CN110759923B - 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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CN110759923B
CN110759923B CN201810832206.9A CN201810832206A CN110759923B CN 110759923 B CN110759923 B CN 110759923B CN 201810832206 A CN201810832206 A CN 201810832206A CN 110759923 B CN110759923 B CN 110759923B
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pyrimido
straight
branched alkyl
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pyrrolopyridazine
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孙青�
张卫东
赵蒙浩
李霞
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Shanghai Pharmaceutical Industry Research Institute Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—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
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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 pyrimido-pyrrolopyridazine derivatives 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 activity of inhibiting macrophage RAW264.7 from generating NO.

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, 361-373.).
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 is 1 Selected from H, C 1 -C 12 Straight or branched alkyl of (2), C 1 -C 12 Linear or branched haloalkyl of、C 1 -C 12 Linear or branched alkoxy of (C) 3 -C 6 Cycloalkyl radical, C 6 -C 20 Aryl of, C 2 -C 10 By one or more (e.g. 1-6, preferably 1-3 or 1-2) R 1a Substituted C 6 -C 20 Or by one or more (e.g. 1-6, preferably 1-3 or 1-2) R 1b Substituted C 2 -C 10 Wherein R is selected from the group consisting of (1-3) heteroaryl (one or more of N, O and S as heteroatoms), wherein 1a And R 1b Each independently selected from hydroxy, nitro, halogen, amino, C 1 -C 6 Straight or branched alkyl of (2), C 1 -C 6 Linear or branched alkoxy or C 1 -C 6 Linear or branched haloalkyl of (a); when R is 1a Or R 1b When there are plural, R 1a Or R 1b The same or different;
R 2 ～R 5 each independently selected from-H or C 1 -C 12 Linear or branched alkyl.
In the present invention, when R is 1 Is C 1 -C 12 When the alkyl group is a straight or branched alkyl group, said C 1 -C 12 The linear or branched alkyl group of (2) is preferably C 1 -C 6 Further preferably C 1 -C 3 More preferably a methyl group or an ethyl group.
When R is 1 Is C 1 -C 12 When the alkyl group is a straight or branched alkyl halide group, said C 1 -C 12 Is preferably C substituted by one or more identical or different halogen atoms 1 -C 12 Said halogens may be on the same or different carbon atoms; said C 1 -C 12 The straight-chain or branched haloalkyl group of (A) is preferably C 1 -C 3 Straight or branched haloalkyl.
When R is 1 Is C 1 -C 12 When said alkoxy is a straight or branched alkoxy group, said C 1 -C 12 The straight-chain or branched alkoxy of (A) is preferably C 1 -C 6 Further preferably C 1 -C 3 The straight-chain or branched alkoxy group of (2) is more preferably a methoxy group or an ethoxy group.
When R is 1 Is C 3 -C 6 When a cycloalkyl group is present, C is 3 -C 6 Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
When R is 1 Is C 6 -C 20 Aryl of (2), C 6 -C 20 Aryl of (A) is preferably C 6 -C 10 More preferably, the aryl group of (1) is phenyl or naphthyl.
When R is 1 Is C 2 -C 10 When said heteroaryl is said C 2 -C 10 Heteroaryl of (A) is preferably C 2 -C 8 The heteroaryl group of (2) is more preferably a pyridyl group or a thienyl group.
When R is 1 Is represented by one or more R 1a Substituted C 6 -C 20 Aryl of (2), C 6 -C 20 Aryl of (A) is preferably C 6 -C 10 Further preferably phenyl or naphthyl.
When R is 1 Is represented by one or more R 1b Substituted C 2 -C 10 When said heteroaryl is said C 2 -C 10 Heteroaryl of (A) is preferably C 2 -C 8 The heteroaryl group of (1) is more preferably a pyridyl group or a thienyl group.
In the present invention, when R is 1a Or R 1b In the case of halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine.
When R is 1a Or R 1b Is C 1 -C 6 When the alkyl group is a straight or branched alkyl group, said C 1 -C 6 The linear or branched alkyl group of (1) is preferably C 1 -C 3 Further, the straight-chain or branched alkyl group of (1) is preferably a methyl group or an ethyl group.
