituted naphthenic base and 3~6 substituted member cycloalkenyls be each independently by
1-3 (such as 2) RnReplaced, when there are multiple RnWhen substitution, RnIt is identical or different；
Rc1~Rc27It is each independently hydrogen, C2-C6Alkenyl；Substituted or unsubstituted C1~C4Alkyl or 3~6 yuan of cycloalkanes
Base；Wherein, substituted C1~C4Being substituted by alkyl is selected from halogen or C by 1~3 (such as 2)1~C4Alkoxy takes
Replaced for base, when there are multiple substituent groups, substituent group is identical or different；
R4And R5It is each independently halogen ,-ORd1、-SRd2、-NRd3Rd4、-C(O)(NRd5Rd6)、-C(O)Rd7、-C(O)
ORd8、-S(O)2Rd9、-S(O)Rd10、-N(Rd11)C(O)Rd12、C2-C6Alkenyl, substituted or unsubstituted phenyl, substitution do not take
" containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S " in generation, 3~6 yuan of naphthenic base；Wherein, the substitution
Substitution in phenyl and substituted " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S " is respectively only
It is on the spot to be selected from halogen, C by 1~3 (such as 2)1-C4Alkyl, nitro, cyano and amino group replaced, it is multiple when having
When substituent group, substituent group is identical or different；
Rd1~Rd12It is each independently hydrogen, the unsubstituted or C that is replaced by 1~3 halogen1-C4Alkyl " contains 1~3
A heteroatomic 3~6 circle heterocyclic ring base in N, O and S ", the unsubstituted or phenyl replaced by nitro or 3~6 yuan of cycloalkanes
Base；
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, unsubstituted or replaced by 1~3 halogen
C1-C4Alkyl or C2-C6Alkenyl.
It is N (R in the general formula I, when the X and the Y can be understood as different0), O or S.
The Ra1、Ra2、Ra3Or Ra4In, the C1-C4The preferred methyl of alkyl, ethyl, n-propyl, isopropyl, normal-butyl,
Isobutyl group or tertiary butyl.The R0, in R ' or R ", the substituted or unsubstituted C1-C4C in alkyl1-C4The preferred first of alkyl
Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.
In the general formula I,It is preferred that-CH2CH2-、-CH2(- the CH=CH- can be suitable by-NH- or-CH=CH-
Formula or anti-configuration).
The R2、R2aOr R2bIn, the preferred fluorine of the halogen, chlorine, bromine or iodine；The R2bPreferably hydrogen, the R2And R2aIt is excellent
Selection of land is hydrogen, chlorine or fluorine simultaneously.
The Z preferably-S (O)2-、-C(O)-、-CH2-、-(CH2)2-、-(CH2)3Or-CH2C(O)-。
The R3Or R1In, it is described substituted or unsubstituted " to contain heteroatomic 5~10 yuan of 1-5 in N, O and S
In heteroaryl " " 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 R3Or R1In, 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 R3Or R1In, 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 R1In, the preferred cyclohexyl of 3~6 yuan of naphthenic base in " substituted or unsubstituted 3~6 yuan of naphthenic base " or
Cyclopenta.
The R1In, the preferred cyclohexenyl group of 3~6 member cycloalkenyls in substituted or unsubstituted 3~6 member cycloalkenyl or
Cyclopentenyl.
The R3In, the halogen is fluorine, chlorine or bromine or iodine.
The R1In, in the substituted or unsubstituted phenyl, substituent group in substituted phenyl can positioned at the ortho position of Z,
Meta position and at one in contraposition or a few places, are preferably in ortho position or the meta position of Z.
The R3In, in the substituted or unsubstituted phenyl, the substituent group in substituted phenyl can be located at five-ring heterocycles
And at one in the ortho position of pyrazine, meta position and contraposition or several places, it is preferably placed at the contraposition of five-ring heterocycles and pyrazine.
The Rb1~Rb27In, " the unsubstituted or C that is replaced by 1~3 halogen1-C4C in alkyl "1~C4Alkane
Base is preferably methyl or ethyl each independently；The C of 1~3 halogen substitution1-C4The preferred trifluoromethyl of alkyl.Described 3~
The preferred cyclopropyl of 6 yuan of naphthenic base, cyclopenta or cyclohexyl.
The Re1、Re2、Re3Or Re4In, the C1-C4The preferred methyl of alkyl, ethyl, n-propyl, isopropyl, normal-butyl,
Isobutyl group or tertiary butyl.
The Rm1Or Rm2In, the preferred fluorine of the halogen, chlorine, bromine or iodine.
The Rm1Or Rm2In, the substituted or unsubstituted C1-C6C in alkyl1-C6The preferred methyl of alkyl, ethyl, just
Propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl.
The Rm1Or Rm2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 5~10
In unit's heteroaryl " " 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 radicals (such as)。
The Rm1Or Rm2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 3~10
" contain heteroatomic 3~10 yuan (such as 5 or 6 of 1-5 (such as 1,2 or 3) in N, O and S in circle heterocyclic ring base "
Member) heterocycle " preferably
The Rm1Or Rm2In, 3~6 yuan of preferred hexamethylenes of naphthenic base in substituted or unsubstituted 3~6 yuan of naphthenic base
Base or cyclopenta.
The Rm1Or Rm2In, the preferred hexamethylene of 3~6 member cycloalkenyls in substituted or unsubstituted 3~6 member cycloalkenyl
Alkenyl or cyclopentenyl.
The Rc1~Rc27In, the substituted or unsubstituted C1~C4C in alkyl1~C4Alkyl is excellent each independently
It is selected as methyl or ethyl.The substitution C1~C4C in the substituent group of alkyl1~C4Alkoxy preferred methoxyl group each independently.
The substituted C1~C4Alkyl each independently preferably-CH2(OCH3) or trifluoromethyl.3~6 yuan of naphthenic base are respectively only
On the spot preferred cyclopropyl, cyclopenta or cyclohexyl.The C2-C6Alkenyl preferred vinyl each independently.
