CN110759923B - Pyrimidopyrrolopyridazine derivatives, intermediates thereof, preparation method, pharmaceutical compositions and uses - Google Patents

Abstract

The invention discloses a pyrimidopyrrolopyridazine derivative, its intermediate, preparation method, pharmaceutical composition and use. The preparation method of the pyrimidopyrrolopyridazine derivative represented by formula I, which comprises: in a solvent, under the action of an additive, the compound represented by formula IV is subjected to the reaction shown below. The preparation method of the invention overcomes the disadvantages of multi-step synthesis and low separation yield in traditional methods, and can rapidly synthesize various novel heterocyclic compounds with important biological activities. The pyrimidopyrrolopyridazine derivatives of the present invention have better activity of inhibiting the production of NO by macrophage RAW264.7.

Description

Pyrimidopyrrolopyridazine derivatives, intermediates, preparation methods, pharmaceutical compositions and uses

technical field

The present invention relates to a pyrimidopyrrolopyridazine derivative, its intermediate, preparation method, pharmaceutical composition and use.

Background technique

Nitrogen-containing heterocycles are an important core of a class of biologically active compounds (Chem. Heterocycl. Compd. 2016, 52, 651-657; Curr. Org. Chem. 2017, 21, 1265-1291). Among them, pyridazine fused heterocycles have attracted wide attention due to their remarkable broad-spectrum biological activities, including diuretic activity (J.Med.Chem.1999,42,779-783), anti-HIV-1 (J.Med.Chem.2000 , 43, 2457-2463), psychoactive effect (J.Med.Chem.2005,48,1367-1383) and platelet aggregation activity (J.Med.Chem.1986,29,2191-2194) and so on. Multistep synthesis and low isolated yields limit the development of such frameworks (Heterocycles 1993, 35.; J. Heterocycl. Chem. 2005, 42, 361-373).

The construction of some reported nitrogen-containing heterocyclic systems is generally carried out under the conditions of catalyst, suitable solvent and high temperature reflux, and the yield is not high. Multi-step reactions and complex reaction conditions make the construction of heterocyclic systems difficult, which limits the development of various drugs (J.Med.Chem.2014,57,7577-7589.; J.Med.Chem.2014,57 , 2683-2691.).

Although many efforts have been devoted to the construction of pyridazine fused compounds, the synthesis of pyrimidopyrrolopyridazines is still a challenging work (J. Heterocycl. Chem. 2005, 42, 361-373.).

Therefore, there is an urgent need in the art to develop a method for efficiently preparing pyrimidopyrrolopyridazine derivatives.

SUMMARY OF THE INVENTION

The problem to be solved by the present invention is to provide a pyrimidopyrrolopyridazine derivative, an intermediate, etc. in order to overcome the defects of long synthesis route and low total yield in the synthesis process of nitrogen-containing heterocyclic derivatives in the prior art. , preparation method, pharmaceutical composition and application. The preparation method of the invention overcomes the shortcomings of traditional methods such as multi-step synthesis and low separation yield, and realizes the efficient synthesis of pyrimidopyrrolopyridazine derivatives with high yield.

The present invention provides a pyrimidopyrrolopyridazine derivative as shown in formula I, a pharmaceutically acceptable salt thereof or a prodrug thereof:

Wherein, R ₁ is selected from H, C ₁ -C ₁₂ linear or branched alkyl, C ₁ -C ₁₂ linear or branched haloalkyl, C ₁ -C ₁₂ linear or branched alkoxy , C ₃ -C ₆ cycloalkyl, C ₆ -C ₂₀ aryl, C ₂ -C ₁₀ heteroaryl, by one or more (for example 1-6, preferably 1-3 or 1-2 a) C ₆ -C ₂₀ aryl substituted by R _1a or a C ₂ -C ₁₀ heteroaryl substituted by one or more (eg 1-6, preferably 1-3 or 1-2) R _1b group (the heteroatom is one or more of N, O and S, and the number of heteroatoms is 1-3), wherein R _1a and R _1b are each independently selected from hydroxyl, nitro, halogen, amino, C ₁ -C ₆ straight or branched chain alkyl, C ₁ -C ₆ straight or branched alkoxy or C ₁ -C ₆ straight or branched haloalkyl; when R _1a or R _1b is When there are multiple, R _1a or R _{1b are} the same or different;

R ₂ to R ₅ are each independently selected from -H or C ₁ -C ₁₂ linear or branched alkyl.

In the present invention, when R ₁ is a C ₁ -C ₁₂ straight chain or branched chain alkyl group, the C ₁ -C ₁₂ straight chain or branched chain alkyl group is preferably a C ₁ -C ₆ straight chain or branched chain The chain alkyl group is more preferably a C ₁ -C ₃ straight or branched chain alkyl group, and still more preferably a methyl group or an ethyl group.

When R ₁ is a C ₁ -C ₁₂ straight-chain or branched-chain haloalkyl group, the C ₁ -C ₁₂ straight-chain or branched-chain haloalkyl group is preferably C substituted with one or more identical or different halogen atoms ₁ -C ₁₂ straight-chain or branched alkyl group, the halogenated can be on the same or different carbon atoms; the C ₁ -C ₁₂ straight-chain or branched chain haloalkyl group is preferably C ₁ -C ₃ straight-chain or branched-chain haloalkyl groups.

When R ₁ is a C ₁ -C ₁₂ linear or branched alkoxy group, the C ₁ -C ₁₂ linear or branched alkoxy group is preferably a C ₁ -C ₆ linear or branched alkoxy The oxy group is more preferably a C ₁ -C ₃ linear or branched alkoxy group, and still more preferably a methoxy group or an ethoxy group.

When R ₁ is C ₃ -C ₆ cycloalkyl, the C ₃ -C ₆ cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

When R ₁ is a C ₆ -C ₂₀ aryl group, the C ₆ -C ₂₀ aryl group is preferably a C ₆ -C ₁₀ aryl group, more preferably phenyl or naphthyl.

When R ₁ is a C ₂ -C ₁₀ heteroaryl group, the C ₂ -C ₁₀ heteroaryl group is preferably a C ₂ -C ₈ heteroaryl group, more preferably pyridyl or thienyl.

When R ₁ is a C ₆ -C ₂₀ aryl group substituted by one or more R _1a , the C ₆ -C ₂₀ aryl group is preferably a C ₆ -C ₁₀ aryl group, more preferably phenyl or naphthyl.

