CN116635371A - A polycyclic pyridazinone derivative as an SOS1 inhibitor, its preparation method and use - Google Patents

Abstract

Provided are polycyclic pyridazinone derivatives as SOS1 inhibitors, their preparation methods and applications. The structure of the polycyclic pyridazinone derivatives is shown in formula (I), which has a significant effect of inhibiting the RAS signaling pathway and treating cancer, and the cancer is pancreatic cancer, colorectal cancer, lung cancer, and hepatocellular carcinoma , kidney cancer, gastric cancer and bile duct cancer.

Description

A polycyclic pyridazinone derivative as an SOS1 inhibitor, its preparation method and use technical field

The invention belongs to the technical field of polycyclic pyridazinone derivatives, and specifically relates to a polycyclic pyridazinone derivative as an SOS1 inhibitor, its preparation method and application.

Background technique

The RAS family protein belongs to a small GTPase, including three subfamilies of KRAS, NRAS and HRAS. The mutated RAS gene is an important oncogene, and RAS gene mutations are found in 20-30% of human tumors, especially pancreatic cancer, colorectal cancer and lung cancer. Various subtypes of RAS proteins have a balance between the GTP-bound activated state and the GDP-bound inactivated state. GTPase-activating proteins (GAPs) can promote the conversion of GTP to GDP, thereby making the RAS protein go inactive. The active state changes, while guanine nucleotide exchange factors (guanine nucleotide exchange factors, GEFs) can promote the release of GDP and the combination of GTP, so that the RAS protein turns to the active state. The activation of RAS protein will promote cell proliferation, apoptosis evasion and metabolic reorganization through RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT signaling pathways, thereby promoting the occurrence and development of tumors.

SOS1 (son of sevenless 1) is a key guanine nucleotide exchange factor (GEF) that can bind to RAS protein, promote the combination of RAS protein and GTP, and turn RAS protein to an active state. Recent studies have found that SOS1 inhibitors can not only inhibit the growth of RAS mutant cells, but also have a synergistic effect with MEK inhibitors, resulting in a significant inhibitory effect on KRAS-driven tumors ^1-2 . The development of SOS1 inhibitors has become a research hotspot. SOS1 inhibitors of different structural types have been reported in many patents, such as WO2018172250, WO2019201848, WO2018115380, WO2019122129, WO2020173935, WO2020180768 and WO2020180770.

However, there are still uncertainties in the effectiveness, safety or selectivity of the compounds and experimental drugs disclosed in these prior art, so it is necessary to research and develop new selective SOS1 inhibitors.

references:

1. Hillig et al. Discovery of poetic SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. PNAS. 116, 2251-2560 (2019).

2. Hofmann et al. BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. CD-20-0142(2020).

Contents of the invention

In order to solve the above-mentioned problems of the prior art, the object of the present invention is to provide a polycyclic pyridazinone derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer, to screen out A compound useful as an SOS1 inhibitor having excellent properties in terms of efficacy, safety, selectivity and the like.

Another object of the present invention is to provide a preparation method of the derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer.

To achieve this purpose of the invention, the present invention adopts the following technical solutions:

In the first aspect, the present invention provides a polycyclic pyridazinone derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, the polycyclic pyridazinone derivative Structure is as shown in formula (I):

Wherein: R ¹ is selected from hydrogen or methyl;

R ² is selected from C ₁ -C ₃ alkyl, -OR ²¹ , halogen, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, 6-10 membered condensed cycloalkyl, 7-10 membered bridge Cycloalkyl, 7-10-membered spirocycloalkyl, 4-7-membered heterocyclyl, 5-7-membered heterocycloalkenyl, 6-10-membered fused heterocyclyl, 7-10-membered bridged heterocyclyl , 7-10 membered spiroheterocyclyl, wherein 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, 6-10 membered condensed cycloalkyl, 7-10 membered bridged cycloalkyl, 7- 10-membered spirocycloalkyl, 4-7-membered heterocyclyl, 5-7-membered heterocycloalkenyl, 6-10-membered fused heterocyclyl, 7-10-membered bridged heterocyclyl, 7-10-membered Spiroheterocyclyl is optionally substituted by 1-3 R ²² ;

R ²¹ is selected from H, C ₁ -C ₃ alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein C ₁ -C ₃ alkyl, 3-7 membered cycloalkyl, 4-7 A membered heterocyclyl is optionally substituted by 1-3 R ²² ;

R ²² is selected from C ₁ -C ₃ alkyl, hydroxyl, halogen, cyano, -NR ^a R ^b , C ₁ -C ₃ alkoxy, -C(O)R ^a , -C(O)OR ^a , -OC(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b , phenyl, 5-6 membered heteroaryl and = O, wherein the alkyl, alkoxy, phenyl, 5-6 membered heteroaryl are optionally further replaced by 1-3 halogen, C ₁ -C ₃ alkyl, hydroxyl, cyano, amino and C ₁ - C ₃ alkoxy is substituted;

R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ alkyl, substituted or unsubstituted 3-6 membered cycloalkyl or substituted or unsubstituted 4-7 membered heterocycle base; here "substituted" means optionally substituted by 1-3 substituents selected from C ₁ -C ₃ alkyl, hydroxyl, halogen, cyano, amino or alkoxy;

Q is selected from N or -CR ³ ;

R ³ is selected from H, C ₁ -C ₃ alkyl, halogen, cyano or -OR ²¹ ;

AR is selected from 6-10 membered aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-4 R ^c ;

R ^c is selected from H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ haloalkyl, 3-6 membered cycloalkane radical, 4-7 membered heterocyclic group, -OR ²¹ , -NR ^a R ^b , NR ^a R ^b -C ₁ -C ₄ alkyl, NR ^a R ^b -C ₁ -C ₄ haloalkyl, 6-10 member Aryl or 5-10-membered heteroaryl, wherein the 6-10-membered aryl or 5-10-membered heteroaryl is optionally substituted by 1-4 R ^d ;

R ^d is selected from H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ haloalkyl, 3-6 membered cycloalkane Base, 4-7 membered heterocyclic group, -OR ²¹ , -NR ^a R ^b , NR ^a R ^b -C ₁ -C ₄ alkyl, NR ^a R ^b -C ₁ -C ₄ haloalkyl;

The heterocyclic group, heteroaryl group, heterocycloalkenyl group, condensed heterocyclic group, bridging heterocyclic group, and spiroheterocyclic group in the formula (I) have 1-7 heteroatoms selected from oxygen, nitrogen One or more of , sulfur and S(O)m, m is 1 or 2.

Preferably, the structure of the polycyclic pyridazinone derivatives is shown in formula (II):

Wherein, R ¹ , R ² , Q and R ^c have the same defined range as above; n=1-4 (eg n=1, n=2, n=3, n=4).

Preferably, for the compound of formula (II), the phenyl group is optionally substituted by 1-3 R ^c , when the number of R ^c is 2-3, the R ^c can be the same or different;

And/or, when said R ^c is a C ₁ -C ₄ haloalkyl group, the halogen atom is fluorine;

And/or, when said R ^c is halogen, the halogen atom is fluorine;

And/or, when said R ^c is -NR ^a R ^b , said R ^a and R ^b may be the same or different.

Preferably, the structure of the polycyclic pyridazinone derivatives is shown in formula (III):

Wherein, R ¹ , R ² and R ^c have the same defined range as above; n=1-4 (eg n=1, n=2, n=3, n=4).

Preferably, for the compound of formula (III), when said R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when said R ²² is 2-3, R ²² the same or different;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heterocyclic group contains 1-2 heteroatoms;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the R ²² is selected from C ₁ -C ₃ alkyl, -NR ^a R ^b , -C(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b and =O.

Preferably, the structure of the polycyclic pyridazinone derivatives is shown in formula (IV):

Wherein, R ¹ , R ² , R ³ and R ^c have the same defined range as above; n=1-4 (eg n=1, n=2, n=3, n=4).

Preferably, for the compound of formula (IV), when said R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when said R ²² is 2-3, R ²² the same or different;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heterocyclic group contains 1-2 heteroatoms;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the R ²² is selected from C ₁ -C ₃ alkyl, -NR ^a R ^b , -C(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b and =O;

And/or, when the R ³ is -OR ²¹ , R ²¹ is selected from unsubstituted C ₁ -C ₃ alkyl or unsubstituted 3-7 membered cycloalkyl.

Preferably, the structure of the polycyclic pyridazinone derivatives is shown in formula (V):

Wherein, R ¹ , R ² , Q and R ^d have the same defined range as above; n=1-4 (eg n=1, n=2, n=3, n=4).

Preferably, when the R ^d is one -NR ^a R ^b , the R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ alkyl;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the R ²² is 2-3, R ²² is the same or different;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heterocyclic group contains 1-2 heteroatoms;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different;

And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the R ²² is selected from C ₁ -C ₃ alkyl, -NR ^a R ^b , -C(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b and =O;

And/or, when said R ² is -OR ²¹ , R ²¹ is a 4-7 membered heterocyclic group;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group is a 5-6 membered heterocyclic group;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heterocyclic group contains 1-2 heteroatoms;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different.

Preferably, the structure of the polycyclic pyridazinone derivatives is shown in formula (VI):

Wherein, R ¹ , R ² and R ^d have the same defined range as above; n=1-4 (eg n=1, n=2, n=3, n=4).

Preferably, when the R ² is -OR ²¹ , the R ²¹ is a 4-7 membered heterocyclic group;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group is a 5-7 membered heterocyclic group;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heterocyclic group contains two heteroatoms;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the two heteroatoms are the same or different;

And/or, the R ^d is selected from halogen, C ₁ -C ₄ alkyl, -NR ^a R ^b , -OR ²¹ , NR ^a R ^b -C ₁ -C ₄ alkyl;

And/or, when the R ^d is one -NR ^a R ^b -C ₁ -C ₄ alkyl, the R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ of alkyl.

Preferably, the structure of the polycyclic pyridazinone derivatives is shown in formula (VII):

Wherein, R ¹ , R ² , R ³ and R ^d have the same defined range as above; n=1-4 (eg n=1, n=2, n=3, n=4).

Preferably, when the R ² is -OR ²¹ , the R ²¹ is a 4-7 membered heterocyclic group;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group is a 5-7 membered heterocyclic group;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heteroatom of the heterocyclic group is nitrogen and/or oxygen;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heterocyclic group contains two heteroatoms;

And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the two heteroatoms are the same or different;

And/or, the R ^d is selected from halogen, C ₁ -C ₄ alkyl, -NR ^a R ^b , -OR ²¹ , NR ^a R ^b -C ₁ -C ₄ alkyl;

And/or, when said R ^d is one NR ^a R ^b -C ₁ -C ₄ alkyl group, said R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ alkyl.

Further preferably, the polycyclic pyridazinone derivatives are selected from any one of the following structures:

Typical compounds of the present invention include, but are not limited to, compounds in the following tables:

In the second aspect, the present invention provides a method for preparing polycyclic pyridazinone derivatives, pharmaceutically acceptable salts, tautomers or stereoisomers thereof as described in the first aspect, wherein Choose one of the following two options:

Option One

The preparation method of the compound described in general formula (I) of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprises the following steps:

Preparation of key intermediate (I-A):

In the first step, the aromatic compound of the general formula (I-1) is subjected to metal-catalyzed cross-coupling to obtain the compound of the general formula (I-2);

In the second step, the compound of general formula (I-2) reacts under catalyst conditions to obtain the chiral sulfonimide compound of general formula (I-3);

In the third step, the compound of general formula (I-3) is reduced by a metal reducing agent to obtain a chiral compound of general formula (I-4);

In the fourth step, the compound of general formula (I-4) is cracked with sulfonamide under acidic conditions to obtain the chiral benzylamine compound of general formula (I-A);

Among them, X halogen is preferably bromine.

The preparation of key intermediate (I-B), method one:

In the first step, the compound of general formula (I-5) obtains the compound of general formula (I-6) through diazotization reaction;

In the second step, the compound of general formula (I-6) and cuprous cyanide obtain the compound of general formula (I-7) through substitution reaction;

In the third step, the cyano group in the compound of general formula (I-7) forms amidine, and then obtains the compound of general formula (I-B) through transesterification reaction with ester group;

Wherein, X, X ¹ is halogen, X is preferably bromine, X ¹ is preferably iodine;

The preparation of key intermediate (I-B), method two:

In the first step, the compound of general formula (I-12) is subjected to a halogenation reaction to obtain the compound of general formula (I-13);

In the second step, the compound of general formula (I-13) obtains the compound of general formula (I-6) through esterification;

In the third step, the compound of general formula (I-6) is subjected to substitution reaction to obtain the compound of general formula (I-14);

In the fourth step, the compound of general formula (I-14) is oxidized to obtain the compound of general formula (I-15);

In the fifth step, the compound of general formula (I-15) reacts with azamide sulfonic acid to obtain the compound of general formula (I-16);

The 6th step, the compound of general formula (I-16) obtains the compound of general formula (I-7) through Abnormal Beckmann rearrangement reaction;

In the seventh step, the cyano group in the compound of general formula (I-7) forms amidine, and then obtains the compound of general formula (I-B) through transesterification with ester group;

Wherein, X, X ¹ are halogen, X is preferably chlorine, X ¹ is preferably iodine;

The preparation of general formula (I):

In the first step, the compound of general formula (I-A) and the compound of general formula (I-B) obtain the compound of general formula (I-8) through imine addition reaction;

In the second step, the compound of general formula (I-8) and hydrazine hydrate obtain the compound of general formula (I-9) through imine addition and ring expansion reaction;

In the third step, the compound of general formula (I-9) and the compound of general formula (I-10) undergo a substitution reaction to obtain the compound of general formula (I-11) (if R ¹ =H, this step is omitted);

In the fourth step, the compound of general formula (I-11) and the compound of general formula (I-25) obtain the compound of general formula (I) through Buchwald/Suzuki reaction in the presence of a metal catalyst and a ligand under basic conditions. compound;

Wherein, X, X ¹ are halogen, X is preferably bromine and chlorine, X ¹ is preferably iodine; W is H, Q, AR, ^R1 and ^R2 have the same defined ranges as above.

Option II

The preparation method of the compound described in general formula (I) of the present invention or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, comprises the following steps:

In the first step, the compound of general formula (I-17) is subjected to substitution reaction to obtain the compound of general formula (I-18);

In the second step, the compound of general formula (I-18) is deprotected under acidic conditions to obtain the compound of general formula (I-19);

In the third step, the compound of general formula (I-19) and the compound of general formula (I-26) obtain the compound of general formula (I-20) under alkaline conditions;

In the fourth step, the compound of general formula (I-20) is oxidized to obtain the compound of general formula (I-21);

In the fifth step, the compound of general formula (I-21) obtains the compound of general formula (I-22) through Bouveault aldehyde synthesis reaction;

The 6th step, the compound of general formula (I-22) and hydrazine hydrate obtain the compound of general formula (I-23) through addition ring closure reaction;

In the seventh step, the compound of general formula (I-23) is subjected to substitution reaction to obtain the compound of general formula (I-24);

In the eighth step, the compound of the general formula (I-24) and the compound of the general formula (I-10) are subjected to a substitution reaction to obtain a compound of the general formula (I-Bb) (if R ¹ =H, this step is omitted);

In the ninth step, the compound of the general formula (I-Bb) and the compound of the general formula (I-A) are subjected to a Buchwald reaction under basic conditions in the presence of a metal catalyst and a ligand to obtain a compound of the general formula (I);

Among them, X ² , X ³ , X ⁴ are halogen, X ² , X ³ are preferably bromine, X ⁴ is preferably iodine; Q is selected from N or CR ³ ; R ³ is selected from H, C ₁ -C ₃ alkyl, Halogen, cyano or -OR ²¹ ; R ¹ is selected from hydrogen or methyl; AR and R ² have the same limitations as above.

For the above preparation method, the reagents that provide basic conditions are selected from organic bases or inorganic bases, and the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropyl one or more of lithium amide, lithium bistrimethylsilylamide, sodium tert-butoxide, sodium methoxide and potassium tert-butoxide, and the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate, One or more of potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;

The reagent providing acidic conditions is one or more of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, methanol solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid kind;

The metal catalysts are palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( Pd(dppf)Cl ₂ ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphinopalladium dichloride (Pd(PPh ₃ ) One or more of Cl ₂ ) and tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ );

The ligands are 2-bicyclohexylphosphine-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 2- Dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1, One or more of 1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1 '-Binaphthyl-2,2'-bisdiphenylphosphine (BINAP);

The reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum tetrahydride;

The oxidant is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;

The above reaction is preferably carried out in a solvent, and the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.

In the third aspect, the present invention provides a pharmaceutical composition, which comprises the polycyclic pyridazinone derivatives, its pharmaceutically acceptable salts, its tautomers or its stereoisomers;

Preferably, the pharmaceutical composition further includes pharmaceutically acceptable carriers and/or excipients.

In the fourth aspect, the present invention provides a polycyclic pyridazinone derivative as described in the first aspect, its pharmaceutically acceptable salt, its tautomer or its stereoisomer or the third aspect Use of the pharmaceutical composition in the preparation of drugs for treating cancer or in the preparation of SOS1 inhibitors;

Preferably, the cancer is pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, kidney cancer, gastric cancer or cholangiocarcinoma.

In the fifth aspect, the present invention provides a method for preventing and/or treating cancer, which comprises administering to humans a therapeutically effective amount of polycyclic pyridazinone derivatives, pharmaceutically acceptable A salt, a tautomer or a stereoisomer thereof, or the pharmaceutical composition as described in the third aspect.

Terminology Explanation

Unless otherwise stated, some terms used in the present invention in the specification and claims are defined as follows:

"Alkyl" means a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms , or a saturated linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention. Further examples of alkyl groups include, including but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 -Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-di Methylbutyl etc. Alkyl groups can be optionally substituted or unsubstituted.

"Alkenyl" refers to 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms linear or branched monovalent hydrocarbon groups, wherein at least one CC is sp ² double bond, wherein the alkenyl group can be independently and optionally substituted by one or more substituents described in the present invention, where specific examples include, but are not limited to vinyl, allyl and allyl Butyl and more. Alkenyl groups can be optionally substituted or unsubstituted.

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl. Cycloalkyl groups can be optionally substituted or unsubstituted.

"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called a spiro atom) shared between the single rings. The ring contains one or more Aromatic systems with double bonds, but none of the rings have fully conjugated π electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the ring and the ring, the spiro cycloalkyl group can be divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to:

"Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, Aromatic systems where none of the rings have fully conjugated pi-electrons, preferably 6 to 12, more preferably 7 to 10 membered. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. Non-limiting examples of "fused cycloalkyl" include, but are not limited to:

"Bridged cycloalkyl" refers to a 5- to 18-membered, full-carbon polycyclic group that contains two or more ring structures and shares two carbon atoms that are not directly connected to each other. One or more rings may contain one or more Aromatic systems with multiple double bonds but none of the rings having fully conjugated pi electrons are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.

"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application, and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms , bicyclic or tricyclic non-aromatic heterocyclic group, wherein at least one ring atom is a heteroatom, such as oxygen, nitrogen, sulfur atom and the like. Preference is given to having a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine Base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl. The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl. A heterocyclyl group can be optionally substituted or unsubstituted.

"Spiroheterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the single rings. The ring contains one or more double bonds, but no An aromatic system with a ring having fully conjugated π electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) _m heteroatoms, the remaining ring atoms are carbon, m=1 or 2. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to:

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with each other. One or more rings may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron aromatic systems, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O) _m heteroatoms, the remaining ring atoms are carbon, m=1 or 2. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to:

"Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems with double bonds, but none of the rings have fully conjugated π-electrons, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur or S(O) _m , and the remaining ring atoms are carbon, m = 1 or 2. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to:

"Aryl" means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C ₆ -C ₁₀ aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably phenyl. Aryl groups can be substituted or unsubstituted. The "aryl" can be fused with a heteroaryl, heterocyclyl or cycloalkyl, wherein the aryl ring is attached to the parent structure, non-limiting examples include but are not limited to:

"Heteroaryl" means an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-isodi Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzo Oxazolyl and Benzisoxazolyl. Heteroaryl groups can be optionally substituted or unsubstituted. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:

"Alkoxy" refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C ₁ -C ₆ alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

"Haloalkyl" refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has a meaning as described herein. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.

"Hydroxy" means an -OH group.

"Halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Benzyl" means _-CH2 -phenyl.

"Carboxy" refers to -C(O)OH.

"Acetyl" refers to -C(O) _CH3 or Ac.

"Carboxylate group" refers to -C(O)O(alkyl) or (cycloalkyl), wherein the definitions of alkyl and cycloalkyl are as above.

"Optional" means that the event it describes can but need not occur. For example, the statement "AR is optionally substituted with 1 or more R ^c " includes situations where the AR group may be substituted with 1 or more R ^c or may not be substituted with R ^c .