The R4Or R5In, the preferred fluorine of the halogen, chlorine, bromine or iodine.Work as R5For halogen when, the Rm1Or Rm2In, it is described
Substituted C1-C6Alkyl such as-CH2CH2F。
The R4Or R5In, the C2-C6Alkenyl such as vinyl.The preferred cyclopropyl of 3~6 yuan of naphthenic base, cyclopenta
Or cyclohexyl.In substituted or unsubstituted " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S "
" containing heteroatomic 3~6 (such as 5 or 6) the circle heterocyclic ring bases of 1~3 (such as 2) in N, O and S " is preferred
The R4Or R5In, the substituted-phenyl or described substituted " heteroatomic in N, O and S containing 1~3
In the substituent group of 3~6 circle heterocyclic ring bases ", the preferred fluorine of the halogen, chlorine, bromine or iodine；The C1-C4The preferred methyl of alkyl or ethyl.
The Rd1~Rd12In, " the unsubstituted or C that is replaced by 1~3 halogen1-C4C in alkyl "1~C4Alkane
Base is preferably methyl or ethyl each independently；The C replaced by 1~3 halogen1-C4Alkyl preferred trifluoro each independently
Methyl.3~6 yuan of naphthenic base preferred cyclopropyl, cyclopenta or cyclohexyl each independently.It is described " containing 1~3 (such as
2) heteroatomic 3~6 yuan (such as 5 or 6 yuan) heterocycles in N, O and S " each independently preferablyIt is described
The phenyl replaced by nitro is preferred each independently
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 unsubstituted or C that is replaced by 1~3 halogen1-C4C in alkyl "1-C4Alkyl
Preferred methyl or ethyl each independently；The C replaced by 1~3 halogen1-C4Alkyl preferred fluoroform each independently
Base.The C2-C6Alkenyl preferred vinyl each independently.
Preferably, simultaneously pyrazine compounds are preferably following general formula II, general formula to five-ring heterocycles shown in the general formula I
Five-ring heterocycles shown in III or general formula IV and pyrazine compounds：
Wherein, R1、R2、R2a、R2bAnd R3It is defined as above described.
It is highly preferred that simultaneously pyrazine compounds are following general formula V-1, general formula V- to five-ring heterocycles shown in the general formula I
2, five-ring heterocycles shown in general formula VI-1, general formula VI-2, general formula VII-1, general formula VII-2 or general formula VIII and Pyrazine chemical combination
Object,
Wherein, R2、R2a、R2b、Rm1And Rm2It is defined as above described.
In five-ring heterocycles shown in the general formula V-2, general formula VI-2 or general formula VII-2 and pyrazine compounds, Rm2It is preferred that
For the substituted or unsubstituted C1-C6Alkyl (preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tertiary fourth
Base)；R5Preferably (such as chlorine works as R for the halogen5For halogen when, Rm2Preferably-CH2CH2F) ,-NRd3Rd4(such as-N
(CH3)2) ,-C (O) (NRd5Rd6) (such as-C (O) N (CH3)2) ,-C (O) Rd7,-C (O) ORd8, the C2-C6
Alkenyl (such as vinyl), it is described it is substituted or unsubstituted " contain 1~3
Heteroatomic 3~6 circle heterocyclic ring base in N, O and S " (such as) or it is 3~6 yuan described
Naphthenic base (such as cyclopenta)；Rd3、Rd4、Rd5Or Rd6Preferably hydrogen, the unsubstituted C1-C4Alkyl, 3~6 membered ring
Alkyl (such as cyclopropyl)；Rd7Preferably described " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S "
(such as), unsubstituted phenyl or replaced by nitro phenyl (such as)；Rd8Preferably institute
State unsubstituted C1-C4Alkyl (such as methyl or ethyl).
In five-ring heterocycles shown in the general formula VI-1 or general formula VI-2 and pyrazine compounds, the Rm1It is preferably described
Substituted or unsubstituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S ", more preferablyInstitute
State Rm1It is preferably placed at the contraposition of Pyrrolopyrazine base.
In five-ring heterocycles shown in the general formula VII-1 or general formula VII-2 and pyrazine compounds, the Rm1Preferably institute
Substituted or unsubstituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S " is stated, more preferably
In five-ring heterocycles shown in the general formula VIII and pyrazine compounds, Rm2The preferably described halogen, NO2, cyano,
- the ORc1,-the NRc3Rc4Or-the NRc16C(O)Rc17；Rc1The preferably described unsubstituted C1~C4Alkyl；Rc3Or Rc4
It is preferred that hydrogen；Rc16It is preferred that hydrogen；Rc17It is preferred that substituted or unsubstituted C1~C4Alkyl, substituted C1~C4Substitution in alkyl is preferred
For by 1 C1~C4The substituent group of alkoxy is replaced.Rm2R (is more preferably worked as in the ortho position or meta position for being preferably in Zm2For nitre
Base ,-NRc3Rc4、-NRc16C(O)Rc17、-NRc18S(O)2Rc19、-NRc20S(O)Rc21、-NRc22C(O)NRc23Rc24Or-NRc25S
(O)NRc26Rc27When, Rm2Ortho position in Z or meta position).
It is highly preferred that simultaneously pyrazine compounds are following any compounds to five-ring heterocycles shown in the general formula I：
The pharmaceutically acceptable salt of five-ring heterocycles shown in heretofore described general formula I and pyridine compounds and their can pass through
Compound of Formula I is made with inorganic acid or organic acid reaction, and the inorganic acid includes hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid etc., institute
It includes ascorbic acid, niacin, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, oxalic acid, apple to state organic acid
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-ring heterocycles shown in the general formula I and pyridine compounds and their can lead to
It crosses and 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
Shown in five-ring heterocycles and pyridine compounds and their be dissolved in the dioxane solutions of HCl saturations, be stirred at room temperature 30 minutes, filter, i.e.,
Corresponding hydrochloride is made.
The pharmaceutically acceptable solvate of five-ring heterocycles shown in heretofore described general formula I and pyridine compounds and their
It 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 water
When molecule, solvate refers to hydrate.
Those skilled in the art are according to the synthetic method of the application specific embodiment disclosure combination this field routine
Five-ring heterocycles and pyrazine compounds shown in the general formula I are prepared.
