CGAS inhibitor triazolopyrimidone derivatives

Abstract

The present invention relates to a compound of formula (I) TIFF2023525908000062.tif38165 (In the formula, R 1 -R 3 and A 1 -A 3 as described in the specification and claims. The compounds of formula (I) can be used as medicines.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for therapy and / or prophylaxis in mammals, particularly compounds that modulate cGAS activity.

[0002] The present invention particularly relates to compounds of formula (I): [ka] (In the formula, R 1 is alkylpiperazinyl(halopyridinyl), morpholino(halopyridinyl), morpholino(halopyrimidinyl), 2-oxa-6-azaspiro[3.3]heptanyl(halopyridinyl), pyrimidinyl(halophenyl), alkylpyrazolyl(halophenyl), ortho-para-dichlorophenyl, ortho-fluoro-para-chlorophenyl, cycloalkylisoxazolyl, phenylpyrazolyl, phenylisoxazolyl, pyrazinylpyrazolyl, alkylpiperazinyl(halopyridinyl), phenyl(alkylpyrazolyl), piperidyl(halopyridinyl), alkylimidazolyl(halophenyl), morpholinophenyl, morpholino(halophenyl), morpholino(halopyridinyl), alkoxyazetidinyl(halopyridinyl), halobiphenyl, pyridinyl(halophenyl), isoxazolyl thiazolylcarbonylamino(halopyridinyl), alkylpyrazolyl(cyanophenyl), pyridazinyl(halophenyl), biphenyl, thiazolylamino(halophenyl), alkylpyrazolyl(alkoxyphenyl), alkylpyrazolyl(alkylphenyl), alkylpyrazolyl(pyridinyl), alkylpyrazolyl(haloalkylphenyl), quinolyl, biphenyl, alkylpyrazolylphenyl, phenylalkyloxy(halophenyl), alkoxy(halophenyl), cycloalkyloxyphenyl, imidazolylphenyl, haloalkyloxyphenyl, cyano(halophenyl), pyrazolylphenyl, benzoxazole, isopropylphenyl, alkoxy(alkylphenyl), pyrimidinylphenyl, halo(alkylphenyl) or (para-ethyloxy)phenyl; R 2 is hydrogen or methyl, R 3 is alkyl, cycloalkyl, alkoxyalkyl, difluoroalkyl, trifluoroalkyl, phenylalkyl, phenylaminoalkyl or cycloalkylalkyl; A 1 is -NH- or oxygen; A 2 is oxygen or sulfur; and A 3 is -CH- or nitrogen) or a pharmaceutically acceptable salt or tautomer thereof, however, [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(2,4-dichlorophenyl)methyl]amino]-5-propyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 5-ethyl-2-[[[4-(1-methylethyl)phenyl]methyl]amino]; [1,2,4]Triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(2,4-dichlorophenyl)methyl]amino]-5-methyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-(1-methylethyl); [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[[4-(1-methylethyl)phenyl]methyl]amino]-5-[(phenylamino)methyl]; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[[4-(1-methylethyl)phenyl]methyl]amino]-5-propyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-[(phenylamino)methyl]; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 5-methyl-2-[[[4-(1-methylethyl)phenyl]methyl]amino]; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-methyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-propyl; and [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-ethyl; The present invention relates to a compound or a pharmaceutically acceptable salt or tautomer thereof, wherein the following is excluded: [Background technology]

[0003] Cytokines are involved in regulating innate immune responses, and dysregulation of pro-inflammatory cytokines is associated with severe systemic inflammatory and autoimmune diseases, many of which nowadays lack efficient treatments.

[0004] Vertebrates possess innate and adaptive immune systems to defend against pathogens and other challenges. The innate immune system is an evolutionarily ancient system present across vertebrates. Unlike the adaptive immune system, it does not require priming or training but functions as a general physical barrier (e.g., skin) or by detecting specific patterns. One universal pattern that triggers the innate immune system is the detection of cytoplasmic double-stranded DNA, which leads to a type I interferon response. The source of cytoplasmic dsDNA can be derived from bacterial or viral infections, but can also be derived from accumulated self-DNA.

[0005] The cytoplasmic enzyme cyclic GMP-AMP synthase (cGAS) is a sensor of cytoplasmic double-stranded DNA. Binding of dsDNA results in the enzymatic conjugation of ATP and GTP to generate the cyclic dinucleotide 2,3-cAMP. 2,3-cGAMP acts as a second messenger and binds to the stimulator of interferon genes (STING) present in the endoplasmic reticulum. Upon binding, STING translocates to the perinuclear Golgi, where it associates with TANK-binding kinase 1 (TBK1) and recruits and phosphorylates interferon response factor 3 (IRF3). Ultimately, this leads to the production of other cytokines, such as type I interferon (IFN), IL-6, TNFα, IL-1, and chemokines, which are essential factors for host defense against invading pathogens. However, inappropriate or chronic production of type I IFN and other pro-inflammatory cytokines is associated with severe systemic inflammation and autoimmune diseases. For example, IFN signaling is involved in SLE, skin diseases (dermatomyositis and cutaneous lupus), interstitial pulmonary fibrosis, Sjögren's syndrome, and type 1 diabetes (G. Triinchieri, J Exp Med. 2010 207(10):2053-63). Other pro-inflammatory cytokines, such as TNFα and IL-1β, play important roles in inflammatory bowel disease, NASH, juvenile inflammatory arthritis, ankylosing spondylitis, and gout.

[0006] Chronic activation of cGAS / STING leads to severe systemic inflammation. Clinical evidence for its role in inflammation comes from monogenic disorders. Patients with deficiencies in nucleic acid-modifying enzymes such as Trex1, RNase H2, and SAMHD1 suffer from Aicardi-Goutiéres syndrome (AGS). The involvement of cGAS / STING was supported in Trex1-deficient mice, which serve as a model of AGS.

[0007] Therefore, inhibiting the cGAS pathway, which is upstream of cytokine-mediated diseases, is a novel strategy for treating patients from multiple autoimmune diseases, including those related to IFN signaling or those driven by TNFα and IL1β.

[0008] Today, many diseases caused by dysregulation of the innate immune system lack efficient treatments. Summary of the Invention [Problem to be solved by the invention]

[0009] The compounds of the present invention bind to cGAS and modulate its activity. [Means for solving the problem]

[0010] The compounds of formula (I) are particularly useful for the treatment or prevention of, for example, cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS). DETAILED DESCRIPTION OF THE INVENTION

[0011] As used herein, the term "alkyl," alone or in combination, refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, particularly a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and more particularly a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched-chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyls, isomeric hexyls, isomeric heptyls, and isomeric octyls, particularly methyl, ethyl, propyl, butyl, and pentyl. Particular examples of alkyl are methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. Methyl, ethyl, propyl, and butyl, such as isobutyl, are further particular examples of "alkyl" in compounds of formula (I).

[0012] The term "cycloalkyl," alone or in combination, refers to a cycloalkyl ring having 3 to 8 carbon atoms, particularly a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Particular examples of "cycloalkyl" are cyclopropyl and cyclobutyl.

[0013] The terms "alkoxy" or "alkyloxy", alone or in combination, refer to a group of the formula alkyl-O-, in which the term "alkyl" has the meaning given above, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Particular examples of "alkoxy" are methoxy and ethoxy.

[0014] The term "oxy", alone or in combination, signifies the group --O--.

[0015] The term "oxo", alone or in combination, means the group =0.

[0016] The terms "halogen" or "halo," alone or in combination, refer to fluorine, chlorine, bromine, or iodine, particularly fluorine, chlorine, or bromine, more particularly fluorine. The term "halo," in combination with another group, refers to substitution of said group with at least one halogen, particularly one to five halogens, particularly one to four halogens, i.e., one, two, three, or four halogens.

[0017] The term "haloalkyl," alone or in combination, refers to an alkyl group substituted with at least one halogen, particularly 1 to 5 halogens, particularly 1 to 3 halogens, and more particularly 3 halogens. Particular "haloalkyl" groups are fluoromethyl, fluoroethyl, fluoropropyl, and fluorobutyl.

[0018] The term "haloalkoxy," alone or in combination, means an alkoxy group substituted with at least one halogen, particularly 1 to 5 halogens, and especially 1 to 3 halogens. Particular "haloalkoxy" groups are fluoromethoxy, fluoroethoxy, and fluoropropyloxy.

[0019] The terms "hydroxyl" and "hydroxy," alone or in combination, refer to an --OH group.

[0020] The term "carbonyl", alone or in combination, signifies the -C(O)- group.

[0021] The term "amino," alone or in combination, means a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0022] The term "alkylamino" is an alkyl group bonded to an -NH- group. The term "dialkylamino" means two alkyl groups bonded to the -N- atom.

[0023] The term "sulfonyl," alone or in combination, means the group -SO2.

[0024] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, especially hydrochloric acid, as well as organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of 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, lysine, arginine, N-ethylpiperidine, piperidine, and polyamine resins. The compound of formula (I) can also exist in the form of a zwitterion. Particularly preferred pharmaceutically acceptable salts of the compound of formula (I) are salts of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid.

[0025] Compounds of formula (I) may exist as tautomers (I'), ie, structural isomers, which interconvert with compounds of formula (I), particularly in solution.

