Fused heterocyclic compounds, preparation method therefor, pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are fused heterocyclic compounds, a preparation method therefor, a pharmaceutical composition and the use thereof. The fused heterocyclic compounds of the present invention are compounds represented by formula (I), pharmaceutically acceptable salts thereof, solvates thereof, or solvates of the pharmaceutically acceptable salts. The compounds of the present invention have excellent agonistic activity on GPR139 receptors.

Description

Condensed heterocyclic compound, preparation method, pharmaceutical composition and application thereof

[0001] This application claims the benefit of Chinese patent application No. 2024101520350, filed February 2, 2024. The entire text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention relates to a fused heterocyclic compound, a preparation method thereof, a pharmaceutical composition and application thereof. Background Art

[0003] G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, with a structure consisting of seven transmembrane helices. They mediate signal transduction through heterotrimeric G proteins composed of α, β, and γ subunits. α There are four major subfamilies of proteins: G q , G s , G i and G 12 / 13 The expression, mutation, and impaired signaling of GPCR proteins are associated with a variety of pathophysiological conditions, including central nervous system (CNS) diseases, cardiovascular and metabolic diseases, etc. More than 30% of known small molecule drugs target GPCRs.

[0004] The orphan receptor GPR139 was identified from bioinformatics analysis of the human genome. It is located on human chromosome 16 and belongs to the class A G protein-coupled receptor (GPCR). GPR139 is highly conserved across species. For example, the amino acid sequence of the human GPR139 protein shares over 94% homology with that of the mouse. In mammals, mRNA expression analysis shows that GPR139 expression is restricted to the central nervous system, suggesting that the receptor has no peripheral function. Its highest expression is in the striatum, pituitary, habenula, thalamus, and hypothalamus (Matsuo et al., Biochem Biophys Res Commun 2005, 331:363-369). GPR139 is highly expressed in the medial habenula of rodents and humans. Multiple studies have suggested a link between the habenula and schizophrenia. Damage to the overall structure of the habenula in rodents can lead to symptoms related to schizophrenia, such as reduced social activity, cognitive impairment, and overreaction to stress stimuli (Wang et al., Neuroreport 2013, 24: 276-280). Chronic schizophrenia patients have a higher frequency of calcification of the habenula compared to healthy controls, and the volume of the habenula also changes (Sandyk et al., Int J Neurosci 1992, 67: 19-30). Functional magnetic resonance imaging (fMRI) studies have shown that when healthy controls make errors in matching tasks, their habenula is activated, while in chronic schizophrenia patients, after matching errors, their habenula is not significantly activated (Shepard et al., Schizophr Bull 2006, 32: 417-421). GPR139 knockout mice exhibit behavioral traits associated with schizophrenia, including decreased spontaneous movement, deficits in social interaction, increased anxiety-related traits, and cognitive impairment. These symptoms can be ameliorated by administration of the μ-opioid naltrexone and the D2 dopamine receptor (D2R) antagonist haloperidol (Dao et al., Neuropsychopharmacology 2021, 47, 902–913). Based on these results, the study suggests that GPR139 is closely associated with the development and progression of various central nervous system diseases, including schizophrenia, Parkinson's disease, and alcohol addiction.

[0005] Due to its importance as a drug target, many studies have reported small molecule ligands of GPR139, including agonists and antagonists. In 2018, the selective GPR139 agonist JNJ-63533054 (EC 50=16nM) can reduce self-drinking and hyperalgesia in alcohol-dependent rats (Kononoff et al., eNeuro 2018, 5), but no significant behavioral regulation was shown in in vivo studies. In 2021, Takeda Corporation of Japan announced a selective GPR139 agonist TAK-041 (EC 50 =22 nM) (Reichard et al., J Med Chem 2021, 64: 11527-11542), which is currently under clinical evaluation for the treatment of negative symptoms of schizophrenia, and some preclinical studies have also provided evidence supporting GPR139 as a molecular target for anhedonia.

[0006] Therefore, compounds that modulate the GPR139 receptor offer therapeutic potential for treating a variety of diseases. Although a series of small molecule ligands for GPR139 have been reported, there is still a lack of GPR139 small molecule compounds with strong functional activity and therapeutic prospects, products containing them, and methods related to their use and manufacture. Summary of the Invention

[0007] To overcome the drawback of the single structure of GPR139 receptor agonists in the prior art, the present invention provides a fused heterocyclic compound, a preparation method, a pharmaceutical composition, and applications thereof. The fused heterocyclic compound of the present invention has a novel structure and exhibits excellent agonist activity against the GPR139 receptor.

[0008] The present invention solves the above technical problems through the following technical solutions.

[0009] The present invention provides a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0010] in,

[0011] X 1 N or CR X1 ;

[0012] X 2 N or CR X2 ;

[0013] X 3 N or CR X3 ;

[0014] X 4 N or CR X4 ;

[0015] X 5 N or CR X5 ;

[0016] R X1 、R X2 、R X3 、R X4 、R X5 are independently H or halogen;

[0017] R 1 H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, OC 1-6 Alkyl, 1 or more R 1-1 Substituted C 1-6 Alkyl, 1 or more R 1-2 Substituted C 3-6 Cycloalkyl, or one or more R 1-3 Replaced OC 1-6 alkyl;

[0018] R 1-1 、R 1-2 and R 1-3 are independently halogen;

[0019] R 2 H or C 1-6 alkyl;

[0020] R 3 and R 4 Independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 1 or more R 4-1 Substituted C 1-6 Alkyl, or one or more R 4-2 Substituted C 3-6 Cycloalkyl;

[0021] R 4-1 are independently halogen, OC 1-6 Alkyl or -NR a R b ;

[0022] R 4-2 are independently halogen, OC 1-6 Alkyl or -NR a R b ;

[0023] R a and R b Independently C 1-6 alkyl;

[0024] Or, R a and R b Together with the nitrogen atom to which it is connected, it forms a 5-6 membered heterocycloalkyl group or is surrounded by one or more R a-1Substituted 5-6 membered heterocycloalkyl; the 5-6 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S;

[0025] R a-1 Independently C 1-6 alkyl;

[0026] Q is C 6-10 Aryl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S;

[0027] n is 0, 1, 2, 3, 4 or 5;

[0028] R 5 are independently halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, 1 or more R 5-1 Substituted C 1-6 Alkyl, or one or more R 5-2 Replaced OC 1-6 alkyl;

[0029] R 5-1 and R 5-2 are independently halogen;

[0030] Or, R 4 、R 5 Together with the atoms it is connected to form (CH2) m , m is 2 or 3.

[0031] In the compound represented by Formula I, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, certain groups have the following definitions. The definitions of the groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "a certain embodiment"): X 1 is N or CH; X 2 N, CH or CR X2 ;X 3 is N or CH; X 4 is N or CH; X 5 N or CH; R X2 is halogen, and the halogen is preferably chlorine.

[0032] In one scheme, R 1 For H.

[0033] In one scheme, R 2 For H.

[0034] In one scheme, R3 and R 4 are independently H or C 1-6 alkyl.

[0035] In a certain solution, Q is C 6-10 Aryl.

[0036] In one embodiment, n is 0, 1 or 2; preferably 1 or 2.

[0037] In one scheme, R 5 are independently halogen, C 1-6 Alkyl, OC 1-6 Alkyl, 1 or more R 5-1 Substituted C 1- 6 alkyl, or one or more R 5-2 Replaced -OC 1-6 Alkyl; preferably, R 5 are independently F, Cl, Br or C 1-6 alkyl.

[0038] In one scheme, R 5-1 and R 5-2 are independently F or Cl.

[0039] In one scheme, R 1 、R 2 、R 3 、R 4 、R a 、R b 、R a-1 and R 5 In the C 1-6 The alkyl group can be C 1-4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl.

[0040] In one scheme, R 1 In the 1-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl, R 3 and R 4 One or more R 4-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl, and R 5 One or more R 5-1 Substituted C 1-6 C in the alkyl group 1-6 The alkyl group can be C 1-4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl.

[0041] In one scheme, R 1 、R 4-1 、R 4-2 and R 5 In the OC 1-6 The alkyl group can be OC 1-4 Alkyl, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example methoxy or ethoxy.

[0042] In one scheme, R 1 In the 1-3 Replaced OC 1-6 OC in alkyl 1-6 Alkyl and R 5 One or more R 5-2 Replaced OC 1-6 OC in alkyl 1-6 The alkyl group can be OC 1-4 Alkyl, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example, methoxy. 6-10 Aryl is preferably phenyl or naphthyl.

[0043] In one scheme, R 5 In the embodiment, the halogen is preferably F, Cl or Br, more preferably Cl or Br.

[0044] In one scheme, R 5-1 、R 5-2 and R X2 wherein the halogen is preferably F or Cl.

[0045] In one plan, for Preferred

[0046] In one embodiment, ring Q is phenyl or naphthyl.

[0047] In one plan, for Preferred

[0048] In one plan, for Preferably More preferably

[0049] In one plan, for For example

[0050] In one embodiment, the compound of formula I is as follows

[0051] in,

[0052] X 1 N or CH;

[0053] X 2 N, CH or CR X2 ; R X2 is a halogen;

[0054] X 3 N or CH;

[0055] X 4 N or CH;

[0056] X 5 N or CH;

[0057] R 1 、R 2 and R 3 independently H;

[0058] R 4 H or C 1-6 alkyl;

[0059] Q is C 6-10 aryl;

[0060] When Q is naphthyl, n is 0;

[0061] When Q is phenyl, n is 0, 1 or 2; each R 5 are independently halogen, C 1-6 Alkyl, OC 1-6 Alkyl, 1 or more R 5-1 Substituted C 1-6 Alkyl, or one or more R 5-2 Replaced -OC 1-6 alkyl;

[0062] Each R 5-1 and R 5-2 are independently halogen.

[0063] In one embodiment, the compound of formula I is as follows

[0064] in,

[0065] X1 N or CH;

[0066] X 2 N or CH;

[0067] X 3 N or CH;

[0068] X 4 N or CH;

[0069] X 5 N or CH;

[0070] R 4 C 1-6 alkyl;

[0071] R 5-a Cl, Br or C 1-6 Alkyl; R 5-b is H;

[0072] or R 5-a is Cl; R 5-b is F or Cl.

[0073] In one embodiment, the structure of the compound represented by Formula I is as shown in Formula I-1 or Formula I-2:

[0074] Among them, R 1 、R 2 、R 3 、R 4 、R 5 , Q and n are defined as described in the previous scheme;

[0075] Preferably, R 1 is H;

[0076] Preferably, R 2 is H;

[0077] Preferably, R 3 H, R 4 Methyl

[0078] Preferably, R 5 is a halogen, such as Cl;

[0079] Preferably, Q is C 6-10 aryl groups, such as phenyl;

[0080] Preferably, n is 1 or 2;

[0081] More preferably, for

[0082] In one embodiment, the structure of the compound represented by Formula I is as shown in Formula I-1A or Formula I-2A:

[0083] Among them, R 5 , Q and n are defined as described in the previous scheme;

[0084] Preferably, Q is C 6-10 aryl groups, such as phenyl;

[0085] Preferably, R 5 is a halogen, such as Cl;

[0086] Preferably, n is 1 or 2;

[0087] More preferably, for

[0088] In a certain embodiment, the compound represented by formula I is selected from any one of the following compounds:

[0089] The present invention also provides a method for preparing the compound of formula I, comprising the following steps: subjecting the compound of formula II and the compound of formula III to a substitution reaction as shown below to obtain the compound of formula I;

[0090] Among them, R 6 is a halogen;

[0091] X 1 、X 2 、X 3 、X 4 、X 5 、R 1 、R 2 、R 3 、R 4 、R 5 , Q and n are defined as above.

