Heteroaryl compounds for the treatment of cancer

Abstract

The present invention relates to a compound of formula (I) [Case 1] TIFF2025526682000126.tif47170(in the formula, A 1 From A 7 and W are as described herein) and pharmaceutically acceptable salts thereof, as well as compositions comprising and methods of using said compounds.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for the treatment and / or prophylaxis in mammals, particularly inhibitors of CD73 useful for treating cancer.

[0002] Hyperactivation of the adenosine pathway contributes to an immunosuppressive tumor microenvironment (TME), which impairs antitumor immunity and limits the effectiveness of immune checkpoint inhibitors. In the final step of the adenosine pathway, the ecto-5'-nucleotidase (CD73) enzyme catalyzes the conversion of AMP to adenosine, which is recognized by adenosine receptors present on multiple immune cell types. This leads to the suppression of effector T cells and natural killer (NK) cells, the activation of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and other changes in the immune system that collectively result in an immunosuppressive environment. CD73 is frequently overexpressed in cancer, and its upregulation is associated with poor clinical prognosis. Preclinical studies in various in vivo tumor models have demonstrated the restoration of immune cell function and tumor growth inhibition upon genetic ablation or pharmacological inhibition of CD73. Therefore, alleviating the immunosuppressive TME by CD73 inhibition may have therapeutic potential to restore antitumor immunity, enhance the efficacy of immunotherapy, and induce tumor regression. Given the growing unmet need for effective cancer treatments, inhibition of CD73 activity by administering small molecules (SMs) holds promise. This disclosure describes the invention of novel small molecule CD73 inhibitors. Summary of the Invention

[0003] The present invention relates to a compound of formula (I) [ka] (In the formula, W is CH or N; A 1 and A 2 are each independently CH or N; A 3 and A 7are each independently C or N, A 4 , A 5 and A 6 are independently O, S, N, and CR 1 or NR 2 and R 1 is H, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or -L 1 -R 3 and R 2 is H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or -L 2 -R 3 and L 1 are O, S, NH, NR 3 , C 1-6 Alkylene, C 3-7 cycloalkylene, heteroarylene, or heterocyclylene; L 2 is C 1-6 Alkylene, C 3-7 cycloalkylene, heteroarylene, or heterocyclylene; R 3 is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloal C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, aryl, heteroaryl, heterocyclyl, arylC 1-6 Alkyl, heterocyclyl C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, aryl haloC 1-6 Alkyl, heterocyclyl haloC 1-6 Alkyl and Heteroaryl HaloC 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0004] The compound of formula (I) exhibits good CD73 inhibition. In another embodiment, the compound of the present invention exhibits excellent cancer cell inhibition. Furthermore, the compound of formula (I) also exhibits good or improved human hepatocyte stability, cytotoxicity, and solubility profiles. DETAILED DESCRIPTION OF THE INVENTION

[0005] definition "C 1-6 The term "alkyl" refers to saturated straight or branched chain alkyl groups containing 1 to 6, especially 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc. 1-6 "Alkyl" groups are methyl, ethyl, and n-propyl.

[0006] "C 1-6 The term "alkylene" refers to a linear or branched saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a divalent branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. 1-6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0007] "C 1~6 The term "alkoxy" refers to C 1~6 It represents alkyl-O-.

[0008] The terms "halogen" and "halo" are used interchangeably herein to refer to fluoro, chloro, bromo, or iodo.

[0009] "Haro C 1~6 The term "alkyl" refers to 1~6 C in which at least one hydrogen atom of the alkyl group is replaced by the same or different halogen atom, in particular a fluoro atom 1~6Indicates an alkyl group. HaloC 1-6 Examples of alkyl include monofluoro-, difluoro- or trifluoro-methyl, -ethyl or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0010] "Haro C 1~6 The term "alkoxy" refers to haloC 1~6 It represents alkyl-O-.

[0011] The term "halophenyl" means a phenyl group in which at least one of the hydrogen atoms of the phenyl group has been replaced by the same or different halogen atom, particularly a chloro or fluoro atom. Examples of halophenyl include chlorophenyl or fluorophenyl.

[0012] The term "halopyridinyl" means a pyridinyl group in which at least one of the hydrogen atoms of the pyridinyl group has been replaced by the same or different halogen atom.

[0013] The term "halopyridazinyl" means a pyridazinyl group in which at least one of the hydrogen atoms of the pyridazinyl group has been replaced by the same or different halogen atom.

[0014] "C 3~7 The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon radical containing 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings having one or more carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0015] "C 3-7The term "cycloalkylene" refers to a divalent C 3-7 It means a cycloalkyl group.

[0016] The terms "heterocyclic group," "heterocyclic," "heterocycle," "heterocyclyl," or "heterocyclo" are used interchangeably and refer to any mono-, bi-, tricyclic, spiro-, or bridged, saturated, partially saturated, or unsaturated non-aromatic ring system having 3 to 20 ring atoms, in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the ring system is a heteroatom, the system is heterocyclic, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl contains 3 to 11 ring atoms ("members"), including mono-, bi-, tricyclic, spiro-, and bridged ring systems in which the ring atoms are carbon and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl contains 4 to 10, or 5 to 10 ring atoms. In one example, a heterocyclyl contains 1 to 4 heteroatoms. In one example, a heterocyclyl includes 1 to 3 heteroatoms. In another example, a heterocyclyl includes a 3- to 7-membered monocyclic ring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl includes a 4- to 6-membered monocyclic ring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl includes a 3-membered monocyclic ring. In another example, a heterocyclyl includes a 4-membered monocyclic ring. In another example, a heterocyclyl includes a 5- to 6-membered monocyclic ring. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, a heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be optionally oxidized (e.g., NO, SO, SO), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR]). + Cl - , [NR4] + OH -Examples of heterocycles include oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothio ... Hydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, 1,1-dioxoisothiazolyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Benzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl yl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl, and 2,3,4a,5,7,7a-hexahydro-[1,4]dioxino[2,3-c]pyrrolyl.

[0017] The term "heterocyclylene" refers to a divalent heterocyclyl group.

[0018] The term "aryl" means a monovalent aromatic carbocyclic mono- or bicyclic ring system containing 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.

[0019] The term "arylene" means a divalent aryl group.

[0020] The term "heteroaryl" refers to any mono-, bi-, or tricyclic aromatic ring system containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur; in exemplary embodiments, at least one heteroatom is nitrogen. See, e.g., Lang's Handbook of Chemistry (Dean, J.A., ed.) 13 thed. Table 7-2

[1985] . This definition includes any bicyclic group in which any of the above heteroaryl rings is fused to an aryl ring, and either the aryl ring or the heteroaryl ring is attached to the remainder of the molecule. In one embodiment, heteroaryl includes 5- to 6-membered monocyclic aromatic groups in which one or more ring atoms is nitrogen, sulfur, or oxygen. In one embodiment, heteroaryl includes 7- to 12-membered bicyclic aromatic groups in which one or more ring atoms is nitrogen, sulfur, or oxygen. Exemplary heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl, 1H-pyrazolo[3,4-d]pyrimidine, 1H-pyrazolo[3,4-d]pyridazine, imidazo[1,5-a]pyrazine, and the like. phenylene, imidazo[5,1-f][1,2,4]triazine, [1,2,4]triazolo[4,3-a]pyrazine, 1H-pyrazolo[3,4-c]pyridazine, 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[4,3-d]pyrimidine, 1H-pyrazolo[3,4-c]pyridine, 1H-pyrazolo[4,3-c]pyridine and purinyl, and benzo-fused derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl, and indolyl.

[0021] The term "heteroarylene" means a divalent heteroaryl group.

[0022] In certain embodiments, the heterocyclyl or heteroaryl group is bonded at a carbon atom of the heterocyclyl or heteroaryl group. For example, carbon-bonded heterocyclyl groups include those bonded at the 2-, 3-, 4-, 5-, or 6-positions of the pyridine ring, the 3-, 4-, 5-, or 6-positions of the pyridazine ring, the 2-, 4-, 5-, or 6-positions of the pyrimidine ring, the 2-, 3-, 5-, or 6-positions of the pyrazine ring, the 2-, 3-, 4-, or 5-positions of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, the 2-, 4-, or 5-positions of the oxazole, imidazole, or thiazole ring, the 3-, 4-, or 5-positions of the isoxazole, pyrazole, or isothiazole ring, the 2-, or 3-positions of the aziridine ring, the 2-, 3-, or 4-positions of the azetidine ring, the 2-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the quinoline ring, or the 1-, 3-, 4-, 5-, 6-, 7-, or 8-positions of the isoquinoline ring.

[0023] In certain embodiments, the heterocyclyl or heteroaryl group is N-linked. For example, nitrogen-linked heterocyclyl or heteroaryl groups include aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole at the 1-position, isoindole or isoindole at the 2-position, morpholine at the 4-position, and carbazole or β-carboline at the 9-position.

[0024] In one embodiment, one skilled in the art will recognize that keto-enol tautomerism can exist for certain structures such as those shown below. [ka]

[0025] Unless otherwise specified, the term "optionally substituted" means that a group can be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any of these range variables) substituents listed for that group, which can be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In another embodiment, an optionally substituted group has five substituents.

[0026] The term "protecting group" or "PG" refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense conventionally associated with synthetic chemistry, can be carried out selectively at an otherwise unprotected reactive site. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino-protecting, carboxy-protecting, or hydroxy-protecting groups.

[0027] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

[0028] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and organic acids selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0029] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperidine, N-ethylpiperidine, and polyamine resins.

[0030] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced through metabolism in the body of a particular compound or its salt. After entering the body, most drugs become substrates for chemical reactions that can alter their physical properties and biological effects. These metabolic transformations usually affect the polarity of the compounds of the present invention and change how the drug is distributed in and excreted from the body. However, in some cases, drug metabolism is required for therapeutic effect.

[0031] The term "therapeutically effective amount" refers to an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition, or disorder, (ii) reduces, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. A therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0032] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, for administration to a mammal, e.g., a human in need thereof.

[0033] The terms "pharmaceutically acceptable excipient," "pharmaceutically acceptable carrier," and "therapeutically inactive excipient" are used interchangeably and refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition used in the preparation of a medicament, such as a disintegrant, binder, filler, solvent, buffer, tonicity agent, stabilizer, antioxidant, surfactant, carrier, diluent, or lubricant, that has no therapeutic activity and is non-toxic to a subject to which it is administered.

[0034] CD73 inhibitors The present invention relates to a compound represented by the formula (I): [ka] (In the formula, W is CH or N; A 1 and A 2 are each independently CH or N; A 3 and A 7 are each independently C or N, A 4 , A 5and A 6 are independently O, S, N, and CR 1 or NR 2 and R 1 is H, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or -L 1 -R 3 and R 2 is H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or -L 2 -R 3 and L 1 are O, S, NH, NR 3 , C 1-6 Alkylene, C 3-7 cycloalkylene, heteroarylene, or heterocyclylene; L 2 is C 1-6 Alkylene, C 3-7 cycloalkylene, heteroarylene, or heterocyclylene; R 3 is C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloal C 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, aryl, heteroaryl, heterocyclyl, arylC 1-6 Alkyl, heterocyclyl C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, aryl haloC 1-6 Alkyl, heterocyclyl haloC 1-6 Alkyl and Heteroaryl HaloC 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0035] Another embodiment of the present invention is a compound of formula (Ia) according to (ii)(i) [ka] (In the formula, W is CH; A 1 is N, R 1 is (C 1-6 alkyl)2amino, (C 1-6 Alkylhalopyrazolyl)C 1-6 Alkoxy, (C 1-6 Alkylhalopyridinyl)C 1-6 Alkoxy, (C 1-6 Alkylpyrazolyl)C 1-6 Alkoxy, (C 1-6 Alkylpyridinyl)C 1-6 Alkoxy, (C 1-6 Alkylpyridinyl)haloC 1-6 Alkoxy, (C 1-6 Alkylthiazolyl)C 1-6 Alkoxy, (cyanophenyl)C 1-6 Alkoxy, (HaloC 1-6 Alkylphenyl)C 1-6 Alkoxy, (halophenyl)C 1-6 Alkoxy, (halopyridazinyl)C 1-6 Alkoxy, (halopyridinyl)C 1-6 Alkoxy, (halopyridinyl) haloC 1-6 Alkoxy, (phenyl C 1-6 Alkyl)pyrazolyl, benzoxazolyl C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl(C 1-6 Alkyl)amino, C 3-7 Cycloalkyl C 1-6 Alkyl (C 1-6 Alkyl)amino, phenyl C 1-6 Alkoxy, Phenyl C 1-6 Alkyl, Phenyl C 1-6 Alkyl (C 1-6Alkyl)amino, phenyl C 1-6 Alkylamino, Phenyl C 3-7 Cycloalkyl, phenylhaloC 1-6 Alkoxy, pyridinyl C 1-6 Alkoxy or pyridinyl halo C 1-6 is an alkoxy, R 2 is C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0036] A further embodiment of the present invention is a compound of formula (Ia) according to (iii)(i) or (ii), or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1-6 Alkylpyridinyl)haloC 1-6 Alkoxy, (halopyridinyl) haloC 1-6 Alkoxy, (phenyl C 1-6 alkyl)pyrazolyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 Alkyl (C 1-6 Alkyl)amino, phenyl C 1-6 Alkoxy, Phenyl C 1-6 Alkyl, Phenyl C 1-6 Alkyl (C 1-6 Alkyl)amino, phenyl C 1-6 Alkylamino, Phenyl C 3-7 Cycloalkyl, phenylhaloC 1-6 Alkoxy, pyridinyl C 1-6 Alkoxy or pyridinyl halo C 1-6 It is an alkoxy.

[0037] A further embodiment of the present invention is (iv) a compound of formula (Ia) according to any one of (i) to (iii), or a pharmaceutically acceptable salt thereof, wherein R 1is (1-phenylethyl)amino, 1-(2-pyridinyl)ethoxy, 1-(2-pyridinyl)ethoxy, 1-cyclopentylethyl(methyl)amino, 1-phenylcyclopropyl, 1-phenylethoxy, 1-phenylethoxy, 1-phenylethyl, 2,2,2-trifluoro-1-(2-pyridinyl)ethoxy, 2,2,2-trifluoro-1-phenyl-ethoxy, 2,2-difluoro-1-(2-pyridinyl)ethoxy, 2,2-difluoro-1-(5-fluoro-2-pyridinyl)ethoxy, 2,2-difluoro-1-(6-methyl-2-pyridinyl)ethoxy, 2,2-difluoro-1-phenyl-ethoxy, 2-benzylpyrazol-3-yl, cyclobutyl or methyl(1-phenylethyl)amino.

[0038] A further embodiment of the present invention is (v) a compound of formula (Ia) according to any one of (i) to (iv), or a pharmaceutically acceptable salt thereof, wherein R 1 is (C 1-6 Alkylpyridinyl)haloC 1-6 Alkoxy, (halopyridinyl) haloC 1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkyl (C 1-6 Alkyl)amino, phenyl C 1-6 Alkoxy, Phenyl C 1-6 Alkyl (C 1-6 Alkyl)amino, phenyl C 1-6 Alkyl, Phenyl C 1-6 Alkylamino, phenylhaloC 1-6 Alkoxy, pyridinyl C 1-6 Alkoxy or pyridinyl halo C 1-6 It is an alkoxy.

[0039] A further embodiment of the present invention is (vi) a compound of formula (Ia) according to any one of (i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 1is (1-phenylethyl)amino, 1-(2-pyridinyl)ethoxy, 1-cyclopentylethyl(methyl)amino, 1-phenylethoxy, 1-phenylethyl, 2,2-difluoro-1-(2-pyridinyl)ethoxy, 2,2-difluoro-1-(5-fluoro-2-pyridinyl)ethoxy, 2,2-difluoro-1-(6-methyl-2-pyridinyl)ethoxy, 2,2-difluoro-1-phenyl-ethoxy or methyl(1-phenylethyl)amino.

[0040] A further embodiment of the present invention is a compound of formula (I) according to any one of (i) to (vi), wherein R 2 is methyl.

[0041] A further embodiment of the present invention is (viii) a compound of formula (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (v): W is CH; A 1 is N, R 1 is (C 1-6 Alkylpyridinyl)haloC 1-6 Alkoxy, (halopyridinyl) haloC 1-6 Alkoxy, C 3-7 Cycloalkyl C 1-6 Alkyl (C 1-6 Alkyl)amino, phenyl C 1-6 Alkoxy, Phenyl C 1-6 Alkyl (C 1-6 Alkyl)amino, phenyl C 1-6 Alkyl, Phenyl C 1-6 Alkylamino, phenylhaloC 1-6 Alkoxy, pyridinyl C 1-6 Alkoxy or pyridinyl halo C 1-6 is an alkoxy, R 2 is C 1-6 is alkyl, or a pharmaceutically acceptable salt thereof.

[0042] A further embodiment of the present invention is (ix) a compound of formula (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i) to (vi): W is CH; A 1 is N, R 1 is (1-phenylethyl)amino, 1-(2-pyridinyl)ethoxy, 1-cyclopentylethyl(methyl)amino, 1-phenylethoxy, 1-phenylethyl, 2,2-difluoro-1-(2-pyridinyl)ethoxy, 2,2-difluoro-1-(5-fluoro-2-pyridinyl)ethoxy, 2,2-difluoro-1-(6-methyl-2-pyridinyl)ethoxy, 2,2-difluoro-1-phenyl-ethoxy or methyl(1-phenylethyl)amino, R 2 is methyl, or a pharmaceutically acceptable salt thereof.

[0043] Another embodiment of the present invention is a compound of formula (Ib) according to (x)(i) [ka] (In the formula, W is CH; A 1 is N, R 1 is H or a halogen, R 2 is C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0044] A further embodiment of the present invention is a compound of formula (Ib) according to (xi)(x), wherein R 1 is a halogen.

[0045] A further embodiment of the present invention is a compound of formula (Ib) according to (xii) (x) or (xi), wherein R 1 is chloro.

[0046] A further embodiment of the present invention is (xiii) a compound of formula (Ib) according to any one of (x) to (xii), wherein R 2 is methyl.

[0047] A further embodiment of the present invention is (xiv) a compound of formula (Ib) according to any one of (x) to (xiii): W is CH; A 1 is N, R 1 is chloro, R 2 is methyl, or a pharmaceutically acceptable salt thereof.

[0048] Another embodiment of the present invention is a compound of formula (Ic) according to (xv)(i) [ka] (In the formula, W is CH; A 1 is N, R 2 is C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0049] A further embodiment of the present invention is a compound of formula (Ic) according to (xvi)(xv), wherein R 2 is methyl.

