CN103497177B - Amino heterocyclic aromatic compound serving as c-Met inhibitor, and preparation method thereof - Google Patents

Amino heterocyclic aromatic compound serving as c-Met inhibitor, and preparation method thereof Download PDF

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CN103497177B
CN103497177B CN201310464100.5A CN201310464100A CN103497177B CN 103497177 B CN103497177 B CN 103497177B CN 201310464100 A CN201310464100 A CN 201310464100A CN 103497177 B CN103497177 B CN 103497177B
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CN103497177A (en
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田红旗
黄功超
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KECHOW PHARMA, Inc.
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BINJIANG PHARMA Inc
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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    • C07—ORGANIC CHEMISTRY
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Abstract

The invention relates to an amino heterocyclic aromatic compound serving as a c-Met inhibitor, and a preparation method thereof, and in particular relates to a compound in the formula (I) in the specification and a pharmaceutically acceptable salt, prodrug, and solvate thereof and a preparation method of the compound and the pharmaceutically acceptable salt, prodrug, and solvate thereof. In the formula (I), X<1>, X<2>, W, A<1>, R<1> and R<2> are as defined in the specification. The invention further discloses a pharmaceutical composition containing the compounds.

Description

Amino heteroaromatic compound as c-Met inhibitor and preparation method thereof
Technical field
The present invention relates to receptor tyrosine kinase（Especially receptor tyrosine kinase c-Met）Inhibitor and its preparation side Method, more specifically, is related to as receptor tyrosine kinase（Especially receptor tyrosine kinase c-Met）The amino aryl of inhibitor Fragrant heterocyclic compound and its pharmaceutically acceptable salt, prodrug, solvate and preparation method thereof, and comprising these materials Pharmaceutical composition.
Background technology
World Health Organization's survey report shows that global cancer condition is increasingly serious, and the number of 20 years from now on new patients will Increase to 15,000,000 by current annual 10000000, the number of death also will increase to 1000 by annual 6,000,000 because of cancer Ten thousand.Wherein primary carcinoma of liver is that the canceration in liver cell with intrahepatic biliary epithelium cell occurs, and is that the mankind are modal pernicious swollen One of knurl；Lung cancer is common malignant tumour, comes from bronchiolar epitheliums at different levels, is divided into cell lung cancer and non-small cell lung cancer；With Growth in the living standard, the change of dietary structure, the incidence of disease of colon cancer is in ascendant trend year by year.
Oneself antineoplastic of listing is more at present, such as alkylating agent medicine, antimetabolite, antitumor antibiotics, immunity Conditioning agent etc., but big drug is larger due to toxicity, and patient does not tolerate.As the molecular mechanism of the generation development to tumour is ground Study carefully more and more clearer, molecular targeted therapy Several Kinds of Malignancy is of great interest and pays much attention to.Molecular targeted agents Effectively, its security is better than cytotoxic chemotherapy agents to selective high, wide spectrum, is the new side of current therapeutic field of tumor development To.
HGF（HGF）It is a kind of PGF, with promoting to include liver cell, epithelial cell, interior The growth of the polytype cell such as chrotoplast, hematopoietic cell, migration and morphogenetic effect.It also participates in the increasing of various kinds of cell Grow, migrate, the invasion and attack transfer to all kinds of tumours has important inducing action.HGF by with acceptor special on its target cell C-Met combines c-Met receptor tyrosin phosphorylations on rear induction after birth, plays HGF by signal transduction pathway in various kinds of cell Biological effect, generation in tumour cell, migrate and transfer process in played an important role.
C-Met is identified in 1991, is the albumen of Immunohistochemistry coding, is that there is a class autonomous phosphorylation to live Property transmembrane receptor, it is with tyrosine kinase activity, related to various oncoproteins and regulatory protein, participate in cellular informatics pass Lead, the regulation and control of cytoskeleton rearrangement, it is considered to be the growth of penetrating property, the crucial regulation of cancerous swelling neoplasia and metabolic processes Thing.In kinds cancer, oneself detects c-Met gene magnifications, change, is mutated and via autocrine or the c-Met of paracrine mechanism Protein overexpression or activate.For example, in Human Gastric carcinoma's tissue, oneself has found that c-Met is overexpressed and expands；In people In class spongioblastoma and lung cancer, thyroid cancer and breast cancer, oneself has found c-Met because of HGF levels and the autocrine signal of increase Conduct and activate.In Human Lung Cancer tissue, it has been found that c-Met signal transductions are raised because of drug resistance mechanism.Although uncommon, Oneself is reported in the sporadic activation with c-Met in heredity papillary kidney, neck squamous cell carcinoma and cancer of the stomach and lung cancer and dashes forward Become.Additionally, increased expression is the modal c-Met found in many human tumors changes (including but not limited to kidney, Oophoroma, hepatocellular carcinoma, non-small cell lung cancer, osteocarcinoma, colon cancer hepatic metastasis, OSCC, cancer of the esophagus, cancer of the stomach, The dirty cancer of film and prostate cancer) it is relevant with prognosis incessantly.Therefore, suppress c-Met activity may to the generation of tumour cell, Important intervention effect is played in invasion and attack and transfer.Grind or oneself enter clinical research c-Met inhibitor have PF-02341066, SGX523 and PHA665752 etc..
Due to key effects of the c-Met in cancer and other diseases, the suppression of c-Met is the discovery that spy for new treatment Not attracting target.
The content of the invention
One aspect of the present invention provides the compound of formula (I) and (II), and its pharmaceutically acceptable salt, prodrug and molten Agent compound.
