Substituted naphthyridines-2-ketonic compound, preparation method, purposes and pharmaceutical composition
Technical field
The invention belongs to medicinal chemistry art, in particular to a kind of substituted naphthyridines-2-ketonic compound, preparation side
Method, purposes and pharmaceutical composition.
Background technology
The research and development of antineoplastic are to be rich in challenge and far reaching field in current life science.In recent years
Come, along with molecular biology develop rapidly and cancer is occurred by people, development, the further understanding of mechanism of action, pernicious
Signal transduction, the regulation and control of cell cycle, apoptotic induction, Angiogenesis and cell in tumour cell and extracellular matrix
The various basic processes such as interaction progressively illustrated.Therefore find and find that selectively acting is in the height of specific target spot
Effect, low toxicity, the new type antineoplastic medicine of high specificity have become one of key areas of current medical research and development, thus produce
One new cancer therapy drug field-molecular targeted agents.
Molecular targeted agents refers to enzyme crucial in the acceptor for cell carcinogenesis or transductive process, from molecular level
The Therapeutic mode of suppression tumor growth.It, subtracts with the characteristic molecular of tumour cell as target spot while playing antitumor action
Lack Normocellular toxic and side effect.
Phosphoinositide 3-kinase (PI3-K) catalysis phosphatidylinositols (PI) second messenger PI(3) P, PI(3,4) P2 and PI
The synthesis of (3,4,5) P3 (PIP3).Under suitable cellular environment, these three lipid control multiple include cell growth, survival,
Differentiation and chemotactic physiological processes.Main PI3-kinases in cancer with merit iso series be by catalytic subunit (p110 α) and
The I class PI3-K α that regulation subunit (p85) forms.The several components of PI3-K/Akt/PTEN path relates to tumour and is formed, and is including
The regulation and control of many cell processes of Cycle Regulation, hyperplasia, survival, Apoptosis and motion play a significant role, and is
The such as important component of the molecular mechanism of the disease such as cancer, diabetes and immune inflammation.
Therefore, PI3-K α is the target of the attractive and prospect of exploitation cancer drug, and this type of medicine will suppress cancer thin
Born of the same parents' hyperplasia, and avoid cellulotoxic preparation's damage to body, and the tolerance that cancer cell is to cellulotoxic preparation.But it is existing
It is relatively big to there is toxic and side effect in PI3-K alpha inhibitor, and the defect that in clinical testing, result for the treatment of is the highest needs exploitation badly new the most at present
PI3-K alpha inhibitor, be applied to field of cancer treatment as cancer treatment drugs.
Summary of the invention
For solve above-mentioned problems of the prior art, the invention provides a kind of substituted naphthyridines-2-ketonic compound,
Preparation method, purposes and pharmaceutical composition.
Specifically, the present invention provides:
(1) compound shown in a kind of Formulas I or its pharmaceutically acceptable salt:
Wherein,
R1Selected from C1-C10Alkyl, C3-C10Cycloalkyl or C3-C10Heterocyclylalkyl, wherein said C3-C10Cycloalkyl or C3-
C10Heterocyclylalkyl is optionally by-OR2Replaced, wherein R2Selected from hydrogen, C1-C6Alkyl or C1-C6Hydroxy alkyl;And
R3Selected from hydrogen or-NHSO2R4, wherein, R4Selected from C1-C6Alkyl, C3-C10Cycloalkyl, C5-C10Aryl or C5-C10Miscellaneous
Aryl, wherein said C1-C6Alkyl, C3-C10Cycloalkyl, C5-C10Aryl or C5-C10Heteroaryl is the most one or more
R5Replaced, described R5It is each independently selected from halogen, cyano group, C1-C6Haloalkyl, C1-C6Alkoxyl.
(2) according to the compound shown in Formulas I described in (1) or its pharmaceutically acceptable salt, wherein, R1It is as follows
Group:
Wherein, R6、R7It is each independently selected from hydrogen or C1-C4Alkyl;It is preferably selected from hydrogen or methyl.
(3) according to the compound shown in Formulas I described in (1) or its pharmaceutically acceptable salt, wherein, R1Selected from C3-C6Ring
Alkyl or C3-C6Heterocyclylalkyl, it is optionally by-OR2Replaced.
(4) according to the compound shown in Formulas I described in (1) or its pharmaceutically acceptable salt, these, it is preferred to, R1
Selected from cyclopropyl, cyclopenta, cyclohexyl or oxacyclohexyl, it is optionally by-OR2Replaced.
(5) according to the compound shown in Formulas I described in (1) or its pharmaceutically acceptable salt, wherein, R2For C1-C6Hydroxyl
Alkyl;More preferably-CH2-CH2-OH。
(6) according to the compound shown in Formulas I described in (1) or its pharmaceutically acceptable salt, wherein, R3For-NHSO2R4,
Wherein,
R4It is preferably selected from C1-C4Alkyl, C3-C5Cycloalkyl, C5-C6Aryl or C5-C6Heteroaryl, wherein said C1-C4Alkane
Base, C3-C5Cycloalkyl, C5-C6Aryl or C5-C6Heteroaryl is optionally by one or more R5Replaced, described R5The most independent
Ground is selected from halogen, cyano group, C1-C6Haloalkyl, C1-C6Alkoxyl.
(7) according to the compound shown in Formulas I described in (6) or its pharmaceutically acceptable salt, wherein, R4Selected from C1-C4Alkane
Base, C3-C5Cycloalkyl, aryl or 5 yuan of heteroaryls, wherein said C1-C4Alkyl, C3-C5Cycloalkyl, aryl or 5 yuan of heteroaryls
Optionally by one or more R5Replaced, described R5It is each independently selected from halogen, cyano group, C1-C6Haloalkyl, C1-C6
Alkoxyl;5 yuan of described heteroaryls preferably comprise a sulphur atom.
(8) according to the compound shown in Formulas I described in (6) or its pharmaceutically acceptable salt, wherein, R4Selected from aryl,
Or 5 yuan of heteroaryls, described aryl or 5 yuan of heteroaryls are optionally by 1-5 R5Replaced, be preferably by 1-2 R5Replaced;
Described R5Selected from halogen, cyano group ,-CF3Or C1-C4Alkoxyl.
(9) according to the compound shown in Formulas I described in (6) or its pharmaceutically acceptable salt, wherein, R4Selected from C1-C4Alkane
Base or C3-C5Cycloalkyl, wherein said C1-C4Alkyl, C3-C5Cycloalkyl is optionally by 1-5 R5Replaced, more preferably quilt
1-3 R5Replaced;Described R5For halogen.
(10) according to the compound shown in Formulas I described in (1) or its pharmaceutically acceptable salt, wherein, the change shown in Formulas I
Compound is selected from following compounds:
Compound 1:
Compound 2:
Compound 3:
Compound 4:
Compound 5:
Compound 6:
Compound 7:
Compound 8:
Compound 9:
Compound 10:
Compound 11:
Compound 12:
Compound 13:
Compound 14:
Compound 15:
Compound 16:
Compound 17:
Compound 18:
Compound 19:
Compound 20:
Compound 21:
And
Compound 22:
(11) according to the preparation method of the compound shown in Formulas I described in any one in (1)-(10), comprising: make formula
There is following reaction in the compound shown in A and the compound shown in formula B in the presence of palladium catalyst, thus obtains shown in Formulas I
Compound:
Wherein, R1And R3As (1) defines;X is halogen, preferably bromine;And R8ForOr
(12) according to method described in (11), wherein, described palladium catalyst be two (triphenylphosphine) palladium chlorides or [1,
1 '-bis-(diphenylphosphino) ferrocene] palladium chloride.
(13) according to the method described in (11), wherein, the compound shown in formula A is prepared via a method which to obtain:
Make the compound shown in formula L, with N-N-halosuccinimides, following halogenating reaction occur, thus obtain shown in formula A
Compound:
(14) according to the method described in (13), wherein, the compound shown in formula L is prepared via a method which to obtain:
Make the compound shown in formula K, with hydroxylamine hydrochloride, following deprotection reaction occur, thus obtain the chemical combination shown in formula L
Thing:
(15) according to the method described in (14), wherein, the compound shown in formula K is prepared via a method which to obtain:
In the presence of potassium tert-butoxide and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, make the chemical combination shown in formula J
There is following cyclization reaction in thing, thus obtains the compound shown in formula K:
(16) according to the method described in (15), wherein, the compound shown in formula J is prepared via a method which to obtain:
Make the compound shown in formula H and ethyl acrylate that following reaction to occur in the presence of palladium catalyst, thus obtain
Compound shown in formula J:
Wherein, X is halogen, preferably bromine;Described palladium catalyst is preferably tetrakis triphenylphosphine palladium, two (triphenylphosphines)
Palladium chloride or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, more preferably tetrakis triphenylphosphine palladium.
(17) according to the method described in (16), wherein, the compound shown in formula H is prepared via a method which to obtain:
The compound shown in formula F and the compound shown in formula G is made to occur in the presence of acid binding agent diisopropyl ethyl amine
Following reaction, thus obtain the compound shown in formula H:
Wherein, X is halogen, preferably bromine.
(18) according to the method described in (17), wherein, the compound shown in formula F is prepared via a method which to obtain:
Make the compound shown in formula E and iodine that following iodide reaction to occur in the presence of lithium diisopropyl amido, thus obtain
To the compound shown in formula F:
Wherein, X is halogen, preferably bromine.
(19) according to the method described in (18), wherein, the compound shown in formula E is prepared via a method which to obtain:
The compound shown in formula C and the compound shown in formula D is made to occur as follows in the presence of catalyst p-methyl benzenesulfonic acid
Reaction, thus obtain the compound shown in formula E:
Wherein, X is halogen, preferably bromine.
(20) according to the method described in (11), wherein,
Work as R8ForTime, the compound shown in formula B is prepared via a method which to obtain:
Make the compound shown in formula M and the compound shown in formula N at catalyst [1,1 '-bis-(diphenylphosphino) ferrocene]
There is following reaction in the presence of palladium chloride, thus obtain the compound shown in formula B:
(21) exist according to the compound shown in Formulas I or its pharmaceutically acceptable salt described in any one in (1)-(10)
Purposes in the medicine of the disease that preparation causes for treating and/or prevent PI3-K kinases and/or mTOR kinases.
(22) according to the purposes described in (21), wherein, described PI3-K kinases is PI3-K alpha kinase.
(23) according to the purposes described in (21), wherein, described disease is cancer or tumour.
(24) according to the purposes described in (21), wherein, described disease is selected from the cancer of the brain, spongioblastoma, head and neck cancer, lung
Cancer, melanoma, liver cancer, kidney, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin
Skin cancer, colon and rectum carcinoma, cancer of pancreas, oophoroma, breast cancer, myelodysplastic syndrome, the cancer of the esophagus, sarcoma, osteosarcoma
And one or more in rhabdomyoma.
(25) drug regimen of a kind of disease for treating and/or prevent PI3-K kinases and/or mTOR kinases to cause
Thing, described pharmaceutical composition comprises in (1)-(10) compound shown in Formulas I described in any one and/or its pharmaceutically
Acceptable salt, and pharmaceutically acceptable auxiliary material.
The present invention compared with prior art has the advantages that:
The present invention provides the naphthyridines-2-ketonic compound that a class is new, compared with existing compound, the formula of the present invention first
Compound shown in I has more excellent anticancer or function of tumor, can suppress multiple simultaneously and be present in intracellular and cell surface
Kinases, including PI3-K kinases and mTOR kinases, therefore have quite or more potent anticancer or function of tumor.
The pharmaceutical composition of the present invention can be used for treating the cancer of the brain, spongioblastoma, head and neck cancer, lung cancer, melanoma, liver
Cancer, kidney, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colon cancer, straight
Intestinal cancer, cancer of pancreas, oophoroma, breast cancer, myelodysplastic syndrome, the cancer of the esophagus, sarcoma, osteosarcoma and rhabdomyoma.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art are according to the basic thought of the present invention, and various modifications may be made or improves, but without departing from this
The basic thought of invention, the most within the scope of the present invention.
In description and claims of this specification, compound is in accordance with chemical structural formula and names, if
When representing same compound, the name of compound is not inconsistent with chemical structural formula, is as the criterion with chemical structural formula or chemical equation.
In the present invention, described " Me " is methyl.
In the present invention, the wave in substituent "" it is meant that substituent on the position of wave
Group is connected by chemical bond with the group of main chain (such as, phenyl ring).
The compound with PI3-K kinase inhibiting activity has been carried out studying in large quantities by the present inventor, unexpectedly sends out
Now by the 1-nitrogen-atoms in the compound shown in formula a is replaced to carbon atom, i.e. replace with pyrimido pyridine ring, it is possible to make institute
The compound obtained is provided simultaneously with two kinds of kinase whose inhibitory activity of PI3K and mTOR.
Wherein R is substituent, may be the same or different.On the basis of the present inventor finds at this, substituent R therein is entered
Go and screened further and optimize, to obtain the kinase whose higher inhibitory activity of PI3K and mTOR two kinds, thus further
Obtain technical scheme.
Specifically, the invention provides:
(1) compound shown in Formulas I
Present invention firstly provides the compound shown in a kind of Formulas I or its pharmaceutically acceptable salt:
Wherein,
R1Selected from C1-C10Alkyl, C3-C10Cycloalkyl or C3-C10Heterocyclylalkyl, wherein said C3-C10Cycloalkyl or C3-
C10Heterocyclylalkyl is optionally by-OR2Replaced, wherein R2Selected from hydrogen, C1-C6Alkyl or C1-C6Hydroxy alkyl;And
R3Selected from hydrogen orI.e.-NHSO2R4, wherein, R4Selected from C1-C6Alkyl, C3-C10Cycloalkyl,
C5-C10Aryl or C5-C10Heteroaryl, wherein said C1-C6Alkyl, C3-C10Cycloalkyl, C5-C10Aryl or C5-C10Heteroaryl
Optionally by one or more R5Replaced, described R5It is each independently selected from halogen, cyano group, C1-C6Haloalkyl, C1-C6
Alkoxyl.
Preferably, R1The group being as follows:
Wherein, R6、R7It is each independently selected from hydrogen or C1-C4Alkyl;It is further preferred that R6、R7It is each independently selected from
Hydrogen or methyl.
Preferably, R1Selected from C3-C6Cycloalkyl or C3-C6Heterocyclylalkyl, it is optionally by-OR2Replaced.
Preferably, R1Selected from cyclopropyl, cyclopenta, cyclohexyl or oxacyclohexyl, it is optionally by-OR2Replaced.
Preferably, R1It is selected fromOrIt is optionally by-OR2Replaced.
Preferably, R2For C1-C6Hydroxy alkyl.It is further preferred that R2For-CH2-CH2-OH。
Preferably, R3ForI.e.-NHSO2R4。
The present inventor is by analyzing the cocrystallization x-ray diffraction pattern of PI3K γ surprisingly it has been found that 2-methoxypyridine
With the compound GSK2126458(Knight of the action site of PI3K γ acceptor with GlaxoSmithKline PLC company,
S.D.et.al.Discovery of GSK2126458, a highly potent inhibitor of PI3K and the
Mammalian target of rapamycin.ACS Med.Chem.Lett.2010,1,39 43) similar, therefore at its 3-
Position introduces sulfoamido substituent can produce hydrogen bond action with the Lys833 of PI3K γ acceptor, thus strengthens the work of compound
Property.Particularly introduce 2 in its 3-position, 4-difluorobenzenesulfonamide base produces Van der Waals phase interaction with PI3K kinases hydrophobic pocket
With, it is possible to further enhance the activity of compound.
Preferably, R4It is preferably selected from C1-C4Alkyl, C3-C5Cycloalkyl, C5-C6Aryl or C5-C6Heteroaryl, wherein said
C1-C4Alkyl, C3-C5Cycloalkyl, C5-C6Aryl or C5-C6Heteroaryl is optionally by one or more R5Replaced, described
R5It is each independently selected from halogen, cyano group, C1-C6Haloalkyl, C1-C6Alkoxyl.