[0050] Another embodiment of the present invention is a compound of formula (Id) according to (xvii)(i) [ka] (In the formula, W is CH; A 1 is N, R 1 is C 3-7 cycloalkyl), or a pharmaceutically acceptable salt thereof.

[0051] A further embodiment of the present invention is a compound of formula (Id) according to (xviii)(xvii), wherein R 1 is cyclobutyl.

[0052] The present invention relates to a compound represented by (i') formula (I) [ka] (In the formula, W is CH or N; A 1 and A 2 are each independently CH or N; A 3 and A 7 are each independently C or N, A 4 , A 5 and A 6 are independently N, CR 1 or NR 2 and R 1 is H, halogen, cyano, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or -L 1 -R 3 and R 2 is H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Alkoxy C 1-6 Alkyl or -L 2 -R 3 and L 1 are O, S, NH, C 1-6 Alkylene, C 3-7 cycloalkylene, heteroarylene, or heterocyclylene; L 2 is C 1-6 Alkylene, C 3-7 cycloalkylene, heteroarylene, or heterocyclylene; R 3 is an optionally substituted aryl, heteroaryl, heterocyclyl, arylC 1-6 Alkyl, heterocyclyl C 1-6 Alkyl or heteroaryl C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0053] Another embodiment of the present invention is a compound of formula (Ia) according to (ii')(i') [ka] (In the formula, W is CH; A 1 is N, R 1 is (cyanophenyl)C 1-6 Alkoxy, (HaloC 1-6 Alkylphenyl)C 1-6 Alkoxy, (halophenyl)C 1-6 Alkoxy, (phenyl C 1-6 alkyl)pyrazolyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-7 Cycloalkyl, phenyl C 1-6 Alkoxy, Phenyl C 1-6 Alkyl, Phenyl C 3-7 Cycloalkyl, pyridinyl C 1-6 is an alkoxy, R 2 is C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0054] A further embodiment of the present invention is (iii') a compound of formula (Ia) according to (i') or (ii'), or a pharmaceutically acceptable salt thereof, wherein R 1 (phenyl C 1-6 Alkyl)pyrazolyl, phenyl C 1-6 Alkoxy, Phenyl C 1-6 Alkyl, Phenyl C 3-7Cycloalkyl or pyridinyl C 1-6 It is an alkoxy.

[0055] A further embodiment of the present invention is (iv') a compound of formula (Ia) according to any one of (i') to (iii'), or a pharmaceutically acceptable salt thereof, wherein R 1 is 1-(2-pyridinyl)ethoxy, 1-phenylcyclopropyl, 1-phenylethoxy, 1-phenylethyl or 2-benzylpyrazol-3-yl.

[0056] A further embodiment of the present invention is a compound of formula (I) according to any one of (v')(i') to (iv'), wherein R 2 is methyl.

[0057] A further embodiment of the present invention is (vi') a compound of formula (Ia) or a pharmaceutically acceptable salt thereof according to any one of (i') to (v'): W is CH; A 1 is N, R 1 (phenyl C 1-6 Alkyl)pyrazolyl, phenyl C 1-6 Alkoxy, Phenyl C 1-6 Alkyl, Phenyl C 3-7 Cycloalkyl or pyridinyl C 1-6 is an alkoxy, R 2 is C 1-6 is alkyl, or a pharmaceutically acceptable salt thereof.

[0058] A further embodiment of the present invention is (vii') a compound of formula (Ia) according to any one of (i') to (vi') or a pharmaceutically acceptable salt thereof: W is CH; A 1 is N, R 1is 1-(2-pyridinyl)ethoxy, 1-phenylcyclopropyl, 1-phenylethoxy, 1-phenylethyl or 2-benzylpyrazol-3-yl, R 2 is methyl, or a pharmaceutically acceptable salt thereof.

[0059] Another embodiment of the present invention is a compound of formula (Ib) according to (viii')(i) [ka] (In the formula, W is CH; A 1 is N, R 1 is H or a halogen, R 2 is C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0060] A further embodiment of the present invention is a compound of formula (Ib) according to (ix')(viii'), wherein R 1 is a halogen.

[0061] A further embodiment of the present invention is a compound of formula (Ib) according to (x'), (viii') or (ix'), wherein R 1 is chloro.

[0062] A further embodiment of the present invention is a compound of formula (Ib) according to any one of (xi')(viii') to (x'), wherein R 2 is methyl.

[0063] A further embodiment of the present invention is a compound of formula (Ib) according to any one of (xii') (viii') to (xi'), W is CH; A 1 is N, R 1 is chloro, R 2 is methyl, or a pharmaceutically acceptable salt thereof.

[0064] Another embodiment of the present invention is a compound of formula (Ic) according to (xiii')(i'): [ka] (In the formula, W is CH; A 1 is N, R 2 is C 1-6 alkyl), or a pharmaceutically acceptable salt thereof.

[0065] A further embodiment of the present invention is a compound of formula (Ic) according to (xiv')(xiii'), wherein R 2 is methyl.

[0066] Another embodiment of the present invention is (xix) the following: 5-(1,3-dimethylpyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-(3-cyclopropyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-(1-methylpyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione; 5-(1-methyltriazolo[4,5-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-(1-phenylcyclopropyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-(2-benzylpyrazol-3-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-(3-Isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-(3-chloro-1-methyl-pyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-(1-phenylethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 3-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile; 4-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile; 5-[3-[1-(2-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(3-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(4-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(4-fluorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(3-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(4-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-[3-(trifluoromethyl)phenyl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(2-methylthiazol-4-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(5-methylthiazol-2-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(4-chloro-1-methyl-pyrazol-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(2-methylpyrazol-3-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(1,3-benzoxazol-2-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-phenylethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-phenyl-ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2,2-trifluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-2,2,2-trifluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-(6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-(6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[methyl(1,2,2-trimethylpropyl)amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-cyclopentylethyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[cyclopentyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[methyl-[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-(3-cyclobutyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(5-fluoro-6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-(6-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-(4-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(6-chloro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(6-chloropyridazin-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; and 5-(3-cyclobutylisoxazolo[5,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione 1. A compound selected from:

[0067] Another embodiment of the present invention relates to a method for preparing a compound according to any one of (xx)(i) to (xv), the method comprising the steps of: a) a compound of formula (XVI), [ka] (XVI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ia): [ka] Obtaining (Ia); b) a compound of formula (XXI), [ka] (XXI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ib-1): [ka] Obtaining (Ib-1); c) a compound of formula (XXVI), [ka] (XXVI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ic): [ka] Obtaining (Ic); d) a compound of formula (XXXII), [ka] (XXXII) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ia-1): [ka] Obtaining (Ia-1); e) a compound of formula (XXXVI), [ka] (XXXVI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (XXXVII): [ka] Step of obtaining (XXXVII) and During the ceremony, each PG is independently an oxygen protecting group, and PG is selected from methyl, tert-butyl, TBS, ethoxymethyl, and benzyl; In steps a), b), c), d) and e), the acid is aqueous trifluoroacetic acid or hydrochloric acid, the dealkylating reagents are TMSCl and NaI, and the hydrogenation is carried out using Pd / C; A 1 , W, R 1 From R 3 is defined as in any one of claims (i) to (xviii) or (i') to (xiv').

[0068] Another embodiment of the present invention is (xxi) a compound or pharmaceutically acceptable salt according to any one of (i) to (xix) or (i') to (xiv') for use as a therapeutically active substance.

[0069] Another embodiment of the present invention relates to (xxii) a pharmaceutical composition comprising a compound according to any one of (i) through (xix) or (i') through (xiv') and a pharmaceutically acceptable excipient.

[0070] Another embodiment of the invention is (xxiii) the use of a compound according to any one of (i) to (xix) or (i') to (xiv') for treating cancer.

[0071] Another embodiment of the present invention is the use according to (xxiv)(xxiii), wherein the cancer is pancreatic cancer, colorectal cancer, gastric cancer, esophageal cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, or melanoma.

[0072] Another embodiment of the invention is (xxv) the use of a compound according to any one of (i) to (xix) or (i') to (xiv') for inhibiting CD73.

[0073] Another embodiment of the invention is (xxvi) the use of a compound according to any one of (i) to (xix) or (i') to (xiv') for the preparation of a medicament for treating or preventing cancer, wherein the cancer is pancreatic cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, melanoma, multiple myeloma, acute myeloid leukemia, or acute and chronic lymphoblastic leukemia.

[0074] Another embodiment of the invention is (xxvii) the use of a compound according to any one of (i) to (xix) or (i') to (xiv') for the preparation of a medicament as a CD73 inhibitor.

[0075] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt according to any one of (i) to (xix) or (i') to (xiv') when prepared according to the process of (xxviii)(xx).

[0076] Pharmaceutical Compositions and Administration Another embodiment provides pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or additive, as well as methods of using the compound of the present invention to prepare such compositions and medicaments. In one example, a compound of formula (I) can be formulated into a galenic dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to recipients at the dosage and concentration used, at ambient temperature, at an appropriate pH, and to the desired degree of purity. The pH of the formulation will depend primarily on the specific application and the concentration of the compound, but is preferably somewhere in the range of about 3 to about 8. In one example, a compound of formula (I) is formulated in acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0077] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical professionals. The "effective amount" of the compound to be administered is determined by such considerations and is the minimum amount necessary to inhibit the enzymatic activity of the CD73 protein in converting AMP to adenosine. In one example, a pharmaceutically effective amount of a compound of the present invention administered parenterally per dose will range from about 0.01 to 100 mg / kg of patient body weight per day, or alternatively, from about 0.1 to 50 mg / kg of patient body weight per day, with a typical initial range of the compound used being 0.3 to 30 mg / kg / day. In another embodiment, oral dosage unit forms, such as tablets and capsules, preferably contain from about 1 to about 1000 mg of a compound of the present invention.

[0078] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural, and intranasal, and, if desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0079] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0080] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, flavors, flavorings, diluents, and other known additives to present the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) aesthetically or to aid in the manufacture of a pharmaceutical product (i.e., a drug product).

[0081] An example of a suitable oral dosage form is a tablet containing about 0.1 mg to 500 mg of a compound of the present invention formulated with about 0.1 to 500 mg of anhydrous lactose, about 0.1 to 500 mg of croscarmellose sodium, about 0.1 to 500 mg of polyvinylpyrrolidone (PVP) K30, and about 0.1 to 500 mg of magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example aerosol formulation can be prepared, for example, by dissolving 1 to 450 mg of a compound of the present invention in a suitable buffer solution, such as phosphate buffer, and adding, if desired, an isotonicity agent, such as a salt such as sodium chloride. The solution can be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0082] Thus, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

[0083] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer.Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer.

[0084] The following embodiments illustrate typical compositions of the present invention and serve as representative only.

[0085] Composition A The compounds of the present invention can be used in a manner known per se as active ingredients to prepare tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0086] Composition B The compounds of the present invention can be used as active ingredients in a manner known per se to prepare capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

[0087] Indications and Treatment Methods The compounds of the present invention inhibit the enzymatic activity of CD73 in converting AMP to adenosine.Therefore, the compounds of the present invention are useful for reducing the adenosine level in TME.The compounds of the present invention are useful for promoting immune-mediated killing of cancer cells that overexpress CD73, such as pancreatic cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, melanoma, multiple myeloma, acute myeloid leukemia, or acute and chronic lymphoblastic leukemia.Alternatively, the compounds of the present invention are useful for promoting immune-mediated killing of cancer cells that depend on the adenosine pathway or malignant solid tumors in which the adenosine pathway is enhanced by dysregulation or mutation of effector pathways such as EGFR-RAS-MAPK, PI3K-AKT-driven signaling, for targeted treatment in pancreatic adenocarcinoma, non-small cell lung cancer, esophageal and gastric adenocarcinoma, etc. More broadly, the compounds may be used in the treatment and prevention of all cancer types that exhibit an immunosuppressive TME.

[0088] Another embodiment includes a method of treating or preventing cancer in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0089] synthesis The compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds and their starting materials are illustrated in the following schemes and examples. All substituents, particularly R 1 ~R 3 and W are as defined above unless otherwise specified. Furthermore, unless expressly stated otherwise, all reactions, reaction conditions, abbreviations and symbols have meanings well known to those skilled in the art of organic chemistry.

[0090] A general synthetic route for preparing compounds of formula (I) is shown below.

[0091] Scheme 1 [ka] wherein each X is independently a halogen.

[0092] Compounds of formula (VI) can be prepared according to Scheme 1. Dihalogenated heteroaryl aldehydes (II) can be cyclized with hydrazine derivatives (III) to give compounds of formula (IV). Compounds of formula (IV) can be treated with various halogenating reagents (e.g., NBS, liquid Br2, or NIS) to give compounds of formula (V). Compounds of formula (V) can be reacted with a halide, R 3 O.H., R. 3 NH2 or (R 3 ) NH (e.g., Buchwald-Hartwig amination, or Ullmann coupling), or by reacting a compound of formula (XI) with a boronic acid R 1 Chan-Lam coupling with B(OH) or with a compound of formula (XI) and a boronic acid R 1B(OH)2 or R 1 Suzuki-Miyaura type coupling with Bpin can give compounds of formula (VI).

[0093] Scheme 2 [ka] Alternatively, the compound of formula (VI) can be prepared according to Scheme 2. Decarboxylative oxidative acylation of the compound of formula (VII) with the compound of formula (VIII) can be achieved using a transition metal (e.g., AgNO) as a catalyst and a persulfate (e.g., NaSO, (NH)SO) as an oxidant under acidic conditions to prepare the compound of formula (IX). The compound of formula (IX) can be treated with the compound of formula (X) to achieve a cyclization reaction to give the compound of formula (VI).

[0094] Compounds of formula (IX) can be prepared from compounds of formula (XI) according to another synthetic route. Regioselective Suzuki-Miyaura-type coupling of trihalogenated heteroarene (XI) with boronic acid (XII) or compounds of formula (XIII) (e.g., boronic acid ester, trifluoroborate) can be carried out in the presence of a palladium catalyst (e.g., Pd(dppf)Cl, Pd(PPh), cataCXium-A-Pd-G, etc.) and a base (e.g., NaCO, KCO, CsCO, etc.) to give compounds of formula (XIV). The use of an oxidizing agent (e.g., NaIO, Oxone) can also provide compounds of formula (XIV). (商標) The alkene group of the compound of formula (XIV) can be oxidatively cleaved to a carbonyl group by treatment with a catalyst (e.g., RuCl, OsO, etc.) in combination with NaOCl to give a compound of formula (IX).

[0095] Scheme 3 [ka] wherein each PG is independently an oxygen protecting group, for example, methyl, tert-butyl, TBS, ethoxymethyl, and benzyl.

[0096] Compounds of formula (Ia) can be prepared according to Scheme 3. Suzuki-Miyaura type coupling of compounds of formula (VI) with heteroarylboronic acids (XV) can be carried out in the presence of a palladium catalyst (e.g., Pd(dppf)Cl, Pd(PPh), cataCXium-A-Pd-G, etc.) and a base (e.g., NaCO, KCO, CsCO, etc.) to provide compounds of formula (XVI). A subsequent deprotection step using an acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid) or dealkylating reagent (e.g., TMSCl and NaI, etc.) or metal (e.g., Pd / C, etc.)-mediated hydrogenation can provide compounds of formula (Ia).

[0097] Scheme 4 [ka] In the formula, Y is halogen, OTf, OMs, or OTs.

[0098] Compounds of formula (Ib-1) can be prepared according to Scheme 4. Regioselective aromatic nucleophilic substitution (S) of dihalogenated heteroarenes (XVII) with hydrazine hydrate with or without a non-nucleophilic base. N The compound of formula (XVIII) can be delivered by the reaction of a reducing agent such as diisobutylaluminum hydride (DIBAL-H) with the methyl ester group of the compound of formula (XVIII) to an aldehyde, followed by tandem intramolecular condensation to give the compound of formula (XIX). The compound of formula (XX) can be delivered by the reaction of a reducing agent such as diisobutylaluminum hydride (DIBAL-H) with the methyl ester group of the compound of formula (XVIII) to an aldehyde, followed by tandem intramolecular condensation to give the compound of formula (XIX). 2 The group R of the compound of formula (XIX) 2 via nucleophilic substitution by Y or via transition metal-mediated coupling reactions (e.g., R 2 Buchwald-Hartwig or Ullmann-Ma amination by Y, R 2 B(OH)2 or R 2 via a Chan-Lam coupling with Bpin, or via an alcohol R2 The compound of formula (XX) can be introduced via a Mitsunobu reaction with OH. Suzuki-Miyaura type cross-coupling of a compound of formula (XX) with a heteroarylboronic acid (XV) can provide a compound of formula (XXI). A subsequent deprotection step using an acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid) or a dealkylating reagent (e.g., TMSCl and NaI) or a metal (e.g., Pd / C)-mediated hydrogenation can provide a compound of formula (Ib-1).

[0099] Scheme 5 [ka] wherein each X is independently a halogen.

[0100] Compounds of formula (Ic) can be prepared according to Scheme 5. Regioselective aromatic nucleophilic substitution reaction (S) of dihalogenated heteroarylamine (XXII) with amine (XXIII) in the presence of a non-nucleophilic base such as N,N-diisopropylethylamine. N Ar) can deliver a compound of formula (XXIV). Treatment of compound of formula (XXIV) with sodium nitrite under acidic conditions can give triazole (XXV). Suzuki-Miyaura-type cross-coupling of triazole (XXV) with heteroarylboronic acid (XV) can provide compound of formula (XXVI). A subsequent deprotection step using an acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid) or dealkylating reagent (e.g., TMSCl and NaI) or metal (e.g., Pd / C)-mediated hydrogenation can provide compound of formula (Ic).

[0101] Scheme 6 [ka] In the formula, Y is halogen, OTf, OMs, or OTs.

[0102] Compounds of formula (Ia-1) can be prepared according to Scheme 6. Acid (XXVII) is treated with oxalyl chloride, followed by reaction with a substituted hydrazine (XXVIII) to give compounds of formula (XXIX). Treatment of compound (XXIX) with an acid such as TFA or HCl results in intramolecular cyclization to give compounds of formula (XXX). Compounds of formula (XXXI) can be prepared by the reaction of R 3 by nucleophilic substitution by Y or by alcohol R 3 The compound of formula (XXXI) can be obtained by Mitsunobu reaction with OH. Suzuki-Miyaura type cross-coupling of the compound of formula (XXXI) with heteroarylboronic acid (XV) can provide the compound of formula (XXXII). The following deprotection step using an acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid) or dealkylating reagent (e.g., TMSCl and NaI) or metal (e.g., Pd / C)-mediated hydrogenation can provide the compound of formula (Ia-1).

[0103] Scheme 7 [ka] In the formula, Y is halogen, OTf, OMs, or OTs.