The present invention also provides the preparation sides of five-ring heterocycles shown in a kind of general formula I as mentioned and pyrazine compounds
Method comprising following steps：In the presence of alkali, by Formula II compound and R1- Z-LG carries out nucleophilic substitution as follows, obtains
To shown compound of formula I；
Wherein, R2、R2a、R2b、R1, X, Y, Z andWDescribed in being defined as above, LG is leaving group.The nucleophilic substitution
Condition be referred to this field such reaction routine selected.The LG can be in such nucleophilic substitution of this field
Conventional use of leaving group, preferably halogen (such as chlorine, bromine or iodine).The alkali is conventional during such is reacted for art technology
The alkali used, such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydrogen etc..The nucleophilic substitution is excellent
Choosing carries out in organic solvent, and the organic solvent is preferably such conventional use of solvent of reaction of this field, such as tetrahydrochysene
Furans or DMF etc..
The present invention also provides such as Formula II compounds represented：
Wherein, R2、R2a、R2b、R1, X, Y andWIt is defined as above described.
Shown in Formula II compound it is preferredR2、R2a
And R2bIt is defined as above described；Such as
The present invention provides a kind of five-ring heterocycles as shown in general formula I and pyrazine compound, its pharmaceutically acceptable salts
Or application of the pharmaceutically acceptable solvate in being used to prepare FGFR inhibitor.
The present invention also provides a kind of five-ring heterocycles such as general formula I shown in simultaneously pyrazine compound, its is pharmaceutically acceptable
Salt or pharmaceutically acceptable solvate are preparing treatment and/or are preventing related to the expression of tyrosine kinase FGFR or activity
Disease 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.
The present invention also provides a kind of pharmaceutical composition, five-ring heterocycles shown in the general formula I it includes therapeutically effective amount and pyrrole
Piperazine 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 "
Replaced individually optionally by one or more substituent groups described in the invention.
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 five-ring heterocycles that structure is completely new and pyrazine chemical combination
Object.Five-ring heterocycles and pyrazine compound in the present invention have excellent FGFR 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 1：3- [2- (3,5- dimethoxy-phenylfs)-ethyl] -5- benzenesulfonyls -5- hydrogen-pyrrolo- [2,3-b]
The preparation of pyrazine (compound 1)
Step 1：The preparation of compound g
By compound e (500mg, 1eq), f (530mg, 1.3eq), CuI (40mg, 0.08eq), triethylamine (79 μ L,
2eq), bis- (triphenylphosphine) palladium chlorides (II) (90mg, 0.05eq) are placed in a reaction flask, and the N of 20mL dryings, N- diformazans is added
Base formamide, with nitrogen displaced air 3 times, 90 DEG C of reaction 6h add water 200mL, ethyl acetate to extract three times after completion of the reaction,
Organic layer concentrates after being dried with anhydrous sodium sulfate, and target compound g (496mg, yield are detached to obtain with combiflash companion：
71%).
1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),8.64(s,1H),8.07–7.99(m,1H),6.81(d,J
=2.2Hz, 2H), 6.70 (dd, J=3.5,1.7Hz, 1H), 6.62 (t, J=2.2Hz, 1H), 3.80 (s, 6H)
ESI(m/z):280.1[M+H]+
Step 2：It is prepared by the Ia of compound
400mg compounds g is dissolved in 20mL absolute ethyl alcohols, is added palladium/carbon of 0.2mg, under normal pressure, is passed through hydrogen also
Original, 50 DEG C of reaction 7h, after the reaction was complete, filters off palladium/carbon, concentrates away ethyl alcohol, target chemical combination is detached to obtain with combiflash companion
Object Ia (320mg, yield：80%).
1H NMR(400MHz,Chloroform-d)δ10.26(s,1H),8.38(s,1H),7.60–7.55(m,1H),
6.75 (dd, J=3.6,1.8Hz, 1H), 6.40 (d, J=2.1Hz, 2H), 6.34 (d, J=2.1Hz, 1H), 3.77 (s, 6H),
3.26 (dd, J=9.6,6.4Hz, 2H), 3.10 (dd, J=9.4,6.5Hz, 2H)
ESI(m/z):284.1[M+H]+
Step 3：The preparation of compound 1
Hydrogen sodium (28mg, 2eq) is dissolved in 5mL anhydrous tetrahydro furans, under stirring in batches by compound g (100mg, 1eq)
It is added, after stirring at normal temperature 30min, benzene sulfonyl chloride (52.8 μ L, 1.3eq) is added dropwise in reaction solution, 5h is stirred at room temperature, waits reacting
After completely, tetrahydrofuran is concentrated away, 20mL water is added, adjusts PH nearly 7, ethyl acetate to extract three times, organic layer anhydrous slufuric acid
It is concentrated after sodium drying, target compound 01 (126mg, yield is detached to obtain with combiflash companion：84%).
1H NMR (400MHz, Chloroform-d) δ 8.32 (s, 1H), 8.28-8.23 (m, 2H), 7.97 (d, J=
4.1Hz, 1H), 7.67-7.59 (m, 1H), 7.53 (t, J=7.8Hz, 2H), 6.81 (d, J=4.2Hz, 1H), 6.33 (s, 3H),
3.76 (s, 6H), 3.24 (dd, J=9.0,6.5Hz, 2H), 3.07 (dd, J=9.0,6.6Hz, 2H)
ESI(m/z):424.1[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- [2- (3,5- Dimethoxyphenyls)-ethyl] -5- (3- aminobenzenesulfonyls) -5- hydrogen-pyrrolo-
The preparation of [2,3-b] pyrazine (compound 4)
Compound 2 (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 4 (37mg, yield are detached to obtain with combiflash companion：
76%).
1H NMR (400MHz, Chloroform-d) δ 8.31 (s, 1H), 7.94 (d, J=4.1Hz, 1H), 7.55 (d, J=
7.9Hz, 1H), 7.50 (t, J=2.1Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 6.88-6.81 (m, 1H), 6.80 (d, J=
4.2Hz, 1H), 6.33 (d, J=1.7Hz, 3H), 3.92 (s, 2H), 3.75 (s, 6H), 3.30-3.20 (m, 2H), 3.13-3.04
(m,2H)
ESI(m/z):439.1[M+H]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data is shown in embodiment 2
Following table.
Embodiment 3：3- [2- (3,5- Dimethoxyphenyls)-ethyl] -5- (3- P-acetamido benzene sulfonyls base) -5- hydrogen-pyrrole
Cough up the preparation of simultaneously [2,3-b] pyrazine (compound 5)
By compound 4 (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 (30mg, yield are detached to obtain with combiflash companion：
54%).
