CN110759923A - Pyrimidopyrrolopyridazine derivatives, intermediates thereof, preparation method, pharmaceutical compositions and uses - Google Patents

Pyrimidopyrrolopyridazine derivatives, intermediates thereof, preparation method, pharmaceutical compositions and uses Download PDF

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CN110759923A
CN110759923A CN201810832206.9A CN201810832206A CN110759923A CN 110759923 A CN110759923 A CN 110759923A CN 201810832206 A CN201810832206 A CN 201810832206A CN 110759923 A CN110759923 A CN 110759923A
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孙青�
张卫东
赵蒙浩
李霞
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract

The invention discloses a pyrimido-pyrrolopyridazine derivative, an intermediate thereof, a preparation method, a pharmaceutical composition and application. A method for preparing a pyrimido-pyrrolopyridazine derivative represented by formula I, comprising: in the solvent, under the action of the additive, the compound shown in the formula IV can be reacted as shown in the specification. The preparation method of the invention overcomes the defects of multi-step synthesis, low separation yield and the like in the traditional method, and quickly synthesizes various novel heterocyclic compounds with important biological activity. The pyrimido-pyrrolopyridazine derivative has better propertiesInhibit NO production activity of macrophage RAW 264.7.

Description

Pyrimidopyrrolopyridazine derivatives, intermediates thereof, preparation method, pharmaceutical compositions and uses
Technical Field
The invention relates to a pyrimido-pyrrolopyridazine derivative, an intermediate thereof, a preparation method, a pharmaceutical composition and application.
Background
Nitrogenous heterocycles are important cores of a class of biologically active compounds (chem. heterocyclic. Compd.2016,52, 651-657; Curr. org. chem.2017,21, 1265-1291). Among them, pyridazine fused heterocycles have received much attention because of their remarkable broad spectrum of biological activities, including diuretic activity (J.Med.chem.1999,42,779-783), anti-HIV-1 (J.Med.chem.2000,43,2457-2463), psychoactive effects (J.Med.chem.2005,48,1367-1383) and platelet aggregation activity (J.Med.chem.1986,29,2191-2194), and the like. The development of such frameworks has been limited by multistep syntheses and low isolation yields (Heterocycles 1993, 35.; J.Heterocy.chem.2005, 42, 361-373).
Some reported nitrogen heterocyclic ring systems are constructed generally under the conditions of catalyst, proper solvent and high-temperature reflux, and the yield is not high. The multi-step reaction and the complex reaction conditions make the construction of the heterocyclic ring system more difficult, and limit the development of various drugs (J.Med.chem.2014,57, 7577-2689; J.Med.chem.2014,57, 2683-2691.).
Although researchers have made a lot of effort in constructing pyridazine fused compounds, the synthesis of pyrimido-pyrrolopyridazines remains a challenging task (J.heterocyclic. chem.2005,42, 361-.
Therefore, there is a need in the art to develop a method for efficiently preparing pyrimido-pyrrolopyridazine derivatives.
Disclosure of Invention
The invention aims to overcome the defects of long synthesis route, low total yield and the like in the synthesis process of the nitrogenous heterocyclic derivative in the prior art, and provides a pyrimido-pyrrolopyridazine derivative, an intermediate, a preparation method, a pharmaceutical composition and application. The preparation method overcomes the defects of multi-step synthesis, low separation yield and the like in the traditional method, realizes the high-efficiency synthesis of the pyrimido-pyrrolopyridazine derivative, and has high yield.
The invention provides a pyrimido-pyrrolopyridazine derivative shown as a formula I, a pharmaceutically acceptable salt thereof or a prodrug thereof:
Figure BDA0001743762340000021
wherein R is1Selected from H, C1-C12Straight or branched alkyl of (2), C1-C12Linear or branched haloalkyl of, C1-C12Linear or branched alkoxy of (C)3-C6Cycloalkyl radical, C6-C20Aryl of (C)2-C10By one or more (e.g. 1-6, preferably 1-3 or 1-2) R1aSubstituted C6-C20Or by one or more (e.g. 1-6, preferably 1-3 or 1-2) R1bSubstituted C2-C10Wherein R is selected from the group consisting of (1-3) heteroaryl (one or more of N, O and S as heteroatoms), wherein1aAnd R1bEach independently selected from hydroxy, nitro, halogen, amino, C1-C6Straight or branched alkyl of (2), C1-C6Linear or branched alkoxy or C1-C6Linear or branched haloalkyl of (a); when R is1aOr R1bWhen there are plural, R1aOr R1bThe same or different;
R2～R5each independently selected from-H or C1-C12Linear or branched alkyl.
In the present invention, when R is1Is C1-C12When the alkyl group is a straight or branched alkyl group, said C1-C12The linear or branched alkyl group of (1) is preferably C1-C6Further preferably C1-C3More preferably a methyl group or an ethyl group.
When R is1Is C1-C12When said C is a straight or branched haloalkyl group1-C12Is preferably C substituted by one or more identical or different halogen atoms1-C12Said halogens may be on the same or different carbon atoms; said C1-C12The straight-chain or branched haloalkyl group of (A) is preferably C1-C3Linear or branched haloalkyl.
When R is1Is C1-C12When said alkoxy is a straight or branched alkoxy group, said C1-C12The straight-chain or branched alkoxy of (A) is preferably C1-C6Further preferably C1-C3The straight-chain or branched alkoxy group of (2) is more preferably a methoxy group or an ethoxy group.
When R is1Is C3-C6When a cycloalkyl group is present, C is3-C6Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
When R is1Is C6-C20Aryl of (2), C6-C20Aryl of (A) is preferably C6-C10More preferably, the aryl group of (1) is phenyl or naphthyl.
When R is1Is C2-C10When said heteroaryl is said C2-C10Heteroaryl of (A) is preferably C2-C8The heteroaryl group of (1) is more preferably a pyridyl group or a thienyl group.
When R is1Is represented by one or more R1aSubstituted C6-C20Aryl of (2), C6-C20Aryl of (A) is preferably C6-C10More preferably, the aryl group of (1) is phenyl or naphthyl.
When R is1Is represented by one or more R1bSubstituted C2-C10When said heteroaryl is said C2-C10Heteroaryl of (A) is preferably C2-C8The heteroaryl group of (1) is more preferably a pyridyl group or a thienyl group.
In the present invention, when R is1aOr R1bIn the case of halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine.
When R is1aOr R1bIs C1-C6When the alkyl group is a straight or branched alkyl group, said C1-C6The linear or branched alkyl group of (1) is preferably C1-C3Further, the straight-chain or branched alkyl group of (1) is preferably a methyl group or an ethyl group.
When R is1aOr R1bIs C1-C6When said alkoxy is a straight or branched alkoxy group, said C1-C6The straight-chain or branched alkoxy of (A) is preferably C1-C3The straight-chain or branched alkoxy group of (4) is more preferably a methoxy group or an ethoxy group.
When R is1aOr R1bIs C1-C6When said C is a straight or branched haloalkyl group1-C6Is preferably C substituted by one or more identical or different halogen atoms1-C6The halogens may be on the same or different carbon atoms; more preferably C1-C3Linear or branched haloalkyl.
When R is2～R5Each independently is C1-C12When the alkyl group is a straight or branched alkyl group, said C1-C12The linear or branched alkyl group of (1) is preferably C1-C6Further preferably C1-C3More preferably a methyl group, an ethyl group or an n-propyl group.
In a preferred embodiment of the invention, R is preferably1Is C1-C3Linear or branched alkyl (e.g. methyl), C6-C10Aryl (e.g. phenyl, naphthyl), C2-C8Or by an R1aSubstituted C6-C10Aryl (e.g. phenyl, naphthyl), and R1aIs halogen (e.g. chlorine), C1-C3A linear or branched alkyl group (e.g., methyl) or nitro group; further preferred is R1Is methyl, phenyl, pyridyl, naphthyl, thienyl or substituted by one R1aSubstituted phenyl, and R1aIs chlorine, methyl or nitro.
In a preferred embodiment of the invention, R is preferably2～R4And is also H.
In a preferred embodiment of the invention, R is preferably2～R3At the same time is C1-C3Straight or branched alkyl of R4Is H; further preferably, R2～R3Simultaneously being methyl, R4Is H.
In a preferred embodiment of the invention, R is preferably2～R3At the same time being H, R4Is C1-C3Linear or branched alkyl of (a); further preferably, R2～R3At the same time being H, R4Is ethyl.
In a preferred embodiment of the invention, R is preferably1Is phenyl, substituted by one R1aSubstituted phenyl, pyridyl, naphthyl or thienyl, and R1aIs chlorine, methyl or nitro, R2～R4At the same time being H, R5Is C1-C3Is a straight or branched alkyl group (for example, methyl, ethyl or n-propyl).
In a preferred embodiment of the invention, R is preferably1Is phenyl, substituted by one R1aSubstituted phenyl, pyridyl, naphthyl or thienyl, and R1aIs chlorine, methyl or nitro, R2～R3At the same time is C1-C3Linear or branched alkyl (e.g. both methyl), R4Is H, R5Is C1-C3Is a straight or branched alkyl group (for example, methyl, ethyl or n-propyl).