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1-3 hydrogen atoms in a group are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

The "substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -C(O)R ^b , -OC(O)R ^b , -NR ^b R ^b , -C(O)NR ^b R ^b , -NR ^b C(O)R ^b , -S(O)NR ^b R ^b or -S(O) ₂ NR ^b R ^b , where R ^b is as defined in the general formula described in (I).

As used herein, the terms "subject," "individual," or "patient" are used interchangeably to refer to any animal, including rats, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates animals and humans. In some embodiments, the patient is human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disease to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed with a cancer with a KRAS G12 or G13 mutation (eg, as determined by an FDA-approved regulatory agency, such as an FDA-approved assay or kit). In some embodiments, the subject has a tumor that is positive for a KRAS G12C mutation, KRAS G12D mutation, KRAS G12S mutation, KRAS G12V mutation, KRAS G12A mutation, KRAS G13D mutation, or KRAS G13C mutation (e.g., a Assay or kit determined). The subject can be a patient with a KRAS G12C mutation, KRAS G12D mutation, KRAS G12V mutation, KRAS G12S mutation, KRAS G12A mutation, KRAS G13D mutation, or KRAS G13C mutation (e.g., an assay or reagent approved by a regulatory agency-such as FDA-approved box) positive tumor patients. The subject can be a subject whose tumor has a KRAS G12C mutation, a KRAS G12D mutation, a KRAS G12V mutation, a KRAS G12S mutation, a KRAS G12A mutation, a KRAS G13D mutation, or a KRAS G13C mutation (e.g., the tumor has been approved by an FDA-approved regulatory agency, determined by the kit or assay). In some embodiments, the subject is suspected of having a KRAS G12 or G13 gene-related cancer. In some embodiments, the subject has clinical records indicating that the subject has a tumor with a KRAS G12C mutation (and optionally clinical records indicating that the subject should be treated with any of the compositions provided herein).

The term "pediatric patient" as used herein refers to a patient under the age of 16 at the time of diagnosis or treatment. The term "children" can also be divided into the following subcategories: neonates (from birth to the first month of life); infants (1 month to two years); children (2 years to 12 years); adolescents (12 Age up to 21 years (up to but not including 22nd birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson we. The Nelson Textbook of Pediatrics, 15th ed. Philadelphia: W.B. Saunders & Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st ed. New York: McGrow-Hill, 2002; and Avery MD, 1st LR. Pediatric Medicine, Second Edition. Baltimore: Williams &Wilkins; 1994.

As used herein, an "effective amount" of a compound refers to an amount sufficient to negatively regulate or inhibit SOS 1 enzymatic activity.

As used herein, a "therapeutically effective dose" of a compound refers to an amount sufficient to improve or somehow reduce symptoms, stop or reverse disease progression, or negatively regulate or inhibit SOS 1 activity. This dosage can be taken as a single dose or it can be taken on a regimen to be effective.

As used herein, "treating" means ameliorating or otherwise altering the symptoms or pathology of a patient's condition, disorder or disease in any way.

As used herein, "amelioration of the symptoms of a particular disease by the use of a particular compound or pharmaceutical composition" means any reduction, whether permanent or temporary, attributable to or associated with the use of the composition permanent, or temporary.

The definition of stereochemistry and the usage of conventions in the present invention generally refer to the following documents:

S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York , 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention part. Diastereoisomers can be separated into individual diastereomers on the basis of their physicochemical differences by methods such as chromatography, crystallization, distillation or sublimation. Enantiomers can be separated by converting a chiral isomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g. a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) , the diastereoisomers are separated and the individual diastereomers are converted into the corresponding pure enantiomers. The intermediates and compounds of the invention may also exist in different tautomeric forms and all such forms are included within the scope of the invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the compound's plane polarized light rotation, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The atoms or groups of atoms of these stereoisomers are connected to each other in the same order, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

"Tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (ie, prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Atomic (valency) tautomers include interconversions of rearranged bonding electrons. Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of the double bond, and conformational isomers of (Z), (E). Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers are within the scope of the present invention.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in human or animal body. Salts of the compounds can be obtained by using a sufficient amount of base or acid either in neat solution or in a suitable inert solution to obtain the corresponding addition salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc., pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic acids and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, pyridonic acid, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, etc. (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).

The invention provides a SOS1 inhibitor with a new structure. The test results show that the polycyclic pyridazinone derivatives exhibit excellent SOS1 inhibitory activity, and at the same time exhibit excellent safety and selectivity, and can be used to prepare and treat cancer , especially drugs for diseases such as pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, kidney cancer, gastric cancer and bile duct cancer.

Description of drawings

Fig. 1 is a graph showing the effect of the compounds involved in the present invention on the KRAS/ERK1/2 signal transduction pathway in K-562 cells.

Fig. 2 is a graph showing the effect of the compounds involved in the present invention on the KRAS/ERK1/2 signal transduction pathway in K-562 cells.

Detailed ways

The method of the present invention will be described below through specific examples to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto. In the following examples, the ¹ H NMR spectrum is measured by Bruker instrument (400 MHz), and the chemical shift is expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. Notation of ¹ H NMR: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, dd = doublet of doublet, dt = triplet double peaks. If the coupling constant is provided, its unit is Hz.

The mass spectrum was measured by LC/MS instrument, and the ionization mode was ESI.

HPLC model: Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5μm); Mobile phase: A:ACN, B:Water (0.1%H ₃ PO ₄ ); Flow rate: 1.0mL/min; gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; wavelength: 220nm; Column oven: 35°C.

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.2mm-0.3mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. -0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and unless otherwise indicated, various starting materials and reagents were either commercially available or synthesized according to known methods, and commercially available materials and reagents were not further purified Direct use, unless otherwise specified, commercially available manufacturers include but not limited to Sinopharm Group, Bailingwei Technology Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Beide Pharmaceutical Technology Co., Ltd. and Shanghai Merrill Chemical Technology Co., Ltd. wait.

CD ₃ OD: deuterated methanol

CDCl ₃ : deuterated chloroform

DMSO-d ₆ : deuterated dimethyl sulfoxide

Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium

Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride

XantPhos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene

XPhos: 2-Dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl

HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate

TLC: Thin Layer Chromatography

HPLC: High Performance Liquid Chromatography

Purity: purity

&:and

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C-30°C.

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purifies compound adopts or the developing agent system of thin-layer chromatography comprises: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagent can also be added Adjust, such as acetic acid or triethylamine, etc.

Preparation of intermediates

Intermediate 1

(R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethylamine IN-1

The first step 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one IN-1b

3-Bromo-5-nitrobenzotrifluoride IN-1a (2.0g, 7.41mmol), tributyl(1-ethoxyethylene)tin (3.5g, 9.69mmol) and bistriphenylphosphine dichloride Palladium (520mg, 0.74mmol) was sequentially added to toluene (25mL), under nitrogen protection, heated to 100°C for overnight reaction, TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, added hydrochloric acid (15mL, 3N), stirred for 30 minutes, filtered with celite, the filtrate was separated, the aqueous phase was extracted with ethyl acetate, the organic phase was combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was filtered through silica gel. Purified by column chromatography, the title compound IN-1b (1.25 g, yield 72%) was obtained as a yellow oil.

¹ H NMR (400MHz, CDCl ₃ )δ8.94(s,1H),8.68(s,1H),8.53(s,1H),2.75(s,3H).

The second step (R,Z)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylene)propane-2-sulfinamide IN-1c

A mixture of compound IN-1b (1.25g, 5.36mmol), (R)-(+)-tert-butylsulfinamide (974mg, 8.04mmol) and tetraethyl titanate (10mL, 47.70mmol) was heated to 80°C After reacting for 3 hours, TLC showed that a small amount of starting material remained. The reaction solution was cooled to room temperature, poured into ice water (60 mL), extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the yellow oily title compound IN- 1c (1.01 g, 56% yield).

The third step (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide IN- 1d

Compound IN-1c (260mg, 0.77mmol) was dissolved in tetrahydrofuran (2.5mL) and water (0.05mL), cooled to -60°C, and sodium borohydride (74mg, 1.95mmol) was added in batches. °C and continued to stir for 1 hour, TLC showed that the reaction was complete. The reaction solution was quenched by adding water dropwise, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound IN-1d as a white solid (150mg, yield 58 %).

¹ H NMR (400MHz, CDCl ₃ ) δ8.43-8.42 (m, 2H), 7.95 (s, 1H), 4.75-4.69 (m, 1H), 3.55 (d, J=4.4Hz, 1H), 1.61 ( d,J=6.8Hz,3H),1.25(s,9H).

The fourth step (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethylamine IN-1

Compound IN-1d (164mg, 0.48mmol) was dissolved in tetrahydrofuran (3mL), concentrated hydrochloric acid (0.5mL) was added dropwise, and the reaction was carried out at room temperature for 1 hour. TLC showed that the reaction was complete. The reaction solution was added dropwise with saturated aqueous sodium carbonate solution to adjust pH = 8, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain the title compound IN-1 (105 mg, crude product) as a yellow oil, which was directly used in in the next step.

LC-MS: m/z=235.1[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ8.56(s,1H),8.32(s,1H),8.24(s,1H),4.24(q,J=6.8Hz,1H),2.22(br, 2H), 1.30(d, J=2.8Hz, 3H).

Intermediate 2

(R)-6-bromo-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-1(2H)-one IN-2

The first step methyl 4-bromo-2-iodobenzoate IN-2b

Methyl 2-amino-4-bromobenzoate IN-2a (2.0g, 8.70mmol) was dispersed in hydrochloric acid (20mL, 120mmol, 6M), cooled to about 0°C, and sodium nitrite (360mg, 5.22mmol) was added dropwise After the addition was completed, the reaction was continued for 1 hour, and potassium iodide (1.4 g, 8.43 mmol) was added dropwise. After the addition, the reaction was continued at room temperature for 2 hours, and the reaction of the raw materials was basically complete as detected by TLC. The reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the yellow oil title compound IN-2b (2.1g, yield 70 %).

The second step Methyl 4-bromo-2-cyanobenzoate IN-2c

Compound IN-2b (2.1g, 6.16mmol) was dissolved in N-methylpyrrolidone (10mL), and cuprous cyanide (834mg, 9.31mmol) was added at room temperature, and the temperature was raised to 60°C to react overnight, and TLC detected that the reaction of the raw materials was complete. The reaction solution was cooled to room temperature, filtered with Celite, the filter cake was washed, the filtrate was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography The title compound IN-2c (1.2 g, yield 80%) was obtained as a white solid.

The third step 5-bromo-3-aminoisoindol-1-one IN-2d

Compound IN-2c (1.2g, 5.00mmol) was dissolved in methanol (20mL). Under the protection of nitrogen, it was cooled to 0°C. After passing through ammonia gas to saturation, the reaction solution was slowly returned to room temperature and reacted for 48 hours. The raw material was detected by TLC. The response is complete. The reaction solution was concentrated to obtain the title compound IN-2d (1.05 g, crude product) as a yellow solid, which was directly used in the next step.

LC-MS: m/z=225.0[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ10.27(br,1H),9.69(br,1H),8.30(s,1H),7.88(dd,J=8.0,1.6Hz,1H),7.64( d,J=8.0Hz,1H).

The fourth step (R)-5-bromo-3-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1H-isoindol-1-one IN -2e

Compound IN-2d (1.05g, crude product) and intermediate IN-1 (1.6g, 6.83mmol) were dissolved in isopropanol (50mL), heated to 90°C for 48 hours, and some raw materials were detected by TLC. The reaction solution was concentrated to obtain the title compound IN-2e (2.3 g, crude product) as a pale yellow solid, which was directly used in the next step.

LC-MS: m/z=442.0[M+H] ⁺

The fifth step (R)-6-bromo-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-1(2H)-one IN- 2

Compound IN-2e (2.25g, crude product) was dissolved in ethanol (40mL), and hydrazine hydrate (636mg, 10.16mmol, 80%) was added at room temperature, heated to 40°C for 2 hours, and TLC detected that the raw material was completely reacted. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound IN-2 (1.1 g, three-step yield 48%) as a yellow solid.

LCMS: m/z=457.0[M+H] ⁺

Intermediate 3

(R)-7-chloro-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazine-4- (3H)-Kone IN-3

The first step 6-chloro-4-iodonicotinic acid IN-3b

2,2,6,6-Tetramethylpiperidine (11.2g, 79.29mmol) was dissolved in tetrahydrofuran (100mL), cooled to about -60°C under nitrogen protection, and n-butyllithium (31.7mL, 79.25 mmol, 2.5M), after adding, slowly return to 0°C and react for half an hour, then cool to about -60°C, add 6-chloronicotinic acid IN-3a (5.0g, 31.74mmol) in batches, and add at -60°C Stirring was continued for 1 hour, and a solution of iodine (9.7 g, 38.22 mmol) in tetrahydrofuran (50 mL) was added dropwise. After the addition was complete, the mixture was slowly returned to room temperature and reacted overnight. TLC showed that most of the raw materials were reacted. The reaction solution was quenched with 1N hydrochloric acid, filtered, and the filter cake was washed and dried to obtain the title compound IN-3b (4.7 g, crude product) as a tan solid, which was directly used in the next step.

The second step 6-chloro-4-ionicotinate methyl ester IN-3c

Compound IN-3b (4.7g, crude product) was dissolved in N,N-dimethylformamide (30mL), potassium carbonate (6.9g, 49.92mmol) was added, and after stirring at room temperature for 10 minutes, methyl iodide (4.7g, 33.11mmol), react overnight at room temperature, and TLC detects that the reaction of raw materials is complete. The reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3c (2.0 g, two-step yield twenty one%).

The third step 6-chloro-4-vinyl nicotinic acid methyl ester IN-3d

Compound IN-3c (3.0g, 10.08mmol) and potassium vinyl trifluoroacetate (1.35g, 10.08mmol) were dissolved in 1,4-dioxane (36mL) and water (12mL), and triethyl Amine (3.06g, 30.24mmol) and Pd(dppf)Cl ₂ dichloromethane complex (200mg, 0.24mmol) were replaced with nitrogen three times, heated to 80°C for 5 hours, and the reaction was complete by LCMS monitoring. The reaction solution was cooled to room temperature, added with water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3d (1.9 g, harvested as light yellow solid) rate 95%).

LC-MS: m/z=198.1[M+H] ⁺

The fourth step 6-chloro-4-formyl nicotinic acid methyl ester IN-3e

Compound IN-3d (1.8g, 9.11mmol) was dissolved in a mixed solvent of ethanol (20mL), tetrahydrofuran (10mL) and water (10mL), and sodium periodate (19.2g, 89.76mmol) was added at room temperature, and stirred dropwise A water (small amount) solution of potassium osmate (catalytic amount) was added, and after the addition was completed, the reaction was continued at room temperature for 0.5 hour, and the reaction was complete as detected by TLC. The reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain a light yellow oil (solidified on standing). The title compound IN-3e (1.3g, recovered rate of 72%).

The fifth step (E)-6-chloro-4-((hydroxyimino)methyl)nicotinic acid methyl ester IN-3f

Compound IN-3e (1.0g, 5.01mmol) and hydroxyaminesulfonic acid (1.70g, 15.04mmol) were dissolved in water (15mL), reacted at room temperature overnight, and TLC detected that the reaction was complete. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound IN-3f (1.05 g, crude product) as an off-white solid, which is directly used in the next step.

LCMS:m/z=215.1[M+H] ⁺

Step 6 6-Chloro-4-cyanonicotinic acid methyl ester IN-3g

Compound IN-3f (1.05 g, crude product) was dissolved in phosphorus oxychloride (10 mL), heated to 100° C. for 2 hours, and TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, the residue was poured into ice water, neutralized with aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was passed through a silica gel column layer Analysis and purification gave the title compound IN-3g (800 mg, 81% yield in two steps) as a white solid.

LCMS: m/z=197.1[M+H] ⁺

Step 7 6-Chloro-1-imino-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one IN-3h

Compound IN-3g (800mg, 4.07mmol) was dissolved in methanol (60mL), cooled to about 0°C, filled with ammonia gas to saturation, and the reaction solution was slowly raised to room temperature to react overnight, and TLC detected that the raw materials were completely reacted. The reaction solution was concentrated to give the title compound IN-3h (766 mg, crude product) as a pale yellow solid, which was directly used in the next step.

LCMS: m/z=182.1[M+H] ⁺

The eighth step (R)-6-chloro-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-3H-pyrrolo[3,4-c ]pyridin-3-one IN-3i

Compound IN-3h (766mg, crude product) was dissolved in isopropanol (30mL), intermediate IN-1 (988mg, 4.22mmol) was added at room temperature, and heated to 85°C for overnight reaction. TLC detected that the raw material was completely reacted. The reaction solution was cooled to room temperature and concentrated to obtain the title compound IN-3i (1.75 g, crude product) as a yellow solid, which was directly used in the next step.

LCMS:m/z=399.1[M+H] ⁺

The ninth step (R)-7-chloro-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazine -4-(3H)-Kone IN-3

Compound IN-3i (1.75g, crude product) was dissolved in ethanol (15mL), hydrazine hydrate (579mg, 9.25mmol, 80%) was added at room temperature, and the temperature was raised to 40°C for 1 hour. TLC detected that the reaction of the raw materials was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-3 (1.0 g, three-step yield 59%) as a yellow solid.

LCMS: m/z=414.4[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ )δ11.86(s,1H),9.19(s,1H),8.54(s,1H),8.43(s,1H),8.34(s,1H),8.26( s,1H),7.41(d,J=2.8Hz,1H),5.18-5.08(m,1H),1.57(d,J=2.8Hz,3H).

Example 1

4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl-6-(((S) -tetrahydrofuran-3-yl)oxy)phthalazin-1(2H)-one 1

The first step 5-bromo-4-formyl-2-methoxyphenyl acetate 1b

Acetyl vanillin 1a (20.0g, 103.0mmol) and potassium bromide (39.96g, 335.8mmol) were dissolved in water (100mL), cooled to 0°C, and liquid bromine (18.27g, 114.3mmol) was added dropwise. After the addition, the mixture was raised to room temperature and stirred for 15 hours. TLC showed that a small amount of starting material remained. The reaction solution was filtered, and the filter cake was washed and dried to obtain the title compound 1b (aqueous crude product), which was directly used in the next step.

The second step 2-bromo-4-hydroxy-5-methoxybenzaldehyde 1c

Compound 1b (crude product) was dissolved in concentrated hydrochloric acid (400mL, 6N), heated to 90°C and reacted overnight, and TLC detected that the reaction of the raw material was basically complete. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed and dried to obtain the title compound 1c (16.8 g, crude product), which was directly used in the next step.

The third step (R)-3-hydroxytetrahydrofuran p-toluenesulfonate 1e

(R)-3-Hydroxytetrahydrofuran 1d (1.0g, 11.35mmol) was dissolved in dichloromethane (8mL), cooled to 0°C, added pyridine (2.5g, 31.61mmol), and p-toluenesulfonyl chloride (3.03 g, 15.89mmol), rose to room temperature and reacted overnight. The reaction solution was concentrated, diluted with water, the aqueous phase was adjusted to pH=1 with hydrochloric acid (3N), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was obtained by silica gel column chromatography to obtain colorless The title compound 1e was oily (2.57 g, 93% yield in three steps).

¹ H NMR (400MHz, CDCl ₃ ) δ7.78(d, J=8.4Hz, 2H), 7.35(d, J=8.4Hz, 2H), 5.11-5.09(m, 1H), 3.91-3.77(m, 4H),2.45(s,3H),2.10-2.02(m,2H).

The fourth step (S)-2-bromo-5-methoxy-4-((tetrahydrofuran-3-yl)oxy)benzaldehyde 1f

Compound 1c (3.7g, crude product), compound 1e (4.3g, 17.75mmol) and cesium carbonate (7.8g, 24.0mmol) were dispersed in N,N-dimethylformamide (20mL), heated to 100°C and reacted overnight , LCMS detects that the reaction of the starting material is complete (TLC shows a point of starting material and product). The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 1f (4.7 g, crude product), which was directly used in the next step.

The fifth step (S)-2-bromo-5-methoxy-4-((tetrahydrofuran-3-yl)oxy)benzoic acid 1g

Potassium permanganate (1.94g, 12.29mmol) and compound 1f (3.7g, crude product) were dispersed in water (120mL), heated to 75°C and stirred for 5 hours. TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, diluted with water, filtered, the filter cake was washed with water and ethyl acetate, the filtrate was separated, the organic phase was discarded, and the aqueous phase was extracted once with ethyl acetate. The aqueous phases were combined, and dilute hydrochloric acid (1N) was added to adjust the acidity. A large amount of white solids were precipitated. After filtration, the filter cake was washed and dried to obtain 1 g of the title compound (2.0 g, crude product), which was directly used in the next step.