[0104] Compounds of formula (XXXII) can alternatively be prepared according to Scheme 7. Suzuki-Miyaura type cross-coupling of compounds of formula (XXX) with heteroarylboronic acids (XV) can provide compounds of formula (XXXIII). Compounds of formula (XXXII) can be prepared by reacting compounds of formula (XXXIII) with alcohols R 3 by Mitsunobu reaction with OH or R 3 It can be obtained by nucleophilic substitution with Y.

[0105] Scheme 8 [ka] wherein each X is independently a halogen; Q is O or NR 2is.

[0106] Compounds of formula (XXXVII) can be prepared according to Scheme 8. Deprotonation of compounds of formula (VII) using TMPMgCl·LiCl with ZnCl2, Zn(OPiv)2, etc., or TMPZnCl·LiCl, etc., can be performed. Subsequent acylation of compounds of formula (XXXIV) with the above organozinc reagents can be achieved with the aid of transition metals (e.g., CuCN·2LiCl) to prepare compounds of formula (IX). Treatment of compounds of formula (IX) with hydroxylamine or hydrazine derivatives can achieve a cyclization reaction to give compounds of formula (XXXV). Suzuki-Miyaura-type cross-coupling of compounds of formula (XXXV) with heteroarylboronic acids (XV) can provide compounds of formula (XXXVI). A subsequent deprotection step using an acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid) or a dealkylating reagent (e.g., TMSCl and NaI, etc.) or metal (e.g., Pd / C, etc.) mediated hydrogenation can provide a compound of formula (XXXVII).

[0107] The compounds of the present invention can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or SFC. In another embodiment, the compounds of the present invention can be obtained according to the above schemes by using the corresponding chiral starting materials.

[0108] The present invention also relates to a process for preparing a compound of formula (I) comprising any of the following steps: a) a compound of formula (XVI), [ka] (XVI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ia): [ka] Obtaining (Ia); b) a compound of formula (XXI), [ka] (XXI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ib-1): [ka] Obtaining (Ib-1); c) a compound of formula (XXVI), [ka] (XXVI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ic): [ka] Obtaining (Ic); d) a compound of formula (XXXII), [ka] (XXXII) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ia-1): [ka] Obtaining (Ia-1); e) a compound of formula (XXXVI), [ka] (XXXVI) is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (XXXVII): [ka] Step of obtaining (XXXVII) and In steps a), b), c), d) and e), the acid can be, for example, trifluoroacetic acid or aqueous hydrochloric acid, the dealkylating reagent can be, for example, TMSCl and NaI, and the hydrogenation is carried out using Pd / C.

[0109] Compounds of formula (I) when prepared by the above process are also an object of the present invention. [Example]

[0110] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0111] Abbreviation The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the invention.

[0112] Abbreviations used herein are as follows: ACN: acetonitrile AcOH: acetic acid BTMPO N,N'-bis(2,4,6-trimethoxyphenyl)oxamide DCE: dichloroethane DCM: dichloromethane DIPEA or DIEA: N,N-diisopropylethylamine DIBAL-H: Diisobutylaluminum hydride DME: Dimethoxyethane DMF: N,N-dimethylformamide DMP Dess-Martin Periodinane EA or EtOAc: Ethyl acetate FA: Formic acid HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate I C 50 :50% inhibitory concentration LCMS Liquid Chromatography Mass Spectrometry MS: Mass spectrometry NBS: N-bromosuccinimide Pd(dppf)Cl2·DCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane PE: Petroleum ether PPh3 Triphenylphosphine Preparative HPLC: Preparative High Performance Liquid Chromatography Preparative TLC: Preparative thin layer chromatography rt: room temperature RT: retention time RuCl[(R,R)-TsDPEN](p-cymene) ((R,R)-2-amino-1,2-diphenylethyl)[(4-tolyl)sulfonyl]amide](p-cymene)ruthenium(II) chloride SFC: Supercritical Fluid Chromatography TFA: Trifluoroacetic acid TLC: Thin Layer Chromatography TMSCHF2 (difluoromethyl)trimethylsilane v / v volume ratio

[0113] General experimental conditions The intermediates and final compounds were purified using one of the following instruments: i) a Biotage SP1 system and Quad12 / 25 cartridge module; ii) an ISCO combi-flash chromatography instrument, with silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS Registration Number: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

[0114] Intermediates and final compounds were analyzed using XBridge (商標) Prep-C18 (5 μm, OBD™ 30 × 100 mm) column, SunFire (商標) Prep-C18 (5 μm, OBD(商標) Purification was performed by preparative HPLC on a reversed-phase column using a Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) column, a Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) column, or a Phenomenex Gemini-C18 (10 μm, 25 × 150 mm). Purification was by Prep-HPLC on a reversed-phase column using a Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detector: Micromass ZQ and UV 2487, Solvent system: acetonitrile and 0.1% ammonium hydroxide in water; acetonitrile and 0.1% FA in water or acetonitrile and 0.1% TFA in water) or a Gilson-281 purification system (Pump 322, Detector: UV 156, Solvent system: acetonitrile and 0.05% ammonium hydroxide in water; acetonitrile and 0.225% FA in water; acetonitrile and 0.05% HCl in water; acetonitrile and 0.075% TFA in water; or acetonitrile and water).

[0115] For SFC chiral separations, intermediates were separated by chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) on a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar80 preparative SFC, solvent systems: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, and UV detection at 254 or 220 nm.

[0116] LC / MS spectra of the compounds were obtained using LC / MS (Waters (商標) Acquisition was performed using an Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ, and the LC / MS conditions were as follows (run time: 3 minutes or 1.5 minutes). Acidic conditions I: A: 0.1% TFA in HO, B: 0.1% TFA in acetonitrile, Acidic conditions II: A: 0.0375% TFA in HO, B: 0.01875% TFA in acetonitrile, Basic condition I: A: 0.1% NH3·H2O in H2O, B: acetonitrile, Basic condition II: A: 0.025% NH3·H2O in H2O, B: acetonitrile, Neutral conditions: A: H2O, B: Acetonitrile.

[0117] Mass Spectrum (MS): Generally, only ions representing the parent mass are reported; unless otherwise stated, the mass ions quoted are the positive mass ions (M−H). + is.

[0118] NMR spectra were acquired using a Bruker Avance 400 MHz or 500 MHz.

[0119] Microwave-assisted reactions were carried out in a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were carried out under an argon or nitrogen atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

[0120] Preparation example The following examples are intended to illustrate the meaning of the present invention but do not in any way represent a limitation within the meaning of the present invention.

[0121] Example 1 5-(1,3-dimethylpyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0122] Step (a): Preparation of 3,6-dichloro-4-isopropenyl-pyridazine (compound 1.3) A solution of 4-bromo-3,6-dichloro-pyridazine (compound 1.1, 0.90 g, 3.95 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added to 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (compound 1.2, 0.73 g, 4.34 mmol), CsCO (2.57 g, 7.9 mmol), and Pd(dppf)Cl. . DCM (289.0 mg, 0.39 mmol) was added. The resulting mixture was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 80 °C for 7 h. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted twice with EA (50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 20 / 1 to 10 / 1) to give compound 1.3 (0.70 g). 1 H NMR (400 MHz, DMSO-d6) δ = 8.01-7.91 (m, 1H), 5.61-5.44 (m, 1H), 5.39-5.21 (m, 1H), 2.13-2.07 (m, 3H).

[0123] Step (b): Preparation of 1-(3,6-dichloropyridazin-4-yl)ethanone (compound 1.4) To a 50 mL round-bottom flask equipped with a magnetic stir bar was added 3,6-dichloro-4-isopropenyl-pyridazine (compound 1.3, 0.60 g, 3.17 mmol), followed by water (10 mL), THF (10 mL), and acetone (10 mL). Sodium metaperiodate (2.04 g, 9.52 mmol) and ruthenium(III) chloride hydrate (65.83 mg, 0.32 mmol) were then added to the mixture at room temperature. The flask was then evacuated and filled with nitrogen three times. The mixture was stirred at room temperature for an additional 16 h. The reaction was quenched with saturated aqueous NaSO (30 mL) and extracted three times with EA (40 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 100 / 1 to 5 / 1) to give compound 1.4 (0.40 g). 1 H NMR (400 MHz, DMSO-d6) δ = 8.29 (s, 1H), 2.58 (s, 3H).

[0124] Step (c): Preparation of 5-chloro-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (compound 1.5) A mixture of 1-(3,6-dichloropyridazin-4-yl)ethanone (compound 1.4, 0.30 g, 1.57 mmol) and methylhydrazine (0.22 g, 4.71 mmol) in 1-butanol (3 mL) was heated in a microwave reactor at 150 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with 1 M HCl (20 mL) and extracted twice with EA (50 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give compound 1.5 (0.40 g), which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 8.47 (s, 1H), 4.16 (s, 3H), 2.55 (s, 3H).

[0125] Step (d): Preparation of 5-(2,4-dimethoxypyrimidin-5-yl)-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (compound 1.7) A solution of 5-chloro-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (compound 1.5, 0.15 g, 0.82 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added to 2,4-dimethoxypyrimidine-5-boronic acid (compound 1.6, 0.15 g, 0.82 mmol), CsCO (0.53 g, 1.64 mmol), and Pd(dppf)Cl. . DCM (0.06 g, 0.08 mmol) was added. The resulting mixture was degassed and purged with N2 three times, and then the mixture was stirred under N2 atmosphere at 100 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EA (20 mL) three times. The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 30 / 1 to 5 / 1) to give compound 1.7 (70.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ = 8.86 (s, 1H), 8.48 (s, 1H), 4.21 (s, 3H), 4.04 (s, 3H), 4.01 (s, 3H), 2.60 (s, 3H).

[0126] Step (e): Preparation of 5-(1,3-dimethylpyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione (Example 1) To a solution of 5-(2,4-dimethoxypyrimidin-5-yl)-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (compound 1.7, 30.0 mg, 0.1 mmol) in methanol (0.1 mL) was added 2M HCl (1.0 mL). The reaction mixture was stirred at 60° C. for 1 hour and then concentrated to give the crude product, which was purified by preparative HPLC to give Example 1 (9.5 mg). MS: calculated 259.1 [(M+H) + ], measured value 259.2 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.51(s,1H),11.45(br d,J=5.6 Hz,1H),8.67(s,1H),8.33(d,J=6.4 Hz,1H),4.18(s,3H),2.57(s,3H)

[0127] Example 2 5-(3-cyclopropyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0128] Step (a): Preparation of cyclopropyl-(3,6-dichloropyridazin-4-yl)methanone (compound 2.3) To a mixture of 3,6-dichloropyridazine (compound 2.1, 0.80 g, 5.37 mmol), 2-cyclopropyl-2-oxoacetic acid (compound 2.2, 0.92 g, 8.05 mmol), silver nitrate (0.18 g, 1.07 mmol), and TFA (0.41 mL, 5.37 mmol) in water (16 mL) was added a solution of NaSO (1.92 g, 8.05 mmol) in water (8 mL) at 60 °C. The resulting mixture was stirred at 60 °C under a N atmosphere for an additional 16 h. After cooling to room temperature, the reaction was diluted with water (50 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give compound 2.3 (0.20 g). MS: Calculated 217.0 [(M+H) + ], measured value 217.2 [(M+H) + ].

[0129] Step (b): Preparation of 5-chloro-3-cyclopropyl-1-methyl-pyrazolo[3,4-c]pyridazine (compound 2.4) To a solution of cyclopropyl-(3,6-dichloropyridazin-4-yl)methanone (compound 2.3, 0.20 g, 0.92 mmol) in 1-butanol (2 mL) was added methylhydrazine (0.62 mL, 4.69 mmol) to give a yellow solution. The resulting mixture was stirred in a microwave reactor at 150 °C for 1 h. After cooling to room temperature, the reaction was diluted with 1 M HCl (5 mL) and extracted three times with EA (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give compound 2.4 (0.28 g), which was used directly in the next step without further purification. MS: calculated 209.0 [(M+H) + ], measured value 209.2 [(M+H) + ].

[0130] Step (c): Preparation of 5-(3-cyclopropyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione (Example 2) 5-(3-Cyclopropyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione (Example 2) was prepared similarly to Example 1 by replacing 5-chloro-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (Compound 1.5) with 5-chloro-3-cyclopropyl-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 2.4) in step (d). 10.8 mg of Example 2 was obtained. MS: calculated 285.1 [(M+H) + ], measured value 285.3 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 8.69 (s, 1H), 8.32 (s, 1H), 4.13 (s, 3H), 2.40-2.32 (m, 1H), 1.11-1.04 (m, 2H), 1.03-0.98 (m, 2H).

[0131] Example 3 5-(1-methylpyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0132] Step (a): Preparation of methyl 6-chloro-4-hydrazino-pyridazine-3-carboxylate (compound 3.2) To a solution of methyl 4,6-dichloropyridazine-3-carboxylate (compound 3.1, 2.0 g, 9.66 mmol) in ethanol (20 mL) was added hydrazine hydrate (1.45 g, 28.97 mmol) at 0 °C. The resulting mixture was warmed to 20 °C and stirred at the same temperature for 2 h. The resulting suspension was filtered, and the filter cake was washed with EtOAc (20 mL). The collected solid was concentrated in vacuo to give compound 3.2 (2.0 g), which was used directly in the next step without further purification. 1 H NMR (400 MHz, Methanol-d4) δ = 7.25 (s, 1H), 3.14 (s, 3H).

[0133] Step (b): Preparation of 6-chloro-1H-pyrazolo[4,3-c]pyridazine (compound 3.3) To a solution of methyl 6-chloro-4-hydrazino-pyridazine-3-carboxylate (compound 3.2, 0.15 g, 0.74 mmol) in DCM (3 mL) was added DIBAL-H (1.0 M in THF, 1.11 mL, 1.11 mmol) dropwise at −78° C. The resulting mixture was warmed to room temperature and stirred at the same temperature for an additional 1 h. The reaction was quenched by the slow addition of HO (20 mL) and extracted three times with DCM (30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give compound 3.3 (50.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ = 8.73 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 0.8 Hz, 1H).

[0134] Step (c): Preparation of 6-chloro-1-methyl-pyrazolo[4,3-c]pyridazine (compound 3.4) To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridazine (compound 3.3, 30.0 mg, 0.19 mmol) in DMF (0.5 mL) was added K2CO3 (53.65 mg, 0.39 mmol) and iodomethane (68.88 mg, 0.49 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted three times with EA (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 5 / 1 to 0 / 1) to give compound 3.4 (22 mg). MS: calculated 169.0 [(M+H) + ], measured value 169.0 [(M+H) + ].

[0135] Step (d): Preparation of 5-(1-methylpyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (Example 3) 5-(1-methylpyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (Example 3) was prepared similarly to Example 1 by replacing 5-chloro-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (Compound 1.5) with 6-chloro-1-methyl-pyrazolo[4,3-c]pyridazine (Compound 3.4) in step (d). 24.9 mg of Example 3 was obtained. MS: calculated 245.0 [(M+H) + ], measured value 245.0 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 11.79-11.47 (m, 2H), 8.81 (s, 1H), 8.63 (s, 1H), 8.59-8.54 (m, 1H), 4.11 (s, 3H).

[0136] Example 4 5-(1-methyltriazolo[4,5-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0137] Step (a): 6-chloro-N 4 Preparation of 4.2-methyl-pyridazine-3,4-diamine (compound 4.2) To a solution of 4-bromo-6-chloro-pyridazin-3-amine (compound 4.1, 5.0 g, 24.0 mmol) in 1-butanol (20 mL), DIEA (8.36 mL, 47.98 mmol) and methylamine (2 M in THF, 24.0 mL, 48.0 mmol) were added under a N atmosphere to give a brown solution. The resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated and purified by preparative HPLC to give compound 4.2 (3.5 g). MS: calculated 159.0 [(M+H) + ], measured value 159.3 [(M+H) + ].

[0138] Step (b): Preparation of 6-chloro-1-methyl-triazolo[4,5-c]pyridazine (compound 4.3) 6-Chloro-N 4 To a solution of 4.2-methyl-pyridazine-3,4-diamine (compound 4.2, 0.50 g, 3.15 mmol) in 6 M HCl (8 mL) was added a solution of sodium nitrite (0.24 g, 3.47 mmol) in water (2 mL) slowly at 0 °C. The resulting mixture was stirred at room temperature for 2 h. After adjusting the pH to 8 with saturated NaHCO (aqueous), the mixture was extracted three times with EA (20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 1 / 1 to 0 / 1) to give compound 4.3 (0.20 g). 1 H NMR (400 MHz, DMSO-d6) δ = 8.69 (s, 1H), 4.36 (s, 3H).

[0139] Step (c): Preparation of 5-(1-methyltriazolo[4,5-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (Example 4) 5-(1-methyltriazolo[4,5-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (Example 4) was prepared similarly to Example 1 by replacing 5-chloro-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (Compound 1.5) with 6-chloro-1-methyl-triazolo[4,5-c]pyridazine (Compound 4.3) in step (d). 70.3 mg of Example 4 was obtained. MS: calculated 246.0 [(M+H) + ], measured value 246.2 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 11.69-11.55 (m, 2H), 8.84 (s, 1H), 8.69-8.58 (m, 1H), 4.38 (s, 3H).

[0140] Example 5 5-[1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0141] Step (a): Preparation of 3,6-dichloro-N-methoxy-N-methyl-pyridazine-4-carboxamide (Compound 5.2) To a solution of 3,6-dichloropyridazine-4-carboxylic acid (compound 5.1, 20.0 g, 103.63 mmol), DIEA (40.73 g, 310.9 mmol), and HATU (59.11 g, 155.45 mmol) in DMF (300 mL) was added N,O-dimethylhydroxylamine hydrochloride (15.16 g, 155.45 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (1 L) and extracted three times with EA (300 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 50 / 1 to 3 / 1) to give compound 5.2 (5.0 g). 1 H NMR (400 MHz, Methanol-d4) δ = 8.09 (s, 1H), 3.60 (s, 3H), 3.41 (s, 3H).

[0142] Step (b): Preparation of 3,6-dichloropyridazine-4-carbaldehyde (compound 5.3) To a solution of 3,6-dichloro-N-methoxy-N-methyl-pyridazine-4-carboxamide (compound 5.2, 10.0 g, 42.36 mmol) in THF (200 mL) was added DIBAL-H (1.0 M in THF, 63.54 mL, 63.54 mmol) dropwise at −78° C. The resulting mixture was stirred at the same temperature for 1 h. The reaction was quenched by slowly adding saturated aqueous citric acid (200 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give compound 5.3 (10.0 g), which was used directly in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ = 10.12 (s, 1H), 8.26 (s, 1H).