In a preferred embodiment of the invention, R is preferably1Is phenyl, pyridyl, naphthyl or thienyl, R2～R3At the same time is C1-C3Linear or branched alkyl (e.g. both methyl), R4Is H, R5Is methyl.
In a preferred embodiment of the invention, R is preferably1Is phenyl, phenyl substituted by a halogen, e.g. chlorine, pyridyl, naphthyl or thienyl, R2～R3At the same time is C1-C3Linear or branched alkyl (e.g. both methyl), R4Is H, R5Is ethyl or n-propyl.
In a preferred embodiment of the invention, R is preferably1Is phenyl, substituted by one R1aSubstituted phenyl, pyridyl, naphthyl or thienyl, and R1aIs chlorine, methyl or nitro, R2～R3At the same time being H, R4Is C1-C3Linear or branched alkyl (e.g. ethyl), R5Is C1-C3Is a straight or branched alkyl group (for example, methyl, ethyl or n-propyl).
In the invention, the pyrimido-pyrrolopyridazine derivative shown in the formula I can be selected from any one of the following compounds:
Figure BDA0001743762340000041
Figure BDA0001743762340000051
the invention also provides a preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I, which comprises the following steps: in a solvent, under the action of an additive, a compound shown in a formula IV is subjected to the following reaction;
Figure BDA0001743762340000061
wherein R is1～R5As defined above.
In the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the solvent can be a solvent conventional in the field of such reactions, and the invention is preferably one or more of halogenated alkane (such as dichloromethane and dichloroethane), nitrile solvent (such as acetonitrile), ether solvent (such as tetrahydrofuran), alcohol solvent (such as methanol and ethanol), amide solvent (such as N, N-dimethylformamide) and aromatic hydrocarbon solvent (such as toluene); further preferably one or more of acetonitrile, tetrahydrofuran, methanol, N-dimethylformamide and toluene; more preferably, the solvent is acetonitrile.
In the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the dosage of the solvent can be the conventional dosage for the reaction in the field, so as to ensure that the reaction is smoothly carried out.
In the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the additive can be organic amine and R6OM1、
Figure BDA0001743762340000062
NaH、XaYb、M3(OAc)2One or more of copper trifluoroacetate, boron trifluoride and boron trifluoride etherate complex; wherein R is6～R7Each independently is C1-C6Straight or branched alkyl (e.g. C)2-C4Straight-chain or branched alkyl radicals of (2), further e.g. ethyl, tert-butyl), M1Selected from alkali metals (e.g. Na or K, also e.g. Na), M2Selected from-H or alkali metals (e.g. Na or K, and also e.g. Na), M3Is selected from Cu or Pd, X is Cu, Mg, Zn, Al or Fe, Y is halogen (such as fluorine, chlorine, bromine or iodine, and chlorine, bromine or iodine), a and b are integers of 1-3 respectively and are selected according to X and Y; preferably, the additive is one or more of N, N-diisopropylethylamine, sodium acetate, sodium tert-butoxide, sodium hydride, acetic acid, copper chloride, copper bromide, copper iodide, magnesium chloride, zinc chloride, aluminum chloride, ferric chloride, copper acetate, palladium acetate and boron trifluoride diethyl etherate; further preferably, the additive is copper chloride.
In the preparation method of the pyrimido-pyrrolopyridazine derivative shown in formula I, the molar ratio of the additive to the compound of formula IV can be a molar ratio which is conventional in the reaction in the field, and preferably, the molar ratio of the additive to the compound of formula IV is 1:0.1-1:1, and more preferably, the molar ratio of the additive to the compound of formula IV is 1:0.1-1:0.2 (for example, 1: 1).
In the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the reaction temperature can be the temperature conventional in the field; preferably, the reaction is carried out at 20 to 80 ℃ (e.g., room temperature, 45 to 55 ℃ or reflux temperature, preferably 45 to 55 ℃, and more preferably 50 ℃). The progress of the reaction can be monitored by means of tests customary in the art (e.g. TLC), generally with the end point of the reaction being the disappearance or no longer reaction of the starting materials; preferably for 4-16 h.
In the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the reaction may further comprise the following post-treatment steps: the reaction mixture is cooled (preferably to room temperature), mixed with ethyl acetate and then treated with saturated NH4And (3) washing the organic phase by using a Cl solution and water, drying, concentrating and purifying by using a flash column chromatography.
In the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the conditions of the flash column chromatography can be the conditions conventional in the operation in the field, preferably, petroleum ether and ethyl acetate are used as eluent, and further preferably, the volume ratio of the petroleum ether to the ethyl acetate is 10:1-1: 1.
In the invention, the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I can also comprise the following steps: in a solvent, performing Michael addition reaction on cycloalkenone amines (HKAs) shown in a formula II and 1, 2-diaza-1, 3-diene (DDs) shown in a formula III to obtain a compound shown in a formula IV;
wherein R is1～R5As defined above.
In the present invention, the cycloalkenone amine can be prepared by methods well known to those of ordinary skill in the art of organic chemistry, and specifically, Huang, Z. -T.; wang, M. -X., Synthesis 1992,12, 1273-; smith, C.D., Synthetic Communications 2001,31, 527-:
in the present invention, the 1, 2-diaza-1, 3-diene can be prepared by methods well known to those skilled in the art of organic chemistry, and in the present invention, reference can be made specifically to Sommer, s., Tetrahedron Letters 1977,18, 117. ion 120 and Attanasi, o.a.; filipponone, P.; mei, a.; the synthesis of Santesunio, S.Synthesis 1984,10, 874-A876, the specific synthetic route is shown below:
Figure BDA0001743762340000082
in the preparation method of the compound shown in the formula IV, the type and the amount of the solvent are as described above.
In the process for the preparation of the compounds of formula IV, the molar ratio of cycloalkenone amine and 1, 2-diaza-1, 3-diene may be in the proportions conventionally used in such reactions in the art, and in the present invention it is preferably in the range of 1:1 to 1:2, such as 1: 1.
In the preparation of the compounds of formula IV, the Michael addition reaction may be supplemented, as desired, with additives conventional in the art for such reactions, e.g., organic amines, R6OM1、
Figure BDA0001743762340000083
NaH、XaYb、M3(OAc)2One or more of copper trifluoroacetate, boron trifluoride and boron trifluoride diethyl etherate complex, wherein R is6～R7Each independently is C1-C6Straight or branched alkyl (e.g. C)2-C4Straight-chain or branched alkyl radicals of (2), further e.g. ethyl, tert-butyl), M1Selected from alkali metals (e.g. Na or K, also e.g. Na), M2Selected from-H or alkali metals (e.g. Na or K, and also e.g. Na), M3Selected from Cu or Pd, X is Cu, Mg, Zn,Al or Fe, Y is halogen (such as fluorine, chlorine, bromine or iodine, and chlorine, bromine or iodine), a and b are independently integers of 1-3, and are selected according to X and Y.
In the process for preparing the compound of formula IV, the Michael addition reaction is preferably carried out in the absence of an additive.
In the process for preparing the compound of formula IV, the reaction temperature of the michael addition reaction may be a temperature conventional in the art for such reactions; the present invention is preferably controlled to a temperature between 20 ℃ and reflux temperature (e.g., room temperature, 50 ℃ or reflux temperature), and more preferably, the reaction temperature of the Michael addition reaction is room temperature (20 ℃ to 25 ℃).
In the preparation of the compound of formula IV, the progress of the Michael addition reaction can be monitored by conventional testing procedures in the art (e.g., TLC), typically with the disappearance or no further reaction of starting materials as an end point of the reaction. The reaction time of the Michael addition reaction is preferably 4 to 16 hours.
In the invention, the preparation method of the pyrimido-pyrrolopyridazine derivative shown in the formula I is preferably prepared by adopting the following one-pot method:
(1) in a solvent, performing Michael addition reaction on cycloalkenone amine shown in a formula II and 1, 2-diaza-1, 3-diene shown in a formula III to obtain a compound shown in a formula IV;
(2) directly mixing the reaction solution obtained in the step (1) with an additive without post-treatment, and then reacting;
Figure BDA0001743762340000091
wherein R is1～R5As defined above.
The specific conditions and parameters involved in steps (1) and (2) above are as described above.
Preferably, when the pyrimido-pyrrolopyridazine derivative represented by formula I is prepared by a one-pot method, the additive may be a metal halide (e.g., cupric chloride, cupric bromide, cupric iodide, zinc chloride); further preferably, the additive is copper chloride.
The invention also provides a compound shown as the formula IV, a tautomer, an optical isomer, a pharmaceutically acceptable salt or a prodrug thereof:
wherein R is1～R5As defined above.
In the present invention, the compound represented by formula IV may be selected from any one of the following compounds:
Figure BDA0001743762340000102
Figure BDA0001743762340000111
the invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps: in a solvent, performing Michael addition reaction on cycloketene amine shown in a formula II and 1, 2-diaza-1, 3-diene shown in a formula III to obtain a compound shown in a formula IV;
Figure BDA0001743762340000121
wherein R is1～R5As previously described, and the specific reaction conditions and parameters of the michael addition reaction are as previously described.
The invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of pyrimido-pyrrolopyridazine derivative shown in the formula I, a tautomer, an optical isomer, a pharmaceutically acceptable salt or a prodrug thereof, and at least one pharmaceutical adjuvant. The mass percentage of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the tautomer, the optical isomer, the pharmaceutically acceptable salt or the prodrug thereof in the pharmaceutical composition is 0.1% -99.9%. The choice of such pharmaceutical excipients depends on the route of administration and on the nature of action and is generally filler, diluent, binder, wetting agent, disintegrant, lubricant, emulsifier or suspending agent.
The invention also provides application of the pyrimido-pyrrolopyridazine derivative shown in the formula I, the tautomer, the optical isomer, the pharmaceutically acceptable salt or the prodrug thereof in preparation of anti-inflammatory drugs.
In the present invention, the anti-inflammatory agent may be an anti-inflammatory agent commonly used in the art, for example, an anti-inflammatory agent having diuretic activity, activity of inhibiting NO production by macrophage RAW264.7, anti-HIV-1, etc.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
In the present invention, room temperature means 20 to 25 ℃.
In the present invention, the reflux temperature refers to the reflux temperature of the solvent at normal atmospheric pressure.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the pyrimido-pyrrolopyridazine derivatives of the present invention are synthesized from cycloalkenone amine and 1, 2-diaza-1, 3-diene as starting materials, preferably by a tandem reaction involving michael addition, aminolysis and aromatization processes. The preparation method overcomes the defects of multi-step synthesis, low separation yield and the like in the traditional method, quickly synthesizes various novel heterocyclic compounds with important biological activity, and has the total yield of 17-65 percent. The pyrimido-pyrrolopyridazine derivative has good activity of inhibiting NO generation of macrophage RAW264.7, and can be used for preparing anti-inflammatory drugs.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Experimental methods in the following examples, in which specific conditions are not specified, according to conventional methods and conditions, or according toAnd selecting the commodity instruction. The starting materials are commercially available or prepared by methods known in the art or according to the methods described herein, wherein HKAs is referred to Huang, z. -t.; wang, M. -X., Synthesis 1992,12, 1273-; smith, C.D., Synthetic Communications 2001,31, 527-; DDs are referenced to Sommer, S., Tetrahedron Letters 1977,18,117-120 and Attanasi, O.A.; filipponone, P.; mei, a.; santesunio, S.Synthesis 1984,10, 874-876, the DDs being mixtures of E/Z isomers. The structure of the compound is determined by nuclear magnetic resonance1H NMR or13C NMR) and Mass Spectrometry (MS), wherein NMR measurement is performed using a Bruker DRX500 type nuclear magnetic resonance apparatus, chemical shifts (. delta.) are expressed in ppm, J values are expressed in Hz, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-D)6) Or deuterated chloroform (CDCl)3) Melting points were determined on an SGWX-4A melting point instrument, uncorrected HRM.X-ray diffraction measurements were performed on an AgllentLC/Msd TOF instrument on a Bruker SMART APEX-II CCD area detector system equipped with a graphite monochromator and a Cu-K α precision sealed tube at 296K.
Example 1:
preparation of Compound II-1
Reference Huang, z. -t.; wang, M. -X., Synthesis 1992,12, 1273-; smith, C.D., Synthetic Communications 2001,31, 527-:
Figure BDA0001743762340000131
acetophenone (10.0mmol) was dissolved in THF (50ml) in ice bath, NaH (20.0mmol) was added and stirred for half an hour, CS was added2(10.0mmol) was added dropwise to the above reaction mixture, the ice bath was kept and stirring was continued for two hours, and finally MeI (20.0mmol) was added dropwise to the reaction mixture, and after half an hour of ice bath, the temperature was slowly raised to room temperature and stirring was continued overnight. The reaction was evaporated to dryness under reduced pressure and diluted with EtOAc (100 mL). The organic phase was washed successively with water (50mL) and saturated brine (50mL), and then with Na2SO4The solution was dried and evaporated to dryness under reduced pressure and used directly for the next reaction.
Dissolving the crude product of the reaction in the previous step in ethanol (10ml), adding 1, 3-propane diamine (15.0mmol), heating to 100 ℃, reacting for four hours, cooling to 0 ℃, separating out a solid, performing suction filtration, and drying to obtain a yellow solid II-1, wherein the yield is as follows: 90 percent.
Preparation of Compound III-1
Reference is made to Sommer, S., Tetrahedron Letters 1977,18, 117-; filipponone, P.; mei, a.; santeusines, S.Synthesis 1984,10, 874-A876, the specific synthetic route is shown below:
sulfuryl chloride (10.0mmol) is added dropwise to ethyl acetoacetate (10.0mmol) under ice bath, after stirring for half an hour, the reaction solution is evaporated to dryness under reduced pressure, and the crude product is directly used in the next reaction.
Semicarbazide hydrochloride (10.0mmol) and sodium acetate (10.0mmol) were dissolved in methanol (50mL) and stirred for half an hour, the crude product from the previous reaction was added to the reaction mixture, stirred overnight, the reaction mixture was evaporated to dryness under reduced pressure and diluted with DCM (100mL), washed with saturated sodium carbonate solution (50mL) X2 to give a red organic phase which was evaporated to dryness under reduced pressure to give a red solid III-1, yield: 80 percent.
Preparation of Compound IV-1
Figure BDA0001743762340000142
In CH3HKAs of formula II-1 (1.0mmol) and DDs of formula III-1 (1.0mmol) were added to CN (25ml), stirred at room temperature, followed by TLC (thin layer chromatography using silica gel GF 254) until complete consumption of HKAs and DDs, the solution was evaporated to dryness under reduced pressure on a rotary evaporator, and the residue was purified by flash column chromatography on silica gel (40-63 μm) with eluent (petroleum ether: ethyl acetate ═ 1:1, v/v) to give a yellow solid IV-1, melting point: 155.2-155.7 ℃, yield: 70 percent of the total weight of the mixture,
Figure BDA0001743762340000151
1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),7.92–7.86(m,2H),7.67(ddt,J＝8.6,7.2,1.3Hz,1H),7.55–7.49(m,2H),3.63–3.53(m,4H),2.15(s,3H),1.85–1.75(m,2H)；13C NMR(125MHz,DMSO-d6)δ192.63,166.51,156.57,151.76,138.56,137.77,135.71,134.96,129.55,129.34,46.95,37.19,20.23,14.01；HRMS(TOF ES+):C17H18N5O3[(M+H)+]calculated value of 340.1404, found 340.1405.
Example 2: preparation of pyrimido-pyrrolopyridazine derivative I-1
Figure BDA0001743762340000152
In CH3HKAs (0.2mmol) of the formula II-1 and DDs (0.2mmol) of the formula III-1 were added to CN (5ml), stirred at room temperature, and followed by TLC (thin layer chromatography using silica gel GF 254) until the HKAs and DDs were completely consumed to obtain the compound of the formula IV-1, which was directly subjected to the subsequent reaction without isolation.
Adding CuCl to the reaction2(0.02mmol), the resulting mixture was stirred at 50 ℃ until the compound represented by the formula IV-1 was completely converted to the product I-1 (monitored by thin layer chromatography using silica gel GF 254). The mixture was cooled to room temperature and diluted with EtOAc (25 mL). The organic phase is saturated with NH4Cl solution (20mL) and water (20mL) and Na2SO4Drying, evaporation of the solution to dryness on a rotary evaporator under reduced pressure and purification of the residue by flash column chromatography on silica gel (particle size 40-63 μm) with eluent (petroleum ether: ethyl acetate ═ 5:1, v/v) gave I-1 as a yellow solid, melting point: 201.2-201.7 ℃, yield: at a rate of 62%,
Figure BDA0001743762340000161
1H NMR(500MHz,CDCl3)δ8.09–8.00(m,2H),7.56–7.46(m,3H),3.83(t,J＝5.7Hz,4H),3.13(s,3H),1.97-1.92(m,2H)；13C NMR(126MHz,CDCl3)δ165.11,155.47,154.83,148.49,134.22,130.55,130.14,128.55,127.80,126.35,47.14,37.73,19.81,18.63；HRMS(TOF ES+):C16H15N4O[(M+H)+]the predicted value of (2) is 279.1240, and the measured value is 279.1243.
Example 3: preparation of pyrimido-pyrrolopyridazine derivative I-2
The preparation process of the pyrimido-pyrrolopyridazine derivative I-2 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-2, melting point: 174.6-175.3 ℃, yield: 65 percent of the total weight of the mixture,
Figure BDA0001743762340000163
1H NMR(500MHz,CDCl3)δ7.96(d,J＝8.2Hz,2H),7.30(d,J＝7.9Hz,2H),3.83(q,J＝5.6Hz,4H),3.11(s,3H),2.46–2.41(m,3H),1.97-1.92(m,2H)；13C NMR(126MHz,CDCl3)δ165.21,155.47,154.52,148.65,140.37,131.38,130.48,128.60,128.33,126.31,47.15,37.73,21.52,19.81,18.60；HRMS(TOF ES+):C17H17N4O[(M+H)+]the predicted value of (2) is 293.1397, and the measured value is 293.1398.