[0092] The present invention also provides a pharmaceutical composition comprising (i) the compound represented by the above formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical excipient.

[0093] The present invention also provides a use of the compound represented by the above formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition in the preparation of a medicament; the medicament can be used to treat and / or prevent schizophrenia, bipolar disorder, depression, cognitive impairment, autism spectrum disorder, sleep disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive-compulsive disorder, anxiety, pain, or fibromyalgia.

[0094] The present invention also provides a use of the compound represented by the above formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to the GPR139 receptor.

[0095] In one embodiment, the drug may be a GPR139 receptor agonist.

[0096] In one embodiment, the GPR139 receptor-related disease can be schizophrenia, bipolar disorder, depression, cognitive impairment, autism spectrum disorder, sleep disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive-compulsive disorder, anxiety disorder, pain or fibromyalgia.

[0097] The present invention also provides a use of the compound represented by the above formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate or the above pharmaceutical composition in the preparation of a GPR139 receptor agonist.

[0098] The present invention also provides a method for treating diseases associated with the GPR139 receptor, comprising administering to a subject in need of such treatment a compound of Formula I (preferably, administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula I), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0099] Definition of terms

[0100] Unless otherwise specified, the terms used in this invention have the following meanings:

[0101] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0102] The term "one or more" or "one or more" means 1, 2, 3, 4, 5 or more.

[0103] The term "alkyl" refers to a saturated, straight-chain or branched, monovalent hydrocarbon radical having a specified number of carbon atoms. For example, C 1-6Alkyl refers to an alkyl group having 1-6 (e.g., 1, 2, 3, 4, 5 or 6) carbon atoms, such as C 1-4 Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.

[0104] The term "cycloalkyl" refers to a saturated, monocyclic or polycyclic hydrocarbon group having the specified number of carbon atoms, wherein the polycyclic rings share one carbon atom, two carbon atoms not directly connected, or two carbon atoms and a bond, for example, C 3-6 Cycloalkyl refers to a cycloalkyl group having 3-6 (eg, 3, 4, 5, 6) ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0105] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). For example, a 5-6 membered heterocycloalkyl group includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, or piperidinyl.

[0106] The term "aryl" refers to a radical having the specified number of carbon atoms (e.g., C 6-10 ) is a cyclic group consisting only of carbon atoms, which is monocyclic or polycyclic, and all rings are aromatic (in accordance with Huckel's rule). 6-10 Aryl, which includes but is not limited to aryl or naphthyl.

[0107] The term "heteroaryl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3 members), a specified heteroatom species (one or more of N, O, and S), which is monocyclic or polycyclic, and at least one ring has aromaticity (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through a ring having aromaticity or a ring that does not have aromaticity. For example, a 5-10 membered heteroaryl group. Heteroaryl includes, but is not limited to, a furan ring, a pyrrole ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, a pyridine ring, a pyrimidine ring, an indole ring, etc.

[0108] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site. For example, -OCH3 refers to methoxy.

[0109] When any variable (such as the group R a-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other. For example, a-1 Substituted 5-6 membered heterocycloalkyl refers to a 5-6 membered heterocycloalkyl group which is replaced by 3 R a-1 Replacement, 3 Ra-1 The definitions are independent of each other and do not affect each other.

[0110] The term "pharmaceutically acceptable salt" refers to a salt formed by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0111] The term "solvate" refers to the combination, physical association and / or solvation of a compound of the present invention with a solvent molecule, such as a disolvate, a monosolvate or a hemisolvate. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase and separable solvates. The compound may exist in the form of a solvate formed with a pharmaceutically acceptable solvent. Solvates can generally function as pharmacological equivalents.

[0112] The term "therapeutically effective amount" refers to the amount of a compound administered to a subject that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0113] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and in the preparation of prescriptions. These excipients are all substances, other than the active ingredient, contained in a pharmaceutical preparation. For details, see the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009).

[0114] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0115] The term "prevent" refers to reducing the risk of developing a disease.

[0116] The term "subject" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include but are not limited to cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0117] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0118] The reagents and raw materials used in the present invention are commercially available.

[0119] The positive improvement effect of the present invention is that the fused heterocyclic compounds of the present invention have excellent agonist activity on the GPR139 receptor. DETAILED DESCRIPTION

[0120] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0121] Example 1: Preparation of (S)-N-(1-(4-fluorophenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-1)

[0122] Step 1: Preparation of (S)-2-bromo-N-(1-(4-fluorophenyl)ethyl)acetamide (Intermediate HR-01-047)

[0123] To a mixed solution of triethylamine (100 mg, 0.991 mmol) and (S)-1-(4-fluorophenyl)ethan-1-amine (165 mg, 1.189 mmol) in DCM (3 mL) was slowly added a solution of bromoacetyl bromide (200 mg, 0.991 mmol) in DCM (1 mL) in an ice bath. The mixture was allowed to react at 0°C for 1.5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The combined organic phases were evaporated under reduced pressure to remove the solvent, and the remaining solid was purified by silica gel column chromatography (eluent: 20-30% ethyl acetate / petroleum ether) to afford the intermediate HR-01-047 (186 mg, 72% yield) as a white solid. 1 H NMR(800MHz,DMSO-d6)δ8.74(d,J=7.9Hz,1H),7.36–7.32(m,2H),7.17–7.13(m,2H ),4.88(p,1H),3.87&3.85(ABq,J=10.8Hz,2H),1.35(d,J=6.9Hz,3H).HRMS(ESI)C 10 H 12 BrFNO +[M+H] + Calculated value: 260.0081; measured value: 260.0077.

[0124] Step 2: Preparation of (S)-N-(1-(4-fluorophenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-1)

[0125] The commercial reagent 1,7-naphthyridin-8(7H)-one (CAS#67967-11-7) (84 mg, 0.57 mmol) was dissolved in DMF solution, and potassium carbonate (157 mg, 1.14 mmol) was added to the above solution. The intermediate HR-01-047 (186 mg, 0.57 mmol) obtained in Step 1 was added with stirring, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined and the solvent was evaporated under reduced pressure. The remaining solid was separated and purified by silica gel column chromatography (eluent: 5% methanol / dichloromethane) to obtain a light yellow solid compound (I-1) (110 mg, 59% yield). 1 H NMR (800MHz, DMSO-d6) δ8.77(dd,J=4.3,1.7Hz,1H),8.71(d,J=7.9Hz,1H),8.11(dd,J=8.1,1.7Hz,1H),7.69(dd,J=8.1,4.3Hz,1H),7.49(d,J =7.3Hz,1H),7.40–7.36(m,2H),7.18–7.13(m,2H),6.58(d,J=7.4Hz,1H),4.94(p,1H),4.68&4.66(ABq,J=15.8Hz,2H),1.38(d,J=6.9Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ166.50,161.34(d,J=242.3Hz),160.44,149.32,141.49,140.80(d,J=3.1Hz),135.52,134 .93,133.91,128.25(2C,d,J=8.1Hz),127.04,115.20(2C,d,J=21.3Hz),102.92,51.51,47.81,22.76.HRMS(ESI)C 18 H 17 FN3O2 + [M+H] + Calculated value: 326.1300; measured value: 326.1299.

[0126] Example 2: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-2)

[0127] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced with (S)-1-(p-tolyl)ethylamine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-2) (58 mg, yield 58%). 1 H NMR (800MHz, DMSO-d6) δ8.77(dd,J=4.3,1.7Hz,1H),8.65(d,J=8.0Hz,1H),8.13–8.09(m,1H),7.69(dd,J=8.0,4.3Hz,1H),7.48(d,J=7.4Hz,1H),7 .23(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),6.58(d,J=7.4Hz,1H),4.89(p ,1H),4.68&4.66(ABq,J=15.8Hz,2H),2.27(s,3H),1.37(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ166.36,160.42,149.30,141.57,141.48,136.00,135.55,134.92, 133.90,129.06(2C),127.03,126.25(2C),102.87,51.46,48.13,22.76,20.92.HRMS(ESI)C 19 H 20 N3O2 + [M+H] + Calculated value: 322.1551; measured value: 322.1552.

[0128] Example 3: Preparation of (S)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-3)

[0129] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced with (S)-1-(4-trifluoromethoxyphenyl)ethylamine. The remaining raw materials, reagents and preparation method were the same as those in Example 1 to obtain a light yellow solid compound (I-3) (148 mg, yield 70%). 1HNMR(800MHz,DMSO-d6)δ8.79–8.75(m,2H),8.11(dd,J=8.1,1.7Hz,1H),7.69(dd,J=8.0,4.3Hz,1H),7.51–7.46(m,3H),7. 33(d,J=8.5Hz,2H),6.59(d,J=7.4Hz,1H),4.96(p,1H),4.70&4.67(ABq,J=15.8Hz,2H),1.40(d,J=7.0Hz,3H).HRMS(ESI)C 19 H 17 F3N3O3 + [M+H] + Calculated value: 392.1217; measured value: 392.1216.

[0130] Example 4: Preparation of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-4)

[0131] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-chlorophenyl)ethanamine hydrochloride. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-4) (65 mg, yield 56%). 1 H NMR (800MHz, DMSO-d6) δ8.77(dd,J=4.3,1.7Hz,1H),8.74(d,J=8.0Hz,1H),8.11(dd,J=8.1,1.8Hz,1H),7.68(dd,J=8.1,4.3Hz,1H),7.48 (d,J=7.4Hz,1H),7.40–7.35(m,4H),6.58(d,J=7.3Hz,1H),4.92(p,J=7.1Hz,1H),4.69&4.66(ABq,J=15.8Hz,2H),1.38(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ165.96,159.81,148.70,143.08,140.85,134.88,134.30,133. 28,130.88,127.84(2C),127.61(2C),126.42,102.31,50.88,47.30,21.97.HRMS(ESI)C 18 H 17 ClN3O2 + [M+H] +Calculated value: 342.1004; Measured value: 342.1004.

[0132] Example 5: Preparation of (S)-N-(1-(4-bromophenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-5)

[0133] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced with (S)-1-(4-bromophenyl)ethylamine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-5) (81 mg, yield 61%). 1 H NMR (800MHz, DMSO-d6) δ8.77(dd,J=4.3,1.7Hz,1H),8.74(d,J=7.8Hz,1H),8.12(d,J=8.1Hz,1H),7.69(dd,J=8.1,4.3Hz,1H),7.54–7.50(m,2H ),7.49(d,J=7.3Hz,1H),7.33–7.30(m,2H),6.59(d,J=7.3Hz,1H),4.90(p,J=7.3Hz,1H),4.69&4.66(ABq,J=15.8Hz,2H),1.38(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ166.59,160.43,149.32,144.15,141.48,135.50,133.91,131. 39(2C),128.62(2C),127.04,119.97,102.93,51.50,48.00,40.30,22.54.HRMS(ESI)C 18 H 17 BrN3O2 + [M+H] + Calculated value: 386.0499; Measured value: 386.0498.