When R is 1a Or R 1b Is C 1 -C 6 When said alkoxy is a straight or branched alkoxy group, said C 1 -C 6 The straight-chain or branched alkoxy of (A) is preferably C 1 -C 3 The straight-chain or branched alkoxy group of (2) is more preferably a methoxy group or an ethoxy group.
When R is 1a Or R 1b Is C 1 -C 6 When said C is a straight or branched haloalkyl group 1 -C 6 Is preferably C substituted by one or more identical or different halogen atoms 1 -C 6 The halogens may be on the same or different carbon atoms; more preferably C 1 -C 3 Linear or branched haloalkyl.
When R is 2 ～R 5 Each independently is C 1 -C 12 When the alkyl group is a straight or branched alkyl group, said C 1 -C 12 The linear or branched alkyl group of (1) is preferably C 1 -C 6 Further preferably C 1 -C 3 More preferably a methyl group, an ethyl group or an n-propyl group.
In a preferred embodiment of the invention, R is preferably 1 Is C 1 -C 3 Linear or branched alkyl (e.g. methyl), C 6 -C 10 Aryl (e.g. phenyl, naphthyl), C 2 -C 8 Or by an R heteroaryl group (e.g. pyridyl, thienyl) 1a Substituted C 6 -C 10 Aryl (e.g. phenyl, naphthyl), and R 1a Is halogen (e.g. chlorine), C 1 -C 3 A linear or branched alkyl group (e.g., methyl) or nitro group; further preferably R 1 Is methyl, phenyl, pyridyl, naphthyl, thienyl or substituted by one R 1a Substituted phenyl, and R 1a Is chlorine, methyl or nitro.
In a preferred embodiment of the invention, R is preferably 2 ～R 4 And is also H.
In a preferred embodiment of the invention, R is preferably 2 ～R 3 At the same time is C 1 -C 3 Straight or branched alkyl of R 4 Is H; further preferably, R 2 ～R 3 Simultaneously being methyl, R 4 Is H.
In a preferred embodiment of the present invention, R is preferably 2 ～R 3 At the same time being H, R 4 Is C 1 -C 3 Linear or branched alkyl of (a); further preferably, R 2 ～R 3 While being H, R 4 Is ethyl.
In a preferred embodiment of the invention, R is preferably 1 Is phenyl, substituted by one R 1a Substituted phenyl, pyridyl, naphthyl or thienyl, and R 1a Is chlorine, methyl or nitro, R 2 ～R 4 While being H, R 5 Is C 1 -C 3 Is a straight or branched alkyl group (for example, methyl, ethyl or n-propyl).
In a preferred embodiment of the invention, R is preferably 1 Is phenyl, substituted by one R 1a Substituted phenyl, pyridyl, naphthyl or thienyl, and R 1a Is chlorine, methyl or nitro, R 2 ～R 3 At the same time is C 1 -C 3 Linear or branched alkyl (e.g. both methyl), R 4 Is H, R 5 Is C 1 -C 3 Is a straight or branched alkyl group (for example, methyl, ethyl or n-propyl).
In a preferred embodiment of the invention, R is preferably 1 Is phenyl, pyridyl, naphthyl or thienyl, R 2 ～R 3 At the same time is C 1 -C 3 Linear or branched alkyl (e.g. both methyl), R 4 Is H, R 5 Is methyl.
In a preferred embodiment of the invention, R is preferably 1 Is phenyl, phenyl substituted by a halogen, e.g. chlorine, pyridyl, naphthyl or thienyl, R 2 ～R 3 At the same time is C 1 -C 3 Linear or branched alkyl (e.g. both methyl), R 4 Is H, R 5 Is ethyl or n-propyl.