Example 4: preparation of pyrimido-pyrrolopyridazine derivative I-3
Figure BDA0001743762340000171
The preparation process of the pyrimido-pyrrolopyridazine derivative I-3 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-3, melting point: 182.9-183.8 ℃, yield: the content of the active carbon is 58 percent,
Figure BDA0001743762340000172
1H NMR(500MHz,CDCl3)δ8.03(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),3.85-3.82(m,4H),3.12(s,3H),1.98-1.94(m,2H)；13C NMR(126MHz,CDCl3)δ164.98,155.14,154.39,148.52,136.47,132.63,131.94,128.52,128.11,126.39,77.27,77.02,76.76,47.13,37.75,19.78,18.64；HRMS(TOF ES+):C16H14ClN4O[(M+H)+]the predicted value of (2) is 313.0851, and the measured value is 313.0852.
Example 5: preparation of pyrimido-pyrrolopyridazine derivative I-4
Figure BDA0001743762340000173
The preparation process of the pyrimido-pyrrolopyridazine derivative I-4 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain yellow solid I-4, melting point: 175.0-176.1 ℃, yield: 60 percent of the total weight of the mixture,
1H NMR(500MHz,CDCl3)δ8.08(t,J＝1.8Hz,1H),7.95(dt,J＝7.6,1.4Hz,1H),7.48(ddd,J＝8.0,2.1,1.1Hz,1H),7.43(t,J＝7.8Hz,1H),3.86-3.83(m,4H),3.13(s,3H),1.99-1.94(m,2H)；13C NMR(126MHz,CDCl3)δ164.91,155.45,154.16,148.35,135.85,133.78,130.62,130.17,129.65,129.04,128.73,126.46,47.14,37.75,19.78,18.66；HRMS(TOF ES+):C16H14ClN4O[(M+H)+]the predicted value of (2) is 313.0851, and the measured value is 313.0851.
Example 6: preparation of pyrimido-pyrrolopyridazine derivative I-5
Figure BDA0001743762340000182
The process for preparing the pyrimido-pyrrolopyridazine derivative I-5 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-5, melting point: 157.1-158.0 ℃, yield: 35 percent of the total weight of the mixture,
Figure BDA0001743762340000183
1H NMR(500MHz,CDCl3)δ9.43(s,1H),8.82(s,1H),8.51(d,J＝7.9Hz,1H),7.55(s,1H),3.87-3.84(m,4H),3.16(s,3H),2.03–1.90(m,2H)；13C NMR(126MHz,CDCl3)δ164.69,155.90,152.23,150.99,150.06,148.14,138.72,130.98,129.11,126.44,123.52,47.09,37.76,19.79,18.69；HRMS(TOF ES+):C15H14N5O[(M+H)+]the predicted value of (2) is 280.1193, and the measured value is 280.1193.
Example 7: preparation of pyrimido-pyrrolopyridazine derivative I-6
The process for preparing the pyrimido-pyrrolopyridazine derivative I-6 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain yellow solid I-6, melting point: 201.2-201.5 ℃, yield: 65 percent of the total weight of the mixture,
Figure BDA0001743762340000192
1H NMR(500MHz,CDCl3)δ8.62(s,1H),8.13(d,J＝8.5Hz,1H),7.94(d,J＝8.3Hz,2H),7.92–7.87(m,1H),7.58–7.48(m,2H),3.86-3.81(m,4H),3.16(s,3H),1.98-1.94(m,2H)；13C NMR(126MHz,CDCl3)δ165.16,155.49,154.80,148.61,134.16,132.76,131.65,130.98,128.97,128.73,127.67,127.46,127.20,127.13,126.39,126.15,77.25,77.00,76.74,47.14,37.74,19.82,18.64；HRMS(TOF ES+):C20H17N4O[(M+H)+]the predicted value of (2) is 329.1397, and the measured value is 329.1398.
Example 8: preparation of pyrimido-pyrrolopyridazine derivative I-7
Figure BDA0001743762340000193
The process for preparing the pyrimido-pyrrolopyridazine derivative I-7 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-7, melting point: 195.8-199.3 ℃, yield: the content of the active ingredients is 38%,
Figure BDA0001743762340000201
1H NMR(500MHz,CDCl3)δ8.40–8.30(m,2H),8.29–8.23(m,2H),3.87-3.82(m,4H),3.16(s,3H),2.00–1.96(m,2H)；13C NMR(126MHz,CDCl3)δ164.65,156.10,153.40,148.77,148.25,140.31,131.64,129.11,126.47,122.93,47.14,37.78,19.75,18.73；HRMS(TOF ES+):C16H14N5O3[(M+H)+]the predicted value of (2) is 324.1091, and the measured value is 324.1091.
Example 9: preparation of pyrimido-pyrrolopyridazine derivative I-8
Figure BDA0001743762340000202
The process for preparing the pyrimido-pyrrolopyridazine derivative I-8 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-8, melting point: 187.0-187.9 ℃, yield: in the range of 52%,
Figure BDA0001743762340000203
1H NMR(500MHz,CDCl3)δ8.06–8.00(m,2H),7.49–7.44(m,2H),3.85-3.82(m,4H),3.54(q,J＝7.6Hz,2H),1.99-1.94(m,2H),1.48(t,J＝7.6Hz,3H)；13C NMR(126MHz,CDCl3)δ164.81,159.85,154.32,148.57,136.44,132.70,131.96,128.77,128.09,125.87,77.27,77.22,77.01,76.76,47.12,37.75,25.61,19.79,13.43；HRMS(TOF ES+):C17H16ClN4O[(M+H)+]the predicted value of (2) is 327.1007, and the measured value is 327.1007.
Example 10: preparation of pyrimido-pyrrolopyridazine derivative I-9
Figure BDA0001743762340000211
The preparation process of the pyrimido-pyrrolopyridazine derivative I-9 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain yellow solid I-9, melting point: 175.2-176.1 ℃, yield: the content of the active carbon is 53 percent,
Figure BDA0001743762340000212
1H NMR(500MHz,CDCl3)δ8.09(t,J＝1.9Hz,1H),7.95(dt,J＝7.6,1.4Hz,1H),7.48(ddd,J＝8.0,2.1,1.2Hz,1H),7.42(t,J＝7.8Hz,1H),3.90–3.80(m,4H),3.54(q,J＝7.6Hz,2H),2.04–1.91(m,2H),1.49(t,J＝7.6Hz,3H)；13C NMR(126MHz,CDCl3)δ164.73,160.10,154.08,148.38,135.94,133.75,130.65,130.13,129.01,128.94,128.75,125.89,77.28,77.02,76.77,47.13,37.74,25.63,19.78,13.44；HRMS(TOF ES+):C17H16ClN4O[(M+H)+]the predicted value of (2) is 327.1007, and the measured value is 327.1007.
Example 11: preparation of pyrimido-pyrrolopyridazine derivative I-10
The preparation process of the pyrimido-pyrrolopyridazine derivative I-10 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-10, melting point: 209.9-210.3 ℃, yield: 60 percent of the total weight of the mixture,
1H NMR(500MHz,CDCl3)δ8.63(dd,J＝1.8,0.8Hz,1H),8.14(dd,J＝8.5,1.8Hz,1H),7.98-7.92(m,2H),7.90(dt,J＝7.8,1.0Hz,1H),7.58-7.49(m,2H),3.86-3.82(m,4H),3.57(q,J＝7.6Hz,2H),2.01-1.92(m,2H),1.52(t,J＝7.6Hz,3H)；13C NMR(126MHz,CDCl3)δ165.00,159.54,155.43,148.65,134.15,132.76,131.71,130.99,128.98,127.69,127.49,127.18,127.13,126.15,125.90,77.27,77.22,77.01,76.76,47.13,37.74,25.64,19.83,13.48；HRMS(TOF ES+):C21H19N4O[(M+H)+]the predicted value of (2) is 343.1553, and the measured value is 343.1553.
Example 12: preparation of pyrimido-pyrrolopyridazine derivative I-11
Figure BDA0001743762340000222
The process for preparing pyrimido-pyrrolopyridazine derivative I-11 was similar to that of I-1, and the kinds of HKAs and DDs were changed to obtain yellow solid I-11, melting point: 183.2-183.9 ℃, yield: 50 percent of the total weight of the mixture is,
Figure BDA0001743762340000223
1H NMR(500MHz,CDCl3)δ8.08–8.01(m,2H),7.52-7.48(m,3H),3.84-3.82(m,4H),3.54(q,J＝7.6Hz,2H),2.00–1.91(m,2H),1.49(t,J＝7.5Hz,3H)；13C NMR(125MHz,CDCl3)δ164.96,159.57,155.43,148.56,134.29,130.57,130.13,128.80,127.77,125.84,77.28,77.02,76.77,47.12,37.73,25.61,19.82,13.48；HRMS(TOF ES+):C17H17N4O[(M+H)+]the predicted value of (2) is 293.1397, and the measured value is 293.1397.