[0134] Example 6: Preparation of (S)-N-(1-(naphthyl-2-yl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-6)

[0135] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced with (S)-(-)-1-(2-naphthyl)ethylamine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-6) (45 mg, yield 37%). 1H NMR(800MHz,DMSO-d6)δ8.88(d,J=7.8Hz,1H),8.78–8.75(m,1H),8.11(d,J=8.1Hz,2H ),7.95(d,J=8.0Hz,1H),7.84(d,J=8.1Hz,1H),7.68(dd,J=8.0,4.3Hz,1H),7.62(d,J= 6.9Hz,1H),7.57–7.54(m,1H),7.54–7.50(m,2H),7.48(d,J=7.3Hz,1H),6.58(d,J=7. 4Hz, 1H), 5.72 (p, J = 7.0Hz, 1H), 4.73&4.69 (ABq, J = 15.8Hz, 2H), 1.53 (d, J = 6.9Hz, 3H). 13 C NMR(201MHz,DMSO-d6)δ166.42,160.43,149.30,141.47,140.20,135.52,134.93,133.89,133.66,130.56, 128.94,127.62,127.04,126.52,125.89,125.78,123.37,122.80,102.89,51.45,44.73,22.07.HRMS(ESI)C 22 H 20 N3O2 + [M+H] + Calculated value: 358.1551; measured value: 358.1550.

[0136] Example 7: Preparation of (S)-N-(1-(3,4-difluorophenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-7)

[0137] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(3,4-difluorophenyl)ethanamine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-7) (64 mg, yield 55%). 1H NMR (800MHz, DMSO-d6) δ8.81(d,J=7.7Hz,1H),8.78–8.74(m,1H),8.13–8.09(m,1H),7.68(dd,J=8.0,4.3Hz,1H),7.52–7.44(m,2H),7.22–7. 15(m,1H),7.11–7.06(m,1H),6.58(d,J=7.3Hz,1H),5.10(p,J=7.1Hz,1H),4.69&4.67(ABq,J=15.9Hz,2H),1.38(d,J=7.0Hz,3H).HRMS(ESI)C 18 H 16 F2N3O2 + [M+H] + Calculated value: 344.1206; measured value: 344.1202.

[0138] Example 8: Preparation of (S)-N-(1-(3,4-dichlorophenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-8)

[0139] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced with (S)-1-(3,4-dichlorophenyl)ethylamine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-8) (89 mg, yield 70%). 1 H NMR (600MHz, DMSO-d6) δ8.78–8.74(m,2H),8.11(dd,J=8.1,1.7Hz,1H),7.68(dd,J=8.1,4.3Hz,1H),7.61–7.57(m,2H),7.48( d,J=7.3Hz,1H),7.34(dd,J=8.4,2.2Hz,1H),6.58(d,J=7.3Hz,1H),4.92(p,J=7.0Hz,1H),4.68(s,2H),1.38(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ166.12,159.81,148.71,145.38,140.85,134.85,134.31,133.29, 130.59,130.11,128.86,127.79,126.43,126.17,102.35,50.93,47.12,21.88.HRMS(ESI)C 18 H 16 Cl2N3O2 + [M+H]+ Calculated value: 376.0615; Measured value: 376.0613.

[0140] Example 9: Preparation of (S)-N-(1-(4-chloro-3-fluorophenyl)ethyl)-2-(8-oxo-1,7-naphthyridin-7(8H)-yl)acetamide (Compound I-9)

[0141] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-chloro-3-fluorophenyl)ethanamine. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-9) (17 mg, yield 23%). 1 H NMR (800MHz, DMSO-d6) δ8.79–8.75(m,2H),8.11(dd,J=8.1,1.7Hz,1H),7.69(dd,J=8.0,4.3Hz,1H),7.54(t,J=8.0Hz,1H),7.49(d,J=7.3Hz,1H),7. 39(dd,J=10.7,2.1Hz,1H),7.22(dd,J=8.3,2.2Hz,1H),6.59(d,J=7.4Hz,1H),4.93(p,J=7.3Hz,1H),4.69(s,2H),1.38(d,J=7.0Hz,3H).HRMS(ESI)C 18 H 16 ClFN3O2 + [M+H] + Calculated value: 360.0910; measured value: 360.0912.

[0142] Example 10: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(1-oxo-2,7-naphthyridin-2(1H)-yl)acetamide (Compound I-10)

[0143] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridin-8(7H)-one was replaced with a commercial reagent 2,7-naphthyridin-1(2H)-one (CAS#67988-50-5). The remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-10) (75 mg, yield 69%). 1H NMR (800MHz, DMSO-d6) δ9.31(s,1H),8.70(d,J=5.5Hz,1H),8.67(d,J=8.0Hz,1H),7.65(d,J=7.3Hz,1H),7.59(d,J=5.5Hz,1H),7.22(d,J= 8.0Hz,2H),7.13(d,J=7.8Hz,2H),6.61(d,J=7.0Hz,1H),4.88(p,1H),4.68&4.65(ABq,J=16.0Hz,2H),2.27(s,3H),1.36(d,J=6.9Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ166.02,160.90,150.87,150.24,142.67,141.43,139.68,135.94, 128.98(2C),126.14(2C),120.35,119.36,102.77,50.87,48.07,22.69,20.81.HRMS(ESI)C 19 H 20 N3O2 + [M+H] + Calculated value: 322.1551; measured value: 322.1555.

[0144] Example 11: Preparation of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(1-oxo-2,7-naphthyridin-2(1H)-yl)acetamide (Compound I-11)

[0145] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,7-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-11) (34 mg, yield 48%). 1 H NMR (600MHz, DMSO-d6) δ9.31(s,1H),8.75(d,J=7.8Hz,1H),8.71(d,J=5.4Hz,1H),7.64(d,J=7.3Hz,1H),7.61–7.56( m,1H),7.41–7.34(m,4H),6.62(d,J=7.3Hz,1H),4.92(p,1H),4.69&4.66(ABq,J=15.9Hz,2H),1.38(d,J=7.0Hz,3H). 13C NMR (201MHz, DMSO-d6) δ166.04,160.70,150.68,150.03,143.35,142.46,139.42,131. 23,128.19(2C),127.91(2C),120.13,119.15,102.61,50.71,47.67,22.31.HRMS(ESI)C 18 H 17 ClN3O2 + [M+H] + Calculated value: 342.1004; measured value: 342.1002.

[0146] Example 12: Preparation of (S)-N-(1-(4-bromophenyl)ethyl)-2-(1-oxo-2,7-naphthyridin-2(1H)-yl)acetamide (Compound I-12)

[0147] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-bromophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,7-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-12) (80 mg, yield 61%). 1 H NMR (800MHz, DMSO-d6) δ9.31(s,1H),8.76(d,J=7.8Hz,1H),8.71(d,J=5.4Hz,1H),7.65(d,J=7.4Hz,1H),7.59(d,J=5.5Hz,1H),7.54 –7.50(m,2H),7.32–7.28(m,2H),6.62(d,J=7.3Hz,1H),4.89(p,J=7.3Hz,1H),4.69&4.66(ABq,J=15.8Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ166.36,161.02,151.00,150.35,144.12,142.78,139.74,131. 43(2C),128.62(2C),120.44,120.02,119.48,102.94,51.02,48.06,22.58.HRMS(ESI)C 18 H 17 BrN3O2 + [M+H] + Calculated value: 386.0499; Measured value: 386.0490.

[0148] Example 13: Preparation of (S)-N-(1-(2-naphthyl)ethyl)-2-(1-oxo-2,7-naphthyridin-2(1H)-yl)acetamide (Compound I-13)

[0149] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-(-)-1-(2-naphthyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,7-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-13) (95 mg, yield 77%). 1 H NMR (800MHz, DMSO-d6) δ9.31(s,1H),8.91(d,J=7.8Hz,1H),8.70(d,J=5.4Hz,1H),8.10( d,J=8.4Hz,1H),7.95(d,J=8.0Hz,1H),7.84(d,J=8.1Hz,1H),7.65(d,J=7.4Hz,1H),7.61 (d,J=6.4Hz,1H),7.59(d,J=5.4Hz,1H),7.57–7.54(m,1H),7.54–7.50(m,2H),6.61(d,J= 7.3Hz, 1H), 5.72 (p, J=6.9Hz, 1H), 4.73&4.68 (ABq, J=16.0Hz, 2H), 1.53 (d, J=6.9Hz, 3H). 13 C NMR(201MHz,DMSO-d6)δ166.20,161.00,150.95,150.33,142.78,140.21,139.77,133.66,130.54,128.94, 127.64,126.53,125.91,125.80,123.37,122.79,120.46,119.48,102.88,51.00,44.75,22.11.HRMS(ESI)C 22 H 20 N3O2 + [M+H] + Calculated value: 358.1551; measured value: 358.1552.

[0150] Example 14: Preparation of (S)-N-(1-(4-fluorophenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-14)

[0151] The 1,7-naphthyridin-8(7H)-one in Example 1 was replaced with a commercial reagent 2,6-naphthyridin-1(2H)-one (CAS#80935-77-9). The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-14) (193 mg, yield 68%). 1 H NMR (800MHz, DMSO-d6) δ9.07(s,1H),8.72(d,J=7.9Hz,1H),8.64(d,J=5.4Hz,1H),7.98(d,J=5.3Hz,1H),7.54(d,J=7.4Hz,1H),7.40 –7.35(m,2H),7.18–7.13(m,2H),6.73(d,J=7.4Hz,1H),4.93(p,J=7.2Hz,1H),4.69&4.67(ABq,J=15.9Hz,2H),1.38(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ165.78,160.93(d,J=242.5Hz),160.06,149.52,145.79,140.34(d,J=3.1Hz),136.15,131 .54,129.46,127.83(2C,d,J=8.1Hz),119.06,114.81(2C,d,J=21.2Hz),101.81,50.97,47.44,22.36.HRMS(ESI)C 18 H 17 FN3O2 + [M+H] + Calculated value: 326.1300; measured value: 326.1301.

[0152] Example 15: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-15)

[0153] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced by (S)-1-(p-tolyl)ethylamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-15) (64 mg, yield 25%). 1H NMR (800MHz, DMSO-d6) δ9.07(s,1H),8.66(d,J=8.0Hz,1H),8.63(d,J=5.4Hz,1H),7.98(d,J=5.4Hz,1H),7.53(d,J=7.3Hz,1H),7.21(d,J=8.0H z,2H),7.13(d,J=8.0Hz,2H),6.73(d,J=7.3Hz,1H),4.88(p,J=7.1Hz,1H),4.68&4.66(ABq,J=15.9Hz,2H),2.27(s,3H),1.36(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ165.64,160.04,149.51,145.77,141.11,136.18,135.62,131.54, 129.46(2C),128.66(2C),125.82,119.06,101.76,50.93,47.75,22.36,20.49.HRMS(ESI)C 19 H 20 N3O2 + [M+H] + Calculated value: 322.1551; Measured value: 322.1551.

[0154] Example 16: Preparation of (S)-N-(1-(4-methoxyphenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-16)

[0155] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced by (S)-1-(4-methoxyphenyl)ethylamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-16) (95 mg, yield 82%). 1 H NMR(800MHz,DMSO-d6)δ9.07(s,1H),8.64–8.62(m,2H),7.98(d,J=5.4Hz,1H),7.54(d,J=7.4Hz,1H),7.26–7.23(m,2H),6 .90–6.87(m,2H),6.73(d,J=6.9Hz,1H),4.88(p,1H),4.67&4.65(ABq,J=15.9Hz,2H),3.73(s,3H),1.35(d,J=7.0Hz,3H). 13C NMR(201MHz,DMSO-d6)δ165.47,159.94,157.88,149.41,145.67,136.08,135.96,131.45, 129.36,126.97(2C),118.97,113.41(2C),101.66,54.85,50.82,47.30,22.26.HRMS(ESI)C 19 H 20 N3O3 + [M+H] + : 338.1500; measured value: 338.1502.

