Bicyclic heterocyclic compounds for cancer treatment

Abstract

The present invention relates to formula (I) [Formula 1] TIFF2026517758000150.tif60170 (in the formula, R 1 ~R 5 The present invention relates to compounds of (T and L as described herein), pharmaceutically acceptable salts thereof, compositions containing such compounds, and methods of using such compounds.

Description

[Technical Field]

[0001] This invention relates to organic compounds useful for the treatment and / or prevention in mammals, specifically to the inhibition of CD73, which is useful for treating cancer. [Background technology]

[0002] Overactivation of the adenosine pathway contributes to an immunosuppressive tumor microenvironment (TME) that impairs antitumor immunity and limits the effectiveness of immune checkpoint inhibitors. In the final stage of the adenosine pathway, the enzyme ecto-5'-nucleotidase (CD73) catalyzes the conversion of AMP to adenosine, which is recognized by adenosine receptors present in multiple immune cell types. This leads to suppression of effector T cells and natural killer (NK) cells, activation of regulatory T cells (Treg) and myeloid 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 removal or pharmacological inhibition of CD73. Therefore, mitigating immunosuppressive TME by CD73 inhibition is considered to have therapeutic potential to restore antitumor immunity, enhance the effectiveness of immunotherapy, and induce tumor regression. Given the growing need for effective cancer treatments, and the fact that this need remains unmet, inhibition of CD73 activity by small molecule (SM) administration is promising. This disclosure describes the invention of a novel small molecule CD73 inhibitor. [Overview of the Initiative]

[0003] The present invention relates to a novel compound of formula (I). [ka] (In the formula, R 1 These are 2,4-dioxo-1H-pyrimidinyl or 3,5-dioxo-2H-1,2,4-triazinyl; R2 is C 1~6 alkyl or dideuterio C 1~6 alkyl; R 3 is C 1~6 alkyl or halo C 1~6 alkyl; R 4 is H; R 5 is (C 1~6 alkoxy C 3~7 cycloalkyl)C 1~6 alkoxy, (C 1~6 alkyltetrahydrofuranyl)oxy, (cyano C 3~7 cycloalkyl)C 1~6 alkoxy, (halo C 1~6 alkoxy)C 1~6 alkyl, (halo C 1~6 alkyl C 3~7 cycloalkyl)C 1~6 alkoxy, (halo C 3~7 cycloalkyl)amino, (halo C 3~7 cycloalkyl)C 1~6 alkoxy, (halopyrrolidinyl)C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkoxy, C 3~7 cycloalkoxy, C 3~7 cycloalkoxy C 1~6 alkyl, cyano C 1~6 alkoxy, dideuterio C 1~6 alkoxy, dideuteriohalo C 1~6 alkoxy, halo C 1~6 alkoxy, halo C 1~6 alkyl, halo C 1~6 alkylamino and halo C 3~7 cycloalkoxy, halo C 3~7 cycloalkyl or halopiperidyl; T is O; L is 1,4 - benzoxazinylene, indazolylene, pyrimidinylene, unsubstituted or halogen - substituted phenylene, or unsubstituted or halogen - substituted pyridylene) or relating to a pharmaceutically acceptable salt thereof.

[0004] Compounds of formula (I) or (I-1) showed good CD73 inhibition. In another embodiment, the compounds of the present invention showed excellent cancer cell inhibition. Furthermore, compounds of formula (I) or (I-1) also showed good or improved human hepatocyte stability, cytotoxicity, and PK profiles. [Modes for carrying out the invention]

[0005] definition "C 1~6 The term "alkyl" refers to saturated, linear, or branched 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 The alkyl groups are methyl, ethyl, and n-propyl.

[0006] "C 1~6 The term "alkoxy" is C 1~6 Represents alkyl-O-.

[0007] The terms "halogen" and "halo" are used interchangeably herein and refer to fluoro, chloro, bromo, or iodine.

[0008] "Hello C 1~6 The term "alkyl" is C 1~6 C in which at least one hydrogen atom of the alkyl group is replaced by the same or a different halogen atom, particularly a fluoro atom. 1~6 Represents an alkyl group. Halo C 1~6 Examples of alkyl groups 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.

[0009] "Juterio C 1~6The term "alkyl" is C 1~6 C in which at least one hydrogen atom of the alkyl group is replaced by a deuterio. 1~6 This represents an alkoxy group.

[0010] "Juterio C 1~6 The term "alkoxy" is C 1~6 C in which at least one hydrogen atom of the alkyl group is replaced by a deuterio. 1~6 This represents an alkoxy group.

[0011] "Hello C 1~6 The term "alkoxy" is a halo C 1~6 Represents alkyl-O-.

[0012] "Juterio Haro C" 1~6 The term "alkoxy" is C 1~6 C in which at least one hydrogen atom of the alkoxy group is replaced by a deuterio. 1~6 Represents an alkoxy group. Deuteriohalo C 1~6 An example of an alkoxy is 1,1-diduterio-2,2,2-trifluoroethoxy.

[0013] "C 3~7 The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group with 3 to 7 ring carbon atoms. Bicyclic means that it consists of two saturated carbon rings, each 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.

[0014] "Hello C 3~7 The term "cycloalkyl" is C 3~7 C in which at least one hydrogen atom of the cycloalkyl group is replaced by the same or a different halogen atom, particularly a fluoro atom. 3~7Represents a cycloalkyl group. Halo C 3~7 Examples of cycloalkyl groups include 2,2-difluorocyclopropyl and 1-fluorocyclopropyl.

[0015] "C 3~7 The term "cycloalkoxy" is C 3~7 This represents a cycloalkyl-O- group.

[0016] The terms “heterocyclic group,” “heterocyclic,” “heterocycle,” “heterocycle,” or “heterocyclo” are used interchangeably to refer to any monocyclic, bicyclic, tricyclic, spiro-type, or bridging saturated, partially saturated, or unsaturated non-aromatic cyclic system having 3 to 20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any of the ring atoms in the cyclic system is a heteroatom, the system is heterocyclic regardless of the bonding site of the cyclic system to the rest of the molecule. For example, heterocyclils include monocyclic, bicyclic, tricyclic, spiro-type, and bridging cyclic systems containing 3 to 11 ring atoms ("members"), where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, heterocyclils contain 4 to 10 or 5 to 10 ring atoms. In one example, the heterocyclyl contains 1 to 4 heteroatoms. In another example, the heterocyclyl contains 1 to 3 heteroatoms. In yet another example, the heterocyclyl contains a 3 to 7-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In yet another example, the heterocyclyl contains a 4 to 6-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, or oxygen. In yet another example, the heterocyclyl contains a 3-membered monoring. In yet another example, the heterocyclyl contains a 4-membered monoring. In yet another example, the heterocyclyl contains a 5 to 6-membered monoring. In some embodiments, the heterocycloalkyl contains at least one nitrogen. In one example, the heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatoms may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatoms may optionally be quaternized (e.g., [NR4]).+ Cl - 、[NR4] + OH -Examples of heterocycles include oxyranyl, azilidinyl, thiranyl, 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, hexahydrothiopyranyl, hexa Hydropyrimidinyl, oxazinyl, thiadinyl, thioxanil, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, oxazepinyl, oxazepanil, diazepanil, 1,4-diazepanil, diazepinyl, thiazepinyl, thiazepanil, tetrahydrothiopyranil, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoiisothiazolidinol, 1,1-dioxoiisothiazolyl, oxazolidinol, imidazolidinol, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Lobenzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiadinyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl Pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, 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.Examples include 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-azapiro[4.5]decane-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl, and 2,3,4a,5,7,7a-hexahydro-[1,4]dioxyno[2,3-c]pyrrolyl.

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

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

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

[0020] The term "heteroaryl" refers to any monocyclic, bicyclic, or tricyclic aromatic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, where, in exemplary embodiments, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, JA, ed.) 13. thSee ed.Table 7-2

[1985] . This definition includes any bicyclic group in which one of the above heteroaryl rings is fused to an aryl ring, and the aryl ring or heteroaryl ring is bonded to the remainder of the molecule. In one embodiment, a heteroaryl includes a 5-6 member monocyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. In one embodiment, a heteroaryl includes a 7-12 member bicyclic aromatic group in which one or more ring atoms are nitrogen, sulfur, or oxygen. Examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, triazinyl, tetradinyl, 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, Examples include 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]pyridylene, 1H-pyrazolo[4,3-d]pyrimidine, 1H-pyrazolo[3,4-c]pyridylene, 1H-pyrazolo[4,3-c]pyridylene and prinyl, as well as benzo-condensed derivatives such as benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indazolyl and indolyl.

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

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

[0023] The term "indazolylen" refers to a divalent indazolyl group.

[0024] The term "pyridylene" refers to a divalent pyridyl group.

[0025] The term "pyrimidinylene" refers to a divalent pyrimidinyl group.

[0026] In certain embodiments, the heterocyclyl or heteroaryl group is nitrogen-bonded. Examples of nitrogen-bonded heterocyclyl or heteroaryl groups include those at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, at position 1 of 1H-indazole, at position 2 of isoindole or isoindoline, at position 4 of morpholine, and at position 9 of carbazole or β-carbolin.

[0027] In one embodiment, those skilled in the art can understand that keto-enol tautomerism may exist for certain structures as shown below: [ka] (In the formula, W is either CH or N).

[0028] Unless otherwise specified, the term "optionally substituted" means that a group may be unsubstituted or may be substituted with one or more substituents listed for that group (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range that can be derived from there) (the substituents may be the same or different). In one embodiment, the optionally substituted group has one substituent. In another embodiment, the optionally substituted group has two substituents. In another embodiment, the optionally substituted group has three substituents. In another embodiment, the optionally substituted group has four substituents. In another embodiment, the optionally substituted group has five substituents.

[0029] The terms "protecting group" or "PG" refer to a group that selectively blocks a reaction site in a polyfunctional compound so that the chemical reaction can selectively proceed at another unprotected reaction site, in the sense conventionally relevant in synthetic chemistry. Protecting groups can be removed at appropriate points. Exemplary protecting groups are amino protecting groups, carboxy protecting groups, or hydroxy protecting groups.

[0030] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. Both acidic and basic addition salts can be considered pharmaceutically acceptable salts.

[0031] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed by an organic acid selected from aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylic acid, and sulfonic acid derivatives, such as an inorganic acid including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, and an organic acid including 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 "mesylate", ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0032] The term "pharmaceutically acceptable basic addition salt" refers to a pharmaceutically acceptable salt formed from 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. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and salts of polyamine resins.

[0033] The term "pharmaceutically active metabolite" refers to a pharmacologically active product produced through the metabolism of a particular compound or a salt thereof in the body. After entering the body, most drugs become substrates for chemical reactions, which can alter their physical properties and biological effects. These metabolic transformations typically affect the polarity of the compound in this invention and alter the pathway by which the drug is distributed within and excreted from the body. However, in some cases, the metabolism of a drug is necessary for its therapeutic effect.

[0034] The term "therapeutic dose" refers to the amount of the compound or molecule of the present invention that, when administered to a subject, (i) treats or prevents a particular disease, symptom, or disorder; (ii) reduces, improves, or eliminates one or more symptoms of a particular disease, symptom, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, symptom, or disorder as described herein. The therapeutic dose varies depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health status of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0035] The term "pharmaceutical composition" refers to a mixture or solution that is administered to a mammal, such as a human, that requires a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient, along with pharmaceutically acceptable additives.

[0036] The terms “pharmaceutically acceptable additive,” “pharmaceutically acceptable carrier,” and “therapeutically inactive additive” may be used interchangeably and refer to any pharmaceutically acceptable component in a pharmaceutical composition used in the formulation of a pharmaceutical product that is non-therapeutic and non-toxic to the target of administration, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants.

[0037] CD73 inhibitors The present invention relates to the compound of formula (i')(I). [ka] (wherein R 1 is 2,4-dioxo-1H-pyrimidinyl or 3,5-dioxo-2H-1,2,4-triazinyl; R 2 is C 1~6 alkyl or deuterio C 1~6 alkyl; R 3 is C 1~6 alkyl or halo C 1~6 alkyl; R 4 is H; R 5 is (C 1~6 alkoxy C 3~7 cycloalkyl)C 1~6 alkoxy, (C 1~6 alkyltetrahydrofuranyl)oxy, (cyano C 3~7 cycloalkyl)C 1~6 alkoxy, (halo C 1~6 alkoxy)C 1~6 alkyl, (halo C 1~6 alkyl C 3~7 cycloalkyl)C 1~6 alkoxy, (halo C 3~7 cycloalkyl)amino, (halo C 3~7 cycloalkyl)C 1~6 alkoxy, (halopyrrolidinyl)C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkoxy, C 3~7 cycloalkoxy, C 3~7 cycloalkoxy C 1~6 alkyl, cyano C 1~6 alkoxy, deuterio C 1~6 alkoxy, deuterio halo C 1~6 alkoxy, halo C 1~6 alkoxy, halo C 1~6 alkyl, haloamino C 1~6 alkyl, halo C 3~7 cycloalkoxy, halo C 3~7 cycloalkyl or halopiperidyl; T is O; L is 1,4-benzooxazinylene, indazoylene, pyrimidinylene, unsubstituted or halogen-substituted phenylene, or unsubstituted or halogen-substituted pyridylene. or relating to a pharmaceutically acceptable salt thereof.

[0038] Another embodiment of the present invention is a compound of formula (I-1) described in (ii')(i'), [ka] (In the formula, R 1 These are 2,4-dioxo-1H-pyrimidinyl or 3,5-dioxo-2H-1,2,4-triazinyl; R 2 C 1~6 Alkyl or deuterio C 1~6 It is alkyl; R 3 C 1~6 Alkyl or Halo C 1~6 It is alkyl; R 4 is H; R 5 is, (C 1~6 Alkoxy C 3~7 Cycloalkyl)C 1~6 Alkoxy, (C 1~6 Alkyltetrahydrofuranyl)oxy, (cyano C 3~7 Cycloalkyl)C 1~6 Alkoxy, (Halo C) 1~6 Alkoxy)C 1~6 Alkyl, (halo C 1~6 Alkyl C 3~7 Cycloalkyl)C 1~6 Alkoxy, (Halo C) 3~7 Cycloalkyl)amino, (halo C 3~7 Cycloalkyl)C 1~6 Alkoxy, (halopyrrolidinyl)C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Alkoxy, C 3~7 Cycloalkoxy, C 3~7 Cycloalkoxy C1~6 Alkyl, cyano C 1~6 Alkoxy, Deuterio C 1~6 Alkoxy, Deuteriohalo C 1~6 Alkoxy, Halo C 1~6 Alkoxy, Halo C 1~6 Alkyl, Halo C 1~6 Alkylamino, Halo C 3~7 Cycloalkoxy, Halo C 3~7 It is cycloalkyl or halopiperidyl; T is O; L is 1,4-benzooxazinylene, indazoylene, pyrimidinylene, unsubstituted or halogen-substituted phenylene, or unsubstituted or halogen-substituted pyridylene. or a pharmaceutically acceptable salt thereof.

[0039] Further embodiments of the present invention are compounds of formula (I) or formula (I-1) as described in (iii'), (i'), or (ii'), or pharmaceutically acceptable salts thereof, where R 1 teeth, [ka] or [ka] That is the case.

[0040] Further embodiments of the present invention include compounds of formula (I) or (I-1) as described in any one of (iv')(i') to (iii'), or pharmaceutically acceptable salts thereof, R 2 is C 1~6 It is alkyl.

[0041] Further embodiments of the present invention are compounds of formula (I) or (I-1) as described in any one of (v)(i') to (iv'), or pharmaceutically acceptable salts thereof, where R 2 It is methyl.

[0042] Further embodiments of the present invention include compounds of formula (I) or (I-1) as described in any one of (vi'), (i') to (v'), or pharmaceutically acceptable salts thereof, where R 3 is Hello C 1~6 It is alkyl.

[0043] Further embodiments of the present invention include compounds of formula (I) or (I-1) as described in any one of (vii')(i) to (vi), or pharmaceutically acceptable salts thereof, where R 3 It is difluoromethyl.

[0044] Further embodiments of the present invention are compounds of formula (I) or (I-1) as described in any one of (viii')(i') to (vii'), where L is pyrimidinylene or pyridylene that is unsubstituted or substituted with a halogen.

[0045] Further embodiments of the present invention are compounds of formula (I) or (I-1) as described in any one of (ix'), (i') to (viii'), or pharmaceutically acceptable salts thereof, wherein L is pyrimidinylene or unsubstituted or fluorosubstituted pyridylene.

[0046] Further embodiments of the present invention are compounds of formula (I) or (I-1) described in any one of (x'), (i') to (ix'), or pharmaceutically acceptable salts thereof, where R 5 (Hello C 1~6 Alkoxy)C 1~6 Alkyl, (halopyrrolidinyl)C 1~6 Alkyl, C 3~7 Cycloalkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy, Halo C 1~6 Alkylamino, Halo C 3~7 Cycloalkoxy or Halo C3~7 It is a cycloalkyl group.

[0047] Further embodiments of the present invention are compounds of formula (I) or (I-1) described in any one of (xi'), (i') to (x'), or pharmaceutically acceptable salts thereof, where R 5 These are (3,3-difluoropyrrolidine-1-yl)methyl, [2,2,2-trifluoro-1-methylethyl]amino, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluoroethoxy, 3,3-difluorocyclobutoxy, 3,3-difluorocyclobutyl, or cyclopropoxymethyl.

[0048] Further embodiments of the present invention include compounds of formula (I) or formula (I-1) as described in (xii)(i') or (ii') (wherein, R 2 teeth, [ka] or [ka] and; R 2 C 1~6 It is alkyl; R 3 is Hello C 1~6 It is alkyl; R 4 is H; R 5 (Hello C 1~6 Alkoxy)C 1~6 Alkyl, (halopyrrolidinyl)C 1~6 Alkyl, C 3~7 Cycloalkoxy C 1~6 Alkyl, Halo C 1~6 Alkoxy, Halo C 1~6 Alkylamino, Halo C 3~7 Cycloalkoxy or Halo C 3~7 It is a cycloalkyl; T is O; L is either pyrimidinylene, or the pyridylene is unsubstituted or substituted with a halogen. or a pharmaceutically acceptable salt thereof.

[0049] A further embodiment of the present invention is the formula (I) or (I-1) described in (xiii’)(xii’), wherein R 2 is

Chemical formula

Chemical formula

[0050] The present invention relates to (i) a compound of formula (I)

Chemical formula

[0051] Another embodiment of the present invention is a compound of formula (I-1) described in (ii)(i), [ka] (In the formula, R 1 These are 2,4-dioxo-1H-pyrimidinyl or 3,5-dioxo-2H-1,2,4-triazinyl; R 2 teeth, C1~6 Alkyl or deuterio C C1~6 It is alkyl; R 3 C 1~6 Alkyl or Halo C 1~6 It is alkyl; R 4 is H; R 5 (Cyano C 3~7 Cycloalkyl)C 1~6 Alkoxy, (Halo C) 1~6 Alkyl C 3~7 Cycloalkyl)C 1~6 Alkoxy, (Halo C) 3~7 Cycloalkyl)C 1~6 Alkoxy, C 1~6 Alkoxy, C 1~6 Alkoxy C 1~6 Alkoxy, C 3~7 Cycloalkoxy C 1~6 Alkyl, cyano C 1~6 Alkoxy, Deuteriohalo C 1~6 Alkoxy, Halo C 1~6 Alkoxy or Halo C 1~6 It is alkyl; T is O; L is 1,4-benzooxazinylene, indazoylene, unsubstituted or halogen-substituted phenylene, unsubstituted or halogen-substituted pyridylene, or pyrimidinylene. or a pharmaceutically acceptable salt thereof.

[0052] Further embodiments of the present invention are compounds of formula (I) or (I-1) as described in (iii)(i) or (ii), or pharmaceutically acceptable salts thereof, where R 1 teeth, [ka] or [ka] That is the case.

[0053] Further embodiments of the present invention include compounds of formula (I) or (I-1) as described in any one of (iv)(i) to (iii), or pharmaceutically acceptable salts thereof, R 2 It is methyl.

[0054] A further embodiment of the present invention is a compound of formula (I) or (I-1) as described in any one of (v)(i) to (iv), or a pharmaceutically acceptable salt thereof, wherein R 3 is halo C 1~6 alkyl.

[0055] A further embodiment of the present invention is a compound of formula (I) or (I-1) as described in any one of (vi)(i) to (v), or a pharmaceutically acceptable salt thereof, wherein R 3 is difluoromethyl.

[0056] A further embodiment of the present invention is a compound of formula (I) or (I-1) as described in any one of (vii)(i) to (vi), wherein L is pyridylene, unsubstituted or substituted with halogen.

[0057] A further embodiment of the present invention is a compound of formula (I) or (I-1) as described in any one of (viii)(i) to (vii), or a pharmaceutically acceptable salt thereof, wherein L is pyridylene, unsubstituted or substituted with fluoro.

[0058] A further embodiment of the present invention is a compound of formula (I) or (I-1) as described in any one of (ix)(i) to (viii), or a pharmaceutically acceptable salt thereof, wherein R 5 is C 3~7 cycloalkoxy C 1~6 alkyl or halo C 1~6 alkoxy.

[0059] A further embodiment of the present invention is a compound of formula (I) or (I-1) as described in any one of (x)(i) to (ix), or a pharmaceutically acceptable salt thereof, wherein R 5 is 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy or cyclopropoxymethyl.

[0060] Further embodiments of the present invention include compounds of formula (I) or formula (I-1) as described in (xi)(i) or (ii) (wherein, R 1 teeth, [ka] or [ka] and; R 2 C 1~6 It is alkyl; R 3 is Hello C 1~6 It is alkyl; R 4 is H; R 5 C 3~7 Cycloalkoxy C 1~6 Alkyl or Halo C 1~6 It is an alkoxy; T is O; L is an unsubstituted or halogen-substituted pyridylene. or a pharmaceutically acceptable salt thereof.

[0061] Further embodiments of the present invention include compounds of formula (I) or (I-1) as described in (xii)(xi) (wherein, R 1 teeth, [ka] or [ka] and; R 2 It is methyl; R 3 It is difluoromethyl; R 4 is H; R 5 These are 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, or cyclopropoxymethyl; T is O; L is either unsubstituted or fluorosubstituted pyridylene. or a pharmaceutically acceptable salt thereof.

[0062] Another embodiment of the present invention is (xiii) below: 5-[3-[(1R)-2,2-difluoro-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[4-(1,1-diduterio-2,2,2-trifluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[4-(2,2-difluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-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-4-(2,2,2-trifluoroethoxy)-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-4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 6-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4triazine-3,5-dione; 6-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4triazine-3,5-dione; 6-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4triazine-3,5-dione; 5-[1-methyl-3-[(1S)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2-methoxyethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(2,2-difluoropropoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoro-1-methylethoxy)-2-pyridyl]ethoxy]pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-1-[4-[(2,2-difluorocyclopropyl)methoxy]-2-pyridyl]-2,2-difluoroethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-(4-ethoxy-2-pyridyl)-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 2-[[2-[(1R)-1-[5-(2,4-dioxo-1H-pyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-4-pyridyl]oxy]acetonitrile; 1-[[2-[(1R)-1-[5-(2,4-dioxo-1H-pyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoro-ethyl]-4-pyridyl]oxymethyl]cyclopropanecarbonitric; 5-[3-[(1R)-2,2-difluoro-1-[4-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(2-methoxyethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1Hpyrimidine-2,4-dione; 5-[3-[(1R)-1-(2-ethoxy-4-pyridyl)-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(1,1,2,2,2-pentaduterioethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(4,4-difluoro-1-piperidyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(4,4-difluorocyclohexyl)amino]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(3,3-difluoropyrrolinidine-1-yl)methyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(1S)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(1R)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(3,3-difluorocyclobutyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[6-(1,1,2,2,2-pentaduterioethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[6-(1,1,2,2,2-pentaduterioethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2-difluoro-1-[2-[(trans)-4-methyltetrahydrofuran-3-yl]oxy-4-pyridyl]ethoxy]pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-[(1-methoxycyclopropyl)methoxy]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; and 5-[3-[(1S)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; A compound selected from or a pharmaceutically acceptable salt thereof.