When R ₁ is a C ₂ -C ₁₀ heteroaryl group substituted by one or more R _1b , the C ₂ -C ₁₀ heteroaryl group is preferably a C ₂ -C ₈ heteroaryl group, more preferably a C 2 -C 8 heteroaryl group Pyridyl or thienyl.

In the present invention, when R _1a or R _1b is halogen, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably chlorine.

When R _1a or R _1b is a C ₁ -C ₆ straight chain or branched chain alkyl group, the C ₁ -C ₆ straight chain or branched chain alkyl group is preferably a C ₁ -C ₃ straight chain or branched chain The alkyl group is more preferably a methyl group or an ethyl group.

When R _1a or R _1b is a C ₁ -C ₆ linear or branched alkoxy group, the C ₁ -C ₆ linear or branched alkoxy is preferably a C ₁ -C ₃ linear or branched chain alkoxy group The branched alkoxy group is more preferably a methoxy group or an ethoxy group.

When R _1a or R _1b is a C ₁ -C ₆ straight-chain or branched-chain haloalkyl group, the C ₁ -C ₆ straight-chain or branched-chain haloalkyl group is preferably replaced by one or more same or different halogen atoms Substituted C ₁ -C ₆ straight-chain or branched-chain alkyl, and the halo may be on the same or different carbon atoms; more preferably C ₁ -C ₃ straight-chain or branched haloalkyl.

When R ₂ to R ₅ are each independently a C ₁ -C ₁₂ straight chain or branched chain alkyl group, the C ₁ -C ₁₂ straight chain or branched chain alkyl group is preferably a C ₁ -C ₆ straight chain alkyl group Or branched chain alkyl, more preferably C ₁ -C ₃ straight or branched chain alkyl, still more preferably methyl, ethyl or n-propyl.

In a preferred embodiment of the present invention, preferably R ₁ is C ₁ -C ₃ straight or branched chain alkyl (eg methyl), C ₆ -C ₁₀ aryl (eg phenyl, naphthyl), C ₂ - _C8 heteroaryl (eg pyridyl, thienyl) or _C6 - _C10 aryl (eg phenyl, naphthyl) substituted with one R _1a , and R _1a is halogen (eg chlorine), C ₁ -C ₃ straight or branched chain alkyl (eg methyl) or nitro; further preferably R ₁ is methyl, phenyl, pyridyl, naphthyl, thienyl or phenyl substituted with one R _1a , and R _1a is chloro, methyl or nitro.

In a preferred embodiment of the present invention, preferably R ₂ to R ₄ are H at the same time.

In a preferred embodiment of the present invention, it is preferred that R ₂ to R ₃ are both C ₁ -C ₃ linear or branched alkyl groups, and R ₄ is H; more preferably, R ₂ to R ₃ are both methyl and R ₄ is H.

In a preferred embodiment of the present invention, preferably R ₂ to R ₃ are H at the same time, and R ₄ is a C ₁ -C ₃ straight-chain or branched alkyl group; more preferably, R ₂ to R ₃ are simultaneously H and R ₄ is ethyl.

In a preferred embodiment of the present invention, preferably R ₁ is phenyl, phenyl substituted with one R _1a , phenyl, pyridyl, naphthyl or thienyl, and R _1a is chlorine, methyl or nitro, and R ₂ to R ₄ is simultaneously H, and R ₅ is a C ₁ -C ₃ straight or branched chain alkyl group (eg methyl, ethyl or n-propyl).

In a preferred embodiment of the present invention, preferably R ₁ is phenyl, phenyl substituted with one R _1a , phenyl, pyridyl, naphthyl or thienyl, and R _1a is chlorine, methyl or nitro, and R ₂ to R ₃ is a straight-chain or branched alkyl group of C ₁ -C ₃ at the same time (for example, a methyl group at the same time), R ₄ is H, and R ₅ is a straight-chain or branched chain alkyl group of C ₁ -C ₃ (for example, a methyl group) , ethyl or n-propyl).

In a preferred embodiment of the present invention, preferably R ₁ is phenyl, pyridyl, naphthyl or thienyl, and R ₂ to R ₃ are both C ₁ -C ₃ straight or branched chain alkyl groups (for example, methyl at the same time). group), R ₄ is H, and R ₅ is methyl.

In a preferred embodiment of the present invention, preferably R ₁ is phenyl, phenyl substituted by a halogen (eg chlorine), pyridyl, naphthyl or thienyl, and R ₂ to R ₃ are simultaneously C ₁ -C ₃ Straight or branched chain alkyl (eg simultaneously methyl), R4 is H, _R5 is ethyl or n _- propyl.

In a preferred embodiment of the present invention, preferably R ₁ is phenyl, phenyl substituted with one R _1a , phenyl, pyridyl, naphthyl or thienyl, and R _1a is chlorine, methyl or nitro, and R ₂ to R ₃ is H at the same time, R ₄ is C ₁ -C ₃ straight or branched chain alkyl (eg ethyl), R ₅ is C ₁ -C ₃ straight or branched chain alkyl (eg methyl, ethyl) base or n-propyl).

In the present invention, the pyrimidopyrrolopyridazine derivative shown in the formula I can be selected from any of the following compounds:

The present invention also provides a method for preparing a pyrimidopyrrolopyridazine derivative represented by formula I, which comprises the following steps: in a solvent, under the action of an additive, the compound represented by formula IV is subjected to the following reaction , you can;

The definitions of R ₁ to R ₅ are as described above.

In the preparation method of the pyrimidopyrrolopyridazine derivatives shown in formula I, the solvent can be a conventional solvent for such reactions in the art, and in the present invention, it is preferably a halogenated alkane (such as dichloromethane, dichloroethane) , nitrile solvents (such as acetonitrile), ether solvents (such as tetrahydrofuran), alcohol solvents (such as methanol, ethanol), amide solvents (such as N,N-dimethylformamide) and aromatic solvents (such as toluene) one or more of acetonitrile, tetrahydrofuran, methanol, N,N-dimethylformamide and toluene; more preferably, the solvent is acetonitrile.

In the preparation method of the pyrimidopyrrolopyridazine derivative shown in formula I, the amount of the solvent can be the conventional amount for this type of reaction in the art, so as to ensure the smooth progress of the reaction.