Wherein
X1Selected from NH2Or OH;
X2Selected from N or CH；
W is selected from C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C (C1-C12Alkyl)2；
A1Selected from C6-C12Aromatic radical, five yuan to ten binary heterocyclic aromatic bases, C3-C12Cycloalkyl, ternary are to 12 circle heterocycles Alkyl, wherein arbitrarily group can independently of one another by one or more R10Replace；
R1Selected from C6-C12Aromatic radical, five yuan to ten binary heterocyclic aromatic bases, C3-C12Cycloalkyl, ternary are to ten binary saturations Or unsaturated heterocycle alkyl, wherein arbitrarily group can independently of one another by one or more R3Replace；
R2Selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, Ternary is to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、- NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-(CR6R7)nC(O)OR4、- (CR6R7)nNCR4R5、-C(=NR6)NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5Or-C (O) NR4R5, wherein any hydrogen Independently of one another by R8Replace；
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The above R8It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) or-S (O)2Replace；
R10Selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary To ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、- NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-(CR6R7)nC(O)OR4、- (CR6R7)nOR4、-(CR6R7)nC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6)NR4R5、-NR4C(O)NR5R6、-NR4S (O)pR5、-C(O)NR4R5、-(CR6R7)nTernary is to ten binary Heterocyclylalkyls ,-(CR6R7)nTernary to twelve-ring alkyl ,- (CR6R7)n(C6-C12Aromatic radical) ,-(CR6R7)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can be independently of one another By R3Replace；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
The alkyl, thiazolinyl, alkynyl, cycloalkyl moiety can be selected from following group by one or more independently of one another It is optionally substituted：Hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido, amino, carboxyl, sulfydryl.
Saturation or unsaturated alkyl, such as C1-C12Alkyl, alkane diyl or thiazolinyl, including with heteroatomic combination, such as alkane Epoxide, can be straight chain or with side chain respectively.
According to the difference of substituent, the isomers that formula (I) and (II) compound can be constituted with optical isomer or difference is mixed Solvate form is present, and the mixture can be separated if appropriate by conventional methods.The invention provides pure isomer and isomery Body mixture, and its production and use, and including combinations thereof thing.For simplicity, hereinafter referred to as formula (I) and (II) compound, which had both referred to pure optical isomer, also referred to the isomer mixture of different proportion if appropriate.
Another aspect of the present invention provide formula (I) and (II) compound, and its pharmaceutically acceptable salt, prodrug and The preparation method of solvate, including：
An additional aspect of the present invention is provided comprising formula (I) and (II) compound or its pharmaceutically acceptable salt, prodrug With the Pharmaceutical composition of solvate.
The compound of formula (I) and (II), and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
X1Selected from NH2Or OH;
X2Selected from N or CH；
W is selected from C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C (C1-C12Alkyl)2；
A1Selected from C6-C12Aromatic radical, five yuan to ten binary heterocyclic aromatic bases, C3-C12Cycloalkyl, ternary are to 12 circle heterocycles Alkyl, wherein arbitrarily group can independently of one another by one or more R10Replace；
R1Selected from C6-C12Aromatic radical, five yuan to ten binary heterocyclic aromatic bases, C3-C12Cycloalkyl, ternary are to ten binary saturations Or unsaturated heterocycle alkyl, wherein arbitrarily group can independently of one another by one or more R3Replace；
R2Selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, Ternary is to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、- NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-(CR6R7)nC(O)OR4、- (CR6R7)nNCR4R5、-C(=NR6)NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5Or-C (O) NR4R5, wherein any hydrogen Independently of one another by R8Replace；
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The above R8It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) or-S (O)2Replace；
R10Selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary To ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、- NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-(CR6R7)nC(O)OR4、- (CR6R7)nOR4、-(CR6R7)nC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6)NR4R5、-NR4C(O)NR5R6、-NR4S (O)pR5、-C(O)NR4R5、-(CR6R7)nTernary is to ten binary Heterocyclylalkyls ,-(CR6R7)nTernary to twelve-ring alkyl ,- (CR6R7)n(C6-C12Aromatic radical) ,-(CR6R7)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can be independently of one another By R3Replace；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
The alkyl, thiazolinyl, alkynyl, cycloalkyl moiety can be selected from following group by one or more independently of one another It is optionally substituted：Hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido, amino, carboxyl, sulfydryl.
Saturation or unsaturated alkyl, such as C1-C12Alkyl, alkane diyl or thiazolinyl, including with heteroatomic combination, such as alkane Epoxide, can be straight chain or with side chain respectively.
According to the difference of substituent, the isomers that formula (I) and (II) compound can be constituted with optical isomer or difference is mixed Solvate form is present, and the mixture can be separated if appropriate by conventional methods.The invention provides pure isomer and isomery Body mixture, and its production and use, and including combinations thereof thing.For simplicity, hereinafter referred to as formula (I) and (II) compound, which had both referred to pure optical isomer, also referred to the isomer mixture of different proportion if appropriate.
And, the formula (I) of claim 1 and (II) compound, and its pharmaceutically acceptable salt, prodrug and solvation Thing, wherein X1For OH.
And, formula (I) and (II) compound, and its pharmaceutically acceptable salt, prodrug and solvate, wherein X1For NH2, X2For N.
And, formula (I) and (II) compound, and its pharmaceutically acceptable salt, prodrug and solvate, wherein X1For NH2, X2For CH.
