Novel sulfonamide derivatives

Abstract

The invention relates to a compound of formula (I) wherein 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: P39771

[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] R1and R2together with the carbon atoms to which they are attached form alkylthiophenyl, perdeuterioalyklthiophenyl, haloalkylthiophenyl, hydroxyalkylthiophenyl, cycloalkylthiophenyl, alkylisothiazolyl, haloalkylisothiazolyl, haloalkoxyisothiazolyl, dialkylpyrazolyl, dihydrospiro-

[0009] DP / 24.09.25 cycloalkylpyranyl, halocycloalkyl-dihydro-2H -pyranyl or haloalkyl-dihydro- 2H-pyranyl;

[0010] R3is hydrogen or alkoxy;

[0011] R4is hydrogen or halogen;

[0012] R5is alkyl, haloalkyl, dialkylamino, halocycloalkyl, haloalkoxyalkyl or halocycloalkylamino; and

[0013] R6is hydrogen;

[0014] or R5and R6, together with the carbon atom to which they are attached, form haloalkylthiazolyl, pyrrolyl, dihydro-1H-imidazolyl;

[0015] or a pharmaceutically acceptable salt thereof.

[0016] 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:

[0017] 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.).

[0018] 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.).

[0019] 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.).

[0020] 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.).

[0021] 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.).

[0022] 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, Müller-Nurasyid M, Berger K, Schormair B, Winkelmann J, Mollenhauer B, Trenkwalder C, Maetzler W, Berg D, Kasten M, Klein C, Höglinger GU, Gasser T, Deuschl 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:

[0023] 10.1073 / pnas.1616332114).

[0024] 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.

[0025] Neurobiol Dis. 2021 Jul;154:105360). Therefore, TMEM175 enhancers may address the underlying disease biology in ALS.

[0026] 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.

[0027] 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. A particular example of “alkyl” is methyl.

[0028] 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 cyclopropyl and cyclobutyl.

[0029] The term “oxy”, alone or in combination, signifies the -O- group.

[0030] 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 example of “alkyloxy” or “alkoxy” is methoxy.

[0031] 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. A particular halogen is fluorine.

[0032] 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, difluoromethyl, trifluoromethyl and trifluoroethyl.

[0033] The term “halocycloalkyl”, alone or in combination, denotes a cycloalkyl group substituted with at least one halogen, particularly substituted with one to three halogens. Particular “haloalkyl” are fluorocyclopropyl, fluorocyclobutyl and difluorocyclopropyl.

[0034] The term “haloalkoxy” or haloalkyloxy”, alone or in combination, denotes an alkoxy group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. A particular “haloalkoxy” is difluoromethoxy.

[0035] The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.

[0036] The term “carbonyl”, alone or in combination, signifies the -C(O)- group.

[0037] The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

[0038] The term “cyano”, alone or in combination, signifies the -CN group.

[0039] 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.

[0040] 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).

[0041] 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.

[0042] 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.

[0043] The invention further relates to:

[0044] A compound of formula (I) wherein R1and R2together with the carbon atoms to which they are attached form alkylthiophenyl, perdeuterioalyklthiophenyl, haloalkylthiophenyl, cycloalkylthiophenyl, alkylisothiazolyl or dihydrospiro-cycloalkylpyranyl;

[0045] A compound of formula (I) wherein R1and R2together with the carbon atoms to which they are attached form methylthiophenyl, trifluoromethylthiophenyl, cyclopropythiophenyl, trideuteriomethylthiophenyl, difluoromethylthiophenyl, difluoroethylthiophenyl, methylisothiazolyl, dihydrospiro-cyclopropylpyranyl or dihydrospiro-cyclobutylpyranyl;

[0046] A compound of formula (I) wherein R3is alkoxy;

[0047] A compound of formula (I) wherein R3is methoxy; A compound of formula (I) wherein R4is hydrogen or fluorine;

[0048] A compound of formula (I) wherein R5is alkyl, haloalkyl, haloalkoxyalkyl, halocycloalkylamino or halocycloalkyl;

[0049] A compound of formula (I) wherein R5is methyl, difluoroethyl, difluoromethoxymethyl, fluorocyclobutylamino or fluorocyclopropyl; and

[0050] A compound of formula (I) wherein R5and R6, together with the carbon atom to which they are attached, form pyrrolyl.

[0051] The invention relates in particular to a compound of formula (I) which is of formula (I-R)

[0052]

[0053] wherein R1to R6are as defined above.

[0054] It is thus particularly advantageous that the asymmetric carbon atom bearing the R3group is of the (R) absolute configuration.

[0055] The invention further relates in particular to a compound of formula (I) wherein R1and R2together with the carbon atoms to which they are attached form

[0056]

[0057] ; or

[0058] wherein

[0059] R7is alkyl, haloalkyl, cycloalkyl, perdeuterioalkyl or hydroxyalkyl; R8is alkyl;

[0060] R9is alkyl or haloalkyl;

[0061] R10is alkyl; and

[0062] R11is alkyl.

[0063] The invention relates in particular to a:

[0064] A compound of formula (I) wherein R7is methyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, cyclopropyl, perdeuteriomethyl or hydroxymethyl;

[0065] A compound of formula (I) wherein R8is hydrogen or methyl;

[0066] A compound of formula (I) wherein R9is methyl or fluoromethyl;

[0067] A compound of formula (I) wherein R10is methyl; and

[0068] A compound of formula (I) wherein R11is methyl.

[0069] The invention further relates to a compound selected from

[0070] N-(2-benzyl-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide; N-(2-benzyl-5-methyl-4-oxo-thieno[2,3-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide; N-[2-[methoxy(phenyl)methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0071] N-[6-[methoxy(phenyl)methyl]-3-methyl-4-oxo-isothiazolo[5,4-d]pyrimidin-5-yl]-4-methyl-benzenesulfonamide;

[0072] N-[5-[methoxy(phenyl)methyl]-3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide;

[0073] N-[2-[(4-fluorophenyl)-methoxy-methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0074] N-(6-(methoxy(phenyl)methyl)- 1,3-dimethyl-4-oxo- 1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)-4-methylbenzenesulfonamide;

[0075] N-[5-(difhioromethyl)-2-[methoxy(phenyl)methyl]-4-oxo-thieno[2,3-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide; N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,r-cyclopropane]-3-yl]-4-methyl-benzenesulfonamide;

[0076] 4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,1'-cyclopropane]-3-yl]benzenesulfonamide;

[0077] N-[5-[methoxy(phenyl)methyl]-1,3-dimethyl-7-oxo-pyrazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide;

[0078] N-[7-(difluoromethyl)-2-[methoxy(phenyl)methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0079] 4-methyl-N-[6-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-y 1] benzenesulfonamide;

[0080] N-[2-[methoxy(phenyl)methyl]-4-oxo-5-(trifluoromethyl)thieno[2,3-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0081] (R)-4-(l-fluorocyclopropyl)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)benzenesulfonamide; N-[7-cyclopropyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin- 3-yl]-4-methyl-benzenesulfonamide;

[0082] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7-(trideuteriomethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0083] N-[7-cyclopropyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin- 3-yl]-4-methyl-benzenesulfonamide;

[0084] 4-methyl-N-[5-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[2,3-d]pyrimidin-3-yl]benzenesulfonamide;

[0085] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0086] (R)-4-(l-fluorocyclopropyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0087] (R)-4-(l,l-difluoroethyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide; (R)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;

[0088] (R)-4-(dimethylamino)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)benzenesulfonamide;

[0089] (R)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro [cyclopropane- 1,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)-4-methylbenzenesulfonamide;

[0090] (S)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;

[0091] 4-(difluoromethoxymethyl)-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl]benzenesulfonamide;

[0092] N-[7-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;

[0093] 4-[(3-fluorocyclobutyl)amino]-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,1-cyclopropane]-3-yl]benzenesulfonamide;

[0094] 4-(difluoromethoxymethyl)-N-[2-[(S)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl]benzenesulfonamide;

[0095] 4-( 1 -fluorocyclopropyl) -N- (7 - (hydroxymethyl) -2- (methoxy (phenyl) methyl) -4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0096] N-[7-(difluoromethyl)-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-yl]-4-(1-fluorocyclopropyl)benzenesulfonamide;

[0097] 2-(difluoromethyl)-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-l,3-benzothiazole-6-sulfonamide;

[0098] N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-1H-indole-6-sulfonamide;

[0099] N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,1-cyclopropane]-3-yl]-1H-indole-6-sulfonamide;

[0100] N-[3-(fluoromethyl)-5-[(4-fluorophenyl)-methoxy-methyl]-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide; 4-(2,2-difluoroethyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano [3,4-d]pyrimidine-8, 1 "-cyclobutane] -3-yl]benzenesulfonamide;

[0101] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide;

[0102] N-[7-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-5-(fluoromethyl)thiophene-2-sulfonamide;

[0103] N-[5-[(4-fluorophenyl)-methoxy-methyl]-3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide;

[0104] 4-(difluoromethoxymethyl)-N-[7-(difluoromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0105] 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(R)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide;

[0106] 4-methyl-N-[7-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0107] 4-methyl-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0108] 4-(2,2-difluoroethyl)-N-[4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano [3,4-d]pyrimidine-8, 1 '-cyclobutane] -3-yl]benzenesulfonamide; and

[0109] 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(S)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide;

[0110] or a pharmaceutically acceptable salt thereof.

[0111] The invention also relates to a compound selected from

[0112] N-[2-[methoxy(phenyl)methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0113] N-[2-[(4-fluorophenyl)-methoxy-methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0114] N-[2-[methoxy(phenyl)methyl]-4-oxo-5-(trifluoromethyl)thieno[2,3-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide; N-[7-cyclopropyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0115] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7-(trideuteriomethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0116] (R)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;

[0117] (R)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro [cyclopropane- 1,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)-4-methylbenzenesulfonamide;

[0118] 4-(difluoromethoxymethyl)-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl]benzenesulfonamide;

[0119] N-[7-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-[((ls,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;

[0120] N-[7-(difluoromethyl)-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-yl] -4-( 1 -fluorocycloprop yl)benzenesulfonamide;

[0121] N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-1H-indole-6-sulfonamide;

[0122] 4-(2,2-difluoroethyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano [3,4-d]pyrimidine-8, 1 "-cyclobutane] -3-yl]benzenesulfonamide;

[0123] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide;

[0124] 4-(difluoromethoxymethyl)-N-[7-(difluoromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0125] 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(R)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide; and

[0126] 4-methyl-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;

[0127] or a pharmaceutically acceptable salt thereof.