[0026] The tautomeric equilibrium between the compound of formula (I) and its tautomeric form (I') can be represented as follows: [ka]

[0027] If one of the starting materials or compounds of formula (I) of the present invention contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (e.g., those described in "Protective groups in Organic Chemistry" by T.W. Greene and P.G.M.Wuts, 3 rd Protecting groups (such as those described in [End Page 109] Ed., 1999, Wiley, New York) can be introduced before critical steps applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0028] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0029] The term "asymmetric carbon atom" refers to a carbon atom that has four different substituents. According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0030] Therefore, the present invention provides R 1Methylpiperazinyl(chloropyridinyl), morpholino(chloropyridinyl), morpholino(chloropyrimidinyl), 2-oxa-6-azaspiro[3.3]heptanyl(chloropyridinyl), methylpyrazolyl(chlorophenyl), ortho-para-dichlorophenyl, ortho-fluoro-para-chlorophenyl, cyclopropylisoxazolyl, phenylpyrazolyl, phenylisoxazolyl, pyrazinylpyrazolyl, methylpiperazinyl(chloropyridinyl), phenyl(methylpyrazolyl), pyrimidinyl(chlorophenyl), piperidyl(chloropyridinyl), methylimidazolyl(chlorophenyl), morpholinophenyl, morpholino(chlorophenyl), morpholino(chloropyridinyl), methoxyazetidinyl(chloropyridinyl), fluorobiphenyl, chlorobiphenyl, pyridinyl(halophenyl), isoxazolyl thiazolylcarbonylamino(chloropyridinyl), methylpyrazolyl(cyanophenyl), pyridazinyl(chlorophenyl), biphenyl, thiazolylamino(chlorophenyl), methylpyrazolyl(methoxyphenyl), methylpyrazolyl(methylphenyl), methylpyrazolyl(pyridinyl), methylpyrazolyl(trifluoromethylphenyl), quinolyl, methylpyrazolylphenyl, phenylmethoxy(chlorophenyl), methoxy(chlorophenyl), methoxy(fluorophenyl), ethoxy(chlorophenyl), cyclopropyloxyphenyl, imidazolylphenyl, trifluoroethoxyphenyl, cyano(chlorophenyl), pyrazolylphenyl, benzoxazole, isopropylphenyl, methoxy(methylphenyl), pyrimidinylphenyl, chloro(methylphenyl) or (para-ethyloxy)phenyl a compound according to the present invention, R 1 2-oxa-6-azaspiro[3.3]heptanyl(halopyridinyl), pyrimidinyl(halophenyl), alkylpyrazolyl(halophenyl) or pyridinyl(halophenyl) a compound according to the present invention, R 12-oxa-6-azaspiro[3.3]heptanyl(chloropyridinyl), pyrimidinyl(chlorophenyl), methylpyrazolyl(chlorophenyl) or pyridinyl(chlorophenyl) a compound according to the present invention, R 2 is hydrogen a compound according to the present invention, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, methoxypropyl, methoxyethyl, difluorobutyl, trifluoromethyl, trifluoroethyl, phenylmethyl, phenylethyl, phenylaminomethyl, cyclopropylmethyl, or cyclobutylmethyl a compound according to the present invention, R 3 is alkyl, difluoroalkyl or phenylalkyl a compound according to the present invention, R 3 is butyl, difluorobutyl or phenylmethyl a compound according to the present invention, A 1 -NH- a compound according to the present invention, A 2 is oxygen a compound according to the present invention, A 3 Ga-CH- The present invention relates to a compound according to the present invention,

[0031] The present invention further comprises: 2-[[4-chloro-6-(4-methylpiperazin-1-yl)-3-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-chloro-6-morpholino-3-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(5-chloro-2-morpholino-pyrimidin-4-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[[5-chloro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-pyridyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(2-chloro-5-pyrimidin-4-yl-phenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(2-methoxyethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(4,4-difluorobutyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(4,4-difluorobutyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(5-cyclopropylisoxazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(3-methoxypropyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(1-phenylpyrazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(5-phenylisoxazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(1-pyrazin-2-ylpyrazol-4-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-chloro-2-(4-methylpiperazin-1-yl)-4-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(2-methyl-5-phenyl-pyrazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyrimidin-2-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-chloro-2-(1-piperidyl)-4-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(4-methylimidazol-1-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(5-methylimidazol-1-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-morpholinophenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-morpholino-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(5-chloro-2-morpholino-4-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-chloro-2-(3-methoxyazetidin-1-yl)-4-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidine-7-thione; 2-[(2-chloro-5-morpholino-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyrimidin-4-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-phenyl-phenyl)methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-ethyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyrimidin-5-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-methyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-ethyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[[2-chloro-5-(4-pyridyl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; N-[5-chloro-4-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]-2-pyridyl]isoxazole-3-carboxamide; 2-[[2-chloro-5-(1-methylimidazol-4-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 4-(1-methylpyrazol-3-yl)-2-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]benzonitrile; 2-[[2-chloro-5-(2-pyridyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyridazin-3-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(4-phenylphenyl)ethylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(thiazol-2-ylamino)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-methoxy-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-methyl-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(1-methylpyrazol-3-yl)-2-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-(1-methylpyrazol-3-yl)-2-(trifluoromethyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(4-pyridyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Propyl-2-(6-quinolylmethylamino)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(3-pyridyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(2,4-dichlorophenyl)ethylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(2,4-dichlorophenyl)ethylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-fluoro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(4-phenylphenyl)ethylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(anilinomethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(3-phenylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-benzyloxy-2-chloro-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[3-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-fluoro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-ethoxy-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(cyclopropoxy)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-imidazol-1-ylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Propyl-2-[[4-(2,2,2-trifluoroethoxy)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 3-chloro-4-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]benzonitrile; 2-[(2-fluoro-4-methoxy-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Propyl-2-[(4-pyrazol-1-ylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-fluoro-4-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-phenylphenyl)methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(cyclobutylmethyl)-2-[(4-phenylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-(1,3-benzoxazol-2-ylmethylamino)-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[(4-isopropylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-Methoxy-2-methyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-methoxy-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Propyl-2-[(4-pyrimidin-2-ylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(2,2,2-trifluoroethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-phenylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-chloro-2-methyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(cyclobutylmethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-isobutyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(cyclopropylmethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-chloro-2-fluoro-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-isopropyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Cyclopropyl-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-ylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(4-ethoxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof.

[0032] The present invention further comprises: 5-butyl-2-[[5-chloro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-pyridyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-Butyl-2-[(2-chloro-5-pyrimidin-4-yl-phenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(4,4-difluorobutyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[[2-chloro-5-(4-pyridyl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 5-benzyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof.

[0033] The synthesis of compounds of formula (I) can be achieved, for example, according to the following scheme: 1 ~R 3 and A 1 ~A 3 is as defined above unless otherwise stated. [ka]

[0034] In Scheme 1, R 1are methylpiperazinyl(chloropyridinyl), morpholino(chloropyridinyl), morpholino(chloropyrimidinyl), 2-oxa-6-azaspiro[3.3]heptanyl(chloropyridinyl), methylpyrazolyl(chlorophenyl), ortho-para-dichlorophenyl, cyclopropylisoxazolyl, phenylpyrazolyl, phenylisoxazolyl, pyrazinylpyrazolyl, methylpiperazinyl(chloropyridinyl), phenyl(methylpyrazolyl), pyrimidinyl(chlorophenyl), piperidyl(chloropyridinyl), methylimidazolyl(chlorophenyl), morpholinophenyl, morpholino(chlorophenyl), morpholino(chloropyridinyl), methoxyazetidinyl(chloropyridinyl), fluorobiphenyl, chlorobiphenyl , pyridinyl(halophenyl), isoxazolylcarbonylamino(chloropyridinyl), methylpyrazolyl(cyanophenyl), pyridazinyl(chlorophenyl), biphenyl, thiazolylamino(chlorophenyl), methylpyrazolyl(methoxyphenyl), methylpyrazolyl(methylphenyl), methylpyrazolyl(pyridinyl), methylpyrazolyl(trifluoromethylphenyl), quinolyl, methylpyrazolylphenyl, phenylmethoxy(chlorophenyl), methoxy(fluorophenyl), ethoxy(chlorophenyl), cyclopropyloxyphenyl, imidazolylphenyl, trifluoroethoxyphenyl, cyano(chlorophenyl), pyrazolylphenyl, pyrimidinylphenyl, or (para-ethyloxy)phenyl; R 2 is as defined above; and R 3 is as defined above, where R 3 is not cyclopropylmethyl or trifluoroethyl.

[0035] Step A: Compounds of formula 3 can be obtained by condensation of 1,3-diaminotriazole 1 with an appropriate β-ketoester 2 in an acidic solvent such as MeOH, HCl or acetic acid at a temperature of about 60-120° C. for 12-15 hours.

[0036] Step B: Compounds of formula (I) can be obtained by reductive amination of amino-triazolopyrimidone 3 with aldehyde or ketone 4 using reducing agent / (Lewis) acid pair NaBH3CN / acetic acid or diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate / scandium(III) trifluoromethanesulfonate in solvents such as THF, methanol or ethanol at about 10-30°C for 12-14 hours. [ka]

[0037] In Scheme 2, R 1 is methylpyrazolyl(chlorophenyl), ortho-para-dichlorophenyl, ortho-fluoro-para-chlorophenyl, biphenyl, methoxy(chlorophenyl), benzoxazole, isopropylphenyl, methoxy(methylphenyl) or chloro(methylphenyl); R 2 is as defined above; R 3 is propyl, isopropyl, isobutyl, cyclopropyl, trifluoromethyl, trifluoroethyl, cyclopropylmethyl, cyclobutylmethyl, phenylmethyl or phenylethyl.

[0038] Step A: Compounds of formula 3 can be obtained by reacting the appropriate amine 1 with N-cyanoimido-S,S-dimethyl-dithiocarbonate 2 in a solvent such as ethanol or methanol at a temperature of about 80° C. for 2-12 hours.

[0039] Step B: The compound of formula 4 can be obtained by reacting the compound of formula 3 with hydrazine hydrate in a solvent such as ethanol at a temperature of about 80° C. for 2 to 12 hours.