And, formula (I) compound, and its pharmaceutically acceptable salt, prodrug and solvate, wherein R2For H；
And, formula (I) and (II) compound, and its pharmaceutically acceptable salt, prodrug and solvate.When W is CHCH3 When, the compound of formula (I) and (II) has following structure：
A1 is selected from C6-C12Aromatic radical, wherein arbitrarily group can independently of one another by one or more R10Replace；
R1It is selected from
R3With definition as claimed in claim 1.
And, formula (I-1a) and (II-1a) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I-1b) and (II-1b) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I-1c) and (II-1c) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, the formula (I) of claim 5 and (II) compound, and its pharmaceutically acceptable salt, prodrug and solvation Thing.When W is-C (CH3)2- when, the compound of formula (I) and (II), have following structure：
A1Selected from C6-12 aromatic radicals, wherein arbitrarily group can independently of one another by one or more R10Replace；
R1It is selected from
R3With definition as claimed in claim 1.
And, formula (I-2a) and (II-2a) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I-2b) and (II-2b) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I-2c) and (II-2c) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I) and (II) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
When W isWhen, the compound of formula (I) and (II) has following structure：
A1Selected from C6-12 aromatic radicals, wherein arbitrarily group can independently of one another by one or more R10Replace；
R1It is selected from
R3With definition as claimed in claim 1.
And, formula (I-3a) and (II-3a) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I-3b) and (II-3b) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I-3c) and (II-3c) compound, and its pharmaceutically acceptable salt, prodrug and solvate.
Wherein
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The R8It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) ,-S (O)2Replace；
R10Selected from halogen ,-NO2、-CN、-CF3；
M is selected from 0,1 or 2；
N is selected from 0,1,2,3 or 4；
P is selected from 1 or 2；
And, formula (I-1a) compound preparation method, i.e. compound（I-1a-1）The preparation of protection group PG is sloughed directly.
And, formula（I-1a-1）The preparation method of compound, i.e. compound（I-1a-2）With compound（I-1a-5）Reaction Prepare.
And, formula（I-1a-2）The preparation method of compound, i.e. compound（I-1a-3）With halogenating agent in alkalescence condition It is prepared by lower generation halogenating reaction.
And, formula（I-1a-3）The preparation method of compound, i.e. compound（I-1a-4）Prepare with borate coupling reaction.
And, formula（I-1a-5）The preparation method of compound, i.e. compound 2 are prepared with sulfiding reagent reaction.
And, in the basic conditions prepared by halo for the preparation method of compound 2, i.e. compound 1.
And, formula (II-1a) compound preparation method, i.e. compound（II-1a-1）Protection group PG system is sloughed directly It is standby.
And, formula（II-1a-1）The preparation method of compound, i.e. compound（II-1a-2）Occur with corresponding borate It is prepared by coupling reaction.
And, formula（II-1a-2）The preparation method of compound, i.e. compound（II-1a-3）In the presence of halogenating agent It is prepared by generation halogenating reaction.
And, formula（II-1a-3）The preparation method of compound, i.e. compound（II-1a-4）In the condition that reducing agent is present It is prepared by lower reduction.
And, formula（II-1a-4）The preparation method of compound, i.e. compound（II-1a-5）With compound 3' in alkaline bar There is nucleophilic addition to prepare under part.
And, the preparation method of compound 3', i.e. compound 2' hydrolyze preparation in the basic conditions.
And, the preparation method of compound 2', i.e. compound 1' reset preparation under the high temperature conditions.
And, the preparation method of compound 1', i.e. 2- nitros -3- pyridones are thio by dimethylamino in the basic conditions It is prepared by formoxyl protection.
Description of the drawings
Fig. 1 is inhibiting rate of the test compound to gastric carcinoma cells MKN45.
Specific embodiment
If do not had it is further noted that being defined using following term in full herein：
Term " prodrug " refers to any derivative that can be converted into corresponding active pharmaceutical compounds in vivo.One In individual embodiment, when the compound of the present invention contains hydroxyl, its prodrug can be the ester which is formed with suitable acid, described Acid includes such as lactic acid, citric acid, ascorbic acid etc..
Term " pharmaceutically acceptable salt ", unless otherwise stated, including the acidity that may be present in the compounds of this invention The salt of group（Such as, but not limited to, sylvite, sodium salt, magnesium salts, calcium salt etc.）Or the salt of basic group（Such as, but not limited to, sulphur Hydrochlorate, hydrochloride, phosphate, nitrate, carbonate etc.）.
Term " solvate " refers to that in the solution solute molecule or ion pass through Coulomb force, Van der Waals for, electric charge The compound molecule compound that the adjacent solvent molecule of gravitational attraction is formed between transmission power, hydrogen bond equimolecular.In one embodiment, Solvent is water, i.e., the compounds of this invention forms hydrate.
In some embodiments of the present invention, there is provided the compound of formula (I) and (II), it is and its pharmaceutically acceptable Salt, prodrug and solvate.