In a preferred embodiment of the invention, R is preferably 1 Is phenyl, substituted by one R 1a Substituted phenyl, pyridyl, naphthyl or thienyl, and R 1a Is chlorine, methyl or nitro, R 2 ～R 3 At the same time being H, R 4 Is C 1 -C 3 Straight or branched alkyl (e.g. ethyl), R 5 Is C 1 -C 3 Is 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 is 1 ～R 5 As 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 formula IIn the preparation method of the pyrimido-pyrrolopyridazine derivative, the additive can be organic amine and R 6 OM 1 、
Figure BDA0001743762340000062
NaH、X a Y b 、M 3 (OAc) 2 One or more of copper trifluoroacetate, boron trifluoride and boron trifluoride etherate complex; wherein R is 6 ～R 7 Each independently is C 1 -C 6 Straight or branched alkyl (e.g. C) 2 -C 4 Straight-chain or branched alkyl radicals of (2), further e.g. ethyl, tert-butyl), M 1 Selected from alkali metals (e.g. Na or K, also e.g. Na), M 2 Selected from-H or alkali metals (e.g. Na or K, and also e.g. Na), M 3 Is 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 formula I, the reaction may further comprise the following post-treatment step: the reaction mixture is cooled (preferably to room temperature), mixed with ethyl acetate and then treated with saturated NH 4 And (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 cycloolefinamines (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;
Figure BDA0001743762340000071
wherein R is 1 ～R 5 As 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-:
Figure BDA0001743762340000081
in the present invention, the 1, 2-diaza-1, 3-diene can be prepared by methods well known to those of ordinary skill in the art of organic chemistry, and in the present invention, reference is made specifically to Sommer, S., Tetrahedron Letters 1977,18, 117-; 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, R 6 OM 1 、
Figure BDA0001743762340000083
NaH、X a Y b 、M 3 (OAc) 2 One or more of copper trifluoroacetate, boron trifluoride and boron trifluoride diethyl etherate complex, wherein R is 6 ～R 7 Each independently is C 1 -C 6 Straight or branched alkyl (e.g. C) 2 -C 4 Straight-chain or branched alkyl radicals of (2), further e.g. ethyl, tert-butyl), M 1 Selected from alkali metals (e.g. Na or K, also e.g. Na), M 2 Selected from-H or alkali metals (e.g. Na or K, and also e.g. Na), M 3 Is 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 independently integers of 1-3, and are selected according to X and Y.
In the process for the preparation of the compound of formula IV, the michael addition reaction is preferably carried out in the absence of additives.
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 methods in the art (e.g., TLC), typically by the disappearance or no longer reacting the starting materials as the 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 is 1 ～R 5 As 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 in a one-pot method, the additive may be a metal halide (e.g., copper chloride, copper bromide, copper 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:
Figure BDA0001743762340000101
wherein R is 1 ～R 5 As 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 is 1 ～R 5 As 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 starting from cycloalkenoneamines and 1, 2-diaza-1, 3-dienes, preferably by a cascade 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 macrophage RAW264.7 from generating NO, 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.
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. 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.; santeusanio, ssis 1984,10, 874-876, DDs are mixtures of E/Z isomers. The structure of the compound is determined by nuclear magnetic resonance 1 H NMR or 13 C 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 ) And TMS is an internal standard. Melting points were determined on an SGWX-4A melting point instrument, uncorrected. HRM was performed on an Agllent LC/Msd TOF instrument. X-ray diffraction measurements were performed at 296K on a Bruker SMART APEX-II CCD area detector system equipped with a graphite monochromator and a Cu-Ka precision sealed tube.
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 added 2 (10.0mmol) was added dropwise to the reaction mixture, the ice bath was maintained and stirring was continued for two hours, finally MeI (20.0mmol) was added dropwise to the reaction mixture, the temperature was slowly raised to room temperature after the ice bath was maintained for half an hour, 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 Na 2 SO 4 The 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.; santeusani, S.Synthesis 1984,10, 874-876, the specific synthetic route is as follows:
Figure BDA0001743762340000141
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 CH 3 HKAs 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
1 H NMR(500MHz,DMSO-d 6 )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)； 13 C NMR(125MHz,DMSO-d 6 )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 + ):C 17 H 18 N 5 O 3 [(M+H) + ]calculated value of 340.1404, found 340.1405.