It is further preferred that R4Selected from C1-C4Alkyl, C3-C5Cycloalkyl, aryl or 5 yuan of heteroaryls, wherein said C1-C4
Alkyl, C3-C5Cycloalkyl, aryl or 5 yuan of heteroaryls are optionally by one or more R5Replaced, described R5Independently of one another
Selected from halogen, cyano group, C1-C6Haloalkyl, C1-C6Alkoxyl.It is further preferred that described 5 yuan of heteroaryls to contain a sulphur former
Son.
It is further preferred that R4Selected from aryl or 5 yuan of heteroaryls, described aryl or 5 yuan of heteroaryls optionally by 1-5
R5Replaced, more preferably by 1-2 R5Replaced;Described R5Selected from halogen, cyano group ,-CF3Or C1-C4Alkoxyl.
Preferably, R4Selected from C1-C4Alkyl or C3-C5Cycloalkyl, wherein said C1-C4Alkyl, C3-C5Cycloalkyl is appointed
Selection of land is by 1-5 R5Replaced, more preferably by 1-3 R5Replaced;Described R5For halogen.
Preferably, the compound shown in Formulas I is selected from following compounds:
Compound 1:
Compound 2:
Compound 3:
Compound 4:
Compound 5:
Compound 6:
Compound 7:
Compound 8:
Compound 9:
Compound 10:
Compound 11:
Compound 12:
Compound 13:
Compound 14:
Compound 15:
Compound 16:
Compound 17:
Compound 18:
Compound 19:
Compound 20:
Compound 21:
And
Compound 22:
The pharmaceutically acceptable salt of the compound shown in the Formulas I of the present invention is selected from:
A) inorganic acid and the salt of organic acid, described acid is selected from: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, fluoroform sulphur
Acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, 1-naphthalene sulfonic aicd, 2-naphthalene sulfonic acids, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, breast
Acid, oxalic acid, butanedioic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and tussol;
B) salt of organic and inorganic base, described cation is selected from: alkali metal cation, alkaline earth metal cation, ammonium sun from
Son, the substituted ammonium cation of aliphatic group, and the substituted ammonium cation of aromatic radical.
(2) preparation method of the compound shown in Formulas I:
Secondly the present invention provides the preparation method of the compound shown in a kind of Formulas I, comprising:
Make the compound shown in formula A and the compound shown in formula B that following reaction to occur in the presence of palladium catalyst, thus
Obtain the compound shown in Formulas I:
Wherein, R1And R3As defined in claim 1;X is halogen, preferably bromine;And R8ForOr
Preferably, described palladium catalyst is two (triphenylphosphine) palladium chlorides or [1,1 '-bis-(diphenylphosphino) two
Cyclopentadienyl iron] palladium chloride.
Preferably, the compound shown in formula A is prepared via a method which to obtain:
Make the compound shown in formula L, with N-N-halosuccinimides, following halogenating reaction occur, thus obtain shown in formula A
Compound:
It is further preferred that the compound shown in formula L is prepared via a method which to obtain:
Make the compound shown in formula K, with hydroxylamine hydrochloride, following deprotection reaction occur, thus obtain the chemical combination shown in formula L
Thing:
It is further preferred that the compound shown in formula K is prepared via a method which to obtain:
In the presence of potassium tert-butoxide and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, make the chemical combination shown in formula J
There is following cyclization reaction in thing, thus obtains the compound shown in formula K:
It is further preferred that the compound shown in formula J is prepared via a method which to obtain:
Make the compound shown in formula H and ethyl acrylate that following reaction to occur in the presence of palladium catalyst, thus obtain
Compound shown in formula J:
Wherein, X is halogen, preferably bromine;It is further preferred that described palladium catalyst be tetrakis triphenylphosphine palladium, two (three
Phenylphosphine) palladium chloride or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, preferably tetrakis triphenylphosphine palladium.
It is further preferred that the compound shown in formula H is prepared via a method which to obtain:
The compound shown in formula F and the compound shown in formula G is made to occur in the presence of acid binding agent diisopropyl ethyl amine
Following reaction, thus obtain the compound shown in formula H:
Wherein, X is halogen, preferably bromine.
It is further preferred that the compound shown in formula F is prepared via a method which to obtain:
Make the compound shown in formula E and iodine that following iodide reaction to occur in the presence of lithium diisopropyl amido, thus obtain
To the compound shown in formula F:
Wherein, X is halogen, preferably bromine.
It is further preferred that the compound shown in formula E is prepared via a method which to obtain:
The compound shown in formula C and the compound shown in formula D is made to occur as follows in the presence of catalyst p-methyl benzenesulfonic acid
Reaction, thus obtain the compound shown in formula E:
Wherein, X is halogen, preferably bromine.
In a preferred embodiment of the invention, the compound shown in formula A is prepared via a method which to obtain:
1) compound shown in formula C and the compound shown in formula D is made to occur such as in the presence of catalyst p-methyl benzenesulfonic acid
Lower reaction, thus obtain the compound shown in formula E:
Wherein, X is halogen, preferably bromine;
2) make the compound shown in formula E and iodine that following iodide reaction occurs in the presence of lithium diisopropyl amido, thus
Obtain the compound shown in formula F:
Wherein, X is halogen, preferably bromine;
3) compound shown in formula F and the compound shown in formula G is made to send out in the presence of acid binding agent diisopropyl ethyl amine
Raw following reaction, thus obtain the compound shown in formula H:
Wherein, X is halogen, preferably bromine;
4) make the compound shown in formula H and ethyl acrylate that following reaction occurs in the presence of palladium catalyst, thus obtain
To the compound shown in formula J:
Wherein, X is halogen, preferably bromine;It is further preferred that described palladium catalyst be tetrakis triphenylphosphine palladium, two (three
Phenylphosphine) palladium chloride or [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride, preferably tetrakis triphenylphosphine palladium;
5) at potassium tert-butoxide and 1, in the presence of 8-diazabicylo [5.4.0] 11 carbon-7-alkene, the change shown in formula J is made
There is following cyclization reaction in compound, thus obtains the compound shown in formula K:
6) make the compound shown in formula K, with hydroxylamine hydrochloride, following deprotection reaction occur, thus obtain the chemical combination shown in formula L
Thing:
;And
7) make the compound shown in formula L, with N-N-halosuccinimides, following halogenating reaction occur, thus obtain shown in formula A
Compound:
Preferably, R is worked as8ForTime, the compound shown in formula B is prepared via a method which to obtain:
Make the compound shown in formula M and the compound shown in formula N at catalyst [1,1 '-bis-(diphenylphosphino) ferrocene]
There is following reaction in the presence of palladium chloride, thus obtain the compound shown in formula B:
(3) compound shown in Formulas I or the purposes of its pharmaceutically acceptable salt
The present invention again provide the compound shown in Formulas I or its pharmaceutically acceptable salt preparation for treatment and/
Or the purposes in the medicine of disease that causes of prevention PI3-K kinases and/or mTOR kinases.
Compound shown in the Formulas I of the present invention is a kind of multi-kinase inhibitor, can suppress simultaneously multiple be present in intracellular
With the kinases of cell surface, including PI3-K kinases and mTOR kinases.It is further preferred that described PI3-K kinases is PI3-K
Alpha kinase.
Preferably, described disease is cancer or tumour.
Preferably, described disease is selected from the cancer of the brain, spongioblastoma, head and neck cancer, lung cancer, melanoma, liver cancer, kidney
Cancer, acute leukemia, chronic leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colon and rectum carcinoma,
In cancer of pancreas, oophoroma, breast cancer, myelodysplastic syndrome, the cancer of the esophagus, sarcoma, osteosarcoma and rhabdomyoma one
Plant or multiple.
(4) for treating and/or prevent the pharmaceutical composition of disease that PI3-K kinases and/or mTOR kinases cause
The present invention finally provides a kind of disease for treating and/or prevent PI3-K kinases and/or mTOR kinases to cause
Pharmaceutical composition, the compound shown in contained I and/or its pharmaceutically acceptable salt in described pharmaceutical composition, with
And pharmaceutically acceptable auxiliary material.
Preferably, the formulation of described pharmaceutical composition is injection, oral formulations, cutaneous permeable agent or suppository.
Mode below by way of example further explains and describes present invention, but these embodiments are understood not to
Limiting the scope of the invention.
In example below, if no special instructions, each reagent the most commercially, such as, is available from lark prestige science and technology limited
Company, AlfaAesar (Tianjin) Chemical Co., Ltd. or Beijing coupling Science and Technology Ltd..
In example below, the computing formula of yield is: yield=products weight × feed molar quality/(raw material weight ×
Product molar quality).
Embodiment 1:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-2,4-difluorobenzenesulfonamide (compound 1)
Preparation method:
The synthesis of the bromo-6-of step 1:3-(2,5-methyl isophthalic acid H-pyrroles's-1-base)-2-picoline
Will be equipped with 2-amino-5-bromo-6-picoline (38.2g, 204mmol), 2,5-acetyl butyryls (36mL, 306mmol),
The there-necked flask of one hydration p-methyl benzenesulfonic acid (1.94g, 10.2mmol) and 380mL toluene connects water knockout drum and condenser pipe and will react
Mixture backflow 6h.After being cooled to room temperature, with ethyl acetate (500mL) diluted reaction mixture, with water (200mL × 2) and full
Wash with saline solution (200mL × 2), be dried with anhydrous sodium sulfate, filter, concentrate.By column chromatography (silica gel, petroleum ether/acetic acid second
Ester=100:1, v/v) purification residues, obtaining product is brown oil (41.4g, yield is 76%).
1H NMR (400MHz, DMSO-d6) δ 8.17 (d, J=8.4Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 5.80 (s,
2H), 2.60 (s, 3H), 2.06 (s, 6H).
The synthesis of the bromo-6-of step 2:3-(2,5-methyl isophthalic acid H-pyrroles's-1-base)-4-iodo-2-picoline
Under argon gas atmosphere, n-BuLi (69.69mmol is configured to the hexane solution 29mL of 2.4M) is added drop-wise to-30
In the diisopropylamine (9.83mL, 69.69mmol) at DEG C solution in anhydrous tetrahydro furan (60mL), and by reactant mixture
30min is stirred at-30 DEG C.After being cooled to-78 DEG C, drip the bromo-6-of 3-(2,5-methyl isophthalic acid H-pyrroles's-1-base)-2-methyl pyrrole
The pyridine (16.8g, 63.36mmol) solution in anhydrous tetrahydro furan (120mL), and reactant mixture is stirred at-78 DEG C
30min.Dropping iodine (17.7g, 69.69mmol) solution in anhydrous tetrahydro furan (120mL), and by reactant mixture-
30min is stirred at 78 DEG C.With saturated ammonium chloride solution cancellation reactant mixture, dilute with water (400mL), be extracted with ethyl acetate
(200mL × 3).Wash, with water (200mL × 2) and saturated aqueous common salt (200mL × 2), the organic layer merged, use anhydrous sodium sulfate
It is dried, filters, concentrate.With column chromatography (silica gel, petrol ether/ethyl acetate=150:1, v/v) purification residues, obtaining product is
Yellow solid (13.09g, yield 53%).
1H NMR (400MHz, DMSO-d6) δ 7.84 (s, 1H), 5.80 (s, 2H), 2.71 (s, 3H), 2.08 (s, 6H)
The synthesis of step 3:3-bromo-N-cyclopenta-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-amine
Sealing in pipe, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles's-1-base)-4-iodo-2-picoline (9.5g,
24.3mmol), cyclopentamine (6.21g, 72.9mmol), diisopropylethylamine (9.42g, 72.9mmol) is at 1-METHYLPYRROLIDONE
(95mL) solution in stirs 24 hours at 160 DEG C.After being cooled to room temperature, with water (500mL) diluted reaction mixture, use second
Acetoacetic ester extraction (200mL × 3).Wash, with water (200mL × 2) and saturated aqueous common salt (200mL × 2), the organic layer merged, use
Anhydrous sodium sulfate is dried, and filters, and concentrates.By column chromatography (silica gel, petrol ether/ethyl acetate=80:1, then petroleum ether/acetic acid second
Ester=50:1, v/v) to obtain product be yellow solid (6.0g, yield is 56%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 6.44 (s, 1H), 5.75 (s, 2H), 5.66 (d, J=7.2Hz, 1H), 3.95-
3.91 (m, 1H), 2.47 (s, 3H), 2.06 (s, 6H), 1.99-1.95 (m, 2H), 1.68-1.55 (m, 6H)
MS(ESI+)m/z348.0[M+H]+
Step 4:(E)-3-(4-(Cyclohexylamino)-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-3-
Base) synthesis of ethyl acrylate
In sealing pipe, by bromo-for 3-N-cyclopenta-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-
Amine (7.2g, 20.67mmol) and the ethyl acrylate (6.6mL, 62.01mmol) solution in triethylamine (70mL) are with argon gas drum
Bubble 5min.Add tetrakis triphenylphosphine palladium (2.39g, 2.067mmol), again mixture with bubbling argon 5min and is sealed little
Pipe.Reaction solution is stirred overnight at 135 DEG C, cools down and concentrate.Add water (200mL), with ethyl acetate (100mL × 3)
The mixture that extraction produces.The organic layer that (100mL × 2) washing merges is washed, by nothing with water (100mL × 2) and saturated common salt
Aqueous sodium persulfate is dried, and filters, and concentrates.By column chromatography (silica gel, petrol ether/ethyl acetate=50:1, then petrol ether/ethyl acetate
=12:1, v/v) to obtain product be yellow oil (6.46g, yield 85%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 7.62 (d, J=16.4Hz, 1H), 6.40 (s, 1H), 6.29 (d, J=16.4Hz,
1H), 6.05 (d, J=6.8Hz, 1H), 5.75 (s, 2H), 4.21 (q, J=7.2Hz, 2H), 3.88-3.84 (m, 1H), 2.38 (s,
3H), 2.08 (s, 6H), 1.91-1.97 (m, 2H), 1.50-1.47 (m, 6H), 1.28 (t, J=7.2Hz, 3H).
MS(ESI+)m/z368.2[M+H]+
Step 5:1-cyclopenta-7-(2,5-dimethyl-1H-pyrroles's-1-base)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one
Synthesis
Under argon gas atmosphere, by (E)-3-(4-(clopentylamino)-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-methyl
Pyridin-3-yl) ethyl acrylate (279mg, 0.76mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene (568 μ L,
3.8mmol) stir at 150 DEG C with the potassium tert-butoxide (43mg, 0.38mmol) solution in DMF (6mL)
Overnight.After being cooled to room temperature, with water (30mL) diluted reaction mixture, it is extracted with ethyl acetate (20mL × 3).With water (20mL
× 2) and saturated aqueous common salt (20mL × 2) washing merge organic layer, be dried with anhydrous sodium sulfate, filter, concentrate.Use column chromatography
(silica gel, petrol ether/ethyl acetate=10:1, then petrol ether/ethyl acetate=8:1, v/v) purification residues obtains product for Huang
Look grease (66mg, yield is 27%).
1H NMR (400MHz, DMSO-d6) δ 8.14 (d, J=9.8Hz, 1H), 7.47 (s, 1H), 6.65 (d, J=9.7Hz,
1H), 5.83 (s, 2H), 5.48-5.28 (m, 1H), 2.74 (s, 3H), 2.19-2.04 (m, 2H), 2.11 (s, 6H), 1.90 (dd,
J=16.7,10.2Hz, 4H), 1.73-1.57 (m, 2H).
MS(ESI+)m/z322.1[M+H]+
Step 6:7-amino-1-cyclopenta-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 1-cyclopenta-7-(2,5-dimethyl-1H-pyrroles's-1-base)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (66mg,
0.21mmol) reflux overnight with the hydroxylamine hydrochloride (73mg, 1.05mmol) mixture in second alcohol and water (4mL:0.4mL).Dense
Contracting reactant mixture with column chromatography (silica gel, petrol ether/ethyl acetate=1:3, then ethyl acetate/triethylamine=100:1, v/
V) purification residues obtains product is yellow blister solid (22mg, yield is 44%).