[0143] Step (c): Preparation of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 5.4) To a solution of 3,6-dichloropyridazine-4-carbaldehyde (compound 5.3, 10.0 g, 56.5 mmol) in n-butanol (60 mL), methylhydrazine (19.52 g, 169.5 mmol) was added, and the resulting mixture was stirred at 150 °C for 2 h. After cooling to room temperature, the mixture was diluted with saturated aqueous ammonium chloride (60 mL) and extracted three times with EA (60 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 100 / 1 to 2 / 1) to give compound 5.4 (2.4 g). 1 H NMR (400 MHz, DMSO-d6) δ = 8.41 (s, 1H), 8.38 (s, 1H), 4.26 (s, 3H).

[0144] Step (d): Preparation of 3-bromo-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound 5.5) To a solution of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound 5.5, 1.5 g, 8.9 mmol) in AcOH (25.0 mL) was added NBS (6.33 g, 35.59 mmol), and the resulting mixture was stirred at 80 °C for 24 hours. The reaction mixture was diluted with water (150 mL) and extracted three times with EA (30 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 50 / 1 to 10 / 1) to give compound 5.5 (1.3 g). 1 H NMR (400 MHz, DMSO-d6) δ = 8.43 (s, 1H), 4.25 (s, 3H).

[0145] Step (e): Preparation of 5-chloro-1-methyl-3-(1-phenylvinyl)pyrazolo[3,4-c]pyridazine (Compound 5.7) A solution of 3-bromo-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound 5.5, 400.0 mg, 1.62 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added to 4,4,5,5-tetramethyl-2-(1-phenylvinyl)-1,3,2-dioxaborolane (compound 5.6, 446.31 mg, 1.94 mmol), Pd(dppf)Cl2. . DCM (118.26 mg, 0.16 mmol) and K2CO3 (446.76 mg, 3.23 mmol) were added. The resulting mixture was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted three times with EA (10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 50 / 1 to 10 / 1) to give compound 5.7 (300.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ = 8.15 (s, 1H), 7.52-7.36 (m, 5H), 6.05 (s, 1H), 5.83 (s, 1H), 4.24 (s, 3H).

[0146] Step (f): Preparation of 5-chloro-1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazine (Compound 5.8) To a 10 mL round-bottom flask equipped with a magnetic stir bar was added 5-chloro-1-methyl-3-(1-phenylvinyl)pyrazolo[3,4-c]pyridazine (compound 5.7, 140.0 mg, 0.52 mmol), followed by EA (4 mL) and PtO2 (11.74 mg, 0.05 mmol). The flask was then evacuated and filled with hydrogen three times. The mixture was stirred under a hydrogen atmosphere at 25 °C for 1 h (15 psi). The reaction mixture was filtered through a Celite pad, and the pad was washed with EtOAc (4 mL). The filtrate was concentrated to give compound 5.8 (140.0 mg), which was used directly in the next step without further purification. MS: calculated 273.1, 275.1 [(M+H) + ], measured values 273.3, 275.3 [(M+H) + ].

[0147] Step (g): Preparation of 5-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazine (Compound 5.9) A solution of 5-chloro-1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazine (compound 5.8, 140.0 mg, 0.51 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added to 2,4-dimethoxypyrimidine-5-boronic acid (compound 1.6, 188.86 mg, 1.03 mmol), Pd(dppf)Cl2, and 2,4-dimethoxypyrimidine-5-boronic acid (compound 1.6, 188.86 mg, 1.03 mmol). . DCM (37.55 mg, 0.05 mmol) and Cs2CO3 (334.48 mg, 1.03 mmol) were added. The resulting mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (5 mL) and extracted three times with EA (5 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 50 / 1 to 10 / 1) to give compound 5.9 (160.0 mg). 1 H NMR(400 MHz,DMSO-d6)δ=8.84(s,1H),7.98(s,1H),7.42-7.24(m,5H),4.66(d,J=7.2 Hz,1H),4.26(s,3H),3.98(s,3H),3.93(s,3H),1.77(d,J=7.2 Hz,3H).

[0148] Step (h): Preparation of 5-[1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 5) A mixture of 5-(2,4-dimethoxypyrimidin-5-yl)-1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazine (compound 5.9, 140.0 mg, 0.37 mmol) and 2M HCl (7.0 mL) was stirred at 50° C. for 1 hour and then concentrated to give the crude product, which was purified by preparative HPLC to give Example 5 (37.4 mg). MS: calculated 349.1 [(M+H) + ], measured value 349.3 [(M+H)+ ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.40(br d,J=2.0 Hz,2H),8.38(s,1H),8.29(s,1H),7.41-7.15(m,5H),4.65(d,J=7.2 Hz,1H),4.23(s,3H),1.74(d,J=7.2 Hz,3H).

[0149] Example 6 5-[1-methyl-3-(1-phenylcyclopropyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0150] Step (a): Preparation of 5-chloro-1-methyl-3-(1-phenylcyclopropyl)pyrazolo[3,4-c]pyridazine (Compound 6.1) To an 8 mL vial equipped with a magnetic stir bar, NaH (60% dispersion in mineral oil, 59.18 mg, 1.48 mmol) was added, followed by DMF (3 mL). Trimethylsulfoxonium iodide (487.74 mg, 2.22 mmol) was then added to the mixture. The flask was evacuated and filled with nitrogen three times. The resulting mixture was stirred under a nitrogen atmosphere at 25 °C for 1 h. 5-Chloro-1-methyl-3-(1-phenylvinyl)pyrazolo[3,4-c]pyridazine (compound 5.7, 200.0 mg) was then added to the mixture at 25 °C. The reaction mixture was stirred for an additional 1 h at 25 °C, quenched with water (20 mL), and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 100 / 1 to 10 / 1) to give compound 6.1 (80.0 mg). MS: calculated value 285.1 [(M+H) +], measured value 285.3 [(M+H) + ].

[0151] Step (b): Preparation of 5-[1-methyl-3-(1-phenylcyclopropyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 6) 5-[1-methyl-3-(1-phenylcyclopropyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 6) was prepared similarly to Example 5 by replacing 5-chloro-1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazine (Compound 5.8) with 5-chloro-1-methyl-3-(1-phenylcyclopropyl)pyrazolo[3,4-c]pyridazine (Compound 6.1) in step (g). 37.4 mg of Example 6 was obtained. MS: calculated 361.1 [(M+H) + ], measured value 361.3 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.41(s,1H),11.37(br d,J=6.0 Hz,1H),8.30(d,J=6.0 Hz, 1H), 8.11 (s, 1H), 7.37-7.22 (m, 5H), 4.20 (s, 3H), 1.60-1.51 (m, 2H), 1.47-1.38 (m, 2H).

[0152] Example 7 5-[3-(2-benzylpyrazol-3-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0153] Step (a): Preparation of 1-benzyl-2-oxide-pyrazol-2-ium (Compound 7.2) A mixture of 1-hydroxypyrazole (4.0 g, 47.57 mmol) and benzyl bromide (7.36 mL, 61.85 mmol) in chloroform (30 mL) was heated to reflux overnight. After cooling to room temperature, the mixture was poured into toluene (100 mL) and extracted three times with 12 M HCl (5 mL). The combined aqueous layers were washed with toluene (20 mL) and carefully basified to pH > 10 with 33% aqueous NaOH in an ice bath. The aqueous layer was extracted three times with CHCl3 (20 mL). After concentration, crude product Compound 7.2 (5.7 g) was obtained, which was used in the next step without further purification. MS: calculated 175.1 [(M+H) + ], measured value 175.2 [(M+H) + ].

[0154] Step (b): Preparation of 1-benzyl-5-bromo-pyrazole (compound 7.3) To a solution of 1-benzyl-2-oxide-pyrazol-2-ium (compound 7.2, 2.5 g, 14.35 mmol) in chloroform (10 mL) was added dropwise a solution of POBr (8229.05 mg, 28.7 mmol, 2.0 equiv.) in chloroform (10 mL) at 0 °C. The resulting mixture was heated to 50 °C and stirred under a nitrogen atmosphere for 2.5 h. The mixture was evaporated to remove chloroform, and the pH was adjusted to 7-8 by adding saturated aqueous NaHCO solution. The aqueous solution was extracted three times with DCM (30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 80 g, 0% to 25% EA in PE) to give compound 7.3 (5.2 g). MS: calculated 237.0, 239.0 [(M+H) + ], measured values 237.0, 239.0 [(M+H) + ]. 1 H NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 2.4 Hz, 1 H), 7.69-7.58 (m, 5 H), 6.72 (d, J = 2.0 Hz, 1 H), 5.8 (s, 2 H).

[0155] Step (c): Preparation of 1-benzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (Compound 7.4) A solution of 1-benzyl-5-bromo-pyrazole (compound 7.3, 150.0 mg, 0.63 mmol) in 1,4-dioxane (2 mL) was added to the solution of bis(pinacolato)diboron (160.65 mg, 0.63 mmol), KOAc (124.18 mg, 1.27 mmol), and Pd(dppf)Cl. . DCM (46.29 mg, 0.06 mmol) was added. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was concentrated to give the crude product, which was purified by flash chromatography (silica gel, 12 g, 0% to 50% EA in PE) to give compound 7.4 (52.0 mg). MS: calculated 285.1 [(M+H) + ], measured value 203.4, [(M+H-C6H 10 ) + ].

[0156] Step (d): Preparation of 3-(2-benzylpyrazol-3-yl)-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 7.5) A solution of 1-benzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (compound 7.4, 137.79 mg, 0.48 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added to 3-bromo-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound 5.5, 120.0 mg, 0.48 mmol), K2CO3 (134.03 mg, 0.97 mmol), and Pd(dppf)Cl2. .DCM (35.47 mg, 0.05 mmol) was added. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 100 / 1 to 10 / 1) to give compound 7.5 (130.0 mg). MS: calculated 325.1 [(M+H) + ], measured value 325.3 [(M+H) + ].

[0157] Step (e): Preparation of 5-[3-(2-benzylpyrazol-3-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 7) 5-[3-(2-benzylpyrazol-3-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 7) was prepared similarly to Example 5 by replacing 5-chloro-1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazine (Compound 5.8) with 3-(2-benzylpyrazol-3-yl)-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 7.5) in step (g). 16.0 mg of Example 7 was obtained. MS: calculated 401.1 [(M+H) + ], measured value 401.4 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.56(s,1H),11.51(br d,J=6.0 Hz,1H),8.82(s,1H),8.38(d,J=6.0 Hz,1H),7.75(d,J=2.0 Hz,1H),7.35-7.10(m,5H),6.98(d,J=2.0 Hz,1H),5.83(s,2H),4.33(s,3H).

[0158] Example 8 5-(3-Isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0159] Step (a): Preparation of tert-butyl N-[(3,6-dichloropyridazine-4-carbonyl)amino]-N-methyl-carbamate (Compound 8.1) 3,6-Dichloropyridazine-4-carboxylic acid (compound 5.1, 1.0 g, 5.18 mmol) was suspended in dichloromethane (12.5 mL) and a catalytic amount of DMF (5 drops). The mixture was cooled to 0 °C. Oxalyl chloride (613.86 μL, 7.25 mmol) was slowly added, and stirring was continued at 0 °C for 20 min. The resulting mixture was warmed to 25 °C and stirred for 20 min until a clear solution was obtained. The solvent and residual oxalyl chloride were completely removed under vacuum, and the residue was redissolved in dichloromethane (12.5 mL). tert-Butyl N-amino-N-methyl-carbamate (833.25 mg, 5.7 mmol) and triethylamine (2.22 mL, 15.54 mmol) were dissolved in dichloromethane (12.5 mL) and cooled to 0 °C. The above solution of acyl chloride was added dropwise under 0°C, and then the solution was gradually warmed to room temperature and stirred for 4 hours until the reaction was complete. The mixture was diluted with dichloromethane (30 mL), washed with water (20 mL x 2), brine (20 mL x 2), and dried over Na2SO4. The organic phase was concentrated to give crude compound 8.1, which was used directly in the next step without further purification. MS: calculated 321.1 [(M+H) + ], measured value 321.1 [(M+H) + ].

[0160] Step (b) Preparation of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (Compound 8.2) The mixture of crude Compound 8.1 and HCl / dioxane (4M, 25 mL) was stirred at 55° C. for an additional 10 hours. The desired product Compound 8.2 was filtered from the solution and dried to give a red solid (762.0 mg). MS: calculated 185.0 [(M+H) + ], measured value 185.1 [(M+H) + ]

[0161] Step (c): Preparation of 5-chloro-3-isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 8.3) To a solution of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 8.2, 100.0 mg, 0.54 mmol) in DMF (2.0 mL) was added K2CO3 (225.4 mg, 1.63 mmol) and 2-iodopropane (275.4 mg, 1.63 mmol). The resulting mixture was heated at 70 °C for 16 h. After cooling to room temperature, the mixture was diluted with EA (50 mL), washed with water (20 mL × 2), brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (eluent: PE / EA, 10 / 1 to 3 / 1) to give compound 8.3 (40.0 mg). MS: calculated 227.1 [(M+H) + ], measured value 227.1 [(M+H) + ].

[0162] Step (d): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-3-isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 8.5) A Schlenk flask was charged with 5-chloro-3-isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazine (compound 8.3, 40 mg, 0.176 mmol), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (compound 8.4, 70.9 mg, 0.265 mmol), NaCO (74.8 mg, 4.0 equiv.), and Pd(dppf)Cl. .DCM (12.9 mg, 0.017 mmol), DME (4.0 mL), and water (1.0 mL) were added. The flask was evacuated and filled with N2 three times, and then the resulting mixture was stirred at 80 °C for 5 h.

[0163] After cooling to room temperature, the mixture was diluted with EA (50 mL), washed with water (20 mL × 2), brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (eluent: PE / EA, 10 / 1 to 3 / 1) to give compound 8.5 (45.0 mg).

[0164] Step (e) Preparation of 5-(3-isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione (Example 8) To a solution of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-3-isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazine (compound 8.5, 45.0 mg, 0.11 mmol) in dichloromethane (2.0 mL) was added TFA (0.1 mL). After stirring at room temperature for 20 minutes, the reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC to give Example 8 (32.0 mg). MS: calculated 303.1 [(M+H) + ], measured value 303.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.54-11.50(m,1H),11.48-11.38(m,1H),8.54(s,1H),8.34(d,J=6.3 Hz,1H),5.11(multiple,J=6.1 Hz,1H),4.06(s,3H),1.42(d,J=6.1 Hz,6H).

[0165] Example 9 5-(3-chloro-1-methyl-pyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0166] Step (a) Preparation of 3,6-dichloro-1H-pyrazolo[4,3-c]pyridazine (Compound 9.1) To an 8 mL round-bottom flask equipped with a magnetic stir bar, 6-chloro-1H-pyrazolo[4,3-c]pyridazine (compound 3.3, 400.0 mg, 2.59 mmol) was added, followed by AcOH (10.0 mL). NCS (1.73 g, 12.94 mmol) and 2,4,6-trimethylaniline (34.99 mg, 0.26 mmol) were then added to the mixture at 25 °C. The mixture was stirred at 70 °C for 1 h. The reaction was quenched by the slow addition of HO (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 1 / 100 to 1 / 2) to give compound 9.1 (700.0 mg). MS: Calculated 189.1 [(M+H) + ], measured value 189.2 [(M+H) + ].

[0167] Step (b) Preparation of 3,6-dichloro-1-methyl-pyrazolo[4,3-c]pyridazine (Compound 9.2) To a solution of 3,6-dichloro-1H-pyrazolo[4,3-c]pyridazine (compound 9.1, 500.0 mg, 2.65 mmol) in DMF (15 mL) was added iodomethane (563.25 mg, 3.97 mmol) and K2CO3 (731.27 mg, 5.29 mmol). The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by the slow addition of HO (20 mL) and extracted three times with EA (15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 100 / 1 to 1 / 1) to give compound 9.2 (150.0 mg). MS: calculated 203.0 [(M+H) + ], measured value 203.0 [(M+H) + ]. 1 H NMR of (400 MHz,DMSO-d6)δ=8.47(s,1H),4.06(s,3H).

[0168] Step (c) Preparation of 5-(3-chloro-1-methyl-pyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (Example 9) 5-(3-chloro-1-methyl-pyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (Example 9) was prepared similarly to Example 1 by replacing 5-chloro-1,3-dimethyl-pyrazolo[3,4-c]pyridazine (Compound 1.5) with 3,6-dichloro-1-methyl-pyrazolo[4,3-c]pyridazine (Compound 9.2) in step (d). 20.0 mg of Example 9 was obtained. MS: calculated 279.0 [(M+H) + ], measured value 279.2 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ = 11.59 (br s, 2H), 8.64 (s, 1H), 8.60 (s, 1H), 4.07 (s, 3H).

[0169] Example 10 5-[1-methyl-3-(1-phenylethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-(1-phenylethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 10) was prepared analogously to Example 8, by replacing 2-iodopropane with 1-bromoethylbenzene in step (c). 34.9 mg of Example 10 was obtained. MS: calculated 365.1 [(M+H) + ], measured value 365.2 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.51(d,J=1.4 Hz,1H),11.44-11.39(m,1H),8.61(s,1H),8.33(d,J=6.3 Hz,1H),7.51(d,J=7.1 Hz,2H),7.40-7.34(m,2H),7.30(d,J=7.3 Hz,1H),6.02(d,J=6.4 Hz,1H),4.02(s,3H),1.70(d,J=6.5 Hz,3H).

[0170] Example 11 3-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile [ka] The title compound was synthesized according to the following scheme: [ka]

[0171] Step (a): Preparation of 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) To a solution of 3-cyanoacetophenone (1 g, 6.9 mmol) in methanol (10 mL) was added sodium borohydride (312.7 mg, 8.3 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 30 minutes. The reaction was then quenched with 1 M HCl (3 mL), diluted with water (100 mL), and extracted three times with DCM (20 mL). The combined organic layers were dried over Na SO and concentrated in vacuo to give compound 11.2 (1.09 g), which was used directly for the next step.

[0172] Step (b): Preparation of 3-(1-chloroethyl)benzonitrile (Compound 11.3) To a solution of 3-(1-hydroxyethyl)benzonitrile (compound 11.2, 1.09 g, 7.4 mmol) in DCM (10 mL) was added SOCl (1.32 g, 810.9 μL, 11.1 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give compound 11.3 (1.2 g), which was used directly in the next step.

[0173] Step (c): Preparation of 3-[1-(5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl)oxyethyl]benzonitrile (Compound 11.4) To a solution of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 8.2, 750 mg, 4.1 mmol) in DMF (15 mL) was added 3-(1-chloroethyl)benzonitrile (compound 11.3, 1.01 g, 6.1 mmol) and K2CO3 (3.37 g, 24.4 mmol). The resulting mixture was stirred at 70 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with HO (100 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 30% EA in PE) to give compound 11.4 (250 mg). MS: calculated 314.1 [(M+H) + ]; Measured value 314.1 [(M+H) + ].