Example 2: preparation of pyrimido-pyrrolopyridazine derivative I-1
Figure BDA0001743762340000152
In CH 3 HKAs (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 reaction 2 (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 NH 4 Cl solution (20mL) and water (20mL) and Na 2 SO 4 Drying, 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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 16 H 15 N 4 O[(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
Figure BDA0001743762340000162
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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 17 H 17 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 16 H 14 ClN 4 O[(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,
Figure BDA0001743762340000181
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 16 H 14 ClN 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 15 H 14 N 5 O[(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
Figure BDA0001743762340000191
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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 20 H 17 N 4 O[(M+H) + ]the predicted value of (2) is 329.1397, and the actual measurement 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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 16 H 14 N 5 O 3 [(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 17 H 16 ClN 4 O[(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 process for preparing the pyrimido-pyrrolopyridazine derivative I-9 was similar to that of I-1, and the kinds of HKAs and DDs were changed to give I-9 as a yellow solid, melting point: 175.2-176.1 ℃, yield: the content of the active carbon is 53 percent,
Figure BDA0001743762340000212
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 17 H 16 ClN 4 O[(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
Figure BDA0001743762340000213
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,
Figure BDA0001743762340000221
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 21 H 19 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 17 H 17 N 4 O[(M+H) + ]the predicted value of (2) is 293.1397, and the actual measurement value is 293.1397.
Example 13: preparation of pyrimido-pyrrolopyridazine derivative I-12
Figure BDA0001743762340000231
The process for preparing the pyrimido-pyrrolopyridazine derivative I-12 was similar to that of I-1, and the kinds of HKAS and DDs were changed to give I-12 as a yellow solid, melting point: 166.5-167.2 ℃, yield: 54 percent of the total weight of the mixture,
Figure BDA0001743762340000232
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 18 H 18 ClN 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 18 H 19 N 4 O[(M+H) + ]the predicted value of (2) is 307.1553, and the actual measurement 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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 22 H 21 N 4 O[(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 case of a high-speed operation of the system at 52%,
Figure BDA0001743762340000252
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 18 H 18 ClN 4 O[(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
Figure BDA0001743762340000253
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,
Figure BDA0001743762340000261
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 19 H 21 N 4 O[(M+H) + ]the predicted value of (2) is 321.1710, and the actual measurement 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: in the content of 42%,
Figure BDA0001743762340000263
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 16 H 17 N 4 OS[(M+H) + ]the predicted value of (2) is 313.1118, and the actual measurement 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 give I-18 as a yellow solid, melting point: 150.4-151.2 ℃, yield: 60 percent of the total weight of the mixture,
Figure BDA0001743762340000272
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 18 H 19 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 20 H 23 N 4 O[(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
Figure BDA0001743762340000283
The process for preparing the pyrimido-pyrrolopyridazine derivative I-20 was similar to that of I-1, and the kinds of HKAs and DDs were changed to give I-20 as a yellow solid, melting point: 137.5-138.1 ℃, yield: in the content of 57 percent,
Figure BDA0001743762340000291
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 19 H 21 N 4 O[(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,
Figure BDA0001743762340000293
Mp 189.7-190.2℃； 1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 19 H 21 N 4 O[(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 case of a high-speed operation of the system at 52%,
Figure BDA0001743762340000302
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 20 H 23 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 21 H 25 N 4 O[(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 give I-24 as a yellow solid, melting point: 176.5-177.3 ℃, yield: in the range of 52%,
Figure BDA0001743762340000321
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 18 H 18 ClN 4 O[(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 the pyrimido-pyrrolopyridazine derivative I-25 was similar to that of I-1, and the kinds of HKAs and DDs were changed to give I-25 as a yellow solid, melting point: 157.6-158.4 ℃, yield: 50 percent of the total weight of the mixture,
Figure BDA0001743762340000323
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 19 H 20 ClN 4 O[(M+H) + ]the predicted value of (2) is 355.1320, and the actual measurement value is 355.1320.