MS(ESI+)m/z244.0[M+H]+
Step 7:7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
N-bromo-succinimide (56mg, 0.315mmol) is added to 7-amino-1-cyclopenta-5-methyl isophthalic acid, 6-naphthalene
Pyridine-2 (1H)-one (100mg, 0.315mmol) is in the solution of DMF (2mL), and by reaction solution in room
1h is stirred under temperature.Add 20mL water, the mixture produced with ethyl acetate (20mL × 5) extraction.With water (20mL × 2) and saturated
The organic layer that salt washing (20mL × 2) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, two
Chloromethanes/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (20mg, yield 76%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 8.29 (s, 1H), 6.50 (s, 2H), 6.29 (s, 1H), 5.27 (p, J=
8.8Hz, 1H), 2.19-1.93 (m, 4H), 1.92-1.75 (m, 2H), 1.73-1.56 (m, 2H).
MS(ESI+)m/z321.9[M+H]+
Step 8:N-(5-bromo-2-methoxypyridine-3-base)-2, the synthesis of 4-difluorobenzenesulfonamide
By 2, dichloromethane (5mL) solution of 4-difluoro chloride (510mg, 2.4mmol, 1.2eq) is added drop-wise to 3-ammonia
Base-5-bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol) in the solution of dichloromethane (5mL),
Reactant mixture is stirred at room temperature overnight.25mL water is added in reactant mixture, produced with dichloromethane extraction
Mixture (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, use anhydrous slufuric acid
Sodium is dried, and filters, and concentrates.Product is obtained for Huang with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residual thing
Look solid (590mg, yield is 78%).
1H NMR (400MHz, DMSO-d6) δ 10.46 (s, 1H), 8.13 (d, J=2.3Hz, 1H), 7.84-7.70 (m, 2H),
7.64-7.51 (m, 1H), 7.23 (td, J=8.5,2.0Hz, 1H), 3.61 (s, 3H).
Step 9:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxy boron ring amyl-2-yls) pyridin-3-yl)-
The synthesis of 2,4-difluorobenzenesulfonamide
By N-(5-bromo-2-methoxypyridine-3-base)-2,4-difluorobenzenesulfonamide (576mg, 1.52mmol), anhydrous vinegar
Acid potassium (300mg, 3.04mmol) and connection pinacol borate (466mg, 1.84mmol) mixture in dioxane (7mL)
Degassing, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (56mg, 0.076mmol) is added in mixture.By institute
The reactant mixture degassing obtained, stirs 3 hours under argon atmosphere at 100 DEG C.After cooling, 30mL water is added to reaction
In mixture, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL
× 2) organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.By column chromatography (silica gel, petrol ether/ethyl acetate
=5:1, v/v) purification residues obtains product yellow solid (480mg, yield is 74%).
1H NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 8.20 (d, J=1.5Hz, 1H), 7.80-7.63 (m, 2H),
7.56 (dd, J=14.3,5.5Hz, 1H), 7.20 (t, J=7.5Hz, 1H), 3.61 (s, 3H), 1.29 (s, 12H).
Step 10:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base)-2, the synthesis of 4-difluorobenzenesulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (90mg, 0.28mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-2,4-difluorobenzene sulphur
Acid amides (143mg, 0.336mmol) and potassium carbonate (166mg, 1.2mmol) are at DMF and water (3mL/0.6mL)
In mixture degassing, and two (triphenylphosphine) palladium chloride (20mg, 0.028mmol) is added in mixture.By gained
Reactant mixture deaerates, and under argon atmosphere, at 100 DEG C, lucifuge reacts 3h.After cooling, 30mL water is added to reaction mixed
In compound, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated aqueous common salt (30mL × 3)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=1:1
Then petrol ether/ethyl acetate=1:2, v/v) to obtain product be yellow solid (103mg, yield is 68%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.19 (s, 1H), 8.28 (d, J=2.4Hz, 1H), 7.94 (s, 1H), 7.92
(d, J=2.4Hz, 1H), 7.76-7.70 (m, 1H), 7.62-7.52 (m, 1H), 7.20 (td, J=8.4,2.4Hz, 1H), 6.44
(s, 2H), 6.30 (s, 1H), 5.38-5.29 (m, 1H), 3.63 (s, 3H), 2.57 (s, 3H), 2.18-2.12 (m, 2H), 2.08-
2.01 (m, 2H), 1.90-1.82 (m, 2H), 1.71-1.64 (m, 2H)
MS(ESI+)m/z541.9[M+H]+.
Embodiment 2:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-4-cvanobenzenesulfonamide (compound 2)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-4-cvanobenzenesulfonamide
Dichloromethane (5mL) solution of 4-cyanobenzenesulfonyl chloride (482mg, 2.4mmol) is added drop-wise to 3-amino-5-bromo-
Reaction, in the solution of dichloromethane (5mL), is mixed by 2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol)
Compound is stirred at room temperature 4h.Water (25mL) is added in reactant mixture, with the produced mixture of dichloromethane extraction
(30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, do with anhydrous sodium sulfate
Dry, filter, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) separating residual thing is that yellow is solid
Body (699mg, yield is 95%).
1H NMR (300MHz, DMSO-d6) δ 10.49 (s, 1H), 8.12 (d, J=2.3Hz, 1H), 8.07 (d, J=8.5Hz,
2H), 7.90 (d, J=8.5Hz, 2H), 7.76 (d, J=2.3Hz, 1H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-4-cvanobenzenesulfonamide
By N-(5-bromo-2-methoxypyridine-3-base)-4-cvanobenzenesulfonamide (368mg, 1.0mmol), acetic anhydride potassium
(196mg, 2mmol) and connection pinacol borate (bis (pinacolato) diboron) (304mg, 1.2mmol) are at dioxy six
Mixture degassing in ring (7mL), and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (37mg, 0.05mmol)
It is added in mixture.The reactant mixture of gained is deaerated, under argon atmosphere, at 100 DEG C, stirs 3h.After cooling, will
30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and
The organic layer that saturated aqueous common salt (30mL × 2) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel,
Petrol ether/ethyl acetate=6:1, v/v) to obtain product be yellow solid (360mg, yield is 87%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.22 (s, 1H), 8.24 (d, J=1.6Hz, 1H), 7.73 (d, J=1.6Hz,
1H), 7.30 (d, J=4.0Hz, 1H), 7.21 (d, J=4.0Hz, 1H), 3.71 (s, 3H), 1.30 (s, 12H).
MS(ESI+)m/z333.9[M+H]+
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-4-cvanobenzenesulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-4-cyano group benzene sulfonyl
Amine (100mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) DMF-water (5mL:
Mixture degassing in 0.20mL), and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol)
It is added in mixture.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.Cooling
After, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL ×
2) organic layer that saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silicon
Glue, dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (75mg, yield to purification residues
It is 71%).
1H NMR (400MHz, DMSO-d6) δ 10.23 (s, 1H), 8.26 (d, J=2.2Hz, 1H), 8.07 (d, J=8.6Hz,
2H), 7.94 (s, 1H), 7.92 (d, J=2.2Hz, 1H), 7.91 (d, J=8.6Hz, 2H), 6.45 (s, 2H), 6.30 (s, 1H),
5.40-5.26 (m, 1H), 3.60 (s, 3H), 2.57 (s, 3H), 2.21-2.10 (m, 2H), 2.09-1.99 (m, 2H), 1.92-
1.80 (m, 2H), 1.73-1.61 (m, 2H).
Embodiment 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-4-(trifluoromethyl) benzsulfamide (compound 3)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-4-(trifluoromethyl) benzsulfamide
Dichloromethane (5mL) solution of 4-(trifluoromethyl) benzene sulfonyl chloride (587mg, 2.4mmol) is added drop-wise to 3-amino-
5-bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will in the solution of dichloromethane (5mL)
Reactant mixture is stirred at room temperature 4h.Water (25mL) is added in reactant mixture, produced mixed with dichloromethane extraction
Compound (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, use anhydrous sodium sulfate
It is dried, filters, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow
Solid (690mg, yield is 84%).
1H NMR (400MHz, DMSO-d6) δ 10.42 (s, 1H), 8.11 (d, J=2.4Hz, 1H), 7.98 (d, J=8.8Hz,
2H), 7.94 (d, J=8.8Hz, 2H), 7.76 (d, J=2.4Hz, 1H), 3.54 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-4-(trifluoromethyl) benzsulfamide
By N-(5-bromo-2-methoxypyridine-3-base)-4-(trifluoromethyl) benzsulfamide (411mg, 1.0mmol), anhydrous
Potassium acetate (196mg, 2mmol) and connection pinacol borate (304mg, 1.2mmol) mixture in dioxane (7mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (37mg, 0.05mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=7:
1, v/v) purification residues obtains product yellow solid (390mg, yield is 85%).
1H NMR (400MHz, DMSO-d6) δ 10.14 (s, 1H), 8.20 (d, J=1.6Hz, 1H), 7.96 (d, J=8.4Hz,
2H), 7.87 (d, J=8.4Hz, 2H), 7.69 (d, J=1.6Hz, 1H), 3.54 (s, 3H), 1.29 (s, 12H)
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-4-(trifluoromethyl) benzsulfamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-4-(trifluoromethyl)
Benzsulfamide (110mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) are at DMF-water
(5mL:0.20mL) in mixture degassing, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg,
0.02mmol) it is added in mixture.The reactant mixture of gained is deaerated, under argon atmosphere, at 100 DEG C, stirs 5 little
Time.After cooling, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).Use water
The organic layer that (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.Use post
It is yellow solid that chromatogram (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=60:1, v/v) purification residues obtains product
(91mg, yield is 78%).
1H NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 8.26 (d, J=2.2Hz, 1H), 8.03-7.90 (m, 6H),
6.45 (s, 2H), 6.30 (s, 1H), 5.41-5.27 (m, 1H), 3.57 (s, 3H), 2.57 (s, 3H), 2.23-2.10 (m, 2H),
2.10-1.95 (m, 2H), 1.94-1.78 (m, 2H), 1.74-1.58 (m, 2H).
Embodiment 4:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-2-(trifluoromethyl) benzsulfamide (compound 4)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-2-(trifluoromethyl) benzsulfamide
Dichloromethane (5mL) solution of 2-(trifluoromethyl) benzene sulfonyl chloride (587mg, 2.4mmol) is added drop-wise to 3-amino-
5-bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will in the solution of dichloromethane (5mL)
Reactant mixture is stirred at room temperature 4h.Water (25mL) is added in reactant mixture, produced mixed with dichloromethane extraction
Compound (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, use anhydrous sodium sulfate
It is dried, filters, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow
Solid (660mg, yield is 80%).
1H NMR (400MHz, CD3OD) δ 8.07-7.89 (m, 3H), 7.88-7.62 (m, 3H), 3.69 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-2-(trifluoromethyl) benzsulfamide
By N-(5-bromo-2-methoxypyridine-3-base)-4-(trifluoromethyl) benzsulfamide (411mg, 1.0mmol), anhydrous
Potassium acetate (196mg, 2mmol) and connection pinacol borate (304mg, 1.2mmol) mixture in dioxane (7mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (37mg, 0.05mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=7:
1, v/v) purification residues obtains product yellow solid (349mg, yield is 76%).
1H NMR (400MHz, DMSO-d6) δ 9.96 (s, 1H), 8.19 (d, J=1.6Hz, 1H), 8.06-7.96 (m, 1H),
7.96-7.90 (m, 1H), 7.88-7.77 (m, 2H), 7.72 (d, J=1.6Hz, 1H), 3.56 (s, 3H), 1.28 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-2-(trifluoromethyl) benzsulfamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-4-(trifluoromethyl)
Benzsulfamide (110mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) are at DMF and water
(5mL/0.20mL) in mixture degassing, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg,
0.02mmol) it is added in mixture.The reactant mixture of gained is deaerated, under argon atmosphere, at 100 DEG C, stirs 5 little
Time.After cooling, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).Use water
The organic layer that (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.Use post
It is yellow solid that chromatogram (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) purification residues obtains product
(76mg, yield is 67%).
1H NMR (400MHz, DMSO-d6) δ 10.00 (s, 1H), 8.26 (d, J=2.2Hz, 1H), 8.05-7.98 (m, 2H),
7.92 (d, J=2.2Hz, 1H), 7.91 (s, 1H), 7.87-7.78 (m, 2H), 6.44 (s, 2H), 6.30 (s, 1H), 5.44-5.22
(m, 1H), 3.59 (s, 3H), 2.56 (s, 3H), 2.22-2.09 (m, 2H), 2.09-1.96 (m, 2H), 1.92-1.78 (m, 2H),
(1.74-1.59 m, 2H).
Embodiment 5:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-2-(trifluoromethyl) benzsulfamide (compound 5)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-3-(trifluoromethyl) benzsulfamide
Dichloromethane (5mL) solution of 3-(trifluoromethyl) benzene sulfonyl chloride (588mg, 2.4mmol) is added drop-wise to 3-amino-
5-bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will in the solution of dichloromethane (5mL)
Reactant mixture is stirred at room temperature overnight.25mL water is added in reactant mixture, produced mixed with dichloromethane extraction
Compound (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, use anhydrous sodium sulfate
It is dried, filters, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) purification residues is yellow
Solid (320mg, yield is 39%).
1H NMR (400MHz, DMSO-d6) δ 10.43 (s, 1H), 8.12 (d, J=2.3Hz, 1H), 8.09-8.05 (m, 2H),
8.00 (d, J=8.0Hz, 1H), 7.82 (t, J=8.0Hz, 1H), 7.77 (d, J=2.3Hz, 1H), 3.54 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-3-(trifluoromethyl) benzsulfamide
By N-(5-bromo-2-methoxypyridine-3-base)-3-(trifluoromethyl) benzsulfamide (270mg, 0.66mmol), nothing
Water acetic acid potassium (130mg, 1.32mmol) and connection pinacol borate (167mg, 0.79mmol) mixing in dioxane (6mL)
Compound deaerates, and is added in mixture by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (25mg, 0.033mmol).
The reactant mixture of gained is deaerated, under argon atmosphere, at 100 DEG C, stirs 3h.After cooling, 30mL water is added to instead
Answer in mixture, be extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt
The organic layer that (30mL × 2) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.By column chromatography (silica gel, petroleum ether/second
Acetoacetic ester=3:1, v/v) purification residues obtains product yellow solid (220mg, yield is 73%).
1H NMR (400MHz, DMSO-d6) δ 10.20 (s, 1H), 8.18 (d, J=1.7Hz, 1H), 8.05 (d, J=7.9Hz,
1H), 8.00 (s, 1H), 7.95 (d, J=7.9Hz, 1H), 7.81 (t, J=7.9Hz, 1H), 7.71 (d, J=1.7Hz, 1H), 3.57
(s, 3H), 1.29 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-3-(trifluoromethyl) benzsulfamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-3-(trifluoromethyl)
Benzsulfamide (110mg, 0.24mmol) and potassium carbonate (83mg, 0.60mmol) DMF and water (4mL:
Mixture degassing in 0.20mL), and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol)
It is added in mixture.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.Cooling
After, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL ×
2) organic layer that saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silicon
Glue, dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (101mg, yield to purification residues
It is 88%).
1H NMR (400MHz, DMSO-d6) δ 10.19 (s, 1H), 8.25 (d, J=2.1Hz, 1H), 8.11 (s, 1H), 8.08-
7.97 (m, 3H), 7.95 (s, 1H), 7.81 (t, J=7.8Hz, 1H), 6.45 (s, 2H), 6.30 (s, 1H), 5.44-5.28 (m,
1H), 3.58 (s, 3H), 2.57 (s, 3H), 2.22-2.10 (m, 2H), 2.10-1.99 (m, 2H), 1.94-1.79 (m, 2H),
(1.75-1.58 m, 2H).
Embodiment 6:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide (compound 6)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide
Dichloromethane (5mL) solution of 4-fluorophenylsulfonyl chloride (467mg, 2.4mmol, 1.2eq) is added drop-wise to 3-amino-5-
Bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will be anti-in the solution of dichloromethane (5mL)
Mixture is answered to be stirred at room temperature overnight.25mL water is added in reactant mixture, with the produced mixing of dichloromethane extraction
Thing (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, do with anhydrous sodium sulfate
Dry, filter, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residual thing is that yellow is solid
Body (590mg, yield is 82%).