[0063] Another embodiment of the present invention is a method for preparing the compound described in any one of (xv')(i)~(xii) or (i')~(xiii'), comprising the following steps: a) Formula (X) in the presence of an acid, dealkylating agent, or metal-mediated hydrogenation [ka] Deprotection of the compound gives formula (Ia) [ka] The process of obtaining the compound; b) Formula (XIII) in the presence of an acid, dealkylating agent, or metal-mediated hydrogenation [ka] Deprotection of the compound of formula (Ib) [ka] The process of obtaining the compound; c) Equation (XV) in the presence of a palladium catalyst [ka] Compounds and organostannanes (XVI) [ka] Through still coupling with, equation (Ic) [ka] The process of obtaining the compound; (In the formula, X is a halogen; each PG is independently an oxygen protecting group; PG is selected from methyl, tert-butyl, TBS, ethoxymethyl and benzyl; R 6 This includes optionally substituted aryl, heteroaryl, heterocyclyl, and aryl C. 1~6 Alkyl, heterocyclyl C 1~6 Alkyl or heteroaryl C 1~6 (It is alkyl.) Regarding methods that include any one of the following, In steps a) and b), the acid is trifluoroacetic acid or an aqueous hydrochloric acid solution; the dealkylation reagents are TMSCl and NaI; and hydrogenation is carried out using Pd / C. In step c), the catalyst is Pd(PPh3)4; R 1 ~R 5 It is defined as being in either (i)~(xii) or (i')~(xiii').

[0064] Another embodiment of the present invention is (xvi') a compound or pharmaceutically acceptable salt described in any one of (i)-(xii) or (i')-(xiv') for use as a therapeutically active substance.

[0065] Another embodiment of the present invention relates to a pharmaceutical composition comprising a compound described in any one of (xvii')(i)-(xii) or (i')-(xiv') and a pharmaceutically acceptable additive.

[0066] Another embodiment of the present invention is the use of any one of the compounds described in (i)-(xii) or (i')-(xiv') for the treatment of cancer (xviii').

[0067] Another embodiment of the present invention is the use described in (xix')(xvii), wherein the cancer is pancreatic cancer, colorectal cancer, gastric cancer, esophageal cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, or melanoma.

[0068] Another embodiment of the present invention is the use of any one of the compounds described in (i)-(xii) or (i')-(xiv') to inhibit (xx')CD73.

[0069] Another embodiment of the present invention is the use of any one of the compounds described in (i)-(xii) or (i')-(xiv') for preparing 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.

[0070] Another embodiment of the present invention is the use of any one of the compounds described in (i)-(xii) or (i')-(xiv') for the preparation of a pharmaceutical as a (xxii')CD73 inhibitor.

[0071] Another embodiment of the present invention is a compound or pharmaceutically acceptable salt described in any one of (i)-(xii) or (i')-(xiv') as prepared according to the method of (xxiii')(xiv).

[0072] Pharmaceutical composition and administration Another embodiment provides a pharmaceutical composition or pharmaceutically acceptable

[0073] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this regard include the specific disease being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the healthcare professional. The “effective dose” of the compound to be administered is determined by such considerations and is the minimum amount required to inhibit the enzymatic activity of the CD73 protein in converting AMP to adenosine. In one example, the pharmaceutically effective dose of the compound of the present invention administered parenterally per single dose is in the range of about 0.01 to 100 mg / kg of patient body weight per day, or alternatively, about 0.1 to 50 mg / kg of patient body weight, with a typical initial range of 0.3 to 30 mg / kg / day for the compound used. In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 mg of the compound of the present invention.

[0074] The compounds of the present invention may be administered by any suitable means, including orally, topically (including buccal and sublingual), rectally, vaginally, percutaneously, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally, and epidurally, as well as intranasally, and, if desired for topical treatment, intrafocal administration. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0075] The compounds of the present invention can 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 components that are conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further activators.

[0076] Typical formulations are prepared by mixing the compound of the present invention with a carrier or additive. Suitable carriers and additives are well known to those skilled in the art and are described in detail, 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, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide a precise presentation of a drug (i.e., the compound of the present invention or its pharmaceutically acceptable composition) or to assist in the manufacture of a pharmaceutical composition (i.e., a pharmaceutical).

[0077] A suitable oral dosage form is a tablet containing approximately 0.1 to 500 mg of the compound of the present invention, formulated with approximately 0.1 to 500 mg of anhydrous lactose, approximately 0.1 to 500 mg of croscarmellose sodium, approximately 0.1 to 500 mg of polyvinylpyrrolidone (PVP) K30, and approximately 0.1 to 500 mg of magnesium stearate. The powdered components 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 of an aerosol formulation can be prepared, for example, by dissolving 1 to 450 mg of the compound of the present invention in a suitable buffer solution, such as phosphate buffer, and optionally adding an isotonic agent, such as a salt of sodium chloride. The solution may be filtered, for example, using a 0.2 micron filter, to remove impurities and contaminants.

[0078] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or additive.

[0079] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of cancer.

[0080] The following embodiments illustrate typical compositions of the present invention, but are used merely as representative examples.

[0081] The compounds of the present invention can be used in a manner known to the extent of their own as active ingredients to produce tablets having the following compositions. Per 425mg tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg

[0082] Composition B The compounds of the present invention can be used in a manner known to the extent of their own as active ingredients to produce capsules having the following compositions. Per 220.0 mg capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg

[0083] 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 in lowering adenosine levels in TME. The compounds of the present invention are useful in 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 targeted therapy in pancreatic adenocarcinoma, non-small cell lung cancer, esophageal and gastric adenocarcinoma, etc., to promote immune-mediated killing of cancer cells that depend on the adenosine pathway or in malignant solid tumors where the adenosine pathway is enhanced by dysregulation or mutation of effector pathways such as EGFR-RAS-MAPK and PI3K-AKT-driven signaling. More broadly, these compounds can be used to treat and prevent all types of cancer that exhibit an immunosuppressive tumor microenvironment (TME).

[0084] Another embodiment includes a method for treating or preventing cancer in a mammal requiring such treatment, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0085] 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 provided in the following scheme and examples. All substituents, especially R 1 ~R 5 Unless otherwise specified, T and L are as defined above. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations, and symbols have meanings familiar to those skilled in the art of organic chemistry.

[0086] The following is a general synthetic route for preparing the compound of formula (I). Scheme 1 [ka] In the formula, each X is independently a halogen.

[0087] The compound of formula (V) can be prepared according to scheme 1. The compound of formula (IV) can be produced by condensation of the compound of formula (II) and the compound of formula (III). The compound of formula (V) can be obtained by treating the compound of formula (IV) with an acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid).

[0088] Scheme 2 [ka] In the formula, each X is independently a halogen; each PG is independently a methyl, oxygen protecting group, such as methyl, tert-butyl, TBS, ethoxymethyl, and benzyl; and Y is OH, OTf, OMs, or a halogen.

[0089] The compound of formula (VIII) can be obtained by following the synthesis of intermediates C1 to C3.

[0090] The compound of formula (Ia) can be prepared according to scheme 2. The compound of formula (VII) can be obtained by Suzuki-Miyaura coupling of the compound of formula (V) with a heteroarylboronic acid (VI) in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2, Pd(PPh3)4, cataCXium-A-Pd-G3, etc.) and a base (e.g., Na2CO3, K2CO3, Cs2CO3, etc.). The compound of formula (IX) can be obtained via the Mitsunobu reaction or nucleophilic substitution between the compound of formula (VII) and the compound of formula (VIII). The defined R of the compound of formula (X) 5 The group can be introduced via a transition metal-mediated coupling reaction (e.g., Buchwald-Hartwig, Ullmann-Ma reaction, or photochemistry). The compound of formula (Ia) can be provided by the following deprotection steps using hydrogenation mediated by an acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid), a dealkylation reagent (e.g., TMSCl and NaI), or a metal (e.g., Pd / C).

[0091] Scheme 3 [ka] In the formula, R 6 This includes optionally substituted aryl, heteroaryl, heterocyclyl, and aryl C. 1~6 Alkyl, heterocyclyl C 1~6 Alkyl or heteroaryl C 1~6 It is alkyl; X is a halogen; Y is OH, OTf, OMs, or a halogen.

[0092] The compound of formula (Ib) can be prepared according to Scheme 3. The compound of formula (XI) can be obtained via a transition metal-mediated coupling reaction of formula (IX) with a basic aqueous solution or a boronic acid ester (e.g., B2pin2), followed by oxidation with H2O2 (aqueous solution) or m-CPBA, etc. The compound of formula (XIII) can be obtained via a Mitsunobu reaction or nucleophilic substitution between the compound of formula (XI) and the compound of formula (XII). The compound of formula (Ib) can be provided by the following deprotection steps using acid (e.g., trifluoroacetic acid, aqueous hydrochloric acid), or dealkylation reagents (e.g., TMSCl and NaI), or metal (e.g., Pd / C), or metal-mediated hydrogenation.

[0093] Scheme 4 [ka] In the formula, X is a halogen; Y is OH, OTf, OMs, or a halogen.

[0094] Alternatively, the compound of formula (X) can be obtained via the Mitsunobu reaction or nucleophilic substitution between the compound of formula (VII) and the compound of formula (XIV).

[0095] The compound of formula (Ic) can be prepared according to scheme 4. The compound of formula (XV) can be obtained via the Mitsunobu reaction or nucleophilic substitution between the compounds of formula (V) and formula (XIV). The compound of formula (Ic) can be provided by still coupling the compound of formula (XV) with organostannane (XVI) in the presence of a palladium catalyst (e.g., Pd(PPh3)4).

[0096] The compounds of the present invention can be obtained as a mixture 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 scheme by using the corresponding chiral starting material.

[0097] The present invention also provides a method for preparing a compound of formula (I), comprising the following steps: a) Formula (X) in the presence of an acid, dealkylating agent, or metal-mediated hydrogenation [ka] Deprotection of the compound gives formula (Ia) [ka] The process of obtaining the compound; b) Formula (XIII) in the presence of an acid, dealkylating agent, or metal-mediated hydrogenation. [ka] Deprotection of the compound of formula (Ib) [ka] The process of obtaining the compound; c) Equation (XV) in the presence of a palladium catalyst [ka] Compounds and organostannanes (XVI) [ka] Through still coupling with, equation (Ic) [ka] The process of obtaining the compound; (In the formula, X is a halogen; each PG is independently an oxygen protecting group; PG can be selected from methyl, tert-butyl, TBS, ethoxymethyl and benzyl; R 6 This includes optionally substituted aryl, heteroaryl, heterocyclyl, and aryl C. 1~6 Alkyl, heterocyclyl C 1~6 Alkyl or heteroaryl C 1~6 (It is alkyl.) Regarding methods that include any one of the following, In steps a) and b), the acid may be, for example, trifluoroacetic acid or an aqueous solution of hydrochloric acid; the dealkylating reagent may be, for example, TMSCl and NaI; and hydrogenation may be carried out using Pd / C; In step c), the catalyst may be, for example, Pd(PPh3)4.

[0098] Compounds of formula (I) produced by the method described above are also subject to the present invention.

[0099] Examples The present invention will be better understood by referring to the following embodiments. However, the embodiments should not be construed as limiting the scope of the present invention.

[0100] Abbreviation The present invention will be better understood by referring to the following embodiments. However, the embodiments should not be construed as limiting the scope of the present invention. The abbreviations used in this specification are as follows: 4Å MS: 4Å Molecular Sieve ACN: Acetonitrile Acetic acid (ATOH) DCE: 1,2-Dichloroethane DCM: Dichloromethane DEAD; Diethyl azodicarboxylate DIAD: Diisopropyl azodicarboxylate DIPEA or DIEA: N,N-diisopropylethylamine DME: Dimethoxyethane DMF: N,N-dimethylformamide DMP: Des Martin Periodine DtBAD: Di-tert-butylazodicarboxylate EA or methoxy: 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 Ir[dF(CF3)ppy]2(dtbbpy)(PF6):(4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(III) hexafluorophosphate LCMS: Liquid Chromatography Mass Spectrometry m-CPBA: Meta-chloroperoxybenzoic acid MS: Mass spectrometry NBS: N-bromosuccinimide NiCl2dtbbpy [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel dichloride 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(p-cymene)[(R,R)-Ts-DPEN]:((R,R-2-amino-1,2-diphenylethyl)[(4-tolyl)sulfonyl]amide](p-cymene)ruthenium(II) chloride SFC: Supercritical Fluid Chromatography Selectfluor N-chloromethyl-N'-fluorotriethylenediammonium bis(N (Tetrafluoroborate) STAB: Sodium triacetoxyborohydride TFA: Trifluoroacetic acid TFE: Trifluoroethyl alcohol t-PentOK: Potassium tert-pentoxide TTMSS: Tris(trimethylsilyl)silane TLC: Thin-layer chromatography TMSCHF2 (difluoromethyl)trimethylsilane v / v volume ratio

[0101] General experimental conditions The intermediate and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel brands and pore sizes: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS registry number: silica gel: 63231-67-4, particle size: 47-60 microns; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

[0102] The intermediates and final compounds were purified by preparative HPLC using XBridge® Prep-C18 (5 μm, OBD® 30 × 100 mm) columns, SunFire® Prep-C18 (5 μm, OBD® 30 × 100 mm) columns, or reverse-phase columns using Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm). Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detectors: Micromass ZQ and UV2487, 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 Gilson-281 purification system (Pump 322, Detector: UV156, Solvent system: Acetonitrile and 0.05% ammonium hydroxide aqueous solution; Acetonitrile and 0.225% FA aqueous solution; Acetonitrile and 0.05% HCl aqueous solution; Acetonitrile and 0.075% TFA aqueous solution; or Acetonitrile and water).

[0103] For SFC chiral separation, intermediates were separated using chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), (S,S)whelk-o1, inner diameter 250 × 30 mm, TCI Chiral MB-S, inner diameter 250 × 30 mm, AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) with a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure 100 bar, and detection UV at 254 or 220 nm.

[0104] The LC / MS spectra of the compounds were obtained using LC / MS (Waters® Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ), with the following LC / MS conditions (trial time 3 minutes or 1.5 minutes). Acidic conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic conditions I: A: 0.1% NH3·H2O in H2O; B: Acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O; B: Acetonitrile; Neutral conditions: A: H2O; B: Acetonitrile. Mass spectra (MS): Generally, only ions showing the primary mass are reported, and unless otherwise stated, the cited mass ions are positive mass ions (MH). + That is the case.

[0105] NMR spectra were acquired using a Bruker Avance 400MHz or 500MHz.

[0106] Microwave-assisted reactions were carried out using a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Unless otherwise specified, reagents were used as received from commercial suppliers without further purification.

[0107] Preparation example The following examples are intended to illustrate the meaning of the present invention, but are not intended to limit it within the scope of the present invention.

[0108] Intermediate A1 5-Chloro-1-methyl-pyrazolo[3,4-c]pyridazine-3-ol [ka] The title compound was synthesized according to the following scheme: [ka]

[0109] Step (a): Preparation of tert-butyl N-[(3,6-dichloropyridazine-4-carbonyl)amino]-N-methyl-carbamate (compounds A1 and A2) 3,6-Dichloropyridazine-4-carboxylic acid (compound A1.1, 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 (614 μL, 7.25 mmol) was slowly added, and the mixture was stirred at 0°C for 20 minutes. The resulting mixture was heated to 25°C and stirred for a further 20 minutes 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 (833.3 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 at 0°C, and the reaction mixture was then slowly warmed to room temperature and stirred for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted twice with DCM (20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated to obtain compound A1.2. MS: Calculated value 321.1[(M+H)] + ]; Measured value 321.1 [(M+H) + ].

[0110] Step (b) Preparation of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine-3-ol (compound A1) The mixture of the crude compound A1.2 and HCl / dioxane (4M, 25 mL) was stirred at 55°C for a further 10 hours. The resulting precipitate was collected by filtration, and the filtration cake was washed three times with water (10 mL) and dried to obtain intermediate A1 (762.0 mg). MS: Calculated value 185.0 [(M+H)] + ]; Measured value 185.1 [(M+H) + ].

[0111] Intermediate A2 5-Chloro-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazine-3-ol [ka] The title compound was synthesized according to the following scheme: [ka]

[0112] Step (a): Preparation of tert-butyl N-[(E)-(4-methoxyphenyl)methyleneamino]-carbamate (compound A2.2) To a solution of tert-butyl N-aminocarbamate (compound A2.1, 20.0 g, 151 mmol) in THF (100 mL), p-anisaldehyde (20 mL, 166 mmol) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The precipitate was collected by filtration and dried to obtain compound A2.2 (33.0 g). MS: Calculated value 286.1 [(M+H)] + ]; Measured value 286.0 [(M+H) + ]. Step (b): Preparation of tert-butyl N-[(E)-(4-methoxyphenyl)methyleneamino]-N-(triduteriomethyl)carbamate (compounds A2 and A3)

[0113] A mixture of tert-butyl N-[(E)-(4-methoxyphenyl)methyleneamino]carbamate (compound A2.2, 33.0 g, 131 mmol) and triduterio(iodo)methane (21.0 g, 145 mmol) in 200 mL of THF was mixed with NaH (60% dispersion in mineral oil, 7.91 g, 198 mmol) under a nitrogen atmosphere at 0°C. The resulting mixture was stirred at room temperature for 2 hours, then quenched with water (200 mL), and extracted three times with DCM (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting at 0% to 100% EA in PE) to obtain compound A2.3 (35.0 g). MS: Calculated value 268.2[(M+H)] + ]; Measured value 268.3 [(M+H) + ].

[0114] Step (c): Preparation of tert-butyl N-amino-N-(triduteriomethyl)carbamate Preparation of compound A2.4 A mixture of tert-butyl N-[(E)-(4-methoxyphenyl)methyleneamino]-N-(triduteriomethyl)carbamate (compound A2.3, 35.0 g, 147 mmol) in methanol (300 mL) and 10% Pd / C (3.5 g) was hydrogenated at 80°C for 16 hours under a hydrogen atmosphere. After filtering off the catalyst, the filtrate was concentrated under vacuum to obtain compound A2.4 (14.3 g). 1 ¹H NMR (400 MHz, chloroform-d) δ 4.02 (s, 2H), 1.33 (s, 9H).

[0115] Step (d): Preparation of tert-butyl N-[(3,6-dichloropyridazine-4-carbonyl)amino]carbamate (compound A2.5) To a solution of 3,6-dichloropyridazine-4-carboxylic acid (compound A1.1, 8.0 g, 41.5 mmol) in DCM (50 mL), oxalyl chloride (10.5 g, 82.9 mmol) was added, followed by the addition of 2 drops of DMF. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The resulting residue was then added at 0°C to a solution of tert-butyl N-amino-N-(triduteriomethyl)carbamate (compound A2.4, 7.42 g, 49.7 mmol) and triethylamine (8.3 g, 83.7 mmol) in DCM (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted three times with DCM (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution in PE at 0% to 100% EA) to obtain compound A2.5 (11.0 g). MS: Calculated value 324.1[(M+H)] + ]; Measured value 324.1 [(M+H) + ].

[0116] Step (e): Preparation of 5-chloro-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazine-3-ol (Intermediate A2) A mixture of tert-butyl N-[(3,6-dichloropyridazine-4-carbonyl)amino]carbamate (compound A2.5, 11.0 g, 33.9 mmol) and HCl (4 M in 1,4-dioxane, 60 mL) was stirred at 60°C for 16 hours. The solid was recovered by filtration, washed three times with water (50 mL), and dried to obtain intermediate A2 (6.2 g). MS: Calculated value 188.0[(M+H)] + ]; Measured value 188.0 [(M+H) + ].

[0117] Intermediate B1: 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine-3-ol [ka] The title compound was synthesized according to the following scheme: [ka]

[0118] Step (a): Preparation of 3-benzyloxy-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound B1.1) To a solution of 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (intermediate A1, 5.0 g, 27.1 mmol) in CH3CN (100 mL), K2CO3 (7.5 g, 54.2 mmol) and benzyl bromide (3.2 mL, 27.1 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The reaction was quenched by slowly adding H2O (100 mL), and then extracted three times with EA (100 mL). The combined organic layer was washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EA from 100 / 1 to 10 / 1) to obtain compound B1.1 (4.2 g). MS: Calculated values ​​275.1, 277.1 [(M+H)] + ]; Measured values ​​275.2, 277.2 [(M+H) +]. 1 H NMR (400MHz, DMSO-d6) δ = 8.41 (s, 1H), 7.60-7.29 (m, 5H), 5.47 (s, 2H), 4.08 (s, 3H).

[0119] Step (b): Preparation of 3-(benzyloxy)-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridazine (compound B1.3) A solution of 3-benzyloxy-5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine (compound B1.1, 4.20 g, 15.29 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) is prepared by adding (2,4-di-tert-butoxypyrimidine-5-yl)boronic acid (compound B1.2, 4.10 g, 15.29 mmol), Cs2CO3 (9.96 g, 30.58 mmol), and Pd(dppf)Cl2 . DCM (0.56 g, 0.76 mmol) was added. The resulting mixture was purged three times with nitrogen and then stirred at 80°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL) and extracted three times with EA (100 mL). The combined organic layer was washed with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with PE / EA from 100 / 1 to 10 / 1) to obtain compound B1.3 (6.0 g). MS: Calculated value 463.2[(M+H)] + ]; Measured value 463.2[(M+H) + ]. . 1 H NMR(400MHz,DMSO-d6)δ=8.77(s,1H),8.36(s,1H),7.57-7.48(m,2H),7.46-7.32(m,3H),5.50(s,2H),4.10(s,3H),1.62(s,9H),1.60(s,9H).

[0120] Step (c): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-1H-pyrazolo[3,4-c]pyridazine-3-ol (intermediate B1) A mixture of 3-benzyloxy-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (compound B1.3, 6.0 g, 12.97 mmol) and Pd / C (690.23 mg, purity 10%) in methanol (110 mL) was hydrogenated at room temperature for 2 hours using a hydrogen balloon. After filtering off the catalyst, the filtrate was concentrated under vacuum to obtain intermediate B1 (4.5 g). MS: Calculated value 373.2[(M+H)] + ]; Measured value 373.3 [(M+H) + ]. 1 H NMR (400MHz, DMSO-d6) δ = 11.70 (s, 1H), 8.76 (s, 1H), 8.34 (s, 1H), 4.02 (s, 3H), 1.63 (s, 9H), 1.62 (s, 9H).

[0121] Intermediate B2: 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazine-3-ol [ka] Intermediate B2 was prepared in the same manner as intermediate B1, by replacing 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine-3-ol (intermediate A1) with 5-chloro-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazine-3-ol (intermediate A2) in step (a). MS: Calculated value 376.2[(M+H)] + ]; Measured value 376.2[(M+H) + ].