1H NMR (400MHz, Chloroform-d) δ 8.31 (d, J=15.4Hz, 2H), 7.98-7.86 (m, 3H), 7.65
(s, 1H), 7.45 (t, J=8.1Hz, 1H), 6.80 (d, J=4.1Hz, 1H), 6.34 (s, 3H), 3.75 (s, 6H), 3.26-
3.15 (m, 2H), 3.04 (t, J=7.8Hz, 2H)
ESI(m/z):481.1[M+H]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data is shown in embodiment 3
Following table.
Embodiment 4：2- { 4- [(3- (3,5- Dimethoxyphenyls ethyl) -5- hydrogen-pyrrolo- [2,3-b] pyrazine) -5- sulphurs
Acyl group] -1- hydrogen-imidazoles -1- bases-(morpholine -4- bases) ethyl ketone (compound 13) preparation
Hydrogen sodium (9.6mg, 2eq) is dissolved in anhydrous n,N-Dimethylformamide (3mL), by compound 12 (50mg, 1eq)
It is added portionwise in reaction solution, after 30min is stirred at room temperature, by 4- (2- chloracetyls) morpholine (24mg, 1.2eq) and catalytic amount
Sodium iodide is added in reaction, is stirred overnight at room temperature, and after the reaction was complete, adds water 30mL, ethyl acetate extracts three times, with quick system
Standby chromatographic isolation obtains target compound 13 (36mg, yield：57%).
1H NMR (400MHz, Chloroform-d) δ 8.34 (s, 1H), 8.05 (d, J=4.1Hz, 1H), 8.01 (d, J=
1.4Hz, 1H), 7.45 (d, J=1.4Hz, 1H), 6.81 (d, J=4.1Hz, 1H), 6.34-6.29 (m, 3H), 4.72 (s, 2H),
3.75(s,6H),3.73–3.68(m,2H),3.68–3.63(m,2H),3.59–3.53(m,2H),3.42–3.36(m,2H),
3.21 (dd, J=9.0,6.5Hz, 2H), 3.03 (dd, J=8.9,6.5Hz, 2H)
ESI(m/z):541.1[M+H]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data is shown in embodiment 4
Following table.
Embodiment 5：4- { 2- { 4- [(3- (3,5- Dimethoxyphenyls ethyl) -5- hydrogen-pyrrolo- [2,3-b] pyrazine) -5-
Sulfonyl] -1- hydrogen-pyrazol-1-yl-ethyl morpholine (compound 19) preparation
By compound 12 (50mg, 1eq), N- (2- chloroethyls) morpholine hydrochloride (29mg, 1.3eq), potassium carbonate (50mg,
3eq), it is dissolved in n,N-Dimethylformamide (5mL), 60 DEG C of stirring 16h, after the reaction was complete, adds water 50mL, ethyl acetate extraction
Three times, target compound 19 (30mg, yield are detached to obtain with combiflash companion：47%).
1H NMR (400MHz, Chloroform-d) δ 8.29 (s, 1H), 8.04 (d, J=4.1Hz, 1H), 7.97 (s,
1H), 7.46 (s, 1H), 6.80 (d, J=4.1Hz, 1H), 6.30 (dt, J=4.3,2.2Hz, 1H), 6.23 (d, J=2.1Hz,
2H), 4.03 (t, J=6.8Hz, 2H), 3.72 (s, 6H), 3.67-3.59 (m, 4H), 3.18 (t, J=7.7Hz, 2H), 3.01
(q, J=7.9,7.1Hz, 2H), 2.31 (d, J=4.2Hz, 4H), 2.21 (t, J=6.4Hz, 2H)
ESI(m/z):527.1[M+H]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data is shown in embodiment 5
Following table.
Embodiment 6：3- [2- (bis- chloro- 3,5- Dimethoxyphenyls of 2,6-) ethyl] -5- benzenesulfonyls -5- hydrogen-pyrrolo-
The preparation of [2,3-b] pyrazine (compound 22)
Compound 1 (100mg, 1eq) is dissolved in 5mL anhydrous acetonitriles, under condition of ice bath be added dropwise sulfonic acid chloride (38.5 ц L,
2eq), 3h is stirred at room temperature, rotates away acetonitrile, elutriation is added to go out solid, filters to obtain compound 22 (100mg, yield：86%).
1H NMR (400MHz, Chloroform-d) δ 8.35 (s, 1H), 8.32 (d, J=7.4Hz, 2H), 7.99 (d, J=
4.2Hz, 1H), 7.63 (t, J=7.3Hz, 1H), 7.56 (t, J=7.7Hz, 2H), 6.81 (d, J=4.2Hz, 1H), 6.54 (s,
1H), 3.96 (s, 6H), 3.39 (dd, J=9.5,6.7Hz, 2H), 3.21-3.12 (m, 2H)
ESI(m/z):492.1[M+H]+
Embodiment 7：3- [2- (bis- chloro- 3,5- Dimethoxyphenyls of 2,6-) ethyl] -5- (imidazo [1,2-b] pyridazine -3-
Sulfonyl) -5- hydrogen-pyrrolo- [2,3-b] pyrazine (compound 23) preparation
Step 1：Chemical compounds IbPreparation
Compound 21 (200mg, 1eq) is dissolved in 5mL methanol, is added sodium hydroxide (3eq) aqueous solution of 1mol/L, 40
DEG C reaction 3h, after the reaction was complete, vacuum distillation remove methanol, with 1mol/L dilute hydrochloric acid tune PH be 6~7, be precipitated yellow solid, take out
Filter detaches to obtain target compound I after drying with combiflash companionb(112mg, yield：78%).
Step 2：The preparation of compound 23
Hydrogen sodium (11mg, 2eq) is dissolved in 3mL anhydrous tetrahydro furans, by chemical compounds I under stirringb(50mg, 1eq) in batches
It is added, after stirring at normal temperature 30min, imidazo [1,2-b] pyridazine -3- sulfonic acid chlorides (37mg, 1.2eq) is added dropwise in reaction solution,
5h is stirred at room temperature, after complete reaction, concentrates away tetrahydrofuran, 20mL water is added, PH nearly 7, ethyl acetate is adjusted to extract three times,
Organic layer concentrates after being dried with anhydrous sodium sulfate, and target compound 23 (50mg, yield are detached to obtain with combiflash companion：
66%).