[0128] The following abbreviations are used in the present description. ACN / MeCN is acetonitrile;

[0129] CD3OD is deuterated methanol;

[0130] DAST is diethylamino sulfur trifluoride;

[0131] DCM is dichloromethane;

[0132] DIBAL-H is diisobutylaluminium hydride;

[0133] DIPEA is N, N-diisopropylethylamine;

[0134] DMA is Dimethylacetamide;

[0135] DMF is N, N-dimethylformamide;

[0136] DMSO is dimethyl sulfoxide;

[0137] EA / EtOAc is ethyl acetate;

[0138] FA is formic acid;

[0139] HATU is Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium;

[0140] HPLC is high pressure liquid chromatography;

[0141] Ir[dF(CF3)ppy]2(dtbpy))PF6 is [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate;

[0142] LED is light-emitting diodes;

[0143] LiHMDS is lithium bis(trimethylsilyl)amide;

[0144] MTBE is methyl tert-butyl ether;

[0145] NCS is N-chlorosuccinimide;

[0146] NMI is N-Methylimidazole;

[0147] o / n is overnight;

[0148] Pd2(dba)3is tris(dibenzylideneacetone)dipalladium;

[0149] PE is petroleum ether; RT is room temperature;

[0150] TCFH is tetramethylchloroformamidinium hexafluorophosphate;

[0151] THF is tetrahydrofuran;

[0152] TLC is thin-layer chromatography;

[0153] CMV is cytomegalovirus;

[0154] FBS is fetal bovine serum;

[0155] HEPES is 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid;

[0156] NMDG is N-methyl-D-glucamine diatrizoate;

[0157] EGTA is ethylene glycol-bis(beta- aminoethyl ether)-N, N, N’, N’ -tetraacetic acid;

[0158] DPBS is Dulbecco’s phosphate-buffered saline;;

[0159] mV is millivolt

[0160] DCPIB is 4-[(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro- 1-oxo- lH-inden-5-yl)oxy]butanoic acid; and

[0161] 4-AP is 4- aminopyridine.

[0162] 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.

[0163] For more information on the general procedures, one can refer to the embodiments relating to the process of making compounds of formula (I) as described herein. LiHMDS, THF, -78C

[0164]

[0165] Scheme 1: Synthesis of the compound of formula (I)

[0166] Amino ester 1 can be reacted with phenyl acetic acid 2 using HATU in presence of a suitable base (e.g. DIPEA or NEta) in DCM, DMF or DMSO at RT or by using TCFH and NMI in acetonitrile or DMF at 0°C-RT, or by using the corresponding acyl chloride in presence of a suitable base (e.g. DIPEA, NEta) in DCM or THF to yield amido ester intermediate 3 (scheme 1). Subsequent reaction with hydrazine in EtOH at temperature varying between RT and 80°C affords cyclized amino intermediate 4, which can then be reacted with sulfonyl chlorides in the presence of LiHMDS in THF at -78 °C to yield the desired sulfonamide of formula I. H2N— NHBoc

[0167] LiOH MeOH

[0168]

[0169] Scheme 2: Synthesis of the compound of formula (I)

[0170] Alternatively, amido ester intermediate 3 can be hydrolyzed by treatment with lithium hydroxide in MeOH at RT to yield the corresponding acid 5 (scheme 2), which can then be reacted with sulfonyl Boc-hydrazide 6 and phosphorus trichloride in 1,4-dioxane, Me-THF, or 2,2-dimethyloxolane at 80 to 100°C to afford the desired cyclized sulfonamide of Formula I.

[0171]

[0172] Scheme 3: Synthesis of compounds of Formula 1

[0173] Alternatively, amino amide 7 can be reacted with enantiomerically pure acyl chloride 8 in presence of a suitable base, such as DIPEA in DCM or THF to yield amide intermediate 9 (scheme 3). Treatment with sodium hydroxide in EtOH at RT for 1 hr results in cyclization and formation of intermediate 10, which can then be reacted with amino diphenylphosphinate and t-BuOK in THF at 0°C to form amino intermediate 11. Subsequent treatment with methyl triflate and t-BuOK in THF at -75°C leads to formation of methylated intermediate 12, which can then be reacted with sulfonyl chlorides in the presence of LiHMDS in THF at -78°C to yield the desired sulfonamide of formula I.

[0174]

[0175] Scheme 4: Synthesis of the compound of formula (II) (n=l,2)

[0176] A solution of methyl l-(prop-2-en-l-yloxy)cyclopropane-l -carboxylate 13 and methyl acrylate is treated with Grubbs 2ndgeneration catalyst in DCM at RT for 3 hours to afford the olefinic intermediate 14 (scheme 4), which then undergoes hydrogenation with palladium on charcoal under hydrogen atmosphere at 0°C to yield intermediate 15.

[0177] Subsequent treatment with t-BuOK in THF at 0°C leads to the formation of cyclized keto ester intermediate 16, which is then converted to amino ester intermediate 17 by treatment with NH4OAC in MeOH at 60°C for 3 hrs. Treatment with an acyl chloride in presence of a suitable base, such as DIPEA, in DCM at RT for 1 hr leads to intermediate 18. Subsequent treatment with LiOH in MeOH at RT for 1 hr affords acid intermediate 19, which can then be reacted with sulfonyl hydrazide 6 and phosphorus trichloride in Me-THF, 1,4-dioxane or 2,2-dimethyloxolane at 80 to 100°C to afford the desired cyclized sulfonamide of Formula II.

[0178]

[0179] Scheme 5: Synthesis of compounds of Formula 11

[0180] Alternatively, intermediate 18 can be reacted with hydrazine in EtOH at temperature varying between RT and 80°C to afford cyclized amino intermediate 20 (scheme 5), which can then be reacted with sulfonyl chlorides in the presence of LiHMDS in THF at -78°C to yield the desired sulfonamide of formula II.

[0181] Pd2(dba)3, xantphos

[0182] DIPEA BnSH Toluene, 100C

[0183] 21

[0184] i) nBuLi, THF, -78C

[0185] ii) SO2CI2

[0186]

[0187] Scheme 6: Synthesis of sulfonyl chloride

[0188] Sulfonly chlorides can be prepared by cross -coupling reaction between aryl bromide 21 and benzyl mercaptan to yield thioether intermediates 22 (scheme 6). Preferred conditions are using Pd₂(dba)₃ with xantphos in presence of a suitable base like DIPEA at 100°C. Subsequent treatment with NCS and AcOH in water at rt yields the desired sulfonyl chlorides 23. Alternatively, aryl bromide 9 can be reacted with n-BuLi in THF at -78 °C followed by addition of SOCl2to yield the desired sulfonyl chlorides 23. Isolation and purification of the compounds

[0189] 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) and (II) or intermediates can be separated using preparative chiral HPLC or SFC purifications. Chiral chromatography purifications were performed using the following conditions:

[0190] A Column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 pm; Mobile Phase A:

[0191] Hex(0.1% FA)— HPLC, Mobile Phase B: EtOH; Flow rate: 40 mL / min;

[0192] Gradient (B%): isocratic 30%

[0193] B Column: CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)—

[0194] HPLC, Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 50%

[0195] C Column: CHIRALCEL OD-H, 2*25 mm, 5 pm; Mobile Phase A: CO2,

[0196] Mobile Phase B: MeOH(10 mMNH3); Flow rate: 100 mL / min; Gradient (B%): isocratic 35% B; Column Temperature(°C): 35; Back Pressure(bar): 100

[0197] D Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A:

[0198] MtBE: Hex=l:l(0.1%FA), Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient: isocratic 10%

[0199] E Column: CHIRAL ART Amylose-C NEO, 2*25 cm, 5 pm; Mobile Phase A:

[0200] Hex(0.1% FA)-HPLC, Mobile Phase B: ETOH; Flow rate: 20 mL / min;

[0201] Gradient: isocratic 30%

[0202] F Column: CHIRALPAK IA, 3*25 cm, 5 pm; Mobile Phase A: Hex (0.1% FA)- HPLC, Mobile Phase B: ETOH; Flow rate: 40 mL / min; Gradient: isocratic 30%

[0203] K Column: CHIRALPAK- IK, 3*25mm, 5pm; Mobile Phase A: Hex (0.1% FA)- HPLC, Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient (B%): isocratic 10%

[0204]

[0205] The invention thus relates to a process for the preparation of a compound of formula (I) comprising one of the following steps:

[0206] (a) The reaction of a compound of formula (A)

[0207]

[0208] (A)

[0209] in the presence of a compound of formula (B)

[0210]

[0211] and a base; or

[0212] (b) The reaction of a compound of formula (C)

[0213] R4

[0214]

[0215] 0 H(C)

[0216] in the presence of a compound of formula (D)

[0217]

[0218] and PCl3;

[0219] wherein R1to R6are as defined above and wherein R is hydrogen or an amine protecting group, like e.g. Boc.

[0220] In step (a), the base is advantageously a non-nucleophilic base, in particular a lithiated organosilicon base, more particularly LiHMDS.

[0221] Step (a) can advantageously be carried out in THF, for example at around -78°C.

[0222] Step (b) can advantageously be carried out in Me-THF, THF, 1,4-dioxane or 2,2-dimethyloxolane.

[0223] Step (b) can be carried out at a temperature comprised between around 80°C and 100°C.

[0224] The invention further relates to:

[0225] A compound of formula (I), when manufactured according to a process of the invention;

[0226] A compound of formula (I) for use as therapeutically active substance;

[0227] A pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier;

[0228] 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;

[0229] 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; 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

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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).

[0236] The invention will now be illustrated by the following examples which have no limiting character. Examples

[0237] Example 1: N-(2-benzyl-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide

[0238]

[0239] a) methyl 4-methyl-3-(2-phenylacetamido)thiophene-2-carboxylate

[0240] To a stirred solution of methyl 3-amino-4-methylthiophene-2-carboxylate (1.00 g, 5.841 mmol, 1 equiv) and DIPEA (3.77 g, 29.205 mmol, 5 equiv) in DCM (20 mL) was added phenylacetyl chloride (1.35 g, 8.761 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-methyl-3-(2-phenylacetamido)thiophene-2-carboxylate (600.0 mg, 35.50% yield) as a light yellow solid. LCMS (ESI) [M + H]+: 290.0.