[0040] Step C: Compounds of formula (I) can be obtained by condensing compounds of formula 4 with an appropriate β-ketoester 5 in an acidic solvent such as HCl or acetic acid in MeOH at a temperature of about 60-120° C. for 12-15 hours. [ka]

[0041] In Scheme 3, R 1 is alkylpyrazolyl (halophenyl) or halobiphenyl, and R 3 is alkyl. Conveniently, R 1 is methylpyrazolyl (chlorophenyl) or chlorobiphenyl. Conveniently, R 3 is propyl.

[0042] Step A: Compounds of formula 3 are prepared by condensing 3-methylsulfanyl-1H-1,2,4-triazol-5-amine 1 with the appropriate β-ketoester 2 in an acidic solvent such as HCl or acetic acid in MeOH at about 60-120° C. for 12-15 hours.

[0043] Step B: Compounds of formula 4 are prepared by oxidizing compounds of formula 3 with an oxidizing agent such as 3-chloroperbenzoic acid in a solvent such as dichloromethane at about 10-30° C. for 2-24 hours.

[0044] Step C: Compounds of formula (I) can be obtained by reacting sulfones of formula 4 with alcohols 5 in a polar solvent such as DMF using a strong base such as NaH at about 100-120°C for 2-12 hours. [ka]

[0045] In Scheme 4, R 1 is ortho-para-dichlorophenyl, and R 3 is phenylalkyl. Conveniently, R 3 is phenylethyl.

[0046] Step A: Iminoethers of formula 2 can be obtained by reacting the appropriate nitrile 1 in ethanol with HCl at about 0° C. for 2-12 hours.

[0047] Step B: The compound of formula 4 can be obtained by acylation of the iminoether of formula 2 with 1,1'-carbonyl-di(1,2,4-triazole) 3 in a solvent such as dichloromethane at about 10-30°C for 10-15 hours.

[0048] Step C: The compound of formula 6 can be obtained by condensing the compound of formula 4 with 3,5-diamino-1,2,4-triazole 5 in a solvent such as methanol at about 80° C. for 10 to 15 hours.

[0049] Step D: Compounds of formula (I) can be obtained by reductive amination of amino-triazolopyrimidone 6 with aldehyde 7 using reducing agent / (Lewis) acid couples such as NaBHCN / acetic acid, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate / scandium(III) trifluoromethanesulfonate or BH.THF / TMSOTf in solvents such as THF, methanol or ethanol at about 10-30°C for 12-14 hours.

[0050] Synthesis of intermediates Aldehydes of formula (C) are commercially available or can be prepared by the methods of Scheme 5 or methods known to those skilled in the art. [ka]

[0051] In Scheme 5, X is halo; R 4 is hydrogen, chloro, fluoro, methyl, methoxy, trifluoromethyl or cyano. 5 is phenyl, pyrimidinyl, pyrazolyl, alkylpyrazolyl, imidazolyl, alkylimidazolyl, alkylimidazolyl, alkylimidazolyl, pyridyl, pyrazinyl or pyridazinyl. Conveniently, X is bromo.

[0052] Step A: Coupling of halo derivative 2a or 2b with an appropriate boronic acid or boronate ester 1 can be achieved using a palladium catalyst, such as palladium(II) acetate, palladium(II) chloride, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, tris(dibenzylideneacetone)dipalladium, tris(dibenzylideneacetone)dipalladium-chloroform adduct, or tetrakis(triphenylphosphine)palladium(0), in combination with a ligand, a base, and a suitable solvent. Conveniently, the ligand can be selected from triphenylphosphine, tricyclohexylphosphine, X-phos, xantphos, or the like, and the base can be potassium phosphate, potassium carbonate, cesium carbonate, triethylamine, or diisopropylethylamine. Conveniently, the reaction is carried out in a suitable solvent selected from dioxane, toluene, dimethylacetamide, dimethylformamide, tetrahydrofuran, dimethoxyethane, diglyme, ethanol, methanol, water or a mixture of the above solvents at a temperature of about 20° C. to about 180° C., with or without microwave irradiation, for 5 minutes to 18 hours.

[0053] Step B: Oxidation of benzyl alcohol 3 to give aldehydes of formula (C) can be accomplished, for example, with MnO in a solvent such as dichloromethane or dichloroethane, or with 2-iodoxybenzoic acid in a solvent such as dichloromethane / DMSO at 0° C. to RT for 2-12 hours.

[0054] Alternatively, alcohols of formula (D) and aldehydes of formula (E) are commercially available or may be prepared by the methods of Scheme 6 or methods known to those skilled in the art. [ka]

[0055] In Scheme 6, A 4 and A 5 is independently selected from —CH— and nitrogen; R 6is chloro; R 7 is hydrogen or alkyl. In Scheme 6, compound 4 is selected from morpholino, methoxyazetidinyl, piperidinyl, methylpiperazinyl, and 2-oxa-6-azaspiro[3.3]heptanyl.

[0056] Step A: Heterocyclic amines are coupled to heteroaromatics via nucleophilic substitution by reacting aldehyde 1, alcohol 2, or carboxylic acid or ester 3 with the appropriate amine 4, optionally in the presence of a base such as K2CO3, CsCO3, at 80-100 °C for 8-15 hours in a solvent such as DMF, NMP, DMA, DMSO, etc.

[0057] Step B: Alcohols of formula (D) can be obtained from esters 5 by reduction with a reducing agent such as LiBH4 or NaBH4 in a solvent such as THF or MeOH at RT for 2-12 hours, or from carboxylic acids 5 by reduction with a reducing agent such as BH3.Me2S in a solvent such as THF at RT for 2-12 hours.

[0058] Step C: Oxidation of the benzyl alcohol of formula (D) to give the aldehyde of formula (E) can be accomplished, for example, with MnO in a solvent such as dichloromethane or dichloroethane, or with 2-iodoxybenzoic acid in a solvent such as dichloromethane / DMSO at 0° C. to RT for 2-12 hours.

[0059] Alternatively, alcohols of formula (F) and aldehydes of formula (G) are commercially available or may be prepared by the methods of Scheme 7 or methods known to those skilled in the art. [ka]

[0060] In Scheme 7, A 6 is -CH- or nitrogen; R 6 is hydrogen or chloro; R 7is hydrogen or alkyl. In Scheme 7, compound 4 can be morpholino or methylpiperazinyl.

[0061] Step A: Heterocyclic amines are coupled to heteroaromatics via nucleophilic substitution by reacting aldehyde 1, alcohol 2, or carboxylic acid or ester 3 with the appropriate amine 4, optionally in the presence of a base such as K2CO3, CsCO3, at 80-100 °C for 8-15 hours in a solvent such as DMF, NMP, DMA, DMSO, etc.

[0062] Step B: Alcohols of formula (F) can be obtained from esters 5 by reduction with a reducing agent such as LiBH4 or NaBH4 in a solvent such as THF or MeOH at RT for 2-12 hours, or from carboxylic acids 5 by reduction with a reducing agent such as BH3.Me2S in a solvent such as THF at RT for 2-12 hours.

[0063] Step C: Oxidation of the benzyl alcohol of formula (F) to give the aldehyde of formula (G) can be accomplished, for example, with MnO in a solvent such as dichloromethane or dichloroethane, or with 2-iodoxybenzoic acid in a solvent such as dichloromethane / DMSO at 0° C. to RT for 2-12 hours.

[0064] Therefore, the present invention also provides a method for producing a pharmaceutical composition comprising the steps of: (a) Formula (B1) [ka] and a compound of formula (B2) [ka] in the presence of a reducing agent and a Lewis acid; or (b) Formula (C1) [ka] and a compound of formula (C2) [ka] in the presence of an acid; (In the formula, R 1 ~R 3 and A 1 ~A 3 is as defined above).

[0065] The reducing agent in step (a) may conveniently be NaBH3CN or diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.

[0066] The Lewis acid in step (a) can be acetic acid or scandium(III) trifluoromethanesulfonate.

[0067] The solvent in step (a) may conveniently be THF, methanol or ethanol.

[0068] Convenient conditions for step (a) are about 0°C to 80°C, particularly about 10°C to 60°C, more particularly about 10°C to 40°C, for 1 to 24 hours, conveniently 12 to 14 hours.

[0069] In step (b), the acid can be HCl or acetic acid.

[0070] In step (b), the solvent is conveniently methanol or acetic acid.

[0071] Convenient conditions for step (b) are about 20°C to 200°C, particularly about 40°C to 150°C, more particularly about 60°C to 120°C, for 1 to 24 hours, conveniently 10 to 15 hours.

[0072] The present invention also relates to compounds according to the invention when prepared according to the process of the invention.

[0073] Other embodiments of the present invention provide pharmaceutical compositions or medicaments containing a compound of the present invention and a therapeutically inert carrier, diluent, or excipient, as well as methods of using the compounds of the present invention to prepare such compositions and medicaments. In one example, a compound of Formula (I) may be formulated by mixing it with a physiologically acceptable carrier, i.e., a carrier that is not toxic to recipients at the dosages and concentrations used in herbal dosage forms, at an appropriate pH and desired purity, at ambient temperature. The pH of the formulation will depend primarily on the particular application and compound concentration, but is preferably in the range of about 3 to about 8. In one example, a compound of Formula (I) is formulated in acetate buffer at pH 5. In other embodiments, the compound of Formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0074] The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners.

[0075] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0076] The compounds of the present invention may be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventionally used in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and additional active agents.

[0077] Typical preparation is prepared by mixing the compound of the present invention with carrier or excipient.Suitable carrier and excipient are well known to those skilled in the art, and are described in detail in, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients.Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives to provide proper presentation of the medicament (i.e., a compound of the invention or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical composition (i.e., a drug product).