[0122] Intermediate C1 (1S)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanol [ka] The title compound was synthesized according to the following scheme: [ka]

[0123] Step (a): Preparation of 4-fluoro-N-methoxy-N-methylbenzamide (compound C1.2) HATU (119.41 g, 314.04 mmol) was added to a solution of 4-fluorobenzoic acid (compound C1.1, 40.0 g, 285.49 mmol) and DIEA (74.28 g, 570.98 mmol) in DCM (600 mL). The resulting mixture was stirred for 15 minutes. Then, O,N-dimethylhydroxylamine HCl (30.63 g, 314.04 mmol) was added dropwise to the mixture, and it was stirred at room temperature for a further 12 hours. The reaction was quenched by slowly adding H2O (500 mL), and then extracted three times with DCM (200 mL). The combined organic layer was washed three times with brine (100 mL), dried on anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with PE / EA from 100 / 1 to 10 / 1) to obtain compound C1.2 (50.0 g). Calculated value 184.1[(M+H) + ]; Measured value 184.2 [(M+H) + ]. 1 H NMR (400MHz, DMSO-d6) δ = 7.69 (dd, J = 5.6, 8.8 Hz, 2H), 7.28 (t, J = 8.8 Hz, 2H), 3.54 (s, 3H), 2.69 (s, 3H).

[0124] Step (b): Preparation of 2,2-difluoro-1-(4-fluorophenyl)ethanone (compound C1.4) A 1000 mL oven-drying three-neck round-bottom flask equipped with a magnetic stirring bar was sealed with a Teflon-lined septum, evacuated, and flame-dried under vacuum. The flask was cooled to 25°C and then filled with nitrogen. 4-Fluoro-N-methoxy-N-methylbenzamide (compound C1.2, 40.0 g, 218.36 mmol), difluoromethyltrimethylsilane (compound C1.3, 35.26 g, 283.87 mmol), and THF (200 mL) were rapidly added. The flask was then evacuated and filled with nitrogen three times. The resulting mixture was cooled to -78°C. t-BuOK (1 M in THF, 393.1 mL, 393.1 mmol) was added dropwise at -78°C for 1 hour, and the reaction mixture was then stirred at the same temperature for a further 4 hours. The reaction mixture was quenched by slowly adding saturated aqueous ammonium chloride (500 mL) and extracted three times with EA (300 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with PE) to obtain compound C1.4 (12.0 g). 1 H NMR (400MHz, DMSO-d6) δ = 8.19-8.02 (m, 2H), 7.53-7.36 (m, 2H), 7.16 (td, J = 52.4, 2.6Hz, 1H).

[0125] Step (c): Preparation of 1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanone (compound C1.5) To a solution of 2,2-difluoro-1-(4-fluorophenyl)ethanone (compound C1.4, 6.0 g, 34.46 mmol) in H2SO4 (60.0 mL), NBS (6.75 g, 37.9 mmol) was added. The resulting mixture was stirred at 60°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (300.0 mL) and extracted twice with EA (150 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with PE) to obtain compound C1.5 (8.0 g). 1H NMR (400MHz, DMSO-d6) δ8.35 (dd, J = 6.6, 2.1 Hz, 1H), 8.15-8.03 (m, 1H), 7.70-7.55 (m, 1H), 7.19 (td, J = 52.4, 2.7Hz, 1H).

[0126] Step (d): Preparation of (1S)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanol (intermediate C1) To a solution of 1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanone (compound C1.5, 4.0 g, 15.81 mmol) in DCM (40 mL), triethylamine (4.41 mL, 31.62 mmol) and formic acid (1.79 mL, 47.43 mmol) were added at 0°C, followed by the addition of a solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] in DCM (2.5 mL). After stirring at 20°C for 16 hours, the reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography (eluting with PE / EA from 1 / 10 to 1 / 5) to obtain intermediate C1 (4.23 g). 1 H NMR(400MHz,DMSO-d6)δ7.75(d,J=6.8Hz,1H),7.48(t,J=6.8Hz,1H),7.40(t,J =8.7Hz,1H),6.36(d,J=5.2Hz,1H),6.05(td,J=55.5,3.7Hz,1H),4.84(m,1H).

[0127] Intermediate C2 (1S)-1-(4-bromo-2-pyridyl)-2,2-difluoroethanol [ka] The title compound was synthesized according to the following scheme: [ka]

[0128] Step (a): Preparation of 4-bromo-N-methoxy-N-methylpicolinamide (compound C2.2) A mixture of 4-bromopyridine-2-carboxylic acid (compound C2.1, 25.0 g, 123.8 mmol), DIEA (80 g, 618.8 mmol), N,O-dimethylhydroxylamine hydrochloride (14.5 g, 148.5 mmol), and HATU (94.1 g, 247.5 mmol) in DMF (250 mL) was stirred at room temperature for 12 hours. The resulting mixture was diluted with EA (2500 mL). The organic layer was washed twice with brine (300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluted with 1 / 1 PE / EA) to obtain compound C2.2 (24.3 g). MS: Calculated values ​​245.0, 247.0 [(M+H)] + ]; Measured values ​​245.0, 247.0 [(M+H) + ].

[0129] Step (b): Preparation of 1-(4-bromopyridine-2-yl)-2,2-difluoroethane-1-one (compound C2.3) A mixture of 4-bromo-N-methoxy-N-methylpyridine-2-carboxamide (compound C2.2, 10 g, 41.0 mmol) and TMSCF2H (compound C1.3, 15.2 g, 122 mmol) in THF (100 mL) was stirred at -30°C for 10 minutes under a nitrogen atmosphere. Then, t-PentOK (1.0 M in cyclohexane, 82 mL, 82.0 mmol) was added dropwise at -30°C. The resulting mixture was stirred at -30°C for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with EA (300 mL), washed twice with saturated NH4Cl aqueous solution (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain compound C2.3 (10 g, crude). Calculated values: 235.9, 237.9 [(M+H)] + ]; Measured values ​​254.0, 256.0 [(M+H+H2O) + ]. 1 H NMR (400MHz, DMSO-d6) δ=8.70(d,J=5.2Hz,1H),8.27(d,J=1.9Hz,1H),8.08-7.00(m,1H),7.25(t,J=53.6Hz,1H).

[0130] Step (c): Preparation of (1S)-1-(4-bromo-2-pyridyl)-2,2-difluoroethanol (intermediate C2) 1-(4-bromo-2-pyridyl)-2,2-difluoroethanone (compound C2.3, 8.0 g, 33.9 mmol), enzyme KRD-145 (Pharmaron, catalog: KRD-145, 800 mg), glucose (20.8 g), glucose dehydrogenase (2.56 g), coenzyme II (4.8 g), Na2HPO4 (7.00 g), NaH2PO4 (3.80 g), and i-PrOH (48 mL) were stirred in water (800 mL) at 35°C for 12 hours. The mixture was extracted three times with ethyl acetate (1000 mL). The combined organic layer was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EA 2 / 1) to obtain intermediate C2 (3.6 g). Calculated values: 238.0, 240.0 [(M+H) + ], measured values ​​238.0, 240.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=8.46(d,J=5.3Hz,1H),7.82-7.63(m,2H),5.91-5.82,(m,1H)6.27(td,J=46.4Hz,3.2Hz,1H),4.89-4.82(m,3.6Hz,1H).

[0131] Intermediate C3 (1S)-1-(3-bromophenyl)-2,2-difluoroethanol [ka] The title compound was synthesized according to the following scheme: [ka]

[0132] Step (a): Preparation of 1-(3-bromophenyl)-2,2-difluoroethanol (compound C3.2) To a solution of 3-bromobenzaldehyde (compound C3.1, 7.9 g, 5.0 mL, 42.7 mmol) in DMF (40 mL), TMSCHF2 (4.0 g, 4.0 mL, 24.5 mmol) and CsF (648.6 mg, 4.3 mmol) were added. The resulting mixture was stirred under nitrogen at room temperature for 2 hours. The reaction mixture was diluted with saturated saline (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in THF (20 mL). HF·3Et3N (4.0 g, 24.5 mmol) was added to the resulting solution at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution at 0%-15% EA in PE, on 120 g of silica gel) to obtain compound C3.2 (7.4 g). 1 H NMR(400MHz,CDCl3)δ=7.63(s,1H),7.54(d,J=7.9Hz,1H),7.38(d,J=7.6Hz,1H),7.31(d ,J=7.8Hz,1H),5.76(td,J=55.7,4.6Hz,1H),4.93-4.75(m,1H),2.47(brd,J=2.8Hz,1H).

[0133] Step (b): Preparation of 1-(3-bromophenyl)-2,2-difluoroethanone (compound C3.3) To a solution of 1-(3-bromophenyl)-2,2-difluoroethanol (compound C3.2, 7.4 g, 31.3 mmol) in DCM (100 mL), DMP (19.9 g, 46.9 mmol) was added. The resulting mixture was stirred under nitrogen at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and saturated aqueous Na2S2O3 (100 mL). After stirring at room temperature for 1 hour, the mixture was extracted twice with DCM (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution at 0%~15% EA in PE, on silica gel, 80 g) to obtain compound C3.3 (6.8 g). 1 H NMR (400MHz, CDCl3) δ=8.23(s,1H),8.04(d,J=7.9Hz,1H),7.86-7.79(m,1H),7.45(t,J=7.9Hz,1H),6.27(t,J=51.2Hz,1H).

[0134] Step (c): Preparation of (1S)-1-(3-bromophenyl)-2,2-difluoroethanol (intermediate C3) To a solution of 1-(3-bromophenyl)-2,2-difluoroethanone (compound C3.3, 2.0 g, 8.5 mmol) in DCM (10 mL), HCO2H (6.0 g, 5.0 mL, 130.4 mmol) and Et3N (5.2 g, 7.2 mL, 51.7 mmol) were added at 0°C, followed by the addition of RuCl(p-cymene)[(R,R)-Ts-DPEN] (540.8 mg, 850 μmol) in small amounts at 0°C. After stirring overnight at room temperature, the reaction mixture was diluted with saturated aqueous NaHCO3 solution (100 mL) and extracted twice with DCM (100 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution at 0%~15% EA in PE, 40 g silica gel) to obtain compound C3 (1.7 g). 1H NMR(400MHz,CDCl3)δ=7.63(s,1H),7.56-7.51(m,1H),7.38(d,J=7.5Hz,1H),7.31(d, J=7.8Hz,1H),5.77(td,J=55.9,4.5Hz,1H),4.90-4.76(m,1H),2.47(d,J=3.8Hz,1H).

[0135] Intermediate C4 (1S)-1-(2-bromo-4-pyridyl)-2,2-difluoroethanol [ka] The title compound was synthesized according to the following scheme: [ka]

[0136] Step (a): Preparation of 2-bromo-N-methoxy-N-methylpyridine-4-carboxamide (compound C4.2) To a solution of 2-bromoisonicotinic acid (compound C4.1, 25.0 g, 124 mmol) and DIEA (48.0 g, 371 mmol) in DMF (150 mL), HATU (29.1 g, 123 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then, N,O-dimethylhydroxylamine hydrochloride (12.0 g, 123 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (600 mL) and extracted three times with EA (600 mL). The organic layer was washed three times with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 330 g, eluted with 0%~100% EA in PE) to obtain compound C4.2 (19.5 g). MS: Calculated values ​​245.0, 247.0 [(M+H)] + ]; Measured values ​​245.0, 247.0 [(M+H) + ].

[0137] Step (b): Preparation of 1-(2-bromo-4-pyridyl)-2,2-difluoroethanone (compound C4.3) To a solution of 2-bromo-N-methoxy-N-methylpyridine-4-carboxamide (compound C4.2, 19.2 g, 78.3 mmol) and difluoromethyl)trimethylsilane (9.71 g, 78.3 mmol) in THF (200 mL), t-PentOK (2 M in THF, 50.5 mL, 101 mmol) was added under a nitrogen atmosphere at -60°C. After stirring at -60°C for 4 hours, the reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted three times with EA (300 mL). The organic layer was washed three times with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0%~100% EA in PE, 330 g of silica gel) to obtain compound C4.3 (12.0 g). MS: Calculated values ​​236.0, 238.0 [(M+H) + ]; Measured values ​​254.0, 256.0 [(M+H+H2O) + ].

[0138] Step (c): Preparation of (1S)-1-(2-bromo-4-pyridyl)-2,2-difluoroethanol (intermediate C4) A mixture of 1-(2-bromo-4-pyridyl)-2,2-difluoroethanone (compound C4.3, 12.0 g, 50.8 mmol), RuCl[(R,R)-Tsdpen](P-cymene) (321 mg, 0.48 mmol), triethylamine (50.0 g, 0.494 mol), and formic acid (56.5 g, 1.23 mol) was stirred overnight at 40°C under a nitrogen atmosphere. The reaction mixture was diluted with water (400 mL) and extracted three times with EA (500 mL). The organic layer was washed three times with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 120 g, eluted with 0%~100% EA in PE) to obtain compound C4 (10.8 g). MS: Calculated values ​​238.0, 240.0[(M+H)] + ]; Measured values ​​238.0, 240.0 [(M+H) + ].

[0139] Intermediate D1 3-[(1R)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine [ka] The title compound was synthesized according to the following scheme: [ka]

[0140] Step (a): Preparation of 3-[(1R)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D1) To a suspension of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-ol (intermediate B1, 3.0 g, 8.06 mmol) in toluene (60 mL), (1S)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanol (intermediate C1, 2.88 g, 11.28 mmol) and triphenylphosphan (4.23 g, 16.11 mmol) were added. Then, diethyl azodicarboxylate (2.93 mL, 16.11 mmol) was added dropwise to the mixture. The reaction mixture was stirred at 60°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted twice with EA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with PE / EA from 1 / 10 to 1 / 5) to obtain intermediate D1 (5.0 g). Calculated values: 609.1, 611.1 [(M+H)] + ]; Measured values ​​609.4, 611.4 [(M+H) + ].

[0141] Intermediate D2 3-[(1R)-1-(4-bromo-2-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine [ka] Intermediate D2 was prepared in the same manner as intermediate D1, by replacing (1S)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanol (intermediate C1) with (1S)-1-(4-bromo-2-pyridyl)-2,2-difluoroethanol (intermediate C2) in step (a). Calculated values: 592.1, 594.1 [(M+H)] + ]; Measured values ​​592.1, 594.1 [(M+H) + ].

[0142] Intermediate D3 3-[(1R)-1-(3-bromophenyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine [ka] Intermediate D3 was prepared in the same manner as D1, by replacing (1S)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanol (intermediate C1) with (1S)-1-(3-bromophenyl)-2,2-difluoroethanol (intermediate C3) in step (a). MS: Calculated value 591.1[(M+H)] + ]; Measured value 477.0[(M+3H-2tBu) + ]. 1 H NMR(400MHz,CDCl3)δ=9.09(s,1H),8.35(s,1H),7.71(s,1H),7.56(brd,J=8.1Hz,1H),7.49( d,J=7.6Hz,1H),7.36-7.30(m,1H),6.35-5.96(m,2H),4.16(s,3H),1.76(s,9H),1.74(s,9H).

[0143] Intermediate D4 3-[(1R)-1-(4-bromo-2-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazine [ka] Intermediate D4 was prepared in the same manner as intermediate D1, by replacing (1S)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanol (intermediate C1) and 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-ol (intermediate B1) with (1S)-1-(4-bromo-2-pyridyl)-2,2-difluoroethanol (intermediate C2) and 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazin-3-ol (intermediate B2) in step (a). MS: Calculated values ​​595.2, 597.2 [(M+H) + ]; Measured values ​​595.2, 597.2 [(M+H) + ].

[0144] Intermediate D5 3-[(1R)-1-(2-bromo-4-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine [ka] Intermediate D5 was prepared in the same manner as intermediate D1, by replacing (1S)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethanol (intermediate C1) with (1S)-1-(2-bromo-4-pyridyl)-2,2-difluoroethanol (intermediate C4) in step (a). MS: Calculated values ​​592.1, 594.1 [(M+H)] + ]; Measured values ​​592.2, 594.20 [(M+H) + ].

[0145] Intermediate E1 2-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-4-ol [ka] The title compound was synthesized according to the following scheme: [ka]

[0146] Step (a): Preparation of 5-(2,4-ditert-butoxypyrimidine-5-yl)-3-[(1R)-1-[4-(5,5-dimethyl-1,3,2dioxaborinan-2-yl)-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine (compound E1.1) A mixture of 3-[(1R)-1-(4-bromo-2-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D2, 6.0 g, 10.1 mmol), bis(neopentyl glycolate)diborone (11.44 g, 50.6 mmol), potassium acetate (7.0 g, 50.6 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (826 mg, 1.01 mmol) in toluene (50 mL) was stirred at 100 °C for 16 hours under nitrogen. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with MeOH in 0 to 10% DCM) to obtain compound E1.1 (10.98 g). MS: Calculated value 626.3[(M+H)] + ]; Measured value 626.4[(M+H) + ].

[0147] Step (b): Preparation of 2-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-4-ol (intermediate E1) To a solution of 5-(2,4-ditert-butoxypyrimidine-5-yl)-3-[(1R)-1-[4-(5,5-dimethyl-1,3,2dioxaborinan-2-yl)-2-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound E1.1, 10.98 g, 17.6 mmol) in THF (183 mL), 30% hydrogen peroxide (20.3 g, 18.3 mL) and 3N NaOH (aqueous solution) (18.3 mL, 54.9 mmol) were added dropwise at 0°C. After stirring at room temperature for 16 hours, the reaction mixture was adjusted to pH 6 with 1N HCl (aqueous solution) and then extracted three times with DCM (300 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with MeOH / DCM from 0 to 10%) to obtain intermediate E1 (4.32 g). MS: Calculated value 530.2[(M+H)] + ]; Measured value 530.2[(M+H) + ].

[0148] Intermediate E2 2-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-4-ol [ka] Intermediate E2 was prepared in the same way as intermediate E1, by replacing 3-[(1R)-1-(4-bromo-2-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazine (intermediate D2) with 3-[(1R)-1-(4-bromo-2-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazine.

[0149] MS of (intermediate D4) in process (a): Calculated value 533.2 [(M+H)] + ]; Measured value 533.2[(M+H) + ].

[0150] Intermediate E3 5-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-2-fluorophenol [ka] The title compound was synthesized according to the following scheme: [ka]

[0151] Step (a): Preparation of 5-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-2-fluorophenol (intermediate E3) To a mixture of 3-[(1R)-1-(3-bromo-4-fluorophenyl)-2,2-difluoroethoxy]-5-(2,4-dittert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D1, 100 mg, 164.1 μmol) and potassium hydroxide (92.1 mg, 1.6 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (14.0 mg, 32.8 μmol) and tris(dibenzylideneacetone)dipalladium (30.1 mg, 32.8 μmol) were added. The mixture was stirred under nitrogen at 100°C for 1.5 hours. After cooling to room temperature, the reaction mixture was adjusted to approximately pH 6 with 1N HCl (aqueous solution), and then extracted three times with EA (10 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with EA / PE from 0 to 4 / 1) to obtain intermediate E3 (80.0 mg). Calculated value: 547.2 [(M+H)] + ]; Measured value 547.3 [(M+H) + ].

[0152] Example 1 5-[3-[(1R)-2,2-difluoro-1-[3-(2,2,2-trifluoroethoxy)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]

[0153] Step (a): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 1.1) To a solution of 3-[(1R)-1-(3-bromophenyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D3) (200.0 mg, 338.2 μmol) in 1,4-dioxane (1 mL), 4 Å MS (300 mg), 2,2,2-trifluoroethanol (125.2 mg, 90.0 μL, 1.3 mmol), N,N'-bis(2-phenylethyl)oxamide (11.0 mg, 37.2 μmol), t-BuONa (81.2 mg, 845.4 μmol), and CuI (6.4 mg, 33.8 μmol) were added. The resulting mixture was stirred at 90°C for 14 hours. After cooling to room temperature, the reaction mixture was quenched with H2O (10 mL) and extracted three times with EA (10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution with 0%-25% EA in PE, 24 g silica gel) to obtain compound 1.1 (183.7 mg). MS: Calculated value 611.2[(M+H)] + ]; Measured value 499.1[(M+3H-2tBu) + ].

[0154] Step (b): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 1) A mixture of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 1.1, 183.7 mg, 300.9 μmol) in methanol (1.5 mL) was mixed with HCl (2.0 M in MeOH, 0.4 mL, 0.8 mmol). The mixture was stirred at 22°C for 2 hours. The reaction mixture was concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 1 (20.4 mg). MS: Calculated value 499.1[(M+H)] + ]; Measured value 499.1[(M+H)+ ]. 1 H NMR(400MHz,DMSO-d6)δ=11.88-10.91(m,2H),8.63(s,1H),8.29(s,1H),7.33(t,J=7.9Hz,1H),7.26-7.18(m,2H),7.03 (dd,J=8.2,2.1Hz,1H),6.52(td,J=54.0,4.0Hz,1H),6.11(td,J=10.6,3.0Hz,1H),4.70(q,J=8.8Hz,2H),3.95(s,3H).

[0155] Example 2 5-[3-[(1R)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0156] Preparation of 2-(chloromethyl)pyridine-4-carboxylate methyl (compound 2.2) To a solution of methyl 2-methylol isonicotinate (compound 2.1, 910 mg, 5.44 mmol) in DCM (20 mL), thionyl chloride (471.02 μL, 6.53 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 0.5 hours. The reaction mixture was concentrated to obtain compound 2.2 (1.0 g), which was used directly in the next step.

[0157] Step (b): Preparation of 2-(cyclopropoxymethyl)pyridine-4-carboxylic acid (compound 2.3) NaH (60% dispersion in mineral oil, 474.11 mg, 11.85 mmol) was added at 0°C to a solution of cyclopropanol (469.37 mg, 8.08 mmol) in DMF (10 mL). The reaction mixture was stirred at the same temperature for 0.5 hours, then 2-(chloromethyl)pyridine-4-carboxylate (compound 2.2, 1000 mg, 5.39 mmol) was added, and the resulting mixture was stirred at room temperature for a further 12 hours. The reaction mixture was acidified to approximately pH 6 with 2N HCl, and then extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 12 g, eluted with 0%-8% methanol in DCM) to obtain compound 2.3 (360 mg). MS: Calculated value 194.1[(M+H)] + ]; Measured value 194.1 [(M+H) + ].

[0158] Step (c): Preparation of 2-(cyclopropoxymethyl)-N-methoxy-N-methylpyridine-4-carboxamide (compound 2.4) HATU (779.35 mg, 2.05 mmol) was added to a solution of 2-(cyclopropoxymethyl)pyridine-4-carboxylic acid (compound 2.3, 360 mg, 1.86 mmol) and DIEA (963.28 mg, 1.3 mL, 7.45 mmol) in dichloromethane (8 mL). The reaction mixture was stirred at room temperature for 0.5 hours, then N-methoxymethanamine hydrochloride (218.1 mg, 2.24 mmol) was added. The resulting mixture was stirred at 20°C for 16 hours, then quenched with water (5 mL), and extracted three times with DCM (10 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, 12 g, elution at 0%~50% EA in PE) to obtain compound 2.4 (300 mg). MS: Calculated value 237.1[(M+H)] + ]; Measured value 237.1 [(M+H) + ].