[0156] Example 17: Preparation of (S)-N-(1-(4-ethoxyphenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-17)

[0157] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced by (S)-1-(4-ethoxyphenyl)ethylamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-17) (83 mg, yield 69%). 1 H NMR (800MHz, DMSO-d6) δ9.08(s,1H),8.63(dd,J=11.4,6.7Hz,2H),7.99(d,J=5.3Hz,1H),7.54(d,J=7.3Hz,1H),7.25–7.22(m,2H),6.88–6.85( m,2H),6.73(d,J=7.2Hz,1H),4.88(p,J=7.4Hz,1H),4.68&4.65(ABq,J=15.9Hz,2H),4.00(q,J=7.0Hz,2H),1.35(d,J=6.9Hz,3H),1.31(t,3H). 13 C NMR(201MHz,DMSO-d6)δ165.88,160.36,157.55,149.83,146.09,136.50,136.21,131.86,129 .78,127.39(2C),119.38,114.31(2C),102.08,63.15,51.24,47.70,22.66,14.87.HRMS(ESI)C 20 H 22 N3O3 + [M+H] +: 352.1656; Measured value: 352.1656.

[0158] Example 18: Preparation of (S)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-18)

[0159] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced by (S)-1-(4-trifluoromethoxyphenyl)ethylamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-18) (167 mg, yield 69%). 1 H NMR (800MHz, DMSO-d6) δ9.07(s,1H),8.77(d,J=7.8Hz,1H),8.63(d,J=5.3Hz,1H),7.98(d,J=5.3Hz,1H),7.54(d,J=7.3Hz,1H),7.48–7. 44(m,2H),7.33(d,J=7.9Hz,2H),6.73(d,J=7.3Hz,1H),4.95(p,1H),4.70&4.67(ABq,J=16.0Hz,2H),1.39(d,J=7.0Hz,3H).HRMS(ESI)C 19 H 20 N3O2 + [M+H] + Calculated value: 392.1217; measured value: 392.1216.

[0160] Example 19: Preparation of (S)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-19)

[0161] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-trifluoromethylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-19) (99 mg, yield 77%). 1H NMR (800MHz, DMSO-d6) δ9.07(s,1H),8.83(d,J=7.6Hz,1H),8.64(d,J=5.3Hz,1H),7.99(d,J=5.3Hz,1H),7.69(d,J=8.4Hz,2H),7.55(d d,J=18.5,7.8Hz,3H),6.73(d,J=7.3Hz,1H),4.99(p,J=7.3Hz,1H),4.72&4.69(ABq,J=15.9Hz,2H),1.41(d,J=7.0Hz,3H).HRMS(ESI)C 19 H 17 F3N3O2 + [M+H] + Calculated value: 376.1268; Measured value: 376.1266.

[0162] Example 20: Preparation of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-20)

[0163] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-20) (134 mg, yield 38%). 1 H NMR (800MHz, DMSO-d6) δ9.07(s,1H),8.74(d,J=7.8Hz,1H),8.64(d,J=5.3Hz,1H),7.98(d,J=5.3Hz,1H),7.54(d,J=7.4Hz, 1H),7.40–7.35(m,4H),6.73(d,J=7.3Hz,1H),4.91(p,J=7.3Hz,1H),4.70&4.67(ABq,J=15.9Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ166.18,160.38,149.83,146.11,143.56,136.45,131.86,131. 44,129.77,128.39(2C),128.13(2C),119.38,102.15,51.29,47.87,22.51.HRMS(ESI)C 18 H 17 ClN3O2 +[M+H] + Calculated value: 342.1004; measured value: 342.1002.

[0164] Example 21: Preparation of (S)-N-(1-(4-bromophenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-21)

[0165] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-bromophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-21) (35 mg, yield 26%). 1 H NMR (800MHz, DMSO-d6) δ9.07(s,1H),8.75(d,J=7.8Hz,1H),8.64(d,J=5.3Hz,1H),7.98(d,J=5.3Hz,1H),7.55–7.50(m,3H ),7.32–7.28(m,2H),6.73(d,J=7.3Hz,1H),4.89(p,J=7.1Hz,1H),4.69&4.67(ABq,J=15.9Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ165.77,159.95,149.41,145.69,143.59,136.03,131.44,130. 89(2C),129.35,128.09(2C),119.49,118.96,101.72,50.86,47.52,22.04.HRMS(ESI)C 18 H 17 BrN3O2 + [M+H] + Calculated value: 386.0499; Measured value: 386.0492.

[0166] Example 22: Preparation of (S)-N-(1-phenylethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-22)

[0167] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced with (S)-1-phenylethylamine, and 1,7-naphthyridine-8(7H)-one was replaced with 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-22) (81 mg, yield 77%).1 H NMR (800MHz, DMSO-d6) δ9.07(s,1H),8.71(d,J=7.9Hz,1H),8.64(d,J=5.4Hz,1H),7.99(d,J=5.3Hz,1H),7.54(d,J=7.3Hz,1H), 7.35–7.32(m,4H),7.25–7.21(m,1H),6.73(d,J=7.4Hz,1H),4.93(p,1H),4.70&4.68(ABq,J=15.9Hz,2H),1.39(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ166.05,160.37,149.83,146.10,144.45,136.49,131.86,129. 78,128.46(2C),126.91,126.20(2C),119.38,102.10,51.26,48.34,22.70.HRMS(ESI)C 18 H 18 N3O2 + [M+H] + Calculated value: 308.1394; Measured value: 308.1398.

[0168] Example 23: Preparation of (S)-N-(1-(naphthyl-2-yl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-23)

[0169] The (S)-1-(4-fluorophenyl)ethylamine in Example 1 was replaced by (S)-(-)-1-(2-naphthyl)ethylamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a light yellow solid compound (I-23) (47 mg, yield 38%). 1H NMR(800MHz,DMSO-d6)δ9.07(s,1H),8.90(d,J=7.8Hz,1H),8.64(d,J=5.3Hz,1 H),8.10(d,J=8.5Hz,1H),7.99(d,J=5.4Hz,1H),7.94(d,J=7.9Hz,1H),7.84(d ,J=8.1Hz,1H),7.61(d,J=6.7Hz,1H),7.57–7.50(m,4H),6.72(d,J=7.4Hz,1H) ,5.72(p,J=7.0Hz,1H),4.73&4.69(ABq,J=16.0Hz,2H),1.53(d,J=6.8Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ165.61,159.94,149.40,145.68,139.68,136.05,133.14,131.44,130.03,129.37, 128.42,127.12,126.01,125.39,125.27,122.85,122.27,118.98,101.67,50.84,44.22,21.58.HRMS(ESI)C 22 H 20 N3O2 + [M+H] + Calculated value: 358.1551; measured value: 358.1554.

[0170] Example 24: Preparation of (S)-N-(1-(3,4-difluorophenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-24)

[0171] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(3,4-difluorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a light yellow solid compound (I-24) (105 mg, yield 87%). 1H NMR(800MHz, DMSO-d6)δ9.07(s,1H),8.82(d,J=7.7Hz,1H),8.63(d,J=5.3Hz,1H),7.98(d,J=5.3Hz,1H),7.53(d,J=7.4Hz,1H),7.49–7.45(m,1H),7 .22–7.17(m,1H),7.12–7.07(m,1H),6.73(d,J=7.3Hz,1H),5.10(p,J=7.0 Hz,1H),4.70&4.67(ABq,J=15.9Hz,2H),1.37(d,J=6.9Hz,3H).HRMS(ESI)C 18 H 16 F2N3O2 + [M+H] + Calculated value: 344.1206; measured value: 344.1202.

[0172] Example 25: Preparation of (S)-N-(1-(3,4-dichlorophenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-25)

[0173] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(3,4-dichlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a light yellow solid compound (I-25) (100 mg, yield 79%). 1 H NMR (800MHz, DMSO-d6) δ9.07 (s, 1H), 8.78 (d, J = 7.7Hz, 1H), 8.64 (d, J = 5.4Hz, 1H), 7.98 (d, J = 5.3Hz, 1H), 7.60 (d, J = 2.1Hz, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.54(d,J=7.3Hz,1H),7.33(dd,J=8.4,2.2Hz,1H),6.73(d,J=7.4Hz,1H),4 .91(p,J=7.0Hz,1H),4.70&4.67(ABq,J=15.9Hz,2H),1.37(d,J=7.0Hz,3H). 13CNMR(201MHz,DMSO-d6)δ166.49,160.50,149.95,146.24,145.96,136.54,131.96,131.25, 130.74,129.87,129.50,128.40,126.80,119.46,102.29,51.52,47.79,22.50.HRMS(ESI)C 18 H 16 Cl2N3O2 + [M+H] + Calculated value: 376.0615; Measured value: 376.0613.

[0174] Example 26: Preparation of (S)-N-(1-(4-chloro-3-fluorophenyl)ethyl)-2-(1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-26)

[0175] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chloro-3-fluorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-26) (50 mg, yield 67%). 1 H NMR (800MHz, DMSO-d6) δ9.08(s,1H),8.77(d,J=7.7Hz,1H),8.64(d,J=5.4Hz,1H),7.99(d,J=5.4Hz,1H),7.56–7.52(m,2H),7.38(d d,J=10.7,2.1Hz,1H),7.21(dd,J=8.3,2.1Hz,1H),6.74(d,J=7.4Hz,1H),4.92(p,J=7.2Hz,1H),4.69(s,2H),1.38(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ165.86, 159.88, 156.79 (d, J = 246.1Hz), 149.33, 146.09 (d, J = 6.0Hz), 145.62, 135.92, 131.34, 130.06 ,129.24,122.99(d,J=3.4Hz),118.83,117.12(d,J=17.6Hz),114.10(d,J=21.2Hz),101.67,50.87,47.22,21.85.HRMS(ESI)C 18 H 16 ClFN3O2+ [M+H] + Calculated value: 360.0910; Measured value: 360.0910.

[0176] Example 27: Preparation of (S)-N-(1-(4-fluorophenyl)ethyl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetamide (Compound I-27)

[0177] The 1,7-naphthyridine-8(7H)-one in Example 1 was replaced with the commercial reagent 1,6-naphthyridine-6(5H)-one (CAS#23616-31-1). The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-27) (87 mg, yield 81%). 1 H NMR (600MHz, DMSO-d6) δ8.92(dd,J=4.5,1.8Hz,1H),8.71(d,J=7.9Hz,1H),8.50(dd,J=8.1,2.4Hz,1H),7.66(d,J=7.5Hz,1H),7.51(dd,J=8.1,4.5 Hz,1H),7.41–7.35(m,2H),7.19–7.12(m,2H),6.68(d,J=7.6Hz,1H),4.9 4(p,J=6.9Hz,1H),4.69&4.77(ABq,J=15.9Hz,2H),1.38(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ166.34,161.62,161.35(d,J=242.1Hz),154.91,153.83,140.78(d,J=2.9Hz),138.47,135 .68,128.25(2C,d,J=8.0Hz),122.10,121.12,115.23(2C,d,J=21.2Hz),106.26,51.05,47.84,22.79.HRMS(ESI)C 18 H 17 FN3O2 + [M+H] + Calculated value: 326.1300; measured value: 326.1304.