LC-MS: m/z=317.02[M+H] ⁺

The sixth step (S)-2-formyl-5-methoxy-4-((tetrahydrofuran-3-yl)oxy)benzoic acid 1h

Compound 1g (2.4g, crude product) was dissolved in tetrahydrofuran (50mL), cooled to -78°C under nitrogen protection, and n-butyl lithium (6.8mL, 17.0mmol, 2.5M n-hexane solution) was added dropwise, and -78 After stirring at ℃ for half an hour, N,N-dimethylformamide (719mg, 9.84mmol) was added dropwise, and after the addition was completed, it was slowly raised to room temperature, and the reaction was complete as detected by TLC. The reaction solution was adjusted to weak acidity by adding dilute hydrochloric acid (1N), extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 1h (1.4 g, three steps Yield 21%).

The seventh step (S)-7-methoxy-6-((tetrahydrofuran-3-yl)oxy)phthalazin-1(2H)-one 1i

Compound 1h (1.0g, 3.76mmol) and hydrazine hydrate aqueous solution (1.96g, 31.36mmol, 80%) were dissolved in isopropanol (10mL), heated to 80°C and stirred for 3 hours. TLC detected that the reaction of the raw materials was basically complete. The reaction solution was cooled to room temperature, diluted with water, concentrated to remove isopropanol, a solid precipitated, filtered, and the filter cake was washed and dried to obtain the title compound 1i (800 mg, crude product), which was directly used in the next step.

LC-MS: m/z=263.1[M+H] ⁺

The eighth step (S)-4-bromo-7-methoxy-6-((tetrahydrofuran-3-yl)oxy)phthalazin-1(2H)-one 1j

Compound 1i (500mg, crude product), benzyltrimethylammonium tribromide (1.49g, 3.82mmol) and potassium carbonate (528mg, 3.82mmol) were dispersed in N,N-dimethylformamide (10mL), and the temperature was raised Stir at 40° C. for 5 hours, and TLC detects that the reaction of the raw materials is basically complete. The reaction solution was diluted with ethyl acetate, washed with saturated brine, washed with water, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 1j (538 mg, two-step yield 67%).

The ninth step (S)-4-bromo-7-methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxy)phthalazin-1(2H)-one 1k

Compound 1j (492mg, 1.44mmol) was dissolved in N,N-dimethylformamide (5mL), sodium hydride (699mg, 1.73mmol, 60%) was added, stirred at room temperature for 30 minutes, iodomethane (409mg, 2.88mmol ), stirred at room temperature for 2 hours, and TLC detected that the basic reaction of the raw materials was complete. Water was added to the reaction solution, a white solid precipitated out, filtered, the filter cake was washed and dried to obtain the title compound 1k (461 mg, crude product), which was directly used in the next step.

The tenth step 7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-6-( ((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1(2H)-one 1l

Compound 1k (161mg, crude product), intermediate IN-1 (130mg, 0.56mmol), potassium tert-butoxide (101mg, 0.90mmol), BINAP (13mg, 0.02mmol) and Pd ₂ (dba) ₃ (21mg, 0.02mmol ) into 1,4-dioxane (5 mL), under nitrogen protection, the temperature was raised to 100° C. and stirred overnight. TLC detects that the reaction of raw materials is complete. The reaction solution was cooled to room temperature, filtered with celite, the filter cake was washed with ethyl acetate, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 1l (50 mg, two-step yield 20%).

LC-MS: m/z=509.2[M+H] ⁺

The eleventh step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methyl-6-( ((S)-tetrahydrofuran-3-yl)oxy)phthalazin-1(2H)-one 1

Compound 1l (52 mg, 0.10 mmol) and palladium/carbon (5 mg, 10%) were dispersed in methanol (5 mL), and reacted at room temperature under hydrogen atmosphere for 3 hours, and TLC detected that the reaction of the raw materials was basically complete. The reaction solution was filtered with celite, the filter cake was washed with methanol, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 1 (22 mg, yield 46%).

LC-MS: m/z=479.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ7.70(s,1H),7.59(s,1H),6.98(s,2H),6.78(s,1H),5.32-5.29(m,1H),4.99 (q,J=6.8Hz,1H),4.08-3.99(m,3H),3.98-3.89(m,4H),3.56(s,3H),2.40-2.31(m,1H),2.24-2.18(m ,1H), 1.58(d, J=6.8Hz, 3H).(98.25%purity by HPLC)

Example 2

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(4-methylpiperazin-1-yl ) Phthalazin-1(2H)-one 2

The first step (R)-6-bromo-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazine-1(2H )-one 2a

Intermediate IN-2 (300mg, 0.66mmol) was dissolved in N,N-dimethylformamide (5mL), potassium carbonate (182mg, 1.32mmol) was added, and after stirring at room temperature for 5 minutes, iodomethane (280mg, 1.97 mmol), react overnight at room temperature, and TLC detects that the reaction of raw materials is complete. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound 2a (280 mg, crude product) as a yellow solid, which is directly used in the next step

The second step (R)-2-methyl-6-(4-methylpiperazin-1-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)phthalazin-1(2H)-one 2c

Compound 2a (280mg, crude product) and N-methylpiperazine 2b (298mg, 2.97mmol) were dissolved in 1,4-dioxane (30mL), cesium carbonate (384mg, 1.18mmol) was added at room temperature, BINAP ( 60mg, 0.10mmol) and Pd ₂ (dba) ₃ (60mg, 0.06mmol), nitrogen replacement 3 times, heated to 100 ℃ overnight reaction, TLC detection of raw material reaction is complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 2c (240 mg, two-step yield 74%) as a tan solid.

LCMS: m/z=491.2[M+H] ⁺

The third step (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(4-methylpiperazine- 1-yl)phthalazin-1(2H)-one 2

Compound 2c (240mg, 0.49mmol) was dissolved in ethyl acetate (10mL) and methanol (3mL), palladium/carbon (50mg, 10%) was added, concentrated hydrochloric acid (3 drops) was added dropwise, and the reaction was carried out at room temperature under hydrogen atmosphere for 2 hours , TLC detects that the reaction of raw materials is complete. The reaction solution was neutralized with ammonia-methanol solution, filtered with celite, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain the title compound 2 (126 mg, yield 56%) as a pale yellow solid.

LCMS: m/z=461.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.01(d, J=9.2Hz, 1H), 7.48(d, J=2.0Hz, 1H), 7.40(dd, J=9.2, 2.0Hz, 1H) ,6.91(d,J=7.2Hz,1H),6.85(s,2H),6.67(s,1H),5.49(s,2H),4.96-4.89(m,1H),3.46(s,4H), 3.39(s,3H),2.58(s,4H),2.31(s,3H),1.51(d,J=7.2Hz,3H).(99.72%purity by HPLC)

Example 3

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methylpiperazin-1-yl)phthalazine-1 (2H)-Kone 3

The first step (R)-6-(4-methylpiperazin-1-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino) Phthalazin-1(2H)-one 3a

Intermediate IN-2 (200mg, 0.44mmol) and N-methylpiperidine 2b (219mg, 2.19mmol) were dissolved in 1,4-dioxane (10mL), cesium carbonate (430mg, 1.32mmol) was added at room temperature ), BINAP (40mg, 0.06mmol) and Pd ₂ (dba) ₃ (40mg, 0.04mmol), after nitrogen replacement 3 times, heated to 100°C and reacted overnight, TLC detected that the reaction of raw materials was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 3a (48 mg, yield 23%) as a tan solid.

The second step (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methylpiperazin-1-yl)phthalein Azin-1(2H)-one 3

Compound 3a (48mg, 0.10mmol) was dissolved in ethyl acetate (10mL) and methanol (3mL), palladium/carbon (50mg, 10%) was added, concentrated hydrochloric acid (2 drops) was added dropwise, and the reaction was carried out at room temperature under hydrogen atmosphere for 2 hours , TLC detects that the reaction of raw materials is complete. The reaction solution was neutralized with ammonia-methanol solution, filtered with celite, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain the title compound 3 (20 mg, yield 44%) as a pale yellow solid.

LCMS: m/z=447.3[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ )δ11.11(s,1H),7.99(d,J＝9.2Hz,1H),7.50(s,1H),7.40(d,J＝9.2Hz,1H) ,6.83-6.72(m,3H),6.66(s,1H),5.47(s,2H),4.95-4.83(m,1H),3.47(s,4H),2.58(s,3H),2.31(s ,3H), 1.49 (d, J=6.8Hz, 3H).(97.85%purity by HPLC)

Example 4

(R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-7-(4-methylpiperazin-1-yl ) pyrido[3,4-d]pyridazin-4(3H)-one 4

The first step (R)-7-chloro-3-methyl-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4 -d]pyridazin-4-(3H)-one 4a

Intermediate IN-3 (460mg, 1.11mmol) was dissolved in N,N-dimethylformamide (5mL), potassium carbonate (268mg, 1.94mmol) was added, and after stirring at room temperature for 5 minutes, iodomethane (275mg, 1.94 mmol), stirred and reacted at room temperature for 2 hours, and TLC detected that the reaction was substantially complete. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound 4a (430 mg, yield 90%) as a yellow solid.

LCMS: m/z=428.2[M+H] ⁺

The second step (R)-3-methyl-7-(4-methylpiperazin-1-yl)-1-((1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)pyrido[3,4-d]pyridazin-4-(3H)-one 4b

Compound 4a (150mg, 0.35mmol) was dissolved in dioxane (10mL), cesium carbonate (352mg, 1.08mmol), N-methylpiperazine (180mg, 1.80mmol), Pd ₂ (dba) ₃ were added at room temperature (50mg, 0.05mmol) and BINAP (50mg, 0.08mmol), after nitrogen replacement for 3 times, heated to 100°C for 5 hours, and TLC detected that the reaction of raw materials was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 4b (105 mg, yield 61%) as a yellow solid.

LCMS: m/z=492.2[M+H] ⁺

The third step (R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-7-(4-methylpiperazine- 1-yl)pyrido[3,4-d]pyridazin-4(3H)-one 4

Compound 4b (105mg, 0.21mmol) was dissolved in ethyl acetate (10mL) and methanol (2mL), concentrated hydrochloric acid (3 drops) and 10% palladium/carbon (catalytic amount) were added, and the reaction was carried out at room temperature under hydrogen atmosphere for 2 hours, TLC Check that the raw material reacts completely. The reaction solution was neutralized with ammonia methanol solution, filtered with celite, the filter cake was washed, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 4 (70 mg, yield 70%) as a yellow solid.

LCMS: m/z=462.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.04(s, 1H), 7.29(s, 1H), 6.96(s, 2H), 6.78(s, 1H), 4.94(q, J=6.8Hz, 1H ),3.97(s,4H),3.49(s,3H),2.97(s,4H),2.64(s,3H),1.58(d,J=6.8Hz,3H).(98.96%purity by HPLC)

Example 5

(R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(4-methylpiperazin-1-yl)pyrido[3 ,4-d]pyridazin-4-(3H)-one 5

The first step (R)-7-(4-methylpiperazin-1-yl)-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino) Pyrido[3,4-d]pyridazin-4(3H)-one 5a

Intermediate IN-3 (150mg, 0.36mmol) was dissolved in 1,4-dioxane (10mL), cesium carbonate (352mg, 1.08mmol) was added at room temperature, N-methylpiperazine 2b (180mg, 1.80mmol ), Pd ₂ (dba) ₃ (50mg, 0.05mmol) and BINAP (50mg, 0.08mmol), after nitrogen replacement 3 times, heated to 100°C and reacted overnight, TLC detected that the reaction of raw materials was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5a (40 mg, crude product) as a yellow solid (purity about 60% by TLC), which was directly used in the next step.

The second step (R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(4-methylpiperazin-1-yl)pyridine And[3,4-d]pyridazin-4-(3H)-one 5

Compound 5a (40mg, crude product) was dissolved in ethyl acetate (5mL) and methanol (1mL), concentrated hydrochloric acid (2 drops) and 10% palladium/carbon (catalytic amount) were added, and the reaction was carried out at room temperature under hydrogen atmosphere for 2 hours, and detected by TLC The raw material reacted completely. After the reaction solution was neutralized with ammonia methanol, it was filtered with celite, the filter cake was washed, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain the title compound 5 (12 mg, two-step yield 7%) as a yellow solid.

LCMS: m/z=448.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.04(s, 1H), 7.27(s, 1H), 6.92(s, 2H), 6.77(s, 1H), 4.94(q, J=6.8Hz, 1H ),3.95(s,4H),2.90(s,4H),2.60(s,3H),1.57(d,J=7.2Hz,3H).(97.91%purity by HPLC)

Example 6

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinophthalazin-1(2H)-one 6

The first step (R)-6-morpholino-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-1(2H)-one 6b

Under nitrogen protection, the intermediate IN-2 (200mg, 0.44mmol) and morpholine 6a (381mg, 4.37mmol) were dissolved in 1,4-dioxane (20mL), and Pd ₂ (dba) ₃ was added at room temperature (82mg, 0.09mmol), BINAP (82mg, 0.13mmol) and cesium carbonate (428mg, 1.31mmol), heated up to 100°C and reacted overnight, TLC detected that the reaction of the raw materials was complete. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 6b (55 mg, yield 27%).

LC-MS: m/z=464.2[M+H] ⁺

The second step (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-morpholinophthalazin-1(2H)-one 6

Compound 6b (55mg, 0.12mmol) was dissolved in methanol (10mL), palladium/carbon (20mg, 10%) was added, and the reaction was carried out at room temperature under hydrogen atmosphere for 2 hours, and the reaction was complete as detected by TLC. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 6 (16 mg, yield 31%).

LC-MS: m/z=434.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.12(d, J=8.8Hz, 1H), 7.45(s, 1H), 7.39(d, J=9.2Hz, 1H), 6.98(s, 2H), 6.80(s,1H),4.98(q,J=6.8Hz,1H),3.91-3.83(m,4H),3.50-3.40(m,4H),1.57(d,J=6.8Hz,3H).( 96.33%purity by HPLC)

Example 7

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methyl-3-oxopiperazin-1-yl ) Phthalazin-1(2H)-one 7

The first step 3-oxopiperazine-1-carboxylate benzyl ester 7b

2-Piperazinone 7a (1.0g, 9.99mmol) was dissolved in ethyl acetate (20mL), water (20mL) and sodium carbonate (3.2g, 30.19mmol) were added, stirred at room temperature for 10 minutes, cooled to 0°C, slowly Benzyl chloroformate (2.1 g, 12.31 mmol) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature overnight, and TLC detected that the reaction was complete. The reaction solution was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 7b (2.3 g, yield 98%).

LC-MS: m/z=235.1[M+H] ⁺

The second step 4-methyl-3-oxopiperazine-1-carboxylate benzyl ester 7c

Compound 7b (2.3g, 9.82mmol) was dissolved in N,N-dimethylformamide (30mL), cooled to 0°C, sodium hydride (780mg, 19.50mmol, 60%) was added in portions, and stirring was continued for 20 Minutes, iodomethane (2.8g, 19.73mmol) was added, raised to room temperature and stirred for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the title compound 7c (2.0 g, yield 82%).

LC-MS: m/z=249.1[M+H] ⁺

The third step 1-methylpiperazin-2-one 7d

Compound 7c (2.0g, 8.06mmol) was dissolved in ethyl acetate (30mL), palladium/carbon (1.0g, 10%) was added, and reacted overnight at room temperature under a hydrogen atmosphere, and the reaction was complete by TLC. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate three times, and the filtrate was concentrated to obtain the title compound 7d (950 mg, crude product), which was directly used in the next step.

LC-MS: m/z=115.2[M+H] ⁺

The fourth step (R)-6-(4-methyl-3-oxopiperazin-1-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amine)phthalazin-1(2H)-one 7e

Compound 7d (200mg, 0.44mmol) and intermediate IN-2 (75mg, 0.66mmol) were dissolved in toluene (10mL), and Pd ₂ (dba) ₃ (80mg, 0.09mmol), BINAP (82mg, 0.13mmol) were added at room temperature ) and cesium carbonate (328 mg, 1.01 mmol), heated to 100 ° C for 4 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 7e (38 mg, 18% yield in two steps).

LC-MS: m/z=491.2[M+H] ⁺

The fifth step (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-methyl-3-oxopiperazine- 1-yl)phthalazin-1(2H)-one 7

Compound 7e (38 mg, 0.08 mmol) was dissolved in ethyl acetate (15 mL), palladium/carbon (50 mg, 10%) was added, and stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 7 (18 mg, yield 51%).

LC-MS: m/z=461.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ11.13(s, 1H), 8.01(d, J=8.8Hz, 1H), 7.56-7.35(m, 2H), 6.85(d, J=7.2Hz, 1H),6.79(s,2H),6.66(s,1H),5.48(s,2H),5.10-4.78(m,1H),4.15-4.06(m,2H),3.82-3.69(m,2H) ,3.57-3.46(m,2H),2.95(s,3H),1.50(d,J＝6.8Hz,3H).(98.33%purity by HPLC)

Example 8

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-(dimethylamino)ethyl)(methyl )amino)-2-methylphthalazin-1(2H)-one 8

The first step (R)-6-((2-(dimethylamino)ethyl)(methyl)amino)-2-methyl-4-((1-(3-nitro-5-(three Fluoromethyl)phenyl)ethyl)amino)phthalazin-1(2H)-one 8b

Compound 2a (100mg, 0.21mmol) and N,N,N'-trimethylethylenediamine 8a (109mg, 1.07mmol) were dissolved in 1,4-dioxane (10mL), and Pd ₂ ( dba) ₃ (20mg, 0.04mmol), BINAP (40mg, 0.06mmol) and cesium carbonate (140mg, 0.43mmol), heated to 100°C for 4 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 8b (50 mg, yield 48%).

LC-MS: m/z=493.3[M+H] ⁺

The second step (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-(dimethylamino)ethyl) (Methyl)amino)-2-methylphthalazin-1(2H)-one 8

Compound 8b (50mg, 0.10mmol) was dissolved in ethyl acetate (10mL), palladium/carbon (30mg, 10%) was added, and stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 8 (28 mg, yield 60%).

LC-MS: m/z=463.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ7.98(d, J=8.8Hz, 1H), 7.27-7.14(m, 2H), 6.93-6.84(m, 3H), 6.68(s, 1H), 5.47(s,2H),5.01-4.86(m,1H),3.72(t,J＝6.4Hz,2H),3.39(s,3H),3.10(s,3H),2.63(s,2H),2.36 (s,6H),1.52(d,J=6.8Hz,3H).(98.53%purity by HPLC)

Example 9

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-(dimethylamino)ethyl)(methyl )amino)phthalazin-1(2H)-one 9

The first step 6-bromo-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-2-(tetrahydro-2H-pyran -2-yl)phthalazin-1(2H)-one 9a

Intermediate IN-2 (500mg, 1.09mmol) was dissolved in tetrahydrofuran (20mL), and 3,4-dihydro-2H-pyran (276mg, 3.28mmol) and pyridinium p-toluenesulfonate (55mg, 0.22mmol) were added , heated to reflux for 3 hours, and most of the raw materials were detected by TLC. 3,4-Dihydro-2H-pyran (276mg, 3.28mmol) was added, heated to reflux overnight, and TLC showed that more than half of the raw materials remained unreacted. 3,4-Dihydro-2H-pyran (460mg, 5.47mmol) was added, heated to reflux overnight, and TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 9a (620 mg, yield 105%).

LC-MS: m/z=541.0[M+H] ⁺

The second step 6-((2-(dimethylamino)ethyl)(methyl)amino)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)benzene Base) ethyl) amino)-2-(tetrahydro-2H-pyran-2-yl)phthalazin-1(2H)-one 9b

Compound 9a (150mg, 0.28mmol) and N,N,N'-trimethylethylenediamine 8a (142mg, 1.39mmol) were dissolved in 1,4-dioxane (10mL), and Pd ₂ ( dba) ₃ (51mg, 0.06mmol), BINAP (52mg, 0.08mmol) and cesium carbonate (183mg, 0.56mmol), heated to 100°C for 3 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 9b (90 mg, yield 58%).

LC-MS: m/z=563.3[M+H] ⁺

The third step (R)-6-((2-(dimethylamino)ethyl)(methyl)amino)-4-((1-(3-nitro-5-(trifluoromethyl)benzene Base) ethyl) amino) phthalazin-1 (2H) -one 9c

Compound 9b (90mg, 0.16mmol) was dissolved in hydrochloric acid/methanol (5mL, 20.0mmol, 4M), stirred at room temperature for 1 hour, and TLC detected that the reaction was complete. The reaction solution was neutralized with methanol and then concentrated. The crude product was purified by Prep-TLC to obtain the title compound 9c (70 mg, yield 82%).

LC-MS: m/z=479.2[M+H] ⁺

The fourth step (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((2-(dimethylamino)ethyl) (Methyl)amino)phthalazin-1(2H)-one 9

Compound 9c (70 mg, 0.15 mmol) was dissolved in ethyl acetate (5 mL) and methanol (3 mL), and reacted under hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 9 (18 mg, yield 28%).