[0159] Step (d): Preparation of 1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoro-ethanone (compound 2.5) Potassium tert-butoxide (296.83 mg, 2.65 mmol) was added at -10°C to a solution of 2-(cyclopropoxymethyl)-N-methoxy-N-methylpyridine-4-carboxamide (compound 2.4, 250 mg, 1.06 mmol) and difluoromethyltrimethylsilane (262.83 mg, 2.12 mmol) in THF (2.5 mL), and the resulting mixture was stirred at the same temperature for a further 1 hour. The reaction mixture was quenched with saturated aqueous solution NH4Cl (2 mL) and extracted three times with EA (10 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 10-70% EA in silica gel, PE) to obtain compound 2.5 (150 mg). MS: Calculated value 228.1[(M+H)] + ]; Measured value 246.1[(M+H2O+H) + ].

[0160] Step (e): Preparation of (1S)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethanol (compound 2.6) To a solution of 1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoro-ethanone (compound 2.5, 150 mg, 660.18 μmol) in DCM (4 mL), formic acid (911.65 mg, 759.7 μL, 19.81 mmol) and triethylamine (801.65 mg, 1.1 mL, 7.92 mmol) were added. Then, RuCl(p-cymene)[(R,R)-Ts-DPEN] (84.0 mg, 132.04 μmol) was added, and the mixture was stirred at 20°C for 1 hour. The resulting organic layer was concentrated, and the residue was purified by flash chromatography (elution in silica gel, PE at 0-40% EA) to obtain compound 2.6 (145 mg). MS: Calculated value 230.1[(M+H)] + ]; Measured value 230.0 [(M+H) + ].

[0161] Step (f): Preparation of 3-[(1R)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (compound 2.7) (1S)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethanol in toluene (3.8 mL) (Compound 2.6, 145 mg, 632.58 μmol) was added dropwise to a suspension of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine-3-ol (intermediate B1, 190 mg, 510.18 μmol) and triphenylphosphine (160.58 mg, 612.21 μmol) to which DIAD (106.62 mg, 612.21 μmol) was added dropwise. The resulting mixture The mixture was stirred under nitrogen at 60°C for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted three times with EA (30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0%-45% EA in PE, 40 g silica gel) to obtain compound 2.7 (60 mg). MS: Calculated value 584.3 [(M+H)] + ]; Measured value 584.5 [(M+H) + ].

[0162] Step (g): Preparation of 5-[3-[(1R)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 2) A mixture of 3-[(1R)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (compound 2.7, 60 mg, 102.8 μmol) in methanol (1 mL) was mixed with 2 M HCl (154.21 μL, 308.42 μmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 2 (37.9 mg). MS: Calculated value 472.1[(M+H)] + ]; Measured value 472.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.6Hz,1H),11.47(br d,J=6.1Hz,1H),8.73(s,1H),8.61(d,J=5.3Hz,1H),8.38(d,J=6.3Hz,1H),7.69(s,1H),7.60(br d,J=5.0Hz,1H),6.66(td,J=53.7,2.5Hz,1H),6.34(td,J=11.9,2.1Hz,1H),4.64(s,2H),4.01(s,3H),3.46-3.38(m,1H),0.58-0.41(m,4H).

[0163] Example 3 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2,2,2-trifluoroethoxy)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]

[0164] Step (a): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 3.1) Potassium carbonate (40.5 mg, 292.8 μmol) was added to a mixture of 5-[(1R)-1-[5-(2,4-dittert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-2-fluorophenol (intermediate E3, 80 mg, 146.4 μmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (40.8 mg, 175.7 μmol) in DMF (2 mL). The mixture was stirred at room temperature for 16 hours. The reaction product was quenched with H2O (3 mL) and extracted three times with EA (10 mL). The combined organic layer was washed three times with H2O (5 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 3 / 1) to obtain compound 3.1 (72.0 mg). Calculated value: 629.2 [(M+H)] + ]; Measured value 629.4[(M+H) + ].

[0165] Step (b): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 3) To a solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 3.1, 72 mg, 114.6 μmol) in methanol (0.5 mL), 2N HCl (aqueous solution) (171.8 μL, 343.6 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 3 (25.7 mg). Calculated value: 517.1[(M+H)] + ]; Measured value 517.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(s,1H),11.45(br d,J=5.4Hz,1H),8.70(s,1H),8.37(d,J=6.1Hz,1H),7.57(d,J=7.9Hz,1H),7.39-7.28(m,2H) ,6.59(td,J=54.4,3.5Hz,1H),6.16(dt,J=3.4,11.1Hz,1H),4.93-4.81(m,2H),4.03(s,3H).

[0166] Example 4 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-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]

[0167] Step (a): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 4.1) A mixture of 2-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-4-ol (intermediate E1, 400 mg, 0.76 mmol) in DMF (10 mL), 2,2,2-trifluoroethyltrifluoromethanesulfonate (193 mg, 0.83 mmol), and potassium carbonate (209 mg, 1.51 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted twice with EA (100 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with EA in PE from 0 to 40%) to obtain compound 4.1 (360 mg). MS: Calculated value 612.2 [(M+H) + ]; Measured value 612.3 [(M+H) + ].

[0168] Step (b): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 4) To a solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 4.1, 176 mg, 0.29 mmol) in DCM (6 mL), TFA (0.2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 4 (37.9 mg). MS: Calculated value 500.1[(M+H)] + ]; Measured value 500.1 [(M+H)+ ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(s,1H),11.45(brd,J=4.8Hz,1H),8.70(d,J=2.0Hz,1H),8.53(d,J=5.8Hz,1H),8.37(d,J=6.3Hz,1H),7.36 (s,1H),7.16(dd,J=5.8,2.5Hz,1H),6.69(td,J=54.3,3.8Hz,1H),6.17(ddd,J=14.4,8.1,3.5Hz,1H),4.93(q,J=8.8Hz,2H),4.02(s,3H).

[0169] Example 5 5-[3-[(1R)-1-[4-(1,1-dijuterio-2,2,2-trifluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0170] Step (a): Preparation of (1,1-diduterio-2,2,2-trifluoro-ethyl)trifluoromethanesulfonate (compound 5.2) To a solution of 1,1-diduterio-1-duteriooxy-2,2,2-trifluoroethane (compound 5.1, 1.19 g, 11.6 mmol) and pyridine (0.98 mL, 12.1 mmol) in DCM (20 mL), trifluoromethanesulfonic anhydride (3.26 g, 11.6 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hour, then washed twice with water (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate (solution of compound 5.2 in DCM) was used directly in the next step.

[0171] Step (b): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-1-[4-(1,1-diduterio-2,2,2-trifluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine (compound 5.3) A mixture of 2-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-4-ol (intermediate E1, 160 mg, 0.300 mmol), (1,1-diduterio-2,2,2-trifluoroethyl)trifluoromethanesulfonate (compound 5.2, 4 mL, approximately 0.6 M solution in DCM), and potassium carbonate (83.5 mg, 0.600 mmol) in DMF (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted twice with EA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution at 0% to 40% EA in PE) to obtain compound 5.3 (180 mg). MS: Calculated value 614.2[(M+H)] + ]; Measured value 614.3 [(M+H) + ].

[0172] Step (c): Preparation of 5-[3-[(1R)-1-[4-(1,1-diduterio-2,2,2-trifluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 5) To a solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-1-[4-(1,1-diduterio-2,2,2-trifluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 5.3, 180 mg, 0.29 mmol) in DCM (6 mL), TFA (0.2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 5 (35 mg). MS: Calculated value 502.1[(M+H)] + ]; Measured value 502.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(s,1H),11.45(brd,J=4.8Hz,1H),8.71(d,J=2.0Hz,1H),8.54(d,J=5.8Hz,1H),8.37(dd,J=6.1,1. 4Hz,1H),7.36(s,1H),7.16(dd,J=5.8,2.5Hz,1H),6.70(td,J=53.8,3.8Hz,1H),6.18(ddd,J=14.4,8.1,3.5Hz,1H),4.02(s,3H).

[0173] Example 6 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 6 was prepared in the same manner as Example 4, by replacing 2-[(1R)-1-[5-(2,4-dittert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoro-ethyl]pyridine-4-ol (intermediate E1) with 2-[(1R)-1-[5-(2,4-dittert-butoxypyrimidine-5-yl)-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoro-ethyl]pyridine-4-ol (intermediate E2) in step (a). Calculated value 503.1[(M+H) + ]; Measured value 503.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.07(br s,2H),8.71(s,1H),8.54(d,J=5.5Hz,1H),8.38(s,1H),7.36(d,J=2.3Hz,1H),7.17(dd,J=5.6,2. 4Hz, 1H), 6.70 (td, J = 54.3, 4.3Hz, 1H), 6.18 (ddd, J = 14.5, 7.9, 3.1Hz, 1H), 4.93 (q, J = 8.7Hz, 2H).

[0174] Example 7 5-[3-[(1R)-1-[4-(2,2-difluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 7 was prepared in the same manner as Example 4, by replacing 2,2,2-trifluoroethyltrifluoromethanesulfonate with 2-bromo-1,1-difluoroethane in step (a). MS: Calculated value 482.1[(M+H)] + ]; Measured value 482.2 [(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ=11.55(s,1H),11.45(brd,J=4.8Hz,1H),8.71(s,1H) ,8.50(d,J=5.5Hz,1H),8.37(d,J=6.3Hz,1H),7.30(d,J=2.5Hz,1H),7.12(dd, J=5.8,2.5Hz,1H),6.70(td,J=53.5,3.8Hz,1H),6.39(td,J=54.3,3.8Hz,1H), 6.17(ddd,J=14.2,7.8,3.3Hz,1H),4.46(td,J=14.7,3.1Hz,2H),4.03(s,3H).

[0175] Examples 8A and 8B 5-[3-[(1R)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-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-(2,2,2-trifluoroethoxy)-3-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]

[0176] Step (a): Preparation of 5-(2,2,2-trifluoroethoxy)pyridine-3-carbaldehyde (compound 8.2) 5-hydroxypyridine-3-carbaldehyde (compound 8.1, 1 g, 8.1 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (2.3 g, 1.4 mL, 9.8 mmol) were added to a solution of DMF (30 mL) and cesium carbonate (4.0 g, 974.9 μL, 12.2 mmol). The resulting mixture was stirred at 20°C for 16 hours, then quenched with H2O (100 mL) and extracted three times with EA (20 mL). The combined organic layer was washed three times with H2O (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 1 / 3) to obtain compound 8.2 (1.76 g). Calculated value 206.0[(M+H)+]; measured value 206.0[(M+H)+].

[0177] Step (b): Preparation of 2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethanol (compound 8.3) Cesium fluoride (148.1 mg, 975.0 μmol) was added to a solution of 5-(2,2,2-trifluoroethoxy)pyridine-3-carbaldehyde (compound 8.2, 1 g, 4.87 mmol) and (difluoromethyl)trimethylsilane (1.2 g, 1.4 mL, 9.8 mmol) in DMF (8 mL). The resulting mixture was stirred under nitrogen at room temperature for 16 hours. The reaction mixture was quenched with H₂O (50 mL) and extracted three times with EA (50 mL). The combined organic layer was washed three times with H₂O (30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with DCM / methanol from 0 / 1 to 30 / 1) to obtain compound 8.3 (1.76 g). Calculated value 258.0 [(M+H) + ]; Measured value 257.9 [(M+H) + ].

[0178] Step (c): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 8.4). To a suspension of 2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethanol (compound 8.3, 298.3 mg, 1.2 mmol), 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-ol (intermediate B1, 360.0 mg, 966.7 μmol), and triphenylphosphine (316.9 mg, 1.2 mmol) in toluene (8 mL), DEAD (210.4 mg, 190.3 μL, 1.2 mmol) was added dropwise at room temperature. The mixture was then stirred under nitrogen at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted three times with EA (50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 1 / 2) to obtain compound 8.4 (160 mg). Calculated value: 612.2 [(M+H)] + ]; Measured value 612.2[(M+H) + ].

[0179] Step (d): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(11R)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine and 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(11S)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compounds 8.4A and 8.4B) Compound 8.4 (700.0 mg) was separated by SFC to obtain two single isomers: Compound 8.4A (faster elution, 60.0 mg) MS: Calculated value 612.2 [(M+H)] + ]; Measured value 612.2[(M+H) + ]; and compound 8.4B (slower elution, 50.0 mg) MS: calculated value 612.2 [(M+H) + ]; Measured value 612.2[(M+H) +SFC conditions: Column: (S,S)whelk-o1, inner diameter 250×30mm, 5μm, mobile phase: CO2 A and ethanol (0.1%NH3H2O) B; gradient: B 30%, flow rate: 80mL / min, back pressure: 100bar, column temperature: 35℃.

[0180] Step (e): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-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-(2,2,2-trifluoroethoxy)-3-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 8A and 8B) To a solution of compound 8.4A (60 mg, 98.1 μmol) in methanol (500 μL), 2N HCl (aqueous solution) (245.3 μL, 490.6 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 8A (16.0 mg). Calculated value: 500.1 [(M+H)] + ]; Measured value 500.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(d,J=1.4Hz,1H),11.45(brd,J=6.1Hz,1H),8.71(s,1H),8.53(s,1H),8.46(d,J=2.8Hz,1H),8.36( d,J=6.1Hz,1H),7.79(brs,1H),6.68(td,J=54.03,3.13Hz,1H),6.29(dt,J=3.2,11.4Hz,1H),4.92(q,J=8.8Hz,2H),4.03(s,3H).

[0181] To a solution of compound 8.4B (50 mg, 81.8 μmol) in methanol (400 μL), 2N HCl (aqueous solution) (204.4 μL, 409.0 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 8B (23.0 mg). Calculated value: 500.1 [(M+H)] + ]; Measured value 500.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(d,J=1.5Hz,1H),11.46(brd,J=5.5Hz,1H),8.71(s,1H),8.54(s,1H),8.48(d,J=2.6Hz,1H),8.37(d,J =6.1Hz,1H),7.81(d,J=1.8Hz,1H),6.68(td,J=54.16,3.00Hz,1H),6.30(dt,J=3.2,11.3Hz,1H),4.92(q,J=8.8Hz,2H),4.03(s,3H).

[0182] Examples 9A and 9B 5-[3-[(1R)-2,2-difluoro-1-[5-fluoro-4-(2,2,2-trifluoroethoxy)-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-4-(2,2,2-trifluoroethoxy)-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]

[0183] Step (a): Preparation of 2-bromo-5-fluoro-4-(2,2,2-trifluoroethoxy)pyridine (compound 9.2) A mixture of 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.81 g, 7.81 mmol), 2-bromo-5-fluoropyridine-4-ol (compound 9.1, 0.50 g, 2.6 mmol), and potassium carbonate (0.72 g, 5.21 mmol) in DMF (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was quenched with water (100 mL) and extracted three times with EA (150 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 5%-20% EA in PE) to obtain compound 9.2 (617 mg). MS: Calculated values ​​273.9, 275.9 [(M+H)] + ]; Measured value 274.0, 274.0 [(M+H) + ]. 1 ¹H NMR (400MHz, chloroform-d): δ 8.23 ​​(d, J=2.6Hz, 1H), 7.11 (d, J=6.0Hz, 1H), 4.52 (q, J=7.7Hz, 2H).

[0184] Step (b): Preparation of 2,2-difluoro-1-[5-fluoro-4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethanone (compound 9.3) A solution of (CH3)2CHMgCl·LiCl (1.3 M, 5.03 mL, 6.54 mmol in THF) in dry THF (8 mL) was added dropwise to a solution of 2-bromo-5-fluoro-4-(2,2,2-trifluoroethoxy)pyridine (compound 9.2 mg, 597 mg, 2.18 mmol) in dry THF (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours, after which a solution of 2,2-difluoro-N-methoxy-N-methylacetamide (909.19 mg, 6.54 mmol, 3.0 equivalents) in anhydrous THF (4 mL) was added dropwise. The resulting mixture was stirred at room temperature for a further 2 hours, then quenched with saturated aqueous ammonium chloride (100 mL), and extracted three times with EA (200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (elution at 5%-20% EA in PE) to obtain compound 9.3 (503 mg). MS: Calculated value 274.0[(M+H)] +]; Measured value 292.0 [(M+H+18) + ].

[0185] Step (c): Preparation of 2,2-difluoro-1-[5-fluoro-4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethanol (compound 9.4) To a solution of 2,2-difluoro-1-[5-fluoro-4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethanone (compound 9.3, 200.0 mg, 0.73 mmol) in MeOH (2.5 mL), NaBH4 (55.5 mg, 1.46 mmol) was added. The resulting mixture was stirred at 0°C for 2 hours, then diluted with saturated aqueous NaHCO3 (20 mL), and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution with 0%~100% EA in PE, on silica gel, 20 g) to obtain compound 9.4 (170.0 mg). MS: Calculated value 276.0 [(M+H)] + ]; Measured value 276.0[(M+H) + ].

[0186] Step (d): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[5-fluoro-4-(2,2,2-trifluoroethoxy)-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-4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 9A and 9B) Examples 9A and 9B were prepared in the same manner as Examples 8A and 8B, except that in step (c), 2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethanol (compound 8.3) was replaced with 2,2-difluoro-1-[5-fluoro-4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethanol (compound 9.4).

[0187] Example 9A MS: Calculated value 518.1[(M+H)] + ]; Measured value 518.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(d,J=1.6Hz,1H),11.46(brd,J=6.1Hz,1H),8.71(s,1H),8.61(d,J=2.8Hz,1H),8.38(d,J=6.1H) z,1H),7.69(d,J=6.8Hz,1H),6.68(dt,J=4.4,53.4Hz,1H),6.15(ddd,J=3.6,8.9,13.1Hz,1H),5.10-5.01(m,2H),4.03(s,3H).

[0188] Example 9 BMS: Calculated value 518.1 [(M+H)] + ]; Measured value 518.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(d,J=1.6Hz,1H),11.46(brd,J=5.3Hz,1H),8.71(s,1H),8.61(d,J=2.9Hz,1H),8.38(d ,J=6.1Hz,1H),7.69(d,J=6.9Hz,1H),6.68(dt,J=3.4,53.5Hz,1H),6.21-6.09(m,1H),5.05-5.01(m,2H),4.03(s,3H).

[0189] Example 10 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-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]

[0190] Step (a): Preparation of 2-chloro-N-methoxy-N-methylpyridine-4-carboxamide (compound 10.2) HATU (26.55 g, 69.82 mmol) was added to a suspension of 2-chloropyridine-4-carboxylic acid (compound 10.1, 10 g, 63.47 mmol) and Et3N (17.69 mL, 126.94 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 30 minutes, then N,O-dimethylhydroxylamine hydrochloride (6.81 g, 69.82 mmol) was added. The resulting mixture was stirred at room temperature for a further 1 hour, then quenched with saturated aqueous NaHCO3 (300 mL), and extracted three times with DCM (100 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, 220 g, eluted at 10%-40% EA in PE) to obtain compound 10.2 (12.3 g). MS: Calculated value 201.1[(M+H)] + ]; Measured value 201.1[(M+H) + ].

[0191] Step (b): Preparation of N-methoxy-N-methyl-2-(2,2,2-trifluoroethoxy)pyridine-4-carboxamide (compound 10.3) To a solution of 2,2,2-trifluoroethanol (1.39 g, 13.9 mmol) in DMF (20 mL), NaH (60% dispersion in mineral oil, 598.2 mg, 14.95 mmol) was added at 0°C. The reaction mixture was stirred at the same temperature for 0.5 hours, then 2-chloro-N-methoxy-N-methylpyridine-4-carboxamide (compound 10.2, 2 g, 9.97 mmol) was added, and the resulting mixture was stirred at 60°C for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous NaCl (50 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 10%-35% EA in PE, 45 g silica gel) to obtain compound 10.3 (982.8 mg). MS: Calculated value 265.1[(M+H)] + ]; Measured value 265.1 [(M+H) + ].

[0192] Step (c): Preparation of 2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethanone (compound 10.4) Potassium tert-butoxide (330.9 mg, 2.95 mmol) was added at room temperature to a solution of N-methoxy-N-methyl-2-(2,2,2-trifluoroethoxy)pyridine-4-carboxamide (compound 10.3, 708.3 mg, 2.68 mmol) and difluoromethyltrimethylsilane (613.9 mg, 4.94 mmol) in THF (10 mL). The resulting mixture was stirred at the same temperature for a further 2 hours. The reaction mixture was quenched with saturated aqueous NaCl (50 mL) and extracted three times with EA (20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0%~30% EA in PE, on silica gel, 24 g) to obtain compound 10.4 (397.2 mg). MS: Calculated value 256.0[(M+H)] + ]; Measured value 256.0[(M+H) + ].

[0193] Step (d): Preparation of (1S)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethanol (compound 10.5) To a solution of 2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethanone (compound 10.4, 4.79 g, 18.77 mmol) in DCM (20 mL), formic acid (7 mL, 182.49 mmol) and triethylamine (10 mL, 71.75 mmol) were added at -20°C. Then, RuCl(p-cymene)[(R,R)-Ts-DPEN] (477.8 mg, 750.9 μmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 (200 mL) and extracted twice with DCM (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution at 10%-35% EA in PE, on silica gel, 45 g) to obtain compound 10.5 (4.3 g). MS: Calculated value 258.0 [(M+H) + ]; Measured value 258.0[(M+H) + ].

[0194] Step (e): 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 10) Example 10 was prepared in the same manner as in Example 2, by replacing (1S)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethanol (compound 2.6) with (1S)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethanol (compound 10.5) in step (f). MS: Calculated value 500.1[(M+H) + ]; Measured value 500.0 [(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.6Hz,1H),11.49-11.40(m,1H),8.72(s,1H),8.37(d,J=6.1Hz,1H),8.26(d,J=5.5Hz,1H ),7.37-7.31(m,1H),7.21(s,1H),6.64(dt,J=2.9,53.7Hz,1H),6.30(dt,J=2.5,11.3Hz,1H),5.07-4.94(m,2H),4.02(s,3H).

[0195] Examples 11A and 11B 5-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-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]

[0196] Step (a): Preparation of 2-(2,2-difluoroethoxy)pyridine-4-carboxylate methyl (compound 11.2) To a solution of 2,2-difluoroethanol (3.7 g, 44.9 mmol) in DMF (35 mL), sodium hydride (60% dispersion in mineral oil, 2.61 g, 65.3 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then a solution of methyl 2-chloropyridine-4-carboxylate (compound 11.1, 7 g, 40.8 mmol) in DMF (10 mL) was added. The resulting mixture was stirred at 20°C for 16 hours, then quenched with H₂O (200 mL), and extracted three times with EA (60 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 20 / 1) to obtain compound 11.2 (5.8 g). Calculated value: 218.1[(M+H)] + ]; Measured value 218.0 [(M+H) + ].

[0197] Step (b): Preparation of [2-(2,2-difluoroethoxy)-4-pyridyl]methanol (compound 11.3). A solution of methyl 2-(2,2-difluoroethoxy)pyridine-4-carboxylate (compound 11.2, 5.8 g, 26.7 mmol) in 20 mL of THF was mixed dropwise with a suspension of LiAlH4 (709.5 mg, 18.7 mmol) in tetrahydrofuran (50 mL) at 0°C. The resulting mixture was stirred at the same temperature for 30 minutes, then diluted with ethyl acetate (60 mL). 40 g of Na2SO4 was added to the mixture while vigorously stirring, followed by the addition of 1 mL of H2O. The resulting mixture was filtered through Celite, washed twice with ethyl acetate (60 mL), and the filtrate was concentrated. The residue was purified by silica gel chromatography (eluting with PE / EA from 1 / 10 to 1 / 1) to obtain compound 11.3 (3.5 g). Calculated value: 190.1[(M+H)] + ]; Measured value 190.0 [(M+H) + ].