1H NMR (400MHz, DMSO-d6) δ 10.21 (s, 1H), 8.08 (d, J=2.3Hz, 1H), 7.82 (dd, J=8.9,
5.2Hz, 2H), 7.72 (d, J=2.3Hz, 1H), 7.43 (t, J=8.9Hz, 2H), 3.63 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-4-fluorobenzenesulfonamide
By N-(5-bromo-2-methoxypyridine-3-base)-4-fluorobenzenesulfonamide (550mg, 1.52mmol), acetic anhydride potassium
(300mg, 3.04mmol) and connection pinacol borate (466mg, 1.84mmol) mixture in dioxane (7mL) take off
Gas, and [1,1'-double (diphenylphosphino) ferrocene] palladium chloride (56mg, 0.076mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=5:
1, v/v) purification residues obtains product is yellow solid (374mg, yield is 60%).
1H NMR (400MHz, DMSO-d6) δ 9.92 (s, 1H), 8.17 (d, J=1.6Hz, 1H), 7.82 (dd, J=8.9,
5.2Hz, 2H), 7.71 (d, J=1.6Hz, 1H), 7.40 (t, J=8.9Hz, 2H), 3.61 (s, 3H), 1.29 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-4-fluorobenzenesulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-4-fluorobenzenesulfonamide
(103mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) DMF-water (4mL:
Mixture degassing in 0.20mL), and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol)
It is added in mixture.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.Cooling
After, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL ×
2) organic layer that saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silicon
Glue, dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (56mg, yield to purification residues
It is 53%).
1H NMR (400MHz, DMSO-d6) δ 9.93 (s, 1H), 8.23 (d, J=2.2Hz, 1H), 7.92 (d, J=2.2Hz,
1H), 7.91 (s, 1H), 7.82 (dd, J=8.9,5.2Hz, 2H), 7.41 (t, J=8.8Hz, 2H), 6.44 (s, 2H), 6.30 (s,
1H), 5.41-5.23 (m, 1H), 3.65 (s, 3H), 2.57 (s, 3H), 2.22-2.09 (m, 2H), 2.08-2.00 (m, 2H),
1.92-1.81 (m, 2H), 1.71-1.61 (m, 2H).
Embodiment 7:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-2-fluorobenzenesulfonamide (compound 7)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-2-fluorobenzenesulfonamide
Dichloromethane (5mL) solution of 2-fluorophenylsulfonyl chloride (467mg, 2.4mmol) is added drop-wise to the 3-bromo-2-of amino-5-
Reaction, in the solution of dichloromethane (5mL), is mixed by methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol)
Thing is stirred at room temperature overnight.25mL water is added in reactant mixture, with the produced mixture (30mL of dichloromethane extraction
× 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, mistake
Filter, concentrates.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow solid
(588mg, yield is 82%).
1H NMR (400MHz, DMSO-d6) δ 10.40 (s, 1H), 8.11 (d, J=2.3Hz, 1H), 7.76-7.66 (m, 3H),
7.49-7.42 (m, 1H), 7.34 (td, J=7.8,1.0Hz, 1H), 3.59 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-2-fluorobenzenesulfonamide
By N-(5-bromo-2-methoxypyridine-3-base)-2-fluorobenzenesulfonamide (580mg, 1.60mmol), acetic anhydride potassium
(315mg, 3.20mmol) and connection pinacol borate (490mg, 1.92mmol) mixture in dioxane (7mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (59mg, 0.08mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=6:
1, v/v) purification residues obtains product yellow solid (350mg, yield is 54%).
1H NMR (400MHz, DMSO-d6) δ 10.12 (s, 1H), 8.18 (d, J=1.7Hz, 1H), 7.72 (d, J=1.7Hz,
1H), 7.71-7.60 (m, 2H), 7.49-7.40 (m, 1H), 7.34-7.25 (m, 1H), 3.59 (s, 3H), 1.29 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-2-fluorobenzenesulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.30mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-2-fluorobenzenesulfonamide
(148mg, 0.36mmol) and potassium carbonate (125mg, 0.90mmol) are in DMF and water (5mL:0.30mL)
Mixture degassing, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (22mg, 0.03mmol) is added to mixture
In.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.After cooling, by 30mL water
It is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated common salt
The organic layer that water (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, dichloromethane
Alkane/10% ammoniacal liquor methanol solution=50:1, v/v) to obtain product be yellow solid (120mg, yield is 76%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.12 (s, 1H), 8.25 (d, J=2.0Hz, 1H), 7.93 (d, J=2.0Hz,
1H), 7.92 (s, 1H), 7.73-7.64 (m, 2H), 7.51-7.40 (m, 1H), 7.30 (t, J=7.6Hz, 1H), 6.44 (s, 2H),
6.30 (s, 1H), 5.41-5.26 (m, 1H), 3.59 (s, 3H), 2.57 (s, 3H), 2.24-2.10 (m, 2H), 2.10-2.00 (m,
2H), 1.95-1.77 (m, 2H), 1.75-1.59 (m, 2H).
MS(ESI+)m/z524.0[M+H]+
Embodiment 8:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-3-fluorobenzenesulfonamide (compound 8)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-3-fluorobenzenesulfonamide
Dichloromethane (5mL) solution of 3-fluorophenylsulfonyl chloride (467mg, 2.4mmol) is added drop-wise to the 3-bromo-2-of amino-5-
Reaction, in the solution of dichloromethane (5mL), is mixed by methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol)
Thing is stirred at room temperature overnight.25mL water is added in reactant mixture, with the produced mixture (30mL of dichloromethane extraction
× 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, mistake
Filter, concentrates.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residual thing is yellow solid
(560mg, yield is 74%).
1H NMR (400MHz, DMSO-d6) δ 10.33 (s, 1H), 8.10 (d, J=2.2Hz, 1H), 7.72 (d, J=2.3Hz,
1H), 7.69-7.50 (m, 4H), 3.63 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-3-fluorobenzenesulfonamide
By N-(5-bromo-2-methoxypyridine-3-base)-3-fluorobenzenesulfonamide (550mg, 1.52mmol), acetic anhydride potassium
(300mg, 3.04mmol) and connection pinacol borate (466mg, 1.84mmol) mixture in dioxane (7mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (59mg, 0.08mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=5:
1, v/v) purification residues obtains product is yellow solid (400mg, yield is 65%).
1H NMR (400MHz, DMSO-d6) δ 10.06 (s, 1H), 8.18 (d, J=1.6Hz, 1H), 7.72 (d, J=1.6Hz,
1H), 7.67-7.57 (m, 1H), 7.56-7.47 (m, 3H), 3.62 (s, 3H), 1.29 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-3-fluorobenzenesulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (81mg, 0.25mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-3-fluorobenzenesulfonamide
(123mg, 0.30mmol) and potassium carbonate (103mg, 0.75mmol) are in DMF and water (4mL:0.25mL)
Mixture degassing, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (20mg, 0.025mmol) is added to mix
In thing.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.After cooling, by 30mL
Water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated food
The organic layer that salt solution (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, dichloromethane
Alkane/10% ammoniacal liquor methanol solution=50:1, v/v) to obtain product be yellow solid (104mg, yield is 80%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.06 (s, 1H), 8.22 (d, J=2.0Hz, 1H), 7.94 (d, J=2.0Hz,
1H), 7.92 (s, 1H), 7.65-7.48 (m, 5H), 6.44 (s, 2H), 6.30 (s, 1H), 5.41-5.24 (m, 1H), 3.65 (s,
3H), 2.56 (s, 3H), 2.24-2.10 (m, 2H), 2.10-1.96 (m, 2H), 1.94-1.78 (m, 2H), 1.74-1.58 (m,
2H).
Embodiment 9:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-5-chlorothiophene-2-sulfonamide (compound 9)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-5-chlorothiophene-2-sulfonamide
Dichloromethane (5mL) solution of 5-chloro-thiophene-2-sulfonic acid chloride (521mg, 2.4mmol) is added drop-wise to 3-amino-5-
Bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will be anti-in the solution of dichloromethane (5mL)
Mixture is answered to be stirred at room temperature 4h.Water (25mL) is added in reactant mixture, with the produced mixing of dichloromethane extraction
Thing (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, do with anhydrous sodium sulfate
Dry, filter, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) separating residual thing is that yellow is solid
Body (755mg, yield is 98%).
1H NMR (300MHz, CD3OD) δ 8.01 (d, J=2.1Hz, 1H), 7.88 (d, J=2.1Hz, 1H), 7.33 (d, J=
3.9Hz, 1H), 7.02 (d, J=3.9Hz, 1H), 3.79 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-5-chlorothiophene-2-sulfonamide
By N-(5-bromo-2-methoxypyridine-3-base)-5-chlorothiophene-2-sulfonamide (595mg, 1.55mmol), anhydrous vinegar
Acid potassium (306mg, 3.1mmol) and connection pinacol borate (472mg, 1.86mmol) mixture in dioxane (10mL)
Degassing, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (60mg, 0.08mmol) is added in mixture.By institute
The reactant mixture degassing obtained, stirs 3h under argon atmosphere at 100 DEG C.After cooling, 30mL water is added to reaction mixed
In compound, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL ×
2) organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=
8:1, v/v) to obtain product be yellow solid (458mg, yield is 69%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.22 (s, 1H), 8.24 (d, J=1.7Hz, 1H), 7.73 (d, J=1.7Hz,
1H), 7.30 (d, J=4.1Hz, 1H), 7.21 (d, J=4.1Hz, 1H), 3.71 (s, 3H), 1.30 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-5-chlorothiophene-2-sulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-5-chlorothiophene-2-sulphur
Acid amides (104mg, 0.24mmol) and potassium carbonate (83mg, 0.60mmol) are at DMF and water (4mL:0.20mL)
In mixture degassing, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) is added to mix
In thing.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.After cooling, by 30mL
Water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated food
The organic layer that salt solution (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, dichloromethane
Alkane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (64mg, yield is 59%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.23 (s, 1H), 8.30 (d, J=2.1Hz, 1H), 7.97 (d, J=2.1Hz,
1H), 7.96 (s, 1H), 7.39 (d, J=4.1Hz, 1H), 7.22 (d, J=4.1Hz, 1H), 6.44 (s, 2H), 6.31 (s, 1H),
5.44-5.24 (m, 1H), 3.74 (s, 3H), 2.58 (s, 3H), 2.21-2.11 (m, 2H), 2.11-1.99 (m, 2H), 1.92-
1.80 (m, 2H), 1.72-1.60 (m, 2H).
Embodiment 10:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base) NSC-249992 (compound 10)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base) NSC-249992
Dichloromethane (5mL) solution of methane sulfonyl chloride (275mg, 2.4mmol, 1.2eq) is added drop-wise to 3-amino-5-
Bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will be anti-in the solution of dichloromethane (5mL)
Mixture is answered to be stirred at room temperature overnight.25mL water is added in reactant mixture, with the produced mixing of dichloromethane extraction
Thing (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, do with anhydrous sodium sulfate
Dry, filter, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=4:1, v/v) separating residual thing is that yellow is solid
Body (498mg, yield is 89%).
1H NMR (400MHz, DMSO-d6) δ 9.49 (s, 1H), 8.09 (d, J=2.3Hz, 1H), 7.78 (d, J=2.3Hz,
1H), 3.91 (s, 3H), 3.10 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of NSC-249992
By N-(5-bromo-2-methoxypyridine-3-base) NSC-249992 (490mg, 1.74mmol), acetic anhydride potassium
(315mg, 3.20mmol) and connection pinacol borate (531mg, 2.09mmol) mixture in dioxane (10mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (64mg, 0.087mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=2:
1, v/v) purification residues obtains product is yellow solid (410mg, yield is 72%).
1H NMR (400MHz, DMSO-d6) δ 9.25 (s, 1H), 8.21 (d, J=1.7Hz, 1H), 7.77 (d, J=1.7Hz,
1H), 3.94 (s, 3H), 3.01 (s, 3H), 1.30 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of NSC-249992
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (97mg, 0.30mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl) NSC-249992
(119mg, 0.36mmol) and potassium carbonate (125mg, 0.90mmol) are in DMF and water (5mL:0.30mL)
Mixture degassing, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (22mg, 0.03mmol) is added to mixture
In.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.After cooling, by 30mL water
It is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated common salt
The organic layer that water (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, dichloromethane
Alkane/10% ammoniacal liquor methanol solution=100:1 then dichloromethane/10% ammoniacal liquor methanol solution=80:1, v/v) purification residues obtains
Product is yellow solid (84mg, yield is 64%).
1H NMR (400MHz, DMSO-d6) δ 9.26 (s, 1H), 8.26 (d, J=2.2Hz, 1H), 7.96 (s, 1H), 7.95
(d, J=2.1Hz, 1H), 6.44 (s, 2H), 6.29 (s, 1H), 5.47-5.29 (m, 1H), 3.95 (s, 3H), 3.04 (s, 3H),
2.57 (s, 3H), 2.23-2.11 (m, 2H), 2.11-1.97 (m, 2H), 1.93-1.77 (m, 2H), 1.74-1.56 (m, 2H).
Embodiment 11:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base) cyclopropanesulfonamide (compound 11)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base) cyclopropanesulfonamide
Dichloromethane (5mL) solution of cyclopropanesulfonyl chloride (338mg, 2.4mmol) is added drop-wise to the 3-bromo-2-of amino-5-
Reaction, in the solution of dichloromethane (5mL), is mixed by methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol)
Thing is stirred at room temperature overnight.25mL water is added in reactant mixture, with the produced mixture (30mL of dichloromethane extraction
× 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, mistake
Filter, concentrates.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=4:1, v/v) purification residues is yellow solid
(493mg, yield is 81%).
1H NMR (400MHz, DMSO-d6) δ 9.54 (s, 1H), 8.10 (d, J=2.3Hz, 1H), 7.79 (d, J=2.3Hz,
1H), 3.91 (s, 3H), 2.78 (s, 1H), 0.99-0.87 (m, 4H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of cyclopropanesulfonamide
By N-(5-bromo-2-methoxypyridine-3-base) cyclopropanesulfonamide (485mg, 1.58mmol), acetic anhydride potassium
(311mg, 3.16mmol) and connection pinacol borate (482mg, 1.90mmol) mixture in dioxane (8mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (60mg, 0.079mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=3:
1, v/v) purification residues obtains product yellow solid (510mg, yield is 91%).
1H NMR (400MHz, DMSO-d6) δ 9.28 (s, 1H), 8.21 (d, J=1.7Hz, 1H), 7.79 (d, J=1.7Hz,
1H), 3.94 (s, 3H), 2.70-2.58 (m, 1H), 1.30 (s, 12H), 0.98-0.79 (m, 4H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of cyclopropanesulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (60mg, 0.186mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl) cyclopropanesulfonamide
(80mg, 0.223mmol) and potassium carbonate (77mg, 0.558mmol) are at DMF and water (2.0mL:0.186mL)
In mixture degassing, and be added to mix by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (15mg, 0.0186mmol)
In compound.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.After cooling, will
30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).Satisfy with water (30mL × 2)
The organic layer merged with saline solution (30mL × 3) washing, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, two
Chloromethanes/10% ammoniacal liquor methanol solution=50:1, v/v) to obtain product be yellow solid (40mg, yield is 46%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 9.27 (s, 1H), 8.26 (d, J=2.2Hz, 1H), 7.99 (d, J=2.1Hz,
1H), 7.96 (s, 1H), 6.45 (s, 2H), 6.29 (s, 1H), 5.44-5.33 (m, 1H), 3.95 (s, 3H), 2.71-2.64 (m,
1H), 2.57 (s, 3H), 2.22-2.11 (m, 2H), 2.11-2.00 (m, 2H), 1.91-1,80 (m, 2H), 1.71-1,60 (m,
2H), 0.97-0.88 (m, 4H).