LC-MS: m/z=449.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.13(d, J=9.2Hz, 1H), 7.28-7.23(m, 2H), 6.95(d, J=1.4Hz, 2H), 6.77(s, 1H ),5.00(q,J=6.8Hz,1H),3.85(t,J=7.2Hz,2H),3.20(s,3H),2.99(t,J=6.8Hz,2H),2.65(s,6H ), 1.58 (d, J=6.8Hz, 3H). (98.53% purity by HPLC)

Example 10

(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-(dimethylamino)piperidin-1-yl) Phthalazin-1(2H)-one 10

The first step 6-(4-(dimethylamino)piperidin-1-yl)-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)B Base)amino)-2-(tetrahydro-2H-pyran-2-yl)phthalazin-1(2H)-one 10b

Compound 9a (150mg, 0.28mmol) and 4-dimethylaminopiperidine 10a (178mg, 1.39mmol) were dissolved in 1,4-dioxane (10mL), and Pd ₂ (dba) ₃ (51mg, 0.06mmol), BINAP (52mg, 0.08mmol) and cesium carbonate (183mg, 0.56mmol), heated to 100°C overnight. The reaction solution was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 10b (90 mg, yield 55%).

LC-MS: m/z=589.3[M+H] ⁺

The second step (R)-6-(4-(dimethylamino)piperidin-1-yl)-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) ethyl Base)amino)phthalazin-1(2H)-one 10c

Compound 10b (90 mg, 0.15 mmol) was dissolved in hydrochloric acid/methanol (5 mL, 20.0 mmol, 4M), and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound 10c (70 mg, crude product), which was directly used in the next step.

LC-MS: m/z=505.3[M+H] ⁺

The third step (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(4-(dimethylamino)piperidine-1 -yl)phthalazin-1(2H)-one 10

Compound 10c (70 mg, crude product) was dissolved in ethyl acetate (5 mL) and methanol (3 mL), and reacted at room temperature under hydrogen atmosphere for 2 hours. The reaction liquid was filtered, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 10 (36 mg, two-step yield 54%).

LC-MS: m/z=475.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.08 (d, J = 8.8Hz, 1H), 7.45 (d, J = 2.4Hz, 1H), 7.36 (dd, J = 9.2, 2.4Hz, 1H), 6.95(s,2H),6.77(s,1H),4.98(q,J=6.8Hz,1H),4.23(d,J=13.2Hz,2H),3.35(s,1H),2.97(t,J =12.0Hz,2H),2.87-2.75(m,1H),2.53(s,6H),2.09(d,J=12.0Hz,2H),1.71-1.61(m,2H),1.58(d,J= 6.8Hz,3H).(97.80%purity by HPLC)

Example 11

N-((R)-1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-4-oxo-3 , 4-dihydropyrido[3,4-d]pyridazin-7-yl)pyrrolidin-3-yl)acetamide 11

The first step ((R)-1-(3-methyl-1-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-4 -Oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)pyrrolidin-3-yl)carbamate tert-butyl ester 11b

Compound 4a (130 mg, 0.30 mmol) was dissolved in 1,4-dioxane (8 mL), and (R)-3-tert-butoxycarbonylaminopyrrolidine 11a (169 mg, 0.91 mmol) was added at room temperature, Pd ₂ ( dba) ₃ (40mg, 0.04mmol), BINAP (40mg, 0.06mmol) and cesium carbonate (198mg, 0.61mmol), replaced with nitrogen 3 times, heated to 100°C overnight, TLC showed that the reaction of raw materials was complete. The reaction solution was cooled to room temperature, added water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography to obtain the title compound 11b (190 mg, crude product) as a yellow solid, which was directly used in Next step.

LC-MS: m/z=578.3[M+H] ⁺

The second step 7-((R)-3-aminopyrrolidin-1-yl)-3-methyl-1-(((R)-1-(3-nitro-5-(trifluoromethyl) Phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-(3H)-one 11c

Compound 11b (190mg, crude product) was dissolved in hydrochloric acid ethanol solution (3mL, 12mmol, 4M) and reacted at room temperature for 1 hour. TLC showed that the reaction of the starting material was complete. The reaction solution was adjusted to alkaline by adding aqueous sodium bicarbonate dropwise, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 11c (90 mg, two steps Yield 63%).

LC-MS: m/z=478.2[M+H] ⁺

The third step N-((R)-1-(3-methyl-1-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino) -4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)pyrrolidin-3-yl)acetamide 11d

Compound 11c (50mg, 0.10mmol) was dissolved in dichloromethane (3mL), triethylamine (44mg, 0.43mmol) and acetic anhydride (23mg, 0.22mmol) were added, and reacted at room temperature for 1 hour. TLC showed that the raw materials were completely reacted. The reaction solution was added with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 11d (57 mg, crude product) as a yellow solid, which was directly used in the next step.

LC-MS: m/z=520.2[M+H] ⁺

The fourth step N-((R)-1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-4-oxo Substitute-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)pyrrolidin-3-yl)acetamide 11

Compound 11d (57mg, crude product) was dissolved in ethanol (10mL) and water (3mL), and reduced iron powder (30mg, 0.54mmol) and ammonium chloride (27mg, 0.50mmol) were added at room temperature, and heated to 90°C for 2 hours , TLC showed that the reaction of the starting material was complete. The reaction solution was lowered to room temperature, filtered, the filtrate was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 11 (25 mg, two steps) as a light yellow solid rate 47%).

LC-MS: m/z=490.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.97(s, 1H), 6.96(s, 2H), 6.88(s, 1H), 6.78(s, 1H), 4.94(q, J=6.8Hz, 1H ),4.55-4.49(m,1H),3.85-3.80(m,1H),3.76-3.62(m,2H),3.53-3.43(m,4H),2.37-2.28(m,1H),2.12-2.03 (m,1H),1.96(s,3H),1.58(d,J=6.8Hz,3H).(97.19%purity by HPLC)

Example 12

(R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylpiperidin-4-yl)pyrido[3 ,4-d]pyridazin-4(3H)-one 12

The first step (R)-7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-((1-(3-nitro-5-(trifluoromethyl base)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4-(3H)-one 12b

Intermediate IN-3 (130mg, 0.31mmol) and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester 12a (105mg, 0.47mmol) were dissolved in 1,4-bis To oxane (4 mL) and water (1 mL), sodium carbonate (67 mg, 0.63 mmol) and Pd(dppf)Cl ₂ (26 mg, 0.03 mmol) were added successively at room temperature, replaced by nitrogen several times, and the temperature was raised to 100°C and stirred for 3 After 1 hour, TLC showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 12b (130mg, yield 87% ).

LC-MS: m/z=475.2[M+H] ⁺

The second step (R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylpiperidin-4-yl)pyridine And[3,4-d]pyridazin-4(3H)-one 12

Compound 12b (120mg, 0.25mmol) was dissolved in ethyl acetate (4mL) and methanol (1mL), concentrated hydrochloric acid (2 drops) and palladium/carbon (catalytic amount, 10%) were added, and stirred at room temperature under hydrogen atmosphere for 5 hours, LCMS showed mostly product. Add ammonia methanol solution to the reaction solution to adjust the pH to alkaline, filter with celite, wash the filter cake with methanol, concentrate the filtrate, and purify the crude product by Prep-TLC to obtain the title compound 12 (31 mg, yield 27%) as a white solid.

LC-MS: m/z=447.2[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δ11.69(s, 1H), 9.32(s, 1H), 8.18(s, 1H), 7.15(d, J=6.8Hz, 1H), 6.79(d, J=8.0Hz, 2H), 6.68(s, 1H), 5.50(s, 2H), 4.90-4.83(m, 1H), 3.19-3.15(m, 2H), 3.02-2.93(m, 1H), 2.47 (s,3H),2.03(s,4H),1.50(d,J=6.8Hz,3H).(95.98%purity by HPLC)

Example 13

(R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(4-(dimethylamino)piperidin-1-yl) Pyrido[3,4-d]pyridazin-4(3H)-one 13

The first step (R)-7-(4-(dimethylamino)piperidin-1-yl)-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)B Base)amino)pyrido[3,4-d]pyridazin-4(3H)-one 13a

Intermediate IN-3 (100mg, 0.24mmol) was dissolved in 4-dimethylaminopiperidine 10a (310mg, 2.42mmol), dimethyl sulfoxide (3 drops) was added dropwise at room temperature, and the temperature was raised to 80°C and stirred for 3 hours , TLC showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to give the title compound 13a (140 mg, crude product), which was directly used in the next step.

LC-MS: m/z=506.3[M+H] ⁺

The second step (R)-1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(4-(dimethylamino)piperidine-1 -yl)pyrido[3,4-d]pyridazin-4(3H)-one 13

Compound 13a (130mg, crude product) was dissolved in ethanol (4mL) and water (2mL), iron powder (72mg, 1.29mmol) and ammonium chloride (70mg, 1.31mmol) were added at room temperature, the temperature was raised to 80°C and stirred for 2 hours, LCMS showed the reaction was complete. The reaction solution was filtered while hot, the filter cake was washed with ethanol several times, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 13 (7.7 mg, two-step yield 6%) as a white solid.

LC-MS: m/z=476.3[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ )δ11.18(s,1H),8.93(s,1H),7.41(s,1H),6.94(d,J=6.8Hz,1H),6.78(s, 2H),6.67(s,1H),5.51(s,2H),4.90-4.83(m,1H),4.80-4.76(m,2H),3.51-3.46(m,1H),3.04-2.98(m, 2H), 2.74(s, 6H), 2.17(d, J=11.2Hz, 2H), 1.69-1.61(m, 2H), 1.50(d, J=6.8Hz, 3H).(97.49% purity by HPLC)

Example 14

(R)-1-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(4-methylpiperazin-1-yl)pyrido[3 ,4-d]pyridazin-4(3H)-one 14

The first step 1-(2-fluoro-3-(trifluoromethyl)phenethyl alcohol 14b

2-Fluoro-3-trifluoromethylbenzaldehyde 14a (10.0g, 52.05mmol) was dissolved in tetrahydrofuran (200mL), cooled to 0°C, and methylmagnesium bromide (9.3g, 78.00mmol) was slowly added dropwise, After dropping, the mixture was slowly raised to room temperature and stirred for 1 hour. TLC showed that the reaction of the raw materials was complete. The reaction solution was quenched by pouring saturated ammonium chloride aqueous solution, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 14b (11.1 g, crude product), which was directly used in the next step.

The second step 2-fluoro-3-(trifluoromethyl)acetophenone 14c

Compound 14b (11.1g, crude product) was dissolved in dichloromethane (200mL), cooled to 0°C, replaced with nitrogen several times, added Dess Martin reagent (26.9g, 63.42mmol), raised to room temperature and stirred for 1 hour, TLC showed The raw material reacted completely. The reaction was also quenched by pouring into saturated aqueous sodium carbonate solution, extracted with dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain yellow liquid title compound 14c (7.3g, 68% yield in two steps).

¹ H NMR (400MHz, CDCl ₃ ) δ8.10-8.06(m, 1H), 7.83-7.79(m, 1H), 7.35(t, J=8.0Hz, 1H), 2.69(d, J=5.2Hz, 3H).

The third step (R, Z)-N-(1-(2-fluoro-3-(trifluoromethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide 14d

Compound 14c (7.3g, 35.41mmol) was dissolved in tetraethyl titanate (80mL), and (R)-(+)-tert-butylsulfinamide (12.9g, 106.4mmol) was added at room temperature, and the addition was completed, slowly The temperature was raised to 100° C. and stirred for 1 hour. TLC showed that the reaction of the starting material was complete. The reaction solution was poured into vigorously stirred ice water, stirred continuously for 10 minutes, filtered, the filter cake was washed repeatedly with ethyl acetate, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 14d (11.0 g, crude product) was used directly in the next step.

LC-MS: m/z=310.1[M+H] ⁺

The fourth step (R)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide 14e

Compound 14d (11.0 g, crude product) was dissolved in tetrahydrofuran (120 mL) and water (2 mL), cooled to about -60°C, and then sodium borohydride (4.0 g, 105.7 mmol) was added in portions. After the addition, the reaction was continued for 2 hours, and TLC showed that the starting material was consumed. The reaction solution was quenched by pouring ice water, extracted with ethyl acetate, and the organic phase was washed several times with water and saturated brine, dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the title compound 14e (3.4 g, 28% yield in two steps) as a yellow oil.

LC-MS: m/z=312.1[M+H] ⁺

The fifth step (R)-1-(2-fluoro-3-(trifluoromethyl)phenethylamine 14f

Compound 14e (3.4g, 10.92mmol) was dissolved in tetrahydrofuran (30mL), concentrated hydrochloric acid (800mg, 21.8mmol) was added, the temperature was raised to 80°C and stirred for 1 hour. TLC showed that the reaction of the starting material was complete. The reaction solution was cooled to room temperature, poured into saturated aqueous sodium bicarbonate solution to adjust the pH to be alkaline, extracted with ethyl acetate, washed the organic phase with saturated brine, dried over sodium sulfate, and concentrated to give the title compound 14f as a yellow liquid (2.0 g, yield 87%) .

LC-MS: m/z=208.1[M+H] ⁺

The sixth step (R)-6-chloro-1-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-3H-pyrrolo[3,4-c] Pyridin-3-one 14g

Compound IN-3h (400mg, 2.20mmol) and compound 14f (411mg, 1.98mmol) were dissolved in isopropanol (15mL), heated to 90°C overnight, and TLC detected that the reaction of the raw materials was basically complete. The reaction solution was cooled to room temperature and concentrated to obtain 14 g (800 mg, crude product) of the title compound as a yellow solid, which was directly used in the next step.

The seventh step (R)-7-chloro-1-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazine- 4-(3H)-Kone 14h

Compound 14g (800mg, crude product) was dissolved in ethanol (10mL), hydrazine hydrate (300mg, 4.79mmol, 80%) was added at room temperature, heated to 40°C for 1 hour, and TLC detected that the reaction of the raw material was basically complete. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 14h (340 mg, two-step yield 44%) as a yellow solid.

The eighth step (R)-1-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-7-(4-methylpiperazin-1-yl)pyridine And[3,4-d]pyridazin-4(3H)-one 14

Compound 14h (80mg, 0.21mmol) and N-methylpiperazine (105mg, 1.05mmol) were dissolved in toluene (10mL), and BINAP (30mg, 0.048mmol), palladium acetate (30mg, 0.13mmol) and Sodium tert-butoxide (81mg, 0.84mmol) was replaced with nitrogen three times, heated to 100°C for 5 hours, and the raw materials were completely reacted as detected by TLC. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 14 (20 mg, yield 21%) as an off-white solid.

LC-MS: m/z=451.2[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ )δ11.18(s,1H),8.92(s,1H),7.71(t,J=7.2Hz,1H),7.63(t,J=7.2Hz,1H) ,7.42-7.30(m,2H),7.06(d,J＝6.8Hz,1H),5.26-5.21(m,1H),3.80(s,4H),2.60(s,4H),2.35(s,3H ), 1.56 (d, J=6.8Hz, 3H). (99.25% purity by HPLC)

Example 15

(R)-1-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(4-methylpiperazin-1-yl)pyrido[3 ,4-d]pyridazin-4-(3H)-one 15

The first step 1-bromo-3-difluoromethyl-2-fluorobenzene 15b

2-Fluoro-3-bromobenzaldehyde 15a (10.0g, 49.26mmol) was dissolved in dichloromethane (200mL), cooled to 0°C, and diethylaminosulfur trifluoride (15.9g, 98.64mmol) was slowly added dropwise ), dropwise finished, slowly rose to room temperature and stirred for 1 hour, TLC showed that the reaction of raw materials was complete. The reaction solution was quenched by pouring into saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain yellow liquid title compound 15b (8.1g , yield 73%).

¹ H NMR (400MHz, CDCl ₃ ) δ7.68(t, J=7.2Hz, 1H), 7.55(t, J=7.2Hz, 1H), 7.14(t, J=8.0Hz, 1H), 6.89(t ,J＝54.8Hz,1H).

The second step 1-(3-(difluoromethyl)-2-fluoroacetophenone 15c

Compound 15b (8.1g, 36.00mmol) was dissolved in 1,4-dioxane (80mL), and triethylamine (9.1g, 89.93mmol) and tributyl (1-ethoxyethylene) were added successively at room temperature Tin (15.6g, 43.20mmol) was bubbled with nitrogen for 15 minutes, bistriphenylphosphine palladium dichloride (250mg, 0.36mmol) was added, replaced with nitrogen several times, heated to 100°C and stirred for 1 hour, TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, dilute hydrochloric acid (14.4 mL, 72.0 mmol, 5M) was added, and stirred at room temperature for 1 hour. TLC showed that the raw material was completely reacted. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15c (5.6 g, yield 83%) as a yellow liquid.

¹ H NMR (400MHz, CDCl ₃ ) δ8.00(t, J=7.2Hz, 1H), 7.79(t, J=6.8Hz, 1H), 7.34(t, J=7.6Hz, 1H), 6.94(t ,J=54.8Hz,1H),2.67(d,J=5.2Hz,3H).

The third step (R,Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide 15d

Compound 15c (5.6g, 29.76mmol) was dissolved in tetraethyl titanate (50mL), and (R)-(+)-tert-butylsulfinamide (10.8g, 89.11mmol) was added at room temperature, and the temperature was slowly raised to 100 °C and stirred for 1 hour, TLC showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, poured into vigorously stirred ice water, continued to stir for 10 minutes, filtered, the filter cake was washed repeatedly with ethyl acetate, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration gave the title compound 15d (9.5 g, crude product) as a yellow oil, which was directly used in the next step.

LC-MS: m/z=292.1[M+H] ⁺

The fourth step (R)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide 15e

Compound 15d (9.5g, crude product) was dissolved in tetrahydrofuran (100mL) and water (2mL), cooled to about -60°C, and sodium borohydride (3.7mg, 97.80mmol) was added in batches. After 2 hours of reaction, TLC showed that the starting material was consumed. The reaction solution was quenched by pouring ice water, extracted with ethyl acetate, combined organic phases, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15e (2.9 g, two step yield 33%).

LC-MS: m/z=294.1[M+H] ⁺

The fifth step (R)-1-(3-(difluoromethyl)-2-fluorophenethylamine 15f

Compound 15e (2.9g, 9.88mmol) was dissolved in tetrahydrofuran (50mL), concentrated hydrochloric acid (720mg, 19.8mmol) was added at room temperature, heated to 80°C and stirred for 1 hour, TLC showed that the starting material was consumed. The reaction solution was cooled to room temperature, poured into a saturated aqueous solution of sodium bicarbonate to adjust the pH to be alkaline, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 15f (2.0 g, crude product) as a brown liquid ), used directly in the next step.

LC-MS: m/z=190.1[M+H] ⁺

The sixth step (R)-6-chloro-1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3H-pyrrolo[3,4-c] Pyridin-3-one 15g

Compound IN-3h (400mg, 2.20mmol) and compound 15f (375mg, 1.98mmol) were dissolved in isopropanol (15mL), heated to 90°C overnight, and TLC detected that the reaction of the raw materials was basically complete. The reaction solution was cooled to room temperature and concentrated to obtain 15 g (826 mg, crude product) of the title compound as a yellow solid, which was directly used in the next step.

The seventh step (R)-7-chloro-1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)pyrido[3,4-d]pyridazine- 4-(3H)-Kone 15h

Compound 15g (800mg, crude product) was dissolved in ethanol (10mL), and hydrazine hydrate (300mg, 4.79mmol, 80%) was added, and the reaction solution was heated to 40°C for 1 hour, and TLC detected that the raw materials were almost completely reacted. The reaction solution was cooled to room temperature, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 15h (360 mg, three-step yield 46%) as a yellow solid.

The eighth step (R)-1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(4-methylpiperazin-1-yl)pyridine And[3,4-d]pyridazin-4-(3H)-one 15

Compound 15h (80mg, 0.22mmol) and N-methylpiperazine (220mg, 2.20mmol) were dissolved in dimethyl sulfoxide (0.5mL), heated to 100°C for 2 hours, and TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, water was added, a solid was precipitated, filtered, and the filter cake was washed to obtain a crude product, which was purified by Prep-TLC to obtain the title compound 15 (43 mg, yield 46%) as a yellow solid.

LC-MS: m/z=433.2[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ )δ11.16(s,1H),8.91(s,1H),7.56(t,J=7.2Hz,1H),7.48(t,J=6.8Hz,1H) ,7.35(s,1H),7.27(t,J=7.6Hz,1H),7.22(t,J=54.4Hz,1H),7.00(d,J=6.8Hz,1H),5.24-5.19(m, 1H), 3.77(s,4H),2.52(s,4H),2.30(s,3H),1.54(d,J＝6.8Hz,3H).(97.61%purity by HPLC)

Example 16

(R)-1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(4-methylpiperazin-1-yl) Pyrido[3,4-d]pyridazin-4-(3H)-one

16

The first step 1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethan-1-one 16a

Potassium nitrate (45.6g, 0.45mmol) was dissolved in concentrated sulfuric acid (100mL), stirred at room temperature for 30 minutes, cooled to about 0°C, compound 15c (8.5g, 45.18mmol) was slowly added dropwise, stirred at 0°C for 5 minutes, TLC showed The response is complete. The reaction solution was slowly added to ice water, extracted with ethyl acetate, combined organic phases, washed with saturated aqueous sodium bicarbonate solution, washed with saturated brine, concentrated, and the crude product was purified by silica gel column to obtain the title compound 16a (9.0 g, yield 86% ).