[0241] b) 3-amino-2-benzyl-7-methylthieno[3,2-d]pyrimidin-4-one

[0242] To a stirred solution of methyl 4-methyl-3-(2-phenylacetamido)thiophene-2-carboxylate (600.0 mg, 2.074 mmol, 1 equiv) in EtOH (5 mL) was added hydrazine hydrate (5 mL) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-amino-2-benzyl-7-methylthieno[3,2-6?]pyrimidin-4-one (500.0 mg, 88.86% yield) as a light yellow solid. LCMS (ESI) [M + H]+: 272.0.

[0243] c) N-(2-benzyl-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide

[0244] To a stirred solution of 3-amino-2-benzyl-7-methylthieno[3,2-6?]pyrimidin-4-one (100.0 mg, 0.369 mmol, 1 equiv) and p-toluenesulfonyl chloride (105.3 mg, 0.553 mmol, 1.5 equiv) in THF (5 mL) was added LiHMDS (0.74 mL, 0.738 mmol, 2 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.) (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue product 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-benzyl-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide (62.4 mg, 39.45% yield) as a white solid. LCMS (ESI) [M + H]+: 426.05.1H NMR (400 MHz, DMSO-tfe) 5 11.67 - 11.41 (m, 1H), 7.84 (d, J= 1.4 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.36 (d, J= 8.1 Hz, 2H), 7.33 -7.28 (m, 2H), 7.24 (td, J= 6.3, 1.8 Hz, 3H), 4.28 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H).

[0245] Example 2: N-(2-benzyl-5-methyl-4-oxo-thieno[2,3-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide

[0246]

[0247] The title compound was obtained in analogy to Example 1 as a white solid (39.7% yield) using 3-amiiK)-2-bcnzyl-5-mcthyhhiciK)|2,3-<7|pyrimidin-4-onc and p-toluenesulfonyl chloride. LCMS (ESI) [M + H]+: 426.00. ’H NMR (400 MHz, DMSO-tfe) 6 11.34 (s, 1H), 7.68 - 7.63 (m, 2H), 7.40 - 7.35 (m, 2H), 7.35 - 7.28 (m, 2H), 7.28 - 7.19 (m, 3H), 7.14 (t, J= 1.3 Hz, 1H), 4.23 (s, 2H), 2.40 (s, 3H), 2.18 (d, J= 1.3 Hz, 3H).

[0248] Example 3: N-[2-[methoxy(phenyl)methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl] -4-methyl-benzenesulfonamide

[0249]

[0250] The title compound was obtained in analogy to Example 1 as a white solid (33.3% yield) using 3-amino-2-[methoxy(phenyl)methyl]-7-methylthieno[3,2-6?]pyrimidin-4-one and p-toluene sulfonyl chloride. LCMS (ESI) [M + H]+: 426.05.1H NMR (400 MHz, DMSO-tfe) 5 11.67 - 11.41 (m, 1H),7.84 (d, J= 1.4 Hz, 1H), 7.67 - 7.63 (m, 2H), 7.53 - 7.28 (m, 7H), 5.9 ((s, 1H), 3.38 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H).

[0251] Example 4: N-[6-[methoxy(phenyl)methyl]-3-methyl-4-oxo-isothiazolo[5,4-d]pyrimidin-5-yl]-4-methyl-benzenesulfonamide

[0252]

[0253] a) methyl 5-(2-methoxy-2-phenylacetamido)-3-methyl- 1,2-thiazole-4-carboxylate

[0254] To a stirred solution of methyl 5-amino-3-methyl-l,2-thiazole-4-carboxylate (0.50 g, 2.904 mmol, 1 equiv) and methoxy (phenyl) acetic acid (1.45 g, 8.712 mmol, 3 equiv) in DMF (1 mL) were added DIPEA (1.88 g, 14.520 mmol, 5 equiv) and HATU (1.66 g, 4.356 mmol, 1.5 equiv) in portions at 0°C. The resulting mixture was stirred for 1 h at room temperature. The residue product 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; detector, UV 254 nm, to afford methyl 5-(2-methoxy-2-phenylacetamido)-3-methyl-l,2-thiazole-4-carboxylate (400.0 mg, 43.00% yield) as a light yellow oil. LCMS (ESI) [M + H]+: 321.0.

[0255] b) 5-(2-methoxy-2-phenylacetamido)-3-methyl- 1,2-thiazole-4-carboxylic acid To a stirred solution of methyl 5-(2-methoxy-2-phenylacetamido)-3-methyl-l,2-thiazole-4-carboxylate (350.0 mg, 1.093 mmol, 1 equiv) in MeOH (2 mL) and water (2 mL) was added lithium hydroxide (130.8 mg, 5.465 mmol, 5 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue product 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; detector, UV 254 nm, to afford 5-(2-methoxy-2-phenylacetamido)-3-methyl-l,2-thiazole-4-carboxylic acid (300.0 mg, 89.64% yield) as a light yellow solid. LCMS (ESI) [M + H]+:307.0.

[0256] c) N-[6-[methoxy(phenyl)methyl]-3-methyl-4-oxo-isothiazolo[5,4-d]pyrimidin-5-yl]-4-methyl-benzenesulfonamide

[0257] To a stirred solution of 5-(2-methoxy-2-phenylacetamido)-3-methyl-l,2-thiazole-4-carboxylic acid (280.0 mg, 0.914 mmol, 1 equiv) and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide (523.4 mg, 1.828 mmol, 2 equiv) in dioxane (5 mL) was added phosphorus trichloride (627.6 mg, 4.570 mmol, 5 equiv) dropwise at room temperature. The resulting mixture was stirred for 1 h at 100 °C. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The residue product 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; detector, UV 254 nm, to afford N-[6-[methoxy(phenyl)methyl]-3-methyl-4-oxo-isothiazolo[5,4-d]pyrimidin-5-yl]-4-methyl-benzenesulfonamide (16.7 mg, 3.96% yield) as a white solid. LCMS (ESI) [M + H]+:

[0258] 457.05. ’H NMR (400 MHz, DMSO-tfe) 6 11.52 (s, 1H), 7.72 - 7.65 (m, 2H), 7.44 - 7.34 (m, 7H), 5.87 (s, 1H), 3.35 (s, 3H), 2.41 (s, 6H).

[0259] Example 5: N- [5- [methoxy(phenyl)methyl] -3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide

[0260]

[0261] a) 4-(2-methoxy-2-phenylacetamido)-3-methyl- 1,2-thiazole-5-carboxylic acid A solution of 4-amino-3-methyl-l,2-thiazole-5-carboxylic acid (300 mg, 1.897 mmol, 1.0 equivalent) in anhydrous DMSO (10 mL) was treated with DIPEA (735.38 mg, 5.691 mmol, 3.0 equivalent) and methoxy (phenyl) acetic acid (378.20 mg, 2.276 mmol, 1.2 equivalent) under nitrogen atmosphere followed by the addition of HATU (865.37 mg, 2.276 mmol, 1.2 equivalent) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. After completion, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4 and then the organic layer was removed under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-(2-methoxy-2-phenylacetamido)-3-methyl-l,2-thiazole-5-carboxylic acid (220 mg, 37.9% yield) as a yellow solid. LCMS(ESI) [M + H]+: 307.

[0262] b) N- [5- [methoxy(phenyl)methyl] -3-methyl-7 -oxo-isothiazolo [4,5-d]pyrimidin-6-yl] -4-methyl-benzenesulfonamide

[0263] The title compound was obtained in analogy to Example 4 as a yellow solid (37.9% yield) using 4-(2-methoxy-2-phenylacetamido)-3-methyl-l,2-thiazole-5-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS(ESI) [M + H]+: 457.0.1H NMR (400 MHz, DMSO-tfe) 3 12- 11.18 (m, 1H), 7.76 - 7.6 (d, J= 8.1 Hz, 2H), 7.51 -7.13 (m, 7H), 6.08 - 5.75 (m, 1H), 3.51 - 3.36 (m, 3H), 2.8 - 2.57 (m, 3H), 2.45 - 2.36 (m, 3H).

[0264] Example 6: N-[2-[(4-fluorophenyl)-methoxy-methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0265]

[0266] The title compound was obtained in analogy to Example 4 as a white solid (71.1% yield) using 3-(2-methoxy-2-phenylacetamido)-4-methylthiophene-2-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 474.10. ’H NMR (300 MHz, DMSO-tfe) 8 10.93 (s, 1H), 7.8O (q, J= 1.1 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.52 - 7.43 (m, 2H), 7.43 - 7.34 (m, 2H), 7.21 - 7.07 (m, 2H), 5.92 (s, 1H), 3.39 (s, 3H), 2.43 (s, 3H), 2.34 - 2.28 (m, 3H).

[0267] Example 7: N-(6-(methoxy(phenyl)methyl)-l,3-dimethyl-4-oxo-l,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)-4-methylbenzenesulfonamide

[0268]

[0269] The title compound was obtained in analogy to Example 4 as a white solid (32.9% yield) using 5-(2-methoxy-2-phenylacetamido)-l,3-dimethylpyrazole-4-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LC-MS (ES, m / z): [M+l] = 454.15 ’H NMR (400 MHz, Acetonitrile-d3) 68.45 (s, 1H), 7.80 - 7.56 (m, 2H), 7.34 (d, J= 7.9 Hz, 7H), 5.83 (s, 1H), 3.62 (d, J = 22.8 Hz, 3H), 3.41 (s, 3H), 2.43 (s, 3H), 2.22 (s, 3H).

[0270] Example 8: N-[5-(difluoromethyl)-2-[methoxy(phenyl)methyl]-4-oxo-thieno[2,3-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0271]

[0272] The title compound was obtained in analogy to Example 4 as a white solid (37.1% yield) using 4-(difluoromethyl)-2-(2-methoxy-2-phenylacetamido)thiophene-3-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 492.05. ’H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 8.06 (t, J= 2.0 Hz, 1H), 7.69 -7.63 (m, 2H), 7.41 - 7.31 (m, 7H), 6.91 (s, 1H), 5.85 (s, 1H), 3.34 (s, 3H), 2.39 (s, 3H). Example 9: N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l'-cyclopropane]-3-yl]-4-methyl-benzenesulfonamide

[0273]

[0274] a) methyl l-(prop-2-en-l-yloxy)cyclopropane-l -carboxylate

[0275] A solution of methyl 1 -hydroxycyclopropane- 1 -carboxylate (10.0 g, 86.121 mmol, 1 equiv) in THF (100 mL) was treated with NaH (4.13 g, 172.242 mmol, 2 equiv) at 0 °C for 30 min under nitrogen atmosphere followed by the addition of allyl bromide (15.63 g, 129.181 mmol, 1.5 equiv) at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched with Water (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (100 x 3 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 (3:1) to afford methyl l-(prop-2-en-l-yloxy)cyclopropane-l -carboxylate (6.0 g, 44.61% yield, 89% purity) as a white solid. LC-MS (ES, m / z): [M+l] = 157.