Wherein
X1Selected from NH2Or OH;
X2Selected from N or CH；
W is selected from C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C (C1-C12Alkyl)2；
A1Selected from C6-C12Aromatic radical, five yuan to ten binary heterocyclic aromatic bases, C3-C12Cycloalkyl, ternary are to 12 circle heterocycles Alkyl, wherein arbitrarily group can independently of one another by one or more R10Replace；
R1Selected from C6-C12Aromatic radical, five yuan to ten binary heterocyclic aromatic bases, C3-C12Cycloalkyl, ternary are to ten binary saturations Or unsaturated heterocycle alkyl, wherein arbitrarily group can independently of one another by one or more R3Replace；
R2Selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, Ternary is to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、- NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-(CR6R7)nC(O)OR4、- (CR6R7)nNCR4R5、-C(=NR6)NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5Or-C (O) NR4R5, wherein any hydrogen Independently of one another by R8Replace；
The R3It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6- C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、-NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-O(C6C7)nNR4R5、-O(C6C7)nOR4、-(CR6R7)nC(O)OR4、-(CR6R7)NC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6) NR4R5、-NR4C(O)NR5R6、-NR4S(O)pR5、-C(O)NR4R5, wherein arbitrarily hydrogen can independently of one another by one or more R8 Replace；Additionally, substituent R3C can be formed with neighbouring atom6-C12Aromatic radical, five yuan of heterocyclic aromatic bases to ten binary, C3- C12Cycloalkyl, ternary are to ten binary Heterocyclylalkyls;
R4, R5, R6And R7It is each independently selected from hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12 Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases；Or any two is connected in R on same nitrogen-atoms4, R5, R6, R7Saturation or unsaturated miscellaneous is formed together with the nitrogen-atoms that can be connected with them respectively Ring, heterocycle described herein are selectively included one or more hetero atoms selected from O, N or S；Or any two is connected in together R on one carbon atom4, R5, R6, R7C is formed together with the carbon atom that can be connected with them respectively3-C12Cycloalkyl, C6-C12 Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by One or more R8Replace；Or R4, R5, R6, R7In two hydrogen atoms arbitrarily on carbon atom by oxo；
The above R8It is each independently selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkanes Base, C6-C12Aromatic radical, ternary to ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases, amino, cyano group, hydroxyl ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n(C6-C12Aromatic radical) ,-O (CH2)nTernary is miscellaneous to ten binary Cycloalkyl ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can independently of one another by R9Replace；
R9Selected from halogen, C1-C12Alkyl, C1-C12Alkoxyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary are to ten binary Heterocyclylalkyl, five yuan to ten binary heterocyclic aromatic bases ,-O (C1-C12Alkyl) ,-O (CH2)n(C3-C12Cycloalkyl) ,-O (CH2)n (C6-C12Aromatic radical) ,-O (CH2)nTernary is to ten binary Heterocyclylalkyls ,-O (CH2)nFive yuan to ten binary heterocyclic aromatic bases, cyanogen Base, wherein arbitrarily hydrogen can independently of one another by halogen, hydroxyl, cyano group, partly or completely perhalogeno C1-C12Alkyl, part or The C of completely halogenated1-C12Alkoxyl ,-C (O) ,-S (O) or-S (O)2Replace；
R10Selected from halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl, C3-C12Cycloalkyl, C6-C12Aromatic radical, ternary To ten binary Heterocyclylalkyls, five yuan to ten binary heterocyclic aromatic bases ,-S (O)mR4、-SO2NR4R5、-S(O)2OR4、-NO2、- NR4R5、-(CR6R7)nOR4、-CN、-C(O)R4、-OC(O)R4、-O(CR6R7)nR4、-NR4C(O)R5、-(CR6R7)nC(O)OR4、- (CR6R7)nOR4、-(CR6R7)nC(O)NCR4R5、-(CR6R7)nNCR4R5、-C(=NR6)NR4R5、-NR4C(O)NR5R6、-NR4S (O)pR5、-C(O)NR4R5、-(CR6R7)nTernary is to ten binary Heterocyclylalkyls ,-(CR6R7)nTernary to twelve-ring alkyl ,- (CR6R7)n(C6-C12Aromatic radical) ,-(CR6R7)nFive yuan to ten binary heterocyclic aromatic bases, wherein arbitrarily hydrogen can be independently of one another By R3Replace；
M is selected from 0,1 or 2；N is selected from 0,1,2,3 or 4；P is selected from 1 or 2；
The alkyl, thiazolinyl, alkynyl, cycloalkyl moiety can be selected from following group by one or more independently of one another It is optionally substituted：Hydroxyl, oxo, halogen, cyano group, nitro, trifluoromethyl, azido, amino, carboxyl, sulfydryl.
Saturation or unsaturated alkyl, such as C1-C12Alkyl, alkane diyl or thiazolinyl, including with heteroatomic combination, such as alkane Epoxide, can be straight chain or with side chain respectively.
According to the difference of substituent, the isomers that formula (I) and (II) compound can be constituted with optical isomer or difference is mixed Solvate form is present, and the mixture can be separated if appropriate by conventional methods.The invention provides pure isomer and isomery Body mixture, and its production and use, and including combinations thereof thing.For simplicity, hereinafter referred to as formula (I) and (II) compound, which had both referred to pure optical isomer, also referred to the isomer mixture of different proportion if appropriate.
Above-mentioned general formula compound (I) and (II) and following preferred formulas (I) and (II) compound be preferably as follows substituent or Group：
X1Preferably OH or NH2；X1More preferably NH2。X2Preferably N or CH；X2More preferably CH.
W is preferably C1-C12Alkyl, C3-C12Cycloalkyl, C (C1-C12Alkyl)2；W is more preferably C1-C6Alkyl, C3-C8Cycloalkanes Base, C (C1-C6Alkyl)2；W is particularly preferably C1-C3Alkyl, C3-C6Cycloalkyl, C (C1-C3Alkyl)2；
W is especially preferably-CH (CH3)-、-C(CH3)2-；
A1Preferably C6-C12Aromatic radical；A1More preferably polysubstituted phenyl；A1Particularly preferably 2,3,6- trisubstituted benzenes Base；
R1Preferably C6-C12Aromatic radical, five yuan to ten binary heterocyclic aromatic bases；R1More preferably five-ring heterocycles aromatic radical； R1Particularly preferably
R2Preferably hydrogen, halogen, C1-C12Alkyl, C2-C12Thiazolinyl, C2-C12Alkynyl；R2More preferably hydrogen, halogen；R2It is special You Xuanwei not hydrogen.