1H NMR (400MHz, Chloroform-d) δ 8.79 (s, 1H), 8.49 (dd, J=4.5,1.5Hz, 1H), 8.28
(s, 1H), 8.20 (d, J=4.1Hz, 1H), 8.07 (dd, J=9.3,1.6Hz, 1H), 7.30-7.26 (m, 1H), 6.81 (d, J
=4.1Hz, 1H), 6.50 (s, 1H), 3.93 (s, 6H), 3.30 (dd, J=9.4,6.6Hz, 2H), 3.09 (dd, J=9.4,
6.6Hz,2H)
ESI(m/z):533.1[M+H]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data is shown in embodiment 7
Following table.
Embodiment 8：3- [2- (bis- chloro- 3,5- Dimethoxyphenyls of 2,6-) ethyl] -5- (positive propionamido- benzene sulfonyls of 2-
Base) -5- hydrogen-pyrrolo- [2,3-b] pyrazine (compound 37) preparation
It by compound 34 (50mg, 1eq), propionyl chloride (18.5 μ L, 2eq), is dissolved in dichloromethane (5mL), catalysis is added
The 4-dimethylaminopyridine of amount reacts at room temperature 5h, after the reaction was complete, concentrates away dichloromethane, detached with combiflash companion
Obtain target compound 37 (30mg, yield：54%).
1H NMR (400MHz, Chloroform-d) δ 9.77 (s, 1H), 8.45 (d, J=7.7Hz, 1H), 8.31 (s,
1H), 8.15 (dd, J=8.2,1.5Hz, 1H), 7.96 (d, J=4.1Hz, 1H), 7.59 (td, J=8.6,8.0,1.4Hz,
1H), 7.23 (ddd, J=8.4,7.4,1.2Hz, 1H), 6.84 (d, J=4.2Hz, 1H), 6.50 (s, 1H), 3.93 (s, 6H),
3.32 (dd, J=8.9,6.5Hz, 2H), 3.13 (dd, J=9.0,6.7Hz, 2H), 2.59 (q, J=7.5Hz, 2H), 1.32 (t,
J=7.5Hz, 3H)
ESI(m/z):562.9[M+H]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data is shown in embodiment 8
Following table.
Embodiment 9：The bromo- 3- of 6- [2- (3,5- dimethoxy-phenylfs)-ethyl] -5- benzenesulfonyls -5- hydrogen-pyrrolo- [2,
3-b] pyrazine (compound 56) preparation
Compound 22 (1.3g, 1eq) is dissolved in the anhydrous THF of 20mL, addition 1,2- dibromos tetrachloroethanes (1.1g,
1.1eq) and N, N- diisopropylamine (2.66mL, 1.4eq), reaction solution is cooled to -78 DEG C.Normal-butyl is added under nitrogen protection
Reaction solution to room temperature is quenched instead with saturated ammonium chloride solution by lithium (0.61mL, 1.4eq), the reaction was continued at -78 DEG C 2 hours
It answers.Tetrahydrofuran is concentrated away, 200mL water is added, adjusts PH nearly 7, ethyl acetate to extract three times, organic layer is dry with anhydrous sodium sulfate
Concentration, target compound 56 (540mg, yield are detached to obtain with combiflash companion after dry：36%).
1H NMR(400MHz,Chloroform-d)δ8.35(s,1H),8.25–8.23(m,2H),7.67–7.59(m,
1H), 7.52 (t, J=7.8Hz, 2H), 6.84 (d, J=4.2Hz, 1H), 6.35 (s, 1H), 3.79 (s, 6H), 3.22 (dd, J=
9.0,6.5Hz, 2H), 3.05 (dd, J=9.0,6.6Hz, 2H) ESI (m/z):568.9[M+H]+
Embodiment 10：4- ([4- (3- (bis- chloro- 3,5- Dimethoxyphenyls of 2,6-))] -5- benzenesulfonyls -5- hydrogen-pyrroles
And [2,3-b] pyrazine -6- bases) phenylmorpholine (compound 57) preparation
Compound 56 (90mg, 1eq) is dissolved in 5mL anhydrous acetonitriles, under condition of ice bath be added dropwise sulfonic acid chloride (38.5 ц L,
2eq), 3h is stirred at room temperature, rotates away acetonitrile, elutriation is added to go out solid, filter the bromo- 3- of intermediate 6- [2- (2,6- bis- chloro- 3,
5- Dimethoxyphenyls)-ethyl] -5- benzenesulfonyls -5- hydrogen-pyrrolo- [2,3-b] pyrazine (85mg, yield：85%).Will in
The bromo- 3- of mesosome 6- [2- (bis- chloro- 3,5- Dimethoxyphenyls of 2,6-)-ethyl] -5- benzenesulfonyls -5- hydrogen-pyrrolo- [2,3-b]
Pyrazine (91.4mg, 1eq), 4- morpholinyl phenyl boric acid pinacol borates (64mg, 1.1eq), triphenylphosphine palladium chloride (6mg,
0.05eq), potassium carbonate (66mg, 3eq) is dissolved in 10mL dioxane and 2mL water, is sealed after degassing, and 85 DEG C are reacted 1 hour.It is dense
20mL water is added in contracting reaction solution, and ethyl acetate extracts three times, and organic layer concentrates after being dried with anhydrous sodium sulfate, is prepared with quick
Chromatographic isolation obtains target compound 57 (45mg, yield：52%).
1H NMR(400MHz,Chloroform-d)δ8.34(s,1H),8.25–8.23(m,2H),7.70–7.62(m,
2H), 7.67-7.59 (m, 1H), 7.52 (t, J=7.8Hz, 2H), 7.09 (d, J=8.7Hz, 1H), 6.84 (d, J=4.2Hz,
1H), 6.35 (s, 1H), 3.79 (s, 6H), 3.22 (dd, J=9.0,6.5Hz, 2H), 3.05 (dd, J=9.0,6.6Hz, 2H),
4.05–3.85(m,4H),3.32–3.30(m,4H)ESI(m/z):653.1[M+H]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data with embodiment 10
It see the table below.
Embodiment 11：3- [2- (3,5- dimethoxy-phenylfs)-ethyl] -5- benzenesulfonyls -5- hydrogen-pyrrolo- [2,3-b]
The preparation of pyrazine (compound 101)
Step 1：The preparation of compound Ib
500mg compounds g is dissolved in 20mL absolute ethyl alcohols, is added palladium/carbon of 0.2mg, under normal pressure, is passed through hydrogen also
Original, 30 DEG C of reaction 5h, after the reaction was complete, filters off palladium/carbon, concentrates away ethyl alcohol, target chemical combination is detached to obtain with combiflash companion
Object I b (150mg, yield：31%).
