CN106008371A - 1-aryl ureido naphthenic base-1-formamide compound and pharmaceutical composition and application thereof - Google Patents

1-aryl ureido naphthenic base-1-formamide compound and pharmaceutical composition and application thereof Download PDF

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CN106008371A
CN106008371A CN201610475847.4A CN201610475847A CN106008371A CN 106008371 A CN106008371 A CN 106008371A CN 201610475847 A CN201610475847 A CN 201610475847A CN 106008371 A CN106008371 A CN 106008371A
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谢阳
谢其光
夏鸿林
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms

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Abstract

The invention discloses a 1-aryl ureido naphthenic base-1-formamide compound shown by the general formula I and medically acceptable salt of the compound, nitrogen oxide, solvate and stereisomer comprising mixtures with various proportions, and T, L1, Y, X, X1, X2, X3, G, D, B ring, RB and m have the meanings defined in the specifications. The invention further relates to a preparation method of the compound and application of the medically acceptable salt of the compound, the nitrogen oxide, the solvate and the stereisomer comprising the mixtures with the various proportions, particularly application in preparation of drugs for protecting, treating, curing or relieving cancer disease. (Please see the chemical formulas in the description.).

Description

1-aryl-ureido cycloalkyl-1-Carbox amide and pharmaceutical composition thereof and Application
Technical field
The present invention relates to new 1-aryl-ureido cycloalkyl-1-Carbox amide and pharmaceutically acceptable salt thereof, Nitrogen oxides, solvate, various scalemic thereof are at interior stereoisomer and the drug regimen containing described compound Thing.The invention still further relates to the preparation method of this compounds, and also relate to its pharmaceutically acceptable salt of this compounds, nitrogen Oxide, solvate, various scalemic thereof, in the purposes of interior stereoisomer, particularly are used for protecting, locating in preparation Manage, treat or alleviate the purposes in the medicine of cancerous condition.
Background technology
From calendar year 2001 so far, more than 20 protein tyrosine kinase inhibitors have been had to be used clinically for all kinds of tumor Treatment, such as, Sorafenib (Sorafenib), by Bayer company and the research and development of Onyx Pharmaceuticals company, its energy (platelet derived growth factor receptor, the one of blood vessel growth factor receptor activate for suppression VEGFR-2, VEGFR-3, PDGFR PDGFR can promote tumor growth), c-Kit (stem cell factor is expressed higher in acute myeloid leukaemia) and Raf swash Enzyme.It is unique can suppress Raf kinase whose VEGFR class inhibitor class medicine.Sorafenib can be used for treating nephrocyte in late period Cancer (RCC) and hepatocarcinoma (HCC).Urea groups, as dominance structure commonly used in drug design, both can do oxygen key receptor, Oxygen key donor can also be done, it is also possible to improve the water solublity of medicine.(list of references: Jiang Jie, Ou Yangguiping. sulfonylurea receptor cheese ammonia The progress [J] of acid kinase inhibitor. fine-chemical intermediate, 2014,44 (5): 14 19.)
Card is rich for Buddhist nun, with cyclopropyl-1, the double Methanamide of 1-as connexon, its to VEGFR2, c-Met, RET, KIT, The IC of FLT1/2/3, TIE-2 and c-Met50It is respectively 0.03,1.3,4,4.6,12/11.3/6,14.3 and 7nmol L-1, right The activity of RON and PDGFR is the most weak, IC50It is respectively 124 and 234nmol L-1.Additionally, in cytoactive is tested, card is rich to be replaced Buddhist nun also can effectively suppress the phosphorylation of VEGFR2 and c-Met, and have inhibitory action, IC to KIT, FLT3 and AXL50It is respectively 1.9,7.8,5.0,7.5 and 42nmol L-1, it also can effectively press down the phosphoric acid of c-Met and VEGFR2 in vivo in tumor model Change.Card is rich has extraordinary curative effect for Buddhist nun to the cancer that the regulation and control of c-Met and VEGFR signal transduction pathway are abnormal, can effectively press down Tumor angiogenesis processed and neoplasm metastasis.This medicine is approved by the fda in the United States for treating transitivity thyroid on November 29th, 2012 Medullary carcinoma.(list of references: Hu Yaning, Hu Shihe, Yuan Haoliang, Zhuan Jin, Chen Yadong, Lu Tao. little molecule c-Met kinase inhibitor Progress [J]. pharmacy be in progress, 2015,39 (3): 170 178.)
Summary of the invention
An aspect of of the present present invention relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxidation Thing, solvate and the stereoisomer including its various scalemic thereof,
B ring is 3-7 unit saturated carbon ring or the heterocycle with 0-3 N, 0-2 O and/or 0-2 S atom,
RBSelected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、 SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkanes Base ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON (R1)2、NR1SO2A or NASO2R1,
R1For H, A, CH ≡ C-CH2-、A-C≡C-CH2-、CH2=C-CH2-, A-CH=C-CH2-、A-C(R2)=C-CH2-、 COOR2、CONHR2、CON(R2)2、-[C(R2)2]g-Ar、-[C(R2)2]g-Het、-[C(R2)2]g-cycloalkyl,
R2For H, A,
A is H, A2,
A2For having side chain or the non-branched-chain alkyl of 1-10 carbon atom, wherein, 0-4 CH2Group is former by O atom or S Son and/or-CH=CH-group are replaced, and/or 0-7 H atom is replaced by halogen, hydroxyl, amino or following groups,
Wherein, M is side chain or the non-branched-chain alkyl with 1-6 carbon atom,
X1For O, S, NR1,
X2For O, S, NR1,
X3For O, S, NR1、CHR1、C(R1)2,
G is-[C (R1)2]j-,
D is A ,-[C (R1)2]g-cycloalkyl ,-[C (R1)2]g-Ar、-[C(R1)2]g-Het,
X is-[C (R2)2]nNR1CO[C(R2)2]n、-[C(R2)2]nCONR1[C(R2)2]n、-[C(R2)2]nCO[C(R2)2]n、
-[C(R2)2]nCOO[C(R2)2]n,
Y is Ar-diyl, heteroaryl-diyl, cycloalkylidene,
L1For O, S, NH, NR1Or L1Do not exist,
T is to have the monocycle of 1-4 N and/or 0-4 O and/or 0-4 S atom, dicyclo or three rings, saturated or insatiable hunger Sum, aromatics or non-aromatic heterocyclic, it can unsubstituted or monosubstituted by following group, two replacements :=O ,=S ,=NR1,=N- CN ,=N-NO2,=N-OR1,=N-COR1,=N-COOR1,=N-OCOOR1, separate between each substituent group；And it can be not Replace or, two replacements, three replacements or four replacements monosubstituted by following group: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、 N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、- [C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, it is separate between each substituent group,
M is 0,1 or 2,
N is 0,1 or 2,
J is 0,1 or 2,
G is 0,1 or 2,
Halogen is fluorine, chlorine, bromine, iodine.
And work as L1In the presence of not, structure fragment T is joined directly together with structure fragment Y, and obtained compound structure is as follows:
More specifically, term " cycloalkyl " refers to non-aromatic, saturated or the undersaturated cyclic hydrocarbon group of part, described ring Alkyl can at random be replaced by one or more substituent groups described herein, and it has 3-20 carbon atom becomes monocycle Ring, or 7-12 carbon atom become the ring of bicyclo-.The example of monocyclic cycloalkyl includes, but are not limited to cyclopropyl, ring fourth Base, cyclopenta, 1-ring amyl-1-thiazolinyl, 1-ring amyl-2-thiazolinyl, 1-ring amyl-3-thiazolinyl, cyclohexyl, 1-hexamethylene-1-thiazolinyl, cycloheptyl Base, ring octyl group.It is pungent that exemplary one-tenth bridge bicyclic cycloalkyl includes, but are not limited to bicyclo-[2.2.1] heptane, bicyclo-[2.2.2] Alkane, bicyclo-[3.2.2] nonane." cycloalkylidene " its by from the single carbon atom of described cychc hydrocarbon or two carbon atoms Two hydrogen atoms of upper removing obtain.
Term " Ar " represents the monovalent aromatic alkyl of aryl, i.e. 6-20 carbon atom, and it is by from Parent Aromatic loop systems Single carbon atom on remove a hydrogen atom obtain.Aryl includes bicyclic groups, and group is included being fused to satisfy by this bicyclo- Sum or the undersaturated aromatic ring of part, or aromatic carbocyclic or the ring of heterocycle.Generally aromatic yl group includes, but are not limited to Following group: benzene, substituted benzene, naphthalene, anthracene, xenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetralyl etc..More specifically,
Ar is phenyl, naphthyl or xenyl, each of which is unsubstituted or monosubstituted by following group, two replacements, three replacements Or four replacements: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、 SON(R1)2、COOR1、CONHR1、CON(R1)2、-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, separate between each substituent group." Ar-diyl " The monovalent aromatic alkyl of i.e. 6-20 carbon atom, it is by removing respectively from two carbon atoms of described Parent Aromatic loop systems Two hydrogen atoms are gone to obtain.
Term " Het " is for having 1-4 N, O and/or the monocycle of S atom or dicyclo or three rings, saturated or undersaturated, fragrant Race or non-aromatic heterocyclic, they can be by unsubstituted or monosubstituted by following group, two replacements, three replacements or four replacements: halogen, nitre Base, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、 CONHR1、CON(R1)2、-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON (A)2、NACON(R1)2、NR1SO2A or NASO2R1, it is separate between each substituent group, more specifically, term " Het " represents " heterocyclic radical " or " heteroaryl ".
" heterocyclic radical " refers to the saturated of 3-20 annular atoms or part is unsaturated (i.e. has one or more double in ring Or three keys) carbon ring group, at least one of which annular atoms is selected from following hetero atom: nitrogen, oxygen, phosphorus, sulfur, can at random by One or more substituent groups described herein replace.Also include such group, wherein heterocyclic group and saturated, part Saturated ring condenses, or condenses with the ring of aromatic carbocyclic or heterocycle.The example of " heterocyclic radical " includes, but are not limited to pyrroles Alkyl, tetrahydrofuran base, THP trtrahydropyranyl, morpholino, tetrahydro-1,4-thiazine generation, piperazinyl, expoxy propane base, imidazolidinyl, 3-azepine Bicyclo-[3.1.0] hexyl, 3-azabicyclic [4.1.0] heptane base, azabicyclic [2.2.2] hexyl, N-pyridine radicals urea, phonetic Pyridine ketone group and 1,1-dioxo-thiomorpholin base.