[0078] The present invention also relates to compounds of formula (I) or (II) for use as therapeutically active substances. 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof.

[0079] The present invention also relates in particular to compounds of formula (I) or 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof; and a therapeutically inert carrier.

[0080] The present invention also relates to compounds of formula (I) or 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof.

[0081] The present invention also relates to a compound of formula (I) or a compound of formula (I) for the treatment or prevention of cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS). 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof.

[0082] The present invention also relates to a compound of formula (I) or a compound of formula (I) for the preparation of a medicament for the treatment or prevention of cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS). 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof.

[0083] The present invention also relates to a compound of formula (I) or a compound of formula (I) for use in the treatment or prevention of cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS). 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof.

[0084] The present invention also relates to a method for treating or preventing, in particular, cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS), comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; or a pharmaceutically acceptable salt or tautomer thereof, administering the compound to a patient in need thereof.

[0085] The invention will now be illustrated by the following examples, which have no limiting character. [Example]

[0086] Abbreviation ATP = adenosine triphosphate; BSA = bovine serum albumin; DCM = dichloromethane; DIEA = diisopropylethylamine; DMA = dimethylacetamide; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DNA = deoxyribonucleic acid; ESI = electrospray ionization; EtOAc = ethyl acetate; EtOH = ethanol; GTP = guanosine triphosphate; HPLC = high performance liquid chromatography; MeOH = methanol; MS = mass spectrometry; NMP = N-methyl-2-pyrrolidone; RT = room temperature; SD = standard deviation; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TMSOTf = trimethylsilyl trifluoromethanesulfonate; TRIS = tris(hydroxymethyl)aminomethane.

[0087] Example 1 2-[(2-fluoro-4-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0088] Step 1: 2-amino-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0089] To a solution of 3,5-diamino-1,2,4-triazole (3.0 g, 30.3 mmol) in acetic acid (30 mL) was added methyl 3-oxohexanoate (4.8 g, 33.3 mmol), and the mixture was stirred at 120° C. for 8 hours. The mixture was concentrated. The crude solid was triturated in EtOH, filtered, and dried in vacuo to give the title compound (1800 mg, 25% yield) as a pale yellow solid.

[0090] Step 2: 2-[(2-fluoro-4-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0091] To a solution of 2-fluoro-4-phenyl-benzaldehyde (199 mg, 1 mmol) and 2-amino-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (0.75 mL, 0.83 mmol), acetic acid (0.09 mL, 1.66 mmol) in methanol (15 mL) was added NaBHCN (78 mg, 1.24 mmol), and the mixture was stirred at 25 °C for 16 hours. The mixture was then concentrated, purified by preparative HPLC, and lyophilized to give the title compound (106 mg, 34%) as a white solid. MS: 378.3 [M+H] + ESI pos.

[0092] Similar to the procedure described in Example 1, Examples 2-57 (Table 1) were prepared starting from the appropriate aldehyde and β-ketoester starting materials. [Table 1] TIFF0007781074000016.tif229165 TIFF0007781074000017.tif229165 TIFF0007781074000018.tif229165 TIFF0007781074000019.tif238165 TIFF0007781074000020.tif225165 TIFF0007781074000021.tif230165 TIFF0007781074000022.tif236165 TIFF0007781074000023.tif245165 TIFF0007781074000024.tif106165

[0093] Example 58 2-[(2,4-dichlorophenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0094] Step 1: 3-cyano-1-[(2,4-dichlorophenyl)methyl]-2-methyl-isothiourea

[0095] A solution of N-cyanoimido-S,S-dimethyl-dithiocarbonate (200 mg, 1.4 mmol) and 2,4-dichlorobenzylamine (361.16 mg, 2.05 mmol) in ethanol (8 mL) was stirred at 80° C. for 2 hours. A white precipitate formed. The mixture was cooled to 25° C. and filtered. The filter cake was washed with EtOH. The solid was dried in vacuo to give the title compound (360 mg, 91% yield) as a white solid. MS: 370.0 [M+H] + ESI pos.

[0096] Step 2: N3-[(2,4-dichlorophenyl)methyl]-1H-1,2,4-triazole-3,5-diamine

[0097] To a solution of 3-cyano-1-[(2,4-dichlorophenyl)methyl]-2-methyl-isothiourea (360 mg, 1.3 mmol) in ethanol (8 mL) was added hydrazine hydrate (0.2 mL, 4.12 mmol). The mixture was stirred at 80° C. for 6 hours. The mixture was then concentrated to give the title compound (310 mg, 73%) as a white solid.

[0098] Step 3: 2-[(2,4-dichlorophenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one 2,2,2-trifluoroacetic acid

[0099] A solution of N3-[(2,4-dichlorophenyl)methyl]-1H-1,2,4-triazole-3,5-diamine (150.0 mg, 0.580 mmol) and methyl 3-oxohexanoate (100 mg, 0.7 mmol) in acetic acid (8 mL) was stirred at 120° C. for 5 hours. The mixture was then concentrated and purified by preparative HPLC (TFA) to give the title compound as a TFA salt (62 mg, 29%, white solid). MS: 352.2 [M+H] + ESI pos.

[0100] Similar to the procedure described for Example 58, Examples 59-78 (Table 2) were prepared starting from the appropriate benzylamine and β-ketoester starting materials and obtained as trifluoroacetate salts. [Table 2] TIFF0007781074000027.tif226165 TIFF0007781074000028.tif225165 TIFF0007781074000029.tif106165

[0101] Example 79 5-(Anilinomethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0102] Steps 1 to 3: 5-(chloromethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0103] The title compound was prepared in three steps using 2,4-dichlorobenzylamine in the first step and methyl 4-chloroacetoacetate in the third step, similar to the procedure described in Example 52. Yellow solid MS: 357.8 [M+H]+ ESI pos. Step 4: 5-(anilinomethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0104] To a solution of 5-(chloromethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (300 mg, 0.84 mmol) and aminobenzene (0.23 mL, 2.5 mmol) in NMP (3 mL) was added DIEA (216 mg, 1.67 mmol), and the mixture was stirred in a microwave at 200 °C for 20 min. The reaction was filtered and purified by preparative HPLC (TFA) to give the crude product, which was triturated in EtOAc (5 mL) to give the title compound (50.5 mg, 13% yield) as a light brown solid. MS: 415.1 [M+H]+ESI pos.

[0105] Example 80 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0106] The title compound was prepared similarly to the procedure described in Example 77, using 2-chlorobenzylamine in the first step.

[0107] Example 81 2-[[5-(1-methylpyrazol-3-yl)-2-(trifluoromethyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0108] Step 1: 5-(1-methylpyrazol-3-yl)-2-(trifluoromethyl)benzaldehyde

[0109] To a mixture of 5-bromo-2-(trifluoromethyl)benzaldehyde (300 mg, 1.2 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (290 mg, 1.4 mmol, 1.2 equiv.) in 1,4-dioxane (3 mL) and water (0.150 mL) was added sodium carbonate (284 mg, 2.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (20.0 mg, 0.02 mmol). The mixture was stirred at 100° C. for 16 hours. The mixture was cooled to room temperature, filtered, and concentrated. The crude product was purified by silica gel chromatography using a gradient of EtOAc / petroleum ether to give the title compound (220 mg, 43% yield) as a yellow solid.

[0110] Step 2: 2-[[5-(1-methylpyrazol-3-yl)-2-(trifluoromethyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0111] 5-(1-methylpyrazol-3-yl)-2-(trifluoromethyl)benzaldehyde was converted to the title compound in a manner similar to that described in Example 1. White solid MS: 432.1 [M+H] + ESI pos.

[0112] Similar to the procedure described for Example 81, Examples 82-84 were prepared starting from the appropriate bromobenzaldehyde starting material (Table 3). [Table 3]

[0113] Example 85 2-[(2-chloro-5-pyridazin-3-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0114] Step 1: (2-chloro-5-pyridazin-3-yl-phenyl)methanol

[0115] To a solution of 3-bromopyridazine (0.21 mL, 2.23 mmol) and [2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (717 mg, 2.68 mmol, 1.2 equiv.) in 1,4-dioxane (10 mL) was added potassium carbonate (926 mg, 6.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (258 mg, 0.22 mmol). The mixture was purged with nitrogen and stirred at 100° C. for 12 hours. The resulting solution was washed with water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous NaSO, and concentrated in vacuo. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate / dichloromethane gradient to give the title compound as a brown semi-solid. MS: 221 [M+H]

[0116] Step 2: 2-chloro-5-pyridazin-3-yl-benzaldehyde

[0117] To a solution of (2-chloro-5-pyridazin-3-yl-phenyl)methanol (100 mg, 0.45 mmol) in dichloromethane (2.9 mL) and DMSO (0.73 mL) was added 2-iodoxybenzoic acid (190 mg, 0.68 mmol). The reaction mixture was stirred at 25° C. for 2 hours. Saturated NaSO and saturated NaHCO were added, and the aqueous phase was extracted with dichloromethane and washed with saturated brine. The combined organic layers were concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (66 mg, 0.3 mmol) as a light brown solid.