[0178] Example 28: Preparation of (S)-N-(1-(p-Tolyl)ethyl)-2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetamide (Compound I-28)

[0179] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 1,6-naphthyridine-6(5H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-28) (102 mg, yield 92%). 1 H NMR (800MHz, DMSO-d6) δ8.92(dd,J=4.5,1.9Hz,1H),8.71(d,J=7.9Hz,1H),8.50(dd,J=8.1,2.6Hz,1H),7.66(d,J=7.6Hz,1H),7.51(dd,J=8.0,4.5H z,1H),7.39–7.36(m,2H),7.17–7.13(m,2H),6.68(d,J=7.5Hz,1H),4.93( p,1H),4.69&4.66(ABq,J=15.9Hz,2H),1.38(d,J=7.0Hz,3H).HRMS(ESI)C 19 H 20 N3O2 + [M+H] + Calculated value: 322.1551; measured value: 322.1557.

[0180] Example 29-1: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(8-oxopyrido[2,3-d]pyridazin-7(8H)-yl)acetamide (Compound I-29)

[0181] In Example 1, (S)-1-(4-fluorophenyl)ethanamine was replaced with (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridin-8(7H)-one was replaced with pyrido[2,3-d]pyridazin-8(7H)-one (prepared by reference method; Brzezinski et al., Tetrahedron 1996, 52:3261-3272). The remaining required raw materials, reagents and preparation method were the same as in Example 1 to obtain a yellow solid compound (I-29) (90 mg, yield 82%). 1H NMR (800MHz, DMSO-d6) δ9.09(dd,J=4.5,1.7Hz,1H),8.55(d,J=8.0Hz,1H),8.45(s,1H),8.41(dd,J=8.0,1.7Hz,1H),7.93(dd,J=8.0,4.5Hz,1 H),7.22(d,J=8.1Hz,2H),7.13(d,J=7.9Hz,2H),4.91(p,1H),4.82&4.79(ABq,J=15.9Hz,2H),2.27(s,3H),1.36(d,J=7.0Hz,3H).HRMS(ESI)C 18 H 19 N4O2 + [M+H] + Calculated value: 323.1503; Measured value: 323.1500.

[0182] Example 29-2: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(8-oxopyrido[2,3-d]pyridazin-7(8H)-yl)acetamide (Compound I-29)

[0183] Step 1: Preparation of 5-hydroxy-6-phenyl-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Intermediate HR-01-138)

[0184] At -78 ° C, n-butyl lithium solution (2.4M hexane solution, 6.42 mL) was added dropwise to a THF (25 mL) solution of N-phenylpicolinamide (CAS#10354-53-7, 1.39 g, 7.01 mmol) under nitrogen protection. The mixture was stirred at -78 ° C for 30 minutes, then the temperature was raised to 0 ° C, and stirred at 0 ° C for 6 minutes. The reaction solution was then cooled to -78 ° C, anhydrous DMF (944 μL, 14.0 mmol) was added dropwise, and after stirring for 30 minutes, the temperature was raised to 0 ° C, and stirred at 0 ° C for 1 hour. Water was added to the reaction solution to quench the reaction, the organic phase was separated, and the aqueous phase was adjusted to pH 8 with 1M hydrochloric acid. The solid was filtered, washed with water and dried at room temperature to obtain a yellow solid intermediate HR-01-138 (632 mg, yield 39%). HRMS (ESI) C 12 H 11 N2O2 + [M+H] + Calculated value: 227.0816; Measured value: 227.0817.

[0185] Step 2: Preparation of pyrido[2,3-d]pyridazin-8(7H)-one (Intermediate HR-01-139)

[0186] To intermediate HR-01-138 (711 mg, 3.14 mmol) was added hydrazine hydrate (5 mL, 98%) to dissolve the product, and the mixture was stirred at 120°C overnight. The reaction solution was concentrated under reduced pressure to remove the solvent, diluted with water, and the pH was adjusted to 6-7 with 2M hydrochloric acid. The solid was filtered, washed with water, and dried at room temperature to obtain intermediate HR-01-139 (309 mg, 66% yield) as a yellow solid. 1 H NMR(800MHz,DMSO-d6)δ12.92(s,1H),9.07(dd,J=4.5,1.7Hz,1H),8.40(s,1H),8.39(dd,J=8.0,1.7Hz,1H),7.92(dd,J=8.0,4.5Hz,1H).HRMS(ESI)C7H6N3O + [M+H] + Calculated value: 148.0506; Measured value: 148.0506.

[0187] Step 3: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(8-oxopyrido[2,3-d]pyridazin-7(8H)-yl)acetamide (Compound I-29)

[0188] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[2,3-d]pyridazine-8(7H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-29) (90 mg, yield 82%). 1 H NMR (800MHz, DMSO-d6) δ9.09(dd,J=4.5,1.7Hz,1H),8.55(d,J=8.0Hz,1H),8.45(s,1H),8.41(dd,J=8.0,1.7Hz,1H),7.93(dd,J=8.0,4. 5Hz,1H),7.22(d,J=8.1Hz,2H),7.13(d,J=7.9Hz,2H),4.91(p,1H),4.82&4.79(ABq,J=15.9Hz,2H),2.27(s,3H),1.36(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ165.64,158.08,154.10,143.01,141.26,136.98,135.67,135. 43,128.75(2C),128.08,126.15,125.90(2C),53.83,47.78,22.37,20.60.HRMS(ESI)C18 H 19 N4O2 + [M+H] + Calculated value: 323.1503; Measured value: 323.1500.

[0189] Example 30: Preparation of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(8-oxopyrido[2,3-d]pyridazin-7(8H)-yl)acetamide (Compound I-30)

[0190] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[2,3-d]pyridazine-8(7H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-30) (83 mg, yield 71%). 1 H NMR(800MHz,DMSO-d6)δ9.10(dd,J=4.4,1.7Hz,1H),8.65(d,J=7.8Hz,1H),8.46(s,1H),8.41(dd,J=8 .0,1.7Hz,1H),7.94(dd,J=8.0,4.4Hz,1H),7.41–7.34(m,4H),4.94(p,J=7.2Hz,1H),4.84&4.81(ABq J=15.9Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ165.66,157.88,153.91,143.19,142.79,136.84,135.24,1 30.97,127.95(2C),127.89,127.68(2C),125.95,53.67,47.39,22.00.HRMS(ESI)C 17 H 16 ClN4O2 + [M+H] + Calculated value: 343.0957; Measured value: 343.0958.

[0191] Example 31-1: Preparation of (S)-N-(1-(p-Tolyl)ethyl)-2-(4-oxopyrido[3,4-d]pyridazin-3(4H)-yl)acetamide (Compound I-31)

[0192] In Example 1, (S)-1-(4-fluorophenyl)ethanamine was replaced with (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridin-8(7H)-one was replaced with pyrido[3,4-d]pyridazin-4(3H)-one (prepared according to the reference method; Yaremenko et al., Tetrahedron 2013, 69: 6799-6803). The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-31) (95 mg, yield 86%). 1 H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.65(d,J=7.9Hz,1H),8.01(s,1H),7.56(d,J=7.4Hz,1H),7.21(d,J=7.8Hz,2H),7.13(d,J=7.8 HRMS(ESI)C 18 H 19 N4O2 + [M+H] + Calculated value: 323.1503; measured value: 323.1501.

[0193] Example 31-2: Preparation of (S)-N-(1-(p-Tolyl)ethyl)-2-(4-oxopyrido[3,4-d]pyridazin-3(4H)-yl)acetamide (Compound I-31)

[0194] Step 1: Preparation of 1-hydroxy-2-phenyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (Intermediate HR-02-009)

[0195] At -78°C, a solution of n-butyllithium (2.4 M in hexane, 8.4 mL) was added dropwise to a solution of tetramethylpiperidone (TEMP, 2.56 mL, 15.1 mmol) in THF (20 mL) under nitrogen. The mixture was stirred at -78°C for 30 minutes. A solution of nicotinamide (CAS #1752-96-1, 1000 mg, 5.04 mmol) in THF (10 mL) was then added dropwise to the reaction solution, and the mixture was stirred at -78°C for 2 hours. Anhydrous DMF (2.34 mL, 30.24 mmol) was added dropwise to the reaction solution, and after stirring at -78°C for 30 minutes, the temperature was raised to room temperature. 1M hydrochloric acid was added to the reaction solution to quench the reaction, followed by addition of saturated sodium bicarbonate to adjust the pH to 10. The mixture was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the remaining solid was separated and purified by silica gel column chromatography (eluent: 5% methanol / dichloromethane) to obtain the intermediate HR-02-009 (860 mg, yield 68%) as a yellow oil. HRMS (ESI) C 12 H 11 N2O2 + [M+H] + Calculated value: 227.0816; Measured value: 227.0816.

[0196] Step 2: Preparation of pyrido[3,4-d]pyridazin-4(3H)-one (Intermediate HR-02-011)

[0197] To a solution of intermediate HR-02-009 (860 mg, 3.80 mmol) in methanol (10 mL) was added hydrazine hydrate (10 mL, 98%), and the mixture was stirred at 120°C overnight. The reaction solution was concentrated under reduced pressure to remove the solvent, diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The remaining solid was separated and purified by silica gel column chromatography (eluent: 5% methanol / dichloromethane) to obtain yellow solid intermediate HR-02-011 (196 mg, yield 35%). HRMS (ESI) C7H6N3O + [M+H] + Calculated value: 148.0506; Measured value: 148.0506.

[0198] Step 3: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(4-oxopyrido[3,4-d]pyridazin-3(4H)-yl)acetamide (Compound I-31)

[0199] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-4(3H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-31) (95 mg, yield 86%). 1 H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.65(d,J=7.9Hz,1H),8.01(s,1H),7.56(d,J=7.4Hz,1H),7.21(d,J=7.8Hz,2H),7.13(d, J=7.8Hz,2H),6.76(d,J=7.3Hz,1H),4.88(p,J=7.1Hz,1H),4.69&4.66(ABq,J=15.9Hz,2H),2.27(s,3H),1.36(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ165.65,158.00,153.03,149.30,141.42,136.87,135.92,134. 37,128.98(2C),126.10(2C),121.36,119.26,53.64,48.03,22.59,20.81.HRMS(ESI)C 18 H 19 N4O2 + [M+H] + Calculated value: 323.1503; measured value: 323.1501.

[0200] Example 32: Preparation of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(4-oxopyrido[3,4-d]pyridazin-3(4H)-yl)acetamide (Compound I-32)

[0201] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-4(3H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-32) (107 mg, yield 91%). 1H NMR (800MHz, DMSO-d6) δ9.46 (s, 1H), 9.06 (d, J = 5.3Hz, 1H), 8.66 (d, J = 7.8Hz, 1H), 8.51 (s, 1H), 7.88 (d, J = 5.3Hz, 1H) ,7.41–7.37(m,2H),7.37–7.33(m,2H),4.93(p,J=7.1Hz,1H),4.83&4.80(ABq,J=16.0Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ165.47,157.59,152.63,148.88,143.14,136.50,133.96,1 31.00,127.97(2C),127.67(2C),120.93,118.85,53.26,47.43,22.01.HRMS(ESI)C 17 H 16 ClN4O2 + [M+H] + Calculated value: 343.0957; Measured value: 343.0959.

[0202] Example 33-1: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-33)

[0203] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced with pyrido[3,4-d]pyridazin-1(2H)-one (prepared by reference method; Bagal et al., J Med Chem 2021, 64:17146-17183). The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-33) (103 mg, yield 94%). 1 H NMR(600MHz,DMSO-d6)δ9.35(s,1H),9.01(d,J=5.3Hz,1H),8.60–8.55(m,2H),8.10(d,J=5.3Hz,1H),7.22(d,J=7.9Hz,2H), 7.14(d,J=7.8Hz,2H),4.91(p,J=7.2Hz,1H),4.82&4.79(ABq,J=16.0Hz,2H),2.28(s,3H),1.36(d,J=7.0Hz,3H).HRMS(ESI)C 18 H19 N4O2 + [M+H] + Calculated value: 323.1503; measured value: 323.1501.