MS(ESI+)m/z470.1[M+H]+.
Embodiment 12:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-3-chloropropane-1-sulfonamide (compound 12)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-3-chloropropane-1-sulfonamide
Dichloromethane (5mL) solution of 3-chloropropane-1-sulfonic acid chloride (425mg, 2.4mmol) is added drop-wise to 3-amino-5-
Bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will be anti-in the solution of dichloromethane (5mL)
Mixture is answered to be stirred at room temperature overnight.25mL water is added in reactant mixture, with the produced mixing of dichloromethane extraction
Thing (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, do with anhydrous sodium sulfate
Dry, filter, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, v/v) separating residual thing is that yellow is solid
Body (402mg, yield is 58%).
1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.12(d,J=2.2Hz,1H),7.78(d,J=2.2Hz,
1H),3.91(s,3H),3.75(t,J=6.5Hz,2H),3.29(t,J=7.6Hz,2H),2.23-2.10(m,2H).
The chloro-N-of step 2:3-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base)
Pyridin-3-yl) synthesis of propane-1-sulfonamide
By N-(5-bromo-2-methoxypyridine-3-base)-3-chloropropane-1-sulfonamide (400mg, 1.16mmol), anhydrous vinegar
Acid potassium (228mg, 2.32mmol) and connection pinacol borate (325mg, 1.28mmol) mixture in dioxane (5mL)
Degassing, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (42mg, 0.058mmol) is added in mixture.By institute
The reactant mixture degassing obtained, stirs 3h under argon atmosphere at 100 DEG C.After cooling, 30mL water is added to reaction mixed
In compound, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL ×
2) organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=
5:1, v/v) to obtain product be yellow solid (308mg, yield is 68%) to purification residues.
1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.22(d,J=1.6Hz,1H),7.78(d,J=1.6Hz,
1H),3.94(s,3H),3.74(t,J=6.5Hz,2H),3.26-3.13(m,2H),2.24-2.10(m,2H),1.30(s,
12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-3-chloropropane-1-sulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), 3-is chloro-
N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-base) pyridin-3-yl) propane-1-sulphur
Acid amides (94mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) DMF and water (4mL:
Mixture degassing in 0.20mL), and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol)
It is added in mixture.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.Cooling
After, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL ×
2) organic layer that saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silicon
Glue, dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (50mg, yield to purification residues
It is 50%).
1H NMR (400MHz, DMSO-d6) δ 8.37 (d, J=2.2Hz, 1H), 8.04 (d, J=2.2Hz, 1H), 7.98 (s,
1H), 6.44 (s, 2H), 6.30 (s, 1H), 5.42-5.29 (m, 1H), 3.94 (s, 3H), 3.74 (t, J=6.4Hz, 2H), 3.37
(t, J=7.4Hz, 2H), 2.58 (s, 3H), 2.48-2.39 (m, 2H), 2.24-2.11 (m, 2H), 2.08-2.00 (m, 2H),
1.90-1.80 (m, 2H), 1.72-1.61 (m, 2H).
Embodiment 13:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base) butane-1-sulfonamide (compound 13)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base) butane-1-sulfonamide
Dichloromethane (5mL) solution of butane-1-sulfonic acid chloride (376mg, 2.4mmol, 1.2eq) is added drop-wise to 3-amino-
5-bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will in the solution of dichloromethane (5mL)
Reactant mixture is stirred at room temperature overnight.25mL water is added in reactant mixture, produced mixed with dichloromethane extraction
Compound (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, use anhydrous sodium sulfate
It is dried, filters, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/v) purification residues is yellow
Solid (469mg, yield is 73%).
1H NMR (400MHz, DMSO-d6) δ 9.50 (s, 1H), 8.09 (d, J=2.3Hz, 1H), 7.77 (d, J=2.3Hz,
1H), 3.90 (s, 3H), 3.15 (t, J=7.6Hz, 2H), 1.74-1.61 (m, 2H), 1.43-1.32 (m, 2H), 0.87 (t, J=
7.4Hz, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of butane-1-sulfonamide
By N-(5-bromo-2-methoxypyridine-3-base) butane-1-sulfonamide (400mg, 1.24mmol), acetic anhydride potassium
(244mg, 2.48mmol) and connection pinacol borate (347mg, 1.36mmol) mixture in dioxane (6mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (46mg, 0.062mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 3h.After cooling, 30mL water is added to reaction mixing
In thing, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL × 2)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=7:
1, v/v) purification residues obtains product yellow solid (401mg, yield is 87%).
1H NMR (400MHz, DMSO-d6) δ 9.27 (s, 1H), 8.20 (d, J=1.7Hz, 1H), 7.78 (d, J=1.6Hz,
1H), 3.93 (s, 3H), 3.05 (t, J=7.4Hz, 2H), 1.75-1.62 (m, 2H), 1.43-1.32 (m, 2H), 1.30 (s,
12H), 0.86 (t, J=7.4Hz, 3H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of butane-1-sulfonamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl) butane-1-sulfonamide
(89mg, 0.24mmol) and potassium carbonate (83mg, 0.60mmol) are in DMF and water (4mL:0.20mL)
Mixture deaerates, and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride PdCl2(dppf) (16mg, 0.02mmol)
It is added in mixture.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.Cooling
After, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL ×
2) organic layer that saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silicon
Glue, dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (67mg, yield to purification residues
It is 69%).
1H NMR (400MHz, DMSO-d6) δ 9.27 (s, 1H), 8.26 (d, J=2.2Hz, 1H), 7.96 (d, J=2.2Hz,
1H), 7.95 (s, 1H), 6.44 (s, 2H), 6.30 (s, 1H), 5.43-5.29 (m, 1H), 3.94 (s, 3H), 3.16-3.02 (t, J
=7.6Hz, 2H), 2.57 (s, 3H), 2.26-2.10 (m, 2H), 2.10-1.97 (m, 2H), 1.93-1.78 (m, 2H), 1.80-
1.58 (m, 4H), 1.47-1.32 (m, 2H), 0.88 (t, J=7.6Hz, 3H).
Embodiment 14:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base) benzsulfamide (compound 14)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base) benzsulfamide
Dichloromethane (5mL) solution of benzene sulfonyl chloride (424mg, 2.4mmol) is added drop-wise to 3-amino-5-bromo-2-methoxy
Reactant mixture, in the solution of dichloromethane (5mL), is existed by yl pyridines (0.406g, 2mmol) and pyridine (237mg, 3mmol)
4hr is stirred under room temperature.Water (25mL) is added in reactant mixture, with the dichloromethane produced mixture of extraction (30mL ×
3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, filter,
Concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=10:1, v/v) purification residues is yellow solid
(580mg, yield is 85%).
1H NMR (300MHz, DMSO-d6) δ 10.16 (s, 1H), 8.05 (d, J=2.2Hz, 1H), 7.81-7.38 (m, 6H),
3.62 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of benzsulfamide
By N-(5-bromo-2-methoxypyridine-3-base) benzsulfamide (580mg, 1.69mmol), acetic anhydride potassium
(332mg, 3.38mmol) and connection pinacol borate (515mg, 2.03mmol) mixture in dioxane (10mL) take off
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (62mg, 0.0845mmol) is added in mixture.By institute
The reactant mixture degassing obtained, stirs 3h under argon atmosphere at 100 DEG C.After cooling, 30mL water is added to reaction mixed
In compound, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) and saturated aqueous common salt (30mL ×
2) organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=
9:1, v/v) to obtain product be yellow solid (470mg, yield is 71%) to purification residues.
1H NMR (300MHz, DMSO-d6) δ 9.86 (s, 1H), 8.15 (d, J=1.3Hz, 1H), 7.77-7.49 (m, 6H),
3.60 (s, 3H), 1.29 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of benzsulfamide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl) benzsulfamide (94mg,
0.24mmol) take off with the potassium carbonate (83mg, 0.60mmol) mixture in DMF-water (4mL:0.20mL)
Gas, and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol) is added in mixture.By gained
Reactant mixture degassing, under argon atmosphere at 100 DEG C stir 5 hours.After cooling, 30mL water is added to reaction mixed
In compound, it is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated aqueous common salt (30mL × 3)
The organic layer that washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.By column chromatography (silica gel, dichloromethane/10% ammoniacal liquor first
Alcoholic solution=100:1, v/v) to obtain product be yellow solid (84mg, yield is 83%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 9.87 (s, 1H), 8.21 (d, J=2.2Hz, 1H), 7.94 (d, J=2.1Hz,
1H), 7.91 (s, 1H), 7.77 (dd, J=7.4,1.4Hz, 2H), 7.64 (t, J=7.4Hz, 1H), 7.56 (t, J=7.5Hz, 2H),
6.44 (s, 2H), 6.31 (s, 1H), 5.44-5.25 (m, 1H), 3.63 (s, 3H), 2.57 (s, 3H), 2.27-2.11 (m, 2H),
2.11-2.00 (m, 2H), 1.98-1.76 (m, 2H), 1.77-1.57 (m, 2H).
Embodiment 15:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-4-methoxybenzenesulphoismide (compound 15)
The synthesis of step 1:N-(5-bromo-2-methoxypyridine-3-base)-4-methoxybenzenesulphoismide
Dichloromethane (5mL) solution of 4-Methoxybenzenesulfonyl chloride (496mg, 2.4mmol) is added drop-wise to 3-amino-5-
Bromo-2-methoxypyridine (0.406g, 2mmol) and pyridine (237mg, 3mmol), will be anti-in the solution of dichloromethane (5mL)
Mixture is answered to be stirred at room temperature 4h.Water (25mL) is added in reactant mixture, with the produced mixing of dichloromethane extraction
Thing (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, do with anhydrous sodium sulfate
Dry, filter, concentrate.Obtaining product with column chromatography (silica gel, petrol ether/ethyl acetate=7:1, v/v) separating residual thing is that yellow is solid
Body (668mg, yield is 90%).
1H NMR (400MHz, DMSO-d6) δ 9.99 (s, 1H), 8.02 (d, J=2.4Hz, 1H), 7.70 (d, J=9.0Hz,
2H), 7.67 (d, J=2.4Hz, 1H), 7.09 (d, J=9.0Hz, 2H), 3.82 (s, 3H), 3.67 (s, 3H).
Step 2:N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-
3-yl) synthesis of-4-methoxybenzenesulphoismide
By N-(5-bromo-2-methoxypyridine-3-base)-4-methoxybenzenesulphoismide (373mg, 1.0mmol), acetic anhydride
The mixture degassing in dioxane (7mL) of potassium (196mg, 2mmol) and connection pinacol borate (304mg, 1.2mmol),
And [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (62mg, 0.0845mmol) is added in mixture.By gained
Reactant mixture deaerates, and stirs 3h under argon atmosphere at 100 DEG C.After cooling, 30mL water is added to reactant mixture
In, it is extracted with ethyl acetate produced mixture (30mL × 3).Wash with water (30mL × 2) and saturated aqueous common salt (30mL × 2)
Wash the organic layer of merging, be dried with anhydrous sodium sulfate, filter, concentrate.With column chromatography (silica gel, petrol ether/ethyl acetate=5:1,
V/v) purification residues obtains product is yellow solid (370mg, yield is 88%).
1H NMR (400MHz, DMSO-d6) δ 9.67 (s, 1H), 8.13 (d, J=1.6Hz, 1H), 7.72 (d, J=1.6Hz,
1H), 7.61 (d, J=9.0Hz, 2H), 7.05 (d, J=9.0Hz, 2H), 3.80 (s, 3H), 3.65 (s, 3H), 1.29 (s, 12H).
Step 3:N-(5-(7-amino-1-cyclopenta-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base) synthesis of-4-methoxybenzenesulphoismide
By 7-amino-3-bromo-1-cyclopenta-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (65mg, 0.20mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-4-methoxybenzene sulphur
Acid amides (101mg, 0.24mmol, 1.2eq) and potassium carbonate (83mg, 0.60mmol) DMF and water (4mL:
Mixture degassing in 0.20mL), and by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (16mg, 0.02mmol)
It is added in mixture.The reactant mixture of gained is deaerated, stirs 5 hours at 100 DEG C under argon atmosphere.Cooling
After, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL ×
2) organic layer that saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silicon
Glue, dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be yellow solid (84mg, yield to purification residues
It is 79%).
1H NMR (400MHz, DMSO-d6) δ 9.68 (s, 1H), 8.18 (d, J=2.0Hz, 1H), 7.91 (d, J=2.0Hz,
1H), 7.88 (s, 1H), 7.71 (d, J=8.9Hz, 2H), 7.06 (d, J=8.9Hz, 2H), 6.43 (s, 2H), 6.30 (s, 1H),
5.43-5.22 (m, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 2.56 (s, 3H), 2.21-2.10 (m, 2H), 2.10-2.00 (m,
2H), 1.92-1.80 (m, 2H), 1.77-1.56 (m, 2H).
Embodiment 16:7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-3-(6-methoxypyridine-3-base)-
5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (compound 16)
Step 1: trans-4-(the bromo-6-of 3-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-base amino) hexamethylene
The synthesis of alcohol
Sealing in pipe, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles's-1-base)-4-iodo-2-picoline (7.8g,
20mmol), trans-4-aminocyclohexanol (4.6g, 40mmol), diisopropyl ethyl amine (7.76g, 60mmol) is at N-methylpyrrole
Solution in alkanone (80mL) stirs 24 hours at 160 DEG C.After being cooled to room temperature, with water (400mL) diluted reaction mixture,
It is extracted with ethyl acetate (200mL × 3).The organic of merging is washed with water (200mL × 2) and saturated aqueous common salt (200mL × 2)
Layer, is dried with anhydrous sodium sulfate, filters, and concentrates.By column chromatography (silica gel, petrol ether/ethyl acetate=5:1, then petroleum ether/second
Acetoacetic ester=4:1, v/v) to obtain product be yellow solid (4.90g, yield is 65%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 6.52 (s, 1H), 5.75 (s, 2H), 5.51 (d, J=8.4Hz, 1H), 4.56
(d, J=4.0Hz, 1H), 3.57-3.35 (m, 2H), 2.46 (s, 3H), 2.05 (s, 6H), 1.90-1.73 (m, 4H), 1.49-
1.27 (m, 4H).
MS(ESI+)m/z378.0[M+H]+.
Step 2:2-(trans-4-(the bromo-6-of 3-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-base amino)
Cyclohexyloxy) synthesis of ethanol
Trans-4-that sodium hydride (70% dispersion liquid in oil, 686mg, 20mmol) is added at 0 DEG C (the bromo-6-of 3-(2,
5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-base amino) cyclohexanol (3.78g, 10mmol) is at N, N-dimethyl methyl
In solution in acid amides (38mL), and the reactant mixture produced is stirred 2.5 hours at 0 DEG C.Add 1,3,2-dioxazole
Thiophene-2,2-dioxide (1.86g, 15mmol), and the reactant mixture produced is stirred 2 hours at 0 DEG C.Use methyl alcohol
(2mL) cancellation reactant mixture, evaporated under reduced pressure.Residue is diluted with 150mL dioxane and 3.78mL water.Add toluene sulphur
Acid monohydrate (3.80g, 20mmol), stirs the reactant mixture produced 3 hours at 40 DEG C.Concentrated reaction mixture,
Dilute with 100mL water, extract (50mL × 3) with dichloromethane.Wash with water (50mL × 2) and saturated aqueous common salt (50mL × 2)
The organic layer merged, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=4:1, so
Rear petrol ether/ethyl acetate=3:1, v/v) to obtain product be yellow oil (760mg, yield is 18%) to purification residues.
1H NMR(300MHz,DMSO-d6)δ6.53(s,1H),5.74(s,2H),5.56(d,J=8.4Hz,1H),4.54
(t,J=5.4Hz,1H),3.59-3.36(m,5H),3.29-3.15(m,1H),2.46(s,3H),2.05(s,6H),1.95-
1.85(m,4H),1.55-1.26(m,4H).