NaH、X_aY_b、M₃(OAc)₂、三氟乙酸铜、三氟化硼和三氟化硼乙醚络合物中的一种或多种；其中，R₆～R₇各自独立地为C₁-C₆的直链或支链烷基(例如C₂-C₄的直链或支链烷基，又例如乙基、叔丁基)，M₁选自碱金属(例如Na或K，又例如Na)，M₂选自-H或碱金属(例如Na或K，又例如Na)，M₃选自Cu或Pd，X为Cu、Mg、Zn、Al或Fe，Y为卤素(例如氟、氯、溴或碘，又例如氯、溴或碘)，a和b各自独立地为1～3的整数，具体根据X和Y进行选择；作为优选，所述添加剂为N,N-二异丙基乙胺、乙酸钠、叔丁醇钠、氢化钠、乙酸、氯化铜、溴化铜、碘化铜、氯化镁、氯化锌、氯化铝、三氯化铁、醋酸铜、醋酸钯和三氟化硼乙醚络合物中的一种或多种；进一步优选，所述添加剂为氯化铜。In the preparation method of the pyrimidopyrrolopyridazine derivative shown in formula I, the additive can be organic amine, R ₆ OM ₁ ,

One or more of NaH, X _a Y _b , M ₃ (OAc) ₂ , copper trifluoroacetate, boron trifluoride and boron trifluoride ether complex; wherein, R ₆ to R ₇ are each independently For C ₁ -C ₆ straight or branched chain alkyl (such as C ₂ -C ₄ straight chain or branched alkyl, and for example ethyl, tert-butyl), M ₁ is selected from alkali metals (such as Na or K, another example Na), M ₂ is selected from -H or an alkali metal (such as Na or K, another example Na), M ₃ is selected from Cu or Pd, X is Cu, Mg, Zn, Al or Fe, Y is halogen (For example, fluorine, chlorine, bromine or iodine, and also for example chlorine, bromine or iodine), a and b are each independently an integer from 1 to 3, and are specifically selected according to X and Y; preferably, the additive is 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 , one or more of palladium acetate and boron trifluoride ether complex; further preferably, the additive is copper chloride.

In the preparation method of the pyrimidopyrrolopyridazine derivative shown in formula I, the molar ratio of the additive to the compound of formula IV can be the conventional molar ratio of this type of reaction in the art. The molar ratio of the compound IV is 1:0.1-1:1, further preferably, the molar ratio of the additive to the compound of formula IV is 1:0.1-1:0.2 (eg 1:1).

In the preparation method of the pyrimidopyrrolopyridazine derivatives shown in formula I, the temperature of the reaction can be the conventional temperature for such reactions in the art; preferably, the reaction is performed at 20-80°C (eg room temperature, 45-55°C or reflux temperature, preferably 45-55°C, more preferably 50°C). The progress of the reaction can be monitored by conventional testing methods in the field (eg TLC), and generally the end of the reaction is the disappearance of the starting material or the no longer reaction; preferably the reaction is 4-16 h.

In the preparation method of the pyrimidopyrrolopyridazine derivatives shown in formula I, the reaction may further comprise the following post-treatment steps: after cooling the reaction solution (preferably to room temperature), after mixing with ethyl acetate, using The organic phase is washed with saturated NH ₄ Cl solution and water, dried, concentrated and purified by flash column chromatography.

In the preparation method of the pyrimidopyrrolopyridazine derivative shown in formula I, the conditions of the flash column chromatography can be the conventional conditions of this type of operation in the field, and preferably, petroleum ether and ethyl acetate are used as the eluents. Deliquoring, more preferably, the volume ratio of petroleum ether and ethyl acetate is 10:1-1:1.

In the present invention, the preparation method of the pyrimidopyrrolopyridazine derivatives shown in formula I may further comprise the following steps: in a solvent, cycloketene amines (HKAs) shown in formula II and formula III are shown in The 1,2-diaza-1,3-diene (DDs) undergoes a Michael addition reaction to obtain the compound shown in formula IV;

The definitions of R ₁ to R ₅ are as described above.

In the present invention, the cycloketene amine can be prepared by a method well known to those of ordinary skill in the field of organic chemistry. In the present invention, specific reference may be made to Huang, Z.-T.; Wang, M.-X., Synthesis 1992, 12 , 1273-1276 and Li, Z.-J.; Smith, C.D., Synthetic Communications 2001, 31, 527-533 preparation, and its specific synthetic route is as follows:

In the present invention, the 1,2-diaza-1,3-diene can be prepared by a method well known to those of ordinary skill in the field of organic chemistry. For details in the present invention, reference may be made to Sommer, S., Tetrahedron Letters 1977, 18, 117 -120 was synthesized with Attanasi, O.A.; Filippone, P.; Mei, A.;

In the preparation method of the compound represented by formula IV, the type and amount of the solvent are as described above.

In the preparation method of the compound represented by formula IV, the molar ratio of cycloketene amine and 1,2-diaza-1,3-diene can be the ratio conventionally used in this type of reaction in the art, and the present invention is preferably the 1:1-1:2, such as 1:1.

NaH、X_aY_b、M₃(OAc)₂、三氟乙酸铜、三氟化硼和三氟化硼乙醚络合物中的一种或多种，其中，R₆～R₇各自独立地为C₁-C₆的直链或支链烷基(例如C₂-C₄的直链或支链烷基，又例如乙基、叔丁基)，M₁选自碱金属(例如Na或K，又例如Na)，M₂选自-H或碱金属(例如Na或K，又例如Na)，M₃选自Cu或Pd，X为Cu、Mg、Zn、Al或Fe，Y为卤素(例如氟、氯、溴或碘，又例如氯、溴或碘)，a和b各自独立地为1～3的整数，具体根据X和Y进行选择。In the preparation method of the compound represented by formula IV, the Michael addition reaction can be added with conventional additives for such reactions in the art as required, such as adding organic amines, R ₆ OM ₁ ,

One or more of NaH, X _a Y _b , M ₃ (OAc) ₂ , copper trifluoroacetate, boron trifluoride and boron trifluoride ether complex, wherein R ₆ to R ₇ are each independently For C ₁ -C ₆ straight or branched chain alkyl (such as C ₂ -C ₄ straight chain or branched alkyl, and for example ethyl, tert-butyl), M ₁ is selected from alkali metals (such as Na or K, another example Na), M ₂ is selected from -H or an alkali metal (such as Na or K, another example Na), M ₃ is selected from Cu or Pd, X is Cu, Mg, Zn, Al or Fe, Y is halogen (For example, fluorine, chlorine, bromine or iodine, and for example, chlorine, bromine or iodine), a and b are each independently an integer of 1 to 3, and are specifically selected according to X and Y.