[0118] Step 3: 2-[(2-chloro-5-pyridazin-3-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one 2-Chloro-5-pyridazin-3-yl-benzaldehyde was converted to the title compound in a similar manner to the procedure described in Example 1. White solid MS: 396 [M+H] +

[0119] Example 86 5-Butyl-2-[(2-chloro-5-pyrimidin-4-yl-phenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0120] The title compound was prepared in three steps similar to the procedure described in Example 85. White powder MS: 410.4 [M+H] + Example 87 2-[[2-chloro-5-(5-methylimidazol-1-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0121] Step 1: 5-(4-methylimidazol-1-yl)-2-nitro-benzoic acid / 5-(5-methylimidazol-1-yl)-2-nitro-benzoic acid

[0122] To a solution of 5-fluoro-2-nitrobenzoic acid (4.0 g, 21.6 mmol) and 4-methylimidazole (2.66 g, 32.4 mmol) in DMF (40 mL) was added potassium carbonate (5.97 g, 43.2 mmol), and the mixture was then stirred at 100° C. for 12 hours. The mixture was poured into water and extracted with ethyl acetate. The aqueous layer was concentrated. The residue was dissolved in DMF (30 mL), filtered, and concentrated to give the title compound (mixture of regioisomers, 6.6 g, 78%) as a yellow oil. MS: 248.0 [M+H] +

[0123] Step 2: 2-amino-5-(4-methylimidazol-1-yl)benzoic acid / 2-amino-5-(5-methylimidazol-1-yl)nitro-benzoic acid

[0124] 5-(4-Methylimidazol-1-yl)-2-nitrobenzoic acid / 5-(5-methylimidazol-1-yl)-2-nitrobenzoic acid (6.5 g, 26.3 mmol) was dissolved in methanol (50 mL). Pd / C (300 mg, 26.3 mmol) was added. The mixture was stirred under a hydrogen atmosphere at 25° C. for 12 hours. The reaction mixture was filtered and concentrated to give the title compound (7.0 g, 73% yield) as a yellow oil.

[0125] Step 3: 2-chloro-5-(4-methylimidazol-1-yl)benzoic acid / 2-chloro-5-(5-methylimidazol-1-yl)benzoic acid

[0126] Cupric chloride (2.6 g, 19.3 mmol) and t-butylnitrile (1.99 g, 19.3 mmol) were dissolved in MeCN (30 mL) and 2-amino-5-(4-methylimidazol-1-yl)benzoic acid / 2-amino-5-(5-methylimidazol-1-yl)benzoic acid (3.5 g, 16.1 mmol) was added. The mixture was stirred at 60° C. for 3 hours and then concentrated. The crude product was dissolved in DMF (20 mL), filtered, and concentrated to give the title compound (mixture of isomers, 1.2 g, 29% yield) as a yellow solid. MS: 237.0 [M+H] +

[0127] Step 4: 2-chloro-5-(4-methylimidazol-1-yl)phenyl]methanol and 2-chloro-5-(5-methylimidazol-1-yl)phenyl]methanol

[0128] A mixture of 2-chloro-5-(4-methylimidazol-1-yl)benzoic acid / 2-chloro-5-(5-methylimidazol-1-yl)benzoic acid (500 mg, 2.1 mmol) was dissolved in THF (20 mL). The mixture was cooled to 0 °C. Borane-dimethyl sulfide (0.21 mL, 2.1 mmol) was added. The mixture was stirred at 25 °C for 12 hours, and then MeOH (10 mL) was added to the mixture, which was then concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give 2-chloro-5-(5-methylimidazol-1-yl)phenyl]methanol (120 mg, 23%) as a yellow oil, and 2-chloro-5-(4-methylimidazol-1-yl)phenyl]methanol (500 mg, 70% purity, 75% yield) as a yellow oil. MS: 223.0 [M+H] for both regioisomers +

[0129] Step 5: 2-chloro-5-(5-methylimidazol-1-yl)benzaldehyde

[0130] [2-Chloro-5-(5-methylimidazol-1-yl)phenyl]methanol (100 mg, 0.45 mmol) and 2-iodoxybenzoic acid (189 mg, 0.67 mmol) were dissolved in dichloromethane (4 mL) and DMSO (1 mL). The mixture was stirred at 25° C. for 3 hours. The mixture was treated with aqueous NaSO and extracted with dichloromethane. The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (30 mg, 29%) as a yellow solid. MS: 221.0 [M+H] + Step 6: 2-[[2-chloro-5-(5-methylimidazol-1-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one 2-Chloro-5-(5-methylimidazol-1-yl)benzaldehyde was converted to the title compound in a similar manner to the procedure described in Example 1. White solid MS: 398.2 [M+H] +

[0131] Example 88 2-[[2-chloro-5-(4-methylimidazol-1-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0132] 2-Chloro-5-(4-methylimidazol-1-yl)phenyl]methanol was converted to the title compound in a manner similar to the procedure described in steps 5 and 6 from Example 87. White solid MS: 398.2 [M+H] +

[0133] Example 89 2-[[2-chloro-5-(thiazol-2-ylamino)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0134] Step 1: [2-chloro-5-(thiazol-2-ylamino)phenyl]methanol

[0135] To a solution of 2-aminothiazole (1.0 g, 9.99 mmol) and 5-bromo-2-chlorobenzyl alcohol (2.43 g, 11.0 mmol) in 1-butanol (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (183 mg, 0.20 mmol), Brettphos (214 mg, 0.4 mmol), and potassium carbonate (2.76 g, 19.97 mmol). The mixture was purged with nitrogen and stirred at 100° C. for 12 hours. The mixture was concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (370 mg, 15%) as a yellow solid. MS: 241.0 [M+H] +

[0136] Step 2: 2-[[2-chloro-5-(thiazol-2-ylamino)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0137] [2-chloro-5-(thiazol-2-ylamino)phenyl]methanol was converted to the title compound in a similar manner to the procedure described in Example 85, steps 2 and 3. White solid MS: 416.0 [M+H] +

[0138] Example 90 N-[5-chloro-4-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]-2-pyridyl]isoxazole-3-carboxamide [ka]

[0139] Step 1: Methyl 5-chloro-2-(isoxazole-3-carbonylamino)pyridine-4-carboxylate

[0140] To a solution of methyl 2,5-dichloropyridine-4-carboxylate (1.1 g, 5.34 mmol), isoxazole-3-carboxamide (748 mg, 5.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (244 mg, 0.27 mmol), and 5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane (309 mg, 0.53 mmol) in 1,4-dioxane (15 mL) was added cesium carbonate (3.48 g, 10.7 mmol), and the mixture was stirred at 120° C. for 12 hours. The mixture was concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give methyl 5-chloro-2-(isoxazole-3-carbonylamino)pyridine-4-carboxylate (300 mg, 10%) as a yellow solid. MS:282.0[M+H] +

[0141] Step 2: N-[5-chloro-4-(hydroxymethyl)-2-pyridyl]isoxazole-3-carboxamide

[0142] To a solution of methyl 5-chloro-2-(isoxazole-3-carbonylamino)pyridine-4-carboxylate (400 mg, 1.4 mmol) in methanol (10 mL) and THF (3 mL) was added sodium borohydride (2.8 mL, 2.8 mmol). The reaction mixture was stirred at 30° C. for 4 hours. Aqueous NaHCO (10 mL) was poured into the mixture. After extraction with ethyl acetate, the combined organic layers were dried over Na SO , filtered, and concentrated. The crude product was purified by silica gel chromatography to give the title compound (210 mg, 29%) as a yellow solid. MS: 254.0 [M+H] +

[0143] Step 3: N-(5-chloro-4-formyl-2-pyridyl)isoxazole-3-carboxamide

[0144] N-[5-chloro-4-(hydroxymethyl)-2-pyridyl]isoxazole-3-carboxamide was converted to the title compound in a similar manner to Step 2 of Example 85. Yellow oil

[0145] Step 4: N-[5-chloro-4-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]-2-pyridyl]-isoxazole-3-carboxamide

[0146] To a solution of N-(5-chloro-4-formyl-2-pyridyl)isoxazole-3-carboxamide (90 mg, 0.29 mmol) and 2-amino-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (55 mg, 0.3 mmol) in THF (4 mL) was added diethyl-1,4-dihydro-2,6-dimethyl-3,5,pyridinedicarboxylate (72 mg, 0.3 mmol) and scandium(III) trifluoromethanesulfonate (0.3 mg, 0.6 μmol). The reaction mixture was stirred at 30° C. for 12 hours. The mixture was concentrated. The crude product was purified by preparative HPLC (basic) using a 0.05% aqueous ammonia hydroxide (v / v) / acetonitrile gradient and lyophilized to give the title compound (2.4 mg, 2% yield) as a white solid. MS:451.3[M+H] +

[0147] Example 91 2-[[2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0148] Step 1: [2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methanol

[0149] To a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.5 g, 21.7 mmol), 5-bromo-2-chlorobenzyl alcohol (0.05 mL, 18.1 mmol), tetrakis(triphenylphosphine)palladium(0) (209 mg, 0.18 mmol) in 1,4-dioxane (30 mL) was added sodium carbonate (3.8 mg, 36.1 mmol), and the mixture was stirred at 100° C. for 16 hours. The mixture was concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (2.2 g, 47%) as a white solid. MS: 223.2 [M+H] +

[0150] Step 2: 2-Methylsulfanyl-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0151] 3-Methylsulfanyl-1H-1,2,4-triazol-5-amine (5.0 g, 38.4 mmol) and methyl 3-oxohexanoate (11.1 g, 76.8 mmol) were dissolved in acetic acid (50 mL), and the mixture was then stirred at 120° C. for 2 hours. The mixture was concentrated. The crude product was triturated in EtOH and filtered. The solid was dried in vacuo to give the title compound (5.5 g, 53%) as a white solid. MS: 225.0 [M+H] +

[0152] Step 3: 2-Methylsulfonyl-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0153] 2-Methylsulfanyl-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (2.0 g, 8.9 mmol) and 3-chloroperoxybenzoic acid (6.2 g, 35.7 mmol) were dissolved in dichloromethane (30 mL), and the mixture was then stirred at 25° C. for 16 hours. Saturated aqueous NaSO and saturated NaHCO solutions were poured into the mixture. A white solid precipitated. The solid was filtered and dried in vacuo to give the title compound (1.3 g, 54%) as a white solid. MS: 257.0 [M+H] +