MS(ESI+)m/z422.0[M+H]+
Step 3:(E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base)-4-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl
Amino)-2-picoline-3-base) synthesis of ethyl acrylate
In sealing pipe, by 2-(trans-4-(the bromo-6-of 3-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-
Base amino) cyclohexyloxy) ethanol (0.76g, 1.8mmol) and ethyl acrylate (575 μ L, 5.40mmol) be at triethylamine (15mL)
In solution with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (0.208g, 0.18mmol), again by mixture with argon gas
Bubbling 5min also seals tubule.Reaction solution is stirred overnight at 130 DEG C, cools down and concentrate.Add 50mL water, use acetic acid second
The mixture that ester (50mL × 3) extraction produces.Having of (50mL × 2) washing merging is washed with water (50mL × 2) and saturated common salt
Machine layer, is dried with anhydrous sodium sulfate, filters, and concentrates.Purify residual by column chromatography (silica gel, petrol ether/ethyl acetate=3:2, v/v)
Staying thing to obtain product is yellow oil (770mg, yield is 97%).
1H NMR(400MHz,DMSO-d6)δ7.60(d,J=16.0Hz,1H),6.47(s,1H),6.28(d,J=16.0Hz,
1H),5.89(d,J=8.0Hz,1H),5.74(s,2H),4.53(t,J=5.6Hz,1H),4.21(q,J=7.2Hz,2H),3.55-
3.36(m,5H),3.25-3.16(m,1H),2.37(s,3H),2.07(s,6H),2.01-1.78(m,4H),1.47-1.30(m,
4H),1.28(t,J=7.2Hz,3H).
MS(ESI+)m/z442.1[M+H]+
Step 3:7-(2,5-dimethyl-1H-pyrroles's-1-base)-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-first
Base-1, the synthesis of 6-naphthyridines-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base)-4-(trans-4-(2-'-hydroxyethoxy
Base) Cyclohexylamino)-2-picoline-3-base) ethyl acrylate (0.77g, 1.74mmol), 1,5-diazabicyclo (5,4,
0) 11 carbon-5-alkene (1.3mL, 8.70mmol) and potassium tert-butoxide (98mg, 0.87mmol) are at DMA
(10mL) solution in is stirred overnight at 150 DEG C.After being cooled to room temperature, with 50mL water diluted reaction mixture, use acetic acid second
Ester extraction (30mL × 3).Wash, with water (30mL × 2) and saturated aqueous common salt (30mL × 2), the organic layer merged, use anhydrous slufuric acid
Sodium is dried, and filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=1.5:1, then petrol ether/ethyl acetate=1:1,
V/v) purification residues obtains product is yellow oil (0.25g, yield is 36%).
1H NMR (300MHz, DMSO-d6) δ 8.12 (d, J=9.6Hz, 1H), 6.61 (d, J=9.6Hz, 1H), 5.84 (s,
2H), 4.53 (t, J=5.2Hz, 1H), 3.55-3.40 (m, 5H), 3.35-3.27 (m, 1H), 2.73 (s, 3H), 2.70-2.55
(m, 2H), 2.12 (s, 6H), 2.08-1.97 (m, 2H), 1.70-1.40 (m, 4H).
MS(ESI+)m/z396.0[M+H]+
Step 4:7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one
Synthesis
By 7-(2,5-dimethyl-1H-pyrroles's-1-base)-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid,
6-naphthyridines-2 (1H)-one (250mg, 0.63mmol) and hydroxylamine hydrochloride (218mg, 3.15mmol) second alcohol and water (5mL:
Mixture in 0.5mL) refluxes overnight.Concentrated reaction mixture (silica gel, dichloromethane/10% ammoniacal liquor methyl alcohol is molten by column chromatography
Liquid=20:1, then dichloromethane/10% ammoniacal liquor methanol solution=15:1, v/v) to obtain product be that yellow blister is solid to purification residues
Body (100mg, yield is 50%).
1H NMR (300MHz, DMSO-d6) δ 7.79 (d, J=9.9Hz, 1H), 6.45 (s, 1H), 6.28 (s, 2H), 6.08
(d, J=9.9Hz, 1H), 4.57 (t, J=5.1Hz, 1H), 3.54-3.43 (m, 5H), 3.42-3.25 (m, 1H), 2.68-2.54
(m, 2H), 2.48 (s, 3H), 2.18-2.05 (m, 2H), 1.63-1.50 (m, 2H), 1.40-1.20 (m, 2H).
MS(ESI+)m/z318.1[M+H]+
The bromo-1-of step 5:7-amino-3-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2
(1H) synthesis of-one
N-bromo-succinimide (56mg, 0.315mmol) is added to 7-amino-1-(trans-4-(2-hydroxyl-oxethyl) ring
Hexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.315mmol) is at the solution of DMF (4mL)
In.Reaction solution is stirred at room temperature 1 hour.Add 50mL water, the mixing produced with ethyl acetate (20mL × 5) extraction
Thing.Wash, with water (20mL × 2) and saturated common salt, the organic layer that (20mL × 2) washing merges, be dried with anhydrous sodium sulfate, mistake
Filter, concentrates.With column chromatography (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=30:1, then dichloromethane/10% ammoniacal liquor methyl alcohol
Solution=20:1, v/v) to obtain product be yellow solid (30mg, yield 32%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 8.27 (s, 1H), 6.50-6.37 (m, 3H), 4.57 (s, 1H), 3.55-3.35
(m, 6H), 2.62-2.53 (m, 2H), 2.49 (s, 3H), 2.18-2.08 (m, 2H), 1.73-1.67 (m, 2H), 1.38-1.25
(m, 2H)
MS(ESI+)m/z395.9[M+H]+.
Step 6:7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-3-(6-methoxypyridine-3-base)-5-first
Base-1, the synthesis of 6-naphthyridines-2 (1H)-one
By the 7-bromo-1-of amino-3-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-
Ketone (30mg, 0.076mmol), 6-methoxypyridine-3-ylboronic acid (17.4mg, 0.115mmol) and potassium carbonate (166mg,
1.20mmol) the degassing of the mixture in DMF and water (3mL:0.6mL).By two (triphenylphosphine) dichloride
Palladium (11mg, 0.0152mmol) is added in mixture.The reactant mixture of gained is deaerated, 100 under argon atmosphere
3h is stirred at DEG C.After cooling, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL
× 3).The organic layer merged with water (30mL × 2) saturated aqueous common salt (30mL × 3) washing, is dried with anhydrous sodium sulfate, filters,
Concentrate.Obtaining product with column chromatography (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=20:1, v/v) purification residues is yellow
Solid (29mg, yield is 90%).
1H NMR (400MHz, DMSO-d6) δ 8.42 (d, J=2.4Hz, 1H), 7.99 (dd, J=8.4,2.4Hz, 1H), 7.93
(s, 1H), 6.83 (d, J=8.4Hz, 1H), 6.48 (s, 1H), 6.35 (s, 2H), 4.58 (s, 1H), 3.88 (s, 3H), 3.55-
3.45 (m, 5H), 3.45-3.30 (m, 1H), 2.70-2.57 (m, 2H), 2.56 (s, 3H), 2.20-2.10 (m, 2H), 1.68-
1.60 (m, 2H), 1.40-1.26 (m, 2H)
MS(ESI+)m/z425.0[M+H]+
Embodiment 17:N-(5-(7-amino-1-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl-2-oxo-
1,2-dihydro-1,6-naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4-difluorobenzenesulfonamide (compound 17)
By the 7-bromo-1-of amino-3-(trans-4-(2-hydroxyl-oxethyl) cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-
Ketone (79.2mg, 0.2mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases)
Pyridin-3-yl)-2,4-difluorobenzenesulfonamide (102.3mg, 0.24mmol) and potassium carbonate (138mg, 1.0mmol) are at N, N-bis-
In NMF and water (2.5mL:0.5mL) mixture degassing, and by two (triphenylphosphine) palladium chloride (14mg,
0.02mmol) it is added in mixture.Being deaerated by the reactant mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge is anti-
Answer 3h.After cooling, 30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With
The organic layer that water (30mL × 2) saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With
It is yellow solid that column chromatography (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=20:1, v/v) purification residues obtains product
(43mg, yield is 35%).
1H NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 8.27 (d, J=2.4Hz, 1H), 7.93 (s, 1H), 7.91
(s, 1H), 7.73 (td, J=8.4,6.4Hz, 1H), 7.66-7.49 (td, J=10.0,2.4Hz, 1H), 7.20 (td, J=8.4,
2.1Hz, 1H), 6.47 (s, 1H), 6.38 (s, 2H), 4.58 (t, J=4.8Hz, 1H), 3.63 (s, 3H), 3.56-3.45 (m,
4H), 3.45-3.35 (m, 1H), 3.36-3.27 (m, 1H), 2.74-2.52 (m, 2H), 2.56 (s, 3H), 2.15 (d, J=
10.0Hz, 2H), 1.65 (d, J=10.8Hz, 2H), 1.41-1.28 (m, 2H).
MS(ESI+)m/z615.90[M+H]+
Embodiment 18:N-(5-(7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-methyl-2-oxo-1,2-dihydro-1,6-
Naphthyridines-3-base)-2-methoxypyridine-3-base)-2,4-difluorobenzenesulfonamide (compound 18)
Step 1:(E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base)-4-(trans-4-hydroxy-cyclohexyl amino)-2-first
Yl pyridines-3-base) synthesis of ethyl acrylate
In sealing pipe, by trans-4-(the bromo-6-of 3-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-base ammonia
Base) molten in triethylamine (97mL) of cyclohexanol (4.86g, 12.85mmol) and ethyl acrylate (2.73mL, 25.70mmol)
Liquid is with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (1.48g, 1.285mmol), again by mixture with bubbling argon
5min also seals tubule.Reaction solution is stirred overnight at 130 DEG C, cools down and concentrate.Add 50mL water, use ethyl acetate
The mixture that (50mL × 3) extraction produces.The organic of (50mL × 2) washing merging is washed with water (50mL × 2) and saturated common salt
Layer, is dried with anhydrous sodium sulfate, filters, and concentrates.Residual is purified by column chromatography (silica gel, petrol ether/ethyl acetate=3:2, v/v)
It is yellow oil (3.77g, yield is 74%) that thing obtains product.
1H NMR (400MHz, DMSO-d6) δ 7.59 (d, J=16.4Hz, 1H), 6.45 (s, 1H), 6.28 (d, J=16.4Hz,
1H), 5.85 (d, J=8.4Hz, 1H), 5.74 (s, 2H), 4.54 (d, J=4.0Hz, 1H), 4.21 (q, J=7.2Hz, 2H), 3.45-
3.35 (m, 2H), 2.37 (s, 3H), 2.07 (s, 6H), 1.88-1.71 (m, 4H), 1.45-1.20 (m, 4H), 1.28 (t, J=
7.2Hz, 3H)
MS(ESI+)m/z398.0[M+H]+
Step 2:7-(2,5-dimethyl-1H-pyrroles's-1-base)-1-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, 6-naphthalene
The synthesis of pyridine-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base)-4-(trans-4-hydroxy-cyclohexyl ammonia
Base)-2-picoline-3-base) ethyl acrylate (3.37g, 8.48mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-
Alkene DBU(6.4mL, 42.4mmol) and molten in DMA (35mL) of potassium tert-butoxide (475mg, 4.24mmol)
Liquid stirs 4h at 150 DEG C.After being cooled to room temperature, with 150mL water diluted reaction mixture, be extracted with ethyl acetate (50mL ×
3).Wash, with water (50mL × 2) and saturated aqueous common salt (50mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, filter,
Concentrate.Residual is purified by column chromatography (silica gel, petrol ether/ethyl acetate=1.5:1, then petrol ether/ethyl acetate=1:1, v/v)
It is yellow oil (1.02g, yield is 31%) that thing obtains product.
1H NMR (300MHz, DMSO-d6) δ 8.11 (d, J=9.6Hz, 1H), 7.69-7.49 (m, 1H), 6.60 (d, J=
9.6Hz, 1H), 5.84 (s, 2H), 4.60 (d, J=3.9Hz, 1H), 3.60-3.40 (m, 1H), 2.72 (s, 3H), 2.69-2.54
(m, 2H), 2.12 (s, 6H), 1.95-1.75 (m, 2H), 1.69-1.36 (m, 4H).
MS(ESI+)m/z352.1[M+H]+
Step 3:7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 7-(2,5-dimethyl-1H-pyrroles's-1-base)-1-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2
(1H)-one (1.01g, 2.87mmol) and hydroxylamine hydrochloride (998mg, 14.35mmol) mixing in second alcohol and water (20mL:2mL)
Compound refluxes overnight.Concentrated reaction mixture and with column chromatography (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=50:1, then
Dichloromethane/10% ammoniacal liquor methanol solution=40:1, v/v) to obtain product be yellow blister solid (100mg, yield to purification residues
It is 50%).
1H NMR (300MHz, DMSO-d6) δ 7.79 (d, J=9.6Hz, 1H), 6.44 (s, 1H), 6.30 (s, 2H), 6.07
(d, J=9.6Hz, 1H), 4.67 (d, J=4.2Hz, 1H), 4.10 (q, J=5.1Hz, 1H), 3.66-3.44 (m, 1H), 2.74-
2.52 (m, 2H), 2.47 (s, 3H), 2.05-1.86 (m, 2H), 1.64-1.45 (m, 2H), 1.41-1.20 (m, 2H).
MS(ESI+)m/z274.1[M+H]+
The bromo-1-of step 4:7-amino-3-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
N-bromo-succinimide (228mg, 1.28mmol) is added to 7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-first
Base-1,6-naphthyridines-2 (1H)-one (538mg, 1.97mmol) is in the solution of DMF (10mL).To react molten
Liquid is stirred at room temperature 1 hour.Add 50mL water, the mixture produced with ethyl acetate (20mL × 5) extraction.With water (20mL
× 2) wash (20mL × 2) and wash, with saturated common salt, the organic layer merged, be dried with anhydrous sodium sulfate, filter, concentrate.Use post look
Spectrum (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=50:1, v/v) purification residues obtain product be yellow solid (312mg,
Yield is 45%).
1H NMR (300MHz, DMSO-d6) δ 8.27 (s, 1H), 6.45 (s, 2H), 5.76 (s, 1H), 4.69 (d, J=
4.2Hz, 1H), 3.62-3.44 (m, 1H), 2.66-2.52 (m, 2H), 2.49 (s, 3H), 2.02-1.90 (m, 2H), 1.63-
1.50 (m, 2H), 1.43-1.25 (m, 2H).
MS(ESI+)m/z352.0[M+H]+.
Step 5:N-(5-(7-amino-1-(trans-4-hydroxy-cyclohexyl)-5-methyl-2-oxo-1,2-dihydro-1,6-naphthalene
Pyridine-3-base)-2-methoxypyridine-3-base)-2, the synthesis of 4-difluorobenzenesulfonamide
By the 7-bromo-1-of amino-3-(trans-4-hydroxy-cyclohexyl)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg,
0.284mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-3-
Base)-2,4-difluorobenzenesulfonamide (145mg, 0.115mmol) and potassium carbonate (276mg, 2mmol) are at DMF
Deaerate with the mixture in water (5mL:1mL), and two (triphenylphosphine) palladium chloride (20mg, 0.0284mmol) is added to mixing
In thing.Being deaerated by the reactant mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 3h.After cooling, by 30mL
Water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated food
The organic layer that salt solution (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, dichloromethane
Alkane/10% ammoniacal liquor methanol solution=60:1, v/v) to obtain product be yellow solid (19mg, yield is 12%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 8.26 (s, 1H), 7.94-7.89 (m, 2H), 7.73 (td,
J=8.8,6.4Hz, 1H), 7.58 (t, J=8.8Hz, 1H), 7.21 (td, J=9.2,2.4Hz, 1H), 6.48 (s, 1H), 6.39 (s,
2H), 4.69 (d, J=4.0Hz, 1H), 3.63 (s, 3H), 2.56 (s, 3H), 2.55 (m, 2H), 1.98 (d, J=8.8Hz, 2H),
1.60 (d, J=10.8Hz, 2H), 1.41-1.30 (m, 2H).