Step 2：The preparation of compound 101
Hydrogen sodium (33mg, 2eq) is dissolved in 5mL anhydrous tetrahydro furans, under stirring in batches by compound Ib (190mg, 1eq)
It is added, after stirring at normal temperature 30min, methylpyrazole sulfonic acid chloride (157mg, 1.3eq) is added dropwise in reaction solution, 6h is stirred at room temperature,
After complete reaction, tetrahydrofuran is concentrated away, 100mL water is added, adjusts PH nearly 7, ethyl acetate to extract three times, organic layer nothing
It is concentrated after aqueous sodium persulfate drying, target compound 101 (219mg, yield is detached to obtain with combiflash companion：76%).
1H NMR(400MHz,DMSO-d6) δ 8.71 (s, 2H), 8.20 (d, J=4.1Hz, 1H), 7.79 (d, J=1.0Hz,
1H), 7.63 (d, J=16.0Hz, 1H), 7.50 (d, J=16.0Hz, 1H), 6.99-6.95 (m, 3H), 6.52 (t, J=
2.2Hz,1H),3.83(s,6H),3.72(s,3H)
ESI(m/z):427.1[M]+
The preparation route of following compounds only need to be replaced reaction substrate accordingly, characterize data with embodiment 11
It see the table below.
Embodiment 12：3- (bis- chloro- 3,5- Dimethoxyphenethyls of 2,6-) -5- (benzenesulfonyl) -6- (1- (piperidines -4-
Base) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine hydrochloride (compound 138) preparation
Compound 127 is dissolved in saturation hydrochloric acid dioxane solution, solvent evaporated is to get change after being stirred at room temperature 30 minutes
Close object 138.
Embodiment 13：3- (bis- chloro- 3,5- Dimethoxyphenethyls of 2,6-) -5- ((1- methyl-1 H- imidazol-4 yls) sulphonyl
Base) -6- (1- (piperidin-4-yl) -1H- pyrazoles -4- bases) -5H- pyrrolo-es [2,3-b] pyrazine hydrochloride preparation
The preparation method is the same as that of Example 12, only need to be replaced reaction substrate accordingly, characterize data see the table below.
Effect example 1：Influence of the compound in molecular level to FGFR enzymatic activitys
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 FGFR kinase domains recombinant protein of fliud flushing starts 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 receptor tyrosine kinase FGFR1 or FGFR2 enzyme
Note：(1)+indicate that compound is more than 50% at 1 μM to FGFR1 or FGFR2 inhibition of enzyme activity rates.
(2) ++ indicate that compound is more than 50% at 0.1 μM to FGFR1 or FGFR2 inhibition of enzyme activity rates.
(3) +++ indicate that compound is more than 50% at 0.01 μM to FGFR1 or FGFR2 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.
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
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.
Claims (12)
1. a kind of five-ring heterocycles as shown in general formula I and pyrazine compound, its pharmaceutically acceptable salt or pharmaceutically acceptable
Solvate,
Wherein, X and Y is each independently C (R ' R "), N (R0), O or S；OrFor-CH=CH-；R0, R ' and R " it is each
From independently being hydrogen or substituted or unsubstituted C1-C4Alkyl；The substituted C1-C4Substituent group in alkyl is selected from following bases
One or more of group：-ORa1、-SRa2With-NRa3Ra4, when there is multiple substituent groups, substituent group is identical or different；Ra1、
Ra2、Ra3And Ra4It is each independently hydrogen or C1-C4Alkyl；
R2、R2aAnd R2bIt is each independently hydrogen or halogen；
Z 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)-；
W is N, CH or CR3；R3For halogen, nitro, cyano ,-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
C1-C6Alkyl, substituted or unsubstituted naphthalene, substituted or unsubstituted " is selected from substituted or unsubstituted phenyl containing 1-5
N, heteroatomic 5~10 unit's heteroaryl in O and S " substituted or unsubstituted " contains hetero atoms of the 1-5 in N, O and S
3~10 circle heterocyclic ring bases "；Wherein, the substituted C1-C6Being substituted by by 1-3 R in alkyl4Replaced, when there are multiple R4
When substitution, R4It is identical or different；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 " and it is described it is substituted " containing 1-5 in N, O and S heteroatomic 3
Substitution in~10 circle heterocyclic ring bases " is each independently by 1-3 Rm1Replaced, when there are multiple Rm1When substitution, Rm1It is identical or
It is 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；
R1For 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：-ORe1、-SRe2Or-NRe3Re4, when there is multiple substituent groups, substituent group is identical or different, Re1、Re2、Re3And Re4Respectively
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 Rm2Replaced, when there are multiple Rm2When substitution, Rm2It is identical or different；
Rm1And Rm2It is each independently 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, substitution or it is unsubstituted
C1-C6Alkyl, substituted or unsubstituted naphthalene, substituted or unsubstituted " is selected from substituted or unsubstituted phenyl containing 1-5
N, heteroatomic 5~10 unit's heteroaryl in O and S " substituted or unsubstituted " contains hetero atoms of the 1-5 in N, O and S
3~10 circle heterocyclic ring bases ", substituted or unsubstituted 3~6 yuan of naphthenic base or substituted or unsubstituted 3~6 member cycloalkenyl；Its
In, the substituted C1-C6Being substituted by by 1-3 R in alkyl5Replaced, when there are multiple R5When substitution, R5It is identical or not
Together；The substituted phenyl, the substituted naphthalene, it is described it is substituted " containing 1-5 in N, O and S heteroatomic 5
~10 unit's heteroaryls ", described take described substituted " containing 1-5 heteroatomic 3~10 circle heterocyclic ring bases in N, O and S "
Substitution in 3~6 yuan of naphthenic base in generation and 3~6 substituted member cycloalkenyls is each independently by 1-3 RnReplaced,
When there is multiple RnWhen substitution, RnIt is identical or different；
Rc1~Rc27It is each independently hydrogen, C2-C6Alkenyl；Substituted or unsubstituted C1~C4Alkyl or 3~6 yuan of naphthenic base；Its
In, substituted C1~C4Being substituted by alkyl is selected from halogen or C by 1~31~C4The substituent group of alkoxy is replaced, when having
When multiple substituent groups, substituent group is identical or different；
R4And R5It is each independently halogen ,-ORd1、-SRd2、-NRd3Rd4、-C(O)(NRd5Rd6)、-C(O)Rd7、-C(O)ORd8、-
S(O)2Rd9、-S(O)Rd10、-N(Rd11)C(O)Rd12、C2-C6Alkenyl, substituted or unsubstituted " contains substituted or unsubstituted phenyl
Have 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S ", 3~6 yuan of naphthenic base；Wherein, the substituted-phenyl and
Substitution in substituted " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S " is each independently
By 1~3 selected from halogen, C1-C4Alkyl, nitro, cyano and amino group replaced, when there is multiple substituent groups, substituent group
It is identical or different；
Rd1~Rd12It is each independently hydrogen, the unsubstituted or C that is replaced by 1~3 halogen1-C4Alkyl " contains 1~3 choosing
From heteroatomic 3~6 circle heterocyclic ring base in N, O and S ", the unsubstituted or phenyl replaced by nitro or 3~6 yuan of naphthenic base；
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, unsubstituted or replaced by 1~3 halogen
C1-C4Alkyl or C2-C6Alkenyl.