In the preparation method of the compound represented by formula IV, the Michael addition reaction is preferably carried out without additives.

In the preparation method of the compound represented by formula IV, the reaction temperature of the Michael addition reaction can be the conventional temperature for such reactions in the art; in the present invention, it is preferably controlled between 20°C and reflux temperature (for example, room temperature, 50°C or reflux temperature), further preferably, the reaction temperature of the Michael addition reaction is room temperature (20-25° C.).

In the preparation method of the compound represented by formula IV, the progress of the Michael addition reaction can be monitored by conventional testing methods in the art (eg TLC), and the end point of the reaction is generally the disappearance or no longer reaction of the starting material. The reaction time of the Michael addition reaction is preferably 4-16h.

In the present invention, the preparation method of the pyrimidopyrrolopyridazine derivative shown in formula I preferably adopts the following one-pot method to prepare:

(1) in the solvent, the cycloketene amine shown in formula II and the 1,2-diaza-1,3-diene shown in formula III undergo Michael addition reaction to obtain the compound shown in formula IV;

(2) the reaction solution obtained in step (1) does not need to be subjected to post-treatment, and is directly mixed with the additive to react;

The definitions of R ₁ to R ₅ are as described above.

The specific conditions and parameters involved in the above steps (1) and (2) are as described above.

Preferably, when the pyrimidopyrrolopyridazine derivative shown in formula I is prepared by a one-pot method, the additive can be a metal halide (such as copper chloride, copper bromide, copper iodide, zinc chloride); Further preferably, the additive is copper chloride.

The present invention also provides a compound shown in formula IV, its tautomer, optical isomer, its pharmaceutically acceptable salt or its prodrug:

The definitions of R ₁ to R ₅ are as described above.

In the present invention, the compound shown in the formula IV can be selected from any of the following compounds:

The present invention also provides a method for preparing a compound represented by formula IV, which comprises the following steps: in a solvent, cycloketene amine represented by formula II and 1,2-diaza-1 represented by formula III , 3-diene undergoes a Michael addition reaction to obtain the compound shown in formula IV, that is;

The definitions of R ₁ to R ₅ are as described above, and the specific reaction conditions and parameters of the Michael addition reaction are as described above.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a pyrimidopyrrolopyridazine derivative represented by formula I, its tautomer, optical isomer, and a pharmaceutically acceptable salt thereof or its prodrug, and at least one pharmaceutical excipient. The mass percentage of the pyrimidopyrrolopyridazine derivative represented by formula I, its tautomer, optical isomer, its pharmaceutically acceptable salt or its prodrug in the pharmaceutical composition is 0.1% -99.9%. The choice of the pharmaceutical excipients varies according to the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrating agent, a lubricant, an emulsifying agent or a suspending agent.

The present invention also provides a pyrimidopyrrolopyridazine derivative as shown in formula I, its tautomer, optical isomer, its pharmaceutically acceptable salt or its prodrug in the preparation of anti-inflammatory drugs applications in .

In the present invention, the anti-inflammatory drug may be an anti-inflammatory drug commonly used in the art, such as an anti-inflammatory drug with diuretic activity, the activity of inhibiting the production of NO by macrophage RAW264.7, and anti-HIV-1.

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

In the present invention, room temperature refers to 20-25°C.

In the present invention, the reflux temperature refers to the reflux temperature of the solvent under the standard atmospheric pressure of the solvent.

The reagents and raw materials used in the present invention are all commercially available.

The positive progressive effect of the present invention is:

The present invention uses cycloketene amine and 1,2-diaza-1,3-diene as raw materials, preferably synthesizes pyrimidopyrrolopyridazine derivatives through a series reaction, the series reaction includes Michael addition, aminolysis and aromatization process. The preparation method of the invention overcomes the disadvantages of multi-step synthesis and low separation yield in traditional methods, and can rapidly synthesize various novel heterocyclic compounds with important biological activities, and the total yield reaches 17-65%. The pyrimidopyrrolopyridazine derivatives of the invention have better activity of inhibiting the production of NO by macrophage RAW264.7, and can be used for preparing anti-inflammatory drugs.

Detailed ways

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description. Raw materials can be obtained from commercial sources, or prepared by methods known in the art, or prepared according to methods described herein, wherein HKAs refer to Huang, Z.-T.; Wang, M.-X., Synthesis 1992, 12, 1273-1276 and Li, Z.-J.; Smith, CD, Synthetic Communications 2001, 31, 527-533 synthesis; DDs reference Sommer, S., Tetrahedron Letters 1977, 18, 117-120 and Attanasi, OA; Filippone, P.; , A.; Santeusanio, S. Synthesis 1984, 10, 874–876 Synthesis, DDs are mixtures of E/Z isomers. The structure of the compound was determined by nuclear magnetic resonance ( ¹ H NMR or ¹³ C NMR) and mass spectrometry (MS), wherein the NMR measurement used Bruker DRX500 nuclear magnetic resonance instrument, chemical shift (δ) was expressed in ppm, J value was expressed in Hz, The solvent was deuterated dimethyl sulfoxide (DMSO-D ₆ ) or deuterated chloroform (CDCl ₃ ), and TMS was the internal standard. Melting points were determined on a SGWX-4A melting point apparatus without correction. HRM was performed on an AgllentLC/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-Kα precision sealed tube.

Example 1:

Preparation of compound II-1

Refer to Huang, Z.-T.; Wang, M.-X., Synthesis 1992, 12, 1273-1276 and Li, Z.-J.; Smith, C.D., Synthetic Communications 2001, 31, 527-533 Preparation, its specific synthesis The route looks like this:

Acetophenone (10.0 mmol) was dissolved in THF (50 ml) under ice bath, NaH (20.0 mmol) was added and stirred for half an hour, CS ₂ (10.0 mmol) was added dropwise to the above reaction solution, and the ice bath was kept stirring After two hours, finally, MeI (20.0 mmol) was dropped into the reaction solution, and the temperature was slowly raised to room temperature after being kept in an ice bath for half an hour, and the mixture was stirred overnight. The reaction was evaporated to dryness under reduced pressure and diluted with EtOAc (100 mL). The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over Na ₂ SO ₄ , and the solution was evaporated to dryness under reduced pressure, which was directly used in the next reaction.