Example 27: preparation of pyrimido-pyrrolopyridazine derivative I-26
Figure BDA0001743762340000331
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 waste water is 51 percent,
Figure BDA0001743762340000332
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 20 H 22 ClN 4 O[(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 range of 57% by weight,
Figure BDA0001743762340000341
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(126MHz,CDCl 3 )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 + ):C 22 H 21 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 23 H 23 N 4 O[(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 was similar to that of I-1, and the kinds of HKAS and DDs were changed to give I-29 as a yellow solid, melting point: 144.6-145.2 ℃, yield: 50 percent of the total weight of the mixture is,
Figure BDA0001743762340000352
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 24 H 25 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 18 H 19 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 19 H 21 N 4 O[(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
Figure BDA0001743762340000372
The process for preparing the pyrimido-pyrrolopyridazine derivative I-32 was similar to that of I-1, and the kinds of HKAs and DDs were changed to give I-32 as a yellow solid, melting point: 120.1-120.6 ℃, yield: 17 percent of the total weight of the mixture,
Figure BDA0001743762340000373
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )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 + ):C 20 H 23 N 4 O[(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
1 H NMR(500MHz,CDCl 3 )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)； 13 C NMR(125MHz,CDCl 3 )δ165.37,149.32,125.46,47.02,37.47,19.99,19.47,18.46；HRMS(TOF ES + ):C 11 H 13 N 4 O[(M+H) + ]the predicted value of (2) is 217.1084, and the actual measurement 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
Figure BDA0001743762340000392
Example 36: effect of different temperatures and additives on the Process for the preparation of pyrimido-Pyrrolopyridazine derivatives
In CH 3 HKAs (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 (25 ℃) and followed by TLC (thin layer chromatography using silica GF 254) until the HKAs and DDs were completely consumed to obtain the compound of 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 NH 4 Cl solution (20mL) and water (20mL) and Na 2 SO 4 Drying, evaporation of the solution to dryness under reduced pressure on a rotary evaporator and flash column chromatography of the residue on silica gel (40-63 μm) using 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), 10mM PBS (-) was added to prepare a solution, and the solution was further diluted to obtain samples with gradient concentrations of 0,0.1,0.5,5, and 20. mu.M. 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% CO 2 Culturing in DMEM culture medium in an incubator conventionally. For the experiment, 1. mu.L/mL of LPS aqueous solution was added to 100mL of 2X 10-concentrated LPS aqueous solution 6 In 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 the cell culture medium was added with an equivalent amount of Griess reagent, and the absorbance was measured.
(3) Evaluation criteria and statistical method
Measuring absorbance at 570nm with NaNO 2 And (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 (7)

1. A pyrimido-pyrrolopyridazine derivative represented by formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003535021560000011
wherein R is 1 Selected from H, C 1 -C 6 Straight or branched alkyl of (2), C 6 -C 10 Aryl of (C) 2 -C 8 Heteroaryl with one or more R 1a Substituted C 6 -C 10 Or by one or more R 1b Substituted C 2 -C 8 Wherein R is 1a And R 1b Each independently selected from nitro, halogen or C 1 -C 6 Straight or branched chain alkyl of (a); when R is 1a Or R 1b When there are plural, R 1a Or R 1b The same or different; said C 2 -C 8 In the heteroaryl, the heteroatom is N, O or S, and the number of the heteroatoms is 1-3;
R 2 ～R 5 each independently selected from-H or C 1 -C 6 Linear or branched alkyl of (a);
the pyrimido-pyrrolopyridazine derivative shown in the formula I is not any one of the following compounds:
Figure FDA0003535021560000012
Figure FDA0003535021560000021
2. pyrimido-pyrrolopyridazine derivatives represented by formula I, tautomers thereof or pharmaceutically acceptable salts thereof according to claim 1,
when R is 1 Is C 1 -C 6 When the alkyl group is a straight or branched alkyl group, said C 1 -C 6 Is C 1 -C 3 Straight or branched chain alkyl of (a);
and/or when R 1 Is C 6 -C 10 Aryl of (2), C 6 -C 10 Aryl of (b) is phenyl or naphthyl;
and/or when R 1 Is C 2 -C 8 When said heteroaryl is said C 2 -C 8 The heteroaryl group of (a) is pyridyl or thienyl;
and/or when R 1 Is represented by one or more R 1a Substituted C 6 -C 10 Aryl of (b), said C 6 -C 10 Aryl of (a) is phenyl or naphthyl;
and/or when R 1 Is represented by one or more R 1b Substituted C 2 -C 8 When said heteroaryl is said C 2 -C 8 The heteroaryl group of (a) is pyridyl or thienyl;
and/or when R 1a Or R 1b When halogen, the halogen is fluorine, chlorine, bromine or iodine;
and/or when R 1a Or R 1b Is C 1 -C 6 When the alkyl group is a straight or branched alkyl group, said C 1 -C 6 Is C 1 -C 3 Linear or branched alkyl of (a);
and/or when R 2 ～R 5 Each independently is C 1 -C 6 When the alkyl group is a straight or branched alkyl group, said C 1 -C 6 Is C 1 -C 3 Linear or branched alkyl.