2. five-ring heterocycles shown in general formula I as described in claim 1 and pyrazine compound, its pharmaceutically acceptable salt or medicine
Acceptable solvate on, which is characterized in that
In the general formula I,For-CH2CH2-、-CH2- NH- or-CH=CH-；
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 R0, in R ' or R ", the substituted or unsubstituted C1-C4C in alkyl1-C4Alkyl be methyl, ethyl,
N-propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or the R2、R2aOr R2bIn, the halogen is fluorine, chlorine, bromine or iodine；
And/or the R3Or R1In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 5~10
In unit's heteroaryl " is to be selected from N, O containing 1-3 " containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S "
With the unit's heteroaryl of heteroatomic 5,6,7,8,9 or 10 in S；
And/or the R3Or R1In, 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 R3Or R1In, 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 R1In, 3~6 yuan of naphthenic base in " substituted or unsubstituted 3~6 yuan of naphthenic base " be cyclohexyl or
Cyclopenta；
And/or the R1In, 3~6 member cycloalkenyls in substituted or unsubstituted 3~6 member cycloalkenyl be cyclohexenyl group or
Cyclopentenyl；
And/or the R3In, the halogen is fluorine, chlorine or bromine or iodine；
And/or the R1In, in the substituted or unsubstituted phenyl, the substituent group in substituted phenyl be located at Z ortho position,
Position and at one in contraposition or a few places；
And/or the R3In, in the substituted or unsubstituted phenyl, the substituent group in substituted phenyl is located at five-ring heterocycles simultaneously
In the ortho position of pyrazine, meta position and contraposition one at 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 or ethyl；
And/or the Rb1~Rb27In, 3~6 yuan of naphthenic base are cyclopropyl, cyclopenta or cyclohexyl；
And/or the Re1、Re2、Re3Or Re4In, the C1-C4Alkyl is methyl, ethyl, n-propyl, isopropyl, normal-butyl, different
Butyl or tertiary butyl；
And/or the Rm1Or Rm2In, the halogen is fluorine, chlorine, bromine or iodine；
And/or the Rm1Or Rm2In, the substituted or unsubstituted C1-C6C in alkyl1-C6Alkyl is methyl, ethyl, just
Propyl, isopropyl, normal-butyl, isobutyl group or tertiary butyl；
And/or the Rm1Or Rm2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 5~
In 10 unit's heteroaryls " is to be selected from containing 1-3 " containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S "
N, heteroatomic 5~6 unit's heteroaryl in O and S；
And/or the Rm1Or Rm2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 3~
It is to contain the 1-2 heteroatomic 5-6 circle heterocyclic rings bases in N, O and S in 10 circle heterocyclic ring bases "；
And/or the Rm1Or Rm2In, 3~6 yuan of naphthenic base in substituted or unsubstituted 3~6 yuan of naphthenic base are cyclohexyl
Or cyclopenta；
And/or the Rm1Or Rm2In, 3~6 member cycloalkenyls in substituted or unsubstituted 3~6 member cycloalkenyl are cyclohexene
Base or cyclopentenyl；
And/or the Rc1~Rc27In, the substitution C1~C4C in the substituent group of alkyl1~C4Alkoxy is each independently
Methoxyl group；
And/or the Rc1~Rc27In, the substituted or unsubstituted C1~C4C in alkyl1~C4Alkyl is each independently
For methyl or ethyl；
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 R4Or R5In, the halogen is fluorine, chlorine, bromine or iodine；
And/or the R4Or R5In, the C2-C6Alkenyl is vinyl；
And/or the R4Or R5In, 3~6 yuan of naphthenic base are cyclopropyl, cyclopenta or cyclohexyl；
And/or the R4Or R5In, it is described it is substituted or unsubstituted " containing 1~3 in N, O and S heteroatomic 3~6
" containing 1~2 heteroatomic 5 yuan or 6 circle heterocyclic ring bases in N, O and S " in circle heterocyclic ring base "；
And/or the R4Or R5In, the substituted-phenyl or described substituted " contain 1~3 hetero atom in N, O and S
3~6 circle heterocyclic ring bases " substituent group in, the halogen be fluorine, chlorine, bromine or iodine；The C1-C4Alkyl is methyl or ethyl；
And/or the Rd1~Rd12In, " the unsubstituted or C that is replaced by 1~3 halogen1-C4C in alkyl "1~C4
Alkyl is each independently methyl or ethyl；
And/or the Rd1~Rd12In, 3~6 yuan of naphthenic base are each independently cyclopropyl, cyclopenta or cyclohexyl；
And/or the Rd1~Rd12In, " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S " is each
From heteroatomic 5~6 circle heterocyclic ring base independently being containing 1~2 in N, O and S；
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 unsubstituted or C that is replaced by 1~3 halogen1-C4C in alkyl "1-C4Alkane
Base is each independently methyl or ethyl；
And/or the Rf1~Rf27In, the C2-C6Alkenyl is each independently vinyl.