[0174] Step (d): Preparation of 3-[1-[5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile (Compound 11.5) To a solution of 3-[1-(5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl)oxyethyl]benzonitrile (compound 11.4, 250 mg, 796.8 μmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was added (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (compound 8.4, 256.4 mg, 956.2 μmol), Pd(dppf)Cl . DCM (65.1 mg, 79.7 μmol) and Na2CO3 (337.8 mg, 3.2 mmol) were added. The resulting mixture was stirred under nitrogen at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL) and extracted three times with EA (10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 0% to 30% EA in PE) to give compound 11.5 (310 mg). MS: calculated 502.3 [(M+H) + ]; Measured value 502.4 [(M+H) + ].

[0175] Step (e): Preparation of 3-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile (Example 11) To a solution of 3-[1-[5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile (Compound 11.5, 310 mg, 618.1 μmol) in dichloromethane (3 mL) was added TFA (500 μL). After stirring at room temperature for 20 minutes, the reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC to give Example 11 (151.9 mg). MS: calculated 390.1 [(M+H) + ]; Measured value 390.2 [(M+H)+ ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.54-11.50(m,1H),11.45-11.38(m,1H),8.64(s,1H),8.33(d,J=6.2 Hz,1H),8.01(s,1H),7.88(d,J=7.9 Hz,1H),7.78(dt,J=7.8,1.4 Hz,1H),7.59(t,J=7.8 Hz,1H),6.07(q,J=6.3 Hz,1H),4.01(s,3H),1.71(d,J=6.5 Hz,3H).

[0176] Example 12 4-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile [ka] 4-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile (Example 12) was prepared analogously to Example 11 by replacing 3-acetylbenzonitrile (compound 11.1) with 4-acetylbenzonitrile in step (a). MS: calculated 390.1 [(M+H) + ], measured value 390.2 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.52(s,1H),11.42(br s,1H),8.64(s,1H),8.34(s,1H),7.87-7.81(m,2H),7.72(d,J=8.2 Hz,2H),6.09(q,J=6.5 Hz,1H),4.00(s,3H),1.70(d,J=6.5 Hz,3H).

[0177] Example 13 5-[3-[1-(2-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; [ka] 5-[3-[1-(2-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 13) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(2-chlorophenyl)ethanol in step (b). MS: calculated 399.1 [(M+H) + ]; Measured value 399.2 [(M+H) + ]. 1 H NMR(500 MHz,DMSO-d6)δ=11.54(s,1H),11.44(br s,1H),8.65(s,1H),8.35(s,1H),7.65(dd,J=7.3,2.1 Hz,1H),7.49(dd,J=7.6,1.8 Hz,1H),7.40-7.30(m,2H),6.29(q,J=6.4,1H),4.00(s,3H),1.70(d,J=6.4,3H).

[0178] Example 14 5-[3-[1-(3-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; [ka] 5-[3-[1-(3-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 14) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(3-chlorophenyl)ethanol in step (b). MS: calculated 399.1 [(M+H) + ]; Measured value 399.2 [(M+H) + ]. 1H NMR(500 MHz,DMSO-d6)δ=11.54(s,1H),11.44(br s,1H),8.63(s,1H),8.34(s,1H),7.58(t,J=1.7 Hz,1H),7.49(d,J=7.6 Hz,1H),7.41(t,J=7.7 Hz,1H),7.37(d,J=7.8 Hz,1H),6.03(q,J=6.4,1H),4.02(s,3H),1.69(d,J=6.4,3H).

[0179] Example 15 5-[3-[1-(4-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; [ka] 5-[3-[1-(4-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 15) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(4-chlorophenyl)ethanol in step (b). MS: calculated 399.1 [(M+H) + ]; Measured value 399.2 [(M+H) + ]. 1 H NMR(500 MHz,DMSO-d6)δ=11.54(d,J=1.7 Hz,1H),11.44(dd,J=6.0,1.4 Hz,1H),8.61(s,1H),8.34(d,J=6.1 Hz,1H),7.60-7.52(m,2H),7.47-7.37(m,2H),6.02(q,J=6.5 Hz,1H),4.01(s,3H),1.68(d,J=6.6,3H).

[0180] Example 16 5-[3-[1-(4-fluorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[3-[1-(4-fluorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 16) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(4-fluorophenyl)ethanol in step (b). MS: calculated 383.1 [(M+H) + ]; Measured value 383.2 [(M+H) + ]. 1 H NMR(500 MHz,DMSO-d6)δ=11.53(br s,1H),11.43(br s,1H),8.60(s,1H),8.34(s,1H),7.62-7.54(m,2H),7.24-7.16(m,2H),6.03(q,J=6.4 Hz,1H),4.02(s,3H),1.69(d,J=6.6 Hz,3H).

[0181] Example 17 5-[1-methyl-3-(1-(2-pyridyl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 17) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(2-pyridyl)ethanol in step (b). MS: calculated 366.1 [(M+H) + ]; Measured value 366.2 [(M+H) + ]. 1H NMR(500 MHz,DMSO-d6)δ=11.56-11.52(m,1H),11.50-11.39(m,1H),8.64(s,1H),8.57(d,J=5.1 Hz,1H),8.35(d,J=6.3 Hz,1H),7.80(td,J=7.7,1.7 Hz,1H),7.55(d,J=7.9 Hz,1H),7.33(t,J=6.3 Hz,1H),6.02(q,J=6.5 Hz,1H),4.00(s,3H),1.72(d,J=6.6 Hz,3H).

[0182] Example 18 5-[1-methyl-3-(1-(3-pyridyl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[1-(3-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 18) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(3-pyridyl)ethanol in step (b). MS: calculated 366.1 [(M+H) + ]; Measured value 366.2 [(M+H) + ]. 1 H NMR(500 MHz,DMSO-d6)δ=11.54(d,J=1.7 Hz,1H),11.47-11.42(m,1H),8.79(s,1H),8.63(s,1H),8.56(d,J=4.7 Hz,1H),8.34(d,J=6.1 Hz,1H),8.06(br d,J=7.8 Hz,1H),7.53-7.45(m,1H),6.10(q,J=6.4 Hz,1H),4.02(s,3H),1.75(d,J=6.6 Hz,3H).

[0183] Example 19 5-[1-methyl-3-(1-(4-pyridyl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[1-(4-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 17) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(4-pyridyl)ethanol in step (b). MS: calculated 366.1 [(M+H) + ]; Measured value 366.3 [(M+H) + ]. 1 H NMR(500 MHz,DMSO-d6)δ=11.55(d,J=1.7 Hz,1H),11.47(br d,J=6.1 Hz,1H),8.82-8.52(m,3H),8.36(d,J=6.3 Hz,1H),7.89-7.59(m,2H),6.30-5.93(m,1H),4.00(s,3H),1.72(d,J=6.6 Hz,3H).

[0184] Example 20 5-[1-methyl-3-[1-[3-(trifluoromethyl)phenyl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[1-[3-(trifluoromethyl)phenyl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 20) was prepared analogously to Example 11 by replacing 3-(1-chloroethyl)benzonitrile (Compound 11.3) with 1-(1-bromoethyl)-3-(trifluoromethyl)benzene in step (c). MS: calculated 433.1 [(M+H) + ]; Measured value 433.1 [(M+H) + ]. 1H NMR(500 MHz,DMSO-d6)δ=11.13-10.54(m,2H),8.64(s,1H),8.35(s,1H),7.97-7.81(m,2H),7.67(s,1H),7.63(d,J=7.6 Hz,1H),6.13(d,J=6.4 Hz,1H),4.01(s,3H),1.73(d,J=6.6 Hz,3H).

[0185] Example 21 5-[1-methyl-3-(1-(2-methylthiazol-4-yl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0186] Step (a): Preparation of 1-(2-methylthiazol-4-yl)ethanol (Compound 21.2) To a solution of 4-formyl-2-methylthiazole (compound 21.1, 500.0 mg, 3.93 mmol) in THF (5 mL) was added MeMgBr (1 M in THF, 6.0 mL, 6.0 mmol) under a N atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The mixture was quenched by the slow addition of saturated aqueous ammonium chloride solution (5 mL). The mixture was then diluted with brine (5 mL) and extracted three times with EA (10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to give compound 21.2 (500.0 mg). MS: calculated 144.0 [(M+H) + ]; Measured value 126.1 [M-OH] + .

[0187] Step (b): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (Compound 21.3) A solution of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 8.2, 3.0 g, 16.2 mmol) in DMF (60 mL) was treated with (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (compound 8.4, 5.2 g, 19.5 mmol), Pd(dppf)Cl . DCM (991.0mg, 1.4mmol), Na2SO4 . 10HO (17.5 g, 54.2 mmol) and CsCO (17.6 g, 54.2 mmol) were added. The resulting mixture was stirred under nitrogen at 85 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with HO (150 mL). The pH of the aqueous phase was then adjusted to pH = 6 using saturated aqueous ammonium chloride, and the mixture was extracted three times with EA (150 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (50% to 100% EA in PE) to give Compound 21.3 (2.7 g). MS: calculated 373.2 [(M+H) + ]; Measured value 373.2 [(M+H) + ].

[0188] Step (c): Preparation of 4-[1-[5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]-2-methyl-thiazole (Compound 21.4) To a suspension of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 21.3, 200.0 mg, 540 μmol), 1-(2-methylthiazol-4-yl)ethanol (compound 21.2, 76.9 mg, 540 μmol), and PPh3 (281.71 mg, 1.1 mmol) in toluene (8 mL) was added DEAD (187.1 mg, 1.1 mmol). The resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with HO (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 0% to 30% EA in PE) to give Compound 21.4 (120.0 mg). MS: calculated 498.2 [(M+H) + ]; Measured value 498.4 [(M+H) + ].

[0189] Step (d): Preparation of 5-[1-methyl-3-(1-(2-methylthiazol-4-yl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 21) To a mixture of 4-[1-[5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]-2-methyl-thiazole (Compound 21.4, 100.0 mg, 0.2 mol) in methanol (3 mL) was added HCl (2.0 M in MeOH, 1.5 mL, 3.0 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC to give Example 21 (56.0 mg). MS: calculated 386.1 [(M+H)+]; found 386.2 [(M+H)+]. 1H NMR(400 MHz,DMSO-d6)δ=11.52(s,1H),11.42(br d,J=5.2 Hz,1H),8.57(s,1H),8.37-8.33(m,1H),7.55(s,1H),6.09(q,J=6.4 Hz,1H),4.07(s,3H),2.66(s,3H),1.75(d,J=6.4 Hz,3H).

[0190] Example 22 5-[1-methyl-3-(1-(5-methylthiazol-2-yl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-Methyl-3-[1-(5-methylthiazol-2-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine 2,4-dione (Example 22) was prepared analogously to Example 21 by substituting 1-(5-methylthiazol-2-yl)ethanol for 1-(2-methylthiazol-4-yl)ethanol (Compound 21.2) in step (c). MS: calculated 386.4 [(M+H)+]; found 386.1 [(M+H)+]. 1 H NMR(400 MHz,DMSO-d6)δ=11.52(s,1H),11.43(br d,J=4.9 Hz,1H),8.60(s,1H),8.36(d,J=6.1 Hz,1H),7.48(s,1H),6.22(q,J=6.5 Hz,1H),4.07(s,3H),2.41(s,3H),1.80(d,J=6.5 Hz,3H).

[0191] Example 23 5-[3-[1-(4-chloro-1-methyl-pyrazol-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[3-[1-(4-chloro-1-methyl-pyrazol-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 23) was prepared analogously to Example 21 by replacing 4-formyl-2-methylthiazole (compound 21.1) with 4-chloro-1-methylpyrazole-3-carboxaldehyde in step (a). MS: calculated 403.1, 405.1 [(M+H) + ]; Measurement value 403.2, 405.2 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.50(s,1H),11.43(br d,J=5.6 Hz,1H),8.53(s,1H),8.34(d,J=6.4 Hz,1H),7.92(s,1H),6.03(q,J=6.4 Hz,1H),4.06(s,3H),3.81(s,3H),1.75(d,J=6.4 Hz,3H).

[0192] Example 24 5-[1-methyl-3-(1-(2-methylpyrazol-3-yl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[1-(2-methylpyrazol-3-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 24) was prepared analogously to Example 11, by replacing 3-(1-hydroxyethyl)benzonitrile (Compound 11.2) with 1-(2-methylpyrazol-3-yl)ethanol in step (b). MS: calculated 369.1 [(M+H) + ], measured value 369.2 [(M+H) + ]. 1H NMR(400 MHz,DMSO-d6)δ=11.51(s,1H),11.45-11.35(m,1H),8.55(s,1H),8.37-8.29(m,1H),7.37(d,J=2.0 Hz,1H),6.45(d,J=2.0 Hz, 1H), 6.16 (q, J = 6.4 Hz, 1H), 4.08 (s, 3H), 3.87 (s, 3H), 1.77 (d, J = 6.4 Hz, 3H).

[0193] Example 25 5-[3-[1-(1,3-benzoxazol-2-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-(1-(2-methylpyrazol-3-yl)ethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 24) was prepared analogously to Example 11 by replacing 3-(1-hydroxyethyl)benzonitrile (compound 11.2) with 1-(1,3-benzoxazol-2-yl)ethanol in step (b). MS: calculated 406.1 [(M+H) + ], measured value 406.2 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.53(s,1H),11.45(br d,J=6.0 Hz,1H),8.63(s,1H),8.35(d,J=6.0 Hz,1H),7.79-7.72(m,2H),7.47-7.37(m,2H),6.30(q,J=6.8 Hz,1H),4.03(s,3H),1.90(d,J=6.4 Hz,3H).

[0194] Example 26 5-[1-methyl-3-[(1S)-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0195] Step (a): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1S)-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (Compound 26.2) To a solution of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 21.3, 300.0 mg, 805.5 μmol) in toluene (8 mL), (1R)-1-(2-pyridyl)ethanol (compound 26.1, 148.8 mg, 1.2 mmol), PPh3 (316.9 mg, 1.2 mmol), and DEAD (220 mg, 200 μL, 1.3 mmol) were added. The resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with HO (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 0% to 30% EA in PE) to give Compound 26.2 (338.6 mg). MS: calculated 478.3 [(M+H) + ]; Measured value 478.3 [(M+H) + ].

[0196] Step (b): Preparation of 5-[1-methyl-3-[(1S)-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 26) To a mixture of 5-(2,4-ditert-butoxypyrimidin-5-yl)-1-methyl-3-[(1S)-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (compound 26.2, 338.6 mg, 709.0 μmol) in methanol (3 mL) was added HCl (2.0 M in MeOH, 1.5 mL, 3.0 mmol). The mixture was stirred at 22 °C for 2 hours. The reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC to give Example 26 (229.0 mg). MS: calculated 366.1 [(M+H) + ]; Measured value 366.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.53(s,1H),11.47(br d,J=4.3 Hz,1H),8.67(s,2H),8.36(d,J=5.8 Hz,1H),8.02(d,J=5.3 Hz,1H),7.74(s,1H),7.51(d,J=3.0 Hz,1H),6.17-6.02(m,1H),4.00(s,3H),1.76(d,J=6.1 Hz,3H).

[0197] Example 27 5-[1-methyl-3-[(1S)-1-phenylethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[(1S)-1-phenylethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 27) was prepared analogously to Example 26 by replacing (1R)-1-(2-pyridyl)ethanol (Compound 26.2) with (1R)-1-phenylethanol in step (a). MS: calculated 365.1 [(M+H) + ], measured value 365.2 [(M+H) + ]. 1H NMR(400 MHz,DMSO-d6)δ=11.51(s,1H),11.42(br s,1H),8.61(s,1H),8.33(s,1H),7.51(d,J=7.3 Hz,2H),7.44-7.34(m,2H),7.33-7.25(m,1H),6.02(q,J=6.5 Hz,1H),4.02(s,3H),1.70(d,J=6.4 Hz,3H).

[0198] Example 28 5-[3-[(1R)-2,2-difluoro-1-phenyl-ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0199] Step (a): Preparation of (1S)-2,2-difluoro-1-phenyl-ethanol (Compound 28.2) To a solution of 2,2-difluoro-1-phenyl-ethanone (compound 28.1, 354.0 mg, 300 μL, 2.3 mmol) in DCM (2 mL) was added HCOOH (1.1 g, 900 μL, 23.5 mmol), EtN (943.8 mg, 1.3 mL, 9.3 mmol), and RuCl[(R,R)-TsDPEN](p-cymene) (14.4 mg, 22.7 μmol). The resulting mixture was stirred under nitrogen at room temperature for 24 h. The reaction mixture was diluted with saturated NaHCO (20 mL) and extracted three times with DCM (20 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 12 g, 0% to 50% EA in PE) to give compound 28.2 (302.0 mg). MS: Calculated 141.0 [(M-OH) + ]; Measured value 141.0 [(M-OH) + ].

[0200] Step (b): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1R)-2,2-difluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazine (Compound 28.3) To a solution of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 21.3, 180.0 mg, 483.3 μmol) in toluene (4 mL), (1S)-2,2-difluoro-1-phenyl-ethanol (compound 28.2, 130.1 mg, 773.3 μmol), PPh3 (202.8 mg, 773.3 μmol), and DEAD (143.0 mg, 130 μL, 821.1 μmol) were added. The resulting mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction mixture was diluted with HO (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 0% to 25% EA in PE) to give Compound 28.3 (219.4 mg). MS: calculated 513.2 [(M+H) + ]; Measured value 513.3 [(M+H) + ].

[0201] Step (c): Preparation of 5-[3-[(1R)-2,2-difluoro-1-phenyl-ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 28) To a mixture of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1R)-2,2-difluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazine (compound 28.3, 219.4 mg, 428.1 μmol) in methanol (1.5 mL) was added HCl (2.0 M in MeOH, 1.0 mL, 2.0 mmol). The mixture was stirred at 22 °C for 2 hours. The reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC to give Example 28 (137.4 mg). MS: calculated 401.1 [(M+H)+ ]; Measured value 401.0 [(M+H) + ]. 1 H NMR(500 MHz,DMSO-d6)δ=11.55(s,1H),11.44(br s,1H),8.69(s,1H),8.36(s,1H),7.63-7.57(m,2H),7.47-7.37(m,3H),6.58(td,J=54,5,3.5 Hz, 1H), 6.19 (td, J=11.4, 3.1 Hz, 1H), 4.02 (s, 3H).