3. Pyrimido-pyrrolopyridazine derivatives, tautomers thereof or pharmaceutically acceptable salts thereof according to claim 2, represented by formula I,
when R is 1 Is C 1 -C 6 When the alkyl group is a straight or branched alkyl group, said C 1 -C 6 The straight or branched alkyl group of (a) is methyl or ethyl;
and/or when R 1a Or R 1b When is halogen, the halogen is chlorine;
and/or when R 1a Or R 1b Is C 1 -C 6 When the alkyl group is a straight or branched alkyl group, said C 1 -C 6 The straight or branched alkyl group of (a) is methyl or ethyl;
and/or when R 2 ～R 5 Each independently is C 1 -C 6 When the alkyl group is a straight or branched alkyl group, said C 1 -C 6 Is methyl, ethyl or n-propyl.
4. Pyrimido-pyrrolopyridazine derivatives, tautomers thereof or pharmaceutically acceptable salts thereof according to formula I of claim 1, wherein R is 1 Is C 1 -C 3 Straight or branched alkyl of (2), C 6 -C 10 Aryl of (C) 2 -C 8 Or by an R 1a Substituted C 6 -C 10 And R is an aryl group of 1a Is halogen, C 1 -C 3 Straight or branched alkyl or nitro of (1);
or, R 2 ～R 4 And is also H;
or, R 2 ～R 3 At the same time is C 1 -C 3 Straight or branched alkyl of R 4 Is H;
or, R 2 ～R 3 At the same time being H, R 4 Is C 1 -C 3 Straight or branched chain alkyl of (a);
or, R 1 Is phenyl, substituted by one R 1a Substituted phenyl, pyridyl, naphthyl or thienyl, and R 1a Is chlorine, methyl or nitro, R 2 ～R 4 At the same time being H, R 5 Is C 1 -C 3 Linear or branched alkyl of (a);
or, R 1 Is phenyl, by an R 1a Substituted phenyl, pyridyl, naphthyl or thienyl, and R 1a Is chlorine, methyl or nitro, R 2 ～R 3 At the same time is C 1 -C 3 Straight or branched alkyl of R 4 Is H, R 5 Is C 1 -C 3 Linear or branched alkyl of (a);
or, R 1 Is phenyl, pyridyl, naphthyl or thienyl, R 2 ～R 3 At the same time is C 1 -C 3 Straight or branched alkyl of R 4 Is H, R 5 Is methyl;
or, R 1 Is phenyl, phenyl substituted by one halogen, pyridyl, naphthyl or thienyl, R 2 ～R 3 At the same time is C 1 -C 3 Straight or branched alkyl of R 4 Is H, R 5 Is ethyl or n-propyl;
or, R 1 Is phenyl, substituted by one R 1a Substituted phenyl, pyridyl, naphthyl or thienyl, and R 1a Is chlorine, methyl or nitro, R 2 ～R 3 While being H, R 4 Is C 1 -C 3 Straight or branched alkyl of R 5 Is C 1 -C 3 Linear or branched alkyl.
5. Pyrimido-pyrrolopyridazine derivatives, tautomers thereof or pharmaceutically acceptable salts thereof according to claim 4, represented by formula I, wherein R is 1 Is methyl, phenyl, pyridyl, naphthyl, thienyl or substituted by one R 1a Substituted phenyl, and R 1a Is chlorine, methyl or nitro;
or, R 2 ～R 3 Simultaneously being methyl, R 4 Is H;
or, R 2 ～R 3 At the same time being H, R 4 Is an ethyl group.
6. A pharmaceutical composition comprising a therapeutically effective amount of a pyrimido-pyrrolopyridazine derivative, its tautomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient;
the pyrimido-pyrrolopyridazine derivative is a pyrimido-pyrrolopyridazine derivative shown in the formula I as claimed in any one of claims 1 to 5, or is selected from any one of the following compounds:
Figure FDA0003535021560000051
Figure FDA0003535021560000061
7. use of a pyrimido-pyrrolopyridazine derivative, a tautomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of an anti-inflammatory agent;
the pyrimido-pyrrolopyridazine derivative is a pyrimido-pyrrolopyridazine derivative shown in the formula I as claimed in any one of claims 1 to 5, or is selected from any one of the following compounds:
Figure FDA0003535021560000071
Figure FDA0003535021560000081
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