Example 13: preparation of pyrimido-pyrrolopyridazine derivative I-12
Figure BDA0001743762340000231
The preparation process of the pyrimido-pyrrolopyridazine derivative I-12 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-12, melting point: 166.5-167.2 ℃, yield: 54 percent of the total weight of the mixture,
1H NMR(500MHz,CDCl3)δ8.07–8.02(m,2H),7.50–7.44(m,2H),3.85-3.82(m,4H),3.55–3.46(m,2H),1.99-1.90(m,4H),1.08(t,J＝7.4Hz,3H)；13C NMR(126MHz,CDCl3)δ164.83,158.88,154.22,148.55,136.44,132.70,131.97,128.70,128.09,126.07,77.27,77.01,76.76,47.12,37.73,33.87,22.82,19.78,13.96；HRMS(TOF ES+):C18H18ClN4O[(M+H)+]the predicted value of (2) is 341.1164, and the measured value is 341.1164.
Example 14: preparation of pyrimido-pyrrolopyridazine derivative I-13
Figure BDA0001743762340000233
The preparation process of the pyrimido-pyrrolopyridazine derivative I-13 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain yellow solid I-13, melting point: 161.4-161.9 ℃, yield: in the range of 52%,
Figure BDA0001743762340000241
1H NMR(500MHz,CDCl3)δ8.17–7.97(m,2H),7.52-7.48(m,3H),3.84-38.2(m,4H),3.56–3.40(m,2H),2.01–1.88(m,4H),1.08(t,J＝7.4Hz,3H)；13C NMR(126MHz,CDCl3)δ164.99,158.59,155.32,148.54,134.30,130.58,130.12,128.72,127.77,126.04,77.28,77.22,77.03,76.77,47.12,37.72,33.88,22.84,19.81,13.98；HRMS(TOF ES+):C18H19N4O[(M+H)+]the predicted value of (2) is 307.1553, and the measured value is 307.1553.
Example 15: preparation of pyrimido-pyrrolopyridazine derivative I-14
Figure BDA0001743762340000242
The process for preparing the pyrimido-pyrrolopyridazine derivative I-14 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain yellow solid I-14, melting point: 207.9-208.6 ℃, yield: in the content of 56%,
Figure BDA0001743762340000243
1H NMR(500MHz,CDCl3)δ8.64(d,J＝2.0Hz,1H),8.15(dd,J＝8.5,1.8Hz,1H),7.94(d,J＝8.3Hz,2H),7.90(dd,J＝8.0,1.5Hz,1H),7.56-7.50(m,2H),3.86-3.81(m,4H),3.56–3.49(m,2H),2.01–1.91(m,4H),1.11(t,J＝7.4Hz,3H)；13C NMR(126MHz,CDCl3)δ165.03,158.56,155.32,148.62,134.14,132.76,131.71,131.00,128.98,128.90,127.69,127.51,127.17,127.13,126.15,126.10,77.28,77.02,76.77,47.13,37.73,33.90,22.85,19.82,14.00；HRMS(TOF ES+):C22H21N4O[(M+H)+]the predicted value of (2) is 357.1710, and the measured value is 357.1710.
Example 16: preparation of pyrimido-pyrrolopyridazine derivative I-15
Figure BDA0001743762340000251
The process for preparing the pyrimido-pyrrolopyridazine derivative I-15 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-15, melting point: 158.9-159.6 ℃, yield: in the range of 52%,
Figure BDA0001743762340000252
1H NMR(500MHz,CDCl3)δ8.09(t,J＝1.9Hz,1H),7.96(dt,J＝7.6,1.4Hz,1H),7.48(ddd,J＝8.0,2.1,1.2Hz,1H),7.42(t,J＝7.8Hz,1H),3.86-3.82(m,4H),3.55–3.43(m,2H),2.02–1.88(m,4H),1.08(t,J＝7.4Hz,3H)；13C NMR(125MHz,CDCl3)δ164.75,159.13,153.98,148.37,135.94,133.74,130.66,130.13,129.01,128.87,128.76,126.09,77.28,77.02,76.77,47.13,37.73,33.88,22.82,19.78,13.96；HRMS(TOF ES+):C18H18ClN4O[(M+H)+]the predicted value of (2) is 341.1164, and the measured value is 341.1164.
Example 17: preparation of pyrimido-pyrrolopyridazine derivative I-16
The process for preparing the pyrimido-pyrrolopyridazine derivative I-16 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-16, melting point: 151.2-151.9 ℃, yield: the content of the active carbon is 53 percent,
1H NMR(500MHz,CDCl3)δ8.01–7.93(m,2H),7.30(d,J＝7.7Hz,2H),3.89–3.75(m,4H),3.55–3.39(m,2H),2.44(s,3H),2.00–1.84(m,4H),1.08(t,J＝7.4Hz,3H)；13C NMR(126MHz,CDCl3)δ165.08,158.29,155.33,148.70,140.34,131.43,130.51,128.59,128.51,126.03,77.27,77.01,76.76,47.13,37.72,33.85,22.83,21.52,19.82,13.97；HRMS(TOF ES+):C19H21N4O[(M+H)+]the predicted value of (2) is 321.1710, and the measured value is 321.1710.
Example 18: preparation of pyrimido-pyrrolopyridazine derivative I-17
Figure BDA0001743762340000262
The process for preparing the pyrimido-pyrrolopyridazine derivative I-17 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain a yellow solid I-17, melting point: 229.0-229.6 ℃, yield: 42 percent of the total weight of the mixture,
Figure BDA0001743762340000263
1H NMR(500MHz,CDCl3)δ9.10(dd,J＝3.9,1.1Hz,1H),7.54(dd,J＝5.1,1.1Hz,1H),7.15(dd,J＝5.1,3.8Hz,1H),4.00-3.98(m,2H),3.85-3.83(m,2H),3.54–3.39(m,2H),2.05–1.98(m,2H),1.95–1.87(m,2H),1.06(t,J＝7.4Hz,3H)；13C NMR(126MHz,CDCl3)δ164.91,157.88,149.87,149.09,139.47,133.79,130.83,127.88,126.30,125.99,77.26,77.01,76.75,47.08,37.72,33.65,22.65,19.66,13.93；HRMS(TOF ES+):C16H17N4OS[(M+H)+]the predicted value of (2) is 313.1118, and the measured value is 313.1119.
Example 19: preparation of pyrimido-pyrrolopyridazine derivative I-18
Figure BDA0001743762340000271
The process for preparing the pyrimido-pyrrolopyridazine derivative I-18 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain yellow solid I-18, melting point: 150.4-151.2 ℃, yield: 60 percent of the total weight of the mixture,
Figure BDA0001743762340000272
1H NMR(500MHz,CDCl3)δ8.12–8.02(m,2H),7.57–7.47(m,3H),3.56(s,2H),3.49(s,2H),3.14(s,3H),1.03(s,6H)；13C NMR(126MHz,CDCl3)δ165.25,154.85,147.87,134.23,133.29,130.55,130.21,130.06,128.35,127.84,77.27,77.22,77.02,76.76,59.82,48.71,27.70,24.66,18.64；HRMS(TOF ES+):C18H19N4O[(M+H)+]the predicted value of (2) is 307.1553, and the measured value is 307.1554.
Example 20: preparation of pyrimido-pyrrolopyridazine derivative I-19
Figure BDA0001743762340000281
The process for preparing the pyrimido-pyrrolopyridazine derivative I-19 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain yellow solid I-19, melting point: 115.5-116.1 ℃, yield: the content of the active carbon is 55 percent,
Figure BDA0001743762340000282
1H NMR(500MHz,CDCl3)δ8.11–8.05(m,2H),7.54–7.47(m,3H),3.55(s,2H),3.53–3.47(m,4H),2.04–1.90(m,2H),1.09(t,J＝7.4Hz,3H),1.04(s,6H)；13C NMR(126MHz,CDCl3)δ165.11,158.57,155.26,147.90,134.31,130.58,130.18,128.37,127.81,126.38,77.26,77.01,76.75,59.81,48.71,33.89,27.71,24.69,22.80,14.01；HRMS(TOF ES+):C20H23N4O[(M+H)+]the predicted value of (2) is 335.1866, and the measured value is 335.1867.
Example 21: preparation of pyrimido-pyrrolopyridazine derivative I-20
The process for preparing pyrimido-pyrrolopyridazine derivative I-20 was similar to that of I-1, and the kinds of HKAs and DDs were changed to obtain yellow solid I-20, melting point: 137.5-138.1 ℃, yield: in the content of 57 percent,
Figure BDA0001743762340000291
1H NMR(500MHz,CDCl3)δ8.12–8.03(m,2H),7.55–7.47(m,3H),3.57-3.52m,4H),3.49(s,2H),1.51(t,J＝7.5Hz,3H),1.04(s,6H)；13C NMR(126MHz,CDCl3)δ165.08,159.54,155.36,147.91,134.31,130.56,130.18,128.44,127.81,126.19,77.26,77.21,77.01,76.75,59.81,48.72,27.71,25.58,24.68,13.44；HRMS(TOF ES+):C19H21N4O[(M+H)+]the predicted value of (2) is 321.1710, and the measured value is 321.1710.