[0202] Examples 29A and 29B 5-[1-methyl-3-[(1R)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[1-methyl-3-[(1S)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0203] Step (a): Preparation of [2,2,2-trifluoro-1-(2-pyridyl)ethyl]trifluoromethanesulfonate (Compound 29.2) To a mixture of 2,2,2-trifluoro-1-(2-pyridyl)ethanol (compound 29.1, 1.8 g, 10.2 mmol), triethylamine (1.54 g, 2.1 mL, 15.2 mmol) and DCM (20 mL) was added trifluoromethanesulfonic anhydride (3.15 g, 1.9 mL, 11.2 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 10 min. The red mixture containing compound 29.2 was added directly to the next step without workup.

[0204] Step (b): Preparation of 5-chloro-1-methyl-3-[2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (Compound 29.3) To a mixture of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 8.2, 1.5 g, 8.1 mmol) in DMF (15 mL) was added potassium carbonate (1.68 g, 12.2 mmol), followed by the addition of [2,2,2-trifluoro-1-(2-pyridyl)ethyl]trifluoromethanesulfonate (compound 29.2, crude product from the previous step) to the above mixture at 0 °C. The mixture was stirred at 60 °C for 3 h. After cooling to room temperature, the reaction was quenched with HO (15 mL), and the mixture was extracted three times with EA (60 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 100 / 1 to 3 / 1) to give compound 29.3 (1.12 g). MS: Calculated 344.7 [(M+H) + ], measured value 344.0 [(M+H) + ].

[0205] Step (c): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (Compound 29.4) A mixture of (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (539.1 mg, 2.0 mmol) and 5-chloro-1-methyl-3-[2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (compound 29.3, 530 mg, 1.6 mmol) in 1,2-dimethoxyethane (8 mL) and water (2 mL) was added to Pd(dppf)Cl2. .DCM (126.3 mg, 154.7 μmol) and Na2CO3 (655.7 mg, 6.2 mmol) were added. The mixture was stirred under nitrogen at 90 °C for 1 h. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted twice with EA (10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA, 100 / 1 to 3 / 1) to give compound 29.4 (900 mg). MS: calculated 532.5 [(M+H) + ], measured value 532.2 [(M+H) + ].

[0206] Step (d): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1R)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine and 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1S)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (Compound 29.5A and Compound 29.5B) Compound 30.4 (900 mg) was separated by SFC to give two single isomers: Compound 29.5A (faster eluting, 400 mg) MS: calculated 532.5 (M+H) + , measured value 532.2 (M+H) + and compound 29.5B (slower eluting, 330 mg) MS: calculated 532.5 (M+H) + , measured value 532.2 (M+H) + SFC 150Mgm column: (s,s) Whelk-O1 250 x 30 mm ID, 5 μm. Mobile phase: A for CO2 and B for IPA (0.1% NH3H2O). Gradient: B 40%. Flow rate: 80 mL / min. Back pressure: 100 bar.

[0207] Step (e): Preparation of 5-[1-methyl-3-[(1R)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[1-methyl-3-[(1S)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 29A and 29B) To a mixture of compound 29.5A (400 mg, 752.5 μmol) in methanol (4 mL) was added 2M HCl (1.3 mL, 2.7 mmol). The mixture was stirred at room temperature for 1 hour, then filtered and washed twice with ice-water methanol (1 mL) to give Example 29A (236.1 mg). MS: calculated 420.3 [(M+H) + ]; Measured value 420.0 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.56(s,1H),11.46(br d,J=6.0 Hz,1H),8.71(s,1H),8.67(d,J=4.9 Hz,1H),8.37(d,J=6.1 Hz,1H),7.93(dt,J=7.7,1.7 Hz,1H),7.79(d,J=7.9 Hz,1H),7.50(ddd,J=7.5,4.9,0.9 Hz,1H),6.59(q,J=6.7 Hz,1H),4.01(s,3 H).

[0208] To a mixture of compound 29.5B (330 mg, 620.9 μmol) in methanol (1.5 mL) was added 2 M HCl (1.6 mL, 3.1 mmol). The mixture was stirred at room temperature for 1 hour, then filtered and washed twice with ice-water methanol (1 mL) to give Example 29B (179.9 mg). MS: calculated 420.3 [(M+H)+]; found 420.1 [(M+H)+]. 1H NMR(400 MHz,DMSO-d6)δ=11.55(s,1H),11.45(br d,J=5.9 Hz,1H),8.71(s,1H),8.66(d,J=4.3 Hz,1H),8.37(d,J=6.3 Hz,1H),7.92(dt,J=7.8,1.6 Hz,1H),7.79(d,J=7.9 Hz,1H),7.50(t,J=6.1 Hz,1H),6.59(q,J=6.7 Hz,1H),4.01(s,3 H).

[0209] Examples 30A and 30B 5-[1-methyl-3-[(1R)-2,2,2-trifluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[1-methyl-3-[(1S)-2,2,2-trifluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Examples 30A and 30B were prepared in the same manner as Examples 29A and 29B, by substituting 2,2,2-trifluoro-1-(2-pyridyl)ethanol (Compound 29.1) with 2,2,2-trifluoro-1-phenylethanol in step (a). Example 30A MS: Calculated 419.3 [(M+H)+]; Found 419.1 [(M+H)+]. 1 H NMR(400 MHz,DMSO-d6)δ=11.55(s,1H),11.45(br d,J=5.1 Hz,1H),8.70(s,1H),8.36(d,J=6.0 Hz,1H),7.74-7.64(m,2H),7.50-7.43(m,3H),6.67(q,J=6.7 Hz,1H),4.03(s,3H). Example 30B MS: calculated 419.3 [(M+H)+]; found 419.1 [(M+H)+]. 1H NMR(400 MHz,DMSO-d6)δ=11.55(s,1H),11.45(br d,J=5.1 Hz,1H),8.70(s,1H),8.36(d,J=6.1 Hz,1H),7.72-7.66(m,2H),7.50-7.43(m,3H),6.67(q,J=6.6 Hz,1H),4.03(s,3H).

[0210] Examples 31A and 31B 5-[3-[(1R)-2,2-Difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-2,2-Difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0211] Step (a): Preparation of 2,2-difluoro-1-(2-pyridyl)ethanol (Compound 31.2) To a solution of pyridine-2-carbaldehyde (compound 31.1, 1.7 g, 1.5 mL, 15.7 mmol) in DMF (20 mL) was added TMSCHF (2.6 g, 3.0 mL, 21.2 mmol) and CsF (238.3 mg, 1.6 mmol). The resulting mixture was stirred under nitrogen at room temperature for 2 h, then diluted with saturated NaCl (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in THF (20 mL). The resulting solution was diluted with HF .3EtN (4.0 g, 4.0 mL, 24.5 mmol) was added at 0 °C. After stirring at 0 °C for 1 h, the reaction was quenched with saturated NaHCO (100 mL), and the mixture was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 80 g, 0% to 50% EA in PE) to give Compound 31.2 (1.77 g). MS: calculated 160.1 [(M+H) + ]; Measured value 160.0 [(M+H) + ].

[0212] Step (b): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-3-[2,2-difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 31.3) To a solution of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 21.3, 500.0 mg, 1.3 mmol) in toluene (13 mL), 2,2-difluoro-1-(2-pyridyl)ethanol (compound 31.2, 277.7 mg, 1.7 mmol), PPh3 (493.0 mg, 1.9 mmol), and DEAD (330.0 mg, 300 μL, 1.9 mmol) were added. The resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was diluted with HO (40 mL) and extracted three times with EA (40 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 30 g, 0% to 30% EA in PE) to give Compound 31.3 (582.0 mg). MS: calculated 514.2 [(M+H) + ]; Measured value 514.3 [(M+H) + ].

[0213] Step (c): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1R)-2,2-difluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine and 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1S)-2,2-difluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (Compounds 31.3A and 31.3B) Compound 31.3 (582.0 mg) was separated by SFC to give two single isomers: Compound 31.3A (faster eluting, 251.4 mg) MS: calculated 514.2 [(M+H)+], found 514.3 [(M+H) + ] and compound 31.3B (slower eluting, 238.3 mg) MS: calculated 514.2 [(M+H) + ], measured value 514.3 [(M+H) + ], SFC 150Mgm, Column: (s,s)Whelk-O1 250 x 30 mm ID 5 μm, Mobile phase: A for CO2, B for MeOH (0.1% NH3 · HO), gradient: B 30%, flow rate: 80 mL / min, back pressure: 100 bar.

[0214] Step (d): 5-[3-[(1R)-2,2-Difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-2,2-Difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 31A and 31B) To a mixture of compound 31.3A (251.4 mg, 489.5 μmol) in methanol (2 mL) was added HCl (2.0 M in MeOH, 400 μL, 800 μmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC to give Example 31A (92.6 mg). MS: calculated 402.1 [(M+H) + ]; Measured value 402.0 [(M+H) + ]. 1H NMR(400 MHz,DMSO-d6)δ=11.55(s,1H),11.45(br d,J=5.1 Hz,1H),8.70(s,1H),8.65(br d,J=4.3 Hz,1H),8.38(d,J=6.3 Hz,1H),7.88(td,J=7.7,1.6 Hz,1H),7.67(d,J=7.9 Hz,1H),7.44(dd,J=6.9,5.1 Hz,1H),6.72(td,J=53.8,3.0 Hz, 1H), 6.29-6.11 (m, 1H), 4.02 (s, 3H).

[0215] To a mixture of compound 31.3B (238.3 mg, 464.2 μmol) in methanol (2 mL) was added HCl (2.0 M in MeOH, 400 μL, 800 μmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product, which was purified by preparative HPLC to give Example 31B (85.0 mg). MS: calculated 402.1 [(M+H) + ]; Measured value 402.0 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.55(s,1H),11.46(br d,J=5.8 Hz,1H),8.70(s,1H),8.65(dd,J=4.8,0.6 Hz,1H),8.38(d,J=6.1 Hz,1H),7.89(td,J=7.7,1.7 Hz,1H),7.67(d,J=7.8 Hz,1H),7.45(ddd,J=7.5,4.8,0.9 Hz,1H),6.72(td,J=53.8,3.4 Hz,1H),6.22(ddd,J=14.1,8.8,3.3 Hz,1H),4.02(s,3H).

[0216] Examples 32A and 32B 5-[3-[(1R)-2,2-Difluoro-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-2,2-Difluoro-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Examples 32A and 32B were prepared in a similar manner to Examples 31A and 31B, by replacing pyridine-2-carbaldehyde (compound 31.1) with 5-fluoropyridine-2-carbaldehyde in step (a). Example 32A MS: calculated 420.1 [(M+H) + ]; Measured value 420.0 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.54(s,1H),11.45(br d,J=5.8 Hz,1H),8.68(s,1H),8.66(d,J=2.4 Hz,1H),8.37(d,J=6.1 Hz,1H),7.88-7.73(m,2H),6.70(td,J=53.9,3.4 Hz,1H),6.34-6.16(m,1H),4.01(s,3H). Example 32B MS: Calculated value 420.1 [(M+H) + ]; Measured value 420.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.54(s,1H),11.45(br d,J=5.9 Hz,1H),8.69(s,1H),8.66(d,J=2.3 Hz,1H),8.37(d,J=6.1 Hz,1H),7.88-7.74(m,2H),6.71(td,J=53.9,3.3 Hz,1H),6.31-6.19(m,1H),4.02(s,3H).

[0217] Examples 33A and 33B 5-[3-[(1R)-2,2-Difluoro-1-(6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-2,2-Difluoro-1-(6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Examples 33A and 33B were prepared in the same manner as Examples 31A and 31B, by substituting 6-methylpyridine-2-carbaldehyde for pyridine-2-carbaldehyde (compound 31.1) in step (a). Example 33A MS: calculated 416.1 [(M+H) + ]; Measured value 416.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.54(s,1H),11.44(br d,J=5.8 Hz,1H),8.70(s,1H),8.37(d,J=6.3 Hz,1H),7.75(t,J=7.8 Hz,1H),7.44(d,J=7.6 Hz,1H),7.29(d,J=7.8 Hz,1H),6.68(td,J=53.7,2.1 Hz,1H),6.22-6.05(m,1H),4.03(s,3H),2.51(s,3H). Example 33B MS: calculated 416.1 [(M+H)+]; found 416.1 [(M+H)+]. 1 H NMR(400 MHz,DMSO-d6)δ=11.54(s,1H),11.44(br d,J=6.0 Hz,1H),8.70(s,1H),8.37(d,J=6.1 Hz,1H),7.75(t,J=7.8 Hz,1H),7.44(d,J=7.6 Hz,1H),7.29(d,J=7.6 Hz,1H),6.68(td,J=53.8,2.6 Hz,1H),6.23-6.07(m,1H),4.02(s,3H),2.50(s,3H).

[0218] Example 34 5-[1-methyl-3-[methyl(1,2,2-trimethylpropyl)amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0219] Step (a): Preparation of 3-bromo-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 5.5) To a 100 mL round-bottom flask equipped with a magnetic stir bar, 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (compound 8.2, 1.0 g, 5.42 mmol) was added, followed by sulfolane (10 mL). POBr (1.71 g, 5.96 mmol) was then added to the mixture at 25 °C under a nitrogen atmosphere. The mixture was stirred at 50 °C under a nitrogen atmosphere for 48 h. The mixture was quenched by the slow addition of HO (100 mL) and then extracted three times with EA (50 mL). The combined organic layer was washed five times with a mixture of brine and HO (1:1, 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: 1% to 20% EA in PE) to give compound 5.5 (954.5 mg). MS: Calculated 246.9 [(M+H) + ]; Measured value 246.9 [(M+H) + ].

[0220] Step (b): Preparation of 5-chloro-1-methyl-N-(1,2,2-trimethylpropyl)pyrazolo[3,4-c]pyridazin-3-amine (Compound 34.2) A Schlenk flask was charged with 3-bromo-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound 5.5, 150 mg, 0.61 mmol), 3,3-dimethylbutan-2-amine (compound 34.1, 92.0 mg, 0.91 mmol), KPO (257.3 mg, 1.21 mmol), CuI (5.7 mg, 30.3 μmol), BTMPO (17.8 mg, 42.4 μmol), and EtOH (0.8 mL). The flask was evacuated and backfilled with N three times, after which the mixture was stirred at 80 °C for 16 h. After cooling to room temperature, the mixture was diluted with EA (50 mL) and filtered through a Celite pad, washing with EA. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography (eluent: 0% to 50% EA in PE) to give Compound 34.2 (130 mg). MS: calculated 268.1 [(M+H) + ]; Measured value 268.1 [(M+H) + ].

[0221] Step (c): Preparation of 5-chloro-N,1-dimethyl-N-(1,2,2-trimethylpropyl)pyrazolo[3,4-c]pyridazin-3-amine (Compound 34.3) To a solution of 5-chloro-1-methyl-N-(1,2,2-trimethylpropyl)pyrazolo[3,4-c]pyridazin-3-amine (compound 34.2, 130 mg, 0.48 mmol) in DMF (3 mL) was added NaH (60% dispersion in mineral oil, 38.8 mg, 0.97 mmol) at 0 °C. The mixture was stirred at 0 °C for 15 min, after which MeI (151 μL, 2.43 mmol) was added. The mixture was gradually warmed to room temperature and stirred for an additional 2 h. The reaction was quenched with HOAc (30 μL), diluted with 30 mL of cold water, and extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0% to 30% EA in PE) to give compound 34.3 (120 mg). MS: Calculated 282.1 [(M+H) + ]; Measured value 282.1 [(M+H) + ].

[0222] Step (d): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-N,1-dimethyl-N-(1,2,2-trimethylpropyl)pyrazolo[3,4-c]pyridazin-3-amine (Compound 34.4) In a Schlenk flask, 5-chloro-N,1-dimethyl-N-(1,2,2-trimethylpropyl)pyrazolo[3,4-c]pyridazin-3-amine (compound 34.3, 120 mg, 0.43 mmol), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (compound 8.4, 173.0 mg, 0.64 mmol), Na2CO3 (174.0 mg), and Pd(dppf)Cl2 were added. . DCM (31.4 mg, 0.043 mmol) was added. 1,2-Dimethoxyethane (4.0 mL) and water (1.0 ml) were added. The flask was evacuated and filled with N2 three times, after which the mixture was stirred at 90 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted twice with EA (50 mL). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0% to 30% EA in PE) to give Compound 34.4 (177.7 mg).

[0223] Step (e): Preparation of 5-[1-methyl-3-[methyl(1,2,2-trimethylpropyl)amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 34) A solution of 2N HCl in MeOH (1.9 mL) was diluted with 14 mL of MeOH. The above solution was added to a solution of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-N,1-dimethyl-N-(1,2,2-trimethylpropyl)pyrazolo[3,4-c]pyridazin-3-amine (compound 34.4, 177.7 mg, 378.4 μmol) in MeOH (5 mL), and the mixture was stirred for 3 hours. The desired product precipitated from the red solution. The red solid was filtered and washed twice with MeOH (2 mL). The solid was dried on an oil pump to give Example 34 (55.4 mg). MS: calculated 358.4 [(M+H)+ ]; Measured value 358.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.45(s,1H),11.36(br d,J=5.0 Hz,1H),8.85(s,1H),8.30(d,J=6.3 Hz,1H),4.20-4.12(m,1H),3.98(s,3H),3.01(s,3H),1.23-1.20(m,3H),0.98(s,9H).

[0224] Example 35 5-[3-[1-Cyclopentylethyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[3-[1-Cyclopentylethyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 35) was prepared analogously to Example 34 by replacing 3,3-dimethylbutan-2-amine (Compound 34.1) with 1-cyclopentylethanamine in step (b). MS: calculated 370.4 [(M+H) + ]; Measured value 370.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.45(br s,1H),11.35(br s,1H),8.74(s,1H),8.29(s,1H),3.99(s,3H),3.94-3.81(m,1 H),2.92(s,3H),2.21-2.10(m,1H),1.82-1.73(m,1H),1.66(ddd,J=12.2,8.0,4.4 Hz,2H),1.60-1.45(m,3H),1.29-1.20(m,2H),1.16(d,J=6.5 Hz,3H).

[0225] Example 36 5-[3-[cyclopentyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[3-[Cyclopentyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 36) was prepared analogously to Example 34, by replacing 3,3-dimethylbutan-2-amine (Compound 34.1) with cyclopentanamine in step (b). MS: calculated 342.3 [(M+H) + ]; Measured value 342.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.45(s,1H),11.36(br d,J=5.25 Hz,1H),8.69(s,1H),8.26(d,J=6.1 Hz,1H),4.49(br t,J=7.6 Hz, 1H), 4.00 (s, 3H), 2.96 (s, 3H), 1.91-1.80 (m, 2H), 1.75-1.56 (m, 6H).