R3Preferably ternary is to ten binary Heterocyclylalkyls；R3More preferably N azetidines, pyrrolidines, piperidines, piperazine, Coffee quinoline, homopiperazine；R3Particularly preferably piperidines, piperazine, morpholine；R3Especially preferably 4- piperidines；
R10Preferably halogen ,-NO2、-CN、-CF3；R10More preferably halogen ,-NO2、-CN；R10Particularly preferably halogen Element；R10Especially preferably fluorine, chlorine；
Each group in above-mentioned logical formula (I) and (II) compound and preferred formula (I) and (II) compound can combination with one another, That is, it is not preferred with (II) compound including the logical formula (I), and the group between the other substituent of different prioritys and group Close.Any of the above combination is not only suitable for final product, and therefore is also applied for precursor and intermediate.
Present invention preferably comprises the formula (I) of above-mentioned preferred substituents and group and combinations thereof and (II) compound.
The present invention more preferably formula (I) comprising above-mentioned more preferably substituent and group and combinations thereof and (II) compound.
Formula (I) comprising above-mentioned particularly preferred substituent and group and combinations thereof specifically preferred according to the invention and (II) chemical combination Thing.
The present invention particularly preferably formula (I) comprising above-mentioned particularly preferred substituent and group and combinations thereof and (II) chemical combination Thing.
In some preferred embodiments, it is proposed that following compounds：
In some preferred embodiments, it is proposed that following compounds：
In some preferred embodiments, it is proposed that following compounds：
Synthesis
The suitable solvent commonly used in organic reaction can be used in each step reaction of present invention below preparation method, example Such as, but it is not limited to the hydrocarbon of aliphatic and aromatic, optional hydrocarbon or halogenation（Such as pentane, hexane, heptane, hexamethylene, oil Ether, gasoline, volatile oil, benzene,toluene,xylene, dichloromethane, dichloroethanes, chloroform, carbon tetrachloride, chlorobenzene and adjacent dichloro Benzene）, aliphatic and aromatic, optional alcohols（Such as methyl alcohol, ethanol, propyl alcohol, isopropanol, the tert-butyl alcohol, ethylene glycol etc.）, ether （Such as ether and butyl oxide, glycol dimethyl ether and diethylene glycol dimethyl ether, tetrahydrofuran and dioxane etc.）, ester（Such as acetic acid Methyl esters or ethyl acetate etc.）, nitrile（Such as acetonitrile or propionitrile etc.）, ketone（Such as acetone, butanone etc.）, acid amides（Such as dimethyl methyl Acid amides, dimethyl acetamide and 1-METHYLPYRROLIDONE etc.）, and dimethyl sulfoxide (DMSO), tetramethylene sulfone and hexamethyl phosphinylidyne three Amine and N, N- DMPU（DMPU）Deng.
Reaction 1：Compound（I-1a-1）The preparation of protection group PG is sloughed directly.
Reaction 2：Compound（I-1a-2）With compound（I-1a-5）Occur in the basic conditions
Reaction 3：Compound（I-1a-3）There is halogenating reaction in the presence of halogenating agent to prepare.
Reaction 4：Compound（I-1a-4）There is coupling reaction and prepare in corresponding borate.
Reaction 5：Compound 2 is prepared with sulfiding reagent reaction.
Reaction 6：In the basic conditions prepared by halo for compound 1.
Synthetic example：
4- ((1- (bis- chloro- 3- fluorophenyls of 2,6-) ethylmercapto group) -6- (1- (pyridazine -4- bases) -1H- pyrazoles -4- bases) piperidines - The synthesis of 3- amine
Step 1:The synthesis of 2- (1- bromoethyls) -1,3- two chloro- 4- fluorobenzene (1)
By 1-（2,6- bis- chloro- 3- fluorophenyls）Ethanol（5g, 23.9mmol）It is dissolved in hydrobromic acid（30ml）In, backflow 3 is little When, it is cooled to room temperature.It is extracted with ethyl acetate, merges the washing of organic phase Jing, anhydrous sodium sulfate drying is concentrated to give product（5.2g, Yield：80%）.
Step 2:1-（2,6- bis- chloro- 3- fluorophenyls）The synthesis of ethyl mercaptan (2)
By compound 2- (1- bromoethyls) -1,3- bis- chloro- 4- fluorobenzene (5g, 18.4mmol）It is dissolved in ethanol (50mL), plus Enter thiocarbamide（2.8g, 36.8mmol), four hours of heating reflux reaction are cooled to room temperature, and revolving removes solvent, the residue for obtaining Thing is added to KOH (4.1g, 73.6mmol）The aqueous solution（50ml）In, four hours of heating reflux reaction are adjusted with hydrochloric acid and are reacted To PH=3, ethyl acetate extraction, organic phases washed with water, anhydrous sodium sulfate drying are concentrated to give product to liquid（3.2g, yield： 82%）.