" heteroaryl " refers to 5-, 6-, the monovalence aromatic group of 7-, 8,9 or 10-ring, and includes 5-20 atom Fused system, containing one or more selected from nitrogen, oxygen, the hetero atom of p and s, can be at random by one or more the application Described substituent group replaces.The example of " heteroaryl " includes, but are not limited to pyridine radicals, imidazole radicals, imidazopyridyl, phonetic Piperidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl, thiazolyl, quinolyl, indyl etc.." miscellaneous Virtue-diyl " refer to that it obtains by removing two hydrogen atoms on two carbon atoms of described heteroaryl structure.The one of the present invention Aspect relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxides, solvate and includes Its various scalemic thereof are at interior stereoisomer, wherein, it is characterised in that the T-L in formula I1-fragment comprises fragment 1 With fragment 2,
Wherein, Z1aFor N, CR5, R5For hydrogen, hydroxyl, halogen, nitro, cyano group, R1、OR1、COR1、COOR1、OCOOR1；Z1bFor N, CR6, R6For hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、 SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkanes Base ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON (R1)2、NR1SO2A or NASO2R1, R3、R4Separate, it each is selected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、 NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2 ]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、 NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, or R3、R4、R5、R6Between any two Forming saturated or undersaturated, aromatics or non-aromatic carbocycle or heterocycle, it can be by unsubstituted or taken by following group list further Generation, two replacements or three replacements: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、 SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkanes Base ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON (R1)2、NR1SO2A or NASO2R1, it is separate between each substituent group,
E ring is the saturated or unsaturated heterocycle of 5-7 unit containing 1-3 N, 0-2 O and/or 0-2 S atom, by following base Single group replacement, two replacements :=O ,=S ,=NR1,=N-CN ,=N-NO2,=N-OR1,=N-COR1,=N-COOR1,=N- OCOOR1, separate between each substituent group；And can be by R7Replace, R7Selected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、 SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C (R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、 NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1,
L2For NH, NR8, O, S, R8For A ,-[C (R1)2]g-Ar、-[C(R1)2]g-Het。
An aspect of of the present present invention relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxidation Thing, solvate and the stereoisomer including its various scalemic thereof, wherein, fragment 1 comprises structures below,
L3For NH, O, S,
R9、R10Separate, it each is selected from hydrogen, A, COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C (R1)2]g-Het、-[C(R1)2]g-cycloalkyl；Or R9、R10Form heterocycle between any two, its can by unsubstituted or further by with Lower group is monosubstituted, two replacements or three replacements: A, OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、 SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,- OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、 NR1SO2A or NASO2R1, separate between each substituent group；
Z2aFor N, CR13a, R13aFor hydrogen, nitro, cyano group,
Z2bFor N, CR13b, R13bFor hydrogen, NHR1、N(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-ring Alkyl, NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1,
R11、R12Separate, it each is selected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、 SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g- Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、 NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1,
Or R11、R12Between form saturated or undersaturated, aromatics or non-aromatic carbocycle or heterocycle, its can by unsubstituted or , two replacements monosubstituted by following group or three replacements further: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、 COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C (R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, separate between each substituent group.
An aspect of of the present present invention relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxidation Thing, solvate and the stereoisomer including its various scalemic thereof, wherein, fragment 2 comprises structures below,
An aspect of of the present present invention relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxidation Thing, solvate and the stereoisomer including its various scalemic thereof, wherein, Y fragment is Ar-diyl, and it is not Replace or or two replacements monosubstituted by following group: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、 SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-OCOR1、OCONHR1、OCON(R1)2、 NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, each substituent group Between separate.
An aspect of of the present present invention relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxidation Thing, solvate and the stereoisomer including its various scalemic thereof, wherein, D is phenyl, pyridine radicals, thiophene Base, furyl, imidazole radicals, it is unsubstituted or monosubstituted by following group, two replacements or three replacements: halogen, nitro, cyano group, N3、 A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON (R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、 NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, each substituent group Between separate.
An aspect of of the present present invention relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxidation Thing, solvate and the stereoisomer including its various scalemic thereof, wherein, X is-NHCO-, X1For NH, X2For O, NH, X3For NH.
Phrase " acceptable salt ", refers to the pharmaceutically acceptable organic or inorganic salt of the compounds of this invention.Exemplary Salt include, but are not limited to sulfate, citrate, acetate, oxalates, chloride, bromide, iodide, nitrate, Bisulfate .gamma.-pyridinecarboxylic acid salt, lactate, salicylate, acid citrate, succinate, maleate, Fumaric acid Salt, gluconate, formates, mesylate and pamoate." acceptable salt " can relate to include another molecule such as horse Come hydrochlorate or other balance ions.Balance ion stable charging in parent compound." acceptable salt " can have more than one Individual charged atom, multiple charged atoms can have multiple balance ion.
If the compounds of this invention is alkali, " the acceptable salt " of needs can be prepared by suitable method, such as, in order to Under this free alkali of mineral acid treatment: hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid；Or the organic acid with following: acetic acid, horse Sour, succinic acid, mandelic acid, fumaric acid, malonic acid, acetone acid, salicylic acid, pyranoside base are sour such as glucuronic acid or gala Alduronic acid, 'alpha '-hydroxy acids such as citric acid or tartaric acid, aminoacid such as glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid Such as methanesulfonic acid or p-methyl benzenesulfonic acid.
If the compounds of this invention is acid, " the acceptable salt " of needs can be prepared by suitable method, such as, with such as Under inorganic base or organic base process this free acid: amine, alkali metal hydroxide or alkaline earth metal hydroxide etc..Suitable The exemplary example of salt includes, but are not limited to the organic salt obtained by aminoacid, primary, secondary, tertiary ammonium salt, and cyclic amine example Such as the salt of piperidines, morpholine and piperazine, and the inorganic salt obtained by sodium, calcium, potassium, magnesium, manganese, ferrum, copper, zinc, aluminum and lithium.
Solvate refers to one or more solvent molecule and the conjugate of the compounds of this invention or complex.Form solvent The example of the solvent of compound include, but are not limited to water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and Ethanolamine.
The compound of the present invention can contain asymmetric center or chiral centre, and therefore there is different stereoisomerism Bodily form formula.All stereoisomer forms of the compounds of this invention, including, but not limited to, diastereomer, enantiomer and steric hindrance Isomer, and their mixture such as racemic mixture, will form the part of the present invention.In this article, when any When the spatial chemistry of particular chiral atom does not determines, all stereoisomers are the most considered.Additionally, the present invention relates to all of several What and position isomer.The compounds of this invention can exist with different tautomeric forms, and all these forms is equal It is included in the scope of the present invention.The compounds of this invention can exist with nonsolvated forms, it is also possible to pharmaceutically acceptable Solvent such as water, ethanol etc. exist with solvation form, so the present invention will include solvation and non-solvated form.
An aspect of of the present present invention relates to a kind of compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxidation Thing, solvate and the stereoisomer including its various scalemic thereof, comprise but be not limited to having structure:
The invention also discloses and prepare the compound described in formula 1 and pharmaceutically acceptable salt, nitrogen oxides, hydration Thing, solvate and the method for the stereoisomer including its various scalemic thereof, be to be situated between as a example by-NHCO-by X Continue, can carry out according to following route and step:
Described step includes:
(1) first step: isocyanate ester compound generates urea-ester class with 1-aminocycloalkyl formic acid esters and the like Compound；
(2) second step: generate urea-acid compounds (fragment A) after the hydrolysis of urea-ester compounds；
(3) the 3rd steps: urea-acid compounds (fragment A) and aminated compounds (fragment B) generate under the effect of condensing agent Target compound.
Our synthesis strategy is, is first to obtain fragment A and fragment B, then carries out the splicing of two fragments.Fragment The synthesis of A, is primarily referred to as the synthetic method of urea.Method mainly has following several strategy:
1) amine and isocyanates direct reaction,
2) two kinds of aminated compoundss generate under the effect of triphosgene,
3) two kinds of aminated compoundss generate under the effect of CDI (carbonyl dimidazoles),
4) two kinds of aminated compoundss generate under the effect of chloro-formate, and chloro-formate includes phenyl chloroformate, chloro-carbonic acid P-nitrophenyl ester, the different propylene of chloro-carbonic acid-2-, chloro-carbonic acid-2-trifluoroethyl ester or chloro-carbonic acid-2-trichloroethyl.
Concrete, we illustrate this compounds reaction scheme with following reaction equation:
Isocyanate ester compound generates urea-methyl ester compounds with 1-aminocycloalkyl methyl formate and the like； Then generate acids after methyl ester hydrolysis and generate acid compounds.The condition of hydrolysis includes LiOH, NaOH, LiI/ pyridine etc..
More specifically, according to the synthetic method of our design, we are prepared for fragment A-1～these 5 chemical combination of fragment A-5 Thing is as the representative of fragment A class urea-acid compounds.
Fragment B, comprises fragment 1 dependency structure and comprises fragment 2 dependency structure, and its preparation method has had a lot Document is reported, can be prepared according to the preparation method of document.
Wherein, comprise the synthesis of fragment 1 dependency structure, be now exemplified below:
Example (1)
(list of references: Tran, A.T.；Wen,D.；West,N.P.；et al.Inhibition studies on Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase.Org.Biomol.Chem.2013,11,8113–8126.)
Example (2)
(list of references: J G storehouse is bright. compound [P]. Chinese patent: CN1321151A.)
Example (3)
(list of references: Kubo, K.；Shimizu,T.；Ohyama,S.；Murooka,H.；et al.Novel Potent Orally Active Selective VEGFR-2Tyrosine Kinase Inhibitors:Synthesis, Structure-Activity Relationships,and Antitumor Activities of N-Phenyl-N′-{4- (4-quinolyloxy)phenyl}ureas.J.Med.Chem.2005,48,1359-1366.)
Example (4)
(list of references: Garofalo, A.；Goossens,L.；Baldeyrou,B.；et al.Design, Synthesis,and DNA-Binding of N-Alkyl(anilino)quinazoline Derivatives.J.Med.Chem.2010,53,8089–8103.)
Example (5)
(list of references: Yao, J.；Chen,J.；He,Z.；et al.Design,synthesis and biological activities of thiourea containing sorafenib analogs as antitumor agents.Bioorg.Med.Chem.2012,20,2923–2929.)
Example (6)
(list of references: Yao, J.；He,Z.；Chen,J.；et al.Design,synthesis and biological activities of sorafenib derivatives as antitumor agents.Bioorg.Med.Chem.Lett.2012,22,6549–6553.)
Example (7)
(list of references: Gong Ping, Zhao Yanfang, Liu Yajing, Zhai Xin. quinoline azole and cinnolines and application [P] thereof. in State's patent: CN102643268B.)
Example (8)
(list of references: Kung, P.；Funk,L.；Meng,J.；et al.Structure activity relationships of quinoline-containing c-Met inhibitors.Eur.J.Med.Chem.2008, 43,1321-1329.)