¹ H NMR (400MHz, CDCl ₃ ) δ8.88-8.86 (m, 1H), 8.66-8.64 (m, 1H), 7.12-6.85 (m, 1H), 2.73 (d, J=4.8Hz, 3H).

The second step (R, Z)-N-(1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinic acid Amide 16b

Compound 16a (9.0g, 38.60mmol) was dispersed in tetraethyl titanate (90mL), and (R)-(+)-tert-butylsulfinamide (7.0g, 57.76mmol) was added at room temperature, and the temperature was slowly raised to 100 °C and stirred for 1 hour, TLC showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, poured into vigorously stirred ice water, continued to stir for 10 minutes, filtered, the filter cake was washed repeatedly with ethyl acetate, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration gave the title compound 16b (9.0 g, crude product) as a yellow oil, which was directly used in the next step.

LC-MS: m/z=337.1[M+H] ⁺

The third step (R)-N-((R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl) ethyl)-2-methylpropane-2- Sulfonamide 16c

Compound 16b (9.0g, crude product) was dissolved in tetrahydrofuran (150mL) and water (2mL), cooled to about -60°C, and sodium borohydride (3.1g, 81.95mmol) was added in batches. After 2 hours of reaction, TLC showed that the starting material was consumed. The reaction solution was quenched by pouring ice water, extracted with ethyl acetate, combined organic phases, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 16c (2.8 g, two steps) as a brown oily product. rate 21%).

LC-MS: m/z=339.1[M+H] ⁺

The fourth step (R)-1-(3-(difluoromethyl)-2-fluoro-5-nitrophenyl)ethan-1-amine 16d

Compound 16c (2.8g, 8.28mmol) was dissolved in tetrahydrofuran (30mL), concentrated hydrochloric acid (1.4mL, 16.52mmol) was added, stirred at room temperature for 1 hour, TLC showed that the starting material was consumed. The reaction solution was cooled to room temperature, poured into saturated aqueous sodium bicarbonate solution to adjust the pH to be alkaline, extracted with ethyl acetate, combined the organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a brown liquid, which solidified into a brown solid title compound 16d (1.8 g, 95% yield).

LC-MS: m/z=235.1[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ )δ8.76-8.74(m,1H),8.41-8.39(m,1H),7.52-7.25(m,1H),4.42(q,J=6.4Hz,1H ),2.48-2.24(m,2H),1.35(d,J＝6.8Hz,3H).

The fifth step (R)-3-(1-aminoethyl)-5-(difluoromethyl)-4-fluoroaniline 16e

Compound 16d (300mg, 1.28mmol) was dissolved in ethanol and water (6mL/2mL), and reduced iron powder (358mg, 6.41mmol) and ammonium chloride (346mg, 6.69mmol) were added at room temperature, and heated to 90°C for 2 hours , TLC detection showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated to obtain the title compound 16e (600 mg, crude product), which was directly used in the next step.

The sixth step (R)-1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-chloro-3H-pyrrolo[3, 4-c]pyridin-3-one 16f

Compound 16e (200 mg, crude product) and compound IN-3h (89 mg, 0.45 mmol) were dispersed in isopropanol (5 mL), heated to 90° C. for 12 hours, and TLC showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated to obtain the title compound 16f (180 mg, crude product) as a yellow solid, which was directly used in the next step.

LC-MS: m/z=369.1[M+H] ⁺

The seventh step (R)-1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-chloro-pyrido[3,4- d] Pyridazin-4-(3H)-one 16g

Compound 16f (180 mg, crude product) was dissolved in methanol (10 mL), and hydrazine hydrate (100 mg, 1.60 mmol, 80%) was added dropwise at room temperature, and heated to 45°C for 1.5 hours after dropping, TLC detection showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain 16 g (44 mg, three-step yield 27%) of the title compound as a yellow solid.

LC-MS: m/z＝382.1[MH] ^-

The eighth step (R)-1-((1-(5-amino-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(4-methylpiperazine-1 -yl)pyrido[3,4-d]pyridazin-4-(3H)-one 16

Compound 16g (20mg, 0.05mmol) was dissolved in DMSO (0.5mL), N-methylpiperazine (52mg, 0.52mmol) was added at room temperature, heated to 85°C for 12 hours, and TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, added water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 16 (7 mg, yield 30%) as a yellow solid.

LC-MS: m/z=448.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.04(s, 1H), 7.33(s, 1H), 6.95-6.82(m, 2H), 6.76-6.72(m, 1H), 5.20(q, J= 6.8Hz,1H),3.99(s,4H),3.00(s,4H),2.66(s,3H),1.58(d,J=7.2Hz,3H).(97.85%purity by HPLC)

Example 17

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylpiperidin-3-yl)pyrido[3 ,4-d]pyridazin-4(3H)-one 17

The first step (R)-5-(1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydro Pyrido[3,4-d]pyridazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 17b

Intermediate IN-3 (110mg, 0.27mmol) and 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester 17a (123mg, 0.40mmol) were dissolved in 1,4- In dioxane (4mL) and water (1mL), sodium carbonate (56mg, 0.53mmol) and Pd(dppf)Cl ₂ (22mg, 0.023mmol) were added successively at room temperature. Stirring at 100°C for 3 hours, TLC showed that the reaction of the starting material was complete. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 17b (120 mg, yield 81%) as a yellow solid.

LC-MS: m/z=561.3[M+H] ⁺

The second step (R)-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(1,2,5,6-tetrahydropyridine -3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 17c

Compound 17b (120 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), added trifluoroacetic acid (1 mL), stirred at room temperature for 1 hour, TLC showed that the starting material was consumed. The reaction liquid was concentrated, and the pH was adjusted to alkaline with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 17c (110 mg, crude product) as a yellow oil, which was directly used in Next step.

LC-MS: m/z=461.2[M+H] ⁺

The third step (R)-7-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1-((1-(3-nitro-5-(trifluoromethyl Base) phenyl) ethyl) amino) pyrido[3,4-d]pyridazin-4(3H)-one 17d

Compound 17c (100 mg, crude product) was dissolved in acetonitrile (2 mL), potassium carbonate (60 mg, 0.43 mmol) and methyl p-toluenesulfonate (32 mg, 0.17 mmol) were added, and stirred overnight at room temperature. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 17d (25 mg, two-step yield 25%) as a yellow solid.

LC-MS: m/z=475.2[M+H] ⁺

The fourth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylpiperidin-3-yl)pyridine And[3,4-d]pyridazin-4(3H)-one 17

Compound 17d (25mg, 0.053mmol) was dissolved in a mixed solvent of ethyl acetate (1mL) and tetrahydrofuran (1mL), palladium/carbon (20mg, 10%) was added at room temperature, and the temperature was raised to 50°C under hydrogen atmosphere and stirred overnight. The reaction solution was filtered with celite, the filter cake was washed several times with methanol, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 17 (10 mg, yield 42%) as a yellow solid.

LC-MS: m/z=447.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.41(s, 1H), 8.09(s, 1H), 6.92(s, 2H), 6.76(s, 1H), 4.96(q, J=6.8Hz, 1H ),3.38-3.32(m,2H),3.14-3.11(m,1H),2.82-2.70(m,1H),2.56(s,3H),2.50-2.37(m,1H),2.14-2.12(m ,1H),1.95-1.78(m,3H),1.57(d,J=7.2Hz,3H).(94.55%purity by HPLC)

Example 18

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(6-methyl-3,6-diazabicyclo[3.1 .1]hept-3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 18

The first step 3-(1-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydro Pyrido[3,4-d]pyridazin-7-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester 18b

Intermediate IN-3 (300 mg, 0.73 mmol) and 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane 18a (575 mg, 2.90 mmol) were dissolved in dimethyl sulfoxide (6 mL), heated to 100° C. and stirred for 2 hours, and TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, water was added, solids were precipitated, filtered, the filter cake was washed and dried to obtain the title compound 18b (400 mg, crude product) as a yellow solid, which was directly used in the next step.

LC-MS: m/z=576.3[M+H] ⁺

The second step 7-(3,6-diazabicyclo[3.1.1]hept-3-yl)-1-(((R)-1-(3-nitro-5-(trifluoromethyl) Phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4(3H)-one 18c

Compound 18b (200 mg, crude product) was dissolved in methanol (2 mL), added with methanolic hydrochloric acid (4 mL, 4M), stirred at room temperature for 3 hours, and the reaction was complete as detected by TLC. The reaction solution was neutralized with ammonia methanol, filtered, and the filtrate was concentrated to obtain the title compound 18c (170 mg, crude product), which was directly used in the next step.

The third step 7-(6-methyl-3,6-diazabicyclo[3.1.1]hept-3-yl)-1-(((R)-1-(3-nitro-5-( Trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-4(3H)-one 18d

Compound 18c (170mg, crude product) and methyl p-toluenesulfonate (65mg, 0.35mmol) were dissolved in acetonitrile (15mL), potassium carbonate (72mg, 0.52mmol) was added, stirred overnight at room temperature, TLC detected a large amount of remaining raw material. The temperature of the reaction solution was raised to 80° C. and stirred for 8 hours, and the reaction of the raw materials was basically complete as detected by TLC. The reaction solution was cooled to room temperature, added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 18d (37mg, three-step yield 21%) .

LC-MS: m/z=490.2[M+H] ⁺

The fourth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(6-methyl-3,6-diazepine Bicyclo[3.1.1]hept-3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 18

Compound 18d (37mg, 0.076mmol) was dissolved in ethanol (10mL) and water (2mL), iron powder (21mg, 0.38mmol) and ammonium chloride (20mg, 0.37mmol) were added at room temperature, heated to 90°C and stirred for 2 hours , TLC detected that the reaction was complete. The reaction solution was filtered while hot, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 18 (20 mg, yield 57%).

LC-MS: m/z=460.2[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ +D ₂ O)δ9.03(s,1H),7.22(s,1H),6.97-6.73(m,3H),4.88(q,J＝6.8Hz,1H ),4.03-3.61(m,6H),2.57(s,3H),2.32-2.22(m,1H),1.83-1.68(m,1H),1.52(d,J＝6.8Hz,3H).(98.46 %purity by HPLC)

Example 19

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((R)-2,4-dimethylpiperazine-1 -yl)pyrido[3,4-d]pyridazin-4(3H)-one 19

The first step (R)-2,4-dimethylpiperazine-1-carboxylate tert-butyl ester 19b

Dissolve (R)-2-methylpiperazine-1-carboxylate tert-butyl ester 19a (12.0 g, 59.92 mmol) in methanol (50 mL), add aqueous formaldehyde (9.7 g, 119.51 mmol, 37%) and palladium /carbon (500 mg, 10%), stirred at room temperature under hydrogen atmosphere for 2.5 hours, and TLC detected that the reaction was complete. The reaction solution was filtered with celite, and the filtrate was concentrated to obtain the title compound 19b (12.2 g, crude product) as a transparent oil, which was directly used in the next step.

The second step (R)-1,3-dimethylpiperazine dihydrochloride 19c

Compound 19b (12.2 g, crude product) was dissolved in methanolic hydrochloric acid solution (20 mL, 4M), stirred at room temperature for 30 minutes, and the reaction was complete as detected by TLC. The reaction solution was concentrated to obtain the title compound 19c (12.0 g, crude product) as a yellowish oil, which was directly used in the next step.

The third step (R)-2,4-dimethylpiperazine-1-carboxylate benzyl ester 19d

Compound 19c (13.2g, crude product) was dissolved in tetrahydrofuran (130mL), water (50mL) and sodium carbonate (37.4g, 352.86mmol) were added at room temperature, cooled to 0°C, benzyl chloroformate (20.9g, 122.52 mmol), dropwise finished, rose to room temperature and stirred for 1 hour, and TLC detected that the reaction of raw materials was complete. The reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 19d (8.9 g, three-step yield 54%) as a yellow oil.

The fourth step (R)-1,3-dimethylpiperazine 19e

Compound 19d (8.9g, 35.84mmol) was dissolved in tetrahydrofuran (80mL), palladium/carbon (2.0g, 10%) was added, stirred at room temperature under hydrogen atmosphere for 1.5 hours, and the reaction was complete as detected by TLC. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain the title compound 19e (1.8 g, crude product) as a yellow oil, which was directly used in the next step.

The fifth step 7-((R)-2,4-dimethylpiperazin-1-yl)-1-(((R)-1-(3-nitro-5-(trifluoromethyl)benzene Base) ethyl) amino) pyrido[3,4-d]pyridazin-4(3H)-one 19f

Compound 19e (311 mg, crude product) was dissolved in dimethyl sulfoxide (1.5 mL), and intermediate IN-3 (120 mg, 0.29 mmol) was added at room temperature, and the temperature was raised to 120° C. to react overnight, and the reaction was complete as detected by TLC. The reaction solution was cooled to room temperature, and water (3 mL) was added to precipitate a solid, which was filtered, and the filter cake was washed and dried to obtain the title compound 19f (45 mg, crude product) as a yellow solid, which was directly used in the next step.

LC-MS: m/z=492.3[M+H] ⁺

The sixth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((R)-2,4-dimethylpiperene Azin-1-yl)pyrido[3,4-d]pyridazin-4(3H)-one 19

Compound 19f (45mg, crude product) was dispersed in ethanol and water (3mL/1mL), reduced iron powder (25mg, 0.45mmol) and ammonium chloride (24mg, 0.45mmol) were added at room temperature, heated to 90°C for 3 hours, TLC detects that the reaction is complete. The reaction solution was filtered with celite while hot, the filter cake was washed, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 19 (28 mg, three-step yield 21%) as a yellow solid.

LC-MS: m/z=462.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.05(s,1H),7.24(s,1H),6.99-6.87(m,2H),6.77(s,1H),5.05-4.91(m,2H) ,4.56(d,J=14.4Hz,1H),3.44-3.34(m,1H),3.30-3.25(m,1H),3.22(d,J=12.0Hz,1H),2.85-2.73(m,1H ), 2.64(s, 4H), 1.57(d, J=6.8Hz, 3H), 1.37(d, J=6.8Hz, 3H).(96.26% purity by HPLC)

Example 20

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((S)-2,4-dimethylpiperazine-1 -yl)pyrido[3,4-d]pyridazin-4(3H)-one 20

The first step 1-benzyl 4-(tert-butyl)(S)-2-methylpiperazine-1,4-dicarboxylate 20b

(S)-4-N-tert-butoxycarbonyl-2-methylpiperazine 20a (3.0 g, 14.98 mmol) was dissolved in ethyl acetate (30 mL) and water (30 mL), and sodium bicarbonate (4.0 g, 47.61mmol), cooled to about 0°C, added benzyl chloroformate (3.8g, 22.28mmol) dropwise, and reacted at 0°C for 1 hour. The reaction solution was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column to obtain the title compound 20b (5.0 g, yield 99.8%) as a yellow oil.

The second step (S)-2-methylpiperazine-1-carboxylate benzyl ester 20c

Compound 20b (5.0 g, 14.95 mmol) was dissolved in dichloromethane (50 mL), added trifluoroacetic acid (10 mL), stirred at room temperature for 1 hour, TLC showed that the reaction was complete. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution was added to adjust the pH to alkaline, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 20c (3.7 g, crude product) as a yellow oil, which was directly for the next step.

LC-MS: m/z=235.2[M+H] ⁺

The third step (S)-2,4-dimethylpiperazine-1-carboxylate benzyl ester 20d

Compound 20c (3.7g, crude product) was dissolved in formic acid (3.1g, 67.35mmol), and aqueous formaldehyde (2.4g, 29.57mmol, 37%) was added at room temperature, heated to 80°C and stirred overnight, TLC showed that the reaction was complete. Cool the reaction solution to room temperature, concentrate the reaction solution, adjust the pH to alkaline with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is purified by a silica gel column to obtain a colorless Liquid title compound 20d (3.1 g, 84% yield for two steps).

LC-MS: m/z=249.2[M+H] ⁺

The fourth step (S)-1,3-dimethylpiperazine 20e

Compound 20d (3.0g, 12.08mmol) was dissolved in tetrahydrofuran (30mL), palladium/carbon (300mg, 10%) was added, stirred overnight at room temperature under hydrogen atmosphere, TLC showed that the starting material was completely reacted. The reaction solution was filtered through a pad of celite, the filter cake was washed with ethyl acetate, and the filtrate was concentrated to give the title compound 20e (500 mg, crude product) as a yellow oil, which was directly used in the next step.

The fifth step 7-((S)-2,4-dimethylpiperazin-1-yl)-1-(((R)-1-(3-nitro-5-(trifluoromethyl)benzene Base) ethyl) amino) pyrido[3,4-d]pyridazin-4(3H)-one 20f

Intermediate IN-3 (80mg, 0.19mmol) was dissolved in dimethyl sulfoxide (0.5mL), compound 20e (230mg, crude product) was added at room temperature, heated to 120°C and stirred overnight, TLC showed that the starting material was consumed. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 20f (90 mg, yield 95%) as a brown solid.

LC-MS: m/z=492.3[M+1] ⁺

The sixth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((S)-2,4-dimethylpiperene Azin-1-yl)pyrido[3,4-d]pyridazin-4(3H)-one 20

Compound 20f (90mg, 0.18mmol) was dissolved in ethanol (4mL) and water (2mL), iron powder (57mg, 1.02mmol) and ammonium chloride (55mg, 1.03mmol) were added at room temperature, after addition, the temperature was raised to 80°C After stirring for 1 hour, TLC showed that the starting material was completely reacted. The reaction solution was filtered while hot, the filter cake was washed with ethanol, the filtrate was concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 20 as a yellow solid (22 mg, yield 26%).

LC-MS: m/z=462.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.06(s, 1H), 7.20(s, 1H), 6.92(s, 2H), 6.77(s, 1H), 4.94(q, J=6.8Hz, 2H ),4.47(d,J=12.4Hz,1H),3.37-3.33(m,1H),3.13-3.02(m,2H),2.54-2.31(m,5H),1.56(d,J=6.8Hz, 3H), 1.35 (d, J=6.8Hz, 3H). (96.68% purity by HPLC)

Example 21

1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(1-methylpiperidin-3-yl)pyrido[3 ,4-d]pyridazin-4-(3H)-one 21

The first step (R)-5-(1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-oxo-3,4-dihydropyridine [3,4-d]pyridazin-7-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate 21a

Compound 15h (110mg, 0.30mmol) and 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester 17a (113mg, 0.37mmol) were dissolved in 1,4-dioxahexa Add sodium carbonate (52mg, 0.49mmol) and Pd(dppf)Cl 2 (20mg, 0.027mmol) to Na2CO3 (52mg, 0.49mmol) and Pd(dppf)Cl ₂ (20mg, 0.027mmol) successively at room temperature, replace with nitrogen several times, raise the temperature to 100°C and stir for 3 hours. TLC showed the starting material was completely reacted. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 21a (120 mg, yield 78%) as a yellow solid.

LC-MS: m/z=516.3[M+H] ⁺

The second step 3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-oxo-3,4-dihydropyridine And[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate tert-butyl ester 21b

Compound 21a (120mg, 0.23mmol) was dissolved in ethyl acetate (2mL) and tetrahydrofuran (2mL), palladium/carbon (40mg, 10%) was added at room temperature, heated to 50°C under hydrogen atmosphere and stirred overnight. The reaction solution was cooled to room temperature, filtered with celite, and the filter cake was washed with methanol. The filtrate was concentrated to give the title compound 21b (110 mg, crude product) as a white solid, which was directly used in the next step.

LC-MS: m/z=518.3[M+H] ⁺

The third step 1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(piperidin-3-yl)pyrido[3, 4-d]pyridazin-4(3H)-one 21c

Compound 21b (50 mg, crude product) was dissolved in dichloromethane (2 mL), added trifluoroacetic acid (1 mL), stirred at room temperature for 1 hour, TLC showed that the reaction was complete. The reaction solution was concentrated, and the pH was adjusted to alkaline by adding ammonia methanol solution (7M), and concentrated. The crude product was purified by Prep-TLC to obtain the title compound 21c (30 mg, two-step yield 69%) as a white solid.

LC-MS: m/z=418.2[M+H] ⁺

The fourth step 1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(1-methylpiperidin-3-yl)pyridine And[3,4-d]pyridazin-4-(3H)-one 21

Compound 21c (30mg, 0.072mmol) was dispersed in methanol (2mL), aqueous formaldehyde (58mg, 0.71mmol, 37%) and palladium/carbon (20mg, 10%) were added, and stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered with celite, the filter cake was washed several times with methanol, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 21 (8 mg, yield 26%) as a white solid.