Step 3:The conjunction of tert-butyl group 4- (4- (6- amino pyridazine -3- bases) -1H- pyrazol-1-yls) piperidines -1- carboxylates (3) Into
Compound 6- chlorine pyridazine -3- amine（2g, 15.4mmol）It is dissolved in toluene（20ml）In, it is subsequently adding 1- (the tertiary fourths of 1- Oxygen carbonyl piperidin-4-yl) pyrazoles -4- boric acid pinacol esters（6.4g, 17.0mmol）, four triphens are sequentially added under nitrogen protection Base phosphine palladium (892mgmg, 0.77mmol) and sodium carbonate (3.3g, 30.9mmol), 80 DEG C are stirred overnight.Reaction adds water dilute after terminating Release, organic phase is extracted with ethyl acetate, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying to filter, concentration, Column chromatography purifying obtains product 3.2g, yield：60.2%）.1HNMR(400MHz,CDCl3)δ：(7.72-7.67 m, 1H), 7.60- 7.55(m,1H),7.52-7.47(m,1H),7.15-7.10（M, 1H）, 5.18 (s, 2H), 4.32-4.26 (m, 3H), 2.92 (m, 2H),2.18-2.15(m,2H),2.00-1.90(m,2H),1.88-1.85(m,3H)。
Step 4：Tert-butyl group 4- (4- (6- amino -5- bromine pyridazine -3- bases) -1H- pyrazol-1-yls) piperidines -1- carboxylates (4) Synthesis
By compound tert-butyl group 4- (4- (6- amino pyridazine -3- bases) -1H- pyrazol-1-yls) piperidines -1- carboxylates（3.2g, 9.3mmol）And sodium acid carbonate（1.6g, 18.6mmol）It is dissolved in ethanol (20mL), bromine is added dropwise in reactant liquor then （1.48g, 9.3mmol）, 16 hours are reacted at room temperature, are filtered, dilute with water, ethyl acetate extraction, organic phase is with anhydrous Sodium sulphate be dried, concentration, column chromatography for separation obtain product (2.2g, 56%).1HNMR(400MHz,CDCl3)δ：7.74-7.69(m, 1H), 7.62-7.56 (m, 1H), 7.53-7.48 (m, 1H), 5.19 (s, 2H), 4.33-4.27 (m, 3H), 2.94 (m, 2H), 2.19-2.16(m,2H),2.02-1.92(m,2H),1.90-1.87(m,3H)。
Step 5：Tert-butyl group 4- (4- (6- amino -5- ((1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl) sulphur) pyridazine -3- bases) - 1H- pyrazol-1-yls) piperidines -1- carboxylates (5) synthesis.
Tert-butyl group 4- (4- (6- amino -5- bromine pyridazine -3- bases) -1H- pyrazol-1-yls) piperidines -1- carboxylates（500mg, 1.2mmol）With 1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl mercaptan（293mg, 1.3mmol）It is dissolved in DMF（3ml）In, add sodium hydride （60%, 76mg, 43.4mmol）, 50 DEG C are reacted 12 hours, are diluted with water, and ethyl acetate extraction, anhydrous sodium sulfate drying are dense Contracting, column chromatography for separation obtain product 300mg, yield：44.7%）.1HNMR(400MHz,CDCl3)δ：(7.72-7.67 m, 1H), 7.60-7.55(m,1H),7.52-7.47(m,1H),7.33-7.28(m,0.5H),7.21-7.18(m,0.5H),7.04-6.99 (m,1H),5.18(s,2H),5.11-5.05(m,1H),4.32-4.26(m,3H),2.92(m,2H),2.18-2.15(m,2H), 2.00-1.90(m,2H),1.88-1.85(m,3H),1.5(s,9H)。
Step 6：4- ((1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl) sulphur) -6- (1- (piperidin-4-yl) -1H- pyrazoles -4- Base) pyridazine -3- amine synthesis
By compound tert-butyl group 4- (4- (6- amino -5- ((1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl) sulphur) pyridazine -3- Base) -1H- pyrazol-1-yls) piperidines -1- carboxylates（200mg, 0.4mmol）It is dissolved in dichloromethane（2ml）In, add trifluoroacetic acid （2ml）, 1 hour of reaction is stirred at room temperature, and meta-alkalescence is neutralized to ammoniacal liquor, dichloromethane extraction merges organic phase, uses full successively With sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentration, column chromatography for separation obtain product （120mg, yield：72.9%）.1HNMR(400MHz,CDCl3)δ：7.59(s,1H),7.57-7.56(m,1H),7.53-7.51 (m,1H)7.35-7.32(m,0.5H),7.23-7.20(m,0.5H),7.06-7.02(m,1H),5.21(m,2H),5.09- 5.07(m,1H),4.48(m,1H),3.73-3.69(m,2H),3.20(m,2H),2.47(m,4H),1.88-1.86(m,3H)。 MS(ES+):m/z468.5[M+1].
Reaction 1：Compound（II-1a-1）The preparation of protection group PG is sloughed directly.
Reaction 2：Compound（II-1a-2）There is coupling reaction with corresponding borate to prepare.
Reaction 3：Compound（II-1a-3）There is halogenating reaction in the presence of halogenating agent to prepare.
Reaction 4：Compound（II-1a-4）It is prepared by the reduction under conditions of reducing agent is present.
Reaction 5：Compound（II-1a-5）With compound（3'）There is nucleophilic addition in the basic conditions to prepare.
Reaction 6：Compound 2' hydrolyzes preparation in the basic conditions.
Reaction 7:Compound 1' resets preparation under the high temperature conditions.
Reaction 8：2- nitro -3- pyridones are prepared by the protection of dimethylamino thioformyl in the basic conditions.
Synthetic example：
3- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethylmercapto group) -5- (1- (pyridin-4-yl) -1H- pyrazoles -4- bases) piperidines -2- The synthesis of amine
Step 1:O- (2- nitropyridine -3- bases)-dimethylthiocarbamate synthesis (1')
3- hydroxyls -2- nitropyridines (5.0g, mmol) is dissolved in DMF (50mL), is added in reactant liquor in batches under ice bath Enter sodium hydride (60%) (g, mmol), after keeping reaction ten minutes to be carried out under ice bath, dimethylamino thio formyl chloride (4.85g, 39.26mmol) adds reactant liquor, reacts 4 hours at room temperature.Water quenching is added to go out reaction, filtration is dried to obtain Compound 1 (5.6g, 69%).