Example 22: preparation of pyrimido-pyrrolopyridazine derivative I-21
Figure BDA0001743762340000292
The preparation process of the pyrimido-pyrrolopyridazine derivative I-21 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain yellow solid I-21, melting point: 189.7-190.2 ℃, yield: the content of the active carbon is 58 percent,
Mp 189.7-190.2℃；1H NMR(500MHz,CDCl3)δ8.02–7.96(m,2H),7.31(d,J＝7.8Hz,2H),3.56(s,2H),3.49(s,2H),3.12(s,3H),2.44(s,3H),1.03(s,6H)；13C NMR(125MHz,CDCl3)δ165.34,155.42,154.53,148.03,140.44,131.41,130.46,128.65,127.97,126.69,77.28,77.03,76.77,59.82,48.71,27.69,24.66,21.54,18.62；HRMS(TOF ES+):C19H21N4O[(M+H)+]the predicted value of (2) is 321.1710, and the measured value is 321.1711.
Example 23: preparation of pyrimido-pyrrolopyridazine derivative I-22
Figure BDA0001743762340000301
The process for preparing the pyrimido-pyrrolopyridazine derivative I-22 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain yellow solid I-22, melting point: 158.6-159.3 ℃, yield: in the range of 52%,
Figure BDA0001743762340000302
1H NMR(500MHz,CDCl3)δ8.03–7.97(m,2H),7.33–7.28(m,2H),3.60–3.50(m,4H),3.48(s,2H),2.44(s,3H),1.49(t,J＝7.6Hz,3H),1.03(s,6H)；13C NMR(125MHz,CDCl3)δ165.16,159.22,155.35,148.07,140.40,131.47,130.49,128.62,128.21,126.15,77.30,77.04,76.79,59.81,48.70,27.69,25.55,24.68,21.54,13.43；HRMS(TOF ES+):C20H23N4O[(M+H)+]the predicted value of (2) is 335.1866, and the measured value is 335.1865.
Example 24: preparation of pyrimido-pyrrolopyridazine derivative I-23
Figure BDA0001743762340000311
The process for preparing the pyrimido-pyrrolopyridazine derivative I-23 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain a yellow solid I-23, melting point: 133.5-134.1 ℃, yield: the content of the active carbon is 53 percent,
Figure BDA0001743762340000312
1H NMR(500MHz,CDCl3)δ8.05–7.97(m,2H),7.31(d,J＝7.9Hz,2H),3.56(s,2H),3.52–3.46(m,4H),2.44(s,3H),1.99-1.91(m,2H),1.09(t,J＝7.4Hz,3H),1.04(s,6H)；13CNMR(126MHz,CDCl3)δ165.20,158.27,155.26,148.06,140.40,131.47,130.49,128.63,128.14,126.34,77.27,77.02,76.76,59.81,48.70,33.86,27.69,24.68,22.79,21.54,14.01；HRMS(TOF ES+):C21H25N4O[(M+H)+]the predicted value of (2) is 349.2023, and the predicted value is 349.2024.
Example 25: preparation of pyrimido-pyrrolopyridazine derivative I-24
Figure BDA0001743762340000313
The process for preparing the pyrimido-pyrrolopyridazine derivative I-24 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain a yellow solid I-24, melting point: 176.5-177.3 ℃, yield: in the range of 52%,
Figure BDA0001743762340000321
1H NMR(500MHz,CDCl3)δ8.09–8.04(m,2H),7.50–7.45(m,2H),3.56(s,2H),3.49(s,2H),3.13(s,3H),1.04(s,6H)；13C NMR(125MHz,CDCl3)δ165.11,155.15,154.34,147.91,136.52,132.64,131.93,128.15,128.13,126.75,77.26,77.01,76.76,59.81,48.72,27.70,24.64,18.66；HRMS(TOF ES+):C18H18ClN4O[(M+H)+]the predicted value of (2) is 341.1164, and the measured value is 341.1164.
Example 26: preparation of pyrimido-pyrrolopyridazine derivative I-25
Figure BDA0001743762340000322
The process for preparing pyrimido-pyrrolopyridazine derivative I-25 was similar to that of I-1, and the kinds of HKAs and DDs were changed to obtain yellow solid I-25, melting point: 157.6-158.4 ℃, yield: 50 percent of the total weight of the mixture is,
Figure BDA0001743762340000323
1H NMR(500MHz,CDCl3)δ8.13–8.02(m,2H),7.57–7.40(m,2H),3.60–3.51(m,4H),3.49(s,2H),1.50(t,J＝7.4Hz,3H),1.04(s,6H)；13C NMR(126MHz,CDCl3)δ164.95,159.84,154.27,147.96,136.51,132.71,131.95,128.42,128.13,126.22,77.26,77.01,76.75,59.81,48.73,27.72,25.60,24.67,13.38；HRMS(TOF ES+):C19H20ClN4O[(M+H)+]the predicted value of (2) is 355.1320, and the measured value is 355.1320.
Example 27: preparation of pyrimido-pyrrolopyridazine derivative I-26
The process for preparing pyrimido-pyrrolopyridazine derivative I-26 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain yellow solid I-26, melting point: 183.4-184.7 ℃, yield: the content of the raw materials is 51%,
Figure BDA0001743762340000332
1H NMR(500MHz,CDCl3)δ8.10–8.05(m,2H),7.51–7.44(m,2H),3.56(s,2H),3.53–3.44(m,4H),2.00–1.90(m,2H),1.09(t,J＝7.3Hz,3H),1.04(s,6H)；13C NMR(125MHz,CDCl3)δ164.96,158.87,154.17,147.93,136.50,132.71,131.96,128.34,128.13,126.39,77.26,77.00,76.75,59.81,48.72,33.88,27.72,24.67,22.78,13.99；HRMS(TOF ES+):C20H22ClN4O[(M+H)+]the predicted value of (2) is 369.1477, and the measured value is 369.1477.
Example 28: preparation of pyrimido-pyrrolopyridazine derivative I-27
Figure BDA0001743762340000333
The process for preparing the pyrimido-pyrrolopyridazine derivative I-27 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain a yellow solid I-27, melting point: 177.5-178.4 ℃, yield: in the content of 57 percent,
Figure BDA0001743762340000341
1H NMR(500MHz,CDCl3)δ8.69–8.63(m,1H),8.16(dd,J＝8.6,1.7Hz,1H),7.98–7.92(m,2H),7.90(dd,J＝7.8,1.5Hz,1H),7.54(ddd,J＝9.1,7.6,1.4Hz,2H),3.56(s,2H),3.51(s,2H),3.17(s,3H),1.04(s,6H)；13C NMR(126MHz,CDCl3)δ165.29,155.44,154.81,147.97,134.19,132.77,131.64,130.99,129.00,128.39,127.69,127.41,127.26,127.17,126.78,126.18,77.27,77.01,76.76,59.85,48.73,27.72,24.66,18.68；HRMS(TOF ES+):C22H21N4O[(M+H)+]the predicted value of (2) is 357.1710, and the measured value is 357.1710.
Example 29: preparation of pyrimido-pyrrolopyridazine derivative I-28
Figure BDA0001743762340000342
The preparation process of pyrimido-pyrrolopyridazine derivative I-28 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain yellow solid I-28, melting point: 171.7-172.6 ℃, yield: 60 percent of the total weight of the mixture,
Figure BDA0001743762340000343
1H NMR(500MHz,CDCl3)δ8.70–8.64(m,1H),8.17(dd,J＝8.5,1.8Hz,1H),7.98–7.92(m,2H),7.90(dd,J＝7.9,1.5Hz,1H),7.53(dddd,J＝14.5,8.3,6.9,1.5Hz,2H),3.58(dd,J＝14.2,6.6Hz,4H),3.51(s,2H),1.53(t,J＝7.5Hz,3H),1.04(s,6H)；13C NMR(125MHz,CDCl3)δ165.12,159.51,155.37,148.02,134.19,132.77,131.71,131.02,129.00,128.62,127.69,127.45,127.22,127.16,126.25,126.16,77.27,77.02,76.76,59.84,48.73,27.73,25.61,24.68,13.44；HRMS(TOF ES+):C23H23N4O[(M+H)+]the predicted value of (2) is 371.1866, and the measured value is 371.1865.
Example 30: preparation of pyrimido-pyrrolopyridazine derivative I-29
Figure BDA0001743762340000351
The process for preparing the pyrimido-pyrrolopyridazine derivative I-29 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-29, melting point: 144.6-145.2 ℃, yield: 50 percent of the total weight of the mixture is,
1H NMR(500MHz,CDCl3)δ8.70–8.64(m,1H),8.17(dd,J＝8.6,1.8Hz,1H),7.99–7.92(m,2H),7.92–7.88(m,1H),7.59–7.48(m,2H),3.60–3.47(m,6H),2.03–1.94(m,2H),1.12(t,J＝7.4Hz,3H),1.05(s,6H)；13C NMR(125MHz,CDCl3)δ165.15,158.54,155.27,148.01,134.19,132.78,131.71,131.03,129.00,128.55,127.69,127.46,127.22,127.16,126.44,126.16,77.27,77.01,76.76,59.84,48.72,33.91,27.73,24.68,22.81,14.03；HRMS(TOF ES+):C24H25N4O[(M+H)+]the predicted value of (2) is 385.2023, and the measured value is 385.2024.