LC-MS: m/z=432.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.42(s, 1H), 8.13(s, 1H), 7.57(t, J=7.2Hz, 1H), 7.44(t, J=6.8Hz, 1H), 7.21(t, J=7.6Hz, 1H), 6.98(t, J=54.8Hz, 1H), 5.32(q, J=7.2Hz, 1H), 3.45-3.31(m, 2H), 3.20-3.12(m ,1H),2.98-2.78(m,1H),2.62(s,3H),2.54-2.42(m,1H),2.17-2.14(m,1H),1.96-1.84(m,3H),1.63(d ,J＝6.8Hz,3H).(96.73%purity by HPLC)

Example 22

1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-methyl-7-(1-methylpiperidin-3-yl ) pyrido[3,4-d]pyridazin-4-(3H)-one 22

The first step 3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-methyl-4-oxo-3, tert-butyl 4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate 22a

Compound 21b (80mg, 0.15mmol) was dissolved in N,N-dimethylformamide (1mL), potassium carbonate (43mg, 0.31mmol) and methyl iodide (33mg, 0.23mmol) were added successively, stirred at room temperature for 4 hours, TLC It shows that the reaction of raw materials is complete. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 22a (100 mg, crude product) as a white solid, which was directly used in the next step.

The second step 1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-methyl-7-(piperidin-3-yl) Pyrido[3,4-d]pyridazin-4(3H)-one 22b

Compound 22a (100 mg, crude product) was dissolved in dichloromethane (2 mL), added trifluoroacetic acid (1 mL), stirred at room temperature for 1 hour, TLC showed that the reaction was complete. The reaction solution was concentrated, and the pH was adjusted to alkaline by adding ammonia methanol solution (7M), and concentrated. The crude product was purified by Prep-TLC to obtain the title compound 22b (50 mg, two-step yield 75%) as a white solid.

LC-MS: m/z=432.2[M+H] ⁺

The third step 1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-methyl-7-(1-methylpiperidine- 3-yl)pyrido[3,4-d]pyridazin-4-(3H)-one 22

Compound 22b (50mg, 0.12mmol) was dispersed in methanol (2mL), aqueous formaldehyde (94mg, 1.16mmol, 37%) and palladium/carbon (30mg, 10%) were added, and stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered with Celite, the filter cake was washed several times with methanol, the filtrate was concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 22 (13 mg, yield 25%) as a pale yellow solid.

LC-MS: m/z=446.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.40(s, 1H), 8.07(s, 1H), 7.59(t, J=7.2Hz, 1H), 7.45(t, J=7.2Hz, 1H), 7.21(t, J=7.6Hz, 1H), 7.01(t, J=54.8Hz, 1H), 5.31(q, J=6.8Hz, 1H), 3.50(s, 3H), 3.28-3.18(m, 2H ),3.06-2.98(m,1H),2.52-2.47(m,1H),2.43(s,3H),2.29-2.15(m,1H),2.13-2.05(m,1H),1.93-1.71(m ,3H), 1.64 (d, J=6.8Hz, 3H).(99.14% purity by HPLC)

Example 23

(R)-1-(((1-(4-(2-(((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-(4-methylpiper Azin-1-yl)pyrido[3,4-d]pyridazin-4(3H)-one 23

The first step (2-((methylamino)methyl)phenyl)boronic acid 23b

O-formylboronic acid 23a (5.0g, 33.35mmol) was dissolved in methylamine ethanol solution (30mL, 7M), palladium/carbon (200mg, 10%) was added, and the reaction was carried out at room temperature under hydrogen atmosphere for 5 hours, and the raw materials were completely reacted by TLC. The reaction solution was filtered through a pad of celite, the filter cake was washed, and the filtrate was concentrated to obtain the title compound 23b (5.3 g, crude product) as a pale yellow effervescent solid, which was directly used in the next step.

The second step (2-(((tert-butoxycarbonyl)(methyl)amino)methyl)phenyl)boronic acid 23c

Compound 23b (5.3g, crude product) was dissolved in tetrahydrofuran (100mL) and water (20mL), sodium carbonate (10.3g, 97.18mmol) was added at room temperature, cooled to 0°C, di-tert-butyl dicarbonate (8.5g , 38.95mmol), after dropping, return to room temperature and react overnight, and TLC detects that the reaction is complete. The reaction solution was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, crude petroleum ether and ethyl acetate were slurried, filtered, and the filter cake was washed and dried to obtain the title compound 23c (7.4 g, two-step yield 84%) as a white solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.14(s, 2H), 7.50(dd, J=7.2, 0.8Hz, 1H), 7.38-7.30(m, 1H), 7.21(t, J=7.2 Hz,1H),7.08(d,J=7.6Hz,1H),4.56(s,2H),2.74(s,3H),1.40(s,9H).

The third step (R)-1-(4-bromothiophen-2-yl) ethyl-1-amine 23e

Compound 23d (1.1 g, 3.59 mmol) was dissolved in methanolic hydrochloric acid solution (10 mL, 4 mol/L) and reacted at room temperature for 1 hour. TLC detected that the reaction of the starting material was complete. The reaction solution was neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 23e (1.0 g, crude product) as a yellow oil, which was directly used in the next step.

The fourth step (R)-(2-(5-(1-aminoethyl)thiophen-3-yl)benzyl)(methyl)carbamate tert-butyl ester 23f

Compound 23e (1.0g, crude product) and compound 23c (1.9g, 7.17mmol) were dissolved in 1,4-dioxane (20mL) and water (5mL), and sodium carbonate (1.5g, 14.15mmol) was added at room temperature And Pd(dppf)Cl ₂ dichloromethane complex (200mg, 0.24mmol), nitrogen replacement 3 times, heated to 100 ° C for 4 hours, TLC detection of raw material reaction is complete. The reaction solution was cooled to room temperature, added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain the title compound 23f (800mg, two-step yield 64% ).

LC-MS: m/z=347.2[M+H] ⁺

The fifth step (R)-(2-(5-(1-((6-chloro-3-oxo-3H-pyrrolo[3,4-c]pyridin-1-yl)amino)ethyl)thiophene -3-yl)benzyl)(methyl)carbamate tert-butyl ester 23g

Compound 23f (800mg, 2.31mmol) and compound IN-3h (400mg, 2.20mmol) were dissolved in isopropanol (20mL), heated to 90°C and stirred overnight. TLC showed that the reaction was almost complete. The reaction solution was cooled to room temperature and concentrated to obtain 23 g (1.1 g, crude product) of the title compound as a brown effervescent solid, which was directly used in the next step.

The sixth step (R)-(2-(5-(1-((7-chloro-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-1-yl)amino ) ethyl) thiophen-3-yl) benzyl) (methyl) tert-butyl carbamate 23h

Compound 23g (1.1g, crude product) was dissolved in methanol (15mL), hydrazine hydrate (269mg, 4.30mmol, 80%) was added at room temperature, heated to 40°C for 2 hours, and the reaction was complete by TLC. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to obtain the title compound 23h (910 mg, 79% yield in two steps) as a yellow-brown oil.

The seventh step (R)-methyl (2-(5-(1-((7-(4-methylpiperazin-1-yl)-4-oxo-3,4-dihydropyrido[3 ,4-d]pyridazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)tert-butyl carbamate 23i

Compound 23h (100 mg, 0.17 mmol) and N-methylpiperazine 2b (95 mg, 0.95 mmol) were dissolved in dimethyl sulfoxide (1 mL), heated to 80° C. for 2 hours, and the reaction was complete as detected by TLC. The reaction solution was cooled to room temperature, added with water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to give the title compound 23i (75 mg, crude product) as a yellow solid, which was directly used in the next step.

The eighth step (R)-1-(((1-(4-(2-(((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-(4- Methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-4(3H)-one 23

Compound 23i (75 mg, crude product) was dissolved in hydrochloric acid/1,4-dioxane solution (3 mL, 4M) and reacted at room temperature for 1 hour, and the reaction was complete as detected by TLC. The reaction solution was neutralized with saturated aqueous sodium carbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 23 as a yellow solid (17 mg, two-step yield 20%).

LC-MS: m/z=490.3[M+H] ⁺

¹ H NMR (400MHz,DMSO-d ₆ )δ11.31(s,1H),8.93(s,1H),7.50-7.46(m,1H),7.44(d,J=1.2Hz,1H),7.34- 7.29(m,3H),7.23(d,J=8.0Hz,2H),7.00(d,J=7.6Hz,1H),5.41-5.25(m,1H),3.76-3.69(m,4H),3.68 (s,2H),2.47-2.40(m,4H),2.28(s,3H),2.24(s,3H),1.67(d,J=6.8Hz,3H).(99.72%purity by HPLC)

Example 24

1-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-(((S)-tetrahydrofuran- 3-yl)oxy)pyrido[3,4-d]pyridazin-4(3H)-one 24

The first step methyl (2-(5-((R)-1-((4-oxo-7-(((S)-tetrahydrofuran-3-yl)oxy)-3,4-dihydropyridine [3,4-d]pyridazin-1-yl)amino)ethyl)thiophen-3-yl)benzyl)tert-butyl carbamate 24a

(S)-(+)-3-Hydroxytetrahydrofuran (1mL) was cooled to 0°C, sodium hydrogen (76mg, 1.90mmol, 60%) was added, and stirred at room temperature for 1 hour, the reaction solution changed from emulsion to orange and transparent, adding Compound 23h (100mg, 0.19mmol), warmed up to 80°C and stirred overnight. The reaction solution was quenched with water, extracted with ethyl acetate, combined organic phases, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 24a (100 mg, yield 91%) as a white solid

LC-MS: m/z=578.3[M+H] ⁺

The second step 1-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-(((S) -tetrahydrofuran-3-yl)oxy)pyrido[3,4-d]pyridazin-4(3H)-one 24

Compound 24a (100 mg, 0.17 mmol) was dissolved in hydrochloric acid/1,4-dioxane solution (1 mL, 4M), stirred at room temperature for 1 hour, TLC showed that the starting material disappeared. Add saturated aqueous sodium bicarbonate solution to the reaction solution to adjust the pH to alkaline, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and the crude product is purified by Prep-TLC to obtain the title compound 24 (7mg, Yield 8%).

LC-MS: m/z=478.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.12(s, 1H), 7.44-7.36(m, 2H), 7.34-7.25(m, 3H), 7.14(s, 1H), 7.11(s, 1H) ,5.77-5.68(m,1H),5.39-5.29(m,1H),4.07-3.80(m,6H),2.39-2.30(m,1H),2.24(s,3H),2.20-2.14(m, 1H), 1.72 (d, J=6.8Hz, 3H). (88.28% purity by HPLC)

Example 25

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(3-(dimethylamino)pyrrolidin-1-yl) Pyrido[3,4-d]pyridazin-4(3H)-one 25

The first step 3-(dimethylamino)pyrrolidine-1-carboxylic acid tert-butyl ester 25b

tert-butyl 3-aminopyrrolidine-1-carboxylate 25a (800mg, 4.30mmol) was dispersed in methanol (10mL), aqueous formaldehyde (3.5g, 43.12mmol, 37%) and palladium on carbon (200mg, 10% ), stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered with Celite, the filter cake was washed several times with methanol, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 25b (900 mg, yield 98%) as a yellow liquid.

LC-MS: m/z=215.2[M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ )δ3.52-3.44(m,1H),3.23-3.17(m,1H),3.04-2.96(m,1H),2.63-2.54(m,1H),2.19(s ,6H),2.01-1.95(m,1H),1.74-1.55(m,2H),1.39(s,6H).

The second step N,N-dimethylpyrrolidin-3-amine 25c

Compound 25b (900mg, 4.20mmol) was dissolved in hydrochloric acid/1,4-dioxane solution (10mL, 4M) and stirred at room temperature for 1 hour. TLC showed that the starting material was completely reacted. The reaction solution was concentrated to give the title compound 25c (700 mg, crude product) as a brown liquid, which was directly used in the next step.

LC-MS: m/z=115.2[M+H] ⁺

The third step 7-(3-(dimethylamino)pyrrolidin-1-yl)-1-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl) ethyl Base)amino)pyrido[3,4-d]pyridazin-4(3H)-one 25d

Intermediate IN-3 (70mg, 0.17mmol) was dissolved in dimethylsulfoxide (0.5mL), compound 25c (58mg, crude product) and N,N-diisopropylethylamine (87mg, 0.68mmol) were added at room temperature ), heated to 80° C. and stirred overnight, and the disappearance of raw materials was monitored by TLC. Add water to the reaction solution, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column to obtain the title compound 25d (50 mg, yield 60%) as a brown solid.

LC-MS: m/z=492.2[M+H] ⁺

The fourth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(3-(dimethylamino)pyrrolidine-1 -yl)pyrido[3,4-d]pyridazin-4(3H)-one 25

Compound 25d (50mg, 0.10mmol) was dissolved in ethanol (2mL) and water (1mL), iron powder (28mg, 0.50mmol) and ammonium chloride (27mg, 0.50mmol) were added at room temperature, heated to 80°C and stirred for 1 hour , TLC showed that the starting material was completely reacted. The reaction solution was filtered while it was hot, the filter cake was washed with ethanol, the filtrate was concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 25 as a yellow solid ( 30mg, yield 64%).

LC-MS: m/z=462.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.98(s,1H),6.94(s,1H),6.92(s,1H),6.87(s,1H),6.77(s,1H),4.95(q ,J＝7.2Hz,1H),3.92-3.83(m,2H),3.57-3.48(m,1H),3.40-3.33(m,1H),3.10-3.05(m,1H),2.44(s,6H ),2.41-2.34(m,1H),2.07-1.93(m,1H),1.57(d,J=7.2Hz,3H).(99.28%purity by HPLC)

Example 26

1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-(3-(dimethylamino)pyrrolidin-1-yl) Pyrido[3,4-d]pyridazin-4(3H)-one 26

Compound 15h (60mg, 0.16mmol) was dissolved in dimethyl sulfoxide (0.5mL), and compound 25c (56mg, 0.49mmol) and N,N-diisopropylethylamine (84mg, 0.65mmol) were added at room temperature, Raise the temperature to 80°C and stir overnight, TLC disappears and the starting material disappears. The reaction solution was added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 26 (25 mg, yield 34%) as a gray solid.

LC-MS: m/z=447.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.00(s, 1H), 7.56(t, J=7.6Hz, 1H), 7.43(t, J=6.8Hz, 1H), 7.20(t, J=8.0 Hz,1H),7.11-6.84(m,2H),5.30(q,J＝6.8Hz,1H),4.04-3.99(m,1H),3.91-3.87(m,1H),3.63-3.50(m, 2H),3.41-3.38(m,1H),2.62(s,6H),2.52-2.45(m,1H),2.17-2.07(m,1H),1.62(d,J=7.2Hz,3H).( 99.44%purity by HPLC)

Example 27

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylpyrrolidin-3-yl)pyrido[3 ,4-d]pyridazin-4(3H)-one 27

The first step (R)-3-(1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydro Pyrido[3,4-d]pyridazin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 27b

Intermediate IN-3 (100mg, 0.24mmol) was dissolved in 1,4-dioxane (5mL) and water (1mL), and 1-tert-butoxycarbonyl-2,5-dihydro-1H- Pyrrole-3-boronic acid pinacol ester 27a (85mg, 0.29mmol), sodium carbonate (76mg, 0.72mmol) and Pd(dppf)Cl ₂ dichloromethane complex (20mg, 0.024mmol), after nitrogen replacement 3 times , heated to 100° C. for 3 hours, and TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, added water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, the crude product was purified by silica gel column chromatography to obtain the title compound 27b (115mg, yield 87% ).

LC-MS: m/z=547.3[M+H] ⁺

The second step 3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydropyridine [3,4-d]pyridazin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 27c

Compound 27b (115mg, 0.21mmol) was dissolved in ethyl acetate (10mL), palladium/carbon (20mg, 10%) was added at room temperature, and reacted at 50°C for 8 hours under a hydrogen atmosphere, and the raw material was completely reacted by LCMS. The reaction solution was cooled to room temperature, filtered with celite, the filter cake was washed, and the filtrate was concentrated to obtain the title compound 27c (100 mg, crude product) as a yellow solid, which was directly used in the next step.

LC-MS: m/z=519.3[M+H] ⁺

The third step 3-(1-(((R)-1-(3-acetylamino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydro Pyrido[3,4-d]pyridazin-7-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 27d

Compound 27c (100mg, crude product) was dissolved in dichloromethane (10mL), N,N-diisopropylethylamine (65mg, 0.50mmol) and acetic anhydride (38mg, 0.37mmol) were added at room temperature, heated to 30°C After 4 hours of reaction, TLC detected that the reaction of the raw materials was basically complete. The reaction solution was cooled to room temperature, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 27d as a yellow solid (50mg, two-step yield 42%) .

The fourth step N-(3-((1R)-1-((4-oxo-7-(pyrrolidin-3-yl)-3,4-dihydropyrido[3,4-d]pyridazine -1-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 27e

Compound 27d (50mg, 0.096mmol) was dissolved in dichloromethane (2mL), added trifluoroacetic acid (1mL), reacted at room temperature for 2 hours, TLC detected that the reaction of the starting material was complete. The reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 27e (38 mg, crude product) as a yellow solid, which was directly used in the next step.

The fifth step N-(3-((1R)-1-((7-(1-methylpyrrolidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4- d] pyridazin-1-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) acetamide 27f

Compound 27e (38 mg, crude product) was dissolved in methanol (3 mL), added formaldehyde aqueous solution (3d) and palladium/carbon (15 mg, 10%), and reacted at room temperature under hydrogen atmosphere for 2 hours, and TLC detected that the raw materials were almost completely reacted. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain the title compound 27f (54 mg, crude product), which was directly used in the next step.

The sixth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-(1-methylpyrrolidin-3-yl)pyridine And[3,4-d]pyridazin-4(3H)-one 27

Compound 27f (54mg, crude product) was dissolved in ethanol (3mL), and aqueous sodium hydroxide solution (3mL, 12mmol, 4M) was added at room temperature, heated to 80°C for overnight reaction, and the reaction was almost complete as detected by TLC. The reaction solution was cooled to room temperature, added with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 27 as a light yellow solid (8mg, three-step yield 19%).

LC-MS: m/z=433.2[M+H] ⁺

¹ HNMR (400MHz, CD ₃ OD) δ9.43(s,1H),8.07(s,1H),6.93(s,2H),6.77(s,1H),4.95(q,J＝6.8Hz,1H) ,4.05-3.75(m,1H),3.40-3.36(m,1H),3.12-3.06(m,3H),2.63(s,3H),2.59-2.42(m,1H),2.27-2.22(m, 1H), 1.58 (d, J=6.8Hz, 3H). (97.64% purity by HPLC)

Example 28

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-7-(1-methylpiperidin-3-yl ) pyrido[3,4-d]pyridazin-4(3H)-one 28

The first step (R)-5-(3-methyl-1-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3 ,4-dihydropyrido[3,4-d]pyridazin-7-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate 28a

Compound 4a (200mg, 0.47mmol) and 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester 17a (217mg, 0.70mmol) were dissolved in 1,4-dioxahexa Pd(dppf)Cl ₂ dichloromethane complex (18mg, 0.022mmol) and sodium carbonate (148mg, 1.40mmol) were added to ring (15mL) and water (3mL) at room temperature, heated to 100°C and stirred for 1 hour, TLC detects that the reaction is complete. The reaction solution was cooled to room temperature, added water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 28a (282 mg, crude product) as a yellow solid, which was directly used in in the next step.

LC-MS: m/z=575.3[M+H] ⁺

The second step 3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-4-oxo-3, tert-butyl 4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate 28b

Compound 28a (282mg, crude product) was dissolved in ethyl acetate (10mL), palladium/carbon (100mg, 10%) was added, and reacted overnight at 50°C under a hydrogen atmosphere, and the reaction of the starting material was detected by LCMS. The reaction solution was cooled to room temperature, filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain the title compound 28b (290 mg, crude product) as a yellow solid, which was directly used in the next step.

LC-MS: m/z=547.3[M+H] ⁺

The third step 3-(1-(((R)-1-(3-acetylamino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-4-oxo-3 ,4-Dihydropyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate tert-butyl ester 28c

Compound 28b (290mg, crude product) was dissolved in dichloromethane (3mL), acetic anhydride (81mg, 0.79mmol) and triethylamine (107mg, 1.06mmol) were added at room temperature, and the temperature was raised to 30°C for 4 hours. TLC showed that the starting material The response is over. The reaction solution was concentrated, and the crude product was subjected to Prep-TLC to obtain the title compound 28c (152 mg, three-step yield 55%) as a pale yellow solid.