Step 2:(sulphur -2- nitropyridine -3- bases) dimethyl-thiocarbamic acid fat synthesis (2')
Compound 1 is dissolved in into diphenyl ether (20mL), 180 DEG C of reactions, two hours is heated to, is cooled to room temperature, column chromatography point From obtain compound 2 (4.9g, 87.5%).
Step 3:The synthesis (3') of 2- nitropyridine -3- mercaptan
Sodium methoxide (1.78g, 33.0mmol) is dissolved in methyl alcohol (3mL), compound 2'(1.5g is subsequently adding, 6.6mmol), react 30 minutes under room temperature.The pH value of reactant liquor is adjusted to 5 with 10% hydrochloric acid, extracted with dichloromethane, had Machine mutually uses saturated common salt water washing, anhydrous sodium sulfate drying, and filtering and concentrating obtains compound 3, and (800mg, 78%), product is directly used In the next step.
Step 4：[1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl] Loprazolam synthesis (4')
1- (2,6- bis- chloro- 3- fluorophenyls) ethanol (2g, 9.57mmol) is dissolved in dichloromethane (20mL), then anti- Triethylamine (1.94g, 19.13mmol) is added in answering liquid, under ice bath cooling condition, methane sulfonyl chloride is added dropwise in reactant liquor again (1.64g, 14.35mmol), reacts 30 minutes at room temperature.Reactant liquor is poured in 30mL water, is extracted with dichloromethane, it is organic Saturated common salt water washing, anhydrous sodium sulfate drying are used mutually, filtering and concentrating obtains compound 4, and (2.6g, 95%), crude product is directly used In the next step.
Step 5：3- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl mercapto) -2 nitropyridines synthesis (5')
The crude product 4 (1.0g, 3.48mmol) and compound 3 (652mg, 4.18mmol) of previous step are dissolved in into DMF (30mL) in, potassium carbonate (963mg, 6.97mmol) is subsequently adding, reaction carries out two hours at 80 DEG C.Question response liquid is cooled down To room temperature, it is poured into water, is extracted with ethyl acetate, merge organic phase, with anhydrous sodium sulfate drying, filters, concentration, column chromatography point From obtain product 5 (760mg, 63%).
Step 6：3- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl mercapto) pyridine -2- amine synthesis (6')
Compound 5 (700mg, 2.02mmol) is dissolved in the mixed solvent of ethanol (10mL) and glacial acetic acid (5mL), is added Reduced iron powder (563mg, 10.08mmol), is heated to reflux 1 hour.Question response liquid is cooled to room temperature, with saturated sodium bicarbonate With ethyl acetate extraction merges organic phase, and anhydrous sodium sulfate drying is filtered, and concentration, column chromatography for separation obtain product 6 (300mg,43%)。1HNMR(400MHz,CDCl3) δ 8.04 (m, 1H), 7.45-7.43 (m, 1H), 7.30-7.17 (m, 1H), 7.03-6.99(m,1H),6.54-6.52(m,1H),5.25(m,2H),5.02(m,1H),1.85-1.83(dd,3H).
Step 7:The bromo- 3- of 5- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl mercapto) pyridine -2- amine synthesis (7')
By compound 6'(160mg, 0.50mmol) be dissolved in DMF (5mL), then in reactant liquor add bromo succinyl Imines, reaction are carried out 1 hour at room temperature.Reactant liquor to entering in water, extracted with ethyl acetate, merge organic phase, with anhydrous Sodium sulphate is dried, and filters, concentration, column chromatography for separation obtain product 7 (110mg, 55%).1HNMR(400MHz,CDCl3)δ8.05 (m,1H),7.54-7.52(m,1H),7.33-7.21(m,1H),7.06-7.02(m,1H),5.16(m,2H),5.06-5.03 (m,1H),1.87-1.84(dd,3H)。
Step 8:5- ((N- t-butoxycarbonyl-piperidin -4- bases) -1H- pyrazoles -4- bases) -3- (1- (bis- chloro- 3- fluorobenzene of 2,6- Base) ethyl mercapto) synthesis (8') of pyridine -2- amine
By compound 7'(110mg, 0.278mmol) it is dissolved in dioxane/water（20mL, 4:1, v/v）In, it is added thereto to 1- (1- t-butoxycarbonylpiperidin -4- bases) pyrazoles -4- boric acid pinacol ester (110mg, 0.29mmol）, under nitrogen protection successively Tetra-triphenylphosphine palladium (9.6mg, 0.008mmol) and cesium carbonate (272mg, 0.84mmol), reaction is added to be stirred overnight at 80 DEG C. Reaction terminate after be diluted with water, organic phase with ethyl acetate (3 × 20mL) extract, merge organic phase, with saturated aqueous common salt (2 × 30mL) wash, anhydrous sodium sulfate drying, filter, concentration, column chromatography purifying (petrol ether/ethyl acetate=10, v/v) obtain product 8 (white solid, 66mg, 41.7%).1HNMR(400MHz,CDCl3)δ1.5(s,9H),1.85-1.88(m,3H),1.90-2.00 (m,2H),2.15-2.18(m,2H),2.92(m,2H),4.26-4.32(m,3H),5.05-5.11(m,1H),5.18(s,2H), 6.99-7.04(m,1H),7.18-7.21(m,0.5H),7.28-7.33(m,0.5H),7.47-7.52(m,1H),7.55-7.60 (m,1H),7.67-7.72(m,1H),8.15(s,1H)。
Step 9:5- (1- (piperidin-4-yl) -1H- pyrazoles -4- bases) -3- (1- (bis- chloro- 3- fluorophenyls of 2,6-) ethyl mercapto) The synthesis of pyridine -2- amine (I-1a-1)