[0276] b) methyl l-{ [(2E)-4-methoxy-4-oxobut-2-en-l-yl]oxy]cyclopropane-l-carboxylate

[0277] A solution of methyl l-(prop-2-en-l-yloxy)cyclopropane-l -carboxylate (6.0 g, 38.41 mmol, 1 equiv) and methyl acrylate (4.96 g, 57.62 mmol, 1.5 equiv) in DCM (70 mL) was treated with 2-[dichloro(phenylmethylidene)(tricyclohexyl-l5[5]-phosphanyl)ruthenio]-l,3-bis(2,4,6-trimethylphenyl)imidazolidine (3.27 g, 3.84 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred at room temperature for additional 3 h. The reaction was quenched with Water (20 mL) at 0 °C. The resulting mixture was extracted with EtOAc (100 x 3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in methyl l-{[(2£’)-4-methoxy-4-oxobut-2-en-l-yl]oxy (cyclopropane- 1-carboxylate (3 g, 36.45%yield) as a white solid. LC-MS (ES, m / z): [M+l] = 215.0. c) methyl l-(4-methoxy-4-oxobutoxy)cyclopropane-l -carboxylate

[0278] A solution of methyl l-{[(2£’)-4-methoxy-4-oxobut-2-en- 1-yl] oxy] cyclopropane- 1-carboxylate (3.0 g, 14.00 mmol, 1 equiv) in MeOH (30 mL) was treated with Pd / C (3.0 g, 28.19 mmol, 2.01 equiv) at 0 °C under H₂ atmosphere. The resulting mixture was stirred at room temperature for additional 3 h. The mixture was filtered, and the filter cake was washed with MeOH (30 mL) (30 x 3 mL). The filtrate was concentrated under vacuum. This resulted in methyl l-(4-methoxy-4-oxobutoxy)cyclopropane-l -carboxylate (2.4 g, 79.25% yield) as a white solid. LC-MS (ES, m / z): [M+l] = 203.0.

[0279] d) methyl 8-oxo-4-oxaspiro[2.5]octane-7-carboxylate

[0280] A solution of methyl l-(4-methoxy-4-oxobutoxy)cyclopropane-l -carboxylate (2.4 g, 11.10 mmol, 1 equiv) in THF (30 mL) was treated with t-BuOK (2.49 g, 22.19 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature for additional 6 h. The resulting mixture was extracted with EtOAc (30 x 3 mL). The combined organic layers were washed with brine (30 x 3 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 (2:1) to afford methyl 8-oxo-4-oxaspiro[2.5]octane-7-carboxylate (800.0 mg, 39.13% yield) as a white solid. LC-MS (ES, m / z): [M+l] = 185.0

[0281] e) methyl 8-amino-4-oxaspiro[2.5]oct-7-ene-7-carboxylate

[0282] A solution of methyl 8-oxo-4-oxaspiro[2.5]octane-7-carboxylate (800.0 mg, 4.343 mmol, 1 equiv) in MeOH (11 mL) was treated with NH4OAC (2.1g, 21.715 mmol, 5 equiv) at room temperature. The resulting mixture was stirred at 60°C for additional 3 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 8-amino-4-oxaspiro[2.5]oct-7-ene-7-carboxylate (500.0 mg, 62.84% yield) as a white solid. LC- MS (ES, m / z): [M+l] = 184.0.

[0283] f) methyl 8-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylate

[0284] A solution of methyl 8-amino-4-oxaspiro[2.5]oct-7-ene-7-carboxylate (500.0 mg, 2.73 mmol, 1 equiv) and DIPEA (1.1 g, 8.18 mmol, 3 equiv) in DCM (10 mL) was treated with (4-fluorophenyl)(methoxy)acetyl chloride (829.43 mg, 4.09 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 8-[2-(4-fluorophenyl)-2- methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylate (240.0 mg, 25.17% yield, 92% purity) as a white solid. LC-MS (ES, m / z): [M+l] = 350.0

[0285] g) 8-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylic acid

[0286] A solution of methyl 8-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylate (240.0 mg, 0.68 mmol, 1 equiv) in MeOH (5 mL) was treated with LiOH (82.27 mg, 3.43 mmol, 5 equiv) in water (1 mL) at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The mixture was acidified to pH 2 with cone. HC1. The resulting mixture was extracted with EtOAc (10 x 3 mL). 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 10 min; detector, UV 254 nm. This resulted in 8-[2-(4-fhiorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylic acid (200.0 mg, 86.82% yield) as a white solid. LC-MS (ES, m / z): [M+l] = 336.0

[0287] h) N- [2- [(4-fluorophenyl)-methoxy-methyl] -4-oxo-spiro [5,6-dihydropyrano [3,4-d]pyrimidine-8,r-cyclopropane]-3-yl]-4-methyl-benzenesulfonamide

[0288] The title compound was obtained in analogy to Example 4 as a white solid (23.6% yield) using 8-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylic acid and 2V-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LC-MS (ES, m / z): [M+l] = 486.0. ’H NMR (400 MHz, Acetonitrile-d3) 58.71 - 8.41 (m, 1H), 7.69 - 7.62 (m, 2H), 7.41 - 7.33 (m, 4H), 7.13 - 7.02 (m, 2H), 5.82 (s, 1H), 3.89 - 3.76 (m, 2H), 3.36 (s, 3H), 2.43 (s, 3H), 2.33 (s, 2H), 1.48 - 1.03 (m, 4H).

[0289] Example 10: 4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l ' -cyclopropane] -3-yl] benzenesulfonamide

[0290]

[0291] The title compound was obtained in analogy to Example 9 as a white solid (9.3% yield) using 8-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylic acid and M-[4-(dimethylamino)benzenesulfonyl]tert-butoxycarbohydrazide. LC-MS (ES, m / z): [M+l] = 515. ’H NMR (400 MHz, Acetonitrile-d3) 68.80 - 7.95 (m 1H), 7.55 - 7.46 (m, 2H), 7.38 (dd, J = 8.6, 5.5 Hz, 2H), 7.11 - 7.01 (m, 2H), 6.74 - 6.65 (m, 2H), 5.90 (s, 1H), 3.90 - 3.74 (m, 2H), 3.37 (d, J= 1.3 Hz, 3H), 3.03 (s, 6H), 2.34 (d, J= 5.2 Hz, 2H), 1.37 (s, 1H), 1.28 - 1.02 (m, 3H).

[0292] Example 11: N-[5-[methoxy(phenyl)methyl]-1,3-dimethyl-7-oxo-pyrazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide

[0293]

[0294] The title compound was obtained in analogy to Example 4 as a white solid (37.1% yield) using 4-(2-methoxy-2-phenylacetamido)-2,5-dimethylpyrazole-3-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 454.20. ’H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.67 (d, J= 8.1 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.32 (s, 5H), 5.72 (s, 1H), 3.88 (s, 3H), 3.30 (s, 3H), 2.54 - 2.47 (m, 2H), 2.41 (s, 4H).

[0295] Example 12: N-[7-(difluoromethyl)-2-[methoxy(phenyl)methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0296]

[0297] a) N- { 7 - [(benzyloxy)methyl] -2- [methoxy(phenyl)methyl] -4-oxothieno [3,2-d] pyrimidin-3-yl } -4-methylbenzenesulfonamide

[0298] The title compound was obtained in analogy to Example 4 as a yellow oil (62.8% yield) using 4-[(benzyloxy)methyl]-3-(2-methoxy-2-phenylacetamido) thiophene-2-carboxylic acid and 2V-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 562.2.

[0299] b) N- [7 -(hydroxymethyl) -2- [methoxy(phenyl)methyl] -4-oxothieno [3, 2-6?] pyrimidin-3-yl] -4-methylbenzenesulfonamide

[0300] A solution of N-{7-[(benzyloxy)methyl]-2-[methoxy(phenyl)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide (350 mg, 0.623 mmol, 1 equiv) in DCM (4 mL) was treated with TiCU (236.38 mg, 1.246 mmol, 2 equiv) at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature. The reaction was quenched with H2O at 0 °C. The resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with H2O (1 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography [Mobile Phase A: Water (0.3% FA), Mobile Phase B: acetonitrile; Gradient: 0% B to 70% B in 30 min] to give N-[7-(hydroxymethyl)-2- [methoxy(phenyl)methyl] -4-oxothieno [3,2-6?] pyrimidin-3-yl] -4-methylbenzenesulfonamide (250 mg, 85.08% yield) as a yellow oil. LCMS (ESI) [M + H]+: 472.2.

[0301] c) N- { 7 -formyl-2- [methoxy(phenyl)methyl] -4-oxothieno [3,2-6?] pyrimidin-3-yl } -4-methylbenzenesulfonamide

[0302] A solution of N- [7-(hydroxymethyl)-2-[methoxy(phenyl)methyl] -4-oxothieno [3, 2-6?] pyrimidin-3-yl]-4-methylbenzenesulfonamide (250 mg, 0.530 mmol, 1 equiv) and MnO₂ (230.4 mg, 2.650 mmol, 5 equiv) in DCM (3 mL) was stirred at room temperature for overnight. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 3 mL). The filtrate was concentrated under reduced pressure to give crude product N-{7-formyl-2- [methoxy(phenyl)methyl] -4-oxothieno [3,2-6?] pyrimidin-3-yl } -4-methylbenzenesulfonamide (100 mg, 45.0% yield) as a yellow oil. LCMS (ESI) [M + H]+: 470.2.

[0303] d) N-[7-(difhioromethyl)-2-[methoxy(phenyl)methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0304] A solution of N- {7-formyl-2-[methoxy(phenyl)methyl] -4-oxothieno [3, 2-6?] pyrimidin-3-yl]-4-methylbenzenesulfonamide (80 mg, 0.170 mmol, 1 equiv) in DCM (2 mL) was treated with diethylamino sulfur trifluoride (54.93 mg, 0.340 mmol, 2 equiv) at 0 °C under nitrogen atmosphere. The mixture was stirred 1 hour at room temperature. The resulting mixture was extracted with DCM (3 x 3 mL). The combined organic layers were washed with water (1 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, ACN in Water (0.1% FA), 10% to 70% gradient in 30 min; detector, UV 254 nm, to afford A-[7-(difhioromethyl)-2-[methoxy(phenyl)methyl]-4-oxothieno[3,2-7] pyrimidin-3-yl]-4-methylbenzenesulfonamide (16.3 mg, 19.46%yield, 98.6%purity) as a white solid. LCMS (ESI) [M + H]+: 492.2. ’H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.63 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.43 - 7.32 (m, 8H), 5.85 (s, 1H), 3.349 (s, 3H), 2.42 (s, 3H).