The crude product of the previous step was dissolved in ethanol (10 ml), 1,3-propanediamine (15.0 mmol) was added, and the temperature was raised to 100° C. After four hours of reaction, the reaction was cooled to 0° C. The solid was precipitated and dried to obtain yellow solid II. -1, Yield: 90%.

Preparation of compound III-1

With reference to Sommer, S., Tetrahedron Letters 1977, 18, 117-120 and Attanasi, O.A.; Filippone, P.; Mei, A.;

Sulfonyl chloride (10.0 mmol) was added dropwise to ethyl acetoacetate (10.0 mmol) under ice bath and stirred for half an hour, the reaction solution was evaporated to dryness under reduced pressure, and the crude product was directly used in the next reaction.

The semicarbazide hydrochloride (10.0 mmol) and sodium acetate (10.0 mmol) were dissolved in methanol (50 ml), stirred for half an hour, the crude product obtained in the previous step was added to the above reaction solution, stirred overnight, and the reaction solution was decompressed. Evaporated to dryness and diluted with DCM (100 mL), washed with saturated sodium carbonate solution (50 ml)×2 to give a red organic phase, which was evaporated to dryness under reduced pressure to give red solid III-1, yield: 80%.

Preparation of compound IV-1

In CH ₃ CN (25 ml) were added HKAs (1.0 mmol) of formula II-1 and DDs (1.0 mmol) of formula III-1, stirred at room temperature, TLC (thin layer chromatography using silica gel GF254) The reaction was followed 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 passed through silica gel (40-63 μm) flash column chromatography with eluent (petroleum ether:ethyl acetate=1:1 , v/v) purification to obtain yellow solid IV-1, melting point: 155.2-155.7 ° C, yield: 70%,

¹ H NMR (500MHz, DMSO-d ₆ ) δ 9.74 (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 ⁺ ): Calculated value for C ₁₇ H ₁₈ N ₅ O ₃ [(M+H) ⁺ ] 340.1404, found value 340.1405.

Example 2: Preparation of Pyrimidopyrrolopyridazine Derivative I-1

In CH ₃ CN (5 ml) were added HKAs (0.2 mmol) of formula II-1 and DDs (0.2 mmol) of formula III-1, stirred at room temperature, TLC (thin layer chromatography using silica gel GF254) The reaction is followed until the HKAs and DDs are completely consumed to obtain the compound represented by the formula IV-1. The compound does not need to be separated, and the subsequent reaction is carried out directly.

After adding CuCl2 ₍ 0.02 mmol) to the reaction, the resulting mixture was stirred at 50°C until complete conversion of the compound of formula IV-1 to product 1-1 (monitored by thin layer chromatography on silica gel GF254). The mixture was cooled to room temperature and diluted with EtOAc (25 mL). The organic phase was washed with saturated NH ₄ Cl solution (20 mL) and water (20 mL), dried over Na ₂ SO ₄ , the solution was evaporated to dryness under reduced pressure on a rotary evaporator, and the residue was passed through silica gel (40-63 μm particle size) ) was purified by flash column chromatography with eluent (petroleum ether:ethyl acetate=5:1, v/v) to obtain yellow solid I-1, melting point: 201.2-201.7°C, yield: 62%,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.09-8.00 (m, 2H), 7.56-7.46 (m, 3H), 3.83 (t, J=5.7 Hz, 4H), 3.13 (s, 3H), 1.97- 1.92 (m, 2H); ¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.11, 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 ⁺ ) : Predicted for C ₁₆ H ₁₅ N ₄ O [(M+H) ⁺ ] 279.1240, found 279.1243.

Example 3: Preparation of Pyrimidopyrrolopyridazine Derivative I-2

The preparation process of the pyrimidopyrrolopyridazine derivative I-2 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-2 is obtained, melting point: 174.6-175.3 °C, yield: 65% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.96 (d, J=8.2 Hz, 2H), 7.30 (d, J=7.9 Hz, 2H), 3.83 (q, J=5.6 Hz, 4H), 3.11 (s , 3H), 2.46-2.41 (m, 3H), 1.97-1.92 (m, 2H); ¹³ C NMR (126MHz, CDCl ₃ ) δ 165.21, 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 ⁺ ): The predicted value of C ₁₇ H ₁₇ N ₄ O[(M+H) ⁺ ] was 293.1397, and the observed value was 293.1398.

Example 4: Preparation of Pyrimidopyrrolopyridazine Derivative I-3

The preparation process of the pyrimidopyrrolopyridazine derivative I-3 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-3 is obtained, melting point: 182.9-183.8 °C, yield: 58% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.03 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 3.85-3.82 (m, 4H), 3.12 (s, 3H) , 1.98-1.94 (m, 2H); ¹³ C NMR (126MHz, CDCl ₃ )δ164.98,155.14,154.39,148.52,136.47,132.63,131.94,128.52,128.11,126.39,77.27,77.02,76.5,19,4 , 18.64; HRMS (TOF ES ⁺ ): predicted 313.0851 for C ₁₆ H ₁₄ ClN ₄ O [(M+H) ⁺ ], found 313.0852.

Example 5: Preparation of Pyrimidopyrrolopyridazine Derivative I-4

The preparation process of the pyrimidopyrrolopyridazine derivative I-4 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-4 is obtained, melting point: 175.0-176.1 °C, yield: 60% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.08 (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} _{; _ _} ) ⁺ ] predicted 313.0851 and found 313.0851.

Example 6: Preparation of Pyrimidopyrrolopyridazine Derivative I-5

The preparation process of the pyrimidopyrrolopyridazine derivative I-5 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-5 is obtained, melting point: 157.1-158.0℃, yield: 35% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 9.43(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 (126 MHz, CDCl ₃ ) δ 164.69, 155.90, 152.23, 150.99, 150.06, 148.14, 138.72, 130.98, 129.11, 126.44, 123.5 47.09, 37.76, 19.79, 18.69; HRMS(TOF ES ⁺ ): Predicted value of C ₁₅ H ₁₄ N ₅ O [(M+H) ⁺ ] 280.1193, found value of 280.1193.

Example 7: Preparation of Pyrimidopyrrolopyridazine Derivative I-6

The preparation process of the pyrimidopyrrolopyridazine derivative I-6 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-6 is obtained, melting point: 201.2-201.5 °C, yield: 65% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.62 (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, ^{148.61,134.1613.76,131.65,130.98,128.97,128.73,127.67.46,127.13,126.15,77.00,76.74,37.74,19.82,18.64} ( _{19.82,18.64,18.64} . ₁₇ N ₄ O[(M+H) ⁺ ] predicted 329.1397, found 329.1398.