LC-MS: m/z=589.3[M+H] ⁺

The fourth step N-(3-((1R)-1-((3-methyl-4-oxo-7-(piperidin-3-yl)-3,4-dihydropyrido[3,4 -d] pyridazin-1-yl) amino) ethyl) -5- (trifluoromethyl) phenyl) acetamide 28d

Compound 28c (152 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), added trifluoroacetic acid (2 mL), and reacted at room temperature for 2 hours. TLC showed that the reaction of the starting material was complete. The reaction solution was adjusted to alkaline by adding saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 28d (143 mg, crude product) as a yellow solid, which was directly used in the next step .

The fifth step N-(3-((1R)-1-((3-methyl-7-(1-methylpiperidin-3-yl)-4-oxo-3,4-dihydropyrido [3,4-d]pyridazin-1-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 28e

Compound 28d (143mg, crude product) was dissolved in methanol (5mL), added formaldehyde aqueous solution (71mg, 0.87mmol, 37%) and palladium/carbon (70mg, 10%), and reacted at room temperature under hydrogen atmosphere for 2 hours, TLC showed that the raw materials reacted over. The reaction solution was filtered with celite, the filter cake was washed with methanol, and the filtrate was concentrated to obtain the title compound 28e (190 mg, crude product) as a yellow oil, which was directly used in the next step.

LC-MS: m/z=503.3[M+H] ⁺

The sixth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-3-methyl-7-(1-methylpiperidine- 3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 28

Compound 28e (190mg, crude product) was dissolved in methanol (4mL), and aqueous sodium hydroxide solution (1.89ml, 7.56mmol, 4N) was added at room temperature, and heated to 80°C for overnight reaction. TLC showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, added water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 28 as a white solid (47mg, three-step yield 39% ).

LC-MS: m/z=461.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.41(s, 1H), 8.07(s, 1H), 6.97(s, 2H), 6.78(s, 1H), 4.96(q, J=6.8Hz, 1H ),3.56(s,3H),3.38-3.26(m,2H),3.15-3.08(m,1H),2.82-2.65(m,1H),2.55(s,3H),2.50-2.36(m,1H ),2.16-2.07(m,1H),1.99-1.70(m,3H),1.60(d,J=7.2Hz,3H).(99.78%purity by HPLC)

Example 29

4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylpiperidin-3-yl)phthalazine-1 (2H)-Kone 29

The first step (R)-5-(4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-1,2-dihydro Phthalazin-6-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate 29a

Intermediate IN-2 (300mg, 0.66mmol) and 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester 17a (325mg, 1.05mmol) were dissolved in 1,4- To dioxane (6mL) and water (2mL), sodium carbonate (150mg, 1.42mmol) and Pd(dppf)Cl ₂ (58mg, 0.08mmol) were added successively at room temperature, replaced by nitrogen several times, and the temperature was raised to 100°C and stirred After 1 hour, TLC showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column to obtain the title compound 29a (260 mg, yield 70%) as a yellow solid.

LC-MS: m/z=560.3[M+H] ⁺

The second step 3-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-1,2-dihydrophthalide Azin-6-yl)piperidine-1-carboxylate tert-butyl ester 29b

Compound 29a (250mg, 0.45mmol) was dissolved in ethyl acetate (8mL), palladium/carbon (60mg, 10%) was added, and the mixture was heated to 50°C under hydrogen atmosphere and stirred overnight. The reaction solution was filtered with Celite, the filter cake was washed several times with methanol, the filtrate was concentrated, and the crude product was purified by silica gel column to obtain the title compound 29b (210 mg, yield 88%) as a white solid.

LC-MS: m/z=532.3[M+H] ⁺

The third step 3-(4-(((R)-1-(3-acetylamino-5-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-1,2-dihydro Phthalazin-6-yl)piperidine-1-carboxylate tert-butyl ester 29c

Compound 29b (210mg, 0.40mmol) was dissolved in dichloromethane (5mL), N,N-diisopropylethylamine (102mg, 0.79mmol) and acetic anhydride (61mg, 0.60mmol) were added successively at room temperature, and the temperature was raised to After stirring at 30°C for 5 hours, TLC showed that the reaction was almost complete. The reaction solution was diluted with water, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 29c (250 mg, crude product) as a white solid, which was directly used in the next step.

LC-MS: m/z=574.3[M+H] ⁺

The fourth step N-(3-((1R)-1-((4-oxo-7-(piperidin-3-yl)-3,4-dihydrophthalazin-1-yl)amino)ethyl )-5-(trifluoromethyl)phenyl)acetamide 29d

Compound 29c (250 mg, crude product) was dissolved in dichloromethane (5 mL), added trifluoroacetic acid (2 mL), stirred at room temperature for 1 hour, TLC showed that the reaction was complete. The reaction solution was concentrated, and the pH was adjusted to be weakly alkaline with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound 29d (200 mg, crude product) as a white solid, which was directly used in in the next step.

LC-MS: m/z=474.3[M+H] ⁺

The fifth step N-(3-((1R)-1-((7-(1-methylpiperidin-3-yl)-4-oxo-3,4-dihydrophthalazin-1-yl) Amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 29e

Compound 29d (200mg, crude product) was dissolved in methanol (4mL), and aqueous formaldehyde (127mg, 1.56mmol, 37%) and palladium/carbon (50mg, 10%) were added successively, and stirred overnight at room temperature under hydrogen atmosphere, TLC showed that the reaction was complete . The reaction solution was filtered with Celite, the filter cake was washed with methanol, and the filtrate was concentrated to give the title compound 29e (200 mg, crude product) as a white solid, which was directly used in the next step.

LC-MS: m/z=488.3[M+H] ⁺

The sixth step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-(1-methylpiperidin-3-yl)phthalein Azin-1(2H)-one 29

Compound 29e (200mg, crude product) was dissolved in ethanol (6mL), and aqueous sodium hydroxide solution (3mL, 15mmol, 5M) was added at room temperature, and heated to reflux overnight. The reaction solution was concentrated, diluted with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC to obtain the title compound 29 (37 mg, yield 21% in four steps) as a yellow solid ).

LC-MS: m/z=446.3[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ11.43(s, 1H), 8.21(s, 1H), 8.13(d, J=8.4Hz, 1H), 7.73(dd, J=8.4, 0.8Hz, 1H), 6.92(d, J=6.8Hz, 1H), 6.80(d, J=6.0Hz, 2H), 6.66(s, 1H), 5.50(s, 2H), 4.92-4.85(m, 1H), 3.03-2.85(m,3H),2.25(s,3H),2.13-1.84(m,3H),1.80-1.76(m,1H),1.71-1.58(m,2H),1.50(d,J＝7.2 Hz,3H).(98.90%purity by HPLC)

Example 30

4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(1-methylpiperidin-3-yl ) Phthalazin-1(2H)-one 30

The first step (R)-5-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)-1-oxo-1 ,2-dihydrophthalazin-6-yl)-3,6-dihydropyridine-1(2H)-tert-butyl carboxylate 30a

Compound 2a (200mg, 0.42mmol) and 1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridine-5-boronic acid pinacol ester 17a (197mg, 0.64mmol) were dissolved in 1,4-dioxahexa Ring (15mL) and water (3mL), add Pd(dppf)Cl ₂ dichloromethane complex (18mg, 0.022mmol) and sodium carbonate (90mg, 0.85mmol) at room temperature, raise the temperature to 100°C under nitrogen protection and stir After 1 hour, TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, added with water, extracted with ethyl acetate, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain the title compound 30a (240 mg, yield 99%).

LC-MS: m/z=574.3[M+H] ⁺

The second step 3-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-1-oxo-1, 2-dihydrophthalazin-6-yl)piperidine-1-carboxylate tert-butyl ester 30b

Compound 30a (240mg, 0.42mmol) was dissolved in tetrahydrofuran (10mL) and ethyl acetate (6mL), palladium/carbon (catalytic amount) was added at room temperature, and the temperature was raised to 50°C under hydrogen atmosphere to react overnight, and TLC detected that the reaction was complete. The reaction solution was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated to obtain the title compound 30b (240 mg, crude product), which was directly used in the next step.

LC-MS: m/z=546.3[M+H] ⁺

The third step 3-(4-(((R)-1-(3-acetylamino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-1-oxo-1 ,2-Dihydrophthalazin-6-yl)piperidine-1-carboxylate tert-butyl ester 30c

Compound 30b (240mg, crude product) and N,N-diisopropylethylamine (108mg, 0.84mmol) were dissolved in 1,4-dioxane (60mL), added acetic anhydride (64mg, 0.63mmol), room temperature After stirring overnight, TLC detected that the reaction was complete. Add water to the reaction solution, extract with dichloromethane, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the title compound 30c (270 mg, crude product), which is directly used in the next step.

The fourth step N-(3-((1R)-1-((3-methyl-4-oxo-7-(piperidin-3-yl)-3,4-dihydrophthalazin-1-yl )amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 30d

Compound 30c (270 mg, crude product) was dissolved in dichloromethane (2 mL), added trifluoroacetic acid (2 mL), stirred at room temperature for 2 hours, and the reaction was complete as detected by TLC. The reaction solution was concentrated, the residue was neutralized with saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 30d (220 mg, crude product), which was directly used in the following step.

LC-MS: m/z=488.3[M+H] ⁺

The fifth step N-(3-((1R)-1-((3-methyl-7-(1-methylpiperidin-3-yl)-4-oxo-3,4-dihydrophthalazine -1-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 30e

Compound 30d (125 mg, crude product) and formaldehyde aqueous solution (62 mg, 0.76 mmol, 37%) were dissolved in methanol (15 mL), palladium/carbon (catalytic amount) was added, and the reaction was carried out at room temperature under hydrogen atmosphere for 2 hours, and the reaction was complete by TLC. The reaction liquid was filtered, and the filtrate was concentrated to obtain the title compound 30e (130 mg, crude product), which was directly used in the next step.

LC-MS: m/z=502.3[M+H] ⁺

The sixth step 4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-6-(1-methylpiperidine- 3-yl)phthalazin-1(2H)-one 30

Compound 30e (130mg, crude product) was dissolved in ethanol (6mL), sodium hydroxide (103mg, 2.58mmol) was added at room temperature, and the temperature was raised to 90°C to react overnight. The reaction of the starting material was basically complete as detected by TLC. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain the title compound 30 (40 mg, 36% yield over five steps).

LC-MS: m/z=460.3[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ8.24 (d, J = 8.4Hz, 1H), 8.11 (d, J = 1.2Hz, 1H), 7.72 (dd, J = 1.2, 8.0Hz, 1H), 7.00-6.97(m,2H),6.78(s,1H),5.00(q,J＝7.2Hz,1H),3.56(s,3H),3.14-3.03(m,3H),2.44(s,3H) ,2.41-2.33(m,1H),2.27-2.19(m,1H),2.02-1.99(m,1H),1.95-1.89(m,1H),1.88-1.76(m,1H),1.71-1.64( m,1H),1.60(d,J＝6.8Hz,3H).(98.98%purity by HPLC)

Example 31

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((R)-1-methylpiperidin-3-yl) Pyrido[3,4-d]pyridazin-4(3H)-one 31-1

1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((S)-1-methylpiperidin-3-yl) Pyrido[3,4-d]pyridazin-4(3H)-one 31-2

The first step (R)-5-(1-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydropyridine [3,4-d]pyridazin-7-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester 31a

Compound 17b (260mg, 0.46mmol) was dissolved in ethanol (10mL) and water (3mL), and reduced iron powder (129mg, 2.31mmol) and ammonium chloride (125mg, 2.31mmol) were added at room temperature, and heated to 90°C for reaction 3 After 1 hour, TLC showed that the starting material was completely reacted. The reaction solution was filtered with Celite, the filtrate was added with water (10 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 31a (296 mg, crude product), used directly in the next step.

The second step (R)-3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4 -Dihydropyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester 31b-1&(S)-3-(1-(((R)-1-( 3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidine -1-tert-butyl carboxylate 31b-2

Compound 31a (290 mg, crude product) was dissolved in ethanol (5 mL), and palladium/carbon (50 mg, 10%) was added, and reacted at room temperature under hydrogen atmosphere for 5 hours. TLC showed that the starting material was completely reacted. The reaction solution was filtered with celite, and the filtrate was concentrated to obtain the title compound 31b (120mg, two-step yield 46%) as a yellow solid. EtOH:Hexane=1:9) gave the title compound 31b-1 (peak No. 1, RT 15.577min) (40 mg, yield 33%) as a pale yellow solid and title compound 31b-2 (peak No. 2, RT 19.628 min) as a pale yellow solid min) (41 mg, yield 34%).

The configuration and properties of the compounds need to be further tested, and 31b-1 and 31b-2 are tentatively determined to be the above configurations.

The third step (R)-3-(1-(((R)-1-(3-acetylamino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3, tert-butyl 4-dihydropyrido[3,4-d]pyridazin-7-yl)piperidine-1-carboxylate 31c-1&(S)-3-(1-(((R)-1- (3-Acetamido-5-(trifluoromethyl)phenyl)ethyl)amino)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-7-yl) tert-butyl piperidine-1-carboxylate 31c-2

Compound 31b-1 (40mg, 0.075mmol) was dissolved in tetrahydrofuran (6mL), N,N-diisopropylethylamine (58mg, 0.45mmol) and acetic anhydride (30mg, 0.30mmol) were added at room temperature, heated to 35 The reaction was carried out at ℃ for 16 hours, and TLC showed that the reaction of the starting material was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL), combined organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 31c-1 (75 mg, crude product) as a yellow solid, which was directly used in in the next step.

Compound 31b-2 (41mg, 0.076mmol) was dissolved in tetrahydrofuran (6mL), N,N-diisopropylethylamine (59mg, 0.46mmol) and acetic anhydride (31mg, 0.31mmol) were added at room temperature, heated to 35 The reaction was carried out at ℃ for 16 hours, and TLC showed that the reaction of the starting material was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL), combined organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give the title compound 31c-2 (75 mg, crude product) as a yellow solid, which was directly used in in the next step.

LC-MS: m/z=575.3[M+H] ⁺

The configuration and properties of the compounds need to be further tested, and 31c-1 and 31c-2 are tentatively determined to be the above configurations.

The fourth step N-(3-((R)-1-((4-oxo-7-((R)-piperidin-3-yl)-3,4-dihydropyrido[3,4- d] pyridazin-1-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 31d-1&N-(3-((R)-1-((4-oxo-7 -((S)-piperidin-3-yl)-3,4-dihydropyrido[3,4-d]pyridazin-1-yl)amino)ethyl)-5-(trifluoromethyl) Phenyl)acetamide 31d-2

Compound 31c-1 (75 mg, crude product) was dissolved in dichloromethane (2 mL), added trifluoroacetic acid (2 mL), and reacted at room temperature for 2 hours. TLC showed that the starting material was completely reacted. The reaction solution was adjusted to pH = 8-9 by adding saturated aqueous sodium bicarbonate (15 mL) dropwise, extracted with ethyl acetate (10 mL), combined the organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow solid title Compound 31d-1 (67 mg, crude product) was directly used in the next step.

Compound 31c-2 (75 mg, crude product) was dissolved in dichloromethane (2 mL), added trifluoroacetic acid (2 mL), and reacted at room temperature for 2 hours. TLC showed that the starting material was completely reacted. The reaction solution was adjusted to pH = 8-9 by adding saturated aqueous sodium bicarbonate (15 mL) dropwise, extracted with ethyl acetate (10 mL), combined the organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to give a yellow solid title Compound 31d-2 (50 mg, crude product) was directly used in the next step.

The configuration and properties of the compounds need to be further tested, and 31d-1 and 31d-2 are tentatively determined to be the above configurations.

The fifth step N-(3-((R)-1-((7-((R)-1-methylpiperidin-3-yl)-4-oxo-3,4-dihydropyrido[ 3,4-d]pyridazin-1-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)acetamide 31e-1&N-(3-((R)-1-((7- ((S)-1-methylpiperidin-3-yl)-4-oxo-3,4-dihydropyrido[3,4-d]pyridazin-1-yl)amino)ethyl)- 5-(Trifluoromethyl)phenyl)acetamide 31e-2

Compound 31d-1 (67 mg, crude product) was dissolved in ethanol (3 mL), added formaldehyde aqueous solution (35 mg, 0.43 mmol, 30%), palladium/carbon (20 mg, 10%), and reacted at room temperature under hydrogen atmosphere for 4 hours, TLC showed Raw materials are reacted. The reaction solution was filtered through Celite, and the filtrate was concentrated to give the title compound 31e-1 (70 mg, crude product) as a yellow solid, which was directly used in the next step.

Compound 31d-2 (50 mg, crude product) was dissolved in ethanol (3 mL), added formaldehyde aqueous solution (35 mg, 0.43 mmol, 30%), palladium/carbon (20 mg, 10%), and reacted at room temperature under hydrogen atmosphere for 4 hours, TLC showed Raw materials are reacted. The reaction solution was filtered through Celite, and the filtrate was concentrated to give the title compound 31e-2 (60 mg, crude product) as a yellow solid, which was directly used in the next step.

The configuration and properties of the compounds need to be further tested, and 31e-1 and 31e-2 are tentatively determined to be the above configurations.

The sixth step 1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-((R)-1-methylpiperidine-3 -yl)pyrido[3,4-d]pyridazin-4(3H)-one 31-1&1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl Base)amino)-7-((S)-1-methylpiperidin-3-yl)pyrido[3,4-d]pyridazin-4(3H)-one 31-2

Compound 31e-1 (70mg, crude product) was dissolved in methanol (3mL), and aqueous sodium hydroxide solution (2mL, 8mmol, 4N) was added at room temperature, heated to 70°C for 16 hours, and TLC showed that the starting material was completely reacted. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL), combined organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (dichloromethane/ammonia methanol solution=10/1) to obtain the title compound 31-1 (15 mg, 45% yield in four steps) as a light yellow solid.

LC-MS: m/z=447.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.43(s, 1H), 8.13(s, 1H), 6.96-6.89(m, 2H), 6.79-6.75(m, 1H), 4.96(q, J= 6.8Hz,1H),3.49-3.39(m,2H),3.28-3.20(m,1H),3.18-2.99(m,1H),2.83-2.62(m,4H),2.24-2.12(m,1H) , 2.03-1.82(m,3H),1.58(d,J＝6.8Hz,3H).(96.67%purity by HPLC)

Compound 31e-2 (60mg, crude product) was dissolved in methanol (3mL), and aqueous sodium hydroxide solution (2mL, 8mmol, 4N) was added at room temperature, and heated to 70°C for 16 hours. TLC showed that the reaction of the starting material was complete. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL), combined organic phases, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by Prep-TLC (dichloromethane/ammonia methanol solution=10/1) to obtain the title compound 31-2 (13 mg, 37% yield in four steps) as a pale yellow solid.

LC-MS: m/z=447.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD) δ9.41(s, 1H), 8.09(s, 1H), 6.98-6.88(m, 2H), 6.81-6.73(m, 1H), 4.95(q, J= 6.8Hz,1H),3.30-3.20(m,2H),3.13-3.01(m,1H),2.75-2.58(m,1H),2.51(s,3H),2.44-2.28(m,1H),2.16 -2.05(m,1H),1.97-1.71(m,3H),1.58(d,J＝6.8Hz,3H).(99.69%purity by HPLC)

The configuration and properties of the compounds need to be further tested, and 31-1 and 31-2 are tentatively determined to be the above configurations.

Test Example 1 Determination of IC ₅₀ of Compounds Inhibiting K-562 Cell Proliferation

Human chronic myelogenous leukemia cells K-562 (CCL-243) used in the present invention were purchased from American Type Culture Collection (ATCC). The cells were grown in RPMI 1640 medium with 10% fetal bovine serum (FBS) and 1% double antibody at 37°C in an environment of 5% CO ₂ .

The inhibitory effect of the compound on the proliferation of K-562 cells cultured in vitro was determined by the following method:

1) Cell inoculation: K-562 cells in good logarithmic growth phase were inoculated into 96-well plates at 20,000 cells/well, 90 μL, and cultured at 37° C., 5% CO ₂ for 24 hours.

2) Dosing: gradiently dilute the compound to be tested with complete medium, take 10 μL of the diluted compound and add it to 90 μL of cells, so that the final concentration of the compound is 10000, 3000, 1000, 300, 100, 30, 10, 3 , 1nM, and a corresponding solvent control was set at the same time. Place in a 37°C, 5% CO ₂ cell culture incubator for 96 hours.

3) Detection: add 10 μL 5mg/mL MTT working solution (ABCONE, M9609) to each well, and after 4 hours at 37°C, add triple solution (10% SDS, 0.5% isopropanol, 0.1mol/L HCL) to the cells The lysate was completely dissolved, and the OD570 and OD690 values were read using a TECAN SPARK microplate reader.

4) Calculation: Calculate the cell growth inhibition rate with the following formula:

Inhibition rate = (control well _{OD570nm-OD690nm} - drug administration well _{OD570nm-OD690nm} ) / control well _{OD570nm-OD690nm} × 100%

_IC50 values were calculated based on compound concentrations and corresponding inhibition rates using Graphpad prism 5.0 software. The test results are shown in Table 1.