[0305] Example 13: 4-methyl-N-[6-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide

[0306]

[0307] 4-methyl-N- [6-methyl-4-oxo-2- [methoxy(phenyl)methyl] thieno [3,2-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 4 as a white solid (2.5% yield) using 3-(2-methoxy-2-phenylacetamido)-5-methylthiophene-2-carboxylic acid and 2V-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. Chiral separation using conditions A afforded 4-methyl-N- [6-methyl-4-oxo-2- [(R)-methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide (32.1% yield, RT=7.04min, first peak) as a white solid. LCMS (ESI) [M+H]+: 456.05.1H NMR (400 MHz, DMSO-de) 6 11.38 (s, 1H), 7.67 (d, 7= 7.9 Hz, 2H), 7.40 - 7.26 (m, 8H), 5.85 (s, 1H), 3.34 (s, 3H), 2.51 (s, 3H), 2.41 (s, 3H).

[0308] Example 14: N-[2-[methoxy(phenyl)methyl]-4-oxo-5-(trifluoromethyl)thieno[2,3-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0309]

[0310] a) ethyl 2-(2-methoxy-2-phenylacetamido)-4-(trifluoromethyl) thiophene-3-carboxylate

[0311] To a stirred solution of ethyl 2-amino-4-(trifluoromethyl) thiophene-3-carboxylate (600 mg, 2.508 mmol, 1 equiv) and methoxy(phenyl)acetic acid (416.81 mg, 2.508 mmol, 1 equiv) in pyridine (0.6 mL) was added phosphoroyl trichloride (0.24 mL, 1.2 equiv) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. The reaction was quenched by the addition of Water / Ice (1 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x10 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 ethyl 2-(2-methoxy-2-phenylacetamido)-4-(trifluoromethyl) thiophene-3-carboxylate (500 mg, 51.46% yield) as a yellow solid.

[0312] b) 2-(2-methoxy-2-phenylacetamido)-4-(trifluoromethyl) thiophene- 3 -carboxylic acid

[0313] To a stirred solution of ethyl 2-(2-methoxy-2-phenylacetamido)-4-(trifluoromethyl) thiophene-3-carboxylate (500 mg, 1.291 mmol, 1 equiv) and LiOH (61.83 mg, 2.582 mmol, 2 equiv) in THF (5 mL) was added H2O (2.0 mL). The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (3x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-(2-methoxy-2-phenylacetamido)-4-(trifluoromethyl) thiophene- 3 -carboxylic acid (300 mg, 64.68% yield) as a yellow oil. LC-MS (ESI, m / z): [M + H]+: 360.0

[0314] c) N-[2-[methoxy(phenyl)methyl]-4-oxo-5-(trifhioromethyl)thieno[2,3-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0315] The title compound was obtained in analogy to Example 4 as a white solid (25.2% yield) using 2-(2-methoxy-2-phenylacetamido)-4-(trifluoromethyl) thiophene-3-carboxylic acid and M-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 510.15. ’H NMR (400 MHz, DMSO-d6) δ 11.67 (d, J= 150.9 Hz, 1H), 8.33 (s, 1H), 7.64 (d, J= 8.2 Hz, 2H), 7.37 (d, J = 7.9 Hz, 7H), 5.89 (s, 1H), 3.37 (s, 3H), 2.38 (s, 3H).

[0316] Example 15: (R)-4-(l-fluorocyclopropyl)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5', 6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)benzenesulfonamide

[0317] F

[0318]

[0319] a) methyl 8-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylate

[0320] The title compound was obtained in analogy to Example 9 as a white solid (25.2% yield) using 8-amino-4-oxaspiro[2.5]oct-7-ene-7-carboxylate and (4-fluorophenyl)(methoxy)acetyl chloride. LCMS (ESI, m / z): [M+l]+= 350.0.

[0321] b) 3'-amino-2'-[(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-4'-one

[0322] A solution of methyl 8-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-oxaspiro[2.5]oct-7-ene-7-carboxylate (240 mg, 0.687 mmol, 1 equiv) in EtOH (0.4 mL) and hydrazine monohydrate (0.4 mL, 0.040 mmol, 0.06 equiv). The resulting mixture was stirred at 80 °C for additional 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by re versed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 3'-amino-2'-[(4-fhiorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-4'-one (150 mg, 65.90% yield) as a white solid. LCMS (ESI, m / z): [M+l]+= 336.0 c) (R)-4-(l-fluorocyclopropyl)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)benzenesulfonamide

[0323] A solution of 3'-amino-2'-[(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-4'-one (70 mg, 0.211 mmol, 1 equiv) and 4-(l-fluorocyclopropyl)benzenesulfonyl chloride (74.36 mg, 0.317 mmol, 1.5 equiv) in THF (2 mL) was added LiHMDS (70.70 mg, 0.422 mmol, 2 equiv) at -78 °C. The resulting mixture was stirred at -78 °C for additional 1 h. The reaction was quenched with water (ImL) at 0 °C. The resulting mixture was extracted with EtOAc (5 x 3mL). The organic layer was concentrated under vacuum. 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 30 min; detector, UV 254 nm. This resulted in 4-(l-fluorocyclopropyl)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)benzenesulfonamide (60 mg, 37.54% yield) as a white solid. Chiral separation using conditions B afforded (R)-4-(l-fhiorocyclopropyl)-N-(2'-((4-fhiorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)benzenesulfonamide (33.3% yield, RT= 9.2min, second peak) as a white solid. LCMS (ESI, m / z): [M+l]+= 530.0. ’H NMR (400 MHz, Acetonitrile-d3) 68.61 (s, 1H), 7.77 (d, J= 8.4 Hz, 2H), 7.38 (dt, J= 8.9, 2.7 Hz, 4H), 7.13 - 7.03 (m, 2H), 5.83 (s, 1H), 3.83 (dq, J= 19.9, 5.7 Hz, 2H), 3.37 (s, 3H), 2.33 (td, J = 5.6, 2.9 Hz, 2H), 1.67 - 1.54 (m, 2H), 1.37 (s, 1H), 1.29 - 1.05 (m, 5H).

[0324] Example 16: N-[7-cyclopropyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0325]

[0326] a) N-{7-bromo-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide

[0327] N-{7-bromo-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide was obtained in analogy to Example 4 as a yellow solid (75.7% yield) using 4-bromo-3-[2-(4-fluorophenyl)-2-methoxyacetamido]thiophene-2-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. Chiral separation using conditions C affordedA-{7-bromo-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-6?]pyrimidin-3-yl}-4-methylbenzenesulfonamide (49.0% yield, RT=4.03min, first peak) as a yellow solid, as well as its enantiomer A-{7-bromo-2-[(S)-(4-fhiorophenyl)(methoxy)methyl]-4-oxothieno[3,2-6?]pyrimidin-3-yl}-4-methylbenzenesulfonamide (48.0% yield, RT=5.63 min, second peak). LC-MS (ESI, m / z): [M+H]+538.0

[0328] b) N-[7-cyclopropyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0329] An oven-dried 8 mL vial was charged with cyclopropanol (53.9 mg, 0.930 mmol, 5 equiv) and 5,7-di-tert-butyl-3-phenylbenzo[t7]oxazol-3-ium tetrafluoroborate (128.5 mg, 0.326 mmol, 1.75 equiv). After the vial was vacuumed and refilled with nitrogen gas twice, MTBE (4 mL) was added and the reaction stirred at r.t. for 5 min. Then, pyridine (25.7 mg, 0.326 mmol, 1.75 equiv) in 1 mL methyl tert-butyl ether was added dropwise at room temperature over the course of 2 min. The resulting solution stirred at r.t. for 10 min. Another oven-dried 20 mL vial was charged with [Ir(dtbbpy)(ppy)2]PF6(2.6 mg, 0.003 mmol, 0.015 equiv), [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (4.5 mg, 0.009 mmol, 0.05 equiv), l-azabicyclo[2.2.2]octane (36.1 mg, 0.326 mmol, 1.75 equiv), 2,3-dihydro-1H-isoindole-1,3-dione (46.5 mg, 0.316 mmol, 1.7 equiv) and A-{7-bromo-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-6?]pyrimidin-3-yl}-4-me thy Ibenzene sulfonamide (100 mg, 0.186 mmol, 1 equiv) and an X-shape magnetic stir bar. DMA (4 mL) was added to this vial under an atmosphere of nitrogen.

[0330] The methyl tert-butyl ether suspension was transferred to a 5 mL syringe under air. Then a syringe filter and new needle were installed on the syringe, before the methyl tert-butyl ether solution was injected through the syringe filter into the dimethylacetamide solution. The reaction mixture was sparged with nitrogen for 15 minutes before sealing with parafilm. The vial was stirred and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate in a PennOC Integrated Photoreactor for 2 hours.

[0331] The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with NaCl(aq) (2 x 10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Column: Xselect CSH Prep C18, 30*150mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 32% to 60% B in 13 min; Wave Length: 254 nm / 220 nm; RT=12.47 min. This resulted in N-[7-cyclopropyl-4- oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (28.4 mg, 30.61% yield) as a white solid. LC-MS (ESI, m / z): [M+H]+500. ’H NMR (400 MHz, Acetonitrile-d3) 68.68 (s, 1H), 7.71-7.63 (m, 2H), 7.45 (t, J = 7.1 Hz, 2H), 7.39 (d, J= 1.8 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.10 (t, J= 8.9 Hz, 2H), 5.90 (s, 1H), 3.42 (s, 3H), 2.42 (s, 3H), 2.30-2.19 (m,lH), 0.98 (d, J= 8.5 Hz, 2H), 0.91 (s, 2H).

[0332] Example 17: 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7-(trideuteriomethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide

[0333]

[0334] The title product was obtained in analogy to Example 16 as a white solid (26.4% yield) using A-{7-bromo-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide and CD3OD. LC-MS (ESI, m / z): [M+l] = 477.1H NMR (400 MHz, Acetonitrile-d3) 57.70-7.63 (m, 2H), 7.62 (s, 1H), 7.49-7.40 (m, 2H), 7.37 - 7.31 (m, 2H), 7.14 - 7.03 (m, 2H), 5.90 (s, 1H), 3.41 (s, 3H), 2.43 (s, 3H).