Example 8: Preparation of Pyrimidopyrrolopyridazine Derivative I-7

The preparation process of the pyrimidopyrrolopyridazine derivative I-7 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-7 is obtained, melting point: 195.8-199.3 °C, yield: 38% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.40-8.30(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 ) δ 164.65, 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 Predicted _324.1091 for _{H14N5O3 [} (M+H) ⁺ ], found 324.1091.

Example 9: Preparation of Pyrimidopyrrolopyridazine Derivative I-8

The preparation process of the pyrimidopyrrolopyridazine derivative I-8 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-8 is obtained, melting point: 187.0-187.9℃, yield: 52% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.06-8.00 (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 (126 MHz, CDCl ₃ ) δ 164.81, 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 ⁺ ): Predicted value of C ₁₇ H ₁₆ ClN ₄ O[(M+H) ⁺ ] was 327.1007, observed value was 327.1007 .

Example 10: Preparation of Pyrimidopyrrolopyridazine Derivative I-9

The preparation process of the pyrimidopyrrolopyridazine derivative I-9 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-9 is obtained, melting point: 175.2-176.1 °C, yield: 53% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.09 (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 )δ164.73,160.10,154.08,148.38,135.94,133.75,130.65,130.13,129.01,128.94,128.75,125.89,77.2,7.7.4,7 25.63, 19.78, 13.44; HRMS (TOF ES ⁺ ): Predicted 327.1007 for C ₁₇ H ₁₆ ClN ₄ O [(M+H) ⁺ ], found 327.1007.

Example 11: Preparation of Pyrimidopyrrolopyridazine Derivative I-10

The preparation process of the pyrimidopyrrolopyridazine derivative I-10 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-10 is obtained, melting point: 209.9-210.3 °C, yield: 60% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.63 (dd, J=1.8, 0.8 Hz, 1H), 8.14 (dd, J=8.5, 1.8 Hz, 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=7.6 Hz, 3H); ¹³ C NMR (126 MHz, CDCl ₃ ) δ 165.00, 159.54, 155.43, 148.65, 134.15, 132.76, 131.71, 130.99, 128.98, 127.69, 127.49, 127.18, 127.1 125.90, 77.27, 77.22, 77.01, 76.76, 47.13, 37.74, 25.64, 19.83, 13.48; HRMS(TOF ES ⁺ ): predicted value of C ₂₁ H ₁₉ N ₄ O[(M+H) ⁺ ] 343.1553, observed value is 343.1553.

Example 12: Preparation of Pyrimidopyrrolopyridazine Derivative I-11

The preparation process of the pyrimidopyrrolopyridazine derivative I-11 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-11 is obtained, melting point: 183.2-183.9℃, yield: 50% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.08-8.01 (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 ) δ 164.96, 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 ⁺ ): The predicted value of C ₁₇ H ₁₇ N ₄ O[(M+H) ⁺ ] was 293.1397, and the observed value was 293.1397.

Example 13: Preparation of Pyrimidopyrrolopyridazine Derivative I-12

The preparation process of the pyrimidopyrrolopyridazine derivative I-12 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-12 is obtained, melting point: 166.5-167.2 °C, yield: 54% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.07-8.02 (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 (126 MHz, CDCl ₃ ) δ 164.83, 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 ⁺ ): The predicted value of C ₁₈ H ₁₈ ClN ₄ O[(M+H) ⁺ ] was 341.1164, and the observed value was 341.1164.

Example 14: Preparation of Pyrimidopyrrolopyridazine Derivative I-13

The preparation process of the pyrimidopyrrolopyridazine derivative I-13 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-13 is obtained, melting point: 161.4-161.9 °C, yield: 52% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.17-7.97 (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 (126 MHz, CDCl ₃ ) δ 164.99, 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 ⁺ ): The predicted value of C ₁₈ H ₁₉ N ₄ O[(M+H) ⁺ ] was 307.1553, and the observed value was 307.1553.

Example 15: Preparation of Pyrimidopyrrolopyridazine Derivative I-14

The preparation process of the pyrimidopyrrolopyridazine derivative I-14 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-14 is obtained, melting point: 207.9-208.6 °C, yield: 56% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.64 (d, J=2.0 Hz, 1H), 8.15 (dd, J=8.5, 1.8 Hz, 1H), 7.94 (d, J=8.3 Hz, 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 (126 MHz, CDCl ₃ ) δ 165.03, 158.56, 155.32, 148.62, 134.14, 132.76, 131.71, 131.00, 128.98, 128.90, 127.69, 127.51, 127.17, 12 126.10, 77.28, 77.02, 76.77, 47.13, 37.73, 33.90, 22.85, 19.82, 14.00; HRMS(TOF ES ⁺ ): predicted value of C ₂₂ H ₂₁ N ₄ O[(M+H) ⁺ ] 357.1710, measured value is 357.1710.

Example 16: Preparation of Pyrimidopyrrolopyridazine Derivative I-15

The preparation process of the pyrimidopyrrolopyridazine derivative I-15 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-15 is obtained, melting point: 158.9-159.6℃, yield: 52% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.09 (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 ⁺ ): predicted 341.1164 for C ₁₈ H ₁₈ ClN ₄ O [(M+H) ⁺ ], found 341.1164.

Example 17: Preparation of Pyrimidopyrrolopyridazine Derivative I-16

The preparation process of the pyrimidopyrrolopyridazine derivative I-16 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-16 is obtained, melting point: 151.2-151.9℃, yield: 53% ,

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 (126 MHz, CDCl ₃ ) δ 165.08, 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 was 321.1710 and the measured value was 321.1710.

Example 18: Preparation of Pyrimidopyrrolopyridazine Derivative I-17

The preparation process of the pyrimidopyrrolopyridazine derivative I-17 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-17 is obtained, melting point: 229.0-229.6 °C, yield: 42% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 9.10 (dd, J=3.9, 1.1 Hz, 1H), 7.54 (dd, J=5.1, 1.1 Hz, 1H), 7.15 (dd, J=5.1, 3.8 Hz, 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=7.4 Hz, 3H); ¹³ C NMR (126 MHz, CDCl ₃ ) δ 164.91, 157.88, 149.87, 149.09, 139.47, 133.79, 130.83, 127.88, 126.30, 125.99, 77.26, 77.01, 76.7, 5, 4.7.08 , 22.65, 19.66, 13.93; HRMS(TOF ES ⁺ ): predicted value of C ₁₆ H ₁₇ N ₄ OS[(M+H) ⁺ ] was 313.1118, and found value was 313.1119.