Table 1 IC ₅₀ (nM) of the compounds of the present invention on K-562 cell proliferation inhibition

Compound number IC ₅₀ (nM) Compound number IC ₅₀ (nM) Compound number IC ₅₀ (nM) BI3406 35.2 11 1619 twenty two 107.7 1 735.7 12 134 twenty three 142.8 2 822.7 13 104 twenty four 231.9 3 111.1 14 362.3 25 125.9 4 150.8 15 279.25 26 137.6 5 44.7 16 43.8 27 91.3 6 2489 17 33.1 28 66.65 7 5917 18 60.0 29 51.0 8 1599 19 63.4 30 143.9 9 988 20 39.3 31-1 43.4 10 121.4 twenty one 97.7 31-2 13.1

Conclusion: As shown in Table 1, the compounds of the examples of the present invention have a proliferation inhibitory effect on K-562 cells, and the activity of several compounds is equivalent to that of BI-3402.

Test Example 2 Effects of Compounds on the Phosphorylation Level of KRAS Downstream Signaling Molecule ERK1/2 in K-562 Cells

The impact of the compound of the present invention on the phosphorylation level of ERK1/2 in K-562 cells is detected by the following method:

1) Cell inoculation: K-562 cells in good logarithmic growth phase were inoculated into a six-well plate at 1*10 ⁶ /well, and cultured overnight at 37°C and 5% CO2.

2) Dosing: After the compound to be tested is serially diluted with complete medium, it is added to the cells so that the final concentration of the compound is 1000, 100, 10, 1 nM. Place in a 37°C, 5% CO ₂ cell culture incubator for 24 hours.

3) Protein sample preparation: collect the cell suspension, centrifuge at 500g for 5 minutes, discard the supernatant, wash 3 times with PBS, and wash with 1×SDS gel loading buffer (50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue) 100 μL to lyse the cells. Cell lysates were denatured by heating at 100°C for 10 minutes.

4) Western blot: SDS-PAGE electrophoresis is performed on the protein sample. After the electrophoresis, the protein is transferred to the PVDF membrane with a wet transfer system, and the PVDF membrane is placed in a blocking solution (5% skimmed milk powder diluted in TBS/T) and blocked at room temperature 1 hour, then I, II anti-reaction; after washing the membrane, use Immobilon Western HRP Substrate luminal reagent to develop color, and take pictures with a Western Blot imager (Tanon, 4600). The following is the information of the antibodies used: p-ERK1/2(CST:4370); ERK1/2(CST:9102); β-tubulin(CST:2146); GAPDH(CST:5174). The results of the compound's effect on the phosphorylation level of ERK1/2 in K-562 cells are shown in Figure 1 and Figure 2 .

Conclusion: Compounds 5, 20, 31-1, and 31-2 in the examples of the present invention have obvious inhibitory effect on the phosphorylation of ERK1/2 in K-562 cells; the inhibitory activity is concentration-gradient dependent; overall, the activity is similar to that of BI-3406 About the same.

Test Example 3 Inhibitory Activity of Compounds on SOS1

Experimental steps:

1. Compound treatment: Prepare the compound at 400-fold final concentration, if the final detection concentration is 5uM, prepare the compound at 400-fold concentration, ie 2mM. Use an automatic microwell pipette to dilute the compound gradient to the number of concentration points set.

2. Transfer the compound to the 384-well reaction plate: transfer 50nL of the above-mentioned diluted compound from the Echo 384-well plate to the 384-well reaction plate with an ultrasonic nanoliter liquid handling system, and transfer 100% of 50nL of the negative control and positive control DMSO.

3. Prepare and transfer 4 times Tag1-SOS1 solution: use Diluent provided in the kit (KRAS-G12C/SOS1BINGDING ASSAY KIT (Cisbio, Cat. No. 63ADK000CB16PEG)) to prepare 4 times Tag1-SOS1 solution, transfer 5ul to 384 wells In the reaction plate, for the negative control wells, transfer 5ul Diluent enzyme replacement solution and centrifuge at 1000rpm for 1 minute.

4. Prepare 4 times Tag2-KRAS G12C solution: Prepare 4 times Tag2-KRAS G12C solution with Diluent provided in the kit, transfer 5ul to a 384-well reaction plate, and centrifuge at 1000rpm for 1 minute.

5. Transfer 2 times detection solution solution: Prepare 2 times Anti-Tag1-Tb3+ and Anti-Tag2-XL665 solution with the Detection Buffer provided in the kit, transfer 10ul to a 384-well reaction plate, centrifuge at 1000rpm for 1 minute, and incubate at room temperature 60 minutes.

6. Reading: Read the data fluorescence signal value (Ex665/Em615) with a microplate reader Envision.

7. Inhibition rate calculation and IC50 fitting

Replicate the values from the plate reader, where the maximum value refers to the reading of the positive control and the minimum value refers to the reading of the negative control. Inhibition rate (%)=(maximum value-sample value)/(maximum value-minimum value)×100%.

Import the data into MS Excel and fit the IC50 value with XLFit excel add-in version5.4.0.8;

Table 2 Inhibitory activity of compounds on SOS1

Compound number IC ₅₀ (nM) Compound number IC ₅₀ (nM) Compound number IC ₅₀ (nM) 3 15 4 13 5 7.6 10 16 12 9.7 13 7.8 14 18 15 14 16 8.0 17 7.7 18 12 19 6.8 20 6.0 twenty one 20 twenty two 29 twenty three 5.4 twenty four 18 25 11 26 30 28 12 29 14 30 twenty three

Test Example 4 Stability experiment of compounds on mouse and human liver microsomes

Experimental steps:

(1). Take out the liver microsomes (20 mg protein/mL) from the -80°C refrigerator, place them on a 37°C water bath constant temperature shaker, and incubate for 3 minutes before melting.

(2). Prepare the mixed solution of the incubation system (without β-NADPH) according to the proportions of the "composition of the experimental incubation system" above.

(3). Prepare a 100 μM working solution of the test compound and set aside.

(4). Control group (without β-NADPH): Add 25 μL of PB solution to 75 μL of the incubation system mixture described in (2), vortex for 30 seconds, mix well, and make a duplicate sample with a total reaction volume of 100 μL. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing, and the sampling time points are 0min and 60min.

(5). Sample group: Add 25 μL of β-NADPH solution (4 mM) to 75 μL of the reaction system described in (2), vortex for 30 s, mix well, and make a duplicate sample with a total reaction volume of 100 μL. Put it into a 37°C water bath constant temperature shaker for incubation, and start timing. The sampling time points are 0min, 5min, 15min, 30min, and 60min.

(6). Take out the sample tube at each time point, and add 300 μL of cold terminator (including internal standard) to terminate the reaction.

(7). Vortex and centrifuge.

(8). Take 150 μL of supernatant and add 150 μL of water, vortex and mix well, and inject into LC-MS/MS for analysis.

Data Analysis: Calculate the half-life (t _1/2 ) and clearance (CL) using the following first-order kinetic formula

C _t ＝C ₀ *e ^-kt

C _t =(1/2)*C ₀

t _1/2 = ln2/k = 0.693/k

CL=V _d *k

Vd=1/protein content in liver microsomes

CL _int(liver) = CL _int(mic) × liver weight to body weight ratio × liver microsomal protein concentration per gram of liver

The parameters in the formula are shown in Table 3:

Table 3 Common parameters of mouse, rat, human liver and blood

The experimental results are shown in Table 4:

Table 4 Liver microsomal stability of compounds in different species

In the human liver microsome stability experiment, it can be seen that the stability of human microsomes of many compounds is comparable to that of BI-3406, and the stability of mouse liver microsomes is superior to that of BI-3406, which is more conducive to drug research.

Mouse pharmacokinetic properties of test example 5 compound

The compound of Example 20 (10 mg/kg) was orally administered to overnight fasted ICR mice (female, n=3). Blood samples were collected before administration and at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours and 8 hours after administration, and centrifuged (4500 rpm) at 4°C for 10 minutes to obtain serum. 100 μL of MeOH/ACN (1:1, v/v) was added to 10 μL of serum to precipitate the mixture, then vortexed for 1 min, and then centrifuged (11000 rpm) for 5 min to obtain the supernatant. 20 μL of the supernatant was dissolved in 20 μL of ACN/H ₂ O (1:1, v/v) and analyzed by ultra-high performance liquid chromatography. The results are shown in Table 5:

Table 5 Pharmacokinetic characteristics of compound 20 in mice

It can be seen from Table 5 that Compound 20 has a better plasma exposure in mice.

The applicant declares that the present invention illustrates a polycyclic pyridazinone derivative as an SOS1 inhibitor of the present invention and its preparation method and application through the above examples, but the present invention is not limited to the above examples, that is, not It means that the present invention can only be implemented depending on the above-mentioned embodiments. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention. These simple modifications All belong to the protection scope of the present invention.

In addition, it should be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable way if there is no contradiction. The combination method will not be described separately.

Claims (12)

A polycyclic pyridazinone derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, It is characterized in that the structure of the polycyclic pyridazinone derivatives is shown in formula (I): Wherein: R ¹ is selected from hydrogen or methyl; R ² is selected from C ₁ -C ₃ alkyl, -OR ²¹ , halogen, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, 6-10 membered condensed cycloalkyl, 7-10 membered bridge Cycloalkyl, 7-10-membered spirocycloalkyl, 4-7-membered heterocyclyl, 5-7-membered heterocycloalkenyl, 6-10-membered fused heterocyclyl, 7-10-membered bridged heterocyclyl , 7-10 membered spiroheterocyclyl, wherein 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, 6-10 membered condensed cycloalkyl, 7-10 membered bridged cycloalkyl, 7- 10-membered spirocycloalkyl, 4-7-membered heterocyclyl, 5-7-membered heterocycloalkenyl, 6-10-membered fused heterocyclyl, 7-10-membered bridged heterocyclyl, 7-10-membered Spiroheterocyclyl is optionally substituted by 1-3 R ²² ; R ²¹ is selected from H, C ₁ -C ₃ alkyl, 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, wherein C ₁ -C ₃ alkyl, 3-7 membered cycloalkyl, 4-7 A membered heterocyclyl is optionally substituted by 1-3 R ²² ; R ²² is selected from C ₁ -C ₃ alkyl, hydroxyl, halogen, cyano, -NR ^a R ^b , C ₁ -C ₃ alkoxy, -C(O)R ^a , -C(O)OR ^a , -OC(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b , phenyl, 5-6 membered heteroaryl and = O, wherein the alkyl, alkoxy, phenyl, 5-6 membered heteroaryl are optionally further replaced by 1-3 halogen, C ₁ -C ₃ alkyl, hydroxyl, cyano, amino and C ₁ - C ₃ alkoxy is substituted; R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ alkyl, substituted or unsubstituted 3-6 membered cycloalkyl or substituted or unsubstituted 4-7 membered heterocycle base; here "substituted" means optionally substituted by 1-3 substituents selected from C ₁ -C ₃ alkyl, hydroxyl, halogen, cyano, amino or alkoxy; Q is selected from N or -CR ³ ; R ³ is selected from H, C ₁ -C ₃ alkyl, halogen, cyano or -OR ²¹ ; AR is selected from 6-10 membered aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-4 R ^c ; R ^c is selected from H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ haloalkyl, 3-6 membered cycloalkane radical, 4-7 membered heterocyclic group, -OR ²¹ , -NR ^a R ^b , NR ^a R ^b -C ₁ -C ₄ alkyl, NR ^a R ^b -C ₁ -C ₄ haloalkyl, 6-10 member Aryl or 5-10-membered heteroaryl, wherein 6-10-membered aryl or 5-10-membered heteroaryl is optionally substituted by 1-4 R ^d ; R ^d is selected from H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxy-C ₁ -C ₄ alkyl, hydroxy-C ₁ -C ₄ haloalkyl, 3-6 membered cycloalkane Base, 4-7 membered heterocyclic group, -OR ²¹ , -NR ^a R ^b , NR ^a R ^b -C ₁ -C ₄ alkyl, NR ^a R ^b -C ₁ -C ₄ haloalkyl; The heterocyclic group, heteroaryl group, heterocycloalkenyl group, condensed heterocyclic group, bridging heterocyclic group, and spiroheterocyclic group in the formula (I) have 1-7 heteroatoms selected from oxygen, nitrogen One or more of , sulfur and S(O)m, m is 1 or 2. The polycyclic pyridazinone derivative, its pharmaceutically acceptable salt, its tautomer or its stereoisomer as claimed in claim 1, is characterized in that, The structure of the polycyclic pyridazinone derivatives is shown in formula (II): Wherein, R ¹ , R ² , Q and R ^c have the same defined range as in claim 1; n=1-4; Preferably, for the compound of formula (II), the phenyl group is optionally substituted by 1-3 R ^c , when the number of R ^c is 2-3, the R ^c can be the same or different; And/or, when said R ^c is a C ₁ -C ₄ haloalkyl group, the halogen atom is fluorine; And/or, when said R ^c is halogen, the halogen atom is fluorine; And/or, when said R ^c is -NR ^a R ^b , said R ^a and R ^b may be the same or different. The polycyclic pyridazinone derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof as claimed in claim 1 or 2, wherein the polycyclic pyridazinones The structure of the class derivative is shown in formula (III): Wherein, R ¹ , R ² and R ^c have the same limiting range as in claim 1; n=1-4; Preferably, for the compound of formula (III), when said R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when said R ²² is 2-3, R ²² the same or different; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heterocyclic group contains 1-2 heteroatoms; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the R ²² is selected from C ₁ -C ₃ alkyl, -NR ^a R ^b , -C(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b and =O. The polycyclic pyridazinone derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof as claimed in claim 1 or 2, wherein the polycyclic pyridazinones The structure of derivatives is as shown in formula (IV): Wherein, R ¹ , R ² , R ³ and R ^c have the same limitation range as in claim 1; n=1-4; Preferably, for the compound of formula (IV), when said R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when said R ²² is 2-3, R ²² the same or different; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heterocyclic group contains 1-2 heteroatoms; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the R ²² is selected from C ₁ -C ₃ alkyl, -NR ^a R ^b , -C(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b and =O; And/or, when the R ³ is -OR ²¹ , R ²¹ is selected from unsubstituted C ₁ -C ₃ alkyl or unsubstituted 3-7 membered cycloalkyl. The polycyclic pyridazinone derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers as claimed in claim 1, wherein the polycyclic pyridazinone derivatives The structure of thing is as shown in formula (V): Wherein, R ¹ , R ² , Q and R ^d have the same limited scope as claim 1; n=1-4; Preferably, for the compound of formula (V), when said R ^d is one -NR ^a R ^b , said R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ alkane base; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the R ²² is 2-3, R ²² is the same or different; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heterocyclic group contains 1-2 heteroatoms; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different; And/or, when the R ² is a 4-7 membered heterocyclic group optionally substituted by 1-3 R ²² , the R ²² is selected from C ₁ -C ₃ alkyl, -NR ^a R ^b , -C(O)R ^a , -NR ^b C(O)R ^a , -NR ^b C(O)OR ^a , -C(O)NR ^a R ^b and =O; And/or, when said R ² is -OR ²¹ , R ²¹ is a 4-7 membered heterocyclic group; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group is a 5-6 membered heterocyclic group; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heterocyclic group contains 1-2 heteroatoms; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, when the heterocyclic group has two heteroatoms, the two heteroatoms are the same or different. The polycyclic pyridazinone derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof as claimed in claim 1 or 5, wherein the polycyclic pyridazinones The structure of the class derivative is shown in formula (VI): Wherein, R ¹ , R ² and R ^d have the same limiting range as claim 1; n=1-4; Preferably, when the R ² is -OR ²¹ , the R ²¹ is a 4-7 membered heterocyclic group; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group is a 5-7 membered heterocyclic group; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heterocyclic group contains two heteroatoms; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the two heteroatoms are the same or different; And/or, the R ^d is selected from halogen, C ₁ -C ₄ alkyl, -NR ^a R ^b , -OR ²¹ , -NR ^a R ^b -C ₁ -C ₄ alkyl; And/or, when the R ^d is one -NR ^a R ^b -C ₁ -C ₄ alkyl, the R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ of alkyl. The polycyclic pyridazinone derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof as claimed in claim 1 or 5, wherein the polycyclic pyridazinones The structure of class derivative is shown in formula (VII): Wherein, R ¹ , R ² , R ³ and R ^d have the same limitation range as in claim 1; n=1-4; Preferably, when the R ² is -OR ²¹ , the R ²¹ is a 4-7 membered heterocyclic group; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the 4-7 membered heterocyclic group is a 5-7 membered heterocyclic group; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heteroatom of the heterocyclic group is nitrogen and/or oxygen; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the heterocyclic group contains two heteroatoms; And/or, when the R ²¹ is a 4-7 membered heterocyclic group, the two heteroatoms are the same or different; And/or, the R ^d is selected from halogen, C ₁ -C ₄ alkyl, -NR ^a R ^b , -OR ²¹ , NR ^a R ^b -C ₁ -C ₄ alkyl; And/or, when said R ^d is one NR ^a R ^b -C ₁ -C ₄ alkyl group, said R ^a and R ^b are independently selected from H, substituted or unsubstituted C ₁ -C ₃ alkyl. The polycyclic pyridazinone derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers as claimed in claim 1, wherein the polycyclic pyridazinone derivatives are selected from any of the following structures: A method for preparing polycyclic pyridazinone derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof as claimed in any one of claims 1-8, which is selected from One of the following two methods: method one, In the first step, the compound of general formula (I-A) and the compound of general formula (I-B) obtain the compound of general formula (I-8) through imine addition reaction; In the second step, the compound of general formula (I-8) and hydrazine hydrate obtain the compound of general formula (I-9) through imine addition and ring expansion reaction; In the third step, the compound of general formula (I-9) and the compound of general formula (I-10) are subjected to substitution reaction to obtain the compound of general formula (I-11); In the fourth step, the compound of general formula (I-11) and the compound of general formula (I-25) obtain the compound of general formula (I) through Buchwald/Suzuki reaction in the presence of a metal catalyst and a ligand under basic conditions. compound; Wherein, X, X ¹ are halogen, X is preferably bromine and chlorine, X ¹ is preferably iodine; W is H, Q, AR, ^R1 and ^R2 have the same defined scope as claim 1; when ^R1 is H, omit the third step. Method Two, In the first step, the compound of general formula (I-17) is subjected to substitution reaction to obtain the compound of general formula (I-18); In the second step, the compound of general formula (I-18) is deprotected under acidic conditions to obtain the compound of general formula (I-19); In the third step, the compound of general formula (I-19) and the compound of general formula (I-26) obtain the compound of general formula (I-20) under alkaline conditions; In the fourth step, the compound of general formula (I-20) is oxidized to obtain the compound of general formula (I-21); In the fifth step, the compound of general formula (I-21) obtains the compound of general formula (I-22) through Bouveault aldehyde synthesis reaction; The 6th step, the compound of general formula (I-22) and hydrazine hydrate obtain the compound of general formula (I-23) through addition ring closure reaction; In the seventh step, the compound of general formula (I-23) is subjected to substitution reaction to obtain the compound of general formula (I-24); In the eighth step, the compound of the general formula (I-24) and the compound of the general formula (I-10) are subjected to a substitution reaction to obtain a compound of the general formula (I-Bb); In the ninth step, the compound of the general formula (I-Bb) and the compound of the general formula (I-A) are subjected to a Buchwald reaction under basic conditions in the presence of a metal catalyst and a ligand to obtain a compound of the general formula (I); Wherein, X ² , X ³ , X ⁴ are halogen, X ² , X ³ are preferably bromine, X ⁴ is preferably iodine; Q is selected from N or CR ³ ; R ³ is selected from H, C1-C3 alkyl, halogen, Cyano or -OR ²¹ ; R ¹ is selected from hydrogen or methyl; AR and R ² have the same limitations as in claim 1; when R ¹ is H, omit the eighth step. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises polycyclic pyridazinone derivatives, pharmaceutically acceptable salts thereof, and tautomorphic compounds as claimed in any one of claims 1-8. Construct or its stereoisomer; Preferably, the pharmaceutical composition further includes a pharmaceutically acceptable carrier and/or excipient. Polycyclic pyridazinone derivatives as described in any one of claims 1-8, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof, or as described in claim 10 Use of the pharmaceutical composition in the preparation of medicines for treating cancer or in the preparation of SOS1 inhibitors; Preferably, the cancer is pancreatic cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, kidney cancer, gastric cancer or cholangiocarcinoma. A method for preventing and/or treating cancer, comprising administering to humans a therapeutically effective amount of the polycyclic pyridazinone derivatives as claimed in any one of claims 1-8, pharmaceutically acceptable Salt, its tautomer or its stereoisomer or the pharmaceutical composition as claimed in claim 10.