[0335] Example 18: N-[7-cyclopropyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0336]

[0337] The title compound was obtained in analogy to Example 16 as a white solid (50.4% yield) using A-{7-bromo-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide and cyclopropanol. LC-MS (ESI, m / z): [M+H]+500. ’H NMR (400 MHz, Acetonitrile-d3) 68.61 (s, 1H), 7.71 - 7.63 (m, 2H), 7.45 (dd, J= 8.6, 5.6 Hz, 2H), 7.41 - 7.35 (m, 1H), 7.38 - 7.31 (m, 2H), 7.14 - 7.05 (m, 2H), 5.90 (s, 1H), 3.42 (s, 3H), 2.43 (s, 3H), 2.20 - 1.93 (m, 1H), 0.98 (d, J= 8.5 Hz, 2H), 0.91 (s, 2H).

[0338] Example 19: 4-methyl-N-[5-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[2,3-d]pyrimidin-3-yl]benzenesulfonamide

[0339]

[0340] a) N-{5-bromo-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[2,3-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide

[0341] The title compound was obtained in analogy to Example 15 as a white solid (67.1% yield) using 3-amino-5-bromo-2-[(4-fluorophenyl)(methoxy)methyl]thieno[2,3-d]pyrimidin-4-one and p-toluenesulfonyl chloride. LC-MS (ESI, m / z) [M + H]+: 538.10

[0342] b) 4-methyl-N-[5-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[2,3-d]pyrimidin-3-yl]benzenesulfonamide

[0343] 4-methyl-N- [5-methyl-4-oxo-2- [(4-fluorophenyl)-methoxy-methyl] thieno [2,3-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 16 as a white solid (26.8% yield) using N-{5-bromo-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[2,3-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide and methanol. Chiral separation using conditions A afforded 4-methyl-N-[5-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[2,3-d]pyrimidin-3-yl]benzenesulfonamide (46.8% yield, RT=10.61min, first peak) as a white solid. LCMS (ESI) [M+H]+: 474.10. ’H NMR (400 MHz, Acetonitrile-d3) 58.61 (s, 1H), 7.65 (dd, J= 8.4, 1.4 Hz, 2H), 7.43 (dd, J= 8.3, 5.5 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 7.09 (t, J= 8.7 Hz, 2H), 6.97 (q, J= 1.3 Hz, 1H), 5.93 (s, 1H), 3.42 (s, 3H), 2.42 (s, 3H), 2.17 (d, J= 1.3 Hz, 3H).

[0344] Example 20: 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide F

[0345] (j FFN--\

[0346] J

[0347] o' Y p

[0348] HfNTs

[0349] o=s=o o

[0350]

[0351] The title product was obtained in analogy to Example 16 as a white solid (7.8% yield) using N-{7-bromo-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide and trifluoroethanol. LC-MS (ESI, m / z):

[0352] [M+H]+= 542. ’H NMR (400 MHz, Acetonitrile-d3) 6, 8.90 - 8.10 (m, 1H) 7.98 (s, 1H), 7.68 (d, 7= 8.3 Hz, 2H), 7.48 - 7.40 (m, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.14 - 7.03 (m, 2H), 5.89 (s, 1H), 3.75 (q, J = 11.0 Hz, 2H), 3.42 (s, 3H), 2.43 (s, 3H).

[0353] Example 21: (R)-4-(l-fluorocyclopropyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0354]

[0355] a) (7?)- [(2-carbamoyl-4-methylthiophen-3-yl)carbamoyl] (phenyl)methyl acetate

[0356] To a stirred solution of 3-amino-4-methylthiophene-2-carboxamide (2.20 g, 14.109 mmol, 1.0 equiv) in DCM (50 mL) was added (1R)-2-chloro-2-oxo-1-phenylethyl acetate (3.00 g, 14.109 mmol, 1.0 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 0% to 60% gradient in 20 min; UV 254 nm) to afford (R)-[(2-carbamoyl-4-methylthiophen-3-yl)carbamoyl](phenyl)methyl acetate (3.5 g, 74.64% yield,) as a yellow solid. LCMS (ESI) [M + H]+: 333.0.

[0357] b) 2-[(R)-hydroxy(phenyl)methyl]-7-methyl-3H-thieno[3,2-d]pyrimidin-4-one

[0358] To a stirred solution of (R)-[(2-carbamoyl-4-methylthiophen-3-yl)carbamoyl](phenyl)methyl acetate (3.50 g, 10.530 mmol, 1.0 equiv) in EtOH / H2O (1:1, 40 mL) was added NaOH (1.68 g, 42.120 mmol, 4.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The mixture was neutralized to pH 8 with citric acid. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 0% to 60% gradient in 20 min; UV 254 nm) to afford 2-[(R)-hydroxy(phenyl)methyl]-7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (2.6 g, 90.67% yield) as a yellow oil. LCMS (ESI) [M + H]+: 273.0.

[0359] c) 3-amino-2-[(R)-hydroxy(phenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-one

[0360] To a stirred solution of 2-[(R)-hydroxy(phenyl)methyl]-7-methyl-3H-thieno[3,2-d]pyrimidin-4-one (2.50 g, 9.180 mmol, 1.0 equiv) and t-BuOK (1.13 g, 10.098 mmol, 1.1 equiv) in THF (40 mL) were added amino diphenylphosphinate (3.21 g, 13.770 mmol, 1.5 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. 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 (10 mmol / L NH4HCO3), 0% to 50% gradient in 20 min; UV 254 nm) to afford 3-amino-2-[(R)-hydroxy(phenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-one (2.3 g, 87.19% yield) as a yellow solid. LCMS (ESI) [M + H]+: 288.0.

[0361] d) 3-amino-2-[(R)-methoxy(phenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-one

[0362] To a stirred solution of 3-amino-2-[(R)-hydroxy(phenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-one (2.30 g, 8.004 mmol, 1.0 equiv) in THF (40 mL) were added t-BuOK (988.0 mg, 8.804 mmol, 1.1 equiv) and triflate ester (1.58 g, 9.605 mmol, 1.2 equiv) at -75 °C under nitrogen atmosphere. The resulting mixture was stirred at -75 °C for 1 h under nitrogen atmosphere. 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 (10 mmol / L NH4HCO3), 0% to 50% gradient in 20 min; UV 254 nm) to afford 3-amino-2-|( / ?)- mcthoxy(phcnyl)mcthyl|-7-mcthylthicno|3,2-d|pyrimidin-4-onc (2 g, 82.91% yield) as a white solid. LCMS (ESI) [M + H]+: 302.0.

[0363] e) (R)-4-(1-fluorocyclopropyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0364] A solution of 3-amino-2-[(R)-methoxy(phenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-one (100.0 mg, 0.332 mmol, 1.0 equiv) in THF (2 mL) was treated with LiHMDS (111.0 mg, 0.664 mmol, 2.0 equiv) at -75 °C for 10 min under nitrogen atmosphere followed by the addition of 4-(l-fluorocyclopropyl)benzenesulfonyl chloride (116.8 mg, 0.498 mmol, 1.5 equiv) at -75 °C. The resulting mixture was stirred at -75 °C for 1 h under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at -75 °C. The resulting mixture was extracted with EtOAc (20 mL). The combined organic layers were washed with water (3 x 20 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: XBridge Shield RP18 OBD Column 30*150 mm, 5pm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min;

[0365] Gradient: 43% B to 63% B in 10 min; Wave Length: 254 nm / 220 nm nm; RT=10.83min) to afford 4-(1-fluorocyclopropyl)-N-{2-[(R)-methoxy(phenyl)methyl]-7-methyl-4-oxothieno[3,2-d]pyrimidin-3-yl}benzenesulfonamide (81.0 mg, 48.86% yield) as a white solid. LCMS (ESI) [M + H]+: 500.15. ’H NMR (400 MHz, DMSO-d6) δ 11.69 (d, J = 143.2 Hz, 1H), 7.95 - 7.86 (m, 1H), 7.82 - 7.74 (m, 2H), 7.48 - 7.29 (m, 7H), 5.93 - 5.82 (m, 1H), 3.37 (s, 3H), 2.42 - 2.30 (m, 2H), 2.14 - 2.05 (m, 1H), 1.67 - 1.55 (m, 2H), 1.34 - 1.22 (m, 2H).

[0366] Example 22: (R)-4-(l,l-difluoroethyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0367]

[0368] a) 1 -(benzylsulfanyl)-4-( 1, 1 -difluoroethyl)benzene To a stirred mixture of l-bromo-4-(l,l-difluoroethyl)benzene (500 mg, 2.262 mmol, 1 equiv), Pd2(dba)3(414.2 mg, 0.452 mmol, 0.20 equiv), XantPhos (523.5 mg, 0.905 mmol, 0.40 equiv) and A, A-Diisopropylethylamine (877.0 mg, 6.785 mmol, 3.00 equiv) in dioxane (8 mL) were added benzyl mercaptan (337.1 mg, 2.714 mmol, 1.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under nitrogen atmosphere. Desired product could be detected by TLC. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford 1-(benzylsulfanyl)-4-(l,l-difluoroethyl)benzene (510 mg, 85.30% yield) as a white solid. ’H NMR (400 MHz, DMSO-d6) δ 7.49 – 7.38 (m, 6H), 7.34 - 7.21 (m, 3H), 4.31 (s, 2H), 1.93 (t, J= 18.7 Hz, 3H).

[0369] b) 4-(l,l-difluoroethyl)benzenesulfonyl chloride

[0370] To a stirred mixture of l-(benzylsulfanyl)-4-(l,l-difluoroethyl)benzene (300 mg, 1.135 mmol, 1 equiv) and water (1 mL) in AcOH (4 mL) were added NCS (454.6 mg, 3.404 mmol, 3.0 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 40 min. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 50 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 (12:1) to afford 4-(l, 1-difluoroethyl)benzenesulfonyl chloride (287 mg, Crude) as a yellow oil.

[0371] c) (R)-4-(1,1-difluoroethyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0372] The title product was obtained in analogy to Example 21 as a white solid (35.8% yield) using 3-amino-2-[(R)-methoxy(phenyl)methyl]-7-methylthieno[3,2-d]pyrimidin-4-one and 4-(1,1-difluoroethyl)benzenesulfonyl chloride. LCMS (ESI): m / z = 506.10 [M + H]+. ’H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.94 – 7.88 (m, 3H), 7.78 (d, J= 8.3 Hz, 2H), 7.37 (dd, J= 15.1, 7.1 Hz, 5H), 5.88 (s, 1H), 3.38 (s, 3H), 2.38 (s, 3H), 2.01 (t, J= 19.0 Hz, 3H).