[0154] Step 4: 2-[[2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0155] 2-Methylsulfonyl-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (300 mg, 1.2 mmol) was dissolved in DMF (10 mL), and then [2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methanol (287 mg, 1.3 mmol) was added to the mixture. The mixture was stirred at 100° C. for 12 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified using a water (0.225% formic acid) / acetonitrile gradient and lyophilized to give the title compound (367 mg, 8%) as a white solid. MS: 399.1 [M+H] +

[0156] Example 92 2-[(2-chloro-4-phenyl-phenyl)methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0157] The title compound was prepared from the appropriate benzyl alcohol by a procedure similar to that described in Example 91. White solid 395.1 [M+H] +

[0158] Example 93 2-[[5-chloro-2-(3-methoxyazetidin-1-yl)-4-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0159] Step 1: [5-chloro-2-(3-methoxyazetidin-1-yl)-4-pyridyl]methanol

[0160] To a solution of (2,5-dichloro-4-pyridyl)methanol (400 mg, 2.3 mmol) and potassium carbonate (932 mg, 6.7 mmol) in NMP (9.8 mL) was added 3-methoxyazetidine (196 mg, 2.3 mmol). The reaction mixture was stirred at 130° C. for 12 hours. The reaction mixture was concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (100 mg, 0.44 mmol, 19%) as a pale yellow oil.

[0161] Step 2: 5-chloro-2-(3-methoxyazetidin-1-yl)pyridine-4-carbaldehyde

[0162] To a solution of 2-iodoxybenzoic acid (184 mg, 0.66 mmol) in DCM (4 mL) was added [5-chloro-2-(3-methoxyazetidin-1-yl)-4-pyridyl]methanol (100.0 mg, 0.440 mmol, 1 equiv.). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was quenched with NaSO (5 mL) and NaHCO (5 mL), then extracted with dichloromethane, dried over NaSO, and filtered. The filtrate was concentrated. The crude product was purified by preparative TLC using petroleum ether / ethyl acetate 3:1 as the eluent to give the title compound (75 mg, 76%) as a yellow oil.

[0163] Step 3: 2-[[2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0164] The title compound was prepared from 5-chloro-2-(3-methoxyazetidin-1-yl)pyridine-4-carbaldehyde by a procedure similar to that described in Example 90, Step 4. Light yellow solid MS: 404.5 [M+H] +

[0165] Similar to the procedure described in Example 93, Examples 94 and 95 were prepared using the appropriate amine in the first step (Table 4). [Table 4]

[0166] Example 96 2-[(5-chloro-2-morpholino-4-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0167] Step 1: 5-chloro-2-morpholino-pyridine-4-carboxylic acid A mixture of 2,5-dichloroisonicotinic acid (1.0 g, 5.2 mmol) and morpholine (6.85 g, 78.7 mmol) in DMA (3 mL) was stirred at 80° C. for 96 hours. The reaction mixture was concentrated. The residue was acidified to pH 1.5 with aqueous HCl and extracted with dichloromethane. The organic extracts were combined and the solvent removed in vacuo to give the title compound (1.55 g, quantitative) as a brown solid. MS: 243.6 [M+H] +

[0168] Step 2: (5-chloro-2-morpholino-4-pyridyl)methanol

[0169] To a solution of 5-chloro-2-morpholino-pyridine-4-carboxylic acid (1.5 g, 6.18 mmol) in THF (20 mL) was added BH3·Me2S (1.55 mL, 15.45 mmol) dropwise in an ice bath, and the mixture was stirred at 30 °C for 12 h. The reaction mixture was quenched by adding 3 mL of MeOH, and the mixture was then concentrated and extracted with EtOAc. The concentrated organic layer was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give (5-chloro-2-morpholino-4-pyridyl)methanol (690 mg, 3.0 mmol, 50%) as a white solid. MS: 229.1 [M+H]+

[0170] Step 3: 2-[(5-chloro-2-morpholino-4-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0171] (5-Chloro-2-morpholino-4-pyridyl)methanol was converted to the title compound in a similar manner to the procedure described in Example 90, steps 3 and 4. Pale yellow solid MS: 404.3 [M+H] +

[0172] Example 97 5-Butyl-2-[[5-chloro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-pyridyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0173] Example 97 was prepared similarly to the procedure described in Example 96, starting from methyl 2,5-dichloropyridine-4-carboxylate and 2-oxa-6-azaspiro[3.3]heptane, using lithium borohydride as the reducing agent in the second step. White solid MS: 430.2 [M+H] +

[0174] Example 98 5-Butyl-2-[(5-chloro-2-morpholino-pyrimidin-4-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0175] Step 1: Methyl 2-morpholinopyrimidine-4-carboxylate

[0176] A solution of methyl 2-chloropyrimidine-4-carboxylate (1.0 g, 5.8 mmol), morpholine (505 mg, 5.8 mmol), and potassium carbonate (1.2 g, 8.7 mmol) in DMF (20 mL) was stirred at 25 °C for 15 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give methyl 2-morpholinopyrimidine-4-carboxylate (460 mg, 36%) as a white solid.

[0177] Step 2: (2-morpholinopyrimidin-4-yl)methanol

[0178] To a solution of methyl 2-morpholinopyrimidine-4-carboxylate (360 mg, 1.61 mmol) in THF (5 mL) was added lithium borohydride (70 mg, 3.2 mmol). The reaction was stirred at 25° C. for 15 hours. The reaction mixture was concentrated. The crude product was purified by preparative HPLC to give the title compound (300 mg, 95%) as a pale yellow oil.

[0179] Step 3: (5-chloro-2-morpholino-pyrimidin-4-yl)methanol

[0180] A solution of (2-morpholinopyrimidin-4-yl)methanol (300 mg, 1.54 mmol) and N-chlorosuccinimide (226 mg, 1.7 mmol) in THF (15 mL) was stirred at 20° C. for 15 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude product was purified by preparative HPLC to give the title compound (240 mg, 68%) as a yellow solid.

[0181] Step 4: 5-butyl-2-[(5-chloro-2-morpholino-pyrimidin-4-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (5-Chloro-2-morpholino-pyrimidin-4-yl)methanol was converted to the title compound in a similar manner to the procedure described in Example 90, steps 3 and 4. White solid MS: 419.2 [M+H] +

[0182] Example 99 2-[(4-chloro-6-morpholino-3-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0183] Step 1: 4-(4-chloro-2-pyridyl)morpholine

[0184] To a mixture of 4-chloro-2-fluoropyridine (2.0 g, 15.2 mmol) and morpholine (1.6 g, 18.3 mmol) in DMF (400 mL) was added N,N-diisopropylethylamine (5.3 mL, 30.4 mmol), and the mixture was then stirred at 80° C. for 12 hours. The mixture was concentrated. The residue was extracted with EtOAc. The combined organic layers were concentrated and purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (2 g, 66%) as a white solid. MS: 199.2 [M+H] +

[0185] Step 2: 4-(4-chloro-5-iodo-2-pyridyl)morpholine

[0186] To a solution of 4-(4-chloro-2-pyridyl)morpholine (1.0 g, 5.03 mmol) in acetonitrile (14 mL) was added N-iodosuccinimide (1.25 g, 5.54 mmol) at 0° C., and the mixture was then stirred at 60° C. for 12 hours. The mixture was concentrated to remove the solvent. The residue was extracted with EtOAc. The combined organic layers were concentrated. The crude product was purified by preparative HPLC to give the title compound (780 mg, 46%) as a pale gray solid. MS: 325.1 [M+H] +

[0187] Step 3: 4-(4-chloro-5-vinyl-2-pyridyl)morpholine

[0188] To a solution of 4-(4-chloro-5-iodo-2-pyridyl)morpholine (600 mg, 1.85 mmol) and potassium trimethyl(vinyl)boranium (451 mg, 3.7 mmol) in ethanol (10 mL) was added triethylamine (0.52 mL, 3.7 mmol) and Pd(dppf)Cl (75 mg, 0.09 mmol). The mixture was then degassed and stirred at 80° C. under a N atmosphere for 20 hours. The mixture was concentrated to remove the solvent and extracted. The combined organic layers were purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (360 mg, 84%) as a pale yellow solid. 225.1 [M+H]

[0189] Step 4: 4-chloro-6-morpholino-pyridine-3-carbaldehyde

[0190] To a solution of 4-(4-chloro-5-vinyl-2-pyridyl)morpholine (200 mg, 0.89 mmol) in 1,4-dioxane (1.5 mL) and water (1 mL) was added sodium periodate (476 mg, 2.23 mmol), followed by osmium potassium dihydrate (3.3 mg, 0.01 mmol). The mixture was then stirred at 25° C. for 2 hours. The suspension was filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC to give the title compound (30 mg, 15%) as a white solid.

[0191] Step 5: 2-[(4-chloro-6-morpholino-3-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one 4-Chloro-6-morpholino-pyridine-3-carbaldehyde was converted to the title compound in a similar manner to the procedure described in Example 90, Step 4. White solid MS: 404.2 [M+H] +

[0192] Example 100 2-[[4-chloro-6-(4-methylpiperazin-1-yl)-3-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one [ka]

[0193] Step 1: 1-(4-chloro-2-pyridyl)-4-methyl-piperazine

[0194] To a solution of N,N-diisopropylethylamine (5.3 mL, 30.4 mmol) and 4-chloro-2-fluoropyridine (2.0 g, 15.2 mmol) in DMF (50 mL) was added 1-methylpiperazine (1.5 g, 15.2 mmol). The reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated. The crude product was purified by preparative HPLC to give the title compound (1.3 g, 40%) as a colorless oil.