[0198] Step (c): Preparation of 2-(2,2-difluoroethoxy)pyridine-4-carbaldehyde (compound 11.4). To a solution of [2-(2,2-difluoroethoxy)-4-pyridyl]methanol (compound 11.3, 3.5 g, 18.5 mmol) in DCM (40 mL), DMP (15.7 g, 37.0 mmol) was added in small increments. The resulting mixture was stirred at 0°C for 1 hour. The reaction was then quenched with saturated aqueous NaHCO3 solution and saturated aqueous Na2S2O3 (150 mL each). After stirring at room temperature for 0.5 hours, the mixture was extracted three times with DCM (150 mL). The combined organic layer was concentrated. The residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 50 / 1) to obtain compound 11.4 (3.3 g). Calculated value 188.0[(M+H)] + ]; Measured value 188.0 [(M+H) + ].

[0199] Step (d): Preparation of 1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethanol (compound 11.5). A solution of 2-(2,2-difluoroethoxy)pyridine-4-carbaldehyde (compound 11.4, 3.3 g, 17.4 mmol) and difluoromethyl-trimethyl-silane (4.3 g, 34.8 mmol) in DMF (10 mL) was mixed with TBAF (1 M in THF, 8.7 mL, 8.7 mmol) at 0°C. After stirring at 20°C for 1 hour, the reaction mixture was quenched with H₂O (40 mL) and extracted three times with EA (60 mL). The combined organic layer was washed seven times with H₂O (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 2 / 1) to obtain compound 11.5 (2 g). Calculated value: 240.1 [(M+H)] + ]; Measured value 239.9 [(M+H) + ].

[0200] Step (c): Preparation of 5-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 11A and 11B) Examples 11A and 11B were prepared in the same manner as Examples 8A and 8B, by replacing 2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethanol (compound 8.3) with 1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethanol (compound 11.5) in step (c).

[0201] Example 11A, calculated value 482.1[(M+H) + ]; Measured value 482.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(s,1H),11.43-11.52(m,1H),8.72(s,1H),8.37(d,J=6.25Hz,1H),8.24(d,J=5.38Hz,1H),7.28(d,J=5.25Hz, 1H),7.14(s,1H),6.64(td,J=53.8,2.8Hz,1H),6.38(tt,J=54.7,3.5H z,1H),6.25-6.33(m,1H),4.56(td,J=15.01,3.50Hz,2H),4.02(s,3H).

[0202] Example 11B, calculated value 482.1[(M+H) + ]; Measured value 482.0 [(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.63Hz,1H),11.42-11.49(m,1H),8.7 2(s,1H),)8.37(d,J=6.13Hz,1H),8.23(d,J=5.38Hz,1H),7.28(dd,J=5.32 ,1.06Hz,1H),7.14(s,1H),6.63(td,J=53.8,2.8Hz,1H),6.38(tt,J=54.7, 3.4Hz, 1H), 6.25-6.33 (m, 1H), 4.56 (td, J=15.04, 3.44Hz, 2H), 4.02 (s, 3H).

[0203] Example 12 6-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4triazine-3,5-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0204] Step (a): Preparation of 6-trimethylstanyl-2H-1,2,4-triazine-3,5-dione (compound 12.2) To a solution of 5-bromo-6-azauracil (compound 12.1, 600 mg, 3.13 mmol) in 1,4-dioxane (10 mL), 1,1,1,2,2,2-hexamethyldistannan (1024 mg, 3.13 mmol) and Pd(PPh3)4 (180 mg, 0.16 mmol) were added. The resulting mixture was stirred at 100°C for 6 hours under a nitrogen atmosphere, cooled to room temperature, and the reaction mixture was diluted with water (50 mL) and extracted three times with EA (100 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (eluting with 0-60% EA in silica gel PE) to obtain compound 12.2 (706 mg).1 H NMR (400MHz, DMSO-d6) δ = 12.44 (s, 1H), 11.67 (s, 1H), 0.26 (s, 9H).

[0205] Step (b): Preparation of 5-chloro-3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 12.3) (1S)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethanol (compound 10.5, 10.3 g, 40.2 mmol) in toluene (78 mL), 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine-3-ol (intermediate A1, 3.9 g, 21.1 mmol), and triphenylphosphine (6.7 g, 25.4 mmol) were suspended, to which DEAD (4.4 g, 4.0 mL, 25.4 mmol) was added dropwise at 60°C. After stirring under nitrogen at 60°C for 0.5 hours, the reaction mixture was concentrated, and the residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 7 / 1) to obtain compound 12.3 (8.6 g). Calculated value: 424.1 [(M+H)] + ]; Measured value 424.0 [(M+H) + ].

[0206] Step (c): Preparation of 6-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4-triazine-3,5-dione (Example 12) In a degassed vial, 5-chloro-3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 12.3, 4.6 g, 10.86 mmol) and 6-trimethylstanyl-2H-1,2,4-triazine-3,5-dione (compound 12.2, 6.0 g, 21.7 mmol) were added in DMF (46 mL). Chlohexyl[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (253.3 mg, 542.8 μmol), methanesulfonate(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(ii) (453.9 mg, 542.8 μmol), and anhydrous zinc chloride (2.2 g, 16.3 mmol) were added. The resulting mixture was stirred under nitrogen at 100°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous solution KF (50 mL), stirred for 30 minutes, and then filtered through Celite. The filtrate was extracted three times with EA (500 mL). The combined organic layers were washed three times with H2O (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (elution with DCM / MeOH from 0 / 1 to 12 / 1), and further purified by Prep-HPLC to obtain Example 12 (2.6 g). Calculated value: 501.1[(M+H)] + ]; Measured value 501.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.42(br s,2H),8.53(s,1H),8.26(d,J=5.38Hz,1H),7.34(dd,J=5.25,0.88Hz,1H),7.22(s,1H) ),6.65(td,J=53.66,2.75Hz,1H),6.28-6.40(m,1H),4.89-5.08(m,2H),4.06(s,3H).

[0207] Examples 13A and 13B 6-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4triazine-3,5-dione and 6-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4triazine-3,5-dione [ka] The title compound was synthesized according to the following scheme. [ka]

[0208] Step (a): Preparation of 5-chloro-3-[1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 13.1) To a solution of 1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethanol (compound 11.5, 615.5 mg, 2.6 mmol) in toluene (5 mL), 5-chloro-1-methyl-pyrazolo[3,4-c]pyridazine-3-ol (intermediate A1, 250 mg, 1.4 mmol), and triphenylphosphine (426.3 mg, 1.6 mmol), DEAD (283.1 mg, 255.9 μL, 1.6 mmol) was added dropwise at 60°C. After stirring under nitrogen at 60°C for 0.5 hours, the reaction mixture was concentrated, and the residue was purified by silica gel chromatography (eluting with PE / EA from 0 / 1 to 5 / 1) to obtain compound 13.1 (220 mg). Calculated value: 406.1 [(M+H)] + ]; Measured value 405.9 [(M+H) + ].

[0209] Step (b): Preparation of 6-[3-[1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4-triazine-3,5-dione (compound 13.2) In a degassed vial, 5-chloro-3-[1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine (compound 13.1, 220 mg, 542.2 μmol) and 6-trimethylstanyl-2H-1,2,4-triazine-3,5-dione (compound 12.2, 299.2 mg, 1.1 mmol) are added in DMF (2.5 mL), and dicyclo Hexyl[2-(2,6-diisopropoxyphenyl)phenyl]phosphan (50.6 mg, 108.5 μmol), methanesulfonate(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(ii) (90.7 mg, 108.5 μmol), and zinc chloride (110.9 mg, 813.4 μmol) were added. After stirring under nitrogen at 100°C for 16 hours, the mixture was concentrated. The residue was purified by preparative HPLC to obtain compound 13.2 (100 mg). Calculated value: 483.1 [(M+H)] + ]; Measured value 483.0 [(M+H) + ].

[0210] Step (c): Preparation of 6-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4-triazine-3,5-dione and 6-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4-triazine-3,5-dione (Examples 13A and 13B)

[0211] Compound 13.2 (100.0 mg) was split by SFC to obtain two single isomers: Example 13A (faster elution, 30.8 mg) MS: Calculated value 483.1 [(M+H)] + ]; Measured value 483.0 [(M+H) + ]. 1 ¹H NMR (400MHz, DMSO-d6) δ=11.79 (br s, 2H), 8.53 (s, 1H), 8.24 (d, J=5.19Hz, 1H), 7.29 (dd, J=5.34, 1.07Hz, 1H), 7.15 (s, 1H), 6.64 (td, J=53.56, 2.75Hz, 1H), 6.38 (tt, J=54.6, 3.7Hz, 1H), 6.29-6.37 (m, 1H), 4.51-4.61 (m, 2H), 4.07 (s, 3H). ; and Example 13B (slower elution, 33.2mg) Calculated value 483.1 [(M+H)] + ]; Measured value 483.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=12.18(br s,2H),8.53(s,1H),8.24(d,J=5.19Hz,1H),7.29(d,J=5.34Hz,1H),7.15(s,1H),6.64(td,J=53. 71,2.75Hz,1H),6.38(tt,J=54.9,3.5Hz,1H),6.29-6.36(m,1H),4.47-4.65(m,2H),4.07(s,3H). SFC conditions: Column: (S,S)whelk-o1, inner diameter 250×30mm, 5μm, mobile phase: CO2 (A), ethanol (0.1%NH3H2O) (B); gradient: B30%, flow rate: 80mL / min, back pressure: 100bar, column temperature: 35℃.

[0212] Examples 14A and 14B 5-[1-methyl-3-[(1S)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[1-methyl-3-[(1R)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-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]

[0213] Step (a): Preparation of 6-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (compound 14.2) To a solution of 6-chloro-4-pyrimidinecarboxylic acid (compound 14.1, 3.0 g, 18.9 mmol) in DCM (60 mL), N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.8 mmol), HATU (7.9 g, 20.8 mmol), and Et3N (3.6 g, 5.0 mL, 35.9 mmol) were added. The resulting mixture was stirred under nitrogen at room temperature for 2 hours. The reaction mixture was diluted with saturated NaHCO3 (200 mL) and extracted three times with DCM (200 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 120 g, eluted at 0%~50% EA in PE) to obtain compound 14.2 (2.4 g). MS: Calculated value 202.0[(M+H)] + ]; Measured value 202.0 [(M+H) + ].

[0214] Step (b): Preparation of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)pyrimidine-4-carboxamide (compound 14.3) To a solution of 6-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (compound 14.2, 1.7 g, 8.5 mmol) in DMF (15 mL), TFE (2.8 g, 2.0 mL, 27.8 mmol) and K2CO3 (2.3 g, 17.0 mmol) were added. The resulting mixture was stirred at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (100 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution with 0%~30% EA in PE, on silica gel, 45 g) to obtain compound 14.3 (1.9 g). MS: Calculated value 266.1[(M+H)] + ]; Measured value 265.9 [(M+H) + ].

[0215] Step (c): Preparation of 1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanone (compound 14.4) A solution of N-methoxy-N-methyl-6-(2,2,2-trifluoroethoxy)pyrimidine-4-carboxamide (compound 14.3, 971.4 mg, 3.7 mmol) in THF (15 mL) was mixed with MeMgBr (1.0 M in THF, 5.0 mL, 5.0 mmol). The resulting mixture was stirred at -78°C for 1 hour. The reaction mixture was diluted with saturated aqueous solution NH4Cl (20 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution with 0%-25% EA in PE, 24 g silica gel) to obtain compound 14.4 (476.6 mg). MS: Calculated value 221.1[(M+H)] + ]; Measured value 221.0 [(M+H) + ].

[0216] Step (d): Preparation of 1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanol (compound 14.5) A solution of 1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanone (compound 14.4, 230.0 mg, 1.0 mmol) in MeOH (2.5 mL) was mixed with NaBH4 (79.1 mg, 2.1 mmol). The resulting mixture was stirred at 0°C for 30 minutes, then diluted with saturated NaHCO3 aqueous solution (20 mL), and extracted three times with EA (20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 12 g, eluted with 0%~35% EA in PE) to obtain compound 14.5 (225.0 mg). MS: Calculated value 223.1[(M+H)] + ]; Measured value 223.0 [(M+H) + ].

[0217] Step (e): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-3-[1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazine (compound 14.6) To a solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-ol (intermediate B, 500.0 mg, 1.3 mmol) in toluene (10 mL), 1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanol (compound 14.5, 387.8 mg, 1.8 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 hour. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution in silica gel at 0% to 35% EA in PE) to obtain compound 14.6 (700.0 mg). MS: Calculated value 577.2 [(M+H)] + ]; Measured value 577.3 [(M+H) + ].

[0218] Step (f): Preparation of 5-(2,4-di-tert--thoxypyrimidine-5-yl)-1-methyl-3-[(1S)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazine and 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-3-[(1R)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazine (compounds 14.6A and 14.6B) Compound 14.6 (700.0 mg) was separated by SFC to obtain two single isomers: Compound 14.6A (slower elution, 307.1 mg) MS: Calculated value 577.2 [(M+H)] + ]; Measured value 577.3 [(M+H) + ]; and compound 14.6B (faster elution, 258.4 mg) MS: calculated value 577.2 [(M+H) + ]; Measured value 577.3 [(M+H) + SFC conditions: Column: TCI chiral MB-S, inner diameter 250 x 30 mm, 5 μm; Mobile phase: CO2 A and i-PrOH B (0.1% NH3·H2O); Gradient: B 7%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 35°C.

[0219] Step (g): Preparation of 5-[1-methyl-3-[(1S)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[1-methyl-3-[(1R)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 14A and 14B) To a solution of compound 14.6A (307.1 mg, 532.6 μmol) in methanol (5 mL), HCl (2.0 M in MeOH, 600 μL, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 14A (199.7 mg). MS: Calculated value 465.1 [(M+H)]+ ]; Measured value 465.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.53(d,J=1.4Hz,1H),11.49-11.41(m,1H),8.87(d,J=0.9Hz,1H),8.68(s,1H),8.3 4(d,J=6.1Hz,1H),7.24(s,1H),5.93(q,J=6.6Hz,1H),5.19-4.96(m,2H),4.00(s,3H),1.72(d,J=6.6Hz,3H).

[0220] To a solution of compound 14B (258.4 mg, 448.2 μmol) in methanol (4 mL), HCl (2.0 M in MeOH, 500 μL, 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 14B (153.0 mg). MS: Calculated value 465.1 [(M+H)] + ]; Measured value 465.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.52(d,J=1.5Hz,1H),11.46-11.38(m,1H),8.86(d,J=1.1Hz,1H),8.68(s,1H),8.3 4(d,J=6.3Hz,1H),7.24(s,1H),5.93(q,J=6.5Hz,1H),5.16-5.00(m,2H),4.00(s,3H),1.71(d,J=6.6Hz,3H).

[0221] Example 15 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2-methoxyethoxy)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]

[0222] Step (a): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2-methoxyethoxy)phenyl]ethoxy]pyrazolo[3,4-c]pyridazine (compound 15.2) DEAD (38.3 mg, 219.6 μmol) was added to a solution of 5-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-2-fluorophenol (intermediate E3, 80.0 mg, 146.4 μmol), 2-methoxyethanol (compound 15.1, 16.7 mg, 219.6 μmol), and PPh3 (57.4 mg, 219.6 μmol) in toluene (0.5 mL). The resulting mixture was stirred at 60°C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by flash chromatography (elution at 0% to 50% EA in silica gel, 24 g) to obtain compound 15.2 (69.0 mg). MS: Calculated value 493.1 [(M+3H-2tBu) + ]; Measured value 493.1[(M+3H-2tBu) + ].

[0223] Step (b): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2-methoxyethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 15) A mixture of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2-methoxyethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (69.0 mg, 114.16 μmol) in methanol (0.5 mL) was mixed with a solution of HCl (2.0 M in MeOH, 0.5 mL). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 15 (19.0 mg). MS: Calculated value 493.1[(M+H)] + ]; Measured value 493.1[(M+H) + ]. 1 h nmr(400MHz,dmso-d6)δ=11.54(d,j=1.5Hz,1h),11.45(dd,j=1.4,6.1hz,1h),8 .70(s,1h),8.36(m,j=6.1hz,1h),7.43(dd,j=1.8,8.3hz,1h),7.26(dd,j=8.5, 11.3hz,1h),7.22-7.14(m,1h),6.60(dt,j=3.5,54.3Hz,1h),6.15(dt,j=3.5,1 1.3Hz,1h),4.26-4.12(m,2h),4.03(s,3h),3.66(t,j=4.5Hz,2h),3.28(s,3h).

[0224] Example 16 5-[3-[(1R)-1-[2-(2,2-difluoropropoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 16 was prepared in the same manner as Example 10, by replacing 2,2,2-trifluoroethanol with 2,2-difluoropropan-1-ol in step (b). Calculated value: 496.1[(M+H)] + ]; Measured value 496.0[(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ=11.55(s,1H),11.45(brd,J=6.0Hz,1H),8.72(s,1H),8.37(d,J=6.3Hz,1H),8.23(d,J=5.3Hz,1H),7.27(d,J=5. 3Hz,1H),7.15(s,1H),6.63(td,J=54.0,2.9Hz,1H),6.35-6.23(m,1H),4.55(td,J=13.1,3.7Hz,2H),4.02(s,3H),1.72(t,J=19.3Hz,3H).

[0225] Example 17 5-[1-methyl-3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoro-1-methylethoxy)-2-pyridyl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 17 was prepared in the same manner as Example 5, by replacing 1,1-diduterio-1-duteriooxy-2,2,2-trifluoroethane (compound 5.1) with 1,1,1-trifluoropropan-2-ol in step (a). MS: Calculated value 514.1[(M+H)] + ]; Measured value 514.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(d,J=1.6Hz,1H),11.45(dd,J=6.0,1.4Hz,1H),8.71(d,J=1.1Hz,1H),8.52(d,J=5.9Hz,1H),8.37(d,J=6.1Hz,1H),7.38 (d,J=5.4,2.5Hz,1H),7.21(dt,J=5.8,2.1Hz,1H),6.87-6.52(m,1H),6.24 -6.08(m,1H),5.60-5.45(m,1H),4.02(s,3H),1.41(dd,J=12.6,6.3Hz,3H).

[0226] Example 18 5-[1-methyl-3-[(1R)-1-[4-[(2,2-difluorocyclopropyl)methoxy]-2-pyridyl]-2,2-difluoroethoxy]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-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-1-[4-[(2,2-difluorocyclopropyl)methoxy]-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine (compound 18.2) To a solution of 2-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-4-ol (intermediate E1, 150 mg, 283.4 μmol) in toluene (5 mL), 2,2-difluorocyclopropyl methanol (compound 18.1, 61.2 mg, 566.5 μmol) and triphenylphosphine (149 mg, 566.5 μmol) were added at room temperature. Then, diisopropyl azodicarboxylate (115 mg, 566.5 μmol) was added dropwise at room temperature. The resulting mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was quenched with water (50 mL) and extracted three times with EA (30 mL). The combined organic layer was concentrated. The residue was purified by silica gel column chromatography (elution at 0% to 70% EA in PE) to obtain compound 18.2 (120 mg). MS: Calculated value 620.3 [(M+H)] + ]; Measured value 620.3 [(M+H) + ].

[0228] Step (b): Preparation of 5-[1-methyl-3-[(1R)-1-[4-[(2,2-difluorocyclopropyl)methoxy]-2-pyridyl]-2,2-difluoroethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 18) To a solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-1-[4-[(2,2-difluorocyclopropyl)methoxy]-2-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 18.2, 115 mg, 185.7 μmol) in DCM (10 mL), TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 18 (47.1 mg). MS: Calculated value 508.1[(M+H)] + ]; Measured value 508.2 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.40(brs,2H),8.71(s,1H),8.46(d,J=5.5Hz,1H),8.38(s,1H),7.25(s,1H),7.05(dd,J=5.4,1.9Hz,1H),6.69(td,J= 54.3,2.3Hz,1H),6.24-6.05(m,1H),4.33-4.20(m,1H),4.16-4.05(m,1H) ),4.03(s,3H),2.31-2.14(m,1H),1.80-1.65(m,1H),1.59-1.43(m,1H).

[0229] Example 19 5-[3-[(1R)-2,2-difluoro-1-[4-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka]

[0230] Example 19 was prepared in the same manner as Example 18, by replacing 2,2-difluorocyclopropylmethanol (compound 18.1) with (1-fluorocyclopropyl)methanol in step (a). MS: Calculated value 490.1[(M+H)] + ]; Measured value 490.3 [(M+H) + ]. 1 h nmr(400MHz,dmso-d6)δ=11.49(br,2h),8.71(s,1h),8.46(d,j=5.8Hz,1h),8.37(s,1h),7.26(d,j=2.5Hz,1h),7.06(dd,j=5.8,2.5 Hz,1h),6.69(td,j=54.5,3.8Hz,1h),6.21-6.09(m,1h),4.41(d,j=22.8Hz,2h),4.03(s,3h),1.17-1.04(m,2h),0.95-0.77(m,2h).

[0231] Example 20 5-[3-[(1R)-1-(4-ethoxy-2-pyridyl)-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 20 was prepared in the same manner as Example 4, by replacing 2,2,2-trifluoroethyltrifluoromethanesulfonate with iodoethane in step (a). MS: Calculated value 446.1[(M+H)] + ]; Measured value 446.0[(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ11.47(s,2H),8.71(s,1H),8.43(brd,J=5.5Hz,1H),8.38(s,1H),7.18(s,1H),7.03-6. 94(m,1H),6.72(t,J=54.0Hz,1H),6.22-6.06(m,1H),4.12(q,J=6.4Hz,2H),4.03(s,3H),1.31(t,J=6.9Hz,3H).

[0232] Example 21 2-[[2-[(1R)-1-[5-(2,4-dioxo-1H-pyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-4-pyridyl]oxy]acetonitrile [ka] Example 21 was prepared in the same manner as Example 4, by replacing 2,2,2-trifluoroethyltrifluoromethanesulfonate with 2-bromoacetonitrile in step (a). MS: Calculated value 457.1[(M+H)] + ]; Measured value 457.2 [(M+H) + ]. 1 h nmr(400MHz,dmso-d6)δ11.55(s,1h),11.45(brd,j=5.8Hz,1h),8.71(s,1h),8.57(d,j=5.8Hz,1h),8.38(d,j=6.0 Hz,1h),7.35(s,1h),7.20-7.12(m,1h),6.71(td,j=53.8,2.5Hz,1h),6.27-6.12(m,1h),5.29(s,2h),4.02(s,3h).

[0233] Example 22 1-[[2-[(1R)-1-[5-(2,4-dioxo-1H-pyrimidine-5-yl)-1-methyl-pyrazolo [3,4-c]pyridazin-3-yl]oxy-2,2-difluoro-ethyl]-4-pyridyl]oxymethyl]cyclopropanecarbonitric [ka] Example 22 was prepared in the same manner as Example 4, by replacing 2,2,2-trifluoroethyltrifluoromethanesulfonate with 1-(bromomethyl)cyclopropanecarbonitrate in step (a). MS: Calculated value 497.1[(M+H)] + ]; Measured value 497.2 [(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ=11.54(s,1H),11.49(brs,1H),8.71(s,1H),8.47( d,J=5.8Hz,1H),8.38(s,1H),7.24(d,J=2.3Hz,1H),7.03(dd,J=5.8,2.5Hz, 1H),6.69(td,J=53.8,3.5Hz,1H),6.15(ddd,J=14.3,7.8,3.6Hz,1H),4.15( s,2H),4.03(s,3H),1.37(dd,J=7.5,5.0Hz,2H),1.17(d,J=7.0,4.5Hz,2H).