Example 19: Preparation of Pyrimidopyrrolopyridazine Derivative I-18

The preparation process of the pyrimidopyrrolopyridazine derivative I-18 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-18 is obtained, melting point: 150.4-151.2 °C, yield: 60% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.12-8.02(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 (126 MHz, CDCl ₃ ) δ 165.25, 154.85, 147.87, 134.23, 133.29, 130.55, 130.21, 130.06, 128.35, 127.84, 77.27, 77.22, 77.02, 76.7, 2.9 24.66, 18.64; HRMS (TOF ES ⁺ ): Predicted 307.1553 for C ₁₈ H ₁₉ N ₄ O [(M+H) ⁺ ], found 307.1554.

Example 20: Preparation of Pyrimidopyrrolopyridazine Derivative I-19

The preparation process of the pyrimidopyrrolopyridazine derivative I-19 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-19 is obtained, melting point: 115.5-116.1 °C, yield: 55% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.11-8.05 (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 (126 MHz, CDCl ₃ ) δ 165.11, 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 ⁺ ): predicted value of C ₂₀ H ₂₃ N ₄ O[(M+H) ⁺ ] is 335.1866, The measured value is 335.1867.

Example 21: Preparation of Pyrimidopyrrolopyridazine Derivative I-20

The preparation process of pyrimidopyrrolopyridazine derivative I-20 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally yellow solid I-20 is obtained, melting point: 137.5-138.1℃, yield: 57% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.12-8.03 (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 ) δ 165.08, 159.54, 155.36, 147.91, 134.31, 130.56, 130.18, 128.44, 127.81, 126.19, 77.26, 77.7, 21, 77.0 59.81, 48.72, 27.71, 25.58, 24.68, 13.44; HRMS(TOF ES ⁺ ): Predicted value of C ₁₉ H ₂₁ N ₄ O[(M+H) ⁺ ] was 321.1710, observed value was 321.1710.

Example 22: Preparation of Pyrimidopyrrolopyridazine Derivative I-21

The preparation process of the pyrimidopyrrolopyridazine derivative I-21 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-21 is obtained, melting point: 189.7-190.2 °C, yield: 58% ,

Mp 189.7-190.2°C; ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.02-7.96 (m, 2H), 7.31 (d, J=7.8 Hz, 2H), 3.56 (s, 2H), 3.49 (s, 2H) ), 3.12 (s, 3H), 2.44 (s, _3H ), ^1.03 (s, 6H); 126.69, 77.28, 77.03, 76.77, 59.82, 48.71, 27.69, 24.66, 21.54, 18.62; HRMS(TOF ES ⁺ ): predicted value of C ₁₉ H ₂₁ N ₄ O[(M+H) ⁺ ] 321.1710, observed value is 321.1711.

Example 23: Preparation of Pyrimidopyrrolopyridazine Derivative I-22

The preparation process of the pyrimidopyrrolopyridazine derivative I-22 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-22 is obtained, melting point: 158.6-159.3 °C, yield: 52% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.03-7.97(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 ⁺ ): predicted value of C ₂₀ H ₂₃ N ₄ O[(M+H) ⁺ ] 335.1866, observed value is 335.1865.

Example 24: Preparation of Pyrimidopyrrolopyridazine Derivative I-23

The preparation process of the pyrimidopyrrolopyridazine derivative I-23 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-23 is obtained, melting point: 133.5-134.1 °C, yield: 53% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.05-7.97 (m, 2H), 7.31 (d, J=7.9 Hz, 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 CNMR (126MHz, CDCl ₃ ) δ 165.20, 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[( +H) ⁺ ] had a predicted value of 349.2023 and a predicted value of 349.2024.

Example 25: Preparation of Pyrimidopyrrolopyridazine Derivative I-24

The preparation process of the pyrimidopyrrolopyridazine derivative I-24 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-24 is obtained, melting point: 176.5-177.3 °C, yield: 52% ,

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), _The ^_ 18.66; HRMS (TOF ES ⁺ ): Predicted 341.1164 for C ₁₈ H ₁₈ ClN ₄ O [(M+H) ⁺ ], found 341.1164.

Example 26: Preparation of Pyrimidopyrrolopyridazine Derivative I-25

The preparation process of the pyrimidopyrrolopyridazine derivative I-25 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-25 is obtained, melting point: 157.6-158.4°C, yield: 50% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.13-8.02 (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 ) δ 164.95, 159.84, 154.27, 147.96, 136.51, 132.71, 131.95, 128.41, 128.13, 126.22, 77.26, 59.01, 76.5 , 48.73, 27.72, 25.60, 24.67, 13.38; HRMS (TOF ES ⁺ ): predicted value of C ₁₉ H ₂₀ ClN ₄ O [(M+H) ⁺ ] was 355.1320, and found value was 355.1320.

Example 27: Preparation of Pyrimidopyrrolopyridazine Derivative I-26

The preparation process of the pyrimidopyrrolopyridazine derivative I-26 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-26 is obtained, melting point: 183.4-184.7 °C, yield: 51% ,

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 (125 MHz, CDCl ₃ ) δ 164.96, 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 ⁺ ): predicted value of C ₂₀ H ₂₂ ClN ₄ O[(M+H) ⁺ ] 369.1477, The found value is 369.1477.

Example 28: Preparation of Pyrimidopyrrolopyridazine Derivative I-27

The preparation process of the pyrimidopyrrolopyridazine derivative I-27 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-27 is obtained, melting point: 177.5-178.4℃, yield: 57% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.69-8.63 (m, 1H), 8.16 (dd, J=8.6, 1.7 Hz, 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 ⁺ ): predicted 357.1710 for C ₂₂ H ₂₁ N ₄ O [(M+H) ⁺ ], found 357.1710.