[0195] Step 2: 1-(5-bromo-4-chloro-2-pyridyl)-4-methyl-piperazine

[0196] To a solution of 1-(4-chloro-2-pyridyl)-4-methyl-piperazine (1.3 mg, 6.14 mmol) in acetonitrile (20 mL) was added N-bromosuccinimide (1.2 g, 6.7 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The reaction mixture was concentrated. The crude product was purified by preparative HPLC to give the title compound (1.2 g, 67%) as a pale yellow oil.

[0197] Step 3: 1-(4-chloro-5-vinyl-2-pyridyl)-4-methyl-piperazine

[0198] To a solution of [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (140 mg, 0.17 mmol) in ethanol (20 mL) was added 1-(5-bromo-4-chloro-2-pyridyl)-4-methyl-piperazine (1.0 g, 3.44 mmol), and the mixture was then cooled to −30° C. and stirred for 10 minutes. Triethylamine (0.96 mL, 6.9 mmol) was then added dropwise. The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated. The crude product was purified by silica gel chromatography using a petroleum ether / ethyl acetate gradient to give the title compound (700 mg, 43%) as a dark brown oil.

[0199] Step 4: 4-chloro-6-(4-methylpiperazin-1-yl)-1-oxide-pyridin-1-ium-3-carbaldehyde

[0200] A solution of 1-(4-chloro-5-vinyl-2-pyridyl)-4-methyl-piperazine (100 mg, 0.21 mmol) in methanol (2 mL) and dichloromethane (2 mL) was cooled to −78° C. The solution was saturated with ozone, and steam ozone was bubbled through with stirring for 10 minutes. The reaction mixture was warmed to ambient temperature and quenched with excess dimethyl sulfide. The crude product was purified by preparative TLC (dichloromethane / MeOH 8:1) to afford the title compound (30 mg, 0.12 mmol, 28%) as a light brown oil.

[0201] Step 5: 2-[[4-chloro-6-(4-methylpiperazin-1-yl)-3-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one

[0202] To a solution of 4-chloro-6-(4-methylpiperazin-1-yl)-1-oxide-pyridin-1-ium-3-carbaldehyde (30 mg, 0.06 mmol) and 2-amino-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (11.3 mg, 0.06 mmol) in THF (5 mL) was added scandium(III) trifluoromethanesulfonate (0.06 mg) and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (14.9 mg, 0.06 mmol). The reaction mixture was stirred at 20° C. for 14 hours. Then, bis(pinacolato)diboron (14.9 mg, 0.06 mmol) was added. The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated. The crude product was purified by preparative HPLC to give the title compound (1 mg, 4%) as a pale yellow solid.

[0203] Example 101 2-[(2,4-dichlorophenyl)methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one [ka]

[0204] Step 1: Ethyl 3-phenylpropanimidate

[0205] To a solution of 3-phenylpropionitrile (2.0 g, 15.25 mmol) in ethanol (4 mL) was added HCl / dioxane (8.7 mL, 122 mmol) while maintaining the temperature at 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction was concentrated in vacuo to a white residue, which was redissolved in ethyl acetate. The organic layer was washed with saturated K2CO3 solution, dried over sodium sulfate, and concentrated to give the title compound (2.0 g, 61%) as a white solid.

[0206] Step 2: Ethyl (1Z)-3-phenyl-N-(1,2,4-triazole-1-carbonyl)propanimidate

[0207] To a solution of ethyl 3-phenylpropanimidate (2.0 g, 11.3 mmol) in dichloromethane (20 mL) was added 1,1'-carbonyl-di(1,2,4-triazole) (1.85 g, 11.3 mmol) while maintaining the temperature at 5°C. The mixture was stirred at 20°C for 12 hours. The reaction was washed with water, dried over sodium sulfate, and concentrated to give the title compound (3.0 g, 98%) as a colorless oil.

[0208] Step 3: 2-amino-5-(2-phenylethyl)-6H-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one

[0209] To a solution of ethyl (1Z)-3-phenyl-N-(1,2,4-triazole-1-carbonyl)propanimidate (1.8 g, 6.61 mmol) in methanol (20 mL) was added 3,5-diamino-1,2,4-triazole (655 mg, 6.61 mmol) while maintaining the temperature at 5° C. The mixture was stirred at 80° C. for 12 hours. The reaction was concentrated. The residue was triturated with MeOH (3 mL) to give the title compound (600 mg, 33%) as a white solid. MS: 257.6 [M+H] +

[0210] Step 4: 2-[(2,4-dichlorophenyl)methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one

[0211] 2-Amino-5-(2-phenylethyl)-6H-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one was converted to the title compound in a similar manner to the procedure described in Example 1. White solid MS: 414.9 [M+H] +

[0212] Example 102 cGAS activity assay-Malachite Green

[0213] Compounds were tested for cGAS inhibition in a coupled enzyme assay based on phosphate detection with malachite green. Final assay conditions were 20 mM TRIS pH 7.5 (Applichem), 5 mM MgCl (Sigma), and 0.01% BSA (Sigma) supplemented with 80 μM ATP (Sigma), 80 μM GTP (Sigma), and 100 nM interferon-stimulated DNA (ISD) (Microsynth). Recombinantly expressed, purified human cGAS (residues 161–522) was used at 25 nM.

[0214] All compounds were prepared as 10 mM stock solutions in DMSO, and a 16-point dilution series with a dilution factor of 2.5 was prepared in DMSO. 1 μL of the DMSO dilution series was transferred to 32.3 μL of reaction buffer, mixed by pipetting up and down, spun at 3000 rpm for 1 minute, and visually inspected for precipitation. 5 μL of 3x enzyme stock solution was transferred to rows 3-24 of an empty 384-well Black / Clear Flat Bottom Polystyrene NBS (Corning) plate. Rows 1-2 were filled with assay buffer. The plate was spun at 1000 rpm (164 × g) for 10 seconds. 5 μL of compound intermediate dilutions were added and mixed by pipetting up to rows 3-24. Rows 1-2 were filled with 3.1% DMSO assay buffer. The plate was spun at 1000 rpm (164 × g) for 10 seconds. The reaction was initiated by adding 5 μL of the 3x nucleotide / DNA mixture to all wells. The plate was spun at 1000 rpm (164 × g) for 10 seconds and incubated in the dark at room temperature (RT) for 4 hours. Five μL of 4 U / mL PPase (Sigma) was added to all wells. The plate was spun at 1000 rpm (164 × g) for 10 seconds. Ten μL of BioMol green Solution (Enzo Life Sciences) was added to all wells. The plate was spun at 1000 rpm (164 × g) for 10 seconds and incubated in the dark at RT for 30 minutes. Absorbance data were collected at 620 nm on an EnVision Multilable Reader (Perkin Elmer) using the following measurement settings: excitation filter 620 nm; excitation from the top; measurement height 1 mm; flash count 30; and integrated flash count 1.

[0215] All plates were checked for abnormalities, and outliers in the blank control (no protein, column 1) and neutral control (no compound, column 2) were excluded using the 3*SD rule. Data were normalized to 0 and 100% by the blank and neutral controls, and each curve was fitted and evaluated using a four-parameter logistic equation to determine the IC50 for cGAS inhibition.

[0216] The results of this assay are shown in Table 5. Table 5 provides the IC50 values ​​(μM) for cGAS inhibition obtained for certain examples of the invention as measured by the above assay. [Table 5] TIFF0007781074000051.tif241165 TIFF0007781074000052.tif111165

[0217] Example A Film-coated tablets containing the following ingredients can be manufactured in a conventional manner: [Table 6]

[0218] The active ingredient is sieved and mixed with microcrystalline cellulose, and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules are then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain kernels of 120 or 350 mg each. The kernels are then coated with an aqueous solution / suspension of the above film coating.

[0219] Example B Capsules containing the following ingredients may be manufactured in a conventional manner: [Table 7]

[0220] The ingredients are sieved, mixed and filled into size 2 capsules.

[0221] Example C The injection solution may have the following composition: [Table 8]