About comprising the synthetic method of fragment 1 dependency structure, except above-mentioned document reports relevant synthesis, at following literary composition Also it is described later in detail in offering: 1) US20130137708A；2)US20090306103A；3)US20150376133A；4) Garofalo,A.；Goossens,L.；Six,P.；et al.Impact of aryloxy-linked quinazolines:A novel series of selective VEGFR-2receptor tyrosine kinase inhibitors.Bioorg.Med.Chem.Lett.2011,21,2106–2122；5) Huang Wei, Cong Xin, Ye Jun, Zhao Xinge, king Good. a kind of fused heterocyclic derivative and application [P] thereof. Chinese patent: CN103183674A；6)Lü,S.；Zheng,W.；Ji,L.； et al.Synthesis,characterization,screening and docking analysis of 4- anilinoquinazoline derivatives as tyrosine kinase inhibitors.Eur.J.Med.Chem.2013,61,84-94；7)Rowbottom,M.W.；Faraoni,R.；Chao,Q., et al.Identification of1-(3-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea Hydrochloride(CEP- 32496),a Highly Potent and Orally Efficacious Inhibitor of V-RAF Murine Sarcoma Viral Oncogene Homologue B1(BRAF)V600E.J.Med.Chem.2012,55,1082–1105； 8)Garofalo,A.；Farce,A.；Ravez,S.；et al.Synthesis and Structure-Activity Relationships of(Aryloxy)quinazoline Ureas as Novel,Potent,and Selective Vascular Endothelial Growth Factor Receptor-2Inhibitors.J.Med.Chem.2012,55, 1189–1204；9)Shreder,K.R.；Wong,M.S.；Nomanbhoy,T.；et al.Synthesis of AX7593,a Quinazoline-Derived Photoaffinity Probe for EGFR.Org.Lett.2004,6(21),3715– 3718；10)Zhai,x.；Li,w.；et al.Design and Synthesis of2-Iminothiazolidin-4-one Moiety Containing Compounds as Potent Antiproliferative Agents.Arch.Pharm.Chem.Life.Sci.2012,345,360–367。
Wherein, comprise the synthesis of fragment 2 dependency structure, be now exemplified below:
Example (1)
(list of references: Mederski, W.W.K.R.；Cezanne,B.；et al.Chlorothiophenecarboxamides as P1surrogates of inhibitors of blood coagulation factor Xa.Bioorg.Med.Chem.Lett.2004,14,5817–5822.)
About comprising the synthetic method of fragment 2 dependency structure, except above-mentioned document reports relevant synthesis, following Document is also described later in detail: 1) Xing, J.；Yang,L.；Li,H.；et al.Identification of anthranilamide derivatives as potential factor Xa inhibitors:Drug design, synthesis and biological evaluation.Eur.J.Med.Chem.2015,95,388-399；2) CN1771237A。
About the synthesis of the compound shown in general structure I, can be with any structure in fragment A and appointing in fragment B One structure is condensed in the presence of condensing agent and forms.More specifically, but the compound protected of this patent includes not office It is limited to any structure representated by A1～A5 and any structure representated by B1～B10 is arranged in pairs or groups at random and is condensed any chemical combination generated Thing.In condensation course, used condensation reagent selected from but be not limited to phosphoric acid salt reagent (PyCloP, PyBroP, PyBOP, PyAOP), ureas reagent (HBTU, HATU, TBTU), benzotriazole condensation reagent (BOMI, BDMP), carbon two acyl Imines reagent (DCC, EDC, DIC), imidazoles reagent (CDI), organic phosphates reagent (DPPA, DPP-Cl, BOP-Cl), acid Halide reagent (chlorination reagent is selected from pivalyl chloride, thionyl chloride, oxalyl chloride, cyanuric chloride, BTC), carbonochloridic acid ester；Used To alkali selected from but be not limited to triethylamine, DIEA, NMM, DMAP, trimethylpyridine, sodium bicarbonate.
Another aspect provides a kind of pharmaceutical composition, comprise the compound of one or more described Formulas I Or its pharmaceutically acceptable salt, solvate or its isomer, and pharmaceutically acceptable carrier, diluent, excipient, Adjuvant, vehicle or combinations thereof.These compositionss also can have been applied in food or health product.
Described pharmaceutical composition can comprise the compound of one or more described Formulas I, it is also possible to further Comprising additional treatment agent, these additional treatment agent are selected from: antineoplastic agent, antiproliferative, antiviral agent, antiinflammatory, immunomodulating Agent, neural factor, treating cardiovascular disease agent, angiopathy therapeutic agent, immunodeficiency disorders therapeutic agent.But it is not limited to The above-mentioned compound listed.
Another aspect provides and prepare for protecting, process, treat or alleviating by described compound of formula I The purposes of the medicine of patient disease, disease or condition of illness, it comprises the change of the present invention to the administration effective dose of needs Compound or its stereoisomer, geometric isomer, tautomer, solvate and " acceptable salt ".Described disease, disease The example of disease or condition of illness includes, but are not limited to cancer, tumor metastasis, viral disorders, bacterial infection disease disease, angiogenic Condition of illness that disease, autoimmune disease, inflammatory conditions are associated with organ transplantation, cardiovascular disease, neural degeneration disease Sick.More specifically, with described compound of formula I prepare for protect, process, treat or alleviate patient's cancer, tumor metastasis, Viral disorders, the purposes of bacterial infection disease disease.More more specific purposes, is to prepare use by described compound of formula I In protecting, process, treat or alleviate cancer, tumor metastasis.
According to the inventive method, prepare for protecting, process, treat or alleviate cancer, tumor by described compound of formula I Transfer, includes, but are not limited to breast carcinoma, ovarian cancer, cervical cancer, carcinoma of prostate, carcinoma of testis, genitourinary tract cancer, esophagus Cancer, laryngeal carcinoma, spongioblast cancer, neuroblast cancer, gastric cancer, skin carcinoma, keratinization spine canceroderm, pulmonary carcinoma, epidermoid carcinoma, maxicell Cancer, non-small cell carcinoma, small cell carcinoma, adenocarcinoma of lung, osteocarcinoma, colon cancer, adenocarcinoma, cancer of pancreas, adenocarcinoma, thyroid carcinoma, follicular carcinoma, Undifferentiated carcinoma, papillary carcinoma, spermatogonium cancer, melanoma, sarcoma, bladder cancer, hepatocarcinoma and cancer of biliary duct, renal carcinoma, bone marrow sample obstacle, Lymph sample obstacle, hair cell cancer, oral cavity and pharyngeal cancer, lip cancer, carcinoma of tongue, mouth cancer, carcinoma of small intestine, colorectal carcinoma, colorectal cancer, rectum Cancer, brain and central nervous system's cancer, Hokdkin disease or leukemia.
Another aspect provides and prepare for preventing with the pharmaceutical composition comprising described compound of formula I Protect, process, treat or alleviate the purposes of the medicine of patient disease, disease or condition of illness.These pharmaceutical compositions comprise one or many The compound of the Formulas I described in Zhong or its pharmaceutically acceptable salt, solvate or its isomer, and pharmaceutically acceptable Carrier, diluent, excipient, adjuvant, vehicle or combinations thereof.Cancer, tumor metastasis, viral disorders, bacterial infection disease Condition of illness that disease, angiogenic disorder, autoimmune disease, inflammatory conditions are associated with organ transplantation, cardiovascular diseases disease Sick, neurodegenerative disease.More specifically, be with the pharmaceutical composition comprising described compound of formula I prepare for protecting, Process, treat or alleviate the purposes of patient's cancer, tumor metastasis.
According to the inventive method, prepare for protecting, process, treating with the pharmaceutical composition of described compound of formula I Or alleviate cancer, tumor metastasis, include, but are not limited to gastric cancer, breast carcinoma, thyroid carcinoma, renal carcinoma, hepatocarcinoma, ovarian cancer, cervix uteri Cancer, pulmonary carcinoma, carcinoma of prostate, carcinoma of testis, genitourinary tract cancer, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, keratinization spine canceroderm, epidermoid carcinoma, Large cell carcinoma, non-small cell carcinoma, small cell carcinoma, adenocarcinoma of lung, osteocarcinoma, colon cancer, cancer of pancreas, adenocarcinoma, papillary carcinoma, melanoma, Sarcoma, bladder cancer, cancer of biliary duct, oral cavity and pharyngeal cancer, lip cancer, carcinoma of tongue, mouth cancer, carcinoma of small intestine, colon cancer, colorectal cancer, rectal cancer, brain and Central nervous system's cancer, Hokdkin disease or leukemia.
According to the inventive method, described cardiovascular disease includes, but are not limited to thrombosis, restenosis, heart fertilizer Greatly, myocardial infarction atherosclerosis, myocardial infarction, angina pectoris and congestive heart failure.
According to the inventive method, described neurodegenerative disease includes, but are not limited to Alzheimer, handkerchief The gloomy disease of gold, amyotrophic lateral sclerosis, Huntington Chorea and cerebral ischemia, and by traumatic damage, glutamate neurotoxicity and anoxia The neurodegenerative disease caused.
According to the inventive method, described inflammation disease includes, but are not limited to prostatitis, mastitis, nephritis, class Rheumatic arthritis, psoriasis, contact dermatitis and delayed hypersensitivity.
The compounds of this invention can be used by any approach of suitable the treated patient's condition.But suitable approach includes not Be confined to oral cavity, parenteral (including subcutaneous, intramuscular, intravenous, intra-arterial, Intradermal), vagina, intraperitoneal, in lung and intranasal.Should Working as understanding, preferred approach can change because of the patient's condition of such as patient.When described compound oral administration, can be by itself and medicine On, acceptable carrier or excipient become pill, capsule, tablet etc..When described compound is configured to parenteral, It can be prepared with pharmaceutically acceptable parenteral carrier.
The present invention can be with arbitrarily easily form of medication administered compound, such as, tablet, powder, capsule, solution, point Dissipate system, suspension, syrup, spray, suppository, gel, Emulsion, patch etc..Such compositions can be containing pharmaceutical preparation Conventional constituents, such as diluent, carrier, pH adjusting agent, sweeting agent, filler and other activating agents.If need parenteral to Medicine, compositions is aseptic, and is to be suitable for injection or the solution of infusion or form of suspension.
Typical preparation is by the compounds of this invention and carrier, diluent or excipient mixing being prepared.Suitable Carrier vector, diluent or excipient mix and include, but are not limited to following material: carbohydrate, wax class, water soluble or Expandable polymer, hydrophilic or hydrophobic material, penetrating judgment, oils, solvent, water etc..Concrete carrier, diluent or tax used Shape agent will depend upon which the mode and purpose that the compounds of this invention is employed.Solvent selects according to safety, is typically chosen aqueous Solvent and solubilized or other non-toxic solvents being dispersed in water.Suitable aqueous solvent include, but are not limited to water, Ethanol, Polyethylene Glycol etc. and mixture thereof.Described preparation can also include one or more buffer agents, solubilizing agent, surface Activator, wetting agent, lubricant, emulsifying agent, suspensoid, preservative, antioxidant, opacifier, fluidizer, coloring agent, sweetener, Aromatic, flavoring agent and additive known to other.Prepare sustained-release preparation to include, but are not limited to polyester, hydrogel, gather Polylactides, the copolymer of Pidolidone, non-degradable ethylene vinyl acetate, degradable poly lactic coglycolic acid.
The compound of the present invention can be used alone, or is used in combination with other therapeutic agents.Therapeutic alliance can provide Synergism, the effect i.e. reached when active component is used together, more than using described compound to be told on respectively Add and.Described therapeutic alliance can be used with scheme concurrently or consecutively.When continuous administration, described combination can with two kinds or Multiple usage is used.The drug regimen that compound can be the most single is used together, or separate administration, and work as separate administration Time, can simultaneously or carry out in succession with any order.
The compound of the present invention or its isomer, solvate, acceptable salt, prepared for protecting, process, controlling Treat or during the purposes of the medicine that alleviates patient disease, disease or condition of illness, can be used in combination with additional treatment agent.Wherein, anti-swollen Tumor medicine is included in targeted therapy and conventional chemotherapy the compound used.Predict the many suitably chemotherapy for therapeutic alliance Agent is in the method for the present invention.Present invention contemplates that, but be not limited to, use multiple anticarcinogen, such as: inducing cell withers The reagent died, polynucleotide；Polypeptide；Medicine；Biosimulation thing；Alkaloid；Alkylating agent；Antitumor antibiotics；Antimetabolite；Swash Element；Platinum compounds；The monoclonal antibody puted together with cancer therapy drug, toxin, or radionuclide；Biological response modifiers (as Interferon and interleukin)；Adoptive immunotherapy agent；Hemopoietic growth factor；The reagent of inducing tumor cell differentiation is (such as total trans dimension Formic acid)；Gene therapeutic agents；Antisense therapy agent and nucleotide；Tumor vaccine；Angiogenic agent etc..
The definition of chemotherapeutics also includes, but are not limited to: the hormone that tumor is worked by (1) is adjusted or presses down The antihormone agent of system, such as estrogen antagonist and selective estrogen receptor modulators, including tamoxifen, raloxifene, Qu Luo Former times is fragrant；(2) inhibitory enzyme aromatase inhibitor (described aromatase regulates adrenal estrogen and produces), such as aminoglutethimide, good fortune Mei Tan；(3) androgen antagonist such as flutamide, nilutamide, leuprorelin and goserelin；(4) kinases inhibitor；(5) Lipid kinase inhibitors；(6) anti-angiogenic agent such as bevacizumab；And the pharmaceutically acceptable salt of any of the above-described kind, acid And derivant.
Chemotherapeutics example includes, but are not limited to imatinib, erlotinib, AMN107, Sutent, reaches sand and replace Buddhist nun, Lapatinib, Sorafenib, bortezomib, oxaliplatin, 5-fluorouracil, folinic acid, rapamycin, alkylating agent such as plug For group and cyclophosphamide；Alkyl sulfonic ester such as busulfan and an improsulfan；Chlormethine propane class such as carboquone；Camptothecine, Yi Li replaces Health, hycamtin, bryostatin, paclitaxel, vinblastine, vincristine, temozolomide；Chlormethine such as chlorambucil；Antibiotic Such as enediyne, antibiotic such as khaki mycin, reach endomycin, aklavine, D actinomycin D, antramycin, bleomycin, Ah mould Element, carubicin, daunorubicin, antimetabolite such as folacin (such as 9,10-dimethylpteroylglutamic acid), purine analogue (such as fludarabine)； Androgen such as calusterone, antiadrenergic drug such as mitotane；Folic acid fill-in such as folinic acid.
Described additives also include the Humanized monoclonal antibodies with antitumor potentiality, and these Humanized monoclonals resist Body includes, but are not limited to alemtuzumab, peace pool pearl monoclonal antibody, Ansai pearl monoclonal antibody, cedelizumab, daclizumab.
Above-mentioned additional treatment agent, can individually be used in combination with the compounds of this invention, it is also possible to multiple additional treatment agent group After conjunction, then it is used in combination with the compound of the present invention.
In summary, above-mentioned additional treatment agent, include, but are not limited to imatinib, erlotinib, AMN107, Sutent, Dasatinib, Lapatinib, Sorafenib, bortezomib, oxaliplatin, 5-fluorouracil, folinic acid, thunder handkerchief Mycin, phosphinothioylidynetrisaziridine, cyclophosphamide, busulfan, an improsulfan, carboquone, camptothecine, irinotecan, hycamtin, paclitaxel, Vinblastine, vincristine, temozolomide, chlorambucil, khaki mycin, reach endomycin, aklavine, D actinomycin D, peace Aspergillin, bleomycin, amycin, carubicin, daunorubicin, 9,10-dimethylpteroylglutamic acid, fludarabine, calusterone, tamoxifen, Raloxifene, droloxifene, aminoglutethimide, formestane, flutamide, nilutamide, leuprorelin, goserelin, bevacizumab, Alemtuzumab, peace pool pearl monoclonal antibody, Ansai pearl monoclonal antibody, cedelizumab, daclizumab, or combinations thereof.
For prevention and/or therapeutic use, the dosage according to the physiologically active compound of the present invention can be in wide scope Change, and can be adjusted according to individual need.Under normal circumstances, the dosage of 1mg～4000mg was suitable, preferably every day Dosage be 10mg～3000mg every day.Under appropriate circumstances, this dosage also can on above-mentioned numerical value or under.This is every Daily dose can be with single dosage or multiple dosed administration.Typical single dosage comprise about 10mg, 20mg, 30mg, 50mg, The described active component of 100mg, 250mg, 300mg, 500mg, 1g or 2g.
Accompanying drawing explanation
Fig. 1 be detailed description of the invention Part II embodiment 3 described in ZJB-3 act on the Survival curves of 2 strain cells Figure；
Fig. 2 be detailed description of the invention Part II embodiment 10 described in ZJB-11 to act on the survival rate of 2 strain cells bent Line chart；
Fig. 3 be detailed description of the invention Part II embodiment 13 described in ZJC-2 act on the Survival curves of 2 strain cells Figure.
Detailed description of the invention
In the examples below, in the way of illustrating the inventive method, only provide the section Example of the present invention.But, this A little embodiments limit the scope of the present invention never in any form, letter to preparation method of the present invention under the concept thereof of the present invention Single improvement broadly falls into the scope of protection of present invention.During it is, illustrated embodiments listed by combining describes the present invention, should When being interpreted as that it is not intended to limit the invention to those embodiments.On the contrary, this invention is intended to include all of change, improvement and The equivalent form of value.It will be appreciated by those skilled in the art that and those similar or many methods of equivalent and materials described herein, They may be used for realizing the present invention.
In the embodiment being described below, unless otherwise indicated, all temperature are all degree Celsius to be given.Unless additionally said Bright, reagent is purchased from commercial supplier or customizes, such as Skien think of, Aladdin, TCI, Sigma etc..
Part I: the preparation of fragment A
The preparation of (embodiment 1) fragment A-1
1-amino-1-methyl cyclohexanecarboxylaand 4g is dissolved in 60mlDCM, under condition of ice bath, is slowly dropped into equivalent different Cyanate, in the solution of 60mlDCM, stirred overnight at room temperature, removal of solvent under reduced pressure, adds 2M hydrochloric acid 150ml (making its pH less than 1), There is solid to occur, filter, washing, dry, obtain product 3.5g.
Above-mentioned product being added 50mlTHF and 10ml water dissolution, adds the LiOH of 5 equivalents, be stirred overnight, decompression removes THF, add water dilution, be filtered to remove insoluble matter, filtrate with 1M salt acid for adjusting pH < 1, have solid to separate out from solvent, filter, filter Cake washes with water, dries overnight in 65 DEG C, products therefrom 2.5g, can not do further purification, direct plunge in drying baker The next step.
1HNMR(500MHz,DMSO-d6) δ: 12.18 (s, 1H), 8.99 (s, 1H), 8.06 (s, 1H), 7.52-7.43 (m, 4H), 6.58 (s, 1H), 1.95-1.37 (m, 10H) ppm；
13CNMR(125MHz,DMSO-d6)δ:176.9,154.9,140.7,132.7,127.4(m),124.8,122.9, 122.6,122.2,116.7,116.6,58.3,33.0,25.8,21.8ppm；
LC-MS, calculates (C15H16ClF3N2O3, M) and it is 364.0802, find [M+H]+: 365.0885,365.0864, 365.0880,365.0863；[2M+H]+: 729.1662,729.1484,729.1664.
The preparation of (embodiment 2) fragment A-2
1-amino-1-methyl cyclohexanecarboxylaand 4g is dissolved in 100mlTHF solution, is slowly dropped into equivalent isocyanates and exists Solution in 50mlDCM, stirred overnight at room temperature.Removal of solvent under reduced pressure, adds 4M hydrochloric acid 150ml (making its pH less than 1), has solid Occur, filter that washing is dried, obtained crude product 3g.
By above-mentioned dissolving crude product in 80mlTHF/40mlMeOH/20mlH2O, adds LiOH 2g, is stirred overnight.Decompression Removing solvent, addition water, to 200ml, is filtered to remove insoluble matter, adds concentrated hydrochloric acid in clear filtrate, and regulation pH, less than 1, has white Color solid occurs, filters, and filter cake is washed, and dries, obtains target product 2.1g, can not do further purification, direct plunge into Next step reaction.
1H NMR(500MHz,DMSO-d6) δ: 12.10 (s, 1H), 8.46 (s, 1H), 7.34 (d, J=7.5Hz, 2H), 7.04 (dd, J=8.0Hz, J=8.0Hz, 2H), 6.33 (s, 1H), 1.94-1.19 (m, 10H) ppm；
13CNMR(125MHz,DMSO-d6)δ:177.1,158.6,156.7,137.5,119.7,116.1,115.9, 58.1,33.1,25.8,21.9ppm；
LC-MS, calculates (C14H17FN2O3, M) and it is 280.1223, find [M+H]+: 281.1583,281.1542, 281.1491,281.1412；[2M+H]+: 561.2592,561.2561,561.2534,561.2527；[M-H]-: 279.1146, 279.1150,279.1147,279.1161；[2M-H]-: 559.2454,559.2412,559.2377,559.2379.
The preparation of (embodiment 3) fragment A-3
1-amino-1-ethylene-acetic acid methyl ester 4g is dissolved in 150mlTHF, is slowly added to equivalent isocyanates in DCM Solution, stirred overnight at room temperature.Decompression removes reaction dissolvent, and adding 1M HCl, regulation pH, less than 1, has solid to separate out, sucking filtration, Crude product 4.6g can be obtained, dry.
Above-mentioned crude product is suspended in 75mlMeOH/15mlH2In O, add LiOH 3g, stirred overnight at room temperature.Decompression rotation removes Solvent, adds 100ml water and DCM extraction, discards organic layer.Water layer adds 2M HCl, regulation pH and, less than 1, has white solid Separate out, sucking filtration.Filter cake is dried and is obtained product 2.5g, can not do further purification, direct plunge into the next step.
1HNMR(500MHz,DMSO-d6) δ: 12.33 (s, 1H), 8.49 (s, 1H), 7.38 (d, J=7.0Hz, 2H), 7.04 (dd, J=8.5Hz, J=8.5Hz, 2H), 6.71 (s, 1H), 1.33-1.01 (m, 4H) ppm；
13CNMR(125MHz,DMSO-d6)δ:175.6,158.8,156.9,156.3,137.4,120.2(m),116.0, 115.8,33.9,17.7ppm；
LC-MS, calculates (C11H11FN2O3, M) and it is 238.0754, find [M+H]+: 239.0826,239.0841, 239.0821；[2M+H]+: 477.1566,477.1571,477.1565.
The preparation of (embodiment 4) fragment A-4
1-amino-1-ethylene-acetic acid methyl ester 2.5g is dissolved in 100ml DCM, is slowly added to equivalent isocyanates DCM solution, stirred overnight at room temperature.Removal of solvent under reduced pressure DCM, adds 1M hydrochloric acid 100ml, adds ethyl acetate, separate acetic acid Methacrylate layer, removal of solvent under reduced pressure, vacuum drying.
Above-mentioned dry product is dissolved in 50mlTHF/10mlH2O, adds LiOH 4g, stirs 6h.Decompression removes molten Agent, addition water, to 100ml, is filtered to remove insoluble matter.In clear filtrate, add concentrated hydrochloric acid 10ml, regulation pH, less than 1, add second Acetoacetic ester, is sufficiently stirred for, and separates ethyl acetate layer, and aqueous layer with ethyl acetate extracts again, merges organic facies, and saturated sodium-chloride is washed Washing, anhydrous sodium sulfate is dried, removal of solvent under reduced pressure, obtains white solid, vacuum drying, obtain 3.5g product, can not do into The purification of one step, direct plunges into the next step.
1H NMR(300MHz,DMSO-d6) δ: 8.71 (s, 1H), 7.75 (d, J=6.5Hz, 2H), 7.29-7.23 (m, 2H),6.85(s,1H),1.33(s,2H),1.02(s,2H)ppm；
13C NMR(125MHz,DMSO-d6)δ:175.1,156.1,153.8,151.9,138.4,119.9,119.7, 118.8,117.6,117.5,33.9,17.7ppm；
LC-MS, calculates (C11H10ClFN2O3, M) and it is 272.0364, find [M+H]+: 273.0466,273.0462, 273.0445,273.0438；[2M+H]+: 545.0804,545.0800,545.0803,545.0793；[M-H]-: 271.0291, 271.0296,271.0295,271.0293；[2M-H]-: 543.0647,543.0668,543.0659,543.0649.
The preparation of (embodiment 5) fragment A-5
1-amino-1-ethylene-acetic acid methyl ester 2.5g is dissolved in 100ml DCM, is slowly added to equivalent isocyanates DCM solution, stirred overnight at room temperature.Removal of solvent under reduced pressure DCM, adds 1M hydrochloric acid 100ml, adds ethyl acetate, separate acetic acid Methacrylate layer, removal of solvent under reduced pressure, vacuum drying.
Above-mentioned dry product is dissolved in 50mlTHF/10mlH2O, adds LiOH 5g, stirs 6h.Decompression removes molten Agent, addition water, to 100ml, is filtered to remove insoluble matter.In clear filtrate, add concentrated hydrochloric acid 10ml, regulation pH, less than 1, add second Acetoacetic ester, is sufficiently stirred for, and separates ethyl acetate layer, and aqueous layer with ethyl acetate extracts again, merges organic facies, and saturated sodium-chloride is washed Washing, anhydrous sodium sulfate is dried, removal of solvent under reduced pressure, obtains yellow foamy solid, vacuum drying, obtains 3.8g product, permissible Do not do further purification, direct plunge into the next step.
1H NMR(300MHz,DMSO-d6)δ:12.40(br,1H),9.00(s,1H),8.09(s,1H),7.55(s,2H), 6.97(s,1H),1.33(s,2H),1.04(s,2H)ppm；
13C NMR(125MHz,DMSO-d6)δ:175.3,156.0,140.7,132.7,127.3(m),124.8,123.4, 122.5,117.2,33.9,17.7ppm；
LC-MS, calculates (C12H10ClF3N2O3, M) and it is 322.0322, find [M+H]+: 323.0446,323.0432, 323.0404,323.0414；[2M+H]+: 645.0730,645.0753,645.0719,645.0748；[M-H]-: 321.0253, 321.0281,321.0252,321.0263；[2M-H]-: 643.0661,643.0655,643.0586,643.0588.
Part II: the preparation of ZJB and ZJC series compound
The preparation of (embodiment 1) ZJB-1
Substrate 1 (sour) 660mg, substrate 2 (amine) 450mg, HATU 850mg, DIEA0.4ml, DMF 40ml, stir under room temperature Mix 24h.Add the saturated sodium bicarbonate solution of 2 times amount, have solid to separate out, filter, obtained filter cake, silica gel column chromatography, wash De-agent CHCl3/ MeOH=10:1, obtains product 470mg.
LC-MS, calculates (C31H30ClF3N6O4, M) and it is 642.1969, find [M+H]+: 643.2306,643.2292, 643.2275,643.2261；[2M+H]+: 1285.4019,1285.3958,1285.3984,1285.4051.
The preparation of (embodiment 2) ZJB-2
Substrate 1 (sour) 780mg, substrate 2 (amine) 490mg, HATU 940mg, DIEA0.43ml, DMF 40ml, stir under room temperature Mix 24h.Adding the water of 2 times amount, have solid to separate out, sucking filtration, filter cake washes with water, after drying, purifies with silica gel column chromatography, eluting Agent (CHCl3/ MeOH=10:1), obtain product 430mg.
1HNMR(300MHz,DMSO-d6) δ: 9.51 (s, 2H), 9.28 (s, 1H), 8.41 (s, 1H), 8.04 (d, J= 8.9Hz,2H),7.85(s,1H),7.55-7.46(m,3H),7.32-7.23(m,2H),7.15(s,1H),6.38(s,1H), 3.93(s,3H),3.91(s,3H),2.08-1.43(m,10H)ppm；
13CNMR(125MHz,DMSO-d6)δ:174.3,157.3,155.1,154.5,153.6,149.7,147.5, 140.6,140.3,132.9,129.1,127.7(m),123.0,122.4,118.6,116.6,116.4,115.4,109.7, 107.8,102.8,59.7,57.0,56.7,32.5,25.8,21.8ppm；
LC-MS, calculates (C31H30ClF3N6O4, M) and it is 642.1969, find [M+H]+: 643.2387,643.2359, 643.2285,643.2206；[2M+H]+: 1285.4045,1285.4023,1285.4052,1285.4011.
The preparation of (embodiment 3) ZJB-3
Substrate 1 (sour) 720mg, substrate 2 (amine) 600mg, HATU 1.1g, DIEA0.52ml, DMF 40ml, stir under room temperature Mix 24h.Add the saturated sodium bicarbonate aqueous solution of 2 times amount, have solid to separate out, after sucking filtration, obtain filter cake.Silica gel column chromatography purifies, Eluant (CHCl3/ MeOH=30:1～20:1), obtain product 800mg.
1HNMR(300MHz,DMSO-d6) δ: 9.74 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 7.69 (d, J= 8.9Hz, 2H), 7.53 (s, 1H), 7.45-7.41 (m, 2H), 7.35 (s, 1H), 7.22 (d, J=8.9Hz, 2H), 7.06 (dd, J =8.9Hz, J=8.9Hz, 2H), 6.82 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 1.43 (s, 2H), 1.01 (s, 2H) ppm；
13CNMR(125MHz,DMSO-d6)δ:172.0,165.8,158.8,156.9,156.6,156.2,153.1, 150.9,149.7,148.7,137.4,137.2,122.9,122.4,120.3,120.2,116.1,115.9,110.6, 107.6,101.6,57.0,56.9,36.0,18.2ppm；
LC-MS, calculates (C27H24FN5O5, M) and it is 517.1761, find [M+H]+: 518.1870,518.2166, 518.1960,518.1828.
The preparation of (embodiment 4) ZJB-4
Substrate 1 (sour) 550mg, substrate 2 (amine) 450mg, HATU 860mg, DIEA0.4ml, DMF 30ml, stir under room temperature Mix 24h.Add the saturated sodium bicarbonate aqueous solution of 2 times amount, have solid to separate out, after sucking filtration, obtain filter cake.Silica gel column chromatography purifies, Eluant (CHCl3/ MeOH=30:1～20:1), obtain product 700mg.
1HNMR(300MHz,DMSO-d6)δ:9.78(s,1H),8.60(s,1H),8.53(s,1H),7.65(s,1H), 7.58 (d, J=7.9Hz, 1H), 7.52 (s, 1H), 7.42-7.36 (m, 4H), 7.07-6.98 (m, 3H), 6.78 (s, 1H), 3.96(s,3H),3.95(s,3H),1.40(s,2H),0.99(s,2H)ppm；
13CNMR(125MHz,DMSO-d6)δ:172.3,165.6,158.8,156.9,156.6,156.1,153.2, 153.1,151.0,149.7,141.0,137.4,130.3,120.2,117.9,117.8,116.1,115.9,114.6, 110.6,107.6,101.5,57.0,56.9,36.1,18.4ppm；
LC-MS, calculates (C27H24FN5O5, M) and it is 517.1761, find [M+H]+: 518.2178,518.2370, 518.2143,518.1875；[2M+H]+: 1035.3590,1035.3661,1035.3635,1035.3602；[M-H]-: 516.1667,516.1674,516.1682,516.1689；[M+Cl]-: 552.1447,552.1454,552.1455, 552.1440；[M+HCOO]-: 562.1717,562.1721,562.1730,562.1743.
The preparation of (embodiment 5) ZJB-5
Substrate 1 (sour) 690mg, substrate 2 (amine) 700mg, HATU 1.4g, DIEA0.6ml, DMF 50ml, continue under room temperature It is stirred overnight.Add the saturated sodium bicarbonate solution of 2 times amount, have solid to separate out, add ethyl acetate and extract 3 times, merge organic Phase, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, and decompression removes organic solvent, silica gel column chromatography, eluant (DCM/MeOH =40:1～20:1), obtain product 900mg.
1HNMR(500MHz,DMSO-d6) δ: 9.81 (s, 1H), 8.61 (s, 1H), 8.60 (d, J=5.5Hz, 1H), 7.80 (d, J=9.0Hz, 2H), 7.60 (s, 1H), 7.44-7.41 (m, 3H), 7.26 (d, J=9.0Hz, 2H), 7.06 (dd, J= 9.0Hz, J=9.0Hz, 2H), 6.81 (s, 1H), 6.62 (d, J=6.0Hz, 1H), 3.97s, 3H), 3.96 (s, 3H), 1.44- 1.42(m,2H),1.02-1.01(m,2H)ppm；
13CNMR(125MHz,DMSO-d6)δ:172.1,158.8,156.9,156.2,155.1,151.0,149.4, 147.0,137.9,137.5,122.9,122.0,120.3,116.1,115.9,107.5,103.9,100.6,57.0,56.9, 36.1,18.2ppm；
LC-MS, calculates (C28H25FN4O5, M) and it is 516.1809, find [M+H]+: 517.2198,517.2299, 517.2342,517.2318；[2M+H]+: 1033.3718,1033.3683,1033.3690,1033.3691；[M-H]-: 515.1739,515.1735,515.1729,515.1728；[M+Cl]-: 551.1511,551.1504,551.1501, 551.1493；[M+HCOO]-: 561.1788,561.1785,561.1787,561.1774；
The preparation of (embodiment 6) ZJB-6
Substrate 1 (sour) 570mg, substrate 2 (amine) 500mg, HATU 960mg, DIEA0.42ml, DMF 50ml, stir under room temperature Mix overnight.Adding the saturated sodium bicarbonate solution of 2 times amount, have solid to separate out, filter, filter cake is dried, silica gel column chromatography, eluant (CHCl3/ MeOH=30:1～15:1), obtain product 760mg.