3. five-ring heterocycles shown in general formula I as claimed in claim 2 and pyrazine compound, its pharmaceutically acceptable salt or medicine
Acceptable solvate on, which is characterized in that
In the general formula I, when describedFor-CH=CH- when ,-the CH=CH- be cis-configuration or anti-configuration；
And/or the R2bFor hydrogen, the R2And R2aIt is hydrogen, chlorine or fluorine simultaneously；
And/or the Z is-S (O)2-、-C(O)-、-CH2-、-(CH2)2-、-(CH2)3Or-CH2C(O)-；
And/or the R3Or R1In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 5~10
In unit's heteroaryl " is containing following any group " containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S "：
And/or the R3Or R1In, 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 R1In, in the substituted or unsubstituted phenyl, the substituent group in substituted phenyl be in Z ortho position or
Meta position；
And/or the R3In, in the substituted or unsubstituted phenyl, the substituent group in substituted phenyl is located at five-ring heterocycles simultaneously
The contraposition of pyrazine；
And/or the Rb1~Rb27In, the C of 1~3 halogen substitution1-C4Alkyl is trifluoromethyl；
And/or the Rm1Or Rm2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 5~
In 10 unit's heteroaryls " is pyrazolyl, pyridyl group " containing 1-5 heteroatomic 5~10 unit's heteroaryls in N, O and S "
Or pyrimidine；The pyrazolyl is preferredThe pyridyl group is preferred The pyrimidine radicals is excellent
Choosing
And/or the Rm1Or Rm2In, it is described it is substituted or unsubstituted " containing 1-5 in N, O and S heteroatomic 3~
" containing a heteroatomic 3~10 circle heterocyclic ring bases in N, O and S of 1-5 " in 10 circle heterocyclic ring bases " is
And/or the Rc1~Rc27In, the substituted C1~C4Alkyl is each independently-CH2(OCH3) or trifluoromethyl；
And/or work as R5For halogen when, the Rm1Or Rm2In, the substituted C1-C6Alkyl is-CH2CH2F；
And/or the R4Or R5In, it is described it is substituted or unsubstituted " containing 1~3 in N, O and S heteroatomic 3~6
In circle heterocyclic ring base " is " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S "
And/or the Rd1~Rd12In, the C replaced by 1~3 halogen1-C4Alkyl is each independently trifluoromethyl；
And/or the Rd1~Rd12In, " containing 1~3 heteroatomic 3~6 circle heterocyclic ring base in N, O and S " is each
From independently being
And/or the Rd1~Rd12In, it is described to be each independently by the phenyl that nitro replaces
And/or the RnIn, the C replaced by 1~3 halogen1-C6Alkyl is trifluoromethyl；
And/or the Rf1~Rf27In, the C replaced by 1~3 halogen1-C4Alkyl is each independently trifluoromethyl.
4. the five-ring heterocycles as shown in claims 1 to 3 any one of them general formula I and pyrazine compound, it can pharmaceutically connect
The salt or pharmaceutically acceptable solvate received, which is characterized in that five-ring heterocycles shown in the general formula I and Pyrazine
Conjunction object is following general formula II, five-ring heterocycles and pyrazine compounds shown in general formula III or general formula IV：
Wherein, R1、R2、R2a、R2bAnd R3Definition with described in any one of claims 1 to 3.
5. the five-ring heterocycles as shown in claims 1 to 3 any one of them general formula I and pyrazine compound, it can pharmaceutically connect
The salt or pharmaceutically acceptable solvate received, which is characterized in that five-ring heterocycles shown in the general formula I and Pyrazine
It is shown in following general formula V-1, general formula V-2, general formula VI-1, general formula VI-2, general formula VII-1, general formula VII-2 or general formula VIII to close object
Five-ring heterocycles and pyrazine compounds,
Wherein, R2、R2a、R2b、Rm1And Rm2Definition with described in any one of claims 1 to 3.
6. five-ring heterocycles and pyrazine compound, its pharmaceutically acceptable salt or pharmacy shown in the general formula I as described in power requires 1
Upper acceptable solvate, which is characterized in that simultaneously pyrazine compounds are following to five-ring heterocycles shown in the general formula I
One compound：
7. the preparation side of a kind of five-ring heterocycles as shown in claim 1~6 any one of them general formula I and pyrazine compounds
Method, which is characterized in that include the following steps：In the presence of alkali, by Formula II compound and R1ZLG carries out nucleophilic displacement of fluorine as follows
Reaction, obtains shown compound of formula I；
Wherein, R2、R2a、R2b、R1, X, Y, Z andWDefinition with described in any one of claim 1~6, LG is leaving group.
8. such as Formula II compound represented：
Wherein, R2、R2a、R2b、R1, X, Y andWDefinition with described in any one of claim 1~6.
9. Formula II compound represented as claimed in claim 8, it is characterised in that：Shown in Formula II compound beR2、R2aAnd R2bDefinition with described in claim 8；
Shown in Formula II compound it is preferred
10. the five-ring heterocycles as shown in claim 1~6 any one of them general formula I and pyrazine compound, it can pharmaceutically connect
Application of the salt or pharmaceutically acceptable solvate received in being used to prepare FGFR inhibitor.
11. the five-ring heterocycles as shown in claim 1~6 any one of them general formula I and pyrazine compound, it can pharmaceutically connect
The salt or pharmaceutically acceptable solvate received are preparing treatment and/or are preventing the expression with tyrosine kinase FGFR or activity
Application in the drug of relevant disease；It is described " expression with tyrosine kinase FGFR or the relevant disease of activity " preferably by
Tumour or cancer caused by the variation of tyrosine kinase FGFR；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 tumour preferred glioma or black
Melanoma.
12. a kind of pharmaceutical composition, it includes therapeutically effective amounts as shown in claim 1~6 any one of them general formula I
Five-ring heterocycles and pyrazine compound, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, and it is a kind of or more
Kind pharmaceutic adjuvant.
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| CN105906630A (en) * | 2015-04-06 | 2016-08-31 | 四川百利药业有限责任公司 | N-(1H-pyrazol-5-yl)pyrimidopyrazole-4,6-di-substituted amine compound used as FGFR inhibitor |
| CN106279119A (en) * | 2015-05-27 | 2017-01-04 | 上海海和药物研究开发有限公司 | The preparation of a kind of Azaindole kinase inhibitors and application thereof |
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