[0204] Example 33-2: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-33)

[0205] Step 1: Preparation of 3-hydroxy-2-phenyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Intermediate HR-01-143)

[0206] Following the procedure of Step 1 of Example 29, substituting N-phenylpyridinecarboxamide with isonicotinamide (CAS#3034-31-9, 2.00 g, 10.1 mmol), the remaining raw materials, reagents, and preparation method were the same as those of Step 1 of Example 29 to obtain a yellow solid compound (HR-01-143) (1.43 g, yield 62%). HRMS (ESI) C 12 H 11 N2O2 + [M+H] + Calculated value: 227.0816; Measured value: 227.0818.

[0207] Step 2: Preparation of pyrido[3,4-d]pyridazin-1(2H)-one (Intermediate HR-01-139)

[0208] Following the procedure of step 2 of Example 29, hydrazine hydrate (12 mL, 98%) was added to the intermediate HR-01-139 (1.39 g, 6.14 mmol). The remaining raw materials, reagents, and preparation methods were the same as those of step 2 of Example 29 to obtain the yellow solid intermediate HR-01-144 (797 mg, yield 88%). HRMS (ESI) C7H6N3O + [M+H] + Calculated value: 148.0506; measured value: 148.0509.

[0209] Step 3: Preparation of (S)-N-(1-(p-tolyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-33)

[0210] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-33) (103 mg, yield 94%). 1 H NMR(600MHz,DMSO-d6)δ9.35(s,1H),9.01(d,J=5.3Hz,1H),8.60–8.55(m,2H),8.10(d,J=5.3Hz,1H),7.22(d,J=7.9Hz ,2H),7.14(d,J=7.8Hz,2H),4.91(p,J=7.2Hz,1H),4.82&4.79(ABq,J=16.0Hz,2H),2.28(s,3H),1.36(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ165.58,157.81,151.44,150.49,141.42,136.55,135.91,132. 23,128.97(2C),126.10(2C),124.19,118.37,53.89,48.02,22.58,20.81.HRMS(ESI)C 18 H 19 N4O2 + [M+H] + Calculated value: 323.1503; measured value: 323.1501.

[0211] Example 34: Preparation of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-34)

[0212] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-34) (110 mg, yield 94%). 1H NMR (600MHz, DMSO-d6) δ9.35(s,1H),9.01(d,J=5.3Hz,1H),8.65(d,J=7.8Hz,1H),8.59(s,1H),8.10(d,J=5 .3Hz,1H),7.42–7.37(m,2H),7.37–7.34(m,2H),4.93(p,J=7.1Hz,1H),4.82(s,2H),1.37(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ165.81,157.82,151.46,150.50,143.56,136.60,132.22,1 31.41,128.39(2C),128.09(2C),124.19,118.37,53.92,47.84,22.42.HRMS(ESI)C 17 H 16 ClN4O2 + [M+H] + Calculated value: 343.0957; Measured value: 343.0959.

[0213] Example 35: Preparation of (S)-N-(1-(p-Tolyl)ethyl)-2-(5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetamide (Compound I-35)

[0214] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced with a commercial reagent pyrido[2,3-d]pyridazin-5(6H)-one (CAS#15370-81-7). The remaining required raw materials, reagents and preparation methods were the same as in Example 1 to obtain a white solid compound (I-35) (85 mg, yield 77%). 1 H NMR (800MHz, DMSO-d6) δ9.16(dd,1H),8.61(dd,J=8.1,2.1Hz,1H),8.58(d,J=8.0Hz,1H),8.49(s,1H),7.88(dd,J=8.1,4.5Hz,1H),7. 21(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),4.90(p,J=7.4Hz,1H),4.82&4.79(ABq,J=16.0Hz,2H),2.27(s,3H),1.36(d,J=7.0Hz,3H). 13C NMR(201MHz,DMSO-d6)δ165.28,158.48,155.73,145.76,141.02,138.79,135.49,134. 20,128.55(2C),126.60,125.68(2C),123.35,53.28,47.59,22.17,20.39.HRMS(ESI)C 18 H 19 N4O2 + [M+H] + Calculated value: 323.1503; measured value: 323.1501.

[0215] Example 36: Preparation of (S)-N-(1-(4-chlorophenyl)ethyl)-2-(5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetamide (Compound I-36)

[0216] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[2,3-d]pyridazine-5(6H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-36) (89 mg, yield 76%). 1 H NMR(800MHz,DMSO-d6)δ9.16(dd,J=4.5,1.8Hz,1H),8.66(d,J=7.9Hz,1H),8.61(dd,J=8.1,2.4Hz,1H),8.50(s,1H),7.8 7(dd,J=8.0,4.5Hz,1H),7.40–7.37(m,2H),7.37–7.34(m,2H),4.93(p,J=7.4Hz,1H),4.82(s,2H),1.37(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ166.03,159.01,156.27,146.29,143.68,139.37,134.73,1 31.51,128.49(2C),128.19(2C),127.14,123.87,53.85,47.94,22.53.HRMS(ESI)C 17 H 16 ClN4O2 + [M+H] + Calculated value: 343.0957; Measured value: 343.0956.

[0217] Example 37: Preparation of (S)-N-(1-(4-bromophenyl)ethyl)-2-(5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetamide (Compound I-37)

[0218] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-bromophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[2,3-d]pyridazine-5(6H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-37) (87 mg, yield 66%). 1 H NMR (800MHz, DMSO-d6) δ9.16(dd,J=4.5,1.8Hz,1H),8.67(d,J=7.8Hz,1H),8.61(d,J=8.1Hz,1H),8.50(s,1H),7.88(d d,J=8.1,4.5Hz,1H),7.54–7.51(m,2H),7.31–7.27(m,2H),4.91(p,J=7.3Hz,1H),4.81(s,2H),1.36(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ166.04,159.01,156.27,146.29,144.13,139.37,134.73,1 31.41(2C),128.58(2C),127.14,123.87,119.98,53.84,48.01,22.48.HRMS(ESI)C 17 H 16 ClN4O2 + [M+H] + Calculated value: 387.0452; Measured value: 387.0453.

[0219] Example 38: Preparation of (S)-N-(1-(p-Tolyl)ethyl)-2-(7-chloro-1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-38)

[0220] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-methylphenyl)ethanamine, and 1,7-naphthyridin-8(7H)-one was replaced with the commercial reagent 7-chloro-2,6-naphthyridin-1(2H)-one (CAS#1393568-79-0). The remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-38) (40 mg, yield 40%). 1H NMR (600MHz, DMSO-d6) δ8.96(s,1H),8.65(d,J=7.9Hz,1H),8.01(s,1H),7.56(d,J=7.4Hz,1H),7.21(d,J=7.8Hz,2H),7.13(d, J=7.8Hz,2H),6.76(d,J=7.3Hz,1H),4.88(p,J=7.2Hz,1H),4.69&4.66(ABq,J=15.9Hz,2H),2.27(s,3H),1.36(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ165.22,158.84,150.07,146.24,140.86,136.29,135.43,131.95, 130.67,128.46(2C),125.61(2C),119.06,101.12,50.77,47.56,22.13,20.28.HRMS(ESI)C 19 H 19 ClN3O2 + [M+H] + Calculated value: 356.1161; Measured value: 356.1161.

[0221] Example 39: Preparation of (S)-N-(1-(4-bromophenyl)ethyl)-2-(7-chloro-1-oxo-2,6-naphthyridin-2(1H)-yl)acetamide (Compound I-39)

[0222] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by 7-chloro-2,6-naphthyridine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-39) (80 mg, yield 76%). 1 H NMR(600MHz, DMSO-d6)δ8.96(s,1H),8.74(d,J=7.8Hz,1H),8.01(s,1H),7.56(d,J=7.4Hz,1H),7.41–7.34( m,4H),6.77(d,J=7.4Hz,1H),4.92(p,J=7.1Hz,1H),4.70&4.67(ABq,J=15.8Hz,2H),1.37(d,J=7.0Hz,3H). 13C NMR (201MHz, DMSO-d6) δ165.55,158.96,150.18,146.36,143.09,136.35,132.05,131. 03,130.77,127.98(2C),127.70(2C),119.16,101.28,50.91,47.47,22.07.HRMS(ESI)C 18 H 16 Cl2N3O2 + [M+H] + Calculated value: 376.0615; Measured value: 376.0615.

[0223] Example 40: Preparation of (S)-N-(1-(3,4-dichlorophenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-40)

[0224] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(3,4-dichlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-40) (114 mg, yield 88%). 1 H NMR (800MHz, DMSO-d6) δ9.35 (s, 1H), 9.01 (d, J = 5.3Hz, 1H), 8.69 (d, J = 7.7Hz, 1H), 8.59 (s, 1H), 8.10 (d, J = 5.3Hz, 1H), 7.6 1–7.57(m,2H),7.33(dd,J=8.2,2.1Hz,1H),4.93(p,J=7.1Hz,1H),4.84&4.81(ABq,J=16.0Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ166.30,158.11,151.76,150.79,146.13,136.93,132.50,131. 40,130.92,129.65,128.55,126.93,124.47,118.63,54.30,47.95,22.57.HRMS(ESI)C 17 H 15 Cl2N4O2 + [M+H] + Calculated value: 377.0567; Measured value: 377.0566.

[0225] Example 41: Preparation of (S)-N-(1-(4-chloro-3-fluorophenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-41)

[0226] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-chloro-3-fluorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazin-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-41) (73 mg, yield 59%). 1 H NMR (800MHz, DMSO-d6) δ9.35(s,1H),9.00(d,J=5.3Hz,1H),8.68(d,J=7.7Hz,1H),8.58(s,1H),8.09(d,J=5.3Hz,1H),7.54(t,J=8.0Hz,1H),7.3 7(dd,J=10.7,2.0Hz,1H),7.20(dd,J=8.3,2.0Hz,1H),4.94(p,J=7.1Hz,1H),4.85&4.82(ABq,J=15.9Hz,2H),1.37(d,J=7.1Hz,3H).HRMS(ESI)C 17 H 15 ClFN4O2 + [M+H] + Calculated value: 361.0863; Measured value: 361.0868.

[0227] Example 42: Preparation of (S)-N-(1-(4-bromophenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-42)

[0228] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-bromophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-42) (87 mg, yield 66%). 1H NMR (800MHz, DMSO-d6) δ9.35(s,1H),9.00(d,J=5.3Hz,1H),8.65(d,J=7.8Hz,1H),8.58(s,1H),8.09(d,J=5.2Hz,1H) ,7.54–7.50(m,2H),7.31–7.27(m,2H),4.90(p,J=7.2Hz,1H),4.82&4.80(ABq,J=15.9Hz,2H),1.36(d,J=7.0Hz,3H). 13 C NMR(201MHz,DMSO-d6)δ166.09,158.10,151.75,150.78,144.29,136.89,132.50,1 31.58(2C),128.75(2C),124.47,120.16,118.65,54.20,48.19,22.65.HRMS(ESI)C 17 H 16 BrN4O2 + [M+H] + Calculated value: 387.0452; measured value: 387.0462.