1HNMR(500MHz,DMSO-d6) δ: 9.57 (s, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 7.67 (d, J= 8.5Hz, 2H), 7.53 (s, 1H), 7.38-7.36 (m, 2H), 7.36 (s, 1H), 7.19 (d, J=9.0Hz, 2H), 7.04 (dd, J =8.5Hz, J=8.5Hz, 2H), 6.27 (s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 2.05-1.21 (m, 10H) ppm；
13CNMR(125MHz,DMSO-d6)δ:174.4,165.9,158.7,156.8,156.3,154.9,153.1, 150.9,149.6,148.4,137.8,137.5,122.9,121.9,119.8,119.7,116.2,116.0,110.6, 107.6,101.5,59.5,56.9,56.8,32.6,25.8,21.9ppm；
LC-MS, calculates (C30H30FN5O5, M) and it is 559.2231, find [M+H]+: 560.2465,560.2581, 560.2542,560.2479；[M-H]-: 558.2162,558.2153,558.2162,558.2160；[M+Cl]-: 594.1925, 594.1921,594.1926,594.1925；[M+HCOO]-: 604.2208,604.2205,604.2204,604.2209.
The preparation of (embodiment 7) ZJB-7
Substrate 1 (sour) 810mg, substrate 2 (amine) 700mg, HATU 1.4g, DIEA0.6ml, DMF 50ml, stir under room temperature Overnight.Adding the saturated sodium bicarbonate solution of 2 times amount, have solid to separate out, filter, filter cake is dried, silica gel column chromatography, eluant (CHCl3/ MeOH=30:1～15:1), obtain product 560mg.
1HNMR(300MHz,DMSO-d6) δ: 9.63 (s, 1H), 8.82 (s, 1H), 8.42 (d, J=5.2Hz, 1H), 7.74 (d, J=7.5Hz, 2H), 7.49 (s, 1H), 7.37 (s, 3H), 7.19 (d, J=7.7Hz, 2H), 7.05 (dd, J=7.6Hz, J =7.6Hz, 2H), 6.41 (d, J=5.2Hz, 1H), 6.27 (s, 1H), 3.91 (s, 6H), 2.06-1.21 (m, 10H) ppm；
13CNMR(125MHz,DMSO-d6)δ:174.7,160.9,156.8,154.9,153.4,152.2,150.2, 149.8,147.3,137.9,137.5,122.5,122.0,119.8,116.2,116.0,108.7,103.8,100.0,59.5, 56.6,32.6,25.8,21.8ppm；
LC-MS, calculates (C31H31FN4O5, M) and it is 558.2278, find [M+H]+: 559.2690,559.2754, 559.2753,559.2738；[M-H]-: 557.2200,557.2201,557.2203,557.2198；[M+Cl]-: 593.1970, 593.1965,593.1969,593.1964；[M+HCOO]-: 603.2254,603.2246,603.2253,603.2245.
The preparation of (embodiment 8) ZJB-9
Substrate 1 (sour) 530mg, substrate 2 (amine) 430mg, HATU 840mg, DIEA0.6ml, DMF 40ml, stir under room temperature Mix overnight.Adding ethyl acetate and saturated sodium bicarbonate solution, separate ethyl acetate layer, saturated sodium-chloride washs, anhydrous sulfur Acid sodium is dried, and decompression removes organic solvent.Silica gel column chromatography, eluant CHCl3/ MeOH=40:1～20:1, obtains product 320mg。
LC-MS, calculates (C24H22FN5O4, M) and it is 463.1656, find [M+H]+: 464.1806,464.2192, 464.2221,464.1873；[2M+H]+: 927.3401,927.3441,927.3485,927.3413；[M-H]-: 462.1581, 462.1568,462.1580,462.1584；[M+Cl]-: 498.1359,498.1343,498.1353,498.1355；[M+ HCOO]-: 508.1635,508.1623,508.1635,508.1640.
The preparation of (embodiment 9) ZJB-10
Substrate 1 (sour) 710mg, substrate 2 (amine) 430mg, HATU 840mg, DIEA0.6ml, DMF 40ml, it is stirred overnight. Adding ethyl acetate and saturated sodium bicarbonate solution, separate ethyl acetate layer, saturated sodium-chloride washs, and anhydrous sodium sulfate is done Dry, decompression removes organic solvent.Silica gel column chromatography, eluant CHCl3/ MeOH=40:1～20:1, obtains product 200mg.
The preparation of (embodiment 10) ZJB-11
Substrate 1 (sour) 620mg, substrate 2 (amine) 430mg, HATU 840mg, DIEA 0.6ml, DMF 40ml, stirred Night.Adding ethyl acetate and saturated sodium bicarbonate solution, separate ethyl acetate layer, saturated sodium-chloride washs, anhydrous sodium sulfate It is dried, silica gel column chromatography, eluant CHCl3/ MeOH=40:1～10:1, obtains product 300mg.
1HNMR(300MHz,DMSO-d6) δ: 9.63 (s, 1H), 8.81 (s, 1H), 8.77 (d, J=4.1Hz, 1H), 8.46 (d, J=4.9Hz, 1H), 7.72 (d, J=7.8Hz, 2H), 7.39-7.01 (m, 8H), 6.27 (s, 1H), 2.76 (d, J= 3.9Hz,3H),2.07-1.21(m,10H)ppm；
13CNMR(125MHz,DMSO-d6)δ:174.7,166.7,164.6,158.7,156.8,154.9,153.3, 151.2,149.1,138.1,137.5,122.7,121.9,119.8,116.2,116.0,114.8,109.7,59.5,32.6, 26.8,25.8,21.8ppm；
LC-MS, calculates (C27H28FN5O4, M) and it is 505.2125, find [M+H]+: 506.2383,506.2479, 506.2424,506.2205；[2M+H]+: 1011.4341,1011.4397,1011.4364,1011.4305；[M-H]-: 504.2046,504.2059,504.2051,504.2055；[M+Cl]-: 540.1819,540.1829,540.1824, 540.1827；[M+HCOO]-: 550.2096,550.2112,550.2099,550.2110.
The preparation of (embodiment 11) ZJB-12
Substrate 1 (sour) 530mg, substrate 2 (amine) 420mg, HATU 840mg, DIEA 0.6ml, DMF 40ml, stirred Night.Adding ethyl acetate and saturated sodium bicarbonate solution, separate ethyl acetate layer, saturated sodium-chloride washs, anhydrous sodium sulfate Being dried, decompression removes organic solvent.Silica gel column chromatography, eluant CHCl3/ MeOH=40:1～20:1, obtains product 150mg.
LC-MS, calculates (C24H22FN5O4, M) and it is 463.1656, find [M+H]+: 464.1832,464.2260, 464.2263,464.1928；[2M+H]+: 927.3392,927.3381,927.3455,927.3464；[M-H]-: 462.1578, 462.1579,462.1581,462.1577；[M+Cl]-: 498.1350,498.1349,498.1353,498.1350；[M+ HCOO]-: 508.1629,508.1633,508.1635,508.1630.
The preparation of (embodiment 12) ZJC-1
Substrate 1 (sour) 760mg, substrate 2 (amine) 430mg, HATU 1.3g, DIEA 0.6ml, DMF 50ml, stir 24h, Adding the saturated sodium bicarbonate aqueous solution of 2 times amount, have solid to separate out, room temperature is placed a period of time, sucking filtration, and silica gel column chromatography carries Pure, eluant (CHCl3/ MeOH=30:1～20:1), obtain product 800mg.
1H NMR(500MHz,DMSO-d6) δ: 9.53 (s, 1H), 8.79 (s, 1H), 7.60 (d, J=8.5Hz, 2H), 7.59-7.24 (m, 2H), 7.25 (d, J=9.0Hz, 2H), 7.03 (dd, J1=9.0Hz, J2=9.0Hz, 2H), 6.24 (s, 1H), 4.15 (s, 2H), 3.93 (t, J=6.0Hz, 2H), 3.65 (t, J=6.0Hz, 2H), 2.03-1.21 (m, 10H) ppm；
13C NMR(125MHz,DMSO-d6)δ:174.7,166.7,158.7,156.8,154.8,138.6,137.5, 137.3,126.4,120.9,119.8,116.2,115.9,68.6,64.3,59.4,49.9,32.6,25.8,21.8ppm；
LC-MS, calculates (C24H27FN4O4, M) and it is 454.2016, find [M+H]+: 455.2134,455.2132, 455.2120,455.2094；[2M+H]+: 909.4203,909.4187,909.4135,909.4106；[M-H]-: 453.1931, 453.1943,453.1947,453.1935；[M+Cl]-: 489.1705,489.1713,489.1715,489.1709；[M+ HCOO]-: 499.1987,499.1995,499.1996,499.1990.
The preparation of (embodiment 13) ZJC-2
Substrate 1 (sour) 450mg, substrate 2 (amine) 300mg, HATU 590mg, DIEA 0.3ml, DMF 50ml, stir 24h. Adding saturated sodium bicarbonate aqueous solution and the ethyl acetate of 2 times amount, separate ethyl acetate layer, aqueous layer with ethyl acetate extracts, and closes And organic facies, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, silica gel column chromatography, eluant (CHCl3/ MeOH=20:1～ 15:1～10:1), obtain product 500mg.
1HNMR(500MHz,DMSO-d6) δ: 9.67 (s, 1H), 8.59 (s, 1H), 7.61 (d, J=9.0Hz, 2H), 7.43- 7.40 (m, 2H), 7.29 (d, J=8.5Hz, 2H), 7.05 (dd, J1=9.0Hz, J2=9.0Hz, 2H), 6.79 (s, 1H), 4.16 (s, 2H), 3.93 (t, J=6.0Hz, 2H), 3.67 (t, J=6.0Hz, 2H), 1.42-0.98 (m, 4H) ppm；
13CNMR(125MHz,DMSO-d6)δ:172.0,166.7,156.9,156.1,154.8,137.8,137.4, 126.3,121.4,120.3,116.1,115.9,68.6,64.3,49.9,36.0,18.2ppm.
LC-MS, calculates (C21H21FN4O4, M) and it is 412.1547, find [M+H]+: 413.1673,413.1670, 413.1647,413.1615；[2M+H]+: 825.3209,825.3207,825.3176,825.3159；[M-H]-: 411.1455, 411.1474,411.1466,411.1463；[M+Cl]-: 447.1230,447.1245,447.1235,447.1229；[M+ HCOO]-: 457.1509,457.1530,457.1520,457.1517.
The preparation of (embodiment 14) ZJC-3
Substrate 1 (sour) 850mg, substrate 2 (amine) 400mg, HATU 1.2g, DIEA 0.7ml, DMF 50ml, stir 24h. Adding saturated sodium bicarbonate aqueous solution and the ethyl acetate of 2 times amount, separate ethyl acetate layer, aqueous layer with ethyl acetate extracts, and closes And organic facies, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, silica gel column chromatography, eluant (CHCl3/ MeOH=30:1～ 15:1～25:1), obtain product 660mg.