[0373] Example 23: (R)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide

[0374]

[0375] To a stirred solution of N-{7-bromo-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide (100 mg, 0.186 mmol, 1 equiv), 2,6-dimethylpyridine (44 mg, 0.41 mmol, 2.2 equiv), 1,1, 1,3,3, 3-hexamethyl-2-(trimethylsilyl)trisilane (47 mg, 0.19 mmol, 1.02 equiv) and l,l-difluoro-2-iodoethane (107 mg, 0.55 mmol, 3.0 equiv) in 1,2-dimethoxyethane (2 mL) were added [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (5 mg, 0.009 mmol, 0.05 equiv) and Ir[dF(CF3)ppy]2(dtbpy))PF6(21 mg, 0.019 mmol, 0.1 equiv) dropwise at room temperature under nitrogen atmosphere. The final reaction mixture was irradiated with LEDs (450 nm) radiation at room temperature overnight. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (3 x 20 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: XBridge Prep OBD C18 Column 30*150 mm, 5pm; Mobile Phase A: Water (0.1% formic acid), Mobile Phase B: acetonitrile; Flow rate: 60 mL / min; Gradient: 39% B to 56% B in 30 min; Wave Length: 254 / 220 nm; RT=12.54 min) to afford (R)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide (12.0 mg, 12.34% yield) as a light yellow solid. LC-MS (ESI, m / z): [M+ H]+: 524.05. ’H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 8.13 (d, J= 5.9 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.51 - 7.27 (m, 4H), 7.19 (t, J = 8.7 Hz, 2H), 6.58 -6.20 (m, 1H), 5.86 (s, 1H), 3.35 (d, J= 7.6 Hz, 2H), 3.33 (s, 3H), 2.41 (s, 3H).

[0376] Example 24: (R)-4-(dimethylamino)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo- 5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)benzenesulfonamide

[0377]

[0378] Chiral separation of 3'-amino-2'-[(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-d]pyrimidin]-4'-one (Example 15) using conditions C afforded 3'-amino-2'-[(R)-(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-4'-one (49.0% yield, RT=2.72min, first peak) and 3'-amino-2'-[(S)-(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-4'-one (49.0% yield, RT=3.8 min, second peak). The title product was obtained in analogy to Example 15 as a white solid (35.0% yield) using 3'-amino-2'-[(R)-(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-4'-one and 4-(dimethylamino)benzenesulfonyl chloride. LC-MS (ES, m / z): [M+l] = 515. ’H NMR (400 MHz, Acetonitrile-d3) 68.32 (s, 1H), 7.51 (d, J= 9.0 Hz, 2H), 7.42 - 7.34 (m, 2H), 7.11-7.02 (m, 2H), 6.74 - 6.66 (m, 2H), 5.90 (s, 1H), 3.77 (d, J = 5.7 Hz, 2H), 3.36 (s, 3H), 3.03 (s, 6H), 2.35 (s, 2H), 1.38 (s, 2H), 1.10 (s, 2H).

[0379] Example 25: (R)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)-4-methylbenzenesulfonamide

[0380]

[0381] The title product was obtained in analogy to Example 24 as a white solid (32.4% yield) using 3'-amino-2'-[(R)-(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-4'-one and p-toluenesulfonyl chloride. LC-MS (ES, m / z): [M+l] = 486.1H NMR (400 MHz, Acetonitrile-d3) δ 8.48 (s, 1H), 7.66 (d, J= 8.1 Hz, 2H), 7.37 (d, J= 8.1 Hz, 4H), 7.08 (t, J= 8.7 Hz, 2H), 5.82 (s, 1H), 3.87 - 3.77 (m, 2H), 3.36 (s, 3H), 2.43 (s, 3H), 2.35 (d, J= 9.2 Hz, 2H), 1.41 (s, 2H), 1.13 (s, 2H).

[0382] Example 26: (S)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide

[0383]

[0384] The title product was obtained in analogy to Example 23 as a white solid (25.4% yield) using N-{7-bromo-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide and 1,1-difluoro-2-iodoethane. LC-MS (ESI, m / z): [M+ H]+: 524.05. ’H NMR (400 MHz, DMSO-d6) δ 11.63 (d, J = 178.3 Hz, 1H), 8.14 (s, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.39 (d, J= 8.1 Hz, 4H), 7.19 (s, 2H), 6.59 -6.12 (m, 1H), 5.84 (d, J= 29.4 Hz, 1H), 3.42 (d, J = 18.6 Hz, 1H), 3.38 (s, 3H), 3.32 (d, J = 18.6 Hz, 1H), 2.41 (s, 3H).

[0385] Example 27: 4- (difluoromethoxymethyl) -N - [2- [(R)- (4-fluorophenyl) -methoxymethyl] -4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl] benzenesulfonamide F

[0386]

[0387] The title product was obtained in analogy to Example 24 as a white solid (35.2% yield) using 3'-amino-2'-[(R)-(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-4'-one and 4-[(difluoromethoxy)methyl]benzenesulfonyl chloride. LC-MS (ES, m / z): [M+l] = 552.1H NMR (400 MHz, Acetonitrile-d3) 68.53 (s, 1H), 7.84 - 7.76 (m, 2H), 7.58 - 7.51 (m, 2H), 7.37 (ddd, J= 8.6, 5.5, 2.5 Hz, 2H), 7.13 - 7.03 (m, 2H), 6.51 (s, 1H), 5.83 (s, 1H), 5.01 (s, 2H), 3.90 - 3.74 (m, 2H), 3.37 (s, 3H), 2.33 (td, J= 5.5, 2.0 Hz, 2H), 1.32 (d, J= 39.7 Hz, 1H), 1.12 (ddt, J= 16.9, 9.6, 4.4 Hz, 3H).

[0388] Example 28: N-[7-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-[((ls,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide

[0389]

[0390] a) N-[7-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-iodobenzenesulfonamide The title compound was obtained in analogy to Example 12 as a yellow solid (33.9% yield) using N- { 2- [(4-fluorophenyl)(methoxy)methyl] -7 -formyl-4-oxothieno [3,2-t / ]pyrimidin-3-yl}-4-iodobenzenesulfonamide and DAST. LC-MS (ESI, m / z) [M + H]+: 621.90

[0391] b) N-[7-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-[(3-fluorocyclobutyl)amino]benzenesulfonamide

[0392] A solution of A-[7-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-6?]pyrimidin-3-yl]-4-iodobenzenesulfonamide (200.0 mg, 0.322 mmol, 1.0 equiv) in dioxane (2 mL) was treated with (ls,3s)-3-fluorocyclobutan-l-amine (34.4 mg, 0.386 mmol, 1.2 equiv) at room temperature under nitrogen atmosphere followed by the addition of Pd2(dba)3(58.7 mg, 0.064 mmol, 0.2 equiv), t-BuONa (92.8 mg, 0.966 mmol, 3.0 equiv) and XPhos (62.4 mg, 0.128 mmol, 0.4 equiv) in portions at room temperature. The resulting mixture was stirred at 80 °C for 1 hour under nitrogen atmosphere. The reaction was quenched with water at room temperature. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 nmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 62 % B in 10 min; Wave Length: 254 / 220 nm;

[0393] RT=9.68min). This resulted in N-[7-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-{[(1s,3s)-3-fluorocyclobutyl]amino}benzenesulfonamide (36.0 mg, 38.40% yield) as a white solid. Chiral separation using conditions D afforded N-[7-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-[((ls,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide (24.5% yield, RT=4.6min, first peak). LC-MS(ESI, m / z) [M + H]+: 583.15. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.28 (s, 1H), 7.46 (d, J= 8.6 Hz, 4H), 7.08 (t, J= 8.6 Hz, 3H), 6.53 (d, J= 8.5 Hz, 2H), 5.94 (s, 1H), 5.64 (d, J = 6.6 Hz, 1H), 5.00 - 4.88 (m, 1H), 4.86 - 4.74 (m, 1H), 3.55 - 3.45 (m, 1H), 3.41 (s, 3H), 2.97 - 2.84 (m, 2H), 2.09 - 1.97 (m, 2H).

[0394] Example 29: 4-[(3-fluorocyclobutyl)amino]-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl]benzenesulfonamide

[0395]

[0396] a) W{2'-|( / ?)-(4-fluorophcnyl)(mcthoxy)mcthyl|-4'-oxo-5',6'-dihydrospiro| cyclopropane-l,8'-pyrano[3,4-t / ]pyrimidin]-3'-yl}-4-iodobenzenesulfonamide

[0397] The title product was obtained in analogy to Example 24 as a white solid (55.5% yield) using 3'-amino-2'-[(7?)-(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-l,8'-pyrano[3,4-t / ]pyrimidin]-4'-one and 4-iodobenzenesulfonyl chloride. LC-MS (ES, m / z): [M+l] = 597.

[0398] b) 4-[(3-fluorocyclobutyl)amino]-N-[2-[(R)-(4-fluorophenyl)-rnethoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl]benzenesulfonamide

[0399] A solution of N-{2'-[(R)-(4-fluorophenyl)(methoxy)methyl]-4'-oxo-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-3'-yl}-4-iodobenzenesulfonamide (100 mg, 0.167 mmol, 1 equiv), (ls,3s)-3-fluorocyclobutan-l-amine hydrochloride (42.1 mg, 0.334 mmol, 2 equiv), Pd2(dba)3 (61.3 mg, 0.067 mmol, 0.4 equiv), Xantphos (19.4 mg, 0.033 mmol, 0.2 equiv), CS2CO3 (218.2 mg, 0.668 mmol, 4 equiv) in dioxane (2 mL). The resulting mixture was stirred at 80 °C for additional 2 h. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (5 x 3 mL). The resulting mixture was concentrated under vacuum. 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; detector, UV 254 nm. This resulted in 4-[(3-fluorocyclobutyl)amino]-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl] -4-oxospiro [5,6-dihydropyrano [3,4-d]pyrimidine- 8, 1 -cyclopropane] -3-yl]benzenesulfonamide (38.2 mg, 40.8% yield) as a white solid. LC-MS (ES, m / z): [M+l] = 559. ’H NMR (400 MHz, Acetonitrile-d3) 58.49-8.10 (m, 1H). 7.45 (d, J= 8.7 Hz, 2H), 7.38 (dd, J = 8.4, 5.5 Hz, 2H), 7.07 (t, J = 8.8 Hz, 2H), 6.59 - 6.52 (m, 2H), 5.89 (s, 1H), 5.61 (d, J = 6.5 Hz, 1H), 4.95 (p, J = 6.7 Hz, 1H), 3.80 (td, J = 12.3, 11.2, 6.6 Hz, 2H), 3.58 - 3.44 (m, 1H), 3.36 (s, 3H), 2.98 - 2.86 (m, 2H), 2.34 (s, 2H), 2.09 - 1.99 (m, 2H), 1.32 (d, J= 39.1 Hz, 2H), 1.13 (d, J= 22.3 Hz, 2H).