[0222] Dissolve the active ingredient in a mixture of polyethylene glycol 400 and water for injection (parts). Adjust the pH to 5.0 by adding acetic acid. Add the remaining amount of water to adjust the volume to 1.0 ml. Filter the solution, fill into vials using an appropriate overage, and sterilize.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ teeth, pyridinyl substituted with two groups, a piperazinyl group substituted with an alkyl group and a halo group; pyridinyl substituted with two groups, a morpholino group and a halo group; pyrimidinyl substituted by two groups, a morpholino group and a halo group; pyridinyl substituted by two groups, a 2-oxa-6-azaspiro[3.3]heptanyl group and a halo group; phenyl substituted by two groups, a pyrimidinyl group and a halo group; phenyl substituted by two groups, a pyrazolyl group substituted by an alkyl group and a halo group; ortho-para-dichlorophenyl, ortho-fluoro-para-chloro-phenyl, cycloalkylisoxazolyl, phenylpyrazolyl, phenylisoxazolyl, pyrazinylpyrazolyl, pyridinyl substituted with two groups, a piperazinyl group substituted with an alkyl group and a halo group; pyrazolyl substituted with two groups, a phenyl group and an alkyl group; pyridinyl substituted with two groups, a piperidyl group and a halo group; phenyl substituted with two groups, an imidazolyl group substituted with an alkyl group and a halo group; morpholinophenyl, phenyl substituted by two groups, a morpholino group and a halo group; pyridinyl substituted with two groups, a morpholino group and a halo group; pyridinyl substituted with two groups, an azetidinyl group substituted with an alkoxy group and a halo group; halobiphenyls, phenyl substituted by two groups, a pyridinyl group and a halo group; pyridinyl substituted with two groups, an isoxazolylcarbonylamino group and a halo group; a phenyl substituted by two groups, a pyrazolyl group substituted by an alkyl group and a cyano group; phenyl substituted by two groups, a pyridazinyl group and a halo group; biphenyl, phenyl substituted by two groups, a thiazolylamino group and a halo group; phenyl substituted by two groups, a pyrazolyl group substituted by an alkyl group and an alkoxy group; phenyl substituted by two groups, a pyrazolyl group substituted by an alkyl group and an alkyl group; pyridinyl substituted by a pyrazolyl group substituted by an alkyl group; phenyl substituted by two groups, a pyrazolyl group substituted by an alkyl group and a haloalkyl group; quinolyl, alkylpyrazolylphenyl, phenyl substituted by two groups, an alkyloxy group substituted by a phenyl group and a halo group; phenyl substituted with two groups, an alkoxy group and a halo group; cycloalkyloxyphenyl, imidazolylphenyl, haloalkyloxyphenyl, phenyl substituted with two groups, a cyano group and a halo group; pyrazolylphenyl, benzoxazole, isopropylphenyl, phenyl substituted with two groups, an alkoxy group and an alkyl group; pyrimidinylphenyl, phenyl substituted with two groups, a halo group and an alkyl group; or Phenyl substituted with para-ethyloxy group and R ２ is hydrogen or methyl; R ３ is alkyl, cycloalkyl, alkoxyalkyl, difluoroalkyl, trifluoroalkyl, phenylalkyl, phenylaminoalkyl or cycloalkylalkyl; A １ is —NH— or oxygen; A ２ is oxygen or sulfur; and A ３ is —CH— or nitrogen. or a pharmaceutically acceptable salt or tautomer thereof (however, [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(2,4-dichlorophenyl)methyl]amino]-5-propyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 5-ethyl-2-[[[4-(1-methylethyl)phenyl]methyl]amino]; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(2,4-dichlorophenyl)methyl]amino]-5-methyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-(1-methylethyl); [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[[4-(1-methylethyl)phenyl]methyl]amino]-5-[(phenylamino)methyl]; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[[4-(1-methylethyl)phenyl]methyl]amino]-5-propyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-[(phenylamino)methyl]; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 5-methyl-2-[[[4-(1-methylethyl)phenyl]methyl]amino]; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-methyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-propyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(4-ethoxyphenyl)methyl]amino]-5-ethyl; [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(5-bromo-2-methoxyphenyl)methyl]amino]-5-methyl [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(5-bromo-2-methoxyphenyl)methyl]amino]-5-(1-methylethyl): [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(5-bromo-2-methoxyphenyl)methyl]amino]-5-propyl; and [1,2,4]triazolo[1,5-a]pyrimidin-7(1H)-one, 2-[[(5-bromo-2-methoxyphenyl)methyl]amino]-5-ethyl (Except).

2. R １ but, pyridinyl substituted by two groups, a 2-oxa-6-azaspiro[3.3]heptanyl group and a halo group; phenyl substituted by two groups, a pyrimidinyl group and a halo group; a phenyl substituted by two groups, a pyrazolyl group substituted by an alkyl group and a halo group, or Phenyl substituted with two groups: a pyridinyl group and a halo group 2. The compound of claim 1, wherein:

3. R １ but, pyridinyl substituted by two groups, a 2-oxa-6-azaspiro[3.3]heptanyl group and a chloro group; phenyl substituted by two groups, a pyrimidinyl group and a chloro group; a phenyl substituted by two groups, a pyrazolyl group substituted by a methyl group and a chloro group, or Phenyl substituted with two groups: pyridinyl and chloro 3. The compound of claim 1 or 2, wherein:

4. R ２ The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or tautomer thereof, wherein is hydrogen.

5. R ３ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or tautomer thereof, wherein is alkyl, difluoroalkyl, or phenylalkyl.

6. R ３ 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or tautomer thereof, wherein is butyl, difluorobutyl or phenylmethyl.

7. A １ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or tautomer thereof, wherein is -NH-.

8. A ２ The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt or tautomer thereof, wherein is oxygen.

9. A ３ The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt or tautomer thereof, wherein is -CH-.

10. 2-[[4-chloro-6-(4-methylpiperazin-1-yl)-3-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-chloro-6-morpholino-3-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(5-chloro-2-morpholino-pyrimidin-4-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[[5-chloro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-pyridyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(2-chloro-5-pyrimidin-4-yl-phenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(2-methoxyethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(4,4-difluorobutyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(4,4-difluorobutyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(5-cyclopropylisoxazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(3-methoxypropyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(1-phenylpyrazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(5-phenylisoxazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(1-pyrazin-2-ylpyrazol-4-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-chloro-2-(4-methylpiperazin-1-yl)-4-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(2-methyl-5-phenyl-pyrazol-3-yl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyrimidin-2-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-chloro-2-(1-piperidyl)-4-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(4-methylimidazol-1-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(5-methylimidazol-1-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-morpholinophenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-morpholino-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(5-chloro-2-morpholino-4-pyridyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-chloro-2-(3-methoxyazetidin-1-yl)-4-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidine-7-thione; 2-[(2-chloro-5-morpholino-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyrimidin-4-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-phenyl-phenyl)methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methoxy]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-ethyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyrimidin-5-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-methyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-ethyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[[2-chloro-5-(4-pyridyl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; N-[5-chloro-4-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]-2-pyridyl]isoxazole-3-carboxamide; 2-[[2-chloro-5-(1-methylimidazol-4-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 4-(1-methylpyrazol-3-yl)-2-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]benzonitrile; 2-[[2-chloro-5-(2-pyridyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-pyridazin-3-yl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(4-phenylphenyl)ethylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(thiazol-2-ylamino)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-methoxy-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-methyl-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(1-methylpyrazol-3-yl)-2-pyridyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[5-(1-methylpyrazol-3-yl)-2-(trifluoromethyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(4-pyridyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-4-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-5-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-propyl-2-(6-quinolylmethylamino)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(3-pyridyl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(2,4-dichlorophenyl)ethylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(2,4-dichlorophenyl)ethylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-fluoro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[1-(4-phenylphenyl)ethylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(anilinomethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(3-phenylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-benzyloxy-2-chloro-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[3-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-fluoro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-ethoxy-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[4-(cyclopropoxy)phenyl]methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-imidazol-1-ylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-propyl-2-[[4-(2,2,2-trifluoroethoxy)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 3-chloro-4-[[(7-oxo-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]methyl]benzonitrile; 2-[(2-fluoro-4-methoxy-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-propyl-2-[(4-pyrazol-1-ylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-fluoro-4-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-phenyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-phenylphenyl)methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(cyclobutylmethyl)-2-[(4-phenylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-(1,3-benzoxazol-2-ylmethylamino)-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[(4-isopropylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(2-phenylethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-methoxy-2-methyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2-chloro-4-methoxy-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-propyl-2-[(4-pyrimidin-2-ylphenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(2,2,2-trifluoroethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-phenylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-chloro-2-methyl-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(cyclobutylmethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-isobutyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-(cyclopropylmethyl)-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-chloro-2-fluoro-phenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-isopropyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-cyclopropyl-2-[(2,4-dichlorophenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(2,4-dichlorophenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-ylphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(4-ethoxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or tautomer thereof, selected from:

11. 5-butyl-2-[[5-chloro-2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-pyridyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[(2-chloro-5-pyrimidin-4-yl-phenyl)methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-5-(4,4-difluorobutyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-butyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 5-benzyl-2-[[2-chloro-5-(4-pyridyl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 5-benzyl-2-[[2-chloro-5-(1-methylpyrazol-3-yl)phenyl]methylamino]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or tautomer thereof, selected from:

12. 12. A process for the preparation of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or tautomer thereof, comprising the steps of: (a) Formula (B1) 【Chemistry 2】 and a compound of formula (B2) 【Transformation 3】 in the presence of a reducing agent and a Lewis acid; or (b) Formula (C1) 【Chemistry 4】 and a compound of formula (C2) 【Transformation 5】 Reaction of the compound of formula (I) in the presence of an acid (In the formula, R １ ~R ３ and A １ ~A ３ is as defined in any one of claims 1 to 11) The method includes one of the following:

13. A compound according to any one of claims 1 to 11 for use as a therapeutically active substance, or 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one or a pharmaceutically acceptable salt or tautomer thereof.

14. A compound according to any one of claims 1 to 11, or 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one or a pharmaceutically acceptable salt or tautomer thereof. A pharmaceutical composition comprising:

15. 15. The pharmaceutical composition according to claim 14 for the treatment or prevention of cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS).

16. for the preparation of a medicament for the treatment or prevention of cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS), A compound according to any one of claims 1 to 11, or 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one 2. Use of a compound selected from:

17. for use in the treatment or prevention of cutaneous skin diseases such as systemic lupus erythematosus (SLE), dermatomyositis or cutaneous lupus, interstitial pulmonary fibrosis, Sjogren's syndrome, type I diabetes, inflammatory bowel disease, non-alcoholic steatohepatitis (NASH), juvenile inflammatory arthritis, ankylosing spondylitis, gout or Aicardi-Goutières syndrome (AGS), A compound according to any one of claims 1 to 11, or 2-[(4-benzyloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; 2-[(4-propan-2-yloxyphenyl)methylamino]-5-propyl-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one; and 2-[(2-chlorophenyl)methylamino]-5-[(2-fluoroanilino)methyl]-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one or a pharmaceutically acceptable salt or tautomer thereof.

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