LC-MS, calculates (C21H20ClFN4O4, M) and it is 446.1157, find [M+H]+: 447.1246,447.1252, 447.1242,447.1241；[2M+H]+: 893.2399,893.2398,893.2393,893.2396；[M-H]-: 445.1087, 445.1079,445.1080,445.1075；[M+Cl]-: 481.0848,481.0851,481.0852,481.0844；[M+ HCOO]-: 491.1138,491.1131,491.1134,491.1129.
The preparation of (embodiment 15) ZJC-4
Substrate 1 (sour) 1g, substrate 2 (amine) 400mg, HATU 1.2g, DIEA 0.7ml, DMF 50ml, stir 24h.Add The saturated sodium bicarbonate aqueous solution of 2 times amount and ethyl acetate, separate ethyl acetate layer, and aqueous layer with ethyl acetate extracts, and is associated with Machine phase, saturated sodium-chloride washs, and anhydrous sodium sulfate is dried, silica gel column chromatography, eluant (CHCl3/ MeOH=30:1), produced Thing 350mg.
LC-MS, calculates (C22H20ClF3N4O4, M) and it is 496.1125, find [M+H]+: 497.1213,497.1207, 497.1200,497.1205；[2M+H]+: 993.2347,993.2333,993.2319,993.2342；[M-H]-: 495.1041, 495.1078,495.1047,495.1044；[M+Cl]-: 531.0815,531.0846,531.0818,531.0815；[M+ HCOO]-: 541.1098,541.1131,541.1099,541.1104.
The synthesis of other compounds is referred to above-mentioned preparation method, is prepared.
Part III: the antitumor activity of product of the present invention
Extracorporeal anti-tumor cytoactive: we are as a example by compound ZJB-3, ZJB-11 and ZJC-2, investigation HepG2, MGC803 cell is after drug treating 48h of variable concentrations gradient, by the impact of mtt assay detection medicine cell growth.Press Carry out according to following steps:
(1) medicine preparation: medicine sampling 20mg, add 2mL DMSO dissolving obtaining mother liquid concentration is 10mg/mL, during dosing Being 100 μ g/mL with culture medium dilution medicine to Cmax, 5 times of Concentraton gradient are diluted to 20 μ g/mL, 4 μ g/mL, 0.8 μ subsequently g/mL、0.16μg/mL。
(2) cell prepares: cultivation HepG2 and MGC803 cell to 80～90% full bottle, with 5 × 104The cell of individual/mL is close Degree inoculation 6 porocyte culture plates (2mL/well), 37 DEG C, 5%CO2Cell culture incubator is cultivated 4h and is changed liquid, treats cell confluency degree Bed board is started when 80%.
(3) MTT experiment: MGC803, HepG2 cell that trophophase growth conditions of taking the logarithm is good, discards culture supernatants, Wash 1 time with PBS, discard PBS, add 1ml trypsin-EDTA and stand digestion 1-3 minute, digested in basis of microscopic observation Discarding pancreatin after Quan, 1640 culture medium adding the hyclone containing 10% terminate digestion, and cell is collected in piping and druming.1200rpm from After heart 5min, counting, regulation cell density is 5 × 104Individual/mL, is inoculated on 96 orifice plates respectively, and every hole 100 μ L, in calorstat In 37 DEG C, 5%CO2, saturated humidity is overnight.After 24h, observation of cell is the most adherent well, and carefully uses pipettor carefully to discard Supernatant culture fluid, is separately added into each medicine of 10 μ L fresh complete medium (the RPMI-1640 culture medium containing 10% hyclone) The each 100 μ L of culture fluid of substrate concentration, multiple 4, the hole of every every concentration of strain cell, in 37 DEG C, 5%CO2Incubator in continue cultivate. Taking out 96 orifice plates after 48h, in every hole, lucifuge adds the MTT solution 10uL of 5 μ g/mL, continues to hatch 4h, discards culture fluid and medicine Liquid, adds dimethyl sulfoxide 100uL, and on micro oscillator, level is slowly shaken 1 minute, and after sufficient crystallising precipitates, enzyme joins Detector detection wavelength is absorbance (OD) at 570nm, records data, and experiment is repeated 3 times, and calculates suppression ratio by formula.Survival Rate=dosing group OD/ matched group OD.
MTT result data as shown in table 1, table 2, table 3, the Survival curves figure of cell as shown in Figure 1, Figure 2, Figure 3 shows, ZJB- 11 for the IC of HepG250=22.52 μ g/mL；IC for MGC80350=26.19 μ g/ml；ZJC-2 is for the IC of HepG250 =6.66 μ g/mL；IC for MGC80350=37.75 μ g/ml.
Table 1ZJB-3 acts on the MTT result data of 2 strain cells
Table 2ZJB-11 acts on the MTT result data of 2 strain cells
Table 3ZJC-2 acts on the MTT result data of 2 strain cells
Part IV: the preparation of pharmaceutical composition
The compound of formula of I of the present invention can be used alone, but be typically and pharmaceutical carrier mixture to, described medicine Will be according to required route of administration and standard pharmaceutical practice with the selection of carrier, separately below with the various medicine agent of this compounds Type illustrates its new opplication in pharmaceutical field.Here, we list tablet, capsule, injection, aerosol, suppository, Drop pill, the preparation method of membrane, although by following specific embodiment the present invention can describe, but amendment and more New change is apparent from for those skilled in this art, but they be included in the scope of the invention it Class.
(1) tablet
With containing compound in claim 1 (as a example by embodiment ZJB-11 compound) 10g, typically press according to pharmaceutics Sheet method adds adjuvant 20g mixing, is pressed into 100, and every tablet weight 300mg, containing active component 100mg.More specifically, can be according to Following prescription tries out.
(2) capsule
With containing compound in claim 1 (as a example by embodiment ZJC-2 compound) 10g, according to pharmaceutics capsule Requirement by adjuvant 20g mix after, load Capsules, each capsule weight 300mg, containing active component 100mg.More specifically Ground, can try out according to following prescription.
(3) injection 1
With containing compound in claim 1 (as a example by embodiment ZJB-11 compound) 20g, according to pharmaceutics routine side Method, carries out activated carbon adsorption, after 0.65um filtering with microporous membrane, inserts nitrogen embedding and makes hydro-acupuncture preparation, and every fills 2ml, Fill 1000 bottles altogether.More specifically, can try out according to following prescription.
(4) injection 2
With containing compound in claim 1 (as a example by embodiment ZJC-2 compound) 20g, according to pharmaceutics routine side Method, is dissolved in appropriate water for injection, and 0.1mol/L salt acid for adjusting pH, to suitably, carries out activated carbon adsorption, leaks with aseptic sucking filtration Bucket two layers of sterilizing filter paper filtering of paving, with sterilized G6 sintered glass funnel fine straining, after filtrate passed examination, are sub-packed in 2ml peace Small jar, aseptically frozen drying about 26 hours, and aseptically sealing by fusing, every ampoule is lived containing 20mg Property composition.More specifically, can try out according to following prescription.
(5) aerosol
With containing compound in claim 1 (as a example by embodiment ZJB-3 compound) 10g, according to pharmaceutics routine side Method, adds appropriate cosolvent and dissolves, such as ethanol, Polyethylene Glycol, propylene glycol, glycerol, oleic acid etc., be sub-packed in pressure vessel, peace It is pressed into propellant after dress valve, such as fluorochloroparaffins, hydrocarbon, to obtain final product.More specifically, can pay according to following prescription All practices.
(6) suppository
With containing compound in claim 1 (as a example by embodiment ZJB-4 compound) 20g, with 100g soybean lecithin Melt with the mixture of 1400g cocoa butter, pour in mould, then cool down.Every suppository 20mg Han active component.
(7) drop pill
With containing compound in claim 1 (as a example by embodiment ZJB-5 compound) 20g, with substrate 180g such as gelatin After adding heat fusing mixing, filtered while hot is put in reservoir.It is respectively the dropper dripping of 90mm, 98mm with the inside and outside footpath of the mouth of pipe, drips speed 80/min, instill and the liquid paraffin containing 43 kerosene condenses pelletization (outer layer is ice-water bath coolant), wash ball with liquid paraffin To without kerosene taste, sucking the liquid paraffin of adhesion with writing paper made from bamboo and get final product, preparing drop pill 1000 ball altogether, every ball contains active component 20mg。
(8) membrane
With containing compound in claim 1 (as a example by embodiment ZJB-7 compound) 20g, by polyvinyl alcohol, medicinal sweet Oil, water etc. stirring expand post-heating filter, 80 eye mesh screens filter, then embodiment 12 compound is joined filtrate is stirred molten Solve, film applicator masking 1000, the every 20mg Han active component.

Claims (19)

1. the compound as shown in formula I and pharmaceutically acceptable salt, nitrogen oxides, solvate and include it Various scalemic thereof at interior stereoisomer,
It is characterized in that,
B ring is 3-7 unit saturated carbon ring or the heterocycle with 0-3 N, 0-2 O and/or 0-2 S atom,
RBSelected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、 SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkanes Base ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON (R1)2、NR1SO2A or NASO2R1,
R1For H, A, CH ≡ C-CH2-、A-C≡C-CH2-、CH2=C-CH2-, A-CH=C-CH2-、A-C(R2)=C-CH2-、 COOR2、CONHR2、CON(R2)2、-[C(R2)2]g-Ar、-[C(R2)2]g-Het、-[C(R2)2]g-cycloalkyl,
R2For H, A,
A is H, A2,
A2For having side chain or the non-branched-chain alkyl of 1-10 carbon atom, wherein, 0-4 CH2Group is by O atom or S atom And/or-CH=CH-group replaces, and/or 0-7 H atom replaced by halogen, hydroxyl, amino or following groups,
Wherein, M is side chain or the non-branched-chain alkyl with 1-6 carbon atom,
Ar is phenyl, naphthyl or xenyl, each of which is unsubstituted or monosubstituted by following group, two replacements, three replacements or four Replace: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON (R1)2、COOR1、CONHR1、CON(R1)2、-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, it is separate between each substituent group,
Het is to have 1-4 N, O and/or the monocycle of S atom or dicyclo or three rings, saturated or undersaturated, aromatics or non-aromatic Heterocycle, they can be by unsubstituted or monosubstituted by following group, two replacements, three replacements or four replacements: halogen, nitro, cyano group, N3、 A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON (R1)2、-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON (R1)2、NR1SO2A or NASO2R1, it is separate between each substituent group,
X1For O, S, NR1,
X2For O, S, NR1,
X3For O, S, NR1、CHR1、C(R1)2,
G is-[C (R1)2]j-,
D is A ,-[C (R1)2]g-cycloalkyl ,-[C (R1)2]g-Ar、-[C(R1)2]g-Het,
X is-[C (R2)2]nNR1CO[C(R2)2]n、-[C(R2)2]nCONR1[C(R2)2]n、-[C(R2)2]nCO[C(R2)2]n、-[C (R2)2]nCOO[C(R2)2]n,
Y is Ar-diyl, heteroaryl-diyl, cycloalkylidene,
L1For O, S, NH, NR1Or L1Do not exist,
T is to have the monocycle of 1-4 N and/or 0-4 O and/or 0-4 S atom, dicyclo or three rings, saturated or unsaturated , aromatics or non-aromatic heterocyclic, it can unsubstituted or monosubstituted by following group, two replacements :=O ,=S ,=NR1,=N-CN, =N-NO2,=N-OR1,=N-COR1,=N-COOR1,=N-OCOOR1, separate between each substituent group；And it can be unsubstituted Or, two replacements, three replacements or four replacements monosubstituted by following group: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N (R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、- [C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, it is separate between each substituent group,
M is 0,1 or 2,
N is 0,1 or 2,
J is 0,1 or 2,
G is 0,1 or 2,
Halogen is fluorine, chlorine, bromine, iodine.