[0234] Example 23 5-[3-[(1R)-2,2-difluoro-1-[4-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 23 was prepared in the same manner as Example 4, by replacing 2,2,2-trifluoroethyltrifluoromethanesulfonate with 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane in step (a).

[0235] MS: Calculated value 540.1 [(M+H) + ]; Measured value 540.2 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.51(brs,2H),8.71(s,1H),8.45(d,J=5.8Hz,1H),8.38(s,1H),7.23(d,J=2.3Hz,1H),7.03(dd,J=5.8,2.3Hz ,1H),6.68(td,J=54.0,3.8Hz,1H),6.15(ddd,J=14.3,7.8,3.4Hz,1H),4.23(s,2H),4.03(s,3H),1.13-1.05(m,2H),1.05-0.97(m,2H).

[0236] Example 24 5-[3-[(1R)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]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]

[0237] Step (a): Preparation of N-methoxy-N-methyl-1-tetrahydropyran-2-ylindazole-6-carboxamide (compound 24.2) To a solution of 1-tetrahydropyran-2-indazole-6-carboxylic acid (compound 24.1, 5.2 g, 21.12 mmol) in DMF (45 mL), HATU (8.43 g, 22.17 mmol), N,O-dimethylhydroxylamine hydrochloride (2.47 g, 25.34 mmol), and DIPEA (13.65 g, 18.39 mL, 105.58 mmol) were added. The resulting mixture was stirred at 20°C for 1 hour, then diluted with water (300 mL) and extracted three times with EA (50 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 120 g, eluted with 15%-90% EA in PE) to obtain compound 24.2 (5.2 g). MS: Calculated value 290.1[(M+H)] + ]; Measured value 290.0 [(M+H) + ].

[0238] Step (b): Preparation of 2,2-difluoro-1-(1-tetrahydropyran-2-indazole-6-yl)ethanone (compound 24.3) Potassium tert-butoxide (698.09 mg, 6.22 mmol) was added at 0°C to a solution of N-methoxy-N-methyl-1-tetrahydropyran-2-yl-indazole-6-carboxamide (compound 24.2, 1.0 g, 3.46 mmol) and difluoromethyltrimethylsilane (858.54 mg, 6.91 mmol) in THF (15 mL). The resulting mixture was stirred at 0°C for 16 hours. The reaction product was quenched with saturated aqueous solution NH4Cl (10 mL) and extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0-25% EA in silica gel PE) to obtain compound 24.3 (300 mg).

[0239] Step (c): Preparation of 2,2-difluoro-1-(1H-indazole-6-yl)ethanone (compound 24.4) To a solution of 2,2-difluoro-1-(1-tetrahydropyran-2-indazole-6-yl)ethanone (compound 24.3, 300 mg, 1.07 mmol) in methanol (3 mL), p-toluenesulfonic acid (204 mg, 1.07 mmol) was added. The resulting mixture was stirred at 50°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography (elution at 0% to 60% EA in silica gel, DCM) to obtain compound 24.4 (200 mg). MS: Calculated value 197.0 [(M+H)] + ]; Measured value 215.0 [(M+H2O+H) + ].

[0240] Step (d): Preparation of 2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethanone (compound 24.5) To a solution of 2,2-difluoro-1-(1H-indazole-6-yl)ethanone (compound 24.4, 200 mg, 1.02 mmol) in DMF (3 mL), cesium carbonate (996.65 mg, 3.06 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (283.99 mg, 1.22 mmol) were added. The resulting mixture was stirred at 20°C for 2 hours. The reaction mixture was quenched 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. The residue was purified by flash chromatography (elution with 0%-15% EA in PE, on silica gel, 12 g) to obtain compound 24.5 (100 mg) and compound 24.6 (90 mg).

[0241] Step (e): Preparation of (1S)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethanol (compound 24.7) To a solution of 2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethanone (compound 24.5 mg, 100 mg, 359.48 μmol) in dichloromethane (10 mL), formic acid (248.2 mg, 5.39 mmol) and triethylamine (218.25 mg, 2.16 mmol) were added. Then RuCl(p-cymene)[(R,R)-Ts-DPEN] (22.87 mg, 35.95 μmol) was added. The resulting mixture was stirred at 20°C for 1 hour. The reaction product was quenched with saturated aqueous NaHCO3 solution (2 mL), diluted with water (20 mL), and extracted three times with DCM (5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution at 0%-25% EA in silica gel, 12 g) to obtain compound 24.7 (86 mg). MS: Calculated value 281.1 [(M+H)] + ]; Measured value 281.1[(M+H) + ].

[0242] Step (f): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 24.8) DIAD (61.73 mg, 354.44 μmol) was added to a suspension of (1S)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethanol (compound 24.7 mg, 86 mg, 306.93 μmol), 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-ol (intermediate B1, 110 mg, 295.37 μmol), and triphenylphosphine (92.97 mg, 354.44 μmol) in toluene (2 mL). The mixture was then stirred under nitrogen at 50°C for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted three times with EA (30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution at 0%-25% EA in 40g silica gel PE) to obtain compound 24.8 (100mg). MS: Calculated value 634.2[(M+H)] + ]; Measured value 523.1 [(M-112+H) + ].

[0243] Step (g): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 24) A solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 24.8 mg, 100 mg, 157.58 μmol) in methanol (1 mL) was mixed with 2 M HCl (236.37 μL, 472.74 μmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 24 (24.8 mg). MS: Calculated value 523.1[(M+H)] + ]; Measured value 523.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.8Hz,1H),11.48-11.37(m,1H),8.74(s,1H),8.36(d,J=6.3Hz,1H),8.23(d,J=0.9Hz,1H),8.08(s, 1H),7.86(d,J=8.3Hz,1H),7.49-7.39(m,1H),6.65(dt,J=3.9,54.2Hz,1H),6.31(dt,J=3.3,11.3Hz,1H),5.52-5.41(m,2H),4.00(s,3H).

[0244] Example 25 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-lifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] [ka]

[0245] Step (a): Preparation of 6-bromo-4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine (Compound 25.2) A solution of 6-bromo-3,4-dihydro-2H-1,4-benzoxazine (compound 25.1, 3.00 g, 8.4 mmol) in TFA (30 mL) was stirred at room temperature under a nitrogen atmosphere for 1 hour, and then NaBH4 (1.27 g, 33.7 mmol) was added in small amounts at 0°C. The resulting mixture was stirred overnight at 70°C, then concentrated, and the residue was diluted with EA (300 mL) and washed twice with brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (eluting with 0% to 100% EA in silica gel and PE) to obtain compound 25.2 (1.2 g). 1 H NMR(400MHz,DMSO-d6)δ7.05(d,J=2.2Hz,1H),6.74(dd,J=8.4,2.2Hz,1H),6.67 (d,J=8.4Hz,1H),4.24(q,J=9.7Hz,2H),4.15-4.10(m,2H),3.46(t,J=4.4Hz,2H)

[0246] Step (b): Preparation of 4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-carbaldehyde (compound 25.3) To a stirred mixture of 6-bromo-4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine (compound 25.2, 1.2 g, 4.05 mmol), palladium(II) acetate (45.5 mg, 0.20 mmol), 1,4-bis(diphenylphosphin)butane (173 mg, 0.41 mmol), and sodium carbonate (1.07 g, 10.1 mmol) in DMF (6 mL), 1,1,3-trioxo-1,2-benzothiazole-2-carbaldehyde (1.28 g, 6.08 mmol) and triethylsilane (943 mg, 8.11 mmol) were added in small amounts at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C under a nitrogen atmosphere. After the reaction product cooled to room temperature, it was quenched with water (50 mL) and extracted three times with EA (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (elution in PE at 0% to 100% EA) to obtain compound 25.3 (620 mg). MS: Calculated value 246.1 [(M+H)]+ ]; Measured value 246.0[(M+H) + ].

[0247] Step (c): Preparation of 2,2-difluoro-1-[4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethanol (compound 25.4) To a stirred mixture of 4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-carbaldehyde (compound 25.3, 620 mg, 2.53 mmol), cesium fluoride (38.4 mg, 0.25 mmol), and 18-crown-6 (134 mg, 0.51 mmol) in DMF (12 mL), (difluoromethyl)trimethylsilane (503 mg, 4.05 mmol) was added dropwise at -20°C under a nitrogen atmosphere. The resulting mixture was stirred at -20°C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (100 mL) and extracted three times with EA (150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0% to 100% EA in PE) to obtain compound 25.4 (153 mg). MS: Calculated value 298.1 [(M+H) + ]; Measured value 297.9 [(M+H) + ].

[0248] Step (d): Preparation of 2,2-difluoro-1-[4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethanone (compound 25.5) A mixture of 2,2-difluoro-1-[4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethanol (compound 25.4, 150 mg, 0.5 mmol), DMP (750 mg, 1.77 mmol), and sodium carbonate (214 mg, 2.02 mmol) in DCM (20 mL) was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was quenched with water (50 mL) and extracted twice with DCM (50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting at 0%~100% EA in PE) to obtain compound 25.5 (115 mg). MS: Calculated value 296.1[(M+H)] + ]; Measured value 296.0[(M+H) + ].

[0249] Step (e): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 25) Example 25 was prepared in the same manner as Example 24, by replacing 2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethanone (compound 24.5) with 2,2-difluoro-1-[4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethanone (compound 25.5)cyclopropane in step (e). MS: Calculated value 540.1[(M+H)] + ]; Measured value 540.4[(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ11.74-11.34(br,2H),8.66(s,1H),8.37(s,1H),7.12(s,1H),6.90-6.72(m,2H), 6.54(td,J=54.6,4.0Hz,1H),6.00(dt,J=11.0,6.8Hz,1H),4.26-4.09(m,4H),4.03(s,3H),3.44(m,2H).

[0250] Example 26 5-[3-[(1R)-2,2-difluoro-1-[2-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]-4-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]

[0251] Step (a): Preparation of 4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoro-ethyl]-N-[(1S)-2,2,2-trifluoro-1-methyl-ethyl]pyridine-2-amine (compound 26.2) To a solution of 3-[(1R)-1-(2-bromo-4-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D5, 200 mg, 0.34 mmol) in 1,4-dioxane (10 mL), (2S)-1,1,1-trifluoropropan-2-amine (compound 26.1, 191 mg, 1.69 mmol), Cs2CO3 (220 mg, 0.68 mmol), Pd2(dba)3 (61.8 mg, 0.07 mmol), and SPhos (27.7 mg, 0.07 mmol) were added. The resulting mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (30 mL) and extracted three times with EA (20 mL). The combined organic layer was washed with brine (20 mL), dried on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20 g, elution with 0%~100% EA in PE) to obtain compound 26.6 (145.0 mg). MS: Calculated value 625.3 [(M+H)]+ ]; Measured value 625.4 [(M+H) + ].

[0252] Step (b): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[2-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 26) 4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-N-[(1S)-2,2,2-lifluoro-1-methylethyl]pyridine-2-amine A solution of compound 26.2 (145.0 mg, 0.28 mmol) was added to a 5 mL DCM (in which 0.5 mL of 4N HCl / dioxane was added). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 26 (65.1 mg). MS: Calculated value 513.1 [(M+H)] + ]; Measured value 513.4 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.53(br s,2H),8.72(s,1H),8.40(s,1H),8.04(d,J=5.3Hz,1H),7.17(d,J=8.8Hz,1H),6.80(dd,J=5.3,1.5Hz,1H),6.77(s,1 H),6.56(td,J=53.8,2.8Hz,1H),6.19-6.09(m,1H),4.96(dd,J=15.5,8.0Hz,1H),4.03(s,3H),1.27(d,J=7.0Hz,3H).

[0253] Example 27 5-[3-[(1R)-2,2-difluoro-1-[2-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 27 was prepared in the same manner as Example 26, by replacing (2S)-1,1,1-trifluoropropane-2-amine (compound 26.1) with (2R)-1,1,1-trifluoropropane-2-amine in step (a). MS: Calculated value 513.1[(M+H)] + ]; Measured value 513.4 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.52(s,2H),8.72(s,1H),8.40(s,1H),8.04(d,J=5.3Hz,1H),7.16(d,J=8.8Hz,1H),6.80(dd,J=5.3,1. 4Hz,1H),6.76(s,1H),6.56(td,J=53.9,3.0Hz,1H),6.13(td,J=12.0,3.0Hz,1H),4.96(m,1H),4.03(s,3H),1.25(d,J=7.0Hz,3H).

[0254] Example 28 5-[3-[(1R)-2,2-difluoro-1-[2-(2-methoxyethoxy)-4-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]

[0255] Step (a): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[2-(2-methoxyethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 28.2) To a solution of 3-[(1R)-1-(2-bromo-4-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D5, 100.0 mg, 0.17 mmol) in 1,4-dioxane (10 mL), 2-methoxyethanol (compound 28.1 mg, 25.7 mg, 0.34 mmol), Cs2CO3 (110 mg, 0.34 mmol), Pd2(dba)3 (23.2 mg, 0.03 mmol), and xanthophos (29.3 mg, 0.05 mmol) were added. The resulting mixture was stirred under a nitrogen atmosphere at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture 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 on anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20 g, elution at 0%-100% EA in PE) to obtain compound 28.2 (64.0 mg). MS: Calculated value 588.3 [(M+H)] + ]; Measured value 588.2 [(M+H) + ].

[0256] Step (e): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[2-(2-methoxyethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 28) To a solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[2-(2-methoxyethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 28.2, 62.0 mg, 0.11 mmol) in DCM (5 mL), TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 28 (29.6 mg). MS: Calculated value 476.1[(M+H)] + ]; Measured value 476.2 [(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ11.34(br s,2H),8.73(s,1H),8.38(s,1H),8.19(d,J=5.2Hz,1H),7.19(dd,J=5.2,1.0Hz,1H),7.03(s,1H),6.62(t d,J=53.8,3.0Hz,1H),6.29-6.22(m,1H),4.49-4.27(m,2H),4.02(s,3H),3.73-3.54(m,2H),3.28(s,3H).

[0257] Example 29 5-[3-[(1R)-1-(2-ethoxy-4-pyridyl)-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 29 was prepared in the same manner as Example 28, by replacing 2-methoxyethanol (compound 28.1) with ethanol in step (a). MS: Calculated value 446.1[(M+H)] + ]; Measured value 446.2 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.40(br s,2H),8.73(s,1H),8.38(s,1H),8.20(d,J=5.3Hz,1H),7.18(dd,J=5.6,1.4Hz,1H),6.99(s,1H),6.62(t d,J=53.5,2.5Hz,1H),6.25(t,J=11.1Hz,1H),4.30(q,J=7.0Hz,2H),4.03(s,3H),1.30(t,J=7.0Hz,3H).

[0258] Example 30 5-[3-[(1R)-2,2-difluoro-1-[2-(1,1,2,2,2-pentaduterioethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 30 was prepared in the same manner as Example 10, by replacing 2,2,2-trifluoroethanol with 1,1,1,2,2-pentaduterio-2-duteriooxyethane in step (b). MS: Calculated value 451.2[(M+H)] + ]; Measured value 451.4 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.35(br s,2H),8.72(s,1H),8.38(s,1H),8.19(d,J=5.3Hz,1H),7.16(dd,J=5.3,1.4Hz, 1H),6.98(s,1H),6.62(td,J=54.0,3.2Hz,1H),6.30-6.18(m,1H),4.02(s,3H).

[0259] Example 31 5-[3-[(1R)-1-[2-(4,4-difluoro-1-piperidyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 31 was prepared in the same manner as Example 26, by replacing (2S)-1,1,1-trifluoropropan-2-amine (compound 26.1) with 4,4-difluoropiperidine in step (a). MS: Calculated value 521.2[(M+H)] + ]; Measured value 521.4 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.16(br s,2H),8.73(s,1H),8.39(s,1H),8.15(d,J=5.1Hz,1H),7.16(s,1H),6.86(d,J=5.1Hz,1H),6.60( td,J=54.3,3.0Hz,1H),6.21-6.07(m,1H),4.03(s,3H),3.69(t,J=5.8Hz,4H),2.06-1.85(m,4H).

[0260] Example 32 5-[3-[(1R)-1-[2-[(4,4-difluorocyclohexyl)amino]-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 32 was prepared in the same manner as Example 26, by replacing (2S)-1,1,1-trifluoropropan-2-amine (compound 26.1) with 4,4-difluorocyclohexaneamine in step (a). MS: Calculated value 535.2[(M+H)] + ]; Measured value 535.3 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ11.49(br s,2H),8.71(s,1H),8.40(s,1H),7.99(d,J=5.3Hz,1H),6.72-6.53(m,4H),6.07(t,J=11.2Hz,1H) ,4.03(s,3H),3.89-3.87(m,1H),2.10-1.97(m,2H),1.90(d,J=13.9Hz,4H),1.48(d,J=9.6Hz,2H).

[0261] Example 33 5-[3-[(1R)-1-[2-[(3,3-difluoropyrrolinidine-1-yl)methyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0262] Step (a): Preparation of 4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-2-carboxylate methyl (compound 33.1) 3-[(1R)-1-(2-bromo-4-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D5, 500 mg, 0.84 mmol), Pd(dppf)Cl2 (61.7 mg, 0.08 mmol), Et3N (256 mg, 2.53 mmol), and methanol (10 mL) were charged into a 30 mL autoclave at room temperature. The resulting mixture was stirred at 100 °C for 4 hours under a carbon monoxide atmosphere (30 atm). After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to obtain compound 33.1 (304 mg). MS: Calculated value 572.2 [(M+H)] + ]; Measured value 572.4 [(M+H) + ].

[0263] Step (b): Preparation of [4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-2-pyridyl]methanol (compound 33.2) To a solution of 4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoro-ethyl]pyridine-2-carboxylate methyl (compound 33.1, 200 mg, 0.35 mmol) in THF (10.0 mL), lithium aluminum hydride (2 M in THF, 0.35 mL, 0.7 mmol) was added dropwise at -78°C. After stirring at -78°C for 2 hours, the reaction mixture was quenched with water (20 mL) at -78°C, warmed to room temperature, and extracted three times with EA (50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to obtain compound 33.2 (93.0 mg). MS: Calculated value 544.2[(M+H)] + ]; Measured value 544.2 [(M+H) + ].

[0264] Step (c): Preparation of 4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-2-carbaldehyde (compound 33.3) To a solution of [4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-2-pyridyl]methanol (compound 33.2, 93 mg, 0.17 mmol) in DCM (5 mL), Na2CO3 (53.4 mg, 0.51 mmol) and DMP (109 mg, 0.26 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction product was quenched with water (30 mL) and extracted three times with EA (50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to obtain compound 33.3 (30.0 mg). MS: Calculated value 542.2[(M+H) + ]; Measured value 542.2 [(M+H) + ].

[0265] Step (d): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-1-[2-[(3,3-difluoroazetidine-1-yl)methyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 33.5) To a solution of 4-[(1R)-1-[5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]pyridine-2-carbaldehyde (compound 33.3, 40.0 mg, 0.07 mmol) in DCE (5 mL), 3,3-difluoropyrrolidine hydrochloride (compound 33.4, 12.7 mg, 0.09 mmol), MgSO4 (17.8 mg, 0.15 mmol), and DIEA (28.6 mg, 0.22 mmol) were added. The resulting mixture was stirred at room temperature for 3 hours. Then, STAB (62.6 mg, 0.3 mmol) was added, and the reaction mixture was stirred at room temperature for a further 1 hour. The reaction mixture was quenched with water (30 mL) and extracted three times with EA (50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to obtain compound 33.5 (31.0 mg). MS: Calculated value 633.3[(M+H)] + ]; Measured value 655.2 [(M+Na) + ].

[0266] Step (e): Preparation of 5-[3-[(1R)-1-[2-[(3,3-difluoropyrrolidin-1-yl)methyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 33) To a solution of 5-(2,4-ditert-butoxypyrimidine-5-yl)-3-[(1R)-1-[2-[(3,3-difluoropyrrolidine-1-yl)methyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 33.5, 30.0 mg, 0.05 mmol) in DCM (5 mL), TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 33 (12.1 mg). MS: Calculated value 521.2[(M+H)] + ]; Measured value 521.2 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.22(br s,2H),8.73(s,1H),8.56(d,J=5.1Hz,1H),8.39(s,1H),7.62(d,J=1.6Hz,1H),7.53-7.48(m,1H),6.66(td,J=53.9,2.9Hz,1H ),6.30(td,J=11.9,2.9Hz,1H),4.00(s,3H),3.78(d,J=1.5Hz,2H),3.00-2.78(m,2H),2.79-2.63(m,2H),2.08-2.29(m,2H).

[0267] Example 34 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-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]

[0268] Step (a): Preparation of 2-(2,2,2-trifluoroethoxymethyl)pyridine-4-carboxylate methyl (Compound 34.1) To a solution of methyl 2-(chloromethyl)pyridine-4-carboxylate (compound 2.1, 5.55 g, 29.9 mmol) in DMF (50 mL), 2,2,2-trifluoroethanol (6.0 mL, 83.4 mmol) and Cs2CO3 (24.4 g, 74.8 mmol) were added at 22°C. The resulting mixture was stirred at 60°C for 16 hours. The reaction mixture was diluted with saturated aqueous NaCl (200 mL) and extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 120 g, 10%-30% EA in PE) to obtain compound 34.1 (3.87 g). MS: Calculated value 250.1[(M+H)] + ]; Measured value 249.9 [(M+H) + ].

[0269] Step (b): Preparation of N-methoxy-N-methyl-2-(2,2,2-trifluoroethoxymethyl)pyridine-4-carboxamide (compound 34.2) To a solution of 2-(2,2,2-trifluoroethoxymethyl)pyridine-4-carboxylate methyl (compound 34.1, 3.87 g, 15.5 mmol) in THF (50 mL), H2O (50 mL) and LiOH·H2O (716.8 mg, 17.1 mmol) were added at 22°C. The resulting mixture was stirred at 22°C for 2 hours. The pH was adjusted to 4 by adding aqueous HCl (2.0 M). This mixture was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was suspended in DCM, and N,O-dimethylhydroxylamine hydrochloride (1.82 g, 18.6 mmol), Et3N (4.0 mL, 28.7 mmol), and HATU (6.47 g, 17.1 mmol) were added at 22°C. The resulting mixture was stirred at 22°C for 2 hours. The reaction mixture was diluted with saturated aqueous solution NaHCO3 (200 mL) and extracted twice with DCM (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 80 g, 30%-70% EA in PE) to obtain compound 34.2 (3.55 g). MS: Calculated value 279.1[(M+H)] + ]; Measured value 279.0 [(M+H) + ].

[0270] Step (c): Preparation of 2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethanone (compound 34.3) To a solution of N-methoxy-N-methyl-2-(2,2,2-trifluoroethoxymethyl)pyridine-4-carboxamide (compound 34.2, 3.55 g, 12.8 mmol) in THF (30 mL), difluoromethyltrimethylsilane (2.5 mL, 27.4 mmol) and potassium tert-butoxide (2.15 g, 19.1 mmol) were added at 0°C. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with saturated aqueous NaCl (100 mL) and extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 80 g, 0%~8% MeOH in DCM) to obtain compound 34.3 (2.67 g). MS: Calculated value 288.1[(M+H2O+H)] + ]; Measured value 287.9 ​​[(M+H2O+H) + ].