[0226] Example 37 5-[1-methyl-3-[[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0227] Step (a): Preparation of 5-chloro-1-methyl-N-[(1S)-1-phenylethyl]pyrazolo[3,4-c]pyridazin-3-amine (Compound 37.2) A Schlenk flask was charged with 3-bromo-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound 5.5, 500 mg, 2.0 mmol), (1S)-1-phenylethanamine (compound 37.1, 367.2 mg, 3.0 mmol), KPO (857.7 mg, 4.0 mmol), CuI (19.2 mg, 101.0 μmol), BTMPO (42.5 mg, 101.0 μmol), and EtOH (3.0 mL). The flask was evacuated and filled with N three times, after which the mixture was stirred at 85 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted twice with EA (50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0% to 30% EA in PE) to give Compound 37.2 (400 mg). MS: calculated 288.1 [(M+H) + ]; Measured value 288.1 [(M+H) + ].

[0228] Step (b): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-N-[(1S)-1-phenylethyl]pyrazolo[3,4-c]pyridazin-3-amine (Compound 37.3) A Schlenk flask was charged with 5-chloro-1-methyl-N-[(1S)-1-phenylethyl]pyrazolo[3,4-c]pyridazin-3-amine (compound 37.2, 50.0 mg, 173.7 μmol), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (compound 8.4, 69.9 mg, 260.6 μmol), NaCO (73.7 mg, 695.1 μmol), and Pd(dppf)Cl .DCM (12.7 mg, 17.4 μmol) was added. 1,2-Dimethoxyethane (1.0 mL) and water (0.25 ml) were added. The flask was evacuated and filled with N2 three times, after which the mixture was stirred at 90 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted twice with EA (50 mL). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0% to 30% EA in PE) to give Compound 37.3 (67.0 mg).

[0229] Step (c): Preparation of 5-[1-methyl-3-[[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 37) A solution of 2N HCl in MeOH (0.7 mL) was diluted with 2.5 mL of MeOH. The above solution was added to a solution of 5-(2,4-ditert-butoxypyrimidin-5-yl)-1-methyl-N-[(1S)-1-phenylethyl]pyrazolo[3,4-c]pyridazin-3-amine (compound 37.3, 67.0 mg, 140.9 μmol) in MeOH (1 mL), and the mixture was stirred for 40 minutes. The desired product precipitated from the red solution. The red solid was filtered, washed twice with MeOH (1 mL), and then dried on an oil pump to give Example 37 (30.0 mg). MS: calculated 364.2 [(M+H) + ]; Measured value 364.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.45(s,1H),11.33(br d,J=4.9 Hz,1H),8.81(s,1H),8.22(d,J=6.1 Hz,1H),7.46-7.39(m,3H),7.30(t,J=7.6 Hz,2H),7.23-7.17(m,1H),4.90(quin,J=6.7 Hz,1H),3.87(s,3H),1.50(d,J=6.9 Hz,3H).

[0230] Example 38 5-[1-methyl-3-[methyl-[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-Methyl-3-[methyl-[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 38) was prepared analogously to Example 34 by replacing 3,3-dimethylbutan-2-amine (Compound 34.1) with (1S)-1-phenylethanamine in step (b). MS: calculated 378.2 [(M+H) + ]; Measured value 378.2 [(M+H) + ]. 1 H NMR(500 MHz,DMSO-d6)δ=11.46(s,1H),11.37(br d,J=4.6 Hz,1H),8.73(s,1H),8.25(d,J=6.1 Hz,1H),7.39-7.33(m,4H),7.31-7.24(m,1H),5.47(q,J=6.9 Hz,1H),4.02(s,3H),2.85(s,3H),1.59(d,J=7.0 Hz,3H).

[0231] Example 39 5-(3-cyclobutyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0232] Step (a): Preparation of cyclobutyl-(3,6-dichloropyridazin-4-yl)methanone (Compound 39.1) In a dry N2 flush flask, add TMPMgCl .A LiCl solution (1 M in THF, 7.7 mL, 7.7 mmol) was charged and cooled to 0 °C using an ice bath. Pretreated Zn(OPiv)2 was added to the mixture in one portion (zinc pivalate, 2.2 g, 8.05 mmol, dried in vacuo at 400 °C or with a heat gun at 300 °C for 30 min before use), and the mixture was gradually warmed to 25 °C over 1.5 h to prepare a calculated 1 M concentration of freshly prepared TMPZnOPiv2. . Mg(OPiv)Cl . A brown solution was obtained as LiCl.

[0233] 3,6-Dichloropyridazine (compound 2.1, 1.04 g, 7.0 mmol) was dissolved in 14 mL of dry THF. To this solution, freshly prepared TMPZnOPiv . Mg(OPiv)Cl . The LiCl solution was added dropwise at 25° C. and stirred for 0.5 h to give the desired organozinc reagent.

[0234] The zinc reagent was cooled to -20 °C, and TMSCl (3.6 mL, 42 mmol) was added in one portion and stirring was continued for 0.5 h. Then, CuCN . 2LiCl (1M in THF, 7.0 mL) and cyclobutanecarbonyl chloride (18.2 mmol) were subsequently added. The resulting mixture was stirred at -20 °C for 1 hour and at 0 °C for 15 hours. The mixture was then quenched with saturated aqueous NH4Cl / NH3 (concentrated) (v / v, 8:1; 56 mL), extracted with ethyl acetate, washed with aqueous KHCO3 (to remove unreacted alkyl acid), brine, and dried over Na2SO4 to give the crude product. The crude product was purified by silica gel flash chromatography (eluent, 10% to 25% EA in PE) to give Compound 39.1 (700 mg). MS: calculated 231.0 [(M+H) + ]; Measured value 231.0 [(M+H) + ].

[0235] Step (b): Preparation of 5-chloro-3-cyclobutyl-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 39.2) Cyclobutyl-(3,6-dichloropyridazin-4-yl)methanone (compound 39.1, 70 mg, 303.0 μmol) and methylhydrazine sulfate (48.0 mg, 333.2 μmol) were added to a flask equipped with a stir bar. To the mixture was added isopropanol (1.5 mL) and TFA (117 μL). The mixture was stirred at 100° C. for 6 hours. After concentration, the crude residue was purified by silica gel flash chromatography (eluent, 10% to 25% EA in PE) to give compound 39.2 (48 mg). MS: calculated 223.1 [(M+H) + ]; Measured value 223.1 [(M+H) + ].

[0236] Step (c): Preparation of 3-cyclobutyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazine (Compound 39.3) A Schlenk flask was charged with 5-chloro-3-cyclobutyl-1-methyl-pyrazolo[3,4-c]pyridazine (compound 39.2, 48.0 mg, 215.6 μmol), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (compound 8.4, 86.7 mg, 323.3 μmol), NaCO (91.4 mg, 862.2 μmol), and Pd(dppf)Cl . DCM (15.7 mg, 21.5 μmol) was added. 1,2-Dimethoxyethane (4.0 mL) and water (1.0 mL) were added. The flask was evacuated and filled with N2 three times, after which the mixture was stirred at 90 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted twice with EA (50 mL). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0% to 25% EA in PE) to give compound 39.3 (70.0 mg).

[0237] Step (d): Preparation of 5-(3-cyclobutyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione (Example 39) A solution of 2N HCl in MeOH (0.9 mL) was diluted with 2.0 mL of MeOH. The above solution was added to a solution of 3-cyclobutyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazine (compound 39.3, 70.0 mg, 162.0 μmol) in MeOH (2.5 mL), and the mixture was stirred for 40 minutes until the reaction was complete. The desired product precipitated from the solution. The solid was filtered and washed twice with MeOH (1 mL). The solid was dried on an oil pump to give Example 39 (40.0 mg). MS: calculated 299.1 [(M+H) + ]; Measured value 299.2 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.49(s,1H),11.40(br d,J=5.3 Hz,1H),8.68(s,1H),8.32(d,J=6.1 Hz,1H),4.20(s,3H),4.00-3.91(m,1H),2.48-2.35(m,4H),2.17-2.06(m,1H),2.01-1.92(m,1H).

[0238] Example 40 5-[3-[(1S)-1-(5-fluoro-6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0239] Step (a): Preparation of 6-(1-ethoxyvinyl)-3-fluoro-2-methyl-pyridine (Compound 40.2) Pd(dppf)Cl2 .A mixture of DCM (214.89 mg, 263.14 μmol), 1-ethoxyvinyltri-n-butyltin (950.34 mg, 896.55 μL, 2.63 mmol), and 6-bromo-3-fluoro-2-methyl-pyridine (compound 40.1, 500 mg, 2.63 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with EA (50 mL) and treated with 10% aqueous KF solution (50 mL). The resulting mixture was stirred at room temperature for 1 hour, filtered, and the solid was washed with EA. The resulting organic layer was concentrated, and the crude residue was purified by flash chromatography (silica gel, 24 g, 0 to 100% EA in PE) to give compound (420 mg). MS: calculated 182.1 [(M+H) + ]; Measured value 182.2 [(M+H) + ].

[0240] Step (b): Preparation of 1-(5-fluoro-6-methyl-2-pyridyl)ethanone (Compound 40.3) To a solution of 6-(1-ethoxyvinyl)-3-fluoro-2-methyl-pyridine (compound 40.2, 370 mg, 2.04 mmol) in THF (20 mL) was added 4N HCl / dioxane (2 mL), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous NaHCO (50 mL) and extracted twice with EA (80 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 25 g, 0 to 100% EA in PE) to give compound 40.3 (260 mg). MS: calculated 154.1 [(M+H) + ]; Measured value 154.2 [(M+H) + ].

[0241] Step (c): Preparation of (1R)-1-(5-fluoro-6-methyl-2-pyridyl)ethanol (Compound 40.4) To a solution of 1-(5-fluoro-6-methyl-2-pyridyl)ethanone (compound 40.3, 260 mg, 1.7 mmol) in DCM (10 mL), EtN (687.15 mg, 946.49 μL, 6.79 mmol), formic acid (781.44 mg, 651.2 μL, 16.98 mmol), and RuCl[(R,R)-TsDPEN(p-cymene)] (10.8 mg, 16.98 μmol) were added at 0 °C, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was purified by flash chromatography (silica gel, 12 g, 0 to 20% MeOH in DCM) to give compound 40.4 (110 mg).

[0242] Step (d): Preparation of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1S)-1-(5-fluoro-6-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (Compound 40.5) To a suspension of (1R)-1-(5-fluoro-6-methyl-2-pyridyl)ethanol (40.4, 68.8 mg, 443.1 μmol), 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (21.3, 110 mg, 295.4 μmol), and Ph3P (131.7 mg, 502.1 μmol) in toluene (10 mL), DEAD (90.8 mg, 82.5 μL, 521.1 μmol) was added, and the resulting mixture was stirred at 60 °C for 3 h under a N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted three times with EA (30 mL). The combined organic layers were concentrated, and the residue was purified by flash chromatography (silica gel, 25 g, 0 to 100% EA in PE) to give compound 40.5 (70 mg). MS: calculated 510.2 [(M+H) + ]; Measured value 510.3 [(M+H) + ].

[0243] Step (e): Preparation of 5-[3-[(1S)-1-(5-fluoro-6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Compound 40.5) 398.1 To a solution of 5-(2,4-di-tert-butoxypyrimidin-5-yl)-1-methyl-3-[(1S)-1-(5-fluoro-6-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazine (compound 40.5, 70 mg, 137.4 μmol) in DCM (5 mL), TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated to give the crude product, which was purified by preparative HPLC to give Example 40 (45 mg). MS: calculated 398.1 [(M+H) + ]; Measured value 398.2 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.51(s,1H),11.42(br d,J=5.6 Hz,1H),8.62(s,1H),8.34(d,J=6.3 Hz,1H),7.61(t,J=9.1 Hz,1H),7.50-7.37(m,1H),6.08-5.88(m,1H),4.01(s,3H),2.46(d,J=3.0 Hz,3H),1.71(d,J=6.5 Hz,3H).

[0244] Example 41 5-[1-methyl-3-[(1S)-1-(6-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[(1S)-1-(6-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 41) was prepared analogously to Example 40, by replacing 1-(5-fluoro-6-methyl-2-pyridyl)ethanone (Compound 40.3) with 1-(6-methyl-2-pyridyl)ethanone in step (c). MS: calculated 380.1 [(M+H)+ ]; Measured value 380.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.52(s,1H),11.47(br d,J=5.8 Hz,1H),8.67(s,1H),8.36(d,J=6.1 Hz,1H),8.05(br s,1H),7.67(br d,J=6.5 Hz,1H),7.51(br d,J=6.9 Hz,1H),6.18-6.08(m,1H),4.01(s,3H),2.64(s,3H),1.78(d,J=6.5 Hz,3H).

[0245] Example 42 5-[1-methyl-3-[(1S)-1-(4-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[1-methyl-3-[(1S)-1-(4-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 42) was prepared analogously to Example 40, by replacing 1-(5-fluoro-6-methyl-2-pyridyl)ethanone (Compound 40.3) with 1-(4-methyl-2-pyridyl)ethanone in step (c). MS: calculated 380.1 [(M+H) + ]; Measured value 380.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.53(s,1H),11.47(br d,J=5.9 Hz,1H),8.68(s,1H),8.59(d,J=5.5 Hz,1H),8.36(d,J=6.3 Hz,1H),7.77(br s,1H),7.52(br d,J=3.5 Hz,1H),6.18-6.06(m,1H),4.01(s,3H),2.46(s,3H),1.77(d,J=6.6 Hz,3H).

[0246] Example 43 5-[3-[(1S)-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[3-[(1S)-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 43) was prepared in analogy to Example 40, by replacing 1-(5-fluoro-6-methyl-2-pyridyl)ethanone (compound 40.3) with 1-(5-fluoro-2-pyridyl)ethanone in step (c). MS: calculated 384.1 [(M+H) + ]; Measured value 384.1 [(M+H) + ]. 1 H NMR (400 MHz, DMSO-d6) δ=11.52(s,1H),11.44(br d,J=6.0 Hz,1H),8.63(s,1H),8.57(d,J=2.9 Hz,1H),8.34(d,J=6.3 Hz,1H),7.76-7.70(m,1H),7.68-7.62(m,1H),6.08-6.00(m,1H),4.01(s,3H),1.72(d,J=6.5 Hz,3H).

[0247] Example 44 5-[3-[(1S)-1-(6-chloro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[3-[(1S)-1-(6-chloro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 44) was prepared analogously to Example 40, by replacing 1-(5-fluoro-6-methyl-2-pyridyl)ethanone (Compound 40.3) with 1-(6-chloro-2-pyridyl)ethanone in step (c). MS: calculated 400.1, 402.1 [(M+H) + ]; Measurement value 400.1, 402.1 [(M+H) + ]. 1 H NMR(400 MHz,DMSO-d6)δ=11.52(s,1H),11.43(br d,J=5.4 Hz,1H),8.65(s,1H),8.35(d,J=6.3 Hz,1H),7.87(t,J=7.8 Hz,1H),7.57(d,J=7.5 Hz,1H),7.46(d,J=7.9 Hz,1H),6.01-5.92(m,1H),4.01(s,3H),1.72(d,J=6.5 Hz,3H)

[0248] Example 45 5-[3-[(1S)-1-(6-chloropyridazin-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] 5-[3-[(1S)-1-(6-chloropyridazin-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 45) was prepared analogously to Example 40, by replacing 1-(5-fluoro-6-methyl-2-pyridyl)ethanone (Compound 40.3) with 1-(6-chloropyridazin-3-yl)ethanone in step (c). MS: calculated 401.1, 403.1 [(M+H) + ]; Measurement value 401.0, 403.0 [(M+H) + ]. 1H NMR(500 MHz,DMSO-d6)δ=11.52(s,1H),11.44(br d,J=6.0 Hz,1H),8.66(s,1H),8.35(d,J=6.3 Hz,1H),8.03-7.98(m,1H),7.95-7.92(m,1H),6.26-6.20(m,1H),4.00(s,3H),1.81(d,J=6.6 Hz,3H).

[0249] Example 46 5-(3-cyclobutylisoxazolo[5,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0250] Step (a): Preparation of 5-chloro-3-cyclobutyl-isoxazolo[5,4-c]pyridazine (Compound 46.1) Cyclobutyl-(3,6-dichloropyridazin-4-yl)methanone (compound 39.1, 50 mg, 303.0 μmol), hydroxylamine hydrochloride (16.5 mg, 238.1 μmol), and K2CO3 (59.8 mg, 432.7 μmol) were added to a flask equipped with a stir bar. Isopropanol (1.0 mL) was added to the mixture. The mixture was stirred at 100 °C for 2 hours. After concentration, the crude residue was purified by silica gel flash chromatography (eluent, 0% to 10% EA in PE) to give compound 46.1 (30 mg). MS: calculated 210.0 [(M+H) + ]; Measured value 210.0 [(M+H) + ].

[0251] Step (b): Preparation of 3-cyclobutyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)isoxazolo[5,4-c]pyridazine (Compound 46.2) A Schlenk flask was charged with 5-chloro-3-cyclobutyl-isoxazolo[5,4-c]pyridazine (compound 46.1, 30.0 mg, 143.1 μmol), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (compound 8.4, 50.0 mg, 186.4 μmol), Na2CO3 (60.7 mg, 572.4 μmol), and Pd(dppf)Cl2. . DCM (10.5 mg, 14.3 μmol) was added. 1,2-Dimethoxyethane (2.0 mL) and water (0.5 mL) were added. The flask was evacuated and filled with N2 three times, after which the mixture was stirred at 90 °C for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (40 mL) and extracted twice with EA (50 mL). The combined organic layers were washed with brine, dried over anhydrous Mg2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography (eluent: 0% to 10% EA in PE) to give Compound 46.2 (23.0 mg).

[0252] Step (c): Preparation of 5-(3-cyclobutylisoxazolo[5,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione (Example 46) A solution of 2N HCl in MeOH (0.3 mL) was diluted with 1.0 mL of MeOH. The above solution was added to a solution of 3-cyclobutyl-5-(2,4-di-tert-butoxypyrimidin-5-yl)isoxazolo[5,4-c]pyridazine (compound 46.2, 23.0 mg, 57.7 μmol) in MeOH (1.0 mL), and the mixture was stirred for 40 minutes until the reaction was complete. After concentration, the desired product was purified by silica gel flash column chromatography (0% to 10% MeOH in CHCl) to give Example 46 (5.0 mg). MS: calculated 286.1 [(M+H) + ]; measured value 286.0 [(M+H)+]. 1H NMR(400 MHz,DMSO-d6)δ=11.58(br s,2H),8.83(s,1H),8.38(s,1H),4.06(dt,J=0.8,8.5 Hz, 1H), 2.50-2.40 (m, 4H), 2.22-2.14 (m, 1H), 2.06-2.02 (m, 1H).