Example 29: Preparation of Pyrimidopyrrolopyridazine Derivative I-28

The preparation process of the pyrimidopyrrolopyridazine derivative I-28 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-28 is obtained, melting point: 171.7-172.6 °C, yield: 60% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.70-8.64 (m, 1H), 8.17 (dd, J=8.5, 1.8 Hz, 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 ) δ 165.12, 159.51, 155.37, 148.02, 134.19, 132.77, 131.71, 131.02, 129.00, 128.62, 127.69, 127.25, 17 127.16, 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) ⁺ ] predicted values 371.1866, the measured value is 371.1865.

Example 30: Preparation of Pyrimidopyrrolopyridazine Derivative I-29

The preparation process of the pyrimidopyrrolopyridazine derivative I-29 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-29 is obtained, melting point: 144.6-145.2 °C, yield: 50% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.70-8.64 (m, 1H), 8.17 (dd, J=8.6, 1.8 Hz, 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 ⁺ ): The predicted value of C ₂₄ H ₂₅ N ₄ O[(M+H) ⁺ ] was 385.2023, and the observed value was 385.2024.

Example 31: Preparation of Pyrimidopyrrolopyridazine Derivative I-30

The preparation process of the pyrimidopyrrolopyridazine derivative I-30 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-30 is obtained, melting point: 172.6-173.0℃, yield: 28% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.14-8.05 (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} _{; _} The predicted value of ₄ O[(M+H) ⁺ ] is 307.1553, the observed value is 307.1552.

Example 32: Preparation of Pyrimidopyrrolopyridazine Derivative I-31

The preparation process of the pyrimidopyrrolopyridazine derivative I-31 is similar to the preparation process of I-1, and the types of HKAs and DDs are changed, and finally a yellow solid I-31 is obtained, melting point: 136.3-136.9℃, yield: 21% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.15-8.08 (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 ) ^{δ164.98,159.60,155.50,147.30,130.80,130.01,128.86,127.54,126.13,77.25,77.00,76.74,58.24,36.97,29.58,25.62,25.5} ):0,13 Predicted _321.1710 for _C19H21N4O [(M ₊ H) ⁺ ], found 321.1710.

Example 33: Preparation of Pyrimidopyrrolopyridazine Derivative I-32

The preparation process of the pyrimidopyrrolopyridazine derivative I-32 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-32 is obtained, melting point: 120.1-120.6℃, yield: 17% ,

¹ H NMR (500MHz, CDCl ₃ ) δ 8.17-8.09 (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 ⁺ ): Predicted 335.1866 for _C20H23N4O [( _{M +} H) ⁺ ], found 335.1867.

Example 34: Preparation of Pyrimidopyrrolopyridazine Derivative I-33

The preparation process of the pyrimidopyrrolopyridazine derivative I-33 is similar to the preparation process of I-1. The types of HKAs and DDs are changed, and finally a yellow solid I-33 is obtained, melting point: 173.3-173.9℃, yield: 61% ,

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.89 (t, J=5.6 Hz, 2H), 3.84-3.74 (m, 2H), 3.00 (d, J=1.2 Hz, 6H), 2.04-1.93 (m, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ) δ 165.37, 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 is 217.1084 and the measured value is 217.1085.

Example 35: Effects of Different Solvents, Temperatures and Additives on the Preparation Process of Compounds of Formula IV

Add HKAs (0.2 mmol) represented by formula II-1 and DDs (0.2 mmol) represented by formula III-1 in the solvent (5 ml), add additives, stir at a certain temperature, TLC (using a thin layer of silica gel GF254) Chromatography) followed the reaction 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 passed through silica gel (40-63 μm particle size) flash column chromatography with eluent (petroleum ether:ethyl acetate) Ester=1:1, v/v) purification to obtain yellow solid IV-1, the experimental results are shown in Table 1.

Table 1.

Example 36: Effects of different temperatures and additives on the preparation process of pyrimidopyrrolopyridazine derivatives

In CH ₃ CN (5 ml), HKAs (0.2 mmol) represented by formula II-1 and DDs (0.2 mmol) represented by formula III-1 were added, stirred at room temperature (25° C.), TLC (using silica gel GF254) Thin-layer chromatography) followed the reaction until the HKAs and DDs were completely consumed to obtain the compound of formula IV-1.

After addition of additives to the reactants, the resulting mixture was stirred at temperature until complete conversion of the compound of formula IV to product 1-1 (monitored by thin layer chromatography on silica gel GF254). The mixture was cooled to room temperature and diluted with EtOAc (25 mL). The organic phase was washed with saturated NH ₄ Cl solution (20 mL) and water (20 mL), dried over Na ₂ SO ₄ , the solution was evaporated to dryness under reduced pressure on a rotary evaporator, and the residue was passed through a silica gel (40-63 μm) flash column Chromatography was purified with the indicated eluent (PE:EA=10:1-1:1) to obtain yellow solid I-1. The experimental results are shown in Table 2.

Table 2.

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 buffered saline) was added to prepare a solution with a concentration of 10 mM, which was further diluted to a gradient concentration of 0, 0.1, 0.5, 5, and 20 μM. A 10 μg/mL LPS aqueous solution (Lipopolysaccharides, lipopolysaccharide, sigma, Cat. L-2880) was used as the inducer.

(2) Experimental method

Mouse macrophage RAW264.7 (purchased from the Cell Resource Center, Shanghai Academy of Biological Sciences) was routinely cultured in DMEM medium at 37°C, 5% CO ₂ incubator. In the experiment, 1 μL/mL LPS aqueous solution was added to 100 mL of the cell suspension with a concentration of 2×10 ⁶ μg/mL. After 18 h, the amount of NO production was indirectly reflected by measuring the nitrite content in the cell supernatant by Griess method: take 100 mL Cell culture medium, add equal amount of Griess (Griess) reagent, measure the absorbance value.

(3) Evaluation Criteria and Statistical Methods

Measure the absorbance at the wavelength of 570nm, draw a standard curve with NaNO ₂ standard solution, and calculate the concentration of nitrite. The experimental results of each group were statistically analyzed by one-way ANNOVA method of SPSS software.

(4) Experimental results

The experimental results show that the target compound has obvious inhibitory activity on LPS-induced NO production in RAW264.7 macrophages. The results are shown in Table 3, indicating that it has anti-inflammatory activity.

table 3.

The experimental results show that the compounds involved in the present invention have better activity of inhibiting the production of NO by macrophage RAW264.7, indicating that the compounds of the present invention can be used to prepare anti-inflammatory drugs.

Claims (7)

1. A pyrimido-pyrrolopyridazine derivative represented by formula I, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

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:

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:

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: