Novel sulfonamide derivatives

Abstract

The invention relates to a compound of formula (I) wherein A1 and R1 to R6 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P39773

[0003] Novel sulfonamide derivatives

[0004] The present invention relates to organic compounds useful for therapy and / or prophylaxis in a mammal, and in particular to compounds that are TMEM175 enhancers. The compound of formula (I) is particularly useful in the treatment or prophylaxis of neurodegenerative diseases, fibrotic disorders or inflammatory disorders, more specifically, synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis and lysosomal storage disorders.

[0005] The invention relates in particular to a compound of formula (I)

[0006]

[0007] wherein

[0008] A1is -CH or nitrogen;

[0009] R1and R2, together with the carbon atoms to which they are attached, form

[0010]

[0011] DP / 24.09.25

[0012]

[0013] R3is halogen, cycloalkyl, halocycloalkyl, phenyl, halophenyl, thiophenyl, alkylthiophenyl, pyridinyl or haloalkylpyridinyl;

[0014] R4is hydrogen, halogen or alkoxy;

[0015] R5is hydrogen or halogen; and

[0016] R6is alkylphenyl, halothiophenyl or haloalkylthiophenyl;

[0017] or a pharmaceutically acceptable salt thereof.

[0018] TMEM175, or Transmembrane Protein 175, is a cation-selective lysosomal ion channel shown to conduct both potassium and proton currents (Hu M, Li P, Wang C, Feng X, Geng Q, Chen W, Marthi M, Zhang W, Gao C, Reid W, Swanson J, Du W, Hume RI, Xu H. Parkinson's disease-risk protein TMEM175 is a proton- activated proton channel in lysosomes. Cell 185: 2292-2308. e20, 2022). TMEM175 contributes to maintenance of the lysosomal membrane potential and stabilization of the lysosomal pH gradient both of which are crucial for proper lysosomal function (Cang, C.; Aranda, K.; Seo, Y.-J.; Gasnier, B.; Ren, D. TMEM175 Is an Organelle K+Channel Regulating Lysosomal Function. Cell 2015, 162, 1101-1112). Lysosomal catabolic activity is dependent upon a variety of enzymes confined to the lysosomal lumen. The majority of these enzymes exhibit pH dependent activity and are optimally functional at an acidic pH between 4.5 to 5.0 (Mellman I. Organelles observed: lysosomes. Science 244: 853-854, 1989. doi:

[0019] 10.1126 / science.244.4906.853). TMEM175 acts as a proton-activated channel that will preferentially expel protons from the lysosomal lumen at pH <4.5. At pH > 5.0, protondependent activation is reduced and the proton flux from the lumen to the cytosol is decreased, helping to maintain the optimal pH range for normal lysosomal function (Hu et al 2022, op. cit.). In mice, knockout of TMEM175 has been shown to reduce the enzymatic degradation of BSA and more specifically, the pH dependent activity of cathepsins B and D are reduced (Wie J, Liu Z, Song H, Tropea TF, Yang L, Wang H, Liang Y, Cang C, Aranda K, Lohmann J, Yang J, Lu B, Chen-Plotkin AS, Luk KC, Ren D. A growth-factor-activated lysosomal K+channel regulates Parkinson’s pathology. Nature 591: 431-437, 2021. doi: 10.1038 / s41586-021-03185-z). TMEM175 has been identified as a novel lysosomal ‘leak-like’ potassium channel representing the major K+permeability of lysosomes (Cang et al., 2015, op. cit.).

[0020] TMEM175 is unique among other canonical potassium channels for several reasons: (1) no sequence homology with other tetrameric potassium channels, (2) it possesses a unique structure (Lee C, Guo J, Zeng W, Kim S, She J, Cang C, Ren D, Jiang Y. The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture. Nature. 2017 Jul 27 ;547 (7664):472-475; Oh S, Paknejad N, Hite RK. Gating and selectivity mechanisms for the lysosomal K+channel TMEM175. Elife. 2020 Mar 31;9:e53430) and assembles as a homodimer of 2 homologous copies of a six-transmembrane helix domain, where (3) the transmembrane helix 1 and 7 serve as the pore forming helix and (4) it is localized at lysosomal and endosomal membranes. Furthermore, TMEM175 is not blocked by cesium (Cs+) as are the majority of potassium channels, but instead can conduct Cs+with a similar permeability as K+. It has been shown to be blocked by 4-AP. Interestingly, TMEM175 is activated by growth factors via AKT in a kinase independent fashion (Wie et al., 2021, op. cit.).

[0021] In knockout studies, it has been shown that TMEM175 regulates lysosomal membrane potential, pH stability, and organelle fusion via potassium conductance on lysosomal and endosomal membranes (Cang et al, 2015, op. cit.).

[0022] TMEM175 with the M393T risk mutation is thought to be a (partial) loss of function mutation because measured currents are reduced (Wie et al., 2021, op. cit.) and the effect on lysosomal pH resembles that of knockout cells with a more alkaline pH during starvation. Furthermore, lysosomal localization of TMEM175 M393T might be reduced as compared to wildtype TMEM175 (Jinn S, Blauwendraat C, Toolan D, Gretzula CA, Drolet RE, Smith S, Nalls MA, Marcus J, Singleton AB, Stone DJ. Functionalization of the TMEM175 p.M393T variant as a risk factor for Parkinson disease. Hum Mol Genet. 2019 Oct 1 ;28( 19):3244-3254). In contrast to wildtype TMEM175, M393T overexpression does not reduce PFF-induced phospho a-synuclein (Jinn et al., 2019, op. cit.).

[0023] The Q65P variant is considered as a gain-of-function mutation under stress. When cells are starved, it leads to a reduction in TMEM175 current that is dependent and gated by AKT. In the Q65P mutant, the starvation-induced reduction in K+ current is delayed and early during starvation, the Q65P TMEM175 lysosomes carry a higher current than wildtype TMEM175. Taken together, these data suggest that the Q65P mutation represents a gain-of-function mutation under stress (Wie et al., 2021, op. cit.).

[0024] Dysfunction in lysosomal activities is linked to various neurodegenerative diseases, including Parkinson's disease, suggesting a potential role for TMEM175 in neurodegenerative disorders (Bahr B.A., Bendiske J. The neuropathogenic contributions of lysosomal dysfunction. J. Neurochem. 2002;83:481-489). Consistent with this hypothesis, TMEM175 has been identified by genome- wide association studies as a genetic risk factor for Parkinson’s disease (PD) (Hopfner F, Mueller SH, Szymczak S, Junge O, Tittmann L, May S, Lohmann K, Grallert H, Lieb W, Strauch K, Miiller-Nurasyid M, Berger K, Schormair B, Winkelmann J, Mollenhauer B, Trenkwalder C, Maetzler W, Berg D, Kasten M, Klein C, Hbglinger GU, Gasser T, Deuschi G, Franke A, Krawczak M, Dempfle A, Kuhlenbaumer G. Rare variants in specific lysosomal genes are associated with Parkinson’s disease. Mov Disord 35: 1245-1248, 2020. doi: 10.1002 / mds.28037), Rapid-eye-movement (REM) sleep behavior disorder (RBD) (Krohn L, et al. Genetic, structural, and functional evidence link TMEM175 to synucleinopathies. Ann. Neurol. 2020;87:139-153. doi: 10.1002 / ana.25629) and Dementia with Lewy Bodies (Chia R, Sabir MS, Bandres-Ciga S, et al.; American Genome Center . Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021;53(3):294-303). Multiple coding variants of TMEM175 have been identified and one variant, TMEM175 M393T, is associated with an increased risk and earlier onset of Parkinson’s disease (Blauwendraat C., Heilbron K., Vallerga C.L., Bandres-Ciga S., von Coelln R., Pihlstrom L., Simon-Sanchez J., Schulte C., Sharma M., Krohn L. et al. (2019) Parkinson's disease age at onset genome- wide association study: defining heritability, genetic loci, and alpha- synuclein mechanisms. Mov. Disord., 34, 866-875). Functional analysis of M393T indicated that M393T is a partial loss of function allele, suggesting that enhancement of TMEM175 activity could provide a therapeutic benefit in Parkinson’s disease (Jinn S, Drolet RE, Cramer PE, Wong AH, Toolan DM, Gretzula CA, Voleti B, Vassileva G, Disa J, Tadin-Strapps M, Stone DJ. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases alpha-synuclein aggregation. Proc Natl Acad Sci USA 114: 2389-2394, 2017. doi:

[0025] 10.1073 / pnas.1616332114).

[0026] TMEM175 has also been identified as a comorbid gene between Amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (Tian Y, Ma G, Li H, Zeng Y, Zhou S, Wang X, Shan S, Xu Y, Xiong J, Cheng G. Shared Genetics and Comorbid Genes of Amyotrophic Lateral Sclerosis and Parkinson's Disease. Mov Disord. 2023 Oct;38(10):1813-1821. doi: 10.1002 / mds.29572. Epub 2023 Aug 3) and as a shared genetic risk loci among Alzheimer’s disease related dementias, Parkinson’s disease and Amyotrophic lateral sclerosis (Wainberg, M., Andrews, S.J. & Tripathy, S.J. Shared genetic risk loci between Alzheimer’s disease and related dementias, Parkinson’s disease, and amyotrophic lateral sclerosis. Alz Res Therapy 15, 113 (2023)). Further, in a proteome-wide association study (PWAS) for Amyotrophic lateral sclerosis, TMEM175 was identified (Ma, Y., Jia, T., Qin, F. et al. Abnormal Brain Protein Abundance and Cross-tissue mRNA Expression in Amyotrophic Lateral Sclerosis. Mol Neurobiol 61, 510-518 (2024)) and lysosomal dysfunction is an important pathogenic disease mechanism in ALS (Root J, Merino P, Nuckols A, Johnson M, Kukar T. Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.

[0027] Neurobiol Dis. 2021 Jul;154:105360). Therefore, TMEM175 enhancers may address the underlying disease biology in ALS.

[0028] Lysosomal storage disorders (Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Publisher Correction: Lysosomal storage diseases. Nat Rev Dis Primers. 2019 May 17;5( 1) :34) are characterized by accumulation of substrates in excess in lysosomes, often resulting from defects in lysosomal function. Since TMEM175 knockout leads to a reduced lysosomal hydrolysis activity and degradation activity (Hu et al 2022, op. cit.), a TMEM175 enhancer may increase lysosomal degradation capacity and thereby reduce pathological storage in lysosomal storage disorders.

[0029] In the present description the term “alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straightchain and branched-chain Ci-Cs alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl more particularly methyl, ethyl, propyl, isopropyl, isobutyl, tert.-butyl and isopentyl. Particular examples of “alkyl” are methyl and propyl, particularly isopropyl.

[0030] The term “cycloalkyl”, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particular “cycloalkyl” are cyclopentyl and cyclohexyl, more particularly cyclopentyl.

[0031] The term “oxy”, alone or in combination, signifies the -O- group.

[0032] The term “alkyloxy” or “alkoxy”, alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec .butoxy and tert.butoxy. Particular examples of “alkyloxy” or “alkoxy” are methoxy and isopropoxy. A particular examples of “alkyloxy” or “alkoxy” is methoxy.

[0033] The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens, i.e. one, two or three halogens. Particular halogens are fluorine, bromine and chlorine, more particularly fluorine and chlorine.

[0034] The term “haloalkyl”, alone or in combination, denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. Particular “haloalkyl” are fluoromethyl, difluoromehtyl and trifluoromethyl.

[0035] The term “halocycloalkyl”, alone or in combination, denotes a cycloalkyl group substituted with at least one halogen, particularly substituted with one to three halogens. A particular halocycloalkyl is difluorocyclohexyl.

[0036] The term “halophenyl”, alone or in combination, denotes a phenyl group substituted with at least one halogen, particularly substituted with one to three halogens, more particularly one halogen. A particular “halophenyl” is fluorophenyl and difluorophenyl.

[0037] The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and 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, N-acetylcystein. In addition these salts may be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, 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, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

[0038] If one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wuts, 3rdEd., 1999, Wiley, New York) can be introduced before the critical step 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-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

[0039] The compound of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0040] The term “asymmetric carbon atom” means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the “R” or “S” configuration.

[0041] The invention further relates to:

[0042] A compound of formula (I) wherein R1is hydrogen or chlorine;

[0043] A compound of formula (I) wherein R2is hydrogen, chlorine, methyl, difluoromethyl or methoxy;

[0044] A compound of formula (I) wherein R3is halogen, cyclopentyl, difluoroyclohexyl, phenyl, fluorophenyl, thiophenyl, methylthiophenyl, pyridinyl or trifluoromethylpyridinyl;

[0045] A compound of formula (I) wherein R4is hydrogen, fluorine or methoxy;

[0046] A compound of formula (I) wherein R4is hydrogen or methoxy;

[0047] A compound of formula (I) wherein R5is hydrogen or fluorine;

[0048] A compound of formula (I) wherein R5is hydrogen;

[0049] A compound of formula (I) wherein R6is methylphenyl, isopropylphenyl, chloro thiophenyl or fluoromethylthiophenyl;

[0050] A compound of formula (I) wherein R7is hydrogen or methyl; and

[0051] A compound of formula (I) wherein R7is hydrogen.

[0052] The invention further relates to a compound selected from N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0053] N-[2-[cyclopentyl(methoxy)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide ;

[0054] N-[2-[methoxy-(5-methyl-2-thienyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0055] N- [2- [methoxy- [6- (trifluoromethyl) - 3 -pyridyl] methyl] - 8 -methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0056] 4-isopropyl-N-[5-methyl-4-oxo-2-(3-pyridylmethyl)quinazolin-3-yl]benzenesulfonamide;

[0057] 5-chloro-N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] thiophene -2- sulfonamide ;

[0058] N-[6-chloro-4-oxo-2-(2-thienylmethyl)quinazolin-3-yl]-4-isopropyl-benzenesulfonamide;

[0059] 4-isopropyl-N-[5-methyl-4-oxo-2-(2-thienylmethyl)quinazolin-3-yl]benzenesulfonamide;

[0060] N-[2-[(4,4-difhiorocyclohexyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0061] N- [2- [difluoro(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3 ,4-d]pyrimidin-3-yl] -4-methyl-benzenesulfonamide;

[0062] 4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrimido [5 ,4-d] pyrimidin- 3 -yl] benzenesulfonamide ;

[0063] N-[7-(difhioromethyl)-4-oxo-2-[(R)-(4-fhiorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin- 3 -yl] - 5 - (fluoromethyl) thiophene-2- sulfonamide ;

[0064] N-[3-[(4-fhiorophenyl)methyl]-5-methyl-l-oxo-2,6-naphthyridin-2-yl]-4-methyl-benzenesulfonamide;

[0065] N-[3-[(4-fhiorophenyl)methyl]-5-methoxy-l-oxo-2,6-naphthyridin-2-yl]-4-methyl-benzenesulfonamide; and

[0066] N- [5-chloro-7 -fluoro-3- f(4-fluorophenyl)methyl] - 1 -oxo-2-isoquinolyl] -4-methyl-benzenesulfonamide;

[0067] or a pharmaceutically acceptable salt thereof. The invention also relates to a compound of formula (I) selected from

[0068] N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0069] N-[2-[cyclopentyl(methoxy)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide ;

[0070] N-[2-[methoxy-(5-methyl-2-thienyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0071] N- [2- [methoxy- [6- (trifluoromethyl) - 3 -pyridyl] methyl] - 8 -methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide; and

[0072] N-[7-(difhioromethyl)-4-oxo-2-[(R)-(4-fhiorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin- 3 -yl] - 5 - (fluoromethyl) thiophene-2- sulfonamide ;

[0073] or a pharmaceutically acceptable salt thereof.

[0074] The following abreviations are used in the present description.

[0075] EtOAc is ethyl acetate;

[0076] DIPEA is N,N-diisopropylethylamine;

[0077] TEA is trimethylamine;

[0078] HPLC is high pressure liquid chromatography;

[0079] LiHMDS is lithium bis(trimethylsilyl)amide;

[0080] DAST is diethylamino sulfur trifluoride;

[0081] DMSO is dimethyl sulfoxide;

[0082] DMF is dimethylformamide;

[0083] ACN / MeCN is acetonitrile;

[0084] THF is tetrahydrofuran;

[0085] DCM is dichloromethane;

[0086] HATU is Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium; TCFH is tetramethylchloroformamidinium hexafluorophosphate;

[0087] NMI is N-Methylimidazole;

[0088] Pd(PPh3)2Ch is bis(triphenylphosphine)palladium(II) dichloride;

[0089] Pd(dppf)C12.CH2C12 is [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct;

[0090] PE / EA is petroleum ether / ethyl acetate;

[0091] FA is formic acid;

[0092] O / N is overnight;

[0093] RT is room temperature;

[0094] CMV is cytomegalovirus;

[0095] FBS is fetal bovine serum;

[0096] HEPES is 4-(2-hydroxyethyl)-l -piperazine ethanesulfonic acid;

[0097] NMDG is N-methyl-D-glucamine diatrizoate;

[0098] EGTA is ethylene glycol-bis(beta- aminoethyl ether)-N,N,N’,N’ -tetraacetic acid;

[0099] DPBS is Dulbecco’s phosphate-buffered saline;

[0100] mV is millivolt;

[0101] DCPIB is 4-[(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro- 1-oxo- lH-inden-5-yl)oxy]butanoic acid; and

[0102] 4-AP is 4- aminopyridine.

[0103] The compound of formula (I) can be generated using any of the reaction conditions described below, and the decision on which route to use is based on intermediate availability. Certain conditions allow for the preparation of enantiomeric ally pure compounds, however with longer synthesis.

[0104] For more information on the general procedures, please refer to the embodiments relating to the process of making the compound of formula (I) as described herein.

[0105]

[0106] Scheme 1: Synthesis of the compound of formula (I)

[0107] Treatment of amine 1 with acid 2 using HATU, DIPEA in DMSO, DMF, or ACN, or TCFH, NMI in DMF, or with an acyl chloride in presence of a suitable base (DIPEA, NEt3 or pyridine) in DCM or DMF, leads to amide intermediate 3 (scheme 1). Preferred conditions are using HATU, DIPEA in DMSO at RT for 2 hrs. The amide intermediate 3 can then be reacted with Boc-hydrazide 4 and phosphorus trichloride in Me-THF, THF, 1,4-dioxane or 2,2-dimethyloxolane at 80 to 100°C to afford the desired cyclized sulfonamide of Formula I. Alternatively, an unprotected sulfonyl hydrazide 5 can be used for the cyclization step under the same conditions.

[0108] Alternatively, the amide intermediate 3 can be reacted with acetic anhydride at 100°C for 1 hr to afford cyclized intermediate 6, which can be subsequently reacted with hydrazine in EtOH at 80°C to afford amino-intermediate 7, which can then be reacted with sulfonyl chloride in the presence of LiHMDS in THF at -78°C to afford the desired sulfonamide of formula I.

[0109] Alternatively, intermediate 6 can be reacted with unprotected sulfonyl hydrazide 5 directly in dioxane at 100°C for 1 hr to afford the desired sulfonamide of formula I.

[0110]

[0111] Scheme 2: Synthesis of the compound of formula (I) Alternatively, amine 8 can be reacted with acylchloride 9 in DMF in presence of pyridine at RT for 1 hr to afford amido-ester intermediate 10, which can then be cyclized by reaction with hydrazine in EtOH at RT for 1 hr to afford amino intermediate 7 (scheme 2). Final coupling with a sulfonyl chloride in the presence of EiHMDS in THF at -78°C leads to the desired sulfonamide of formula I.

[0112]

[0113] Scheme 2: Synthesis of compounds of Formula 11

[0114] Reaction between heteroaryl iodide 11 and alkyne 12 via Sonogashira coupling in presence of a palladium catalyst, such as Pd(PPh3)2Ch, Cui, and a suitable base such as TEA at 80°C for 3 hours afforded intermediate 13, which can then be cyclized to amino intermediate 14 by treatment with hydrazine in ethanol at 80°C for 16 hours. Subsequent treatment with p-toluene sulfonyl chloride in presence of LiHMDS in THF at -78 °C, or in pyridine at 100°C, leads to the desired sulfonamide of formula II.

[0115] Isolation and purification of the compounds

[0116] Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, supercritical fluid chromatography or a combination of these procedures. However, other equivalent separation or isolation procedures could, of course, also be used. Mixtures of chiral compounds of formula (I) or intermediates can be separated using preparative chiral HPLC or SFC purifications. Chiral chromatography purifications were performed using the following conditions:

[0117]

[0118] The invention thus also relates to a process for the preparation of a compound of formula (I) comprising one of the following step:

[0119] (a) The reaction of a compound of formula (A)

[0120]

[0121] in the presence of R6SO2NHNHR and PCh;

[0122] (b) The reaction of a compound of formula (B)

[0123]

[0124] in the presence of R6SO2NHNHR;

[0125] (c) The reaction of a compound of formula (C)

[0126]

[0127] in the presence of R6SO2C1 and a base; or

[0128] (d) The reaction of a compound of formula (D)

[0129]

[0130] in the presence of R6SO2C1 and a base;

[0131] wherein R1to R6are as defined above and wherein R is hydrogen or an amine protecting group like Boc. Step (a) can be carried out in Me-THF, THF, 1,4-dioxane or 2,2-dimethyloxolane. Step (a) can advantageously be performed at a temperature between around 80°C to 100°C.

[0132] Step (b) can be performed in dioxane. Step (b) can advantageoulsy be carried out at 100°C.

[0133] The base of step (c) can advantageously be LiHMDS. Step (c) can be carried out in THF. Step (c) can be performed at around -78°C.

[0134] The base of step (d) can advantageously be LiHMDS. Step (d) can be carried out in THF. Step (d) can be performed at around -78°C.

[0135] The invention further relates to:

[0136] A compound of formula (I), when manufactured according to a process of the invention;

[0137] A compound of formula (I) for use as therapeutically active substance;

[0138] A pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier;

[0139] The use of a compound of formula (I) for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders;

[0140] The use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders;

[0141] A compound of formula (I) for use in the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders; and

[0142] A method for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders, which method comprises administering an effective amount of a compound of formula (I) to a patient in need thereof. Another embodiment of the invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

[0143] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context 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 scheduling of administration, and other factors known to medical practitioners.

[0144] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0145] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

[0146] A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., 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 formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0147] The invention will now be illustrated by the following examples which have no limiting character. Examples

[0148] Example 1: N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0149]

[0150] a) 3-(2-cyclopentylacetamido)-2-methylpyridine-4-carboxylic acid

[0151] A solution of 3-amino-2-methylpyridine-4-carboxylic acid (200 mg, 1.314 mmol, 1 equiv), cyclopentaneacetic acid (336.9 mg, 2.628 mmol, 2 equiv), HATU (999.6 mg, 2.628 mmol, 2 equiv) and DIPEA (339.7 mg, 2.628 mmol, 2 equiv) in DMSO (5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 90% gradient in 60 min; detector, UV 254 nm. This resulted in 3-(2-cyclopentylacetamido)-2-methylpyridine-4-carboxylic acid (150 mg, 43.50% yield) as a yellow solid. LCMS (ESI) [M + H]+: 263

[0152] b) N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0153] A solution of 3-(2-cyclopentylacetamido)-2-methylpyridine-4-carboxylic acid (140 mg, 0.534 mmol, 1 equiv), V'-(4-mcthylbcnzcncsulfonyl) / e / 7-butoxycarbohydrazidc (305.6 mg, 1.068 mmol, 2 equiv) and phosphorus trichloride (219.8 mg, 1.602 mmol, 3 equiv) in 2-methyloxolane (5 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was quenched with water at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 90% gradient in 20 min; detector, UV 254 nm. This resulted in N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (30.5 mg, 13.85% yield) as a white solid. LCMS (ESI) [M + H]+: 413.00. ’H NMR (400 MHz, DMSO-tfe) 6 11.48 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.68 -7.62 (m, 2H), 7.59 (d, J= 5.2 Hz, 1H), 7.38 (d, J= 8.0 Hz, 2H), 2.96 (s, 1H), 2.76 (s, 4H), 2.49 - 2.42 (m, 1H), 2.40 (s, 3H), 1.83 (s, 2H), 1.63 - 1.45 (m, 4H), 1.16 (s, 2H). Example 2: N-[2-[cyclopentyl(methoxy)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0154]

[0155] a) 2- [cyclopentyl(methoxy)methyl] - 8- mcthy I py rido 13 ,4-<71 [ 1 ,3] oxazin-4-one

[0156] To a stirred solution of 3-(2-cyclopentyl-2-methoxyacetamido)-2-methylpyridine-4-carboxylic acid (80.0 mg, 0.274 mmol, 1 equiv) in acetic anhydride (1 mL) at room temperature. The resulting mixture was stirred for 1 h at 100 °C. The resulting mixture was concentrated under reduced pressure. This resulted in 2-[cyclopentyl(methoxy)methyl]-8-methylpyrido[3,4-6?][l,3]oxazin-4-one (40.0 mg, 53.28% yield) as a light yellow solid. LCMS (ESI) [M + H]+: 275

[0157] b) 3-amino-2-|cyclopcntyl(mcthoxy)mcthyl|-8-mcthylpyrido|3,4-d|pyrimidin-4-onc

[0158] To a stirred solution of 2-[cyclopentyl(methoxy)methyl]-8-methylpyrido[3,4- <7|| 1 ,3|oxazin-4-onc (40.0 mg, 0.146 mmol, 1 equiv) in EtOH (2 mL) was added hydrazine hydrate (2 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (The residue was purified by re versed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford 3-amino-2-[cyclopcntyl(mcthoxy)mcthyl|-8-mcthylpyrido|3,4-<7|pyrimidin-4-onc (17.0 mg, 40.43% yield) as a light yellow solid. LCMS (ESI) [M + H]+: 289

[0159] c) N-[2-[cyclopentyl(methoxy)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0160] To a stirred solution of 3-amino-2-[cyclopentyl(methoxy)methyl]-8-methylpyrido[3,4-<7|pyrimidin-4-onc (17.0 mg, 0.059 mmol, 1 equiv) and -tolucncsulfonyl chloride (33.7 mg, 0.177 mmol, 3 equiv) in THE (5 mL) was added LiHMDS (14.8 mg, 0.088 mmol, 1.5 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (5 mL) at -78 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. The residue product was purified by reverse phase flash with the following conditions (The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford N-[2-[cyclopentyl(methoxy)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (12.9 mg, 49.35% yield) as a white solid. LCMS (ESI) [M + H]+: 443.10. ’H NMR (400 MHz, DMSO-tfe) 6 11.57 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.69 -7.59 (m, 3H), 7.42 - 7.35 (m, 2H), 4.71 (s, 1H), 3.30 (s, 3H), 2.78 (s, 3H), 2.41 (s, 3H), 1.54 (m, 9H).

[0161] Example 3: N-[2-[methoxy-(5-methyl-2-thienyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0162]

[0163] a) 2-[methoxy(5-methylthiophen-2-yl)methyl]-8-methylpyrido[3,4-6?][l,3]oxazin-4-one

[0164] A solution of 3-[2-methoxy-2-(5-methylthiophen-2-yl)acetamido]-2-methylpyridine-4-carboxylic acid (300 mg, 0.936 mmol, 1 equiv) in acetic anhydride (4 mL) was stirred at 120 °C for 1 hour under nitrogen atmosphere. Water was added and then the mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-[methoxy(5-methylthiophen-2-yl)methyl]-8-methylpyrido[3,4-6?][l,3]oxazin-4-one (166 mg, 58.63% yield) as yellow oil.

[0165] b) N-[2-[methoxy-(5-methyl-2-thienyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] -4-methyl-benzenesulfonamide A solution of 2-[methoxy(5-methylthiophen-2-yl)methyl]-8-methylpyrido[3,4-*[l,3]oxazin-4-one (100 mg, 0.331 mmol, 1 equivalent) and 4-toluene sulfonyl hydrazide (73.91 mg, 0.397 mmol, 1.2 equivalent) in dioxane (5 mL) was stirred at 100 °C for 1 hour under nitrogen atmosphere. After completion, the mixture was purified by reverse phase flash chromatography to afford A-{2-[methoxy(5-methylthiophen-2-yl)methyl]-8-methyl-4-oxopyrido[3,4-*pyrimidin-3-yl}-4-methylbenzenesulfonamide (26.7 mg, 16.95% yield) as a white solid. LCMS (ESI) [M + H]+: 471.00. ’H NMR (400 MHz, Acetonitrile-*) 6 8.47 (d, J = 5.2 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.49 (dd, J = 5.3, 0.8 Hz, 1H), 7.36 - 7.28 (m, 2H), 6.88 (d, J= 3.4 Hz, 1H), 6.64 (dq, J = 3.5, 1.1 Hz, 1H), 6.05 (s, 1H), 3.37 (s, 3H), 2.83 (s, 3H), 2.47 - 2.40 (m, 6H).

[0166] Example 4: N-[2-[methoxy-[6-(trifluoromethyl)-3-pyridyl]methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0167]

[0168] The title compound was obtained in analogy to Example 2 as a white solid (42.5% yield) using 3-amino-2-{methoxy[6-(trifluoromethyl)pyridin-3-yl]methyl}-8-methylpyrido[3,4-*pyrimidin-4-onc and -tolucncsulfonyl chloride. LCMS (ESI): [M+H]+: 520.12. ’H NMR (400 MHz, Acetonitrile-*) 58.83 (s, 1H), 8.48 (d, J= 5.2 Hz, 1H), 8.09 (d, J= 8.1 Hz, 1H), 7.80 (d, J= 8.1 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.47 (d, J= 5.3 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 6.11 (s, 1H), 3.52 (s, 3H), 2.70 (s, 3H), 2.43 (s, 3H).

[0169] Example 5: 4-isopropyl-N-[5-methyl-4-oxo-2-(3-pyridylmethyl)quinazolin-3-yl] benzenesulfonamide

[0170]

[0171] The title compound was obtained in analogy to Example 1 (10.8% yield) using 2-methyl-6-(2-(pyridin-3-yl)acetamido)benzoic acid and 4-isopropylbenzenesulfonohydrazide. LCMS (ESI) [M+H]+: 449.1. 1H NMR (300 MHz, DMSO-d6) 511.75-10.99 (m, 1H), 5 8.56 - 8.41 (m, 2H), 7.79 - 7.52 (m, 4H), 7.47 - 7.28 (m, 4H), 7.28 - 7.05 (m, 1H), 4.32 (s, 2H), 3.06 - 2.86 (m, 1H), 2.33 (s, 3H), 1.21 (d, J = 6.9 Hz, 6H).

[0172] Example 6: 5-chloro-N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0173]

[0174] The title compound was obtained in analogy to Example 1 as a white solid (12.9% yield) using 3-(2-cyclopentylacetamido)-2-methylpyridine-4-carboxylic acid and 7V-(5-chlorothiophcn-2-ylsulfonyl) / e / 7-butoxycarbohydrazidc. LCMS (ESI): [M+H]+: 439.05. ’H NMR (400 MHz, DMSO-tfe) 5 12.01 (s, 1H), 8.48 (d, J= 5.3 Hz, 1H), 7.66 (d, J= 5.2 Hz, 1H), 7.52 (d, J= 4.1 Hz, 1H), 7.25 (d, J= 4.1 Hz, 1H), 2.93 (d, J= 7.0 Hz, 2H), 2.77 (s, 3H), 2.49 - 2.39 (m, 1H), 1.94 - 1.82 (m, 2H), 1.68 - 1.54 (m, 3H), 1.54 - 1.47 (m, 1H), 1.28 - 1.15 (m, 2H).

[0175] Example 7: N-[6-chloro-4-oxo-2-(2-thienylmethyl)quinazolin-3-yl]-4-isopropyl-benzenesulfonamide

[0176]

[0177] a) 3-amino-6-chloro-2-(thiophen-2-ylmethyl)quinazolin-4-one

[0178] A solution of methyl 5-chloro-2-[2-(thiophen-2-yl)acetamido]benzoate (1 g, 3.228 mmol, 1 equiv) in EtOH (5 mL) and hydrazine hydrate (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The product was precipitated by the addition of water. The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-amino-6-chloro-2-(thiophen-2-ylmethyl)quinazolin-4-one (560 mg, 59.46% yield) as a light yellow solid. MS (ESIpos): m / z =292.00 [M+H]+.

[0179] b) N-[6-chloro-4-oxo-2-(2-thienylmethyl)quinazolin-3-yl]-4-isopropyl-benzenesulfonamide

[0180] To a stirred solution of 3-amino-6-chloro-2-(thiophen-2-ylmethyl)quinazolin-4-one (300 mg, 1.028 mmol, 1 equiv), NaiSiCU (358.05 mg, 2.056 mmol, 2 equiv) and 4-isopropylbenzenesulfonyl chloride (449.77 mg, 2.056 mmol, 2 equiv) in THF (10 mL) was added LiHMDS (2 mL) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 30 min at -78 °C. The product was precipitated by the addition of water. The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (0.1% formic acid system) to afford A-[6-chloro-4-oxo-2-(thiophen-2-ylmethyl)quinazolin-3-yl]-4-isopropylbenzenesulfonamide (36.3 mg, 7.29% yield) as a light yellow solid. LCMS (ESI): [M+H]+: 474.00.1H NMR (400 MHz, DMSO-J6) 5 11.60 (s, 1H), 7.86 (dd, J= 8.6, 2.5 Hz, 1H), 7.76 (t, J= 1.8 Hz, 1H), 7.67 (d, J= 8.3 Hz, 3H), 7.43 - 7.40 (m, 3H), 6.98 - 6.94 (m, 2H), 4.44 (s, 2H), 3.03 - 2.95 (m, 1H), 1.22 (dd, 7= 6.9, 1.2 Hz, 6H).

[0181] Example 8: 4-isopropyl-N-[5-methyl-4-oxo-2-(2-thienylmethyl)quinazolin-3-yl] benzenesulfonamide

[0182]

[0183] The title compound was obtained in analogy to Example 7 as a white solid (15.8% yield) using 3-amino-5-methyl-2-(thiophen-2-ylmethyl) quinazolin-4-one and 4-isopropylbenzenesulfonyl chloride. LCMS (ESI): [M+H]+: 454.05.!H NMR (400 MHz, DMSO-tfe) d 11.40 (s, 1H), 7.63 (d, J = 8.0 Hz, 3H), 7.48 -7.37 (m, 4H), 7.23 (d, J= 7.4 Hz, 1H), 6.98 (d, J= 3.8 Hz, 2H), 4.73 (s, 1H), 4.24 (s, 1H), 2.98 (p, J= 6.9 Hz, 1H), 2.31 (s, 3H), 1.20 (d, J = 6.9 Hz, 6H).

[0184] Example 9: N-[2-[(4,4-difluorocyclohexyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0185]

[0186] The title compound was obtained in analogy to Example 1 as a white solid (12.6% yield) using 3-[2-(4,4-difluorocyclohexyl)acetamido]-2-methylpyridine-4-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 463.10. ’H NMR (400 MHz, Methanol-^) 68.38 (d, J= 5.3 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.59 (dd, J = 5.3, 0.7 Hz, 1H), 7.36 - 7.28 (m, 2H), 2.97 (d, J = 6.8 Hz, 2H), 2.83 (s, 3H), 2.43 (s, 3H), 2.21 (s, 1H), 2.13 - 1.98 (m, 2H), 1.95 - 1.69 (m, 4H), 1.45 - 1.25 (m, 2H).

[0187] Example 10: N-[2-[difluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0188]

[0189] The title compound was obtained in analogy to Example 7 as a white solid (51.8% yield) using 3-amino-2-[difluoro(phenyl)methyl]-8-methylpyrido[3,4-t / ]pyrimidin-4-one and p-toluene sulfonyl chloride. LCMS (ESI): [M+H]+: 457.05.1H NMR (400 MHz, DMSO-tfe) 8 11.24 (s, 1H), 8.61 (s, 1H), 7.72 (d, J = 5.2 Hz, 1H), 7.60 (d, J= 7.9 Hz, 2H), 7.53 (s, 1H), 7.48 (d, J= 6.7 Hz, 4H), 7.34 (s, 2H), 2.74 (s, 3H), 2.41 (s, 3H).

[0190] Example 11: 4- (difluoromethoxymethyl) -N - [8-methyl-4-oxo-2- [(R)- (4-fluorophenyl) -methoxy-methyl]pyrimido[5,4-d]pyrimidin-3-yl]benzenesulfonamide

[0191]

[0192] a) A-(4-chloro-6-methylpyrimidin-5-yl) -2-(4-fluorophenyl)-2-methoxyacetamide

[0193] To a stirred solution of 4-chloro-6-methylpyrimidin-5-amine (800 mg, 5.572 mmol, 1 equiv) and (4-fluorophenyl) (methoxy)acetyl chloride (1354.8 mg, 6.686 mmol, 1.2 equiv) in THF (10 mL) was added LiHMDS (1.0 M in THF) (11.14 mL, 11.144 mmol, 2 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 h under nitrogen atmosphere. The reaction was poured into sat. NH4C1 (aq.) at -78 °C, the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 20 min, UV 254 nm. This resulted in N-(4-chloro-6-methylpyrimidin-5-yl) -2-(4-fluorophenyl)-2-methoxyacetamide (500 mg, 28.97% yield) as a white solid. LC-MS (ESI, m / z): [M + H]+: 310.0

[0194] b) methyl 5-[2-(4-fluorophenyl)-2-methoxyacetamido] -6-methylpyrimidine-4-carboxylate

[0195] To a stirred solution of N-(4-chloro-6-methylpyrimidin-5-yl)-2-(4-fluorophenyl)-2-methoxyacetamide (500 mg, 1.614 mmol, 1 equiv) and EtaN (490.07 mg, 4.842 mmol, 3 equiv) in methanol (5 mL) was added Pd(dppf)Ch.CH2C12 (395.49 mg, 0.484 mmol, 0.3 equiv) in portions at room temperature, the resulting mixture was stirred at 60 °C for overnight under carbon monoxide atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min, UV 254 nm. This resulted in methyl 5-[2-(4-fluorophenyl)-2-methoxyacetamido] -6-methylpyrimidine-4-carboxylate (200 mg, 37.17% yield) as a yellow oil. LC-MS (ESI, m / z): [M + H]+: 334.0

[0196] c) 5-[2-(4-fluorophenyl)-2-methoxyacetamido]-6-methylpyrimidine-4-carboxylic acid

[0197] To a stirred solution of methyl 5-[2-(4-fluorophenyl)-2-methoxyacetamido] -6-methylpyrimidine-4-carboxylate (200 mg, 0.600 mmol, 1 equiv) and LiOH (28.7 mg, 1.200 mmol, 2 equiv) in THF (2 mL) was added water (1 mL). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with water (3 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-[2-(4-fluorophenyl)-2-methoxyacetamido]-6-methylpyrimidine-4-carboxylic acid (180 mg, 93.95% yield) as a yellow oil. LC-MS (ESI, m / z): [M + H]+: 320.0

[0198] d) 2-[(4-fluorophenyl) (methoxy)methyl]-8-methylpyrimido[5,4-d] [l,3]oxazin-4-one

[0199] A solution of 5-[2-(4-fluorophenyl)-2-methoxyacetamido]-6-methylpyrimidine-4-carboxylic acid (200 mg, 0.626 mmol, 1 equiv) in acetic anhydride (5 mL) was stirred at 120 °C for 3 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in 2-[(4-fluorophenyl) (methoxy)methyl]-8-methylpyrimido[5,4-d] [l,3]oxazin-4-one (180 mg, crude) as a yellow oil. The crude product mixture was used in the next step directly without further purification. LC-MS (ESI, m / z): [M + H]+: 302.0 e) 3-amino-2-[(4-fluorophenyl) (methoxy)methyl]-8-methyl-[l,3]diazino[5,4-d]pyrimidin-4-one

[0200] A solution of 2-[(4-fluorophenyl) (methoxy)methyl]-8-methylpyrimido[5,4-d][l,3]oxazin-4-one (180 mg, 0.597 mmol, 1 equiv) and hydrazine hydrate (2 mL) in ethyl alcohol (2 mL) was stirred at 80 °C for 2 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x lOmL) and concentrated under reduced pressure, the mixture in AcOH was stirred at 120 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was poured into water at room temperature, the resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 3-amino-2-[(4-fluorophenyl) (methoxy)methyl]-8-methyl-[l,3]diazino[5,4-d]pyrimidin-4-one (150 mg, 79.63% yield) as a yellow oil. LC-MS (ESI, m / z): [M + H]+: 316.0

[0201] f) 4-(difhioromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrimido [5 ,4-d] pyrimidin- 3 -yl] benzenesulfonamide

[0202] To a stirred solution of 3-amino-2-[(4-fluorophenyl) (methoxy)methyl]-8-methyl-[l,3] diazino[5,4-d]pyrimidin-4-one (150 mg, 0.476 mmol, 1 equiv) and 4- [(difluoromethoxy) methyl] benzenesulfonyl chloride (146.5 mg, 0.571 mmol, 1.2 equiv) in THF (2 mL) was added LiHMDS (1.0 M in THF) (238.8 mg, 1.428 mmol, 3 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 30 min under nitrogen atmosphere. The reaction was poured into sat. NH4CI (aq.) at -78 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 20 min, UV 254 nm. This resulted in 4-(difhioromethoxymethyl)-N- [8-methyl-4-oxo-2- [(4-fluorophenyl)-methoxy-methyl]pyrimido[5,4-d]pyrimidin-3-yl]benzenesulfonamide (80 mg, 31.40% yield) as a yellow oil. Chiral separation using conditions A afforded 4-(difhioromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrimido[5,4-d]pyrimidin-3-yl]benzenesulfonamide as a white solid (25.33% yield, 21.27min, second peak). LC-MS (ESI, m / z): [M + H]+: 536.10. ’H NMR (400 MHz, DMSO-tfe) 6 11.70 (s, 1H), 9.09 (s, 1H), 7.83 (d, J= 8.1 Hz, 2H), 7.57 (d, J= 8.0 Hz, 2H), 7.47 (s, 2H), 7.21 (s, 2H), 6.85 (t, J = 75.3 Hz, 1H), 5.87 (s, 1H), 5.05 (s, 2H), 3.39 (s, 3H), 2.86 (s, 3H). Example 12: N-[7-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-5-(fluoromethyl)thiophene-2-sulfonamide

[0203]

[0204] a) [5-( { 7 - [(benzyloxy)methyl] -2- [(4-fhiorophenyl)(methoxy)methyl] -4-oxothieno [3,2-6?]pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate

[0205] The title compound was obtained in analogy to Example 1 as a white solid (64.1% yield) using 4-[(benzyloxy)methyl]-3-[2-(4-fluorophenyl)-2-methoxyacetamido]thiophene-2-carboxylic acid and (5-{ |( / e / 7-butoxycarbonyl)amino|aminosulfonyl }thiophen-2-yl)methyl acetate. LCMS (ESI) [M + H]+: 644.0

[0206] b) [5-( { 2- [(4-fluorophenyl)(methoxy)methyl] -7 -(hydroxymethyl)-4-oxothieno [3 ,2-6?]pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate

[0207] To a stirred solution of [5-({7-[(benzyloxy)methyl]-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-6?]pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate (2.40 g, 3.728 mmol, 1.0 equiv) in DCM (100 mL) was added Titanium (IV) chloride (1.0M in dichloromethane) (7.46 mL, 7.456 mmol, 2.0 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0°C. The aqueous layer was extracted with CH2Q2 (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (10:1) to afford [5-({2-[(4-fluorophenyl)(methoxy)methyl]-7-(hydroxymethyl)-4-oxothieno[3,2-6?]pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate (2 g, 96.90% yield) as a yellow solid. LCMS (ESI) [M + H]+: 554.0

[0208] c) [5-( { 2- [(4-fhiorophenyl)(methoxy)methyl] -7 -formyl-4-oxothieno 13 ,2-<71 py ri m idi n-3 -yl } sulfamoyl)thiophen-2-yl] methyl acetate To a stirred solution of [5-({2-[(4-fluorophenyl)(methoxy)methyl]-7-(hydroxymethyl)-4-oxothieno[3,2-6?]pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate (2.00 g, 3.613 mmol, 1.0 equiv) in DCM (500 mL) were added MnCL (3.14 g, 36.130 mmol, 10.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for overnight under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH2CI2 (I L). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (10:1) to afford [5-({2-[(4-fluorophenyl)(methoxy)methyl]-7-formyl-4-oxothieno[3,2-6?]pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate (1.6 g, 80.29% yield) as a yellow solid. LCMS (ESI) [M + H]+: 552.0

[0209] d) (5- { [7 -(difluoromethyl)-2- [(4-fluorophenyl)(methoxy)methyl] -4-oxothieno [3,2-6?]pyrimidin-3-yl]sulfamoyl}thiophen-2-yl)methyl acetate

[0210] To a stirred solution of [5-({2-[(4-fluorophenyl)(methoxy)methyl]-7-formyl-4-oxothieno[3,2-d]pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate (1.60 g, 2.901 mmol, 1.0 equiv) in DCM (100 mL) was added DAST (1.87 g, 11.604 mmol, 4.0 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0 °C. The aqueous layer was extracted with CH2CI2 (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Q2 / MeOH (10:1) to afford (5-{[7-(difhioromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-6?]pyrimidin-3-yl]sulfamoyl}thiophen-2-yl)methyl acetate (1.3 g, 78.13% yield) as a yellow solid. LCMS (ESI) [M + H]+: 574.0

[0211] e) N- [7-(difluoromethyl)-2- [(4-fhiorophenyl)(methoxy)methyl] -4-oxothieno [3,2-6?]pyrimidin-3-yl]-5-(hydroxymethyl)thiophene-2-sulfonamide

[0212] To a stirred solution of (5-{[7-(difhioromethyl)-2-[(4-fhiorophenyl)(methoxy)methyl]-4-oxothieno[3,2-6?]pyrimidin-3-yl]sulfamoyl}thiophen-2-yl)methyl acetate (1.30 g, 2.266 mmol, 1.0 equiv) in THE (10 mL) / H20 (4 mL) was added LiOH (217.1 mg, 9.064 mmol, 4.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 60 °C under nitrogen atmosphere. The mixture was acidified to pH 5 with HC1 (aq.). The resulting mixture was diluted with ethyl acetate (30 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% LA), 0% to 50% gradient in 10 min; UV 254 nm. to afford W|7-(difluoromcthyl)-2-|(4-fluorophcnyl)(mcthoxy)mcthyl |-4- oxothicno|3,2-d|pyrimidin-3-yl|-5-(hydroxymcthyl)thiophcnc-2-sulfonamidc (700 mg, 58.10% yield) as a white solid. LCMS (ESI) [M + H]+: 532.0

[0213] f) N-[7-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-5-(fluoromethyl)thiophene-2-sulfonamide

[0214] To a stirred solution of W|7-(difluoromcthyl)-2-|(4-fluorophcnyl)(mcthoxy)mcthyl|-4-oxothieno[3,2-6?]pyrimidin-3-yl]-5-(hydroxymethyl)thiophene-2-sulfonamide (250.0 mg, 0.470 mmol, 1 equiv) in DCM (40 mL) was added DAST (303.2 mg, 1.880 mmol, 4.0 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (50 mL) at 0 °C. The aqueous layer was extracted with CH2CI2 (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5pm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 40% B to 57% B in 30 min; Wave Length: 254 / 220 nm; RTl(min): 11.87 min) to afford N-[7-(difhioromethyl)-4-oxo-2-[(4-fhiorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-5-(fhioromethyl)thiophene-2-sulfonamide (160 mg, 63.76% yield) as a white solid. Chiral separation using conditions B afforded N-[7-(difhioromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-5-(fluoromethyl)thiophene-2-sulfonamide as a white solid (40.8% yield, 10.16min, first peak). LCMS (ESI) [M + H]+: 534.10. ’H NMR (400 MHz, Acetonitrile-^) 59.02 (s, 1H), 8.42 - 8.31 (m, 1H), 7.67 -7.43 (m, 3H), 7.30 - 6.87 (m, 4H), 5.95 (s, 1H), 5.65 (s, 1H), 5.53 (s, 1H), 3.47 (s, 3H). Example 13 : N- [3- [(4-fluorophenyl)methyl] -5-methyl- l-oxo-2,6-naphthyridin-2-yl]-4-methyl-benzenesulfonamide

[0215]

[0216] The title compound was obtained in analogy to Example 14 as a white solid (45.0% yield) using 2-amino-3-[(4-fluorophenyl) methyl]-5-methyl-2,6-naphthyridin-l-one and p- toluene sulfonyl chloride. LC-MS (ESI, m / z): [M + H]+: 438.10. ’H NMR (400 MHz, DMSO-tfe) 5 11.18 (s, 1H), 8.41 (d, J = 5.4 Hz, 1H), 7.63 -7.58 (m, 2H), 7.56 (d, J = 5.4 Hz, 1H), 7.34 (d, J= 8.0 Hz, 2H), 7.28 - 7.22 (m, 2H), 7.17 - 7.10 (m, 2H), 6.72 (s, 1H), 4.13 (d, J= 60.9 Hz, 2H), 2.69 (s, 3H), 2.39 (s, 3H).

[0217] Example 14: N- [3- [(4-fluorophenyl)methyl] -5-methoxy- l-oxo-2,6-naphthyridin-2-yl] -4-methyl-benzenesulfonamide

[0218]

[0219] a) 3-bromo-2-methoxypyridine-4-carboxylic acid

[0220] A mixture of 3-bromo-2-chloropyridine-4-carboxylic acid (3 g, 12.688 mmol, 1 equiv) and sodium methoxide (30% in methanol) (2.06 g, 38.06 mmol, 3 equiv) in MeOH (10 mL) was stirred at 80 °C for 12 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 50 mL), dried over anhydrous NaiSCU. After filtration, the filtrate was concentrated under reduced pressure to afford 3-bromo-2-methoxypyridine-4-carboxylic acid (2 g, 67.94% yield) as a white solid. LCMS (ESI) [M + H]+: 232.0

[0221] b) methyl 3-bromo-2-methoxypyridine-4-carboxylate

[0222] A solution of 3-bromo-2-methoxypyridine-4-carboxylic acid (2 g, 8.619 mmol, 1 equiv) in H2SO4 (2 mL) and MeOH (20 mL) was stirred at 80 °C for 8 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 3-bromo-2-methoxypyridine-4-carboxylate (1.6 g, 75.44% yield) as a white solid. LCMS (ESI) [M + H]+: 246.0

[0223] c) methyl 3-[3-(4-fluorophenyl)prop-l-yn-l-yl]-2-methoxypyridine-4-carboxylate A mixture of methyl 3-bromo-2-methoxypyridine-4-carboxylate (1 g, 4.064 mmol, 1 equiv), l-fluoro-4-(prop-2-yn-l-yl)benzene (0.82 g, 6.096 mmol, 1.5 equiv), Pd(PPh3)2Ch (0.29 g, 0.406 mmol, 0.1 equiv) and Cui (0.15 g, 0.813 mmol, 0.2 equiv) in TEA (10 mL) was stirred at 80 °C 3 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 20 mL), dried over anhydrous NaiSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford methyl 3-[3-(4-fluorophenyl)prop-l-yn-l-yl]-2-methoxypyridine-4-carboxylate (500 mg, 41.11% yield) as a yellow liquid. LCMS (ESI) [M + H]+: 300.0

[0224] d) 2-amino-3-[(4-fluorophenyl)methyl]-5-methoxy-2,6-naphthyridin-l-one

[0225] A solution of methyl 3-[3-(4-fluorophenyl)prop-l-yn-l-yl]-2-methoxypyridine-4-carboxylate (500 mg, 1.671 mmol, 1 equiv) in EtOH (5 mL) and hydrazine monohydrate (1 mL) was stirred at 80 °C for 16 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (0.1% acid), 10% to 75% gradient in 20 min, UV 254 nm to afford 2-amino-3-[(4-fluorophenyl)methyl]-5-methoxy-2,6-naphthyridin-l-one (200 mg, 40.00% yield) as a yellow liquid. LCMS (ESI) [M + H]+: 300.0

[0226] e) N- [3- [(4-fhiorophenyl)methyl] -5-methoxy- 1 -oxo-2,6-naphthyridin-2-yl] -4-methyl-benzenesulfonamide

[0227] A solution of 2-amino-3-[(4-fluorophenyl)methyl]-5-methoxy-2,6-naphthyridin-l-one (100 mg, 0.334 mmol, 1 equiv) in THF (5 mL) was treated with LiHMDS (1.0 M in THF) (0.67 mL, 0.668 mmol, 2 equiv) at -78 °C for 10 min under nitrogen atmosphere followed by the addition of -tolucncsulfonyl chloride (76.4 mg, 0.401 mmol, 1.2 equiv) dropwise at -78 °C. The resulting mixture was stirred at -78 °C for additional 15 min. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated solution of NaCl (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Column: XBridge Prep OBD C18 Column 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 36% B to 66% B in 20 min; Wave Length: 254 / 220 nm; RT= 9.37 min to afford N-[3-[(4-fluorophenyl)methyl] -5-methoxy- 1 -oxo-2,6-naphthyridin-2-yl] -4-methyl-benzenesulfonamide (31.7 mg, 10.46% yield) as a white solid. LCMS (ESI) [M + H]+: 454.0.1H NMR (400 MHz, CD3CN) 58.56 (s, 1H), 8.06 (d, J = 5.5 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.32 (d, J= 8.1 Hz, 2H), 7.29 - 7.18 (m, 3H), 7.15 - 7.05 (m, 2H), 6.46 (d, J = 0.9 Hz, 1H), 4.19 (s, 2H), 4.02 (s, 3H), 2.43 (s, 3H).

[0228] Example 15: N-[5-chloro-7-fluoro-3-[(4-fluorophenyl)methyl]-l-oxo-2-isoquinolyl]-4-methyl-benzenesulfonamide

[0229]

[0230] The title compound was obtained in analogy to Example 14 as a white solid (37.4% yield) using 2-amino-5-chloro-7-fhioro-3-[(4-fhiorophenyl)methyl]isoquinolin- 1-one and p-toluene sulfonyl chloride. LCMS (ESI) [M+H]+: 475.05.1H NMR (400 MHz, CD3CN) 5 8.69 (s, 1H), 7.70 - 7.62 (m, 3H), 7.56 (ddd, J = 8.8, 2.7, 0.7 Hz, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.29 - 7.20 (m, 2H), 7.18 - 7.05 (m, 2H), 6.60 (s, 1H), 4.28 (d, J= 16.3 Hz, 1H), 4.09 (d, J = 16.2 Hz, 1H), 2.44 (s, 3H).

[0231] Example 16: Biological experiments

[0232] a) The potency of exemplary compounds of formula (I) was determined using thallium fluorescence.

[0233] Cell Culture

[0234] Flip-IN Hek293-Trex or Hek293 Trex cells stably expressing TMEM175 under a tetracycline inducible CMV promoter were used for these studies. Cells were maintained in DMEM-HG supplemented with heat inactivated 10% FBS (Gemini), 2mM sodium pyruvate, lOmM Hepes, 50ug / ml Hygromycin and 5ug / ml Blasticidin at 37°C in 5% CO2. All cells were induced with 0.2ug / ml or 2ug / ml Doxycycline 18-24 hour prior to thallium assay.

[0235] Assay solution and compound preparation The assay solution consisted of (in mM): 132 Na-Gluconate, 10 K-Gluconate, 1.8 Ca-Gluconate, 0.8 Mg-Gluconate, 10 HEPES, pH 7.4. Test agents were dissolved in DMSO to give 10 mM stocks. 10-point dose response curves were constructed using the Labcyte Echo 550 acoustic dispenser to generate final test concentrations of 30, 15, 7.5, 3.75, 1.88, 0.94, 0.47, 0.23, 0.12, 0.06 uM.

[0236] Assay Protocol

[0237] All thallium fluorescence studies were performed using the Molecular Devices FLIPR TETRA™ fluorescence platform. Plates seeded with Hek-293FlipIN Trex cells expressing TMEM175 channels were loaded with lOpl of a thallium sensitive AM-ester fluorescent dye made up in IX Hank’s buffer + 20mM HEPES. The dye loading buffer contained an extracellular fluorescence quenching agent allowing the dye to remain in the plate throughout the assay. Cells were incubated with dye for 45-60 minutes at room temperature, protected from light.

[0238] After the dye loading incubation time, cell plates and assay plates were loaded into the FLIPR TETRA instrument. The FLIPR program measured a 20 second baseline, after which the embedded 384- well pipetting head added lOul of 2X test agent or controls made up in chloride free assay buffer containing ImM thallium sulfate. Changes in fluorescence (measured at 490nm excitation and 520nm emission) were measured for a 3-minute period.

[0239] Data Analysis

[0240] Percent activation was calculated from changes in fluorescent response using the following equation:

[0241] % activation = ((RFU test agent - RFU buffer) / (RFU positive control - RFU buffer))* 100

[0242] EC50 values were calculated using IDBS ActivityBase software using a 4-parameter logistic fit. Fit criteria were defined as follows: Fit minimum values were allowed to float between -10% to 5%, Fit maximum values were allowed to float between 40% and 120%. The data are reported in Table 1 (first column).

[0243] b) The potency of exemplary compounds of formula (I) was determined using the SyncroPatch 384 (Nanion) high throughput electrophysiology platform.

[0244] Cell Culture

[0245] Flip-IN Hek293-Trex or Hek293 Trex cells stably expressing TMEM175 under a tetracycline inducible CMV promoter were used for these studies. Cells were maintained in DMEM-HG supplemented with heat inactivated 10% FBS (Gemini), 2mM sodium pyruvate, lOmM Hepes, 50ug / ml Hygromycin and 5ug / ml Blasticidin at 37°C in 5% CO2. Cells were cultured in T-225 flasks (Nunc) for 3-4 days to reach 85-95% confluence prior to electrophysiological recording and cells were seeded in PDL coated plates 24hours prior to testing. All cells were induced with 0.2ug / ml or 2ug / ml Doxycycline 18-24hour prior to electrophysiological recording or fluorescent assays, respectively.

[0246] Solutions

[0247] Solutions were of the following composition:

[0248] Extracellular recording solution (in mM): 105 NaCl, 40 NMDG, 4 KC1, 5 CaCh, 1 MgCh, 10 HEPES, pH 7.4. Seal enhancer solution (in mM): 90 NaCl, 3 KC1, 35 CaCh, 10 MgCh, 10 HEPES, pH 7.4. Intracellular recording solution (in mM): 150 CsF, 1 Mg- ATP, 10 EGTA, 10 HEPES, 5 MgCh, 0.01 Escin, pH 7.2.