[0229] Example 43: Preparation of (S)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-43)

[0230] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(4-trifluoromethoxyphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-43) (118 mg, yield 88%). 1 H NMR (800MHz, DMSO-d6) δ9.35(s,1H),9.00(d,J=5.3Hz,1H),8.68(d,J=7.8Hz,1H),8.58(s,1H),8.09(d,J=5.3Hz,1 H),7.47–7.43(m,2H),7.33(d,J=8.2Hz,2H),4.97(p,J=7.2Hz,1H),4.82(s,2H),1.38(d,J=7.0Hz,3H).HRMS(ESI)C 18 H 16 F3N4O3 + [M+H] +Calculated value: 393.1170; measured value: 393.1174.

[0231] Example 44: Preparation of (S)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-2-(8-oxopyrido[2,3-d]pyridazin-7(8H)-yl)acetamide (Compound I-44)

[0232] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-trifluoromethylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced with pyrido[2,3-d]pyridazine-8(7H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-44) (80 mg, yield 62%). 1 H NMR (800MHz, DMSO-d6) δ9.09(dd,J=4.4,1.7Hz,1H),8.74(d,J=7.6Hz,1H),8.46(s,1H),8.41(dd,J=8.0,1.7Hz,1H),7.94(dd,J=8 .0,4.4Hz,1H),7.70(d,J=8.1Hz,2H),7.56(d,J=8.0Hz,2H),5.01(p,J=7.1Hz,1H),4.84(s,2H),1.41(d,J=7.0Hz,3H).HRMS(ESI)C 18 H 16 F3N4O2 + [M+H] + Calculated value: 377.1220; measured value: 377.1230.

[0233] Example 45: Preparation of (S)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)-2-(5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetamide (Compound I-45)

[0234] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-(4-trifluoromethylphenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced with the commercial reagent pyrido[2,3-d]pyridazine-5(6H)-one. The remaining required raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-45) (117 mg, yield 91%). 1H NMR (800MHz, DMSO-d6) δ9.18–9.14(m,1H),8.76(d,J=7.6Hz,1H),8.63–8.59(m,1H),8.51–8.48(m,1H),7.90–7.85(m,1H ),7.70(dd,J=8.4,3.4Hz,2H),7.56(d,J=8.0Hz,2H),5.05–4.98(m,1H),4.85(s,2H),1.41(d,J=7.0Hz,3H).HRMS(ESI)C 18 H 16 F3N4O2 + [M+H] + Calculated value: 377.1220; measured value: 377.1224.

[0235] Example 46: Preparation of (S)-N-(1-(3,4-dichlorophenyl)ethyl)-2-(8-oxopyrido[2,3-d]pyridazin-7(8H)-yl)acetamide (Compound I-46)

[0236] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(3,4-dichlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[2,3-d]pyridazine-8(7H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a yellow solid compound (I-46) (94 mg, yield 73%). 1 H NMR (800MHz, DMSO-d6) δ9.09(dd,J=4.5,1.7Hz,1H),8.67(d,J=7.7Hz,1H),8.46(s,1H),8.41(dd,J=8.0,1.7Hz,1H),7.93(dd,J=8.0,4.5Hz ,1H),7.59(dd,J=5.2,3.1Hz,2H),7.33(dd,J=8.3,2.1Hz,1H),4.93(p,J=7.1Hz,1H),4.84&4.82(ABq,J=16.1Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ166.38,158.41,154.45,146.02,143.32,137.41,135.78,131. 20,130.74,129.46,128.43,128.38,126.77,126.49,54.23,47.75,22.40.HRMS(ESI)C 17 H 15Cl2N4O2 + [M+H] + Calculated value: 377.0567; Measured value: 377.0568.

[0237] Example 47: Preparation of (S)-N-(1-(3,4-dichlorophenyl)ethyl)-2-(5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetamide (Compound I-47)

[0238] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(3,4-dichlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[2,3-d]pyridazine-5(6H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-47) (120 mg, yield 93%). 1 H NMR (800MHz, DMSO-d6) δ9.16(dd,J=4.5,1.7Hz,1H),8.69(d,J=7.7Hz,1H),8.61(dd,J=7.9,1.9Hz,1H),8.50(s,1H),7.88(dd,J=8.1,4 .5Hz,1H),7.61–7.58(m,2H),7.33(dd,J=8.3,2.1Hz,1H),4.93(p,J=7.1Hz,1H),4.85&4.81(ABq,J=16.0Hz,2H),1.37(d,J=7.0Hz,3H). 13 C NMR (201MHz, DMSO-d6) δ165.82,158.61,155.87,145.88,145.55,138.99,134.30,130. 80,130.33,129.05,127.97,126.75,126.34,123.47,53.55,47.35,21.99.HRMS(ESI)C 17 H 15 Cl2N4O2 + [M+H] + Calculated value: 377.0567; Measured value: 377.0565.

[0239] Example 48: Preparation of (S)-N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-48)

[0240] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(2-chloro-4-fluorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazin-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-48) (97 mg, yield 79%). 1 H NMR (800MHz, DMSO-d6) δ9.34(s,1H),9.00(d,J=5.3Hz,1H),8.80(d,J=7.4Hz,1H),8.58(s,1H),8.08(d,J=5.3Hz,1H),7.52(dd,J=8. 7,6.1Hz,1H),7.38(dd,J=8.8,2.7Hz,1H),7.29–7.24(m,1H),5.18(p,J=7.0Hz,1H),4.83(s,2H),1.34(d,J=7.0Hz,3H).HRMS(ESI)C 17 H 15 ClFN4O2 + [M+H] + Calculated value: 361.0863; Measured value: 361.0864.

[0241] Example 49: Preparation of (S)-N-(1-(2-chloro-4-fluorophenyl)ethyl)-2-(5-oxopyrido[2,3-d]pyridazin-6(5H)-yl)acetamide (Compound I-49)

[0242] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced with (S)-1-((2-chloro-4-fluorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced with pyrido[2,3-d]pyridazin-5(6H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to give a white solid compound (I-49) (115 mg, yield 93%). 1H NMR (800MHz, DMSO-d6) δ9.16 (dd, J=4.5, 1.7Hz, 1H), 8.80 (d, J=7.4Hz, 1H), 8.6 0(dt,J=8.0,1.1Hz,1H),8.49(s,1H),7.87(dd,J=8.1,4.5Hz,1H),7.52(dd,J= 8.7,6.1Hz,1H),7.38(dd,J=8.8,2.6Hz,1H),7.26(td,J=8.5,2.7Hz,1H),5.18 (p,J=7.0Hz,1H),4.83(s,2H),3.32(s,3H),1.34(d,J=6.9Hz,3H).HRMS(ESI)C 17 H 15 ClFN4O2 + [M+H] + Calculated value: 361.0863; Measured value: 361.0869.

[0243] Example 50: Preparation of (S)-N-(1-(2,4-dichlorophenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-50)

[0244] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(2,4-dichlorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-50) (100 mg, yield 77%). 1 H NMR (600MHz, DMSO-d6) δ9.34 (s, 1H), 9.00 (d, J = 5.3Hz, 1H), 8.83 (d, J = 7.3Hz, 1H), 8.58 (s, 1H), 8.08 (d, J = 5. 3Hz,1H),7.56(d,J=2.0Hz,1H),7.52–7.44(m,2H),5.16(p,J=7.0Hz,1H),4.83(s,2H),1.34(d,J=7.0Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ166.17,158.04,151.72,150.73,141.49,136.85,132.63,132.42(d, J=4.0Hz),129.05,128.70,128.11,124.39,118.58,54.07,45.99,40.47,21.23.HRMS(ESI)C17 H 15 Cl2N4O2 + [M+H] + Calculated value: 377.0567; Measured value: 377.0570.

[0245] Example 51: Preparation of (S)-N-(1-(3,4-difluorophenyl)ethyl)-2-(1-oxopyrido[3,4-d]pyridazin-2(1H)-yl)acetamide (Compound I-51)

[0246] The (S)-1-(4-fluorophenyl)ethanamine in Example 1 was replaced by (S)-1-(3,4-difluorophenyl)ethanamine, and 1,7-naphthyridine-8(7H)-one was replaced by pyrido[3,4-d]pyridazine-1(2H)-one. The remaining raw materials, reagents and preparation methods were the same as those in Example 1 to obtain a white solid compound (I-51) (96 mg, yield 82%). 1 H NMR (600MHz, DMSO-d6) δ9.35(s,1H),9.00(d,J=5.3Hz,1H),8.65(d,J=7.8Hz,1H),8.58(s,1H),8.09(d,J=5.2Hz,1H),7.42 –7.34(m,2H),7.20–7.14(m,1H),4.93(p,J=7.1Hz,1H),4.84&4.81(ABq,J=16.0Hz,2H),1.36(d,J=7.0Hz,3H).HRMS(ESI)C 17 H 15 F2N4O2 + [M+H] + Calculated value: 345.1158; measured value: 345.1161.

[0247] Biological Test Example 1: Agonist Activity of the Compounds of the Invention on GPR139

[0248] The agonist activity of the compounds of the present invention on GPR139 was determined by Ca 2+ The calcium flux assay (Molecular Devices) was used for determination. The specific operation method is as follows:

[0249] 1. Cell culture (CHO-K1 cell line, cell culture medium: 500 mL Ham's F12 + 50 mL 10% FBS + 5 mL 1% PS (Penicillin-Streptomycin);

[0250] 2. In a 10 cm culture dish, wash the cells with 2 mL of PBS buffer (HyClone, Cat#SH30028.02), remove the buffer, and then add 1 mL of trypsin (Thermo, Cat#25300054) to digest the cells for 2 minutes;

[0251] 3. Add 2 mL of cell culture medium (Ham's F12 + 10% FBS + 1% PS) to stop digestion, mix thoroughly by pipetting, and centrifuge at 1000 rpm for 3 minutes;

[0252] 4. Resuspend the cells in 1 mL of cell culture medium (Ham's F12 + 10% FBS + 1% PS) and count the cells to adjust the cell density to 3×10 6 cells / mL and add 10 mL of culture medium;

[0253] 5. Transient cell transfection [transfection ratio 1 μg GPR139 DNA / 10 cm + 16 μL TransIT-2020 + 1000 μL Opti-MEM];

[0254] 6. Add 1 μg DNA to 500 μL Opti-MEM, mix well by pipetting, and incubate at room temperature for 5 minutes;

[0255] 7. Add 16 μL TransIT-2020 to 500 μL Opti-MEM, mix well by pipetting, and incubate at room temperature for 5 minutes;

[0256] 8. Add the TransIT-2020 solution dropwise to the DNA suspension, incubate at room temperature for 15 minutes, add to a 10 cm cell dish, and incubate at 37°C, 5% CO2 for 20 hours.

[0257] 9. Remove the cells from the 10 cm culture dish, wash the cells with 2 mL of PBS buffer, remove the buffer, and then add 1 mL of trypsin to digest the cells for 2 minutes;

[0258] 10. Add 2 mL of cell culture medium (Ham's F12 + 10% FBS + 1% PS) to terminate digestion, mix thoroughly by pipetting, and centrifuge at 1000 rpm for 3 minutes;

[0259] 11. Resuspend the cells in 1 mL of cell culture medium (Ham's F12 + 10% FBS + 1% PS) and count the cells to adjust the cell density to 3.75 × 10 5 cells / mL;

[0260] 12. Add 40 μL of cell solution to each well of a 384-well black plate (Greiner, Cat#781091), with 15,000 cells per well, and incubate at 37°C, 5% CO2 for 16 hours.