[0271] Step (d): Preparation of (1S)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethanol (compound 34.4) To a solution of 2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethanone (compound 34.3, 2.67 g, 9.92 mmol) in DCM (10 mL), formic acid (2.0 mL, 52.1 mmol), triethylamine (3.0 mL, 21.5 mmol), and RuCl(p-cymene)[(R,R)-Ts-DPEN] (315.5 mg, 496.0 μmol) were added at 0°C. The resulting mixture was stirred at 22°C for 2 hours. The reaction mixture was diluted with saturated aqueous solution NaHCO3 (100 mL) and extracted three times with DCM (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 80 g, 25%-50% EA in PE) to obtain compound 34.4 (1.46 g). MS: Calculated value 272.1 [(M+H)] + ]; Measured value 271.9 [(M+H) + ].

[0272] Step (e): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 34.5) 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-ol (intermediate B1, 1.20 g, 3.22 mmol) in DCE (26 mL) was mixed with (1S)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethanol (compound 34.4, 1.22 g, 4.51 mmol), triphenylphosphine (1.23 g, 4.67 mmol), and DEAD (740 μL, 4.67 mmol) at 60°C. The resulting mixture was stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous solution NaHCO3 (100 mL) and extracted three times with DCM (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 80 g, 10%-40% EA in PE) to obtain compound 34.5 (1.76 g). MS: Calculated value 514.1 [(M-112+H)] + ]; Measured value 514.1 [(M-112+H) + ].

[0273] Step (f): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 34) A mixture of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 34.5, 660.0 mg, 1.06 mmol) in methanol (6 mL) was mixed with HCl (2.0 M in MeOH, 2.1 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 34 (353.1 mg). MS: Calculated value 514.1[(M+H)] + ]; Measured value 514.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.6Hz,1H),11.45(br d,J=5.8Hz,1H),8.72(s,1H),8.60(d,J=5.1Hz,1H),8.38(d,J=6.2Hz,1H),7.65(s,1H),7.56(d,J=5.1Hz,1 H),6.65(td,J=53.7,2.8Hz,1H),6.33(td,J=11.8,2.3Hz,1H),4.77(s,2H),4.28-4.11(m,2H),4.01(s,3H).

[0274] Examples 35A and 35B 5-[3-[(1R)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]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]

[0275] Step (a): Preparation of 1-(6-chloropyrimidine-4-yl)-2,2-difluoroethanone (Compound 35.1) To a solution of methyl 6-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (compound 14.2, 6.0 g, 29.8 mmol) in THF (100 mL), TMSCHF2 (8.0 mL, 56.5 mmol) and t-BuOK (4.01 g, 35.7 mmol) were added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was diluted with saturated aqueous NaHCO3 (200 mL) and extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 120 g, 0%~30% EA in PE) to obtain compound 35.1 (3.13 g). MS: Calculated value 193.0[(M+H)] + ]; Measured value 210.9 [(M+H2O+H) + ].

[0276] Step (b): Preparation of 2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanone (compound 35.2) To a suspension of NaH (60% dispersion in mineral oil, 4.15 g, 103.9 mmol) in DMF (100 mL), 2,2,2-trifluoroethanol (9.0 mL, 125.1 mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 10 minutes, and then 1-(6-chloropyrimidine-4-yl)-2,2-difluoro-ethanone (compound 35.1, 10.0 g, 51.9 mmol) was added. The resulting mixture was stirred at 22°C for 2 hours. The reaction mixture was diluted with saturated aqueous NaCl (400 mL) and extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 120 g, 0%~35% EA in PE) to obtain compound 35.2 (7.16 g). MS: Calculated value 257.0 [(M+H) +]; Measured value 274.9 [(M+H2O+H) + ].

[0277] Step (c): Preparation of 2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanol (compound 35.3) To a solution of 2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanone (compound 35.2, 3.62 g, 14.1 mmol) in MeOH (30 mL), NaBH4 (641.6 mg, 17.0 mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was diluted with saturated aqueous NaCl (200 mL), extracted three times with EA (100 mL), and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 80 g, 0%~35% EA in PE) to obtain compound 35.3 (3.27 g). MS: Calculated value 259.1[(M+H)] + ]; Measured value 258.9 [(M+H) + ].

[0278] Step (d): Preparation of 5-(2,4-ditert-butoxypyrimidine-5-yl)-3-[2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 35.4) To a suspension of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine-3-ol (intermediate B1, 900 mg, 2.42 mmol) in DCE (24 mL), 2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanol (compound 35.3, 1.87 g, 7.25 mmol), phenoxy(diphenyl)phosphan (2.69 g, 9.67 mmol), and DtBAD (2.23 g, 9.67 mmol) were added at 60°C. The resulting mixture was stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous NaCl (100 mL) and extracted three times with DCM (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 80 g, 10%-30% EA in PE) to obtain compound 35.4 (800 mg). MS: Calculated value 513.2[(M+H)] + ]; Measured value 501.1 [(M-112+H) + ].

[0279] Step (e): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine and 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1S)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compounds 35.4A and 35.4B) Compound 35.4 (800 mg) was separated by SFC to obtain two single isomers: Compound 35.4A (faster elution, 190 mg) MS: Calculated value 501.1 [(M-112+H)] + ]; Measured value 501.1 [(M-112+H) + ]; and compound 35.4B (slower elution, 142 mg) MS: calculated value 501.1 [(M-112+H) + ]; Measured value 501.1 [(M-112+H)+ SFC conditions: Column: Inner diameter (ID) 250 × 20 mm 5 μm, Mobile phase: CO2 (A), EtOH (0.1% NH3·H2O) (B), Gradient: B 10%, Flow rate: 60 mL / min, Back pressure: 100 bar, Column temperature: 35°C.

[0280] Step (f): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 35A and 35B) To a solution of compound 35.4A (263.7 mg, 430.5 μmol) in methanol (5 mL), HCl (2.0 M in MeOH, 600 μL, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 35A (84.9 mg). MS: Calculated value 501.1[(M+H)] + ]; Measured value 501.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(s,1H),11.46(br d,J=5.9Hz,1H),8.94(s,1H),8.73(s,1H),8.38(d,J=6.3Hz,1H),7.42(s,1H),6 .74(td,J=53.3,2.6Hz,1H),6.34-6.14(m,1H),5.17-5.05(m,2H),4.02(s,3H).

[0281] A mixture of compound 35.4B (182.5 mg, 297.9 μmol) in methanol (4 mL) was mixed with HCl (2.0 M in MeOH, 400 μL, 800 μmol). The reaction mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 35B (89.4 mg). MS: Calculated value 501.1[(M+H)]+ ]; Measured value 501.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(br s,1H),11.46(br d,J=4.8Hz,1H),8.94(s,1H),8.73(s,1H),8.38(d,J=6.0Hz,1H),7.42(s,1H), 6.74(t,J=52.8Hz,1H),6.31-6.16(m,1H),5.11(q,J=8.8Hz,2H),4.02(s,3H).

[0282] Examples 36A and 36B 5-[3-[(1R)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-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-[4-(trifluoromethoxymethyl)-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]

[0283] Step (a): Preparation of 1-(6-chloropyrimidine-4-yl)-2,2-difluoroethanone (Compound 36.2) To a solution of (2-bromo-4-pyridyl)methanol (compound 36.1, 6.0 g, 31.9 mmol) in EA (60 mL), selectfluor (17.0 g, 47.9 mmol), KF (7.42 g, 127.6 mmol), AgOTf (24.6 g, 95.7 mmol), 2-fluoropyridine (9.0 mL, 104.8 mmol), and TMSCF3 (15.0 mL, 93.9 mmol) were added at 22°C. The resulting mixture was stirred at 22°C for 24 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 (200 mL) and extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 120 g, 0%~12% EA in PE) to obtain compound 36.2 (957.0 mg). MS: Calculated values ​​256.0, 258.0 [(M+H)] + ]; Measured values ​​255.8, 257.8 [(M+H) + ].

[0284] Step (b): Preparation of 2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethanone (compound 36.3) To a solution of 1-(6-chloropyrimidine-4-yl)-2,2-difluoroethanone (compound 36.2, 697.3 mg, 2.72 mmol) in THF (10 mL), i-PrMgCl·LiCl (1.3 M in THF, 10 mL, 13.0 mmol) was added at 0°C. The resulting mixture was stirred at 22°C for 30 minutes, and then 2,2-difluoro-N-methoxy-N-methylacetamide (1.5 mL, 12.9 mmol) was added. The reaction mixture was stirred at 22°C for 1 hour. The reaction mixture was diluted with saturated aqueous solution NH4Cl (50 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 24 g, 0%~25% EA in PE) to obtain compound 36.3 (372.0 g). MS: Calculated value 258.0 [(M+H) + ]; Measured value 273.9 [(M+H2O+H) + ].

[0285] Step (c): Preparation of 2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethanol (compound 36.4) To a solution of 2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethanone (compound 36.3, 372.0 mg, 1.46 mmol) in MeOH (6 mL), NaBH4 (165.5 mg, 4.37 mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was diluted with saturated aqueous NaCl (50 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 24 g, 0%~30% EA in PE) to obtain compound 36.4 (233.0 mg). MS: Calculated value 258.1[(M+H)] + ]; Measured value 257.9 [(M+H) + ].

[0286] Step (d): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 36.5) To a suspension of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazin-3-ol (intermediate B1, 500.0 mg, 1.34 mmol) in toluene (12 mL), 2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethanol (compound 36.4, 517.9 mg, 2.01 mmol), triphenylphosphine (528.2 mg, 2.01 mmol), and DEAD (340 μL, 2.15 mmol) were added at 60°C. The resulting mixture was stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with saturated aqueous solution NaCl (50 mL) and extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, 80 g, 10%-40% EA in PE) to obtain compound 36.5 (700 mg). MS: Calculated value 612.1 [(M+H)] + ]; Measured value 500.1 [(M-112+H) + ].

[0287] Step (e): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine and 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1S)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compounds 36.5A and 36.5B) Compound 36.5 (700 mg) was separated by SFC to obtain two single isomers: Compound 36.5A (faster elution, 318 mg) MS: Calculated value 500.1 [(M-112+H)] + ]; Measured value 500.1 [(M-112+H) + ]; and compound 36.5B (slower elution, 303 mg) MS: calculated value 500.1 [(M-112+H) + ]; Measured value 500.1 [(M-112+H) +SFC conditions: Column: OX inner diameter 250 x 30 mm 5 μm, mobile phase: CO2 A and i-PrOH B (0.1% NH3·H2O), gradient: B 50%, flow rate: 60 mL / min, back pressure: 100 bar, column temperature: 35°C.

[0288] Step (f): Preparation of 5-[3-[(1R)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-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-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 36A and 36B) To a solution of compound 36.5A (318 mg, 0 mg, 520.0 μmol) in methanol (5 mL), HCl (2.0 M in MeOH, 700 μL, 1.4 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 36A (210.4 mg). MS: Calculated value 500.1 [(M+H)] + ]; Measured value 500.0 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.54(s,1H),11.45(br d,J=5.5Hz,1H),8.70(s,1H),8.69(d,J=4.9Hz,1H),8.38(d,J=6.3Hz,1H),7.70(s,1H),7.46 (d,J=5.4Hz,1H),6.72(td,J=53.4,3.6Hz,1H),6.31-6.20(m,1H),5.29(s,2H),4.01(s,3H).

[0289] To a solution of compound 36.5B (303.0 mg, 495.4 μmol) in methanol (5 mL), HCl (2.0 M in MeOH, 700 μL, 1.4 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 36B (213.3 mg). MS: Calculated value 500.1 [(M+H)] + ]; Measured value 500.0 [(M+H) + ]. 1 H NMR(500MHz,DMSO-d6)δ=11.56(d,J=1.7Hz,1H),11.46(dd,J=6.0,1.4Hz,1H),8.71(s,1H),8.69(d,J=5.0Hz,1H),8.38(d,J=6.1H) z,1H),7.70(s,1H),7.53-7.37(m,1H),6.73(td,J=53.8,3.1Hz,1H),6.26(ddd,J=14.0,8.9,3.2Hz,1H),5.29(s,2H),4.01(s,3H).

[0290] Examples 37A and 37B 5-[3-[(1R)-1-[2-[(1S)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1R)-1-[2-[(1R)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka]

[0291] The title compound was synthesized according to the following scheme: [ka]

[0292] Step (a): Preparation of 1-(4-bromo-2-pyridyl)ethanol (compound 37.2) To a solution of 1-(4-bromo-2-pyridyl)ethanol (compound 37.1, 5 g, 25 mmol) in methanol (50 mL), sodium borohydride (1.1 g, 30 mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 0.5 hours. The reaction product was quenched with 1 N HCl. Methanol was removed under vacuum, and the resulting mixture was extracted three times with DCM (20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 37.2 (4.8 g). Calculated value: 201.9 [(M+H)] + ], measured value 201.9 [(M+H) + ].

[0293] Step (b): Preparation of 4-bromo-2-(1-bromoethyl)pyridine (compound 37.3) To a suspension of 1-(4-bromo-2-pyridyl)ethanol (compound 37.2, 4.8 g, 23.8 mmol) in DCM (60 mL), carbon tetrabromide (10.2 g, 30.9 mmol) and triphenylphosphine (8.1 g, 30.9 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (PE / EA from 100 / 1 to 10 / 1) to obtain compound 37.3 (6 g). Calculated value: 263.9 [(M+H)] + ]; Measured value 263.9 [(M+H) + ].

[0294] Step (c): Preparation of 4-bromo-2-[1-(cyclopropoxy)ethyl]pyridine (compound 37.4) A solution of cyclopropanol (3 g, 50.9 mmol) in DMF (40 mL) was mixed with sodium hydride (60% dispersion in mineral oil, 3.4 g, 84.9 mmol) at 0°C. The resulting mixture was stirred at room temperature for 30 minutes, and then 4-bromo-2-(1-bromoethyl)pyridine (compound 37.3, 4.5 g, 17 mmol) was added. The reaction mixture was stirred at room temperature for another 30 minutes. The reaction mixture was quenched with H2O (20 mL) and extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA from 30 / 1 to 15 / 1) to obtain compound 37.4 (2.9 g), which was used directly in the next step without characterization.

[0295] Step (d): Preparation of 2-[1-(cyclopropoxy)ethyl]-4-vinylpyridine (compound 37.5) To a suspension of 4-bromo-2-[1-(cyclopropoxy)ethyl]pyridine (compound 37.4, 2.3 g, 9.5 mmol) and potassium vinyl trifluoroborate (3.2 g, 23.8 mmol) in isopropanol (45 mL), triethylamine (1.4 g, 2 mL, 14.3 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(ii) dichloromethane adduct (193.9 mg, 237.5 μmol) were added. After stirring at 82 °C under nitrogen for 1.5 hours, the reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA from 30 / 1 to 20 / 1) to obtain compound 37.5 (2.1 g). Calculated value: 190.1 [(M+H)] + ]; Measured value 190.1[(M+H) + ]

[0296] Step (e): Preparation of 2-[1-(cyclopropoxy)ethyl]pyridine-4-carbaldehyde (compound 37.6) A suspension of 2-[1-(cyclopropoxy)ethyl]-4-vinylpyridine (compound 37.5, 2.1 g, 11.0 mmol) in 1,4-dioxane (80 mL) / water (40 mL) is mixed with NaIO4 (7.1 g, 33.0 mmol) and K2OsO4. . 2H₂O (202.5 mg, 549.5 μmol) was added. The resulting mixture was stirred at 20°C for 2 hours. The reaction products were quenched with saturated Na₂S₂O₃ and saturated NaHCO₃, respectively. The resulting mixture was stirred at room temperature for 1 hour and extracted three times with EA (150 mL). The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA from 1 / 10 to 1 / 3) to obtain compound 37.6 (1.4 g). Calculated value 192.1[(M+H) + ]; Measured value 224.0 [(M+MeOH+H) + ].

[0297] Step (f): Preparation of 1-[2-[1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethanol (compound 37.7) CsF (222.4 mg, 1.5 mmol) was added to a mixture of 2-[1-(cyclopropoxy)ethyl]pyridine-4-carbaldehyde (compound 37.6, 1.4 g, 7.3 mmol) and (difluoromethyl)trimethylsilane (1.8 g, 14.6 mmol) in DMF (15 mL). The resulting mixture was stirred at 20°C for 2 hours. The reaction product was quenched with H2O (10 mL) and extracted three times with EA (20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA from 1 / 1 to 1 / 1) to obtain compound 37.7 (520 mg). Calculated value 244.1 [(M+H)] + ]; Measured value 244.0 [(M+H) + ].

[0298] Step (g): Preparation of 1-[2-[1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoro-ethanone (compound 37.8) A mixture of 1-[2-[1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethanol (compound 37.7, 520 mg, 2.1 mmol) in DCM (20 mL) was mixed with DMP (1.8 g, 4.3 mmol) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated Na2S2O3 and saturated NaHCO3, respectively, and extracted three times with DCM (50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA from 1 / 4 to 1 / 4) to obtain compound 37.8 (530 mg). Calculated value 242.1[(M+H)] + ]; Measured value 261.0 [(M+H2O+H) + ].

[0299] Step (h): Preparation of (1S)-1-[2-[1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethanol (compound 37.9) To a mixture of 1-[2-[1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoro-ethanone (compound 37.8, 530 mg, 2.2 mmol) in DCM (4.0 mL), formic acid (2 g, 1.7 mL, 43.9 mmol), triethylamine (1.8 g, 2.4 mL, 17.6 mmol), and RuCl(p-cymene)[(R,R)-Ts-DPEN] (69.9 mg, 109.9 μmol) were added at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was carefully quenched with saturated NaHCO3 and extracted three times with DCM (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EA from 1 / 4 to 1 / 1) to obtain compound 37.9 (520 mg). Calculated value 244.1[(M+H) + ]; Measured value 244.0 [(M+H) + ]

[0300] Step (i): Preparation of 3-[(1R)-1-[2-[1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-5-(2,4-ditert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (compound 37.10) DEAD (374.1 mg, 338.2 μL, 2.2 mmol) was added dropwise to a suspension of (1S)-1-[2-[1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethanol (compound 37.9, 496.4 mg, 2 mmol) in toluene (6 mL), 5-(2,4-dittert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine-3-ol (intermediate B1, 400 mg, 1.1 mmol) and triphenylphosphan (597.8 mg, 2.2 mmol) at 60°C. The resulting mixture was stirred under nitrogen at 60°C for 30 minutes. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA from 1 / 1 to 3 / 2) to obtain compound 37.10 (280 mg). Calculated value 598.3[(M+H) + ]; Measured value 598.6 [(M+H) + ].

[0301] Step (j): Preparation of 3-[(1R)-1-[2-[(1S)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-5-(2,4-ditert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine and 3-[(1R)-1-[2-[(1R)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-5-(2,4-ditert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (compounds 37.10A and 37.10B) Compound 37.10 (280 mg) was separated by SFC to obtain two single isomers: compound 37.10A (faster elution, 107 mg) calculated value 598.3[(M+H)+]; measured value 598.6.0[(M+H)+]; and compound 37.10B (slower elution, 100 mg) calculated value 598.3[(M+H)+]; measured value 598.6[(M+H)+]. SFC conditions: column: IK250×30 mm, 5 μm; mobile phase: CO2 A, ethanol (0.1% NH3H2O) B; gradient: B 25%, flow rate: 80 mL / min, back pressure: 100 bar, column temperature: 35 °C.

[0302] Step (k): Preparation of 5-[3-[(1R)-1-[2-[(1S)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 37A and 37B) A mixture of compound 37.10A (107 mg, 179 μmol) in methanol (1.7 mL) was mixed with 2 M hydrogen chloride (447.6 μL, 895.2 μmol). The resulting mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 37A (49.5 mg). Calculated value: 486.2 [(M+H)] + ]; Measured value 486.8 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.56(d,J=1.75Hz,1H),11.45-11.51(m,1H),8.74 (s,1H),8.62(d,J=5.13Hz,1H),8.38(d,J=6.25Hz,1H),7.71(s,1H),7.61(br d,J=5.13Hz,1H),6.68(td,J=53.78,2.75Hz,1H),6.36(td,J=11.79,2.44Hz,1H),4.65(q,J=6.59Hz,1H),4.00(s,3 H),3.14(tt,J=6.02,3.05Hz,1H),1.39(d,J=6.63Hz,3H),0.37-0.46(m,1H),0.29-0.36(m,1H),0.18-0.29(m,2H).

[0303] A mixture of compound 37.10B (100 mg, 167.3 μmol) in methanol (1.6 mL) was mixed with 2 M hydrogen chloride (418.3 μL, 836.6 μmol). The resulting mixture was stirred at room temperature for 1 hour, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 37B (56.2 mg). Calculated value: 486.2 [(M+H)] + ]; Measured value 486.8 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.75Hz,1H),11.47(br d,J=5.00Hz,1H),8.73(s,1H),8.60(d,J=5.13Hz,1H),8.37(d,J=6.25Hz,1H),7.74(s,1H),7.59(br d,J=4.88Hz,1H),6.67(td,J=53.41,2.75Hz,1H),6.30-6.41(m,1H),4.66(q,J=6.55Hz,1H),4.00( s,3H),3.23(dt,J=6.03,3.05Hz,1H),1.37(d,J=6.63Hz,3H),0.49-0.57(m,1H),0.30-0.46(m,3H).

[0304] Example 38 5-[3-[(1R)-1-[2-(3,3-difluorocyclobutyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] The title compound was synthesized according to the following scheme: [ka]

[0305] Step (a): Preparation of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-1-[2-(3,3-difluorocyclobutyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine (Compound 38.2) 3-[(1R)-1-(2-bromo-4-pyridyl)-2,2-difluoroethoxy]-5-(2,4-di-tert-butoxypyrimidine-5-yl)-1-methylpyrazolo[3,4-c]pyridazine (intermediate D5, 500 mg, 0.84 mmol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel dichloride (67.2 mg, 0.1 mL) in ethylene glycol dimethyl ether (5 mL) A mixture of 7 mmol) 3-bromo-1,1-difluorocyclobutane (compound 38.1, 433 mg, 2.53 mmol), tris(trimethylsilyl)silane (0.31 mL, 1.01 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (47.4 mg, 0.04 mmol), and sodium carbonate (268 mg, 2.53 mmol) was irradiated with blue LED light at 25°C for 3 hours under a nitrogen atmosphere. The reaction mixture was quenched with water and extracted three times with EA (30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20 g, 0%~100% EA in PE) to obtain the desired product compound 38.2 (146 mg). MS: Calculated value 604.3[(M+H)] + ]; Measured value 604.3 [(M+H) + ].

[0306] Step (b): Preparation of 5-[3-[(1R)-1-[2-(3,3-difluorocyclobutyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Example 38) A solution of 5-(2,4-di-tert-butoxypyrimidine-5-yl)-3-[(1R)-1-[2-(3,3-difluorocyclobutyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine (compound 38.2, 140 mg, 0.23 mmol) in DCM (5 mL) was mixed with 4N HCl / dioxane (0.5 mL). The resulting mixture was stirred at room temperature for 2 hours, then concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 186 (37.6 mg). MS: Calculated value 492.1[(M+H)] + ]; Measured value 492.2[(M+H) + ]. 1 h nmr(400MHz,dmso-d6)δ11.26(br s,2h),8.72(d,j=1.6Hz,1h),8.65(d,j=5.1Hz,1h),8.39(s,1h),7.59(s,1h),7.50(dd,j=5.1,1.6Hz,1h),6.64(td, j=53.8,2.9Hz,1h),6.28(td,j=12.4,11.9,2.9Hz,1h),4.01(s,3h),3.56(qt,j=8.6,4.2Hz,1h),3.02-2.76(m,4h).