By compound 8'(66mg, 0.12mmol) it is dissolved in dichloromethane (5mL), trifluoroacetic acid (0.2mL) is then added dropwise, React 2 hours at room temperature.After reaction terminates, meta-alkalescence is neutralized to ammoniacal liquor, dichloromethane (2 × 20mL) extraction is associated with Machine phase, is washed with saturated sodium bicarbonate solution (2 × 30mL) and saturated aqueous common salt (2 × 30mL), anhydrous sodium sulfate drying successively, Filter, concentration, obtain final product compound I-1a-1 (Light brown solid, 56mg, 99%).1HNMR(400MHz,CDCl3)δ1.86-1.88 (m,3H),2.47(m,4H),3.20(m,2H),3.69-3.73(m,2H),4.48(m,1H),5.07-5.09(m,1H),5.21 (m,2H),7.02-7.06(m,1H),7.20-7.23(m,0.5H),7.32-7.35(m,0.5H),7.51-7.53(m,1H), 7.56-7.57(m,1H),7.59(s,1H),8.16(m,1H)。
Active testing part：
The active testing experimental procedure of gastric carcinoma cells MKN45：
1. bed board.Cell in exponential phase is digested with digestive juice, fresh culture terminates, and cell is counted Cell concentration is adjusted to 2*105/ml with fresh culture by number, adds 200 μ L per hole, if zeroing hole（Only add culture medium）3 Individual, other edges are filled with aseptic PBS.
2. cultivate.It is incubated 48 hours in 5%CO2 at 37 DEG C, allows cell to be paved with bottom hole 60% or so.
3. it is administered.If zeroing hole, control group, experimental group.Each dosage sets 3 multiple holes.Medicine DMSO is dissolved, is made into 10mmol/L mother liquors, then be diluted with DMSO, make 1mmol/L, 100 μm of ol/L, 10 μm of ol/L, 1mol/L, 0.1mol/L solution, during administration, take 1 μ L culture mediums of above-mentioned strength solution be diluted to 1mL, i.e. administration concentration for 10 μm of ol/L, 1 μmol/L、100nmol/L、10nmol/L、1nmol/L、0.1nmol/L、0nmol/L（Control group, plus 1 μ LDMSO culture mediums It is diluted to 1ml）.During administration, liquid in original hole is exhausted, add the fresh culture containing variable concentrations medicine, per 200 μ of hole l.It is administered daily, continuous three days.
● zeroing hole, only add culture medium；
● control group, containing the solvent with experimental group same volume, diluted with complete medium.Per 200 μ l of hole；
● experimental group, the medicine culture medium for having dissolved is diluted to into 0.1,1,10,100,1000,10000nM concentration, often 200 μ l of hole.
4. 72h is incubated at 37 DEG C in 5%CO2.
5.MTT terminates.After 72h, 20 μ LMTT solution are added per hole（5mg/ml）, continue culture 4h.
6. culture, the careful nutrient solution exhausted in hole are terminated.
7. 150 μ l dimethyl sulfoxide (DMSO)s are added per hole（DMSO）, low speed concussion 10min, after thing to be crystallized fully dissolves, in enzyme Mark instrument, surveys its light absorption value at 490nm wavelength.
The compounds of this invention is numbered shown according to the form below 2.The IC50 values of whole compound 1-4 are both less than 1000nM.
Test compound according to the form below 1 is numbered, and acquired results are as shown in table 1 below.
1. test compound of table
Inhibiting rate active testing of the test compound to gastric carcinoma cells MKN45, acquired results are as shown in Fig. 1 of annex.

Claims (3)

1. formula (the I-1a, I-1b) compound as c-Met inhibitor, and its pharmaceutically acceptable salt：
Wherein
The R3It is each independently selected from piperidines, piperazine, morpholine；
R10Selected from halogen.
2. formula (the I-2a, I-2b) compound as c-Met inhibitor, and its pharmaceutically acceptable salt：
Wherein
The R3It is each independently selected from piperidines, piperazine, morpholine；
R10Selected from halogen.
3. formula (the I-3a, I-3b) compound as c-Met inhibitor, and its pharmaceutically acceptable salt：
Wherein
The R3It is each independently selected from piperidines, piperazine, morpholine；
R10Selected from halogen.
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CN101754759A (en) * 2007-05-18 2010-06-23 史密丝克莱恩比彻姆公司 Quinoline derivatives as PI3 kinase inhibitors
WO2011138751A2 (en) * 2010-05-04 2011-11-10 Pfizer Inc. Heterocyclic derivatives as alk inhibitors
CN102532141A (en) * 2010-12-08 2012-07-04 中国科学院上海药物研究所 (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof

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Publication number Priority date Publication date Assignee Title
CN101754759A (en) * 2007-05-18 2010-06-23 史密丝克莱恩比彻姆公司 Quinoline derivatives as PI3 kinase inhibitors
WO2011138751A2 (en) * 2010-05-04 2011-11-10 Pfizer Inc. Heterocyclic derivatives as alk inhibitors
CN102532141A (en) * 2010-12-08 2012-07-04 中国科学院上海药物研究所 (1,2,4)-triazolo-(4,3-b) (1,2,4)-triazine compounds, as well as preparation method and use thereof

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