[0261] 13. Prepare the test compound into a 10 mM DMSO solution, then dilute to 30 μM with 0.1% BSA (HBSS + 20 mM HEPES, pH 7.4), and then perform a 3-fold serial dilution to 16 concentration points. For the agonist positive control, TAK-041, start at 30 μM and perform a 3-fold serial dilution to 10 concentration points.

[0262] 14. Use a pipette to transfer different concentrations of the test compound to a 384-well plate (Greiner, Cat#784201), 20 μL per well, and centrifuge at 1000 rpm for 1 minute.

[0263] 15. Remove the cell culture medium from the 384-well black plate and add 20 μL of 1× dye (FLIPR Calcium 6 Assay Explorer Kit, Cat# R8190) solution to each well. Incubate at 37°C for 60 minutes; incubate at room temperature for 10 minutes.

[0264] 16. Using a FLIPR (Molecular Devices) instrument, transfer the test compound at various concentrations to a 384-well black plate, 10 μL per well, and read calcium flux using the FLIPR (maximum excitation: 470–495 nm, maximum emission: 515–575 nm).

[0265] 17. Data were analyzed using GraphPad Prism (version 8.0) and presented as mean ± standard deviation. Concentration-response curves were fitted using nonlinear regression.

[0266] Results: The agonist activities of the compounds of the present invention on GPR139 are shown in Tables 1 and 2.

[0267] Table 1.

[0268] Note: a The values ​​are mean values, n=2. b NT means not tested.

[0269] In the above table, E max =maximum effect of the compound of the present application / maximum effect of TAK-041.

[0270] Compound E of the present invention max Basically, the agonist activity is 70% or above, and all are full agonists of GPR139. Compared with TAK-041, the compounds of the present invention have equivalent or better agonist activity.

[0271] Table 2.

[0272] Note: a Values ​​are mean ± SEM, n ≥ 3. b NT means not tested.

[0273] In the above table, E max =maximum effect of the compound of the present application / maximum effect of TAK-041.

[0274] Compound E of the present invention max Basically, the activity is 70% or above, and all are full agonists of GPR139. Compared with TAK-041, the present invention has equivalent or better agonist activity.

[0275] Biological Test Example 2: Pharmacokinetic Study of Compounds in Mice after Intraperitoneal Injection

[0276] After a single intraperitoneal injection of the compound into male mice, plasma, brain tissue, and cerebrospinal fluid were collected at different time points. The concentrations of the compound in mouse plasma, brain tissue, and cerebrospinal fluid (CSF) were determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetic characteristics and brain tissue distribution of the compound in mice.

[0277] 2.1 Experimental design

[0278] Eighteen male C57 mice were randomly divided into two groups of nine mice based on body weight. The mice were fasted (but not water) for 12-14 hours prior to dosing and fed 4 hours after dosing. The compound vehicle was 10% DMSO + 10% solutol (polyethylene glycol-12 hydroxystearate) + 80% saline.

[0279] 2.2 Sample collection

[0280] Plasma sampling: At blood collection time points (30 minutes, 2 hours, and 6 hours) after intraperitoneal injection of the test substance, 0.1 mL of blood was collected from the orbital cavity under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and stored in an ice bath. Centrifuge at 5000 rpm, 4°C for 10 minutes, and collect the upper serum. All plasma samples were stored at -80°C before analysis. At brain tissue and cerebrospinal fluid collection time points (30 minutes, 2 hours, and 6 hours), the brain tissue was collected after the mouse was euthanized by bleeding, cleaned, accurately weighed, and homogenized with 50% methanol-water solution at a ratio of 1:4 (g / mL). The homogenate samples were stored at -80°C pending analysis.

[0281] 2.3 Data Processing

[0282] The data acquisition and control system software was Analyst 1.5.1 (Applied Biosystems). The peak integration method for the chromatogram samples was automatic integration; the ratio of the sample peak area to the internal standard peak area was used as an indicator and regressed with the sample concentration. Regression method: linear regression with a weighting factor of 1 / X. 2 Pharmacokinetic parameters were analyzed using WinNonlin Professional v6.3 (Pharsight, USA) using a non-compartmental model. max The area under the plasma concentration-time curve AUC is the maximum measured plasma concentration. (0→t) Calculated by the trapezoidal method, T max The experimental data were expressed as "mean ± standard deviation" (n≥3) or "mean" (n=2).

[0283] 2.4 Experimental Results

[0284] Compounds I-1 to I-51 of the present invention exhibit good brain penetration, relatively high free drug concentrations in cerebrospinal fluid, and excellent metabolic properties, making them suitable for further pharmacodynamic studies. Compounds I-34 and I-47, in particular, exhibit excellent brain penetration and metabolic properties.

[0285] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, in, X 1 N or CR X1 ; X 2 N or CR X2 ; X 3 N or CR X3 ; X 4 N or CR X4 ; X 5 N or CR X5 ; R X1 、R X2 、R X3 、R X4 、R X5 are independently H or halogen; R 1 H, halogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, OC 1-6 Alkyl, 1 or more R 1-1 Substituted C 1-6 Alkyl, 1 or more R 1-2 Substituted C 3-6 Cycloalkyl, or one or more R 1-3 Replaced OC 1-6 alkyl; R 1-1 、R 1-2 and R 1-3 are independently halogen; R 2 H or C 1-6 alkyl; R 3 and R 4 Independently H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 1 or more R 4-1 Substituted C 1-6 Alkyl, or one or more R 4-2 Substituted C 3-6 Cycloalkyl; R 4-1 are independently halogen, OC 1-6 Alkyl or -NR a R b ; R 4-2 are independently halogen, OC 1-6 Alkyl or -NR a R b ; R a and R b Independently C 1-6 alkyl; Or, R a and R b Together with the nitrogen atom to which it is connected, it forms a 5-6 membered heterocycloalkyl group or is surrounded by one or more R a-1 Substituted 5-6 membered heterocycloalkyl; the 5-6 membered heterocycloalkyl is a 5-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S; R a-1 Independently C 1-6 alkyl; Q is C 6-10 Aryl or 5-10 membered heteroaryl; the 5-10 membered heteroaryl is a 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S; n is 0, 1, 2, 3, 4 or 5; R 5 are independently halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, 1 or more R 5-1 Substituted C 1-6 Alkyl, or one or more R 5-2 Replaced OC 1-6 alkyl; R 5-1 and R 5-2 are independently halogen; Or, R 4 、R 5 Together with the atoms it is connected to form (CH2) m , m is 2 or 3.

2. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I satisfies one or more of the following conditions: (1)X 1 is N or CH; X 2 N, CH or CR X2 ;X 3 is N or CH; X 4 is N or CH; X 5 is N or CH; R X2 is halogen, preferably chlorine; (2)R 1 is H; (3)R 2 is H; (4)R 3 and R 4 are independently H or C 1-6 alkyl; (5)Q is C 6-10 aryl; (6) n is 0, 1 or 2; preferably 1 or 2; (7)R 5 are independently halogen, C 1-6 Alkyl, OC 1-6 Alkyl, 1 or more R 5-1 Substituted C 1-6 Alkyl, or one or more R 5-2 Replaced -OC 1-6 Alkyl; preferably, R 5 are independently F, Cl, Br or C 1-6 alkyl; (8)R 5-1 and R 5-2 are independently F or Cl.

3. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I satisfies one or more of the following conditions: (1)R 1 、R 2 、R 3 、R 4 、R a 、R b 、R a-1 and R 5 In the C 1-6 Alkyl is C 1-4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl; (2)R 1 In the 1-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl, R 3 and R 4 One or more R 4-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl, and R 5 One or more R 5-1 Substituted C 1-6 C in the alkyl group 1-6 Alkyl is C 1-4 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example methyl; (3)R 1 、R 4-1 、R 4-2 and R 5 In the OC 1-6 Alkyl is OC 1-4 Alkyl, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example methoxy or ethoxy; (4)R 1 In the 1-3 Replaced OC 1-6 OC in alkyl 1-6 Alkyl and R 5 One or more R 5-2 Replaced OC 1-6 OC in alkyl 1-6 Alkyl is OC 1-4 Alkyl, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example methoxy; (5) In Q, the C 6-10 Aryl is phenyl or naphthyl; (6)R 5 wherein the halogen is F, Cl or Br; more preferably Cl or Br; (7)R 5-1 、R 5-2 and R X2 wherein the halogen is F or Cl.

4. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I satisfies one or more of the following conditions: (1) for Preferred (2) Ring Q is phenyl or naphthyl; (3) for Preferably More preferably (4) for For example 5. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I satisfies any of the following schemes: Scheme 1: The compound represented by formula I is shown below in, X 1 N or CH; X 2 N, CH or CR X2 ; R X2 is a halogen; X 3 N or CH; X 4 N or CH; X 5 N or CH; R 1 、R 2 and R 3 independently H; R 4 H or C 1-6 alkyl; Q is C 6-10 aryl; When Q is naphthyl, n is 0; When Q is phenyl, n is 0, 1 or 2; each R 5 are independently halogen, C 1-6 Alkyl, OC 1-6 Alkyl, 1 or more R 5-1 Substituted C 1-6 Alkyl, or one or more R 5-2 Replaced -OC 1-6 alkyl; Each R 5-1 and R 5-2 are independently halogen; Scheme 2: The compound represented by formula I is shown below in, X 1 N or CH; X 2 N or CH; X 3 N or CH; X 4 N or CH; X 5 N or CH; R 4 C 1-6 alkyl; R 5-a Cl, Br or C 1-6 Alkyl; R 5-b is H; or R 5-a Cl; R 5-b is F or Cl; Scheme 3: The structure of the compound represented by Formula I is shown in Formula I-1 or Formula I-2: Among them, R 1 、R 2 、R 3 、R 4 、R 5 , Q and n are defined as described in any one of claims 1-4; Preferably, R 1 is H; Preferably, R 2 is H; Preferably, R 3 H, R 4 Methyl Preferably, R 5 is a halogen, such as Cl; Preferably, Q is C 6-10 aryl groups, such as phenyl; Preferably, n is 1 or 2; More preferably, for Scheme 4: The structure of the compound represented by Formula I is shown in Formula I-1A or Formula I-2A: Among them, R 5 , Q and n are defined as described in any one of claims 1-4; Preferably, Q is C 6-10 aryl groups, such as phenyl; Preferably, R 5 is a halogen, such as Cl; Preferably, n is 1 or 2; More preferably, for 6. The compound of formula I according to claim 1, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate, characterized in that: The compound represented by formula I is selected from any one of the following compounds, 7. A method for preparing a compound of formula I, comprising the following steps: The compound represented by formula II and the compound represented by formula III are subjected to the substitution reaction shown below to prepare the compound represented by formula I; Among them, R 6 is a halogen; X 1 、X 2 、X 3 、X 4 、X 5 、R 1 、R 2 、R 3 、R 4 、R 5 , Q and n are defined as described in any one of claims 1-6.

8. A pharmaceutical composition comprising (i) a compound of formula I according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutical excipient.

9. Use of a compound of formula I according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament or a GPR139 receptor agonist; the medicament is used to treat and / or prevent schizophrenia, bipolar disorder, depression, cognitive impairment, autism spectrum disorder, sleep disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive-compulsive disorder, anxiety disorder, pain, or fibromyalgia.

10. Use of a compound of formula I according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing and / or treating diseases associated with the GPR139 receptor; Preferably, the drug is a GPR139 receptor agonist; And / or, the GPR139 receptor-related disease is schizophrenia, bipolar disorder, depression, cognitive impairment, autism spectrum disorder, sleep disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorder, obsessive-compulsive disorder, anxiety disorder, pain or fibromyalgia.

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