Example 31: preparation of pyrimido-pyrrolopyridazine derivative I-30
Figure BDA0001743762340000361
The process for preparing the pyrimido-pyrrolopyridazine derivative I-30 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-30, melting point: 172.6-173.0 ℃, yield: the content of the active carbon is 28%,
Figure BDA0001743762340000362
1H NMR(500MHz,CDCl3)δ8.14–8.05(m,2H),7.53–7.44(m,3H),4.07(ddd,J＝12.9,5.2,3.7Hz,1H),3.59–3.47(m,2H),3.12(s,3H),2.07-20.3(m,1H),1.72–1.55(m,3H),1.05(t,J＝7.4Hz,3H)；13C NMR(125MHz,CDCl3)δ165.12,155.53,154.83,147.23,134.10,130.77,130.03,128.60,127.55,126.63,77.28,77.02,76.77,58.26,36.98,29.57,25.33,18.63,10.62；HRMS(TOF ES+):C18H19N4O[(M+H)+]the predicted value of (2) is 307.1553, and the measured value is 307.1552.
Example 32: preparation of pyrimido-pyrrolopyridazine derivative I-31
Figure BDA0001743762340000363
The process for preparing the pyrimido-pyrrolopyridazine derivative I-31 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain a yellow solid I-31, melting point: 136.3-136.9 ℃, yield: 21 percent of the total weight of the mixture,
Figure BDA0001743762340000371
1H NMR(500MHz,CDCl3)δ8.15–8.08(m,2H),7.54–7.45(m,3H),4.08(ddd,J＝12.9,5.1,3.8Hz,1H),3.59–3.49(m,4H),2.09-2.03(m,1H),1.72–1.56(m,4H),1.50(t,J＝7.6Hz,3H),1.06(t,J＝7.3Hz,3H)；13C NMR(125MHz,CDCl3)δ164.98,159.60,155.50,147.30,130.80,130.01,128.86,127.54,126.13,77.25,77.00,76.74,58.24,36.97,29.58,25.62,25.33,13.50,10.62；HRMS(TOF ES+):C19H21N4O[(M+H)+]the predicted value of (2) is 321.1710, and the measured value is 321.1710.
Example 33: preparation of pyrimido-pyrrolopyridazine derivative I-32
The preparation process of the pyrimido-pyrrolopyridazine derivative I-32 is similar to that of I-1, and the kinds of HKAs and DDs are changed to finally obtain a yellow solid I-32, melting point: 120.1-120.6 ℃, yield: 17 percent of the total weight of the mixture,
Figure BDA0001743762340000373
1H NMR(500MHz,CDCl3)δ8.17–8.09(m,2H),7.54–7.44(m,3H),4.08(ddd,J＝12.9,5.2,3.8Hz,1H),3.60–3.44(m,4H),2.09-2.04(m,1H),1.70-1.58(m,2H),1.74–1.57(m,4H),1.10-1.05(m,6H)；13C NMR(125MHz,CDCl3)δ164.99,158.61,155.41,147.28,134.16,130.82,130.02,128.81,127.54,126.36,77.24,77.19,76.99,76.74,58.25,36.96,33.88,29.59,25.33,22.86,13.97,10.62；HRMS(TOF ES+):C20H23N4O[(M+H)+]the predicted value of (2) is 335.1866, and the measured value is 335.1867.
Example 34: preparation of pyrimido-pyrrolopyridazine derivative I-33
Figure BDA0001743762340000381
The process for preparing pyrimido-pyrrolopyridazine derivative I-33 was similar to that of I-1, and the kinds of HKAs and DDs were changed to finally obtain yellow solid I-33, melting point: 173.3-173.9 ℃, yield: the content of the organic solvent is 61 percent,
Figure BDA0001743762340000382
1H NMR(500MHz,CDCl3)δ3.89(t,J＝5.6Hz,2H),3.84–3.74(m,2H),3.00(d,J＝1.2Hz,6H),2.04–1.93(m,2H)；13C NMR(125MHz,CDCl3)δ165.37,149.32,125.46,47.02,37.47,19.99,19.47,18.46；HRMS(TOF ES+):C11H13N4O[(M+H)+]the predicted value of (2) is 217.1084, and the measured value is 217.1085.
Example 35: influence of different solvents, temperatures and additives on the preparation of the compounds of the formula IV
HKAs (0.2mmol) of the formula II-1 and DDs (0.2mmol) of the formula III-1 were added to a solvent (5ml), additives were added, the reaction was followed by TLC (thin layer chromatography using silica gel GF 254) with stirring at a certain temperature until the HKAs and DDs were completely consumed, the solution was evaporated to dryness under reduced pressure on a rotary evaporator, and the residue was purified by flash column chromatography on silica gel (particle size 40-63 μm) with an eluent (petroleum ether: ethyl acetate ═ 1:1, v/v) to give a yellow solid IV-1, the experimental results are shown in Table 1.
Table 1.
Figure BDA0001743762340000391
Example 36: effect of different temperatures and additives on the Process for the preparation of pyrimido-Pyrrolopyridazine derivatives
In CH3CN(5ml) of HKAs represented by the formula II-1 (0.2mmol) and DDs represented by the formula III-1 (0.2mmol) were added thereto, stirred at room temperature (25 ℃ C.), followed by TLC (thin layer chromatography using silica gel GF 254) until the HKAs and DDs were completely consumed to obtain a compound represented by the formula IV-1.
After addition of the additive to the reaction mixture, the resulting mixture was stirred at a certain temperature until complete conversion of the compound of formula IV to the product I-1 (monitored by thin layer chromatography using silica gel GF 254). The mixture was cooled to room temperature and diluted with EtOAc (25 mL). The organic phase is saturated with NH4Cl solution (20mL) and water (20mL) and Na2SO4Drying, evaporation of the solution to dryness under reduced pressure on a rotary evaporator and purification of the residue by flash column chromatography on silica gel (40-63 μm) with the indicated eluent (PE: EA ═ 10:1-1:1) gave I-1 as a yellow solid with the experimental results shown in table 2.
Table 2.
Figure BDA0001743762340000401
Figure BDA0001743762340000402
Effect example 1: target compound inhibits LPS-induced NO production activity of RAW264.7
(1) Sample configuration
After the target compound was dissolved in DMSO (Merck), PBS (-) (phosphate buffer) was added to prepare a 10mM solution, which was further diluted to 0,0.1,0.5,5, and 20. mu.M samples. LPS aqueous solution (Lipopolysaccharides, lipopolysaccharide, sigma, Cat. L-2880) with 10. mu.g/mL is used as inducer.
(2) Experimental methods
Mouse macrophage RAW264.7 (purchased from Shanghai institute of Biotechnology cell resource center) at 37 deg.C, 5% CO2Culturing in DMEM culture solution in an incubator. For the experiment, 1. mu.L/mL LPS aqueous solution was added to 100mL of 2X 106In the cell suspension of mu g/mL, the content of nitrite in cell supernatant is measured by a Griess method after 18h to indirectly reflect the NO generation amount: 100mL of cells were taken for cultureTo the solution, Griess (Griess) reagent was added in an equal amount, and the absorbance was measured.
(3) Evaluation criteria and statistical method
Measuring absorbance at 570nm with NaNO2And (5) drawing a standard curve by using the standard solution, and calculating the concentration of the nitrite. The statistical analysis of the experimental results of each group was carried out by the SPSS software one-way ANNOVA method.
(4) Results of the experiment
The experimental result shows that the target compound has obvious inhibitory activity on NO generation of RAW264.7 macrophage induced by LPS, and the result is shown in Table 3, which shows that the target compound has anti-inflammatory activity.
Table 3.
Figure BDA0001743762340000411
Figure BDA0001743762340000421
The experimental result shows that the compound provided by the invention has better activity of inhibiting macrophage RAW264.7 from generating NO, and the compound can be used for preparing anti-inflammatory drugs.

Claims (11)

1. A pyrimido-pyrrolopyridazine derivative represented by formula I, a tautomer, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof:
Figure FDA0001743762330000011
wherein R is1Selected from H, C1-C12Straight or branched alkyl of (2), C1-C12Linear or branched haloalkyl of, C1-C12Linear or branched alkoxy of (C)3-C6Cycloalkyl radical, C6-C20Aryl of (C)2-C10Heteroaryl with one or more R1aSubstituted C6-C20Or by one or more R1bSubstituted C2-C10Wherein R is1aAnd R1bEach independently selected from hydroxy, nitro, halogen, amino, C1-C6Straight or branched alkyl of (2), C1-C6Linear or branched alkoxy or C1-C6Linear or branched haloalkyl of (a); when R is1aOr R1bWhen there are plural, R1aOr R1bThe same or different;
R2～R5each independently selected from-H or C1-C12Linear or branched alkyl.