[0249] Cell Preparation

[0250] Cells were harvested for electrophysiological recording upon reaching appropriate confluence. Cells were first washed in DPBS (Hyclone, Cat #SH30028.03) and then 2 ml of Accutase (MP Biomedicals #1000449) was added at 28 °C until -90% of cells were suspended. F12 HAM’s media + 1 mM L-glutamine (Hyclone, SH30026.02) was then added to the flask to dilute the accutase. Cells were then triturated until a single cell suspension was achieved, a cell count was performed, and cells were centrifuged for 2 min. at 1,000 rpm. Media was then aspirated, and cells were resuspended in Earle’s balanced salt solution to a concentration of 0.75 X 106 cells / ml and allowed to recover for 25 min at 10°C.

[0251] SyncroPatch Recording

[0252] At the beginning of each assay, 20 pl of cell suspension was dispensed into each well of a multi-hole 384- well SyncroPatch chip by the onboard pipettor. Cell sealing was initiated, and seal enhancer solution was added to facilitate seal formation. Upon completion of sealing, cells were washed 3 times with extracellular recording solution and the assay voltage protocol was started. Human TMEM175 channels were evaluated using a voltage protocol where cells were voltage-clamped at a holding potential of 0 mV. Ionic currents were evoked every 5 sec with a 200 msec voltage ramp from -100 mV to 60 mV, followed by series of 100 msec voltage steps to -80, 0 mv and +40 mV. The current amplitude at the 100 msec 0 mV step was used to for analysis. Baseline current was assessed for 4 minutes prior to the addition of test compound for 2.5 min. This was followed by addition of the positive control, 10 pM DCPIB for an additional 2.5 min. The experiment was completed with addition of 2 mM 4-AP to fully block the channel.

[0253] Data Analysis

[0254] Data were collected on the SyncroPatch platform using PatchControl software (Nanion) and processed and analyzed using DataControl Software (Nanion). The average leak-subtracted current was determined for control, test compound and DCPIB conditions by subtracting the remaining current following block by 4-AP. Percent activation of test compound was determined from the leak-corrected current using the following equation:

[0255] % Activation = ((Test compoundCorr -ControlCorr) / (DCPIBCorr - ControlCorr))*100

[0256] The % activation data were then plotted as a function of compound concentration and fit will a Hill equation to derive EC50. The data are reported in Table 1 (second column).

[0257]

[0258] Table 1

[0259] Example A

[0260] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0261]

[0262]

[0263] The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.

[0264] Example B

[0265] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0266]

[0267]

[0268] The components are sieved and mixed and filled into capsules of size 2.

[0269] Example C

[0270] Injection solutions can have the following composition:

[0271]

[0272] The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by addition of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims

1. Claims1. A compound of formula (I)4. 6.wherein7.A1is -CH or nitrogen;8.R1and R2, together with the carbon atoms to which they are attached, form10. 12.R3is halogen, cycloalkyl, halocycloalkyl, phenyl, halophenyl, thiophenyl, alkylthiophenyl, pyridinyl or haloalkylpyridinyl;13.R4is hydrogen, halogen or alkoxy;14.R5is hydrogen or halogen; and15.R6is alkylphenyl, halothiophenyl or haloalkylthiophenyl;16.or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R1is hydrogen or chlorine.

3. A compound according to claim 1 or 2, wherein R2is hydrogen, chlorine, methyl, difluoromethyl or methoxy.

4. A compound according to any one of claims 1 to 3, wherein R3is halogen, cyclopentyl, difluoroyclohexyl, phenyl, fluorophenyl, thiophenyl, methylthiophenyl, pyridinyl or trifluoromethylpyridinyl.

5. A compound according to any one of claims 1 to 4, wherein R4is hydrogen, fluorine or methoxy.

6. A compound according to any one of claims 1 to 5, wherein R4is hydrogen or methoxy.

7. A compound according to any one of claims 1 to 6, wherein R5is hydrogen or fluorine.

8. A compound according to any one of claims 1 to 7, wherein R5is hydrogen.

9. A compound according to any one of claims 1 to 8, wherein R6is methylphenyl, isopropylphenyl, chlorothiophenyl or fluoromethylthiophenyl.

10. A compound according to any one of claims 1 to 9, wherein R7is hydrogen or methyl.

11. A compound according to any one of claims 1 to 10, wherein R7is hydrogen.

12. A compound according to any one of claims 1 to 11 selected from27.N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl- benzenesulfonamide;28.N-[2-[cyclopentyl(methoxy)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]- 4-methyl-benzenesulfonamide ;29.N-[2-[methoxy-(5-methyl-2-thienyl)methyl]-8-methyl-4-oxo-pyrido[3,4- d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;30.N-[2-[methoxy-[6-(trifhioromethyl)-3-pyridyl]methyl]-8-methyl-4-oxo-pyrido[3,4- d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;31.4-isopropyl-N-[5-methyl-4-oxo-2-(3-pyridylmethyl)quinazolin-3- yl] benzenesulfonamide ;32.5-chloro-N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3- yl] thiophene-2- sulfonamide ; N-[6-chloro-4-oxo-2-(2-thienylmethyl)quinazolin-3-yl]-4-isopropyl- benzenesulfonamide;33.4-isopropyl-N-[5-methyl-4-oxo-2-(2-thienylmethyl)quinazolin-3- y 1] benzenesulfonamide ;34.N-[2-[(4,4-difluorocyclohexyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3- yl]-4-methyl-benzenesulfonamide;35.N- [2- [difluoro(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3 ,4-d]pyrimidin-3-yl] -4- methyl-benzenesulfonamide;36.4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy- methyl] pyrimido [5 ,4-d] pyrimidin- 3 -yl] benzenesulfonamide ;37.N-[7-(difhioromethyl)-4-oxo-2-[(R)-(4-fhiorophenyl)-methoxy-methyl]thieno[3,2- d]pyrimidin- 3 -yl] - 5 - (fluoromethyl) thiophene-2- sulfonamide ;38.N-[3-[(4-fhiorophenyl)methyl]-5-methyl-l-oxo-2,6-naphthyridin-2-yl]-4-methyl- benzenesulfonamide;39.N-[3-[(4-fhiorophenyl)methyl]-5-methoxy-l-oxo-2,6-naphthyridin-2-yl]-4-methyl- benzenesulfonamide; and40.N- [5-chloro-7 -fluoro-3- [(4-fluorophenyl)methyl] - 1 -oxo-2-isoquinolyl] -4-methyl- benzenesulfonamide;41.or a pharmaceutically acceptable salt thereof.

13. A compound according to any one of claims 1 to 12 selected from43.N-[2-(cyclopentylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl- benzenesulfonamide;44.N-[2-[cyclopentyl(methoxy)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]- 4-methyl-benzenesulfonamide ;45.N-[2-[methoxy-(5-methyl-2-thienyl)methyl]-8-methyl-4-oxo-pyrido[3,4- d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;46.N-[2-[methoxy-[6-(trifhioromethyl)-3-pyridyl]methyl]-8-methyl-4-oxo-pyrido[3,4- d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide; and N-[7-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2- d]pyrimidin- 3 -yl] - 5 - (fluoromethyl) thiophene-2- sulfonamide ;47.or a pharmaceutically acceptable salt thereof.

14. A process for the preparation of a compound according to any one of claims 1 to 13 comprising one of the following step:49.(a) The reaction of a compound of formula (A)51. 53.in the presence of R6SO2NHNHR and PCh;54.(b) The reaction of a compound of formula (B)56. 58.in the presence of R6SO2NHNHR;59.(c) The reaction of a compound of formula (C)61. 63.in the presence of R6SO2C1 and a base; or64.(d) The reaction of a compound of formula (D)65. 67.in the presence of R6SO2C1 and a base;68.wherein R1to R6are as defined in any one of claims 1 to 10 and wherein R is hydrogen or an amine protecting group.

15. A compound according to any one of claims 1 to 13, when manufactured according to a process of claim 14.

16. A compound according to any one of claims 1 to 13 for use as therapeutically active substance.

17. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 13 and a therapeutically inert carrier.

18. The use of a compound according to any one of claims 1 to 13 for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders.

19. The use of a compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders.

20. A compound according to any one of claims 1 to 13 for use in the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders.

21. A method for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 13 to a patient in need thereof.

22. The invention as hereinbefore described.

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