MS(ESI+)m/z571.9[M+H]+
Embodiment 19:7-amino-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,
The synthesis (compound 19) of 6-naphthyridines-2 (1H)-one
The bromo-6-of step 1:3-(2,5-dimethyl-1H-pyrroles's-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrans-4-base ammonia
Base) synthesis of pyridine
Sealing in pipe, by bromo-for 3-6-(2,5-dimethyl-1H-pyrroles's-1-base)-4-iodo-2-picoline (6.00g,
15.35mmol), tetrahydrochysene-2H-pyrans-4-amine (3.11g, 30.70mmol), diisopropyl ethyl amine (5.95g, 46.05mmol)
Solution in METHYLPYRROLIDONE (60mL) heats 24 hours at 160 DEG C.After being cooled to room temperature, add 300mL
Water, is extracted with ethyl acetate produced mixture (150mL × 3).Wash with water (150mL × 2) and salt solution (150mL × 2)
The organic layer merged, is dried with anhydrous sodium sulfate, filters and concentrate.With column chromatography (silica gel, petrol ether/ethyl acetate=8:1, v/
V) purification residues obtains product is yellow solid (1.52g, yield 27%).
1H NMR (400MHz, DMSO-d6) δ 6.62 (s, 1H), 5.75 (s, 2H), 5.70 (d, J=7.2Hz, 1H), 3.89-
3.82 (m, 2H), 3.80-3.72 (m, 1H), 3.43 (t, J=10.9Hz, 2H), 2.48 (s, 3H), 2.05 (s, 6H), 1.95-
1.85 (m, 2H), 1.70-1.56 (m, 2H).
MS(ESI+)m/z364.0[M+H]+.
Step 2:(E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrans-4-base
Amino) pyridin-3-yl) synthesis of ethyl acrylate
Sealing in pipe, by bromo-for 3-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrans-
4-base amino) pyridine (1.71g, 4.69mmol) and ethyl acrylate (1.50mL, 14.07mmol) be in triethylamine (30mL)
Solution is with bubbling argon 5min.Add tetrakis triphenylphosphine palladium (0.542g, 0.47mmol), again by mixture with bubbling argon
5min also seals tubule.Reaction solution is stirred overnight at 130 DEG C, cools down and concentrate.Add 100mL water, use ethyl acetate
The mixture that (50mL × 3) extraction produces.The organic of (50mL × 2) washing merging is washed with water (50mL × 2) and saturated common salt
Layer, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=10:1, then petroleum ether/
Ethyl acetate=5:1, v/v) to obtain product be yellow oil (540mg, yield 30%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 7.52 (d, J=16.4Hz, 1H), 6.40 (s, 1H), 6.35 (d, J=16.4Hz,
1H), 6.05 (d, J=6.8Hz, 1H), 5.75 (s, 2H), 4.21 (q, J=7.2Hz, 2H), 3.90-3.77 (m, 2H), 3.75-
3.62 (m, 1H), 3.43 (t, J=11.2Hz, 2H), 2.38 (s, 3H), 2.08 (s, 6H), 1.84-1.72 (m, 2H), 1.65-
1.51 (m, 2H), 1.28 (t, J=7.2Hz, 3H).
MS(ESI+)m/z384.1[M+H]+.
Step 3:7-(2,5-dimethyl-1H-pyrroles's-1-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthalene
The synthesis of pyridine-2 (1H)-one
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-methyl-4-(tetrahydrochysene-2H-pyrrole
Mutter-4-base amino) pyridin-3-yl) ethyl acrylate (313mg, 0.82mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-
5-alkene (627 μ L, 4.1mmol) and the potassium tert-butoxide (46mg, 0.41mmol) solution in DMA (5mL) exist
Stir 7 hours at 150 DEG C.After being cooled to room temperature, with 30mL water diluted reaction mixture, it is extracted with ethyl acetate (20mL × 3).
Wash, with water (20mL × 2) and saturated aqueous common salt (20mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, filter, dense
Contracting.Obtain with column chromatography (silica gel, petrol ether/ethyl acetate=5:1, then petrol ether/ethyl acetate=2:1, v/v) purification residues
It is yellow oil (72mg, yield is 26%) to product.
1H NMR (400MHz, CDCl3) δ 7.94 (d, J=9.7Hz, 1H), 7.28 (s, 1H), 6.73 (d, J=9.7Hz, 1H),
5.96 (s, 2H), 5.30-5.09 (m, 1H), 4.19-4.09 (m, 2H), 3.55 (t, J=11.2Hz, 2H), 3.00-2.84 (m,
2H), 2.82 (s, 3H), 2.21 (s, 6H), 1.72-1.62 (m, 2H).
Step 4:7-amino-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1, the synthesis of 6-naphthyridines-2 (1H)-one
By 7-(2,5-dimethyl-1H-pyrroles's-1-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2
(1H)-one (721mg, 2.14mmol) and hydroxylamine hydrochloride (743mg, 10.7mmol) mixing in alcohol-water (15mL:1.5mL)
Compound refluxes overnight.Concentrated reaction mixture and with column chromatography (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=50:1, then
Dichloromethane/10% ammoniacal liquor methanol solution=25:1, v/v) to obtain crude product be yellow solid (684mg, thick yield to purification residues
It is 114%).
1H NMR (400MHz, DMSO-d6) δ 7.82 (d, J=9.6Hz, 1H), 6.52 (s, 1H), 6.35 (s, 2H), 6.10
(d, J=9.6Hz, 1H), 5.20-4.90 (m, 1H), 4.01 (dd, J=11.2,4.0Hz, 2H), 3.45 (t, J=11.2Hz, 2H),
2.85-2.70 (m, 2H), 2.48 (s, 3H), 1.53-1.46 (m, 2H).
Step 5:7-amino-3-bromo-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1, the conjunction of 6-naphthyridines-2 (1H)-one
Become
N-bromo-succinimide (294mg, 1.65mmol) is added to 7-amino-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-
4-yl)-1,6-naphthyridines-2 (1H)-one crude product (564mg, 2.18mmol) is in the solution of DMF (17mL).
Reaction solution is stirred at room temperature 1h.Add 100mL water, the mixture produced with ethyl acetate (50mL × 5) extraction.Use water
The organic layer that (50mL × 2) and saturated common salt washing (50mL × 2) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.
Obtaining product with column chromatography (silica gel, dichloromethane/10% ammoniacal liquor methanol solution=25:1, v/v) purification residues is yellow solid
(335mg, yield 46%).
1H NMR (300MHz, DMSO-d6) δ 8.30 (s, 1H), 6.52 (s, 1H), 6.50 (s, 2H), 4.90-4.70 (m,
1H), 4.01 (dd, J=11.2,4.1Hz, 2H), 3.45 (t, J=11.2Hz, 2H), 2.84-2.65 (m, 2H), 2.50 (s, 3H),
(1.60-1.50 m, 2H).
Step 6:7-amino-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-
Naphthyridines-2 (1H)-one
By 7-amino-3-bromo-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one (101mg,
0.3mmol), N-(2-methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridine-3-
Base)-2,4-difluorobenzenesulfonamide (154mg, 0.36mmol) and potassium carbonate (138mg, 1mmol) at DMF and
Mixture degassing in water (2.5mL:0.5mL), and two (triphenylphosphine) palladium chloride (21mg, 0.03mmol) is added to mixing
In thing.Being deaerated by the reactant mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 4h.After cooling, by 30mL
Water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2) saturated food
The organic layer that salt solution (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, dichloromethane
Alkane/10% ammoniacal liquor methanol solution=30:1, v/v) to obtain product be yellow solid (103mg, yield is 68%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 10.20 (s, 1H), 8.27 (s, 1H), 7.94 (d, J=6.9Hz, 2H), 7.73
(dd, J=14.8,8.4Hz, 1H), 7.58 (t, J=8.8Hz, 1H), 7.20 (t, J=8.5Hz, 1H), 6.54 (s, 1H), 6.45 (s,
2H), 5.02-4.89 (m, 1H), 4.04 (dd, J=11.2,4.0Hz, 2H), 3.62 (s, 3H), 3.47 (t, J=11.2Hz, 2H),
2.87-2.74 (d, J=9.0Hz, 2H), 2.57 (s, 3H), 1.57 (dd, J=11.2,2.0Hz, 2H).
MS(ESI+)m/z557.9[M+H]+.
Embodiment 20:7-amino-3-(6-methoxypyridine-3-base)-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,
The synthesis (compound 20) of 6-naphthyridines-2 (1H)-one
By 7-amino-3-bromo-5-methyl isophthalic acid-(tetrahydrochysene-2H-pyrans-4-base)-1,6-naphthyridines-2 (1H)-one (101mg,
0.3mmol), pyridine-4-boric acid (55mg, 0.36mmol) and potassium carbonate (138mg, 1mmol) are at DMF-water
(2.5mL:0.5mL) the mixture degassing in, and two (triphenylphosphine) palladium chloride (21mg, 0.03mmol) is added to mixture
In.Being deaerated by the reactant mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge is reacted 4 hours.After cooling, will
30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).Satisfy with water (30mL × 2)
The organic layer merged with saline solution (30mL × 3) washing, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, two
Chloromethanes/10% ammoniacal liquor methanol solution=30:1, v/v) to obtain product be yellow solid (70mg, yield is 64%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 8.43 (d, J=2.2Hz, 1H), 8.00 (dd, J=8.6,2.2Hz, 1H), 7.95
(s, 1H), 6.84 (d, J=8.6Hz, 1H), 6.54 (s, 1H), 6.41 (s, 2H), 5.03-4.79 (m, 1H), 4.02 (dd, J=
11.2,4.0Hz, 2H), 3.88 (s, 3H), 3.47 (t, J=11.4Hz, 2H), 2.88-2.75 (m, 2H), 2.57 (s, 3H), 1.57
(dd, J=11.2,2.0Hz, 2H).
MS(ESI+)m/z367.0[M+H]+.
Embodiment 21:N-(5-(7-amino-1-isopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-2, the synthesis (compound 21) of 4-difluorobenzenesulfonamide
The synthesis of the bromo-6-of step 1:3-(2,5-dimethyl-1H-pyrroles's-1-base)-N-isopropyl-2-picoline-4-amine
Sealing in pipe, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles's-1-base)-4-iodo-2-picoline (15g,
38.5mmol) stir at 160 DEG C with the diisopropyl ethyl amine (4.96g, 38.5mmol) solution in isopropylamine (75mL)
24 hours.After being cooled to room temperature, reduced pressure concentration reactant mixture.It is extracted with ethyl acetate (500mL) and dissolves the residue produced,
Wash with water (200mL × 2) and saturated aqueous common salt (200mL × 2), be dried with anhydrous sodium sulfate, filter, concentrate.Use column chromatography
(silica gel, petrol ether/ethyl acetate=150:1, then petrol ether/ethyl acetate=50:1, v/v) purification residues obtains product and is
Yellow solid (7.5g, yield is 61%).
1H NMR (400MHz, DMSO-d6) δ 6.44 (s, 1H), 5.74 (s, 2H), 5.60 (d, J=8.3Hz, 1H), 3.87-
3.77 (m, 1H), 2.47 (s, 3H), 2.06 (s, 6H), 1.20 (d, J=6.3Hz, 6H).
MS(ESI+)m/z322.0[M+H]+.
Step 2:(E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base-)-4-(isopropylamino)-2-picoline-
3-yl) synthesis of ethyl acrylate
In sealing pipe, by bromo-for 3-N-cyclopenta-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-
Amine (7.5g, 23.4mmol) and the ethyl acrylate (5.0mL, 46.7mmol) solution in triethylamine (55mL) are with bubbling argon
5min.Add tetrakis triphenylphosphine palladium (1.35g, 11.68mmol), again mixture with bubbling argon 5min and is sealed little
Pipe.Reaction solution is stirred overnight at 130 DEG C, cools down and concentrate.Add 200mL water, extract with ethyl acetate (100mL × 3)
Take the mixture of generation.The organic layer that (100mL × 2) washing merges is washed, with anhydrous with water (100mL × 2) and saturated common salt
Sodium sulphate is dried, and filters, and concentrates.The crude product produced is that yellow oil (8.00g, yield 100%) is the most straight
Connect for next step.
1H NMR (400MHz, DMSO-d6) δ 7.61 (d, J=16.2Hz, 1H), 6.40 (s, 1H), 6.30 (d, J=16.2Hz,
1H), 5.94 (d, J=8.1Hz, 1H), 5.74 (s, 2H), 4.22 (q, J=7.1Hz, 2H), 3.81-3.70 (m, 1H), 2.38 (s,
3H), 2.07 (s, 6H), 1.28 (t, J=7.1Hz, 3H), 1.17 (d, J=6.3Hz, 6H).
MS(ESI+)m/z342.1[M+H]+
Step 3:7-(2,5-dimethyl-1H-pyrroles's-1-base)-1-isopropyl-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one
Synthesis
Under argon gas atmosphere, by (E)-3-(6-(2,5-dimethyl-1H-pyrroles's-1-base-)-4-(isopropylamino)-2-first
Yl pyridines-3-base) ethyl acrylate (8.0g, 23.5mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene
(17.5mL, 117.3mmol) and the potassium tert-butoxide (1.32g, 11.75mmol) solution in DMA (80mL)
It is stirred overnight at 150 DEG C.After being cooled to room temperature, with 400mL water diluted reaction mixture, be extracted with ethyl acetate (200mL ×
3).Wash, with water (200mL × 2) and saturated aqueous common salt (200mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, mistake
Filter, concentrates.Purify residual by column chromatography (silica gel, petrol ether/ethyl acetate=10:1, then petrol ether/ethyl acetate=5:1, v/v)
Staying thing to obtain product is yellow oil (2.7g, yield is 39%).
1H NMR (400MHz, DMSO-d6) δ 8.13 (d, J=9.8Hz, 1H), 7.46 (s, 1H), 6.63 (d, J=9.8Hz,
1H), 5.83 (s, 2H), 5.38-5.17 (m, 1H), 2.73 (s, 3H), 2.11 (s, 6H), 1.51 (d, J=6.8Hz, 6H).
Step 4:7-amino-1-isopropyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 7-(2,5-dimethyl-1H-pyrroles's-1-base)-1-isopropyl-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (2.7g,
9.2mmol) reflux overnight with the hydroxylamine hydrochloride (3.2g, 4.58mmol) mixture in second alcohol and water (40mL/4mL).Concentrate
Reactant mixture with column chromatography (silica gel, petrol ether/ethyl acetate=1:3, then ethyl acetate/triethylamine=100:1, v/v)
It is yellow blister solid (1.3g, yield is 65%) that purification residues obtains product.
1H NMR (400MHz, DMSO-d6) δ 7.80 (d, J=9.6Hz, 1H), 6.43 (s, 1H), 6.30 (s, 2H), 6.09
(d, J=9.6Hz, 1H), 5.32 (q, J=7.2Hz, 1H), 2.48 (s, 3H), 1.49 (d, J=7.2Hz, 6H).
Step 5:7-amino-3-bromo-1-isopropyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
N-bromo-succinimide (1.14g, 6.41mmol add in three batches) is added to 7-amino-1-isopropyl-5-first
Base-1,6-naphthyridines-2 (1H)-one (1.39g, 6.41mmol) is in the solution of DMF (14mL).To react molten
Liquid is stirred at room temperature 1 hour.Add 60mL water, the mixture produced with ethyl acetate (30mL × 3) extraction.With water (50mL
× 2) wash (50mL × 2) and wash, with saturated common salt, the organic layer merged, be dried with anhydrous sodium sulfate, filter, concentrate.Use post look
Spectrum (silica gel, petrol ether/ethyl acetate=3:1, then petrol ether/ethyl acetate/triethylamine=50:50:1, v/v) purification residues
Obtaining product is yellow solid (1.02g, yield 54%).
1H NMR (400MHz, CDCl3) δ 8.15 (s, 1H), 6.30 (s, 1H), 4.70 (br s, 2H), 4.12 (q, J=
7.2Hz, 1H), 2.60 (s, 3H), 1.60 (d, J=7.2Hz, 6H).
MS (ESI+) m/z296.0,298.0 [M+H]+.