[0307] Examples 39A and 39B 5-[3-[(1R)-2,2-difluoro-1-[6-(1,1,2,2,2-pentaduterioethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-2,2-difluoro-1-[6-(1,1,2,2,2-pentaduterioethoxy)pyrimidine-4-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Examples 39A and 39B were prepared in the same manner as Examples 35A and 35B, by replacing 2,2,2-trifluoroethanol with 1,1,2,2,2-pentaduterioethanol in step (b).

[0308] Example 39A MS: Calculated value 452.2[(M+H)] + ]; Measured value 452.2 [(M+H) + ]. 1 h nmr(400MHz,dmso-d6)δ=11.46(br s,2h),8.83(d,j=1.2Hz,1h),8.72(d,j=1.1Hz,1h),8.38(s,1h),7.15(s,1h),6.71(td,j=53.5,2.5Hz,1h),6.26-6.09(m,1h),4.03(s,3h).

[0309] Example 39B MS: Calculated value 452.2[(M+H)] + ]; Measured value 452.2 [(M+H) + ]. 1 h nmr(400MHz,dmso-d6)δ=11.46(br s,2h),8.83(d,j=1.2Hz,1h),8.72(d,j=1.1Hz,1h),8.38(s,1h),7.15(s,1h),6.71(td,j=53.5,2.5Hz,1h),6.24-6.10(m,1h),4.03(s,3h).

[0310] Example 40: 5-[1-methyl-3-[(1R)-2,2-difluoro-1-[2-[(trans)-4-methyltetrahydrofuran-3-yl]oxy-4-pyridyl]ethoxy]pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 40 was prepared in the same manner as Example 28, by replacing 2-methoxyethanol with (trans)-4-methyltetrahydrofuran-3-ol in step (a). MS: Calculated value 502.2[(M+H)] +]; Measured value 502.1 [(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.48(d,J=1.8Hz,1H),11.38(dd,J=1.6,6.0Hz,1H),8.64(s,1H),8.3 0(d,J=6.3Hz,1H),8.13(d,J=5.4Hz,1H),7.13(dd,J=0.9,5.3Hz,1H),6.96(s,1H),6.52(dt,J= 2.8,54.3Hz,1H),6.24-6.12(m,1H),5.05-4.92(m,1H),3.95(s,3H),3.94-3.85(m,2H),3.64(d dd,J=1.9,5.3,10.4Hz,1H),2.34-2.18(m,1H),1.28-1.14(m,1H),0.99(dd,J=2.6,7.1Hz,3H).

[0311] Example 41 5-[3-[(1R)-2,2-difluoro-1-[2-[(1-methoxycyclopropyl)methoxy]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione [ka] Example 41 was prepared in the same manner as Example 28, by replacing 2-methoxyethanol with (1-methoxycyclopropyl)methanol in step (a). MS: Calculated value 502.2[(M+H)] + ]; Measured value 502.1 [(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.5Hz,1H),11.45(dd,J=1.5,6.1Hz,1H), 8.72(s,1H),8.37(d,J=6.1Hz,1H),8.18(d,J=5.2Hz,1H),7.19(dd,J=1.2,5.3 Hz,1H),7.06(s,1H),6.63(dt,J=3.2,53.9Hz,1H),6.30-6.21(m,1H),4.43-4. 33(m,2H),4.02(s,3H),3.24(s,3H),0.79(d,J=1.8Hz,2H),0.70-0.64(m,2H).

[0312] Examples 42A and 42B 5-[3-[(1R)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-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]

[0313] Step (a): Preparation of 6-(3,3-difluorocyclobutoxy)-N-methoxy-N-methylpyrimidine-4-carboxamide (compound 42.1) To a solution of 3,3-difluorocyclobutanol (3.22 g, 29.76 mmol) and 6-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (compound 14.2, 3.0 g, 14.88 mmol) in DMF (30 mL), cesium fluoride (6.78 g, 44.64 mmol) was added, and the resulting mixture was stirred at 80°C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (300 mL) and extracted three times with EA (100 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, PE 0%~50% EA) to obtain compound 42.1 (3.3 g). MS: Calculated value 274.1[(M+H)] + ]; Measured value 274.0 [(M+H) + ].

[0314] Step (b): Preparation of 1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoro-ethanone (compound 42.2) To a solution of (difluoromethyl)trimethylsilane (4.09 g, 32.94 mmol) and 6-(3,3-difluorocyclobutoxy)-N-methoxy-N-methylpyrimidine-4-carboxamide (compound 42.1, 4500 mg, 16.47 mmol) in THF (50 mL), tBuOK (2.4 g, 21.41 mmol) was added at 0°C. The resulting mixture was stirred at 0°C for 60 minutes. The reaction mixture was diluted with water (100 mL) and extracted twice with EA (80 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 80 g, PE with 0 to 90% EA) to obtain compound 42.2 (2700 mg). MS: Calculated value 274.1[(M+H)] + ]; Measured value 282.1[(M+H) + ].

[0315] Step (c): Preparation of 5-[3-[(1R)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione and 5-[3-[(1S)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione (Examples 42A and 42B) Examples 42A and 42B were prepared in the same manner as Examples 35A and 35B, by replacing 2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethanol (compound 35.3) with 1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoro-ethanone (compound 42.2) in step (d).

[0316] Example 42A MS: Calculated value 509.1[(M+H)] + ]; Measured value 509.1[(M+H) + ]. 1 H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.8Hz,1H),11.46(dd,J=1.5,6.1Hz,1H),8.87(d,J=1.1Hz,1H),8.72(s,1H),8.38(d,J=6.1Hz,1H),7.25( s,1H),6.72(dt,J=2.5,53.3Hz,1H),6.21(ddd,J=2.9,8.7,14.8Hz,1H) ,5.27-5.14(m,1H),4.02(s,3H),3.26-3.07(m,2H),2.89-2.68(m,2H).

[0317] Example 42B MS: Calculated value 509.1[(M+H)] + ]; Measured value 509.1[(M+H) + ]. 1H NMR(400MHz,DMSO-d6)δ=11.55(d,J=1.5Hz,1H),11.49-11.41(m,1H),8.87(d,J=1.0Hz,1H),8.72(s,1H),8.38(d,J=6.1Hz,1H),7.25(s,1 H),6.72(dt,J=2.9,53.2Hz,1H),6.21(ddd,J=2.6,8.7,14.9Hz,1H),5.27-5.14(m,1H),4.02(s,3H),3.26-3.04(m,2H),2.87-2.69(m,2H).

[0318] Reference compound: Compound G531, disclosed in International Publication No. 2021222522 as Example 531, was selected as the reference compound for this application. [ka]

[0319] (G531) Biological examples Example 43: Human CD73 Biochemical Assay The objective of this assay was to identify and characterize inhibitors of human CD73 enzyme activity. Serial dilutions (1:3) of the compound were prepared in corresponding wells of a 384-well plate using an Echo 555 liquid handler (Labcyte). 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, 0.2 mM octyl glucoside, and 1 mM NaH2PO4) was added to the assay plate and incubated with the compound at room temperature for 15 minutes. 15 μL of AMP working solution (containing 10 mM Tris pH 7.5, 100 mM NaCl, 0.01% BSA, and 0.2 mM octyl glucoside, resulting in a final concentration of 5.56 μM AMP) was added, followed by incubation at room temperature for 10 minutes. The reaction was stopped by adding 75 μL of stop solution (5% TCA in H2O containing 250 nM 13C5-adenosine) to each well for a 10-minute incubation. After centrifugation, 75 μL of the mixture was transferred to a new 384-well plate for LC / MS analysis.

[0320] Samples from 384-well plates were loaded onto an autosampler deck, and then ADDA-LC-MS / MS was injected. 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 ACE 5 Phenyl, 50 × 2.1 mm. Analysis was performed using a SCIEX triple quadrupole mass spectrometer operating in cation mode. Elutions from the HPLC column were directly introduced into electrospray ionization (ESI). Multiple reaction monitoring (MRM) was used to determine the 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) semi-quantification method. [Table 1]

[0321] Example 44: CD73 cell assay Serial dilutions (1:3) of the compound 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 incubation with the compound for 30 minutes, 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 in a 5% CO2 incubator (Thermo Fisher Scientific) at 37°C for 45 minutes. After the reaction was complete, 50 μL of the 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. Then, 10 μL of malachite B was added to each corresponding well of the plate and incubated for 30 minutes. Finally, absorbance values ​​were read at 620 nM using an Envision plate reader. The inhibition rate was calculated using the formula {% inhibition = 100 × [1 - (X - MIN) / (MAX - MIN)]}. In the formula, 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]

[0322] Example 45: Cell proliferation assay The objective of this assay was to characterize the efficacy of CD73 inhibitors in the rescue of adenosine-mediated inhibition of T cell proliferation. CD4+ or CD8+ T cells were isolated from peripheral blood mononuclear cells (PBMCs, HemaCare) by immunomagnetically negative selection using the EasySep® Isolation Kit (STEMCELL Technologies) according to the supplier's protocol. Pan T cells were pelleted by centrifugation at 300 gravity (g) for 5 minutes at room temperature and resuspended in PBS. CellTrace® Violet staining solution (Invitrogen) was added at a ratio of 1:5,000 and incubated at 37°C for 20 minutes under protection from light. Next, complete culture medium [RPMI-1640 (Gibco), 10% fetal bovine serum (Gibco), 2 mM GlutaMAX (Gibco), and 1 mM sodium pyruvate (Gibco), 100 U / mL penicillin-streptomycin (Gibco), and MEM non-essential amino acid (NEAA) cell culture supplement (1:100, Gibco)] was added, mixed, and incubated at 37°C for 5 minutes. The cells were then pelletized by centrifugation at 300 g at room temperature for 5 minutes and resuspended in fresh, preheated 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) were added to the cells at final concentrations of 200 μM and 5 μM, respectively. Cells were incubated in a 5% CO2 incubator at 37°C for 72 hours. Then, 200 μL of PBS was added to each well, and the cells were centrifuged at 300 g at 4°C for 10 minutes. The supernatant was discarded. 50 μL of Human TruStain FcX (trademark) (Fc receptor blockade solution, BioLegend), diluted 1:100 with PBS, was added to each well, gently mixed, and incubated at 4°C for 20 minutes. 50 μL of staining solution (BioLegend) was added to each well, gently mixed, and incubated at 4°C for 30 minutes. The cells were centrifuged at 300 g at 4°C for 10 minutes, and the supernatant was discarded.The cell pellet was washed with 250 μL of cell staining buffer and centrifuged at 300 g at 4°C for 10 minutes. The supernatant was discarded, and the cells were resuspended in 60 μL of cell staining buffer and analyzed by flow cytometry. [Table 3]

[0323] Example 46: T cell cytokine release function assay The objective of this assay was to characterize the efficacy of CD73 inhibitors in rescuing adenosine-mediated inhibition of T cell cytokine release function. Pan T cells were isolated from peripheral blood mononuclear cells (PBMCs, HemaCare) by immunomagnetically negative selection using the EasySep® Isolation Kit (STEMCELL Technologies) according to the supplier's protocol. The T cells were then pelleted by centrifugation at 300 g for 5 minutes at room temperature and resuspended in fresh, preheated 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) were added to the cells at final concentrations of 200 μM and 5 μM, respectively. The cells were incubated in a 5% CO2 incubator at 37°C for up to 72 hours. 50 μL of supernatant was collected to determine the IFN gamma level using the Luminex assay (Thermo Fischer Scientific).

Claims

1. Compound of formula (I) 【Chemistry 1】 (In the formula, R １ These are 2,4-dioxo-1H-pyrimidinyl or 3,5-dioxo-2H-1,2,4-triazinyl; R ２ C １～６ Alkyl or deuterio C １～６ It is alkyl; R ３ C １～６ Alkyl or Halo C １～６ It is alkyl; R ４ is H; R ５ is (C １～６ alkoxy C ３～７ cycloalkyl)C １～６ alkoxy, (C １～６ alkyltetrahydrofuranyl)oxy, (cyano C ３～７ cycloalkyl)C １～６ alkoxy, (halo C １～６ alkoxy)C １～６ alkyl, (halo C １～６ alkyl C ３～７ cycloalkyl)C １～６ alkoxy, (halo C ３～７ cycloalkyl)amino, (halo C ３～７ cycloalkyl)C １～６ alkoxy, (halopyrrolidinyl)C １～６ alkyl, C １～６ alkoxy, C １～６ alkoxy C １～６ alkoxy, C ３～７ cycloalkoxy C １～６ alkyl, cyano C １～６ alkoxy, deuterio C １～６ alkoxy, deuteriohalo C １～６ alkoxy, halo C １～６ alkoxy, halo C １～６ alkyl, halo C １～６ alkylamino, halo C ３～７ cycloalkoxy, halo C ３～７ cycloalkyl or halopiperidyl; T is O; L is 1,4-benzoxazinylene, indazoylene, pyrimidinylene, unsubstituted or halogen-substituted phenylene, or unsubstituted or halogen-substituted pyridylene. or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 having the structure of formula (I-1) 【Chemistry 2】 (In the formula, R １ These are 2,4-dioxo-1H-pyrimidinyl or 3,5-dioxo-2H-1,2,4-triazinyl; R ２ C １～６ Alkyl or deuterio C １～６ It is alkyl; R ３ C １～６ Alkyl or Halo C １～６ It is alkyl; R ４ is H; R ５ is, (C １～６ Alkoxy C ３～７ Cycloalkyl) C １～６ Alkoxy, (C １～６ Alkyltetrahydrofuranyl)oxy, (cyano C ３～７ Cycloalkyl) C １～６ Alkoxy, (Halo C) １～６ Alkoxy) C １～６ Alkyl, (Halo C) １～６ Alkyl C ３～７ Cycloalkyl) C １～６ Alkoxy, (Halo C) ３～７ Cycloalkyl)amino, (halo C ３～７ Cycloalkyl) C １～６ Alkoxy, (halopyrrolidinyl) C １～６ Alkyl, C １～６ Alkoxy, C １～６ Alkoxy C １～６ Alkoxy, C ３～７ Cycloalkoxy C １～６ Alkyl, cyano C １～６ Alkoxy, Deuterio C １～６ Alkoxy, Deuteriohalo C １～６ Alkoxy, Halo C １～６ Alkoxy, Halo C １～６ Alkyl, Halo C １～６ Alkylamino, Halo C ３～７ Cycloalkoxy, Halo C ３～７ It is cycloalkyl or halopiperidyl; T is O; L is 1,4-benzoxazinylene, indazoylene, pyrimidinylene, unsubstituted or halogen-substituted phenylene, or unsubstituted or halogen-substituted pyridylene. or a pharmaceutically acceptable salt thereof.

3. R １ but 【Transformation 3】 【Chemistry 4】 The compound according to claim 1 or 2.

4. R ２ C １～６ A compound according to any one of claims 1 to 3, wherein it is alkyl.

5. R ２ The compound according to any one of claims 1 to 4, wherein is methyl.

6. R ３ ga HaroC １～６ A compound according to any one of claims 1 to 5, wherein it is alkyl.

7. R ３ The compound according to any one of claims 1 to 6, wherein is difluoromethyl.

8. The compound according to any one of claims 1 to 7, wherein L is pyrimidinylene, or unsubstituted or halogenated pyridylene.

9. The compound according to any one of claims 1 to 8, wherein L is pyrimidinylene, or unsubstituted or fluorosubstituted pyridylene.

10. R ５ is (haloC １～６ alkoxy)C １～６ alkyl, (halopyrrolidinyl)C １～６ alkyl, C ３～７ cycloalkoxyC １～６ alkyl, haloC １～６ alkoxy, haloC １～６ alkylamino, haloC ３～７ cycloalkoxy or haloC ３～７ cycloalkyl, and is a compound according to any one of claims 1 to 9.

11. R ５ The compound according to any one of claims 1 to 10, wherein the compound is (3,3-difluoropyrrolidine-1-yl)methyl, [2,2,2-trifluoro-1-methyl-ethyl]amino, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluoroethoxy, 3,3-difluorocyclobutoxy, 3,3-difluorocyclobutyl, or cyclopropoxymethyl.

12. R １ but, 【Transformation 5】 or 【Transformation 6】 And; R ２ However, C １～６ It is alkyl; R ３ is halo C １～６ alkyl; R ４ H is; R ５ However, (Hello C １～６ Alkoxy) C １～６ Alkyl, (halopyrrolidinyl) C １～６ Alkyl, C ３～７ Cycloalkoxy C １～６ Alkyl, Halo C １～６ Alkoxy, Halo C １～６ Alkylamino, Halo C ３～７ Cycloalkoxy or Halo C ３～７ It is a cycloalkyl; T is O; L is either pyrimidinylene, unsubstituted, or halogen-substituted pyridylene. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

13. R １ but, 【Transformation 7】 or 【Transformation 8】 And; R ２ is methyl; R ３ It is difluoromethyl; R ４ H is; R ５ However, these are (3,3-difluoropyrrolidine-1-yl)methyl, [2,2,2-trifluoro-1-methyl-ethyl]amino, 2,2,2-trifluoroethoxy, 2,2,2-trifluoroethoxymethyl, 2,2-difluoroethoxy, 3,3-difluorocyclobutoxy, 3,3-difluorocyclobutyl, or cyclopropoxymethyl; T is O; L is either a pyrimidinylene, an unsubstituted pyridylene, or a fluorosubstituted pyridylene. The compound according to claim 12 or a pharmaceutically acceptable salt thereof.

14. The following compounds can be selected: 5-[3-[(1R)-2,2-difluoro-1-[3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(cyclopropoxymethyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2,2,2-trifluoroethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[4-(1,1-diduterio-2,2,2-trifluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy-1-methylpyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-(triduteriomethyl)pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[4-(2,2-difluoroethoxy)-2-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[5-(2,2,2-trifluoroethoxy)-3-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-4-(2,2,2-trifluoroethoxy)-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-4-(2,2,2-trifluoroethoxy)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 6-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4-triazine-3,5-dione; 6-[3-[(1R)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4-triazine-3,5-dione; 6-[3-[(1S)-1-[2-(2,2-difluoroethoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-2H-1,2,4-triazine-3,5-dione; 5-[1-methyl-3-[(1S)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-fluoro-3-(2-methoxyethoxy)phenyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(2,2-difluoropropoxy)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoro-1-methylethoxy)-2-pyridyl]ethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-1-[4-[(2,2-difluorocyclopropyl)methoxy]-2-pyridyl]-2,2-difluoroethoxy]pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-(4-ethoxy-2-pyridyl)-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 2-[[2-[(1R)-1-[5-(2,4-dioxo-1H-pyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-4-pyridyl]oxy]acetonitrile; 1-[[2-[(1R)-1-[5-(2,4-dioxo-1H-pyrimidine-5-yl)-1-methyl-pyrazolo[3,4-c]pyridazin-3-yl]oxy-2,2-difluoroethyl]-4-pyridyl]oxymethyl]cyclopropanecarbonitric; 5-[3-[(1R)-2,2-difluoro-1-[4-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[1-(2,2,2-trifluoroethyl)indazole-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(2,2,2-trifluoroethyl)-2,3-dihydro-1,4-benzoxazine-6-yl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-[[(1S)-2,2,2-trifluoro-1-methyl-ethyl]amino]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-[[(1R)-2,2,2-trifluoro-1-methyl-ethyl]amino]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(2-methoxyethoxy)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-(2-ethoxy-4-pyridyl)-2,2-difluoroethoxy]-1-methyl-pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(1,1,2,2,2-pentaduterioethoxy)-4-pyridyl]ethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(4,4-difluoro-1-piperidyl)-4-pyridyl]-2,2-difluoro-ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(4,4-difluorocyclohexyl)amino]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(3,3-difluoropyrrolidine-1-yl)methyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-(2,2,2-trifluoroethoxymethyl)-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl]ethoxy-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[4-(trifluoromethoxymethyl)-2-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(1S)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-[(1R)-1-(cyclopropoxy)ethyl]-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[2-(3,3-difluorocyclobutyl)-4-pyridyl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[6-(1,1,2,2,2-pentaduterioethoxy)pyrimidine-4-yl]ethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1S)-2,2-difluoro-1-[6-(1,1,2,2,2-pentaduterioethoxy)pyrimidine-4-yl]ethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[1-methyl-3-[(1R)-2,2-difluoro-1-[2-[(trans)-4-methyltetrahydrofuran-3-yl]oxy-4-pyridyl]ethoxy]pyrazolo[3,4-c]pyridazine-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-2,2-difluoro-1-[2-[(1-methoxycyclopropyl)methoxy]-4-pyridyl]ethoxy]-1-methyl-pyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; 5-[3-[(1R)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; and 5-[3-[(1S)-1-[6-(3,3-difluorocyclobutoxy)pyrimidine-4-yl]-2,2-difluoroethoxy]-1-methylpyrazolo[3,4-c]pyridazin-5-yl]-1H-pyrimidine-2,4-dione; or a pharmaceutically acceptable salt thereof.

15. A method for preparing a compound according to any one of claims 1 to 14, comprising the following steps: a) Compound of formula (X) 【Chemistry 9】 The compound of formula (Ia) is obtained by deprotecting it in the presence of an acid, a dealkylating agent, or metal-mediated hydrogenation. 【Chemistry 10】 The process of obtaining; b) Compound of formula (XIII) 【Chemistry 11】 The compound of formula (Ib) is obtained by deprotecting it in the presence of an acid, a dealkylating agent, or metal-mediated hydrogenation. 【Chemistry 12】 The process of obtaining; c) Compound of formula (XV) in the presence of a palladium catalyst 【Chemistry 13】 and Organostannan (XVI) 【Chemistry 14】 The compound of formula (Ic) is formed by still coupling with 【Chemistry 15】 The process of obtaining; Includes any of the following: X is a halogen, each PG is independently an oxygen protecting group, and PG is selected from methyl, tert-butyl, TBS, ethoxymethyl and benzyl, R ６ These may be substituted with aryl, heteroaryl, heterocyclyl, or aryl C. １～６ Alkyl, heterocyclyl C １～６ Alkyl or heteroaryl C １～６ It is alkyl; In steps a) and b), the acid is trifluoroacetic acid or an aqueous hydrochloric acid solution, the dealkylation reagents are TMSCl and NaI, and the hydrogenation is carried out using Pd / C; In step c), the catalyst is Pd(PPh ３ ) ４ And; R １ ~R ５ and L are as defined in any one of claims 1 to 13. method.

16. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14 for use as a therapeutically active substance.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable additive.

18. Use of the compound according to any one of claims 1 to 14 for the treatment of cancer.

19. The use according to claim 18, wherein the cancer is pancreatic cancer, colorectal cancer, stomach cancer, esophageal cancer, liver cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, or melanoma.

20. Use of any one of the compounds according to claims 1 to 14 for inhibiting CD73.

21. Use of a compound according to any one of claims 1 to 14 for the preparation of a medicament for the treatment or prevention of 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.

22. Use of a compound according to any one of claims 1 to 14 for the preparation of a pharmaceutical as a CD73 inhibitor.

23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 14, as produced according to the method of claim 15.

24. The invention as described earlier in this specification.

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