[0253] Biological Examples Example 47: Human microsome stability assay Human liver microsomes (Cat. No.: 452117, Corning, USA) were preincubated with test compounds in 100 mM potassium phosphate buffer, pH 7.4, for 10 minutes at 37°C. The reaction was initiated by adding an NADPH-regenerating system. The final incubation mixture contained 1 μM test compound, 0.5 mg / mL liver microsomal protein, 1 mM MgCl2, 1 mM NADP, 1 unit / mL isocitrate dehydrogenase, and 6 mM isocitrate in 100 mM potassium phosphate buffer, pH 7.4. After incubation times of 0, 3, 6, 9, 15, and 30 minutes at 37°C, the reaction was terminated by adding 300 μL of cold ACN (containing the internal standard) to 100 μL of the incubation mixture. After precipitation and centrifugation, 100 μL of the supernatant was removed and 300 μL of water was added. The amount of compound remaining in the sample was measured by LC-MS / MS. Controls without the NADPH regenerating system at 0 and 30 minutes were also prepared and analyzed. Results were classified as low (<7.0 mL / min / kg), medium (7.0-16.2 mL / min / kg), and high (16.2-23.2 mL / min / kg). The test results are summarized in Table 1. [Table 1]

[0254] Example 48: CD73 Cell Assay Serial dilutions (1:3) of compounds were prepared in corresponding wells of a 384-well plate using an Echo 555 liquid handler (Labcyte). 40 μL of MDA-MB-231 cells (ATCC, HTB-26, breast cancer, final concentration 20,000 cells / mL) suspended in assay buffer (20 mM HEPES pH 7.4, 137 mM NaCl, 5.4 mM KCl, 1.3 mM CaCl2, 4.2 mM NaHCO3, 1 mg / mL glucose) were added to the corresponding wells of the plate. After 30 minutes of incubation with compounds, 40 μL of AMP working solution (200 μM AMP in assay buffer) was added to each well of the assay plate. The assay plate was then incubated at 37°C for 45 minutes in a 5% CO2 incubator (Thermo Fisher Scientific). After the reaction was completed, 50 μL of supernatant was collected and transferred to a new 384-well plate. 10 μL of malachite A was added to each well of the assay plate and incubated for 10 minutes. 10 μL of malachite B was then added to each corresponding well of the plate and incubated for 30 minutes. Finally, absorbance values were read at 620 nM on an Envision plate reader. Calculate percent inhibition by using the formula {% inhibition = 100 × [I - (X - MIN) / (MAX - MIN)]}, where X is equal to the well signal, Max is equal to the neutral control signal, and MIN is equal to the inhibitor control signal. [Table 2]

[0255] Example 49: CD73 potency assay using LC / MS The purpose of this assay is to identify and characterize inhibitors of CD73 enzyme activity. Using an Echo 555 liquid handler (Labcyte), serial dilutions (1:3) of compounds were prepared in corresponding wells of a 384-well plate. 10 μL of enzyme working solution (containing 0.05 nM recombinant CD73 protein, 10 mM Tris pH 7.5, 100 mM NaCl, 0.01% BSA, and 0.2 mM octylglucoside) was added to the assay plate and incubated with the compounds for 15 minutes at room temperature. 15 μL of AMP working solution (containing 10 mM Tris pH 7.5, 100 mM NaCl, 0.01% BSA, 0.2 mM octylglucoside, and a final concentration of 1000 μM AMP) was added, followed by incubation for 10 minutes at room temperature. The reaction is stopped by adding 75 μL of stop solution (5% TCA in HO containing 250 nM 13C5-adenosine) to each well for 10 min of incubation. After centrifugation, 75 μL of the mixture was transferred to a new 384-well plate for LC / MS analysis.

[0256] Samples from a 384-well plate were loaded onto the autosampler deck and then injected into the ADDA-LC-MS / MS. The aqueous mobile phase was 0.1% formic acid in water. The organic mobile phase was 0.1% formic acid in acetonitrile. The flow rate was maintained at 0.8 mL / min using a Shimadzu pump. The column was an ACE 5 Phenyl, 50 x 2.1 mm. Analysis was performed on a SCIEX triple quadrupole mass spectrometer operating in positive ion mode. The effluent from the HPLC column was directly introduced into electrospray ionization (ESI). Multiple reaction monitoring (MRM) was used to determine analyte and internal standard (IS) responses. The MRM for adenosine was 268.1 / 136.1, and the MRM for 13C5-adenosine (IS) was 273.2 / 136.2. Data were calculated using the peak area ratio (PAR) semiquantitative method. [Table 3]

[0257] Example 50: Cell proliferation assay The purpose of this assay is to characterize the efficacy of CD73 inhibitors in rescuing adenosine-mediated inhibition of T cell proliferation. CD4+ or CD8+ T cells were isolated from peripheral blood mononuclear cells (PBMCs, HemaCare) by immunomagnetic negative selection using the EasySep™ Isolation Kit (STEMCELL Technologies) according to the supplier's protocol. CD4+ or CD8+ T cells were pelleted by centrifugation at 300 g for 5 minutes at room temperature and resuspended in PBS. CellTrace™ Violet staining solution (Invitrogen) was added at 1:5,000 and incubated at 37°C for 20 minutes protected from light. Complete culture medium [RPMI-1640 (Gibco), 10% fetal bovine serum (Gibco), 2 mM GlutaMAX (Gibco), 1 mM sodium pyruvate (Gibco), 100 U / mL penicillin-streptomycin (Gibco), and MEM non-essential amino acids (NEAA) cell culture supplement (1:100, Gibco)] was then added, mixed, and incubated at 37°C for 5 minutes. The cells were then pelleted by centrifugation at 300 g for 5 minutes at room temperature and resuspended in fresh prewarmed complete culture medium. 50 μL of cells were seeded per well into a 96-well U-bottom plate. 50 μL of CD3 / CD28 bead-containing medium and 50 μL of compound-containing medium were added to the cells. 50 μL of medium containing AMP and EHNA hydrochloride (Sigma-Aldrich) was added to the cells at final concentrations of 200 μM and 5 μM, respectively. The cells were incubated at 37°C in a 5% CO2 incubator for 72 hours. Then, 200 μL of PBS was added to each well, and the cells were centrifuged at 300g for 10 minutes at 4°C. The supernatant was discarded. 50 μL of Human TruStain FcX™ (Fc receptor blocking solution, BioLegend) diluted 1:100 in PBS was added to each well, mixed gently, and incubated at 4°C for 20 minutes. 50 μL of staining solution (BioLegend) was added to each well, mixed gently, and incubated at 4°C for 30 minutes. The cells were centrifuged at 300g for 10 minutes at 4°C, and the supernatant was discarded.The cell pellet was washed with 250 μL of cell staining buffer and centrifuged at 300 g for 10 minutes at 4° C. The supernatant was discarded, and the cells were resuspended in 60 μL of cell staining buffer and analyzed on a flow cytometer. [Table 4]

[0258] Example 51: T cell cytokine release functional assay The purpose of this assay was to characterize the efficacy of CD73 inhibitors in rescuing adenosine-mediated inhibition of T cell cytokine release function. CD4+ or CD8+ T cells were isolated from peripheral blood mononuclear cells (PBMCs) by immunomagnetic negative selection using the EasySep™ Isolation Kit (STEMCELL Technologies) according to the supplier's protocol. CD4+ or CD8+ T cells were then pelleted by centrifugation at 300 g for 5 minutes at room temperature and resuspended in fresh, prewarmed complete culture medium. 50 μL of cells were seeded per well in a 96-well U-bottom plate. 50 μL of CD3 / CD28 bead-containing medium and 50 μL of compound-containing medium were added to the cells. 50 μL of medium containing AMP and EHNA hydrochloride (Sigma-Aldrich) was added to the cells at final concentrations of 200 μM and 5 μM, respectively. Cells were incubated at 37°C in a 5% CO2 incubator for up to 72 hours. 50 μL of supernatant was collected and the levels of IL2 and IFN-gamma were determined using ELISA-MSD kits (Meso Scale Discovery).

Claims

1. Formula (I) 【Chemical 1】 (In the formula, W is CH or N; A １ and A ２ are each independently CH or N; A ３ and A ７ are each independently C or N; A ４ , A ５ and A ６ are each independently O, S, N, or CR １ or NR ２ and R １ is H, halogen, cyano, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Alkoxy C １－６ Alkyl or -L １ -R ３ and R ２ is H, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Alkoxy C １－６ Alkyl or -L ２ -R ３ and L １ is O, S, NH, NR ３ , C １－６ Alkylene, C ３－７ cycloalkylene, heteroarylene, or heterocyclylene; L ２ is C １－６ Alkylene, C ３－７ cycloalkylene, heteroarylene, or heterocyclylene; R ３ is C １－６ Alkyl, C ３－７ Cycloal, C ３－７ Cycloal C １－６ Alkyl, C １－６ Alkoxy C １－６ Alkyl, aryl, heteroaryl, heterocyclyl, aryl C １－６ Alkyl, heterocyclyl C １－６ Alkyl, heteroaryl C １－６ Alkyl, aryl halo C １－６ Alkyl, heterocyclyl halo C １－６ Alkyl and heteroaryl haloC １－６ alkyl), or a pharmaceutically acceptable salt thereof.

2. Formula (Ia) 【Chemistry 2】 (In the formula, W is CH; A １ is N, R １ is (C １－６ alkyl) ２ Amino, (C １－６ Alkylhalopyrazolyl)C １－６ Alkoxy, (C １－６ Alkylhalopyridinyl)C １－６ Alkoxy, (C １－６ Alkylpyrazolyl) C １－６ Alkoxy, (C １－６ alkylpyridinyl)C １－６ Alkoxy, (C １－６ Alkylpyridinyl) halo C １－６ Alkoxy, (C １－６ Alkylthiazolyl) C １－６ Alkoxy, (cyanophenyl)C １－６ Alkoxy, (haloC １－６ alkylphenyl)C １－６ Alkoxy, (halophenyl)C １－６ Alkoxy, (halopyridazinyl) C １－６ Alkoxy, (halopyridinyl)C １－６ Alkoxy, (halopyridinyl) halo C １－６ Alkoxy, (phenyl C １－６ alkyl)pyrazolyl, benzoxazolyl C １－６ Alkoxy, C １－６ Alkoxy, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl (C １－６ alkyl)amino, C ３－７ Cycloalkyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkoxy, phenyl C １－６ Alkyl, phenyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkylamino, Phenyl C ３－７ Cycloalkyl, phenylhaloC １－６ Alkoxy, pyridinyl C １－６ Alkoxy or pyridinyl halo C １－６ is an alkoxy, R ２ is C １－６ alkyl), 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

3. R １ However, (C １－６ Alkylpyridinyl) halo C １－６ Alkoxy, (halopyridinyl) halo C １－６ Alkoxy, (phenyl C １－６ alkyl)pyrazolyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkoxy, phenyl C １－６ Alkyl, phenyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkylamino, Phenyl C ３－７ Cycloalkyl, phenylhaloC １－６ Alkoxy, pyridinyl C １－６ Alkoxy or pyridinyl halo C １－６ 3. The compound of claim 1 or 2, which is alkoxy.

4. R １ is (1-phenylethyl)amino, 1-(2-pyridinyl)ethoxy, 1-(2-pyridinyl)ethoxy, 1-cyclopentylethyl(methyl)amino, 1-phenylcyclopropyl, 1-phenylethoxy, 1-phenylethoxy, 1-phenylethyl, 2,2,2-trifluoro-1-(2-pyridinyl)ethoxy, 2,2,2-trifluoro-1-phenyl-ethoxy, 2,2-difluoro-1-(2-pyridinyl)ethoxy, 2,2-difluoro-1-(5-fluoro-2-pyridinyl)ethoxy, 2,2-difluoro-1-(6-methyl-2-pyridinyl)ethoxy, 2,2-difluoro-1-phenyl-ethoxy, 2-benzylpyrazol-3-yl, cyclobutyl, or methyl(1-phenylethyl)amino.

5. R １ However, (C １－６ Alkylpyridinyl) halo C １－６ Alkoxy, (halopyridinyl) halo C １－６ Alkoxy, C ３－７ Cycloalkyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkoxy, phenyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkyl, phenyl C １－６ Alkylamino, phenylhaloC １－６ Alkoxy, pyridinyl C １－６ Alkoxy or pyridinyl halo C １－６ The compound of any one of claims 1 to 4, which is alkoxy.

6. R １ is (1-phenylethyl)amino, 1-(2-pyridinyl)ethoxy, 1-cyclopentylethyl(methyl)amino, 1-phenylethoxy, 1-phenylethyl, 2,2-difluoro-1-(2-pyridinyl)ethoxy, 2,2-difluoro-1-(5-fluoro-2-pyridinyl)ethoxy, 2,2-difluoro-1-(6-methyl-2-pyridinyl)ethoxy, 2,2-difluoro-1-phenyl-ethoxy, or methyl(1-phenylethyl)amino.

7. R ２ The compound of any one of claims 1 to 6, wherein is methyl.

8. W is CH; A １ is N, R １ However, (C １－６ Alkylpyridinyl) halo C １－６ Alkoxy, (halopyridinyl) halo C １－６ Alkoxy, C ３－７ Cycloalkyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkoxy, phenyl C １－６ Alkyl (C １－６ alkyl)amino, phenyl C １－６ Alkyl, phenyl C １－６ Alkylamino, phenylhaloC １－６ Alkoxy, pyridinyl C １－６ Alkoxy or pyridinyl halo C １－６ is an alkoxy, R ２ But C １－６ is alkyl, The compound according to any one of claims 2 to 7, or a pharmaceutically acceptable salt thereof.

9. W is CH; A １ is N, R １ is (1-phenylethyl)amino, 1-(2-pyridinyl)ethoxy, 1-cyclopentylethyl(methyl)amino, 1-phenylethoxy, 1-phenylethyl, 2,2-difluoro-1-(2-pyridinyl)ethoxy, 2,2-difluoro-1-(5-fluoro-2-pyridinyl)ethoxy, 2,2-difluoro-1-(6-methyl-2-pyridinyl)ethoxy, 2,2-difluoro-1-phenyl-ethoxy or methyl(1-phenylethyl)amino; R ２ is methyl, 9. The compound according to any one of claims 2 to 8, or a pharmaceutically acceptable salt thereof.

10. Formula (Ib) 【Chemistry 3】 (In the formula, W is CH; A １ is N, R １ is H or a halogen, R ２ is C １－６ alkyl), 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

11. R １ The compound of claim 10, wherein is a halogen.

12. R １ 12. The compound of claim 10 or 11, wherein is chloro.

13. R ２ The compound of any one of claims 10 to 12, wherein is methyl.

14. W is CH; A １ is N, R １ But it's Chloro. R ２ is methyl, 14. The compound according to any one of claims 10 to 13, or a pharmaceutically acceptable salt thereof.

15. Formula (Ic) 【Chemistry 4】 (In the formula, W is CH; A １ is N, R ２ is C １－６ alkyl), 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

16. R ２ The compound of claim 15, wherein is methyl.

17. Formula (Id) 【Chemistry 5】 (In the formula, W is CH; A １ is N, R １ is C ３－７ cycloalkyl), 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt thereof.

18. R １ 18. The compound of claim 17, wherein is cyclobutyl.

19. 5-(1,3-dimethylpyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-(3-cyclopropyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-(1-methylpyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione; 5-(1-methyltriazolo[4,5-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-(1-phenylethyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-(1-phenylcyclopropyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-(2-benzylpyrazol-3-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-(3-isopropoxy-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-(3-chloro-1-methyl-pyrazolo[4,3-c]pyridazin-6-yl)-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-(1-phenylethoxy)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 3-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile; 4-[1-[5-(2,4-dioxo-1H-pyrimidin-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxyethyl]benzonitrile; 5-[3-[1-(2-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(3-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(4-chlorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(4-fluorophenyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(3-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(4-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-[3-(trifluoromethyl)phenyl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(2-methylthiazol-4-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(5-methylthiazol-2-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(4-chloro-1-methyl-pyrazol-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[1-(2-methylpyrazol-3-yl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-(1,3-benzoxazol-2-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-phenylethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-phenyl-ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-2,2,2-trifluoro-1-(2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2,2-trifluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-2,2,2-trifluoro-1-phenyl-ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-(2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-(6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-(6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[methyl(1,2,2-trimethylpropyl)amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[1-cyclopentylethyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[cyclopentyl(methyl)amino]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[methyl-[(1S)-1-phenylethyl]amino]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-(3-cyclobutyl-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(5-fluoro-6-methyl-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-(6-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1S)-1-(4-methyl-2-pyridyl)ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(5-fluoro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(6-chloro-2-pyridyl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-(6-chloropyridazin-3-yl)ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; and 5-(3-cyclobutylisoxazolo[5,4-c]pyridazin-5-yl)-1H-pyrimidine-2,4-dione 1. A compound selected from:

20. The following steps: a) a compound of formula (XVI), 【Chemistry 6】 with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ia): 【Chemistry 7】 obtaining b) a compound of formula (XXI), 【Chemistry 8】 is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ib-1): 【Chemistry 9】 obtaining c) a compound of formula (XXVI), 【Chemistry 10】 with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ic): 【Chemistry 11】 obtaining d) a compound of formula (XXXII), 【Chemistry 12】 is deprotected with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (Ia-1): 【Chemistry 13】 obtaining e) a compound of formula (XXXVI), 【Chemistry 14】 with an acid or a dealkylating reagent, or by hydrogenation to give a compound of formula (XXXVII): 【Chemistry 15】 The process of obtaining 20. A method for preparing a compound according to any one of claims 1 to 19, comprising: During the ceremony, each PG is independently an oxygen protecting group, PG is selected from methyl, tert-butyl, TBS, ethoxymethyl, and benzyl; In steps a), b), c), d) and e), the acid is trifluoroacetic acid or aqueous hydrochloric acid, the dealkylating reagents are TMSCl and NaI, and the hydrogenation is carried out using Pd / C; A １ ,W.,R. １ From R ３ is as defined in any one of claims 1 to 18.

21. 20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

22. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

23. 20. Use of a compound according to any one of claims 1 to 19 for the treatment of cancer.

24. 24. The use of claim 23, wherein the cancer is pancreatic cancer, colorectal cancer, gastric cancer, esophageal cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer or melanoma.

25. 20. Use of a compound according to any one of claims 1 to 19 to inhibit CD73.

26. 20. Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament for treating or preventing cancer, wherein the cancer is pancreatic cancer, colorectal cancer, gastric cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, melanoma, multiple myeloma, acute myeloid leukemia, or acute and chronic lymphoblastic leukemia.

27. 20. Use of a compound according to any one of claims 1 to 19 for the preparation of a medicament as a CD73 inhibitor.

28. 21. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, when prepared according to the method of claim 20.

29. 10. The invention as hereinbefore described.

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