Step 6:N-(5-(7-amino-1-isopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base)-2, the synthesis of 4-difluorobenzenesulfonamide
By 7-amino-3-bromo-1-isopropyl-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (100mg, 0.34mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-2,4-difluorobenzene sulphur
Acid amides (173mg, 0.41mmol) and potassium carbonate (110mg, 1.02mmol) DMF-water (4mL:0.34mL,
Mixture degassing in 12:1), and [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (25mg, 0.034mmol) is added
In mixture.Being deaerated by the reactant mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 5h.After cooling,
30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).With water (30mL × 2)
The organic layer that saturated aqueous common salt (30mL × 3) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel,
Dichloromethane/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be that (40mg, yield is yellow solid to purification residues
23%).
1H NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 8.28 (d, J=1.9Hz, 1H), 7.93 (d, J=2.0Hz,
1H), 7.92 (s, 1H), 7.73 (dt, J=8.4,6.5Hz, 1H), 7.63-7.52 (m, 1H), 7.27-7.12 (m, 1H), 6.45
(s, 1H), 6.39 (s, 2H), 5.35-5.30 (m, 1H), 3.62 (s, 3H), 2.56 (s, 2H), 1.53 (d, J=7.0Hz, 6H).
MS(ESI+)m/z516.1[M+H]+.
Embodiment 22:N-(5-(7-amino-1-cyclopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-
2-methoxypyridine-3-base)-2,4-difluorobenzenesulfonamide (compound 22)
The synthesis of step 1:3-bromo-N-cyclopropyl-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-amine
Sealing in pipe, by bromo-for 3-6-(2,5-methyl isophthalic acid H-pyrroles's-1-base)-4-iodo-2-picoline (6g,
15.4mmol) and DIEA(1.98g, 15.4mmol) solution in cyclopropylamine (30mL) stirs 48 hours at 90 DEG C.Cooling
To room temperature, reduced pressure concentration reactant mixture.It is extracted with ethyl acetate (200mL) and dissolves the residue produced, with water (100mL
× 2) wash with saturated aqueous common salt (100mL × 2), be dried with anhydrous sodium sulfate, filter, concentrate.With column chromatography (silica gel, oil
Ether/ethyl acetate=150:1 then petrol ether/ethyl acetate=50:1, v/v) to obtain product be yellow solid to purification residues
(1.6g, yield is 33%).
1H NMR (400MHz, DMSO-d6) δ 6.63 (s, 1H), 6.62 (brs, 1H), 5.76 (s, 2H), 2.47 (s, 3H),
2.09 (s, 6H), 2.02-1.95 (m, 1H), 0.83-0.76 (m, 2H), 0.61-0.51 (m, 2H).
MS(ESI+)m/z320.0[M+H]+.
Step 2:(E)-3-(4-(cyclopropylamino)-6-(2,5-dimethyl-1H-pyrroles's-1-base-)-2-picoline-
3-yl) synthesis of ethyl acrylate
In sealing pipe, by bromo-for 3-N-cyclopropyl-6-(2,5-dimethyl-1H-pyrroles's-1-base)-2-picoline-4-
Amine (1g, 3.1mmol) and the ethyl acrylate (0.68mL, 6.2mmol) solution in triethylamine (10mL) are with bubbling argon
5min.Add tetrakis triphenylphosphine palladium (0.362g, 0.31mmol), again mixture with bubbling argon 5min and is sealed little
Pipe.Reaction solution is stirred overnight at 130 DEG C, cools down and concentrate.Add 50mL water, extract with ethyl acetate (50mL × 3)
The mixture produced.Wash, with water (50mL × 2) and saturated common salt, the organic layer that (50mL × 2) washing merges, use anhydrous slufuric acid
Sodium is dried, and filters, and concentrates.With column chromatography (silica gel, petrol ether/ethyl acetate=50:1 then petrol ether/ethyl acetate=5:1, v/
V) purification residues obtains product is yellow oil (0.58g, yield is 55%).
1H NMR (400MHz, CDCl3) δ 7.67 (d, J=16.4Hz, 1H), 6.76 (s, 1H), 6.24 (d, J=16.4Hz,
1H), 5.88 (s, 2H), 5.03 (s, 1H), 4.30 (q, J=7.1Hz, 2H), 2.48 (s, 3H), 2.46-2.39 (m, 1H), 2.20
(s, 6H), 1.36 (t, J=7.1Hz, 3H), 0.92-0.77 (m, 2H), 0.63-0.52 (m, 2H).
Step 3:1-cyclopropyl-7-(2,5-dimethyl-1H-pyrroles's-1-base)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one
Synthesis
Under argon gas atmosphere, by (E)-3-(4-(cyclopropylamino)-6-(2,5-dimethyl-1H-pyrroles's-1-base-)-2-first
Yl pyridines-3-base) ethyl acrylate (1.08g, 3.2mmol), 1,5-diazabicyclo (5,4,0) 11 carbon-5-alkene DBU
(2.36mL, 15.9mmol) and the potassium tert-butoxide (0.179g, 1.6mmol) solution in DMA (20mL) exist
It is stirred overnight at 150 DEG C.After being cooled to room temperature, with 100mL water diluted reaction mixture, it is extracted with ethyl acetate (50mL × 3).
Wash, with water (50mL × 2) and saturated aqueous common salt (50mL × 2), the organic layer merged, be dried with anhydrous sodium sulfate, filter, dense
Contracting.Obtain with column chromatography (silica gel, petrol ether/ethyl acetate=4:1, then petrol ether/ethyl acetate=2:1, v/v) purification residues
It is yellow oil (0.42g, yield is 45%) to product.
1H NMR (400MHz, DMSO-d6) δ 8.11 (d, J=9.8Hz, 1H), 7.49 (s, 1H), 6.61 (d, J=9.8Hz,
1H), 5.84 (s, 2H), 3.05-2.91 (m, 1H), 2.72 (s, 3H), 2.15 (s, 6H), 1.35-1.24 (m, 2H), 0.83-
0.70 (m, 2H).
Step 4:7-amino-1-cyclopropyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
By 1-cyclopropyl-7-(2,5-dimethyl-1H-pyrroles's-1-base)-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one
The mixture backflow in alcohol-water (5mL/0.5mL) of (0.42g, 1.43mmol) and hydroxylamine hydrochloride (0.498g, 7.17mmol)
Overnight.Concentrated reaction mixture and with column chromatography (silica gel, petrol ether/ethyl acetate=1:3, then ethyl acetate/triethylamine=
100:1, v/v) to obtain product be yellow blister solid (273mg, yield is 89%) to purification residues.
1H NMR (400MHz, DMSO-d6) δ 7.79 (d, J=9.6Hz, 1H), 6.53 (s, 1H), 6.38 (s, 2H), 6.06
(d, J=9.6Hz, 1H), 2.80-2.68 (m, 1H), 2.46 (s, 3H), 1.20-1.15 (m, 2H), 0.75-0.62 (m, 2H).
Step 5:7-amino-3-bromo-1-cyclopropyl-5-methyl isophthalic acid, the synthesis of 6-naphthyridines-2 (1H)-one
N-bromo-succinimide (181mg, 0.8eq) is added to 7-amino-1-cyclopropyl-5-methyl isophthalic acid, 6-naphthyridines-2
(1H)-one (273mg, 1.27mmol) is in the solution of DMF (4mL).Reaction solution is stirred at room temperature
1h.Add 20mL water, the mixture produced with ethyl acetate (20mL × 3) extraction.Wash with water (20mL × 2) and saturated common salt
The organic layer that (20mL × 2) washing merges, is dried with anhydrous sodium sulfate, filters, and concentrates.By column chromatography (silica gel, petroleum ether/second
Acetoacetic ester=1:1, then petrol ether/ethyl acetate: triethylamine=50:50:1, v/v) to obtain product be that yellow is solid to purification residues
Body (200g, yield 53%).
1H NMR (400MHz, CDCl3) δ 8.26 (s, 1H), 6.54 (s, 2H), 6.53 (s, 1H), 2.92-2.79 (m, 1H),
2.48 (s, 3H), 1.30-1.16 (m, 2H), 0.77-0.66 (m, 2H).
Step 6:N-(5-(7-amino-1-cyclopropyl-5-methyl-2-oxo-1,2-dihydro-1,6-naphthyridines-3-base)-2-
Methoxypyridine-3-base)-2, the synthesis of 4-difluorobenzenesulfonamide
By 7-amino-3-bromo-1-cyclopropyl-5-methyl isophthalic acid, 6-naphthyridines-2 (1H)-one (60mg, 0.205mmol), N-(2-
Methoxyl group-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan alkane-2-bases) pyridin-3-yl)-2,4-difluorobenzene sulphur
Acid amides (105mg, 0.246mmol) and potassium carbonate (85mg, 0.615mmol) are at DMF-water (4mL:0.3mL)
In mixture degassing, and be added to mix by [1,1 '-bis-(diphenylphosphino) ferrocene] palladium chloride (15mg, 0.021mmol)
In compound.Being deaerated by the reactant mixture of gained, under argon atmosphere, at 100 DEG C, lucifuge reacts 5h.After cooling, will
30mL water is added in reactant mixture, is extracted with ethyl acetate produced mixture (30mL × 3).Satisfy with water (30mL × 2)
The organic layer merged with saline solution (30mL × 3) washing, is dried with anhydrous sodium sulfate, filters, and concentrates.With column chromatography (silica gel, two
Chloromethanes/10% ammoniacal liquor methanol solution=100:1, v/v) to obtain product be that (20mg, yield is yellow solid to purification residues
19%).
1H NMR (400MHz, DMSO-d6) δ 10.18 (s, 1H), 8.29 (d, J=2.2Hz, 1H), 7.93 (d, J=2.2Hz,
1H), 7.92 (s, 1H), 7.73 (td, J=8.5,6.4Hz, 1H), 7.66-7.49 (m, 1H), 7.20 (td, J=8.5,2.3Hz,
1H), 6.55 (s, 1H), 6.49 (s, 2H), 3.62 (s, 3H), 2.87-2.80 (m, 1H), 2.55 (s, 3H), 1.30-1.13 (m,
2H), 0.79-0.66 (m, 2H).
Embodiment 23 biochemistry detection PI3K-alpha active
Vitro kinase test experience is used to assess the compound of the present invention usefulness to PI3K-α.Use ADP-GloTMKinases
Detection kit, measures the external activity of PI3K-α by ADP level produced in detection kinase reaction.In kinase assay
In experiment, kinases consumption ATP generation ADP, ADP-Glo reagent consumes completely by termination kinase reaction and by remaining ATP,
Rear addition kinase assay reagent, is converted into new ATP by ADP.Luciferase in detection reagent is at ATP and O2Can under Can Yuing
Catalytic fluorometry element, produces the fluorescein of oxidized form, AMP and produce light quantum, thus transfers chemical signal to optical signal
(Luminecence), the intensity of optical signal is proportionate with ADP generation amount in kinase reaction such that it is able to quantitatively detect kinases
The activity of PI3K-α.ADP-GloTMKinase assay kit is purchased from Promega company.
All test experience are the most at room temperature carried out, use Corning3674 white 384 orifice plates, kinases PI3K-α from
BPS Biosciences, kinase substrate is P1P2/PS (Invitrogen), uses ELIASA EnVision (Perkin
Elmer) optical signal is read.Detection buffer solution includes 40mM Tris-HCl (pH7.5), 3mM MgCl2And 0.01%BSA;To swash
The kinase reaction solution that enzyme PI3K-α uses detection buffer to be 4nM concentration;Substrate reactions solution includes 100uM P1P2/
PS and 100uM ATP.First compound dissolved dilution in 100%DMSO, to 2mM, is re-used detection buffer solution and is diluted to
0.05mM.First add, in detection plate, the compound and 2 μ L kinase reaction solution that 1 μ L concentration is 0.05mM, mix rear chamber
Temperature lucifuge hatches 15min;Being subsequently added 2 μ L kinase reaction solution, reaction cumulative volume is 5 μ L, is kept away in room temperature by reactant mixture
Light reaction 45min;It is subsequently added and reacts isopyknic 5 μ L ADP-GloTMReagent terminates reaction, mixes rear room temperature and places
40min;Being eventually adding 10 μ L kinase assay reagent, room temperature lucifuge places 30min, then reading numerical values on Envision.
Inhibition percentage calculates based on below equation:
Inhibition percentage=[1-(RLUCompound-RLUmin)/(RLUmax-RLUmin)]×100%
Wherein RLUCompoundFor the cold light reading under given compound concentration, RLUminFor be added without kinase whose in the case of cold
Photoreading, RLUmaxFor being added without the cold light reading in the case of compound.By using in Excel, XLfit program calculates
The IC of compound50。
Experimental result is shown in Table 1.
Embodiment 24 biochemistry detection mTOR activity
Use vitro kinase calibrating experimental evaluation compound for the usefulness of mTOR.By measuring the phosphoric acid of substrate 4E-BP1
Change level measures the kinase activity of mTOR.In time resolution resonance energy transfer is tested, mTOR kinases passes through phosphorylation GFP
The substrate GFP-4E-BP1 of label, when substrate excess, the content of phosphorylated substrate is the highest.The specific antibody of one Tb mark
Tb-chelate labeled anti-4E-BP1 [pT46] can terminate reaction, and induced fluorescence energy is from Tb resonance transfer
Phosphorylation to GFP, 4E-BP1 substrate calculates by being transferred to the energy proportion of GFP from Tb.MTOR TR-FRET kinases is examined
Test agent box is purchased from Invitrogen company.
All test experience are the most at room temperature carried out, black 384 hole using PE company article No. to be Greiner784076
Plate, kinases mTOR is from Invitrogen, and kinase substrate is GFP-4E-BP1 (Invitrogen), uses ELIASA Envision
(Perkin Elmer) reads fluorescence signal.Detection buffer solution includes 50mM HEPES, 5mM MgCl2、0.01%BSA、1mM
DTT, 1mM EGTA and 0.01%Triton X-100;It is 0.31ng/ μ L concentration that kinases mTOR uses detection buffer
Kinase reaction solution;Substrate reactions solution includes 0.8uM GFP-4E-BP1 and 60uM ATP.First by compound at 100%DMSO
Middle dissolved dilution, to 1mM, then carries out the serial dilution of 3 times, altogether 10 concentration point of dilution, re-uses detection buffer solution and is diluted to
100uM.First add, in detection plate, the compound and 2 μ L kinase reaction solution that 0.5 μ L concentration is 100uM, mix rear chamber
Temperature lucifuge hatches 15min;Being subsequently added 2.5 μ L kinase reaction solution, reaction cumulative volume is 5 μ L, by reactant mixture in room temperature
Lucifuge reaction 40min;It is subsequently added and reacts isopyknic 5 μ L TR-FRET detection reagent and (include 2nM Tb-chelate
Labeled anti-4E-BP1 [pT46] and the EDTA of 30mM) terminate reaction, mix rear room temperature lucifuge and place 60min;So
After read the numerical value under 495 and 520nm transmitting light after 340nm excites on Envision instrument respectively.
Inhibition percentage calculates based on below equation:
Inhibition percentage=[1-(compound-min)/(max-min)] × 100%
Fluorescence reading ratio under wherein " compound " is given compound concentration, min for be added without kinase whose in the case of
Fluorescence ratio, max is to be added without the fluorescence ratio in the case of compound.By using in Excel, XLfit program is counted
Calculate the IC of compound50。
Experimental result is shown in Tables 1 and 2.
Table 1PI3K-α biological data
From the data of table 1 it can be seen that all compounds of the present invention are respectively provided with obvious inhibitory action to PI3K.Its
In, the IC of compound 1250Value is 1.725 μMs;The IC of compound 3,4,14,1550Value reaches 100-200nM;Remaining compound
IC50Value reaches 1-100nM.
Table 2mTOR biological data
From the data of table 2 it can be seen that all compounds of the present invention have obvious inhibitory action equally to mTOR.Its
In, the IC of compound 11 and 2150Value reaches 100-200nM;The IC of remaining compound50Value reaches 1-100nM.