Compound the most according to claim 1, it is characterised in that the T-L in formula I1-fragment comprises fragment 1 and fragment 2,
Wherein, Z1aFor N, CR5, R5For hydrogen, hydroxyl, halogen, nitro, cyano group, R1、OR1、COR1、COOR1、OCOOR1；Z1bFor N, CR6, R6For hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、 SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,- OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、 NR1SO2A or NASO2R1, R3、R4Separate, it each is selected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N (R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、- [C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1,
Or R3、R4、R5、R6Forming saturated or undersaturated, aromatics or non-aromatic carbocycle or heterocycle between any two, it can not taken Generation or, two replacements monosubstituted by following group or three replacements further: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N (R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、- [C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, it is separate between each substituent group,
E ring is the saturated or unsaturated heterocycle of 5-7 unit containing 1-3 N, 0-2 O and/or 0-2 S atom, by following group list Replacement, two replacements :=O ,=S ,=NR1,=N-CN ,=N-NO2,=N-OR1,=N-COR1,=N-COOR1,=N-OCOOR1, Between each substituent group separate；And can be by R7Replace, R7Selected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N (R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、- [C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、 NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1,
L2For NH, NR8, O, S, R8For A ,-[C (R1)2]g-Ar、-[C(R1)2]g-Het。
Compound the most according to claim 2, it is characterised in that fragment 1 comprises structures below,
L3For NH, O, S,
R9、R10Separate, it each is selected from hydrogen, A, COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g- Het、-[C(R1)2]g-cycloalkyl；Or R9、R10Forming heterocycle between any two, it can be by unsubstituted or further by following group list Replacement, two replacements or three replacements: A, OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、 COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、 OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or Person NASO2R1, separate between each substituent group；
Z2aFor N, CR13a, R13aFor hydrogen, nitro, cyano group,
Z2bFor N, CR13b, R13bFor hydrogen, NHR1、N(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkanes Base, NR1COA、NACOR1、NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1,
R11、R12Separate, it each is selected from hydrogen, halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、 SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g- Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、 NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1,
Or R11、R12Between form saturated or undersaturated, aromatics or non-aromatic carbocycle or heterocycle, it can be by unsubstituted or further , two replacements monosubstituted by following group or three replacements: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、 SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2]g-Ar、-[C(R1)2]g- Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、NR1CONHA、NACONHR1、 NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, separate between each substituent group.
Compound the most according to claim 2, it is characterised in that fragment 2 comprises structures below,
Compound the most according to claim 1, it is characterised in that Y fragment is Ar-diyl., it is unsubstituted or by following base Single group replaces or two replacements: halogen, nitro, cyano group, N3、A、OR1、SR1、NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、 SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、 NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, separate between each substituent group.
Compound the most according to claim 1, it is characterised in that D is phenyl, pyridine radicals, thienyl, furyl or miaow Oxazolyl, it is unsubstituted or monosubstituted by following group, two replacements or three replacements: halogen, nitro, cyano group, N3、A、OR1、SR1、 NHR1、N(R1)2、COR1、SO2NHR1、SO2N(R1)2、SONHR1、SON(R1)2、COOR1、CONHR1、CON(R1)2、-[C(R1)2 ]g-Ar、-[C(R1)2]g-Het、-[C(R1)2]g-cycloalkyl ,-OCOR1、OCONHR1、OCON(R1)2、NR1COA、NACOR1、 NR1CONHA、NACONHR1、NR1CON(A)2、NACON(R1)2、NR1SO2A or NASO2R1, separate between each substituent group.
Compound the most according to claim 1, it is characterised in that X is-NHCO-, X1For NH, X2For O, NH, X3For NH.
Compound the most according to claim 1, it is characterised in that comprise having structure:
Compound the most according to claim 1, and pharmaceutically acceptable salt, nitrogen oxides, hydrate, solvate And the stereoisomer including its various scalemic thereof, it is characterised in that it is prepared as follows,
Described step includes:
(1) first step: isocyanate ester compound generates urea-ester compounds with 1-aminocycloalkyl formic ether compounds；
(2) second step: generate urea-acid compounds (fragment A) after the hydrolysis of urea-ester compounds；
(3) the 3rd steps: urea-acid compounds (fragment A) and aminated compounds (fragment B) generate target under the effect of condensing agent Compound.
10. a pharmaceutical composition, comprises the compound described in one or more claim 1-8 or it is pharmaceutically acceptable Salt, solvate or its isomer, and pharmaceutically acceptable carrier, diluent, excipient, adjuvant, vehicle or they Combination.
11. pharmaceutical compositions according to claim 10, it is characterised in that pharmaceutical composition can further comprise Additional treatment agent, these additional treatment agent are selected from: antineoplastic agent, antiproliferative, antiviral agent, antiinflammatory, immunomodulator, god Through the factor, treating cardiovascular disease agent, angiopathy therapeutic agent and immunodeficiency disorders therapeutic agent.
12. pharmaceutical compositions according to claim 11, it is characterised in that wherein said additional treatment agent is that her horse is replaced Buddhist nun, erlotinib, AMN107, Sutent, Dasatinib, Lapatinib, Sorafenib, bortezomib, oxaliplatin, 5- Fluorouracil, folinic acid, rapamycin, phosphinothioylidynetrisaziridine, cyclophosphamide, busulfan, an improsulfan, carboquone, camptothecine, Yi Li replace Health, hycamtin, paclitaxel, vinblastine, vincristine, temozolomide, chlorambucil, khaki mycin, reach endomycin, Acker Draw mycin, D actinomycin D, antramycin, bleomycin, amycin, carubicin, daunorubicin, 9,10-dimethylpteroylglutamic acid, fludarabine, Calusterone, tamoxifen, raloxifene, droloxifene, aminoglutethimide, formestane, flutamide, nilutamide, leuprorelin, Goserelin, bevacizumab, alemtuzumab, peace pool pearl monoclonal antibody, Ansai pearl monoclonal antibody, cedelizumab, daclizumab, or they Combination.
13. 1 kinds use the compound described in claim 1 to prepare for protecting, process, treat or alleviate patient disease, disease The purposes of the medicine of disease or condition of illness, described disease, disease or condition of illness is cancer, tumor metastasis, viral disorders, bacterial infection disease Condition of illness that disease, angiogenic disorder, autoimmune disease, inflammatory conditions are associated with organ transplantation, cardiovascular disease Or neurodegenerative disease.
14. 1 kinds use the pharmaceutical composition described in claim 10 to prepare for protecting, process, treat or alleviate patient's disease The purposes of the medicine of disease, disease or condition of illness, described disease, disease or condition of illness is cancer, tumor metastasis, viral disorders, blood vessel Condition of illness, cardiovascular disease or the nerve that generative nature disease, autoimmune disease, inflammatory conditions are associated with organ transplantation Degenerative disease.
15. compounds according to claim 13 application in preparing medicine, it is characterised in that described disease, disease Disease or condition of illness are selected from cancer, tumor metastasis, viral disorders, bacterial infection disease disease.
16. compounds according to claim 15 application in preparing medicine, it is characterised in that described disease, disease Disease or condition of illness are selected from cancer, tumor metastasis.
17. compounds according to claim 16 application in preparing medicine, it is characterised in that described cancer, tumor Transfer is selected from gastric cancer, breast carcinoma, thyroid carcinoma, renal carcinoma, hepatocarcinoma, ovarian cancer, cervical cancer, pulmonary carcinoma, carcinoma of prostate, carcinoma of testis, life Grow urinary tract cancer, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, keratinization spine canceroderm, epidermoid carcinoma, large cell carcinoma, non-small cell carcinoma, minicell Cancer, adenocarcinoma of lung, osteocarcinoma, colon cancer, cancer of pancreas, adenocarcinoma, papillary carcinoma, melanoma, sarcoma, bladder cancer, cancer of biliary duct, oral cavity and pharynx Cancer, lip cancer, carcinoma of tongue, mouth cancer, carcinoma of small intestine, colon cancer, colorectal cancer, rectal cancer, brain and central nervous system's cancer, Hokdkin disease or Leukemia.
18. pharmaceutical compositions according to claim 14 application in preparing medicine, it is characterised in that described disease Disease, disease or condition of illness are selected from cancer, tumor metastasis.
19. pharmaceutical compositions according to claim 18 application in preparing medicine, it is characterised in that described cancer Disease, tumor metastasis are selected from gastric cancer, breast carcinoma, thyroid carcinoma, renal carcinoma, hepatocarcinoma, ovarian cancer, cervical cancer, pulmonary carcinoma, carcinoma of prostate, testis Cancer, genitourinary tract cancer, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, keratinization spine canceroderm, epidermoid carcinoma, large cell carcinoma, non-small cell carcinoma, little Cell carcinoma, adenocarcinoma of lung, osteocarcinoma, colon cancer, cancer of pancreas, adenocarcinoma, papillary carcinoma, melanoma, sarcoma, bladder cancer, cancer of biliary duct, oral cavity With pharyngeal cancer, lip cancer, carcinoma of tongue, mouth cancer, carcinoma of small intestine, colon cancer, colorectal cancer, rectal cancer, brain and central nervous system's cancer, He Jiejinshi Disease or leukemia.
CN201610475847.4A 2016-06-24 2016-06-24 1-aryl ureido naphthenic base-1-formamide compound and pharmaceutical composition and application thereof Pending CN106008371A (en)

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WO2018165466A1 (en) * 2017-03-10 2018-09-13 Regents Of The University Of Minnesota Indole and indazole compounds and therapeutic uses thereof
USRE50030E1 (en) 2013-12-13 2024-07-02 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma

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CN1714076A (en) * 2002-11-21 2005-12-28 神经研究公司 Novel aryl ureido benzoic acid derivatives and their use

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CN1714076A (en) * 2002-11-21 2005-12-28 神经研究公司 Novel aryl ureido benzoic acid derivatives and their use
WO2005030140A2 (en) * 2003-09-26 2005-04-07 Exelixis, Inc. C-met modulators and methods of use

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USRE50030E1 (en) 2013-12-13 2024-07-02 Dana-Farber Cancer Institute, Inc. Methods to treat lymphoplasmacytic lymphoma
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