2. Pyrimido-pyrrolopyridazine derivatives represented by formula I, tautomers, optical isomers, pharmaceutically acceptable salts thereof or prodrugs thereof according to claim 1,
when R is1Is C1-C12When the alkyl group is a straight or branched alkyl group, said C1-C12The linear or branched alkyl group of (1) is preferably C1-C6Further preferably C1-C3More preferably methyl or ethyl;
and/or when R1Is C1-C12When said C is a straight or branched haloalkyl group1-C12Is preferably C substituted by one or more identical or different halogen atoms1-C12Said halogens may be on the same or different carbon atoms; said C1-C12The straight-chain or branched haloalkyl group of (A) is preferably C1-C3Linear or branched haloalkyl of (a);
and/or when R1Is C1-C12When said alkoxy is a straight or branched alkoxy group, said C1-C12The straight-chain or branched alkoxy of (A) is preferably C1-C6Further preferably C1-C3More preferably a methoxy group or an ethoxy group;
and/or when R1Is C3-C6When a cycloalkyl group is present, C is3-C6Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and/or when R1Is C6-C20Aryl of (2), C6-C20Aryl of (A) is preferably C6-C10Further preferably phenyl or naphthyl;
and/or when R1Is C2-C10When said heteroaryl is said C2-C10Heteroaryl of (A) is preferably C2-C8Further preferably a pyridyl group or a thienyl group;
and/or when R1Is represented by one or more R1aSubstituted C6-C20Aryl of (2), C6-C20Aryl of (A) is preferably C6-C10Further preferably phenyl or naphthyl;
and/or when R1Is represented by one or more R1bSubstituted C2-C10When said heteroaryl is said C2-C10Heteroaryl of (A) is preferably C2-C8Further preferably a pyridyl group or a thienyl group;
and/or when R1aOr R1bWhen halogen is used, the halogen is preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine;
and/or when R1aOr R1bIs C1-C6When the alkyl group is a straight or branched alkyl group, said C1-C6The linear or branched alkyl group of (1) is preferably C1-C3Further preferably a methyl group or an ethyl group;
and/or when R1aOr R1bIs C1-C6When said alkoxy is a straight or branched alkoxy group, said C1-C6The straight-chain or branched alkoxy of (A) is preferably C1-C3Further preferably a methoxy group or an ethoxy group;
and/or when R1aOr R1bIs C1-C6When said C is a straight or branched haloalkyl group1-C6Is preferably C substituted by one or more identical or different halogen atoms1-C6The halogens may be on the same or different carbon atoms; more preferably C1-C3Linear or branched haloalkyl of (a);
and/or when R2～R5Each independently is C1-C12When the alkyl group is a straight or branched alkyl group, said C1-C12The linear or branched alkyl group of (1) is preferably C1-C6Further preferably C1-C3More preferably a methyl group, an ethyl group or an n-propyl group.
3. Pyrimido-pyrrolopyridazine derivatives of formula I, their tautomers, their optical isomers, their pharmaceutically acceptable salts or their prodrugs according to claim 1, wherein R is1Is C1-C3Straight or branched alkyl of (2), C6-C10Aryl of (C)2-C8Or by an R1aSubstituted C6-C10And R is an aryl group of1aIs halogen, C1-C3Straight or branched alkyl or nitro of (1); further preferred is R1Is methyl, phenyl, pyridyl, naphthyl, thienyl or substituted by one R1aSubstituted phenyl, and R1aIs chlorine, methyl or nitro;
or, R2～R4And is also H;
or, R2～R3At the same time is C1-C3Straight or branched alkyl of R4Is H; further preferably, R2～R3Simultaneously being methyl, R4Is H;
or, R2～R3At the same time being H, R4Is C1-C3Linear or branched alkyl of (a); further preferred is，R2～R3At the same time being H, R4Is ethyl;
or, R1Is phenyl, substituted by one R1aSubstituted phenyl, pyridyl, naphthyl or thienyl, and R1aIs chlorine, methyl or nitro, R2～R4At the same time being H, R5Is C1-C3Linear or branched alkyl of (a);
or, R1Is phenyl, substituted by one R1aSubstituted phenyl, pyridyl, naphthyl or thienyl, and R1aIs chlorine, methyl or nitro, R2～R3At the same time is C1-C3Straight or branched alkyl of R4Is H, R5Is C1-C3Linear or branched alkyl of (a);
or, R1Is phenyl, pyridyl, naphthyl or thienyl, R2～R3At the same time is C1-C3Straight or branched alkyl of R4Is H, R5Is methyl;
or, R1Is phenyl, phenyl substituted by one halogen, pyridyl, naphthyl or thienyl, R2～R3At the same time is C1-C3Straight or branched alkyl of R4Is H, R5Is ethyl or n-propyl;
or, R1Is phenyl, substituted by one R1aSubstituted phenyl, pyridyl, naphthyl or thienyl, and R1aIs chlorine, methyl or nitro, R2～R3At the same time being H, R4Is C1-C3Straight or branched alkyl of R5Is C1-C3Linear or branched alkyl.
4. The pyrimido-pyrrolopyridazine derivative of formula I, its tautomer, its optical isomer, its pharmaceutically acceptable salt or its prodrug according to claim 1, wherein the pyrimido-pyrrolopyridazine derivative of formula I is selected from any one of the following compounds:
Figure FDA0001743762330000031
Figure FDA0001743762330000041
5. a method for preparing pyrimido-pyrrolopyridazine derivatives represented by formula I according to any one of claims 1 to 4, comprising the steps of: in a solvent, under the action of an additive, a compound shown in a formula IV is subjected to the following reaction;
Figure FDA0001743762330000051
wherein R is1～R5The definitions of (A) and (B) are as defined in claim 1.
6. The method for preparing pyrimido-pyrrolopyridazine derivative represented by formula I according to claim 5, wherein the solvent is one or more of halogenated alkane, nitrile solvent, ether solvent, alcohol solvent, amide solvent and aromatic solvent; further preferably, the solvent is one or more of acetonitrile, tetrahydrofuran, methanol, N-dimethylformamide and toluene; more preferably, the solvent is acetonitrile;
and/or the additive is organic amine and R6OM1、NaH、XaYb、M3(OAc)2One or more of copper trifluoroacetate, boron trifluoride and boron trifluoride etherate complex; wherein R is6～R7Each independently is C1-C6Straight or branched alkyl of, M1Selected from alkali metals, M2Selected from-H or alkali metals, M3Selected from Cu or Pd, X is Cu, Mg, Zn, Al or Fe, Y is halogen, a and b are each independently integers of 1-3Specifically, the selection is carried out according to X and Y; preferably, the additive is one or more of N, N-diisopropylethylamine, sodium acetate, sodium tert-butoxide, sodium hydride, acetic acid, copper chloride, copper bromide, copper iodide, magnesium chloride, zinc chloride, aluminum chloride, ferric chloride, copper acetate, palladium acetate and boron trifluoride diethyl etherate; further preferably, the additive is copper chloride;
and/or the molar ratio of the additive to the compound of formula IV is 1:0.1 to 1:1, preferably the molar ratio of the additive to the compound of formula IV is 1:0.1 to 1: 0.2;
and/or the temperature of the reaction is 20-80 ℃, and preferably the temperature of the reaction is 45-55 ℃.
7. The method for preparing pyrimido-pyrrolopyridazine derivatives represented by formula I according to claim 5, wherein the method for preparing pyrimido-pyrrolopyridazine derivatives represented by formula I further comprises the steps of: in a solvent, performing Michael addition reaction on cycloketene amine shown in a formula II and 1, 2-diaza-1, 3-diene shown in a formula III to obtain a compound shown in a formula IV;
Figure FDA0001743762330000061
preferably, in the step of preparing the compound represented by formula IV, the obtained reaction solution is directly mixed with an additive without post-treatment and then reacted;
Figure FDA0001743762330000062
wherein R is1～R5The definitions of (A) and (B) are as defined in any one of claims 1 to 4;
preferably, the additive is a metal halide, and more preferably, the additive is copper chloride.
8. A compound of formula IV, a tautomer, an optical isomer, a pharmaceutically acceptable salt thereof, or a prodrug thereof:
Figure FDA0001743762330000071
wherein R is1～R5The definitions of (A) and (B) are as defined in any one of claims 1 to 4.
9. A method for preparing a compound shown as formula IV, comprising the steps of: in a solvent, performing Michael addition reaction on cycloketene amine shown in a formula II and 1, 2-diaza-1, 3-diene shown in a formula III to obtain a compound shown in a formula IV;
wherein R is1～R5The definitions of (A) and (B) are as defined in any one of claims 1 to 4.
10. A pharmaceutical composition comprising a therapeutically effective amount of the pyrimido-pyrrolopyridazine derivative represented by formula I, its tautomer, its optical isomer, its pharmaceutically acceptable salt or its prodrug as claimed in any one of claims 1 to 4, and at least one pharmaceutical excipient.
11. An application of pyrimido-pyrrolopyridazine derivative shown as a formula I, a tautomer, an optical isomer, a pharmaceutically acceptable salt or a prodrug thereof in preparing anti-inflammatory drugs.
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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2009054401A1 (en) * 2007-10-26 2009-04-30 Kagoshima University Anti-viral agent comprising heterocyclic aromatic compound as active ingredient
CN105492444A (en) * 2013-07-02 2016-04-13 百时美施贵宝公司 Tricyclic pyri do-carboxam i d e derivatives as ROCK inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009054401A1 (en) * 2007-10-26 2009-04-30 Kagoshima University Anti-viral agent comprising heterocyclic aromatic compound as active ingredient
CN105492444A (en) * 2013-07-02 2016-04-13 百时美施贵宝公司 Tricyclic pyri do-carboxam i d e derivatives as ROCK inhibitors

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