[0400] Example 30: 4- (difluoromethoxymethyl) -N- [2- [(S) - (4-fluorophenyl) -methoxymethyl] -4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl] benzenesulfonamide

[0401]

[0402] The title product was obtained in analogy to Example 24 as a white solid (10.7% yield) using 3'-amino-2'-[(S)-(4-fluorophenyl)(methoxy)methyl]-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-4'-one and 4- [(difluoromethoxy)methyl]benzenesulfonyl chloride. LC-MS (ES, m / z): [M+l] = 552.1H NMR (400 MHz, Acetonitrile-d6) δ 8.62 (s, 1H), 7.83 - 7.76 (m, 2H), 7.58 - 7.51 (m, 2H), 7.43 - 7.32 (m, 2H), 7.13 - 7.03 (m, 2H), 6.51 (s, 1H), 5.83 (s, 1H), 5.01 (s, 2H), 3.89 - 3.74 (m, 2H), 3.37 (s, 3H), 2.36 - 2.29 (m, 2H), 1.32 (d, J = 39.3 Hz, 2H), 1.21 - 1.11 (m, 2H).

[0403] Example 31: 4-(l-fluorocyclopropyl)-N-(7-(hydroxymethyl)-2-(methoxy(phenyl)methyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0404] F

[0405]

[0406] The title compound was obtained in analogy to Example 12 as a white solid (12.6% yield) using N-{7-[(benzyloxy)methyl]-2-[methoxy(phenyl)methyl]-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-(1-fluorocyclopropyl)benzenesulfonamide and Titanium (IV) chloride. LCMS (ESI) [M + H]+: 516.15. ’H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.04 (s, 1H), 7.77 (d, J= 8.3 Hz, 2H), 7.48 - 7.29 (m, 7H), 5.86 (s, 1H), 5.26 (d, J = 59.6 Hz, 1H), 4.73 (s, 2H), 3.35 (s, 3H), 1.62 (dd, J= 19.6, 1.8 Hz, 2H), 1.26 (d, J= 18.9 Hz, 2H).

[0407] Example 32: N-[7-(difluoromethyl)-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2-d] pyrimidin-3-yl] -4- ( 1 -fluorocyclopropyl)benzenesulfonamide

[0408]

[0409] N-[7-(difluoromethyl)-4-oxo-2-[methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-yl]-4-(l-fluorocyclopropyl)benzenesulfonamide was obtained in analogy to Example 12 as a white solid (40.4% yield) using 4-(l-fluorocyclopropyl)-V-{7-formyl-2-[methoxy(phenyl)methyl] -4-oxothieno [3, 2-d] pyrimidin-3-yl}benzenesulfonamide and DAST. Chiral separation using conditions E afforded N-[7-(difluoromethyl)-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-yl]-4-(l-fluorocyclopropyl)benzenesulfonamide (40.0% yield, RT=6.12min, first peak) as a white solid. LCMS (ESI) [M + H]+: 536.15. ’H NMR (400 MHz, Acetonitrile-d3) 68.28 (t, J = 1.9 Hz, 1H), 7.78 (d, J= 8.3 Hz, 2H), 7.42 (dd, J= 7.3, 2.5 Hz, 2H), 7.38 - 7.30 (m, 5H), 7.03 (t, J= 54.7 Hz, 1H), 5.92 (s, 1H), 3.41 (s, 3H), 1.66 - 1.55 (m, 2H), 1.28 - 1.16 (m, 2H).

[0410] Example 33: 2-(difluoromethyl)-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-l,3-benzothiazole-6-sulfonamide

[0411]

[0412] 2-(difluoromethyl)-N-[7-methyl-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-l,3-benzothiazole-6-sulfonamide was obtained in analogy to Example 4 as a white solid (28.2% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-methylthiophene-2-carboxylic acid and N'-[2-(difluoromethyl)-1,3-benzothiazol-6-ylsulfonyl]tert-butoxycarbohydrazide. Chiral separation using conditions A afforded 2-(difluoromethyl)-N - [7 -methyl-4-oxo-2- [(R)-(4-fluorophenyl)-rnethoxy-methyl] thieno [3,2-d]pyrimidin-3-yl]-l,3-benzothiazole-6-sulfonamide (34.8% yield, RT=5.21min, first peak) as a white solid. LCMS (ESI) [M+H]+: 567.05.1H NMR (400 MHz, Acetonitrile-d3) δ 8.59 (d, J= 1.8 Hz, 1H), 8.27 (d, J= 8.7 Hz, 1H), 8.04 (dd, J= 8.7, 1.9 Hz, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.33 - 7.01 (m, 3H), 6.03 (s, 1H), 3.48 (s, 3H), 2.38 (s, 3H).

[0413] Example 34: N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-lH-indole-6-sulfonamide

[0414]

[0415] a) N-{2-[(4-fluorophenyl)(methoxy)methyl]-7-methyl-4-oxothieno[3,2-d]pyrimidin-3-yl}-3-nitro-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide To a stirred solution of 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-methylthiophene-2-carboxylic acid (400 mg, 1.237 mmol, 1 equiv) in dioxane (5 mL) was added V'-{3-nitro-4-[2-(trimethylsilyl)ethynyl]benzenesulfonyl}tert-butoxycarbohydrazide (1.02 g, 2.474 mmol, 2 equiv) and trichloropho sphane (0.51 g, 3.711 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for additional 12 h at 60 °C. The reaction was quenched with H2O at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by re versed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.5% FA), 30% to 50% gradient in 15 min, UV 254 nm. This resulted in A-{2-[(4-fhiorophenyl)(methoxy)methyl]-7-methyl-4-oxothieno[3,2-t / ]pyrimidin-3-yl}-3-nitro-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide (260 mg, 35.0% yield) as a yellow solid. LCMS (ESI) [M+H]+: 601.10.

[0416] b) 3-amino- N- { 2- [(4-fluorophenyl)(methoxy)methyl] -7 -methyl-4-oxothieno [3,2-<7| pyri m idi n-3-yl } -4- [2-(trimethylsilyl)ethynyl]benzenesulfonamide

[0417] To a stirred solution of A-{2-[(4-fluorophenyl)(methoxy)methyl]-7-methyl-4-oxothieno[3,2-6?]pyrimidin-3-yl}-3-nitro-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide (260 mg, 0.433 mmol, 1 equiv) and B2(OH)4 (116.4 mg, 1.299 mmol, 3 equiv) in DMF (3 mL) was added 4-(pyridin-4-yl)pyridine (0.68 mg, 0.004 mmol, 0.01 equiv) at 0 °C. The resulting mixture was stirred for additional 1 h at 25°C. 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), 30% to 50% gradient in 20 min, UV 254 nm. This resulted in 3-amino-V-{2-[(4-fluorophenyl)(methoxy)methyl]-7-methyl-4-oxothieno [3,2-t / ]pyrimidin-3-yl } -4- [2-(trimethylsilyl)ethynyl]benzenesulfonamide (210 mg, 85.01% yield) as a yellow solid. LCMS (ESI) [M+H]+: 571.12.

[0418] c) N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl] - lH-indole-6-sulfonamide

[0419] To a stirred solution of 3-amino-N-{2-[(4-fluorophenyl)(methoxy)methyl]-7-methyl-4-oxothieno[3,2-d]pyrimidin-3-yl}-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide (100 mg, 0.175 mmol, 1 equiv) in DMF (1 mL) was added Cui (13.4 mg, 0.070 mmol, 0.4 equiv) at 25 °C. The resulting mixture was stirred for additional 1 h at 120 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: Column: Xselect CSH Prep Cl 8, 30*150mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 48% to 59% B in 12 min; Wave Length: 254 / 220 nm; RT=9.92 min). This resulted in N-[7-methyl-4-oxo-2-[(4-fhiorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-lH-indole-6-sulfonamide (50 mg, 57.24% yield) as a light green solid. Chiral separation using conditions A afforded N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-lH-indole-6-sulfonamide (41.4% yield, RT=7.53min, first peak) as a white solid. LCMS (ESI) [M+H]+: 499.08.1H NMR (400 MHz, DMSO-d6) δ 11.37 (d, J= 188.3 Hz, 2H), 7.87 (d, J= 17.5 Hz, 2H), 7.76 - 7.64 (m, 2H), 7.44 - 7.28 (m, 3H), 7.21 - 7.10 (m, 2H), 6.63 - 6.58 (m, 1H), 5.78 (d, J = 63.9 Hz, 1H), 3.32 (s, 3H), 2.38 (s, 2H), 2.11 (s, 1H).

[0420] Example 35: N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3-yl]-lH-indole-6-sulfonamide

[0421]

[0422] N- [4-oxo-2- [(4-fluorophenyl)-methoxy-methyl] spiro [5,6-dihydropyrano [3,4-d]pyrimidine-8,l-cyclopropane]-3-yl]-lH-indole-6-sulfonamide was obtained in analogy to Example 34 as a white solid (38.1% yield) using 3-amino-A-{2'-[(4-fluorophenyl)(methoxy)methyl]-4'-oxo-5', 6'-dihydrospiro[cyclopropane- l,8-pyrano[3, 4-6?]pyrimidin]-3'-yl}-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide and Cui. Chiral separation using conditions F afforded N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8, l-cyclopropane]-3-yl]- lH-indole-6- sulfonamide (30.3% yield, RT=7.20min, first peak) as a white solid. LCMS (ESI) [M+H]+: 565.11. ’H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.23 (d, J = 164.2 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.39 (dd, J = 8.3, 1.7 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.21 -7.11 (m, 2H), 6.63 - 6.57 (m, 1H), 5.64 (s, 1H), 3.80 (d, J= 28.0 Hz, 2H), 3.20 (s, 3H), 2.26 (d, J= 29.3 Hz, 2H), 1.26 (dd, J= 73.6, 46.6 Hz, 4H).

[0423] Example 36: N-[3-(fluoromethyl)-5-[(4-fluorophenyl)-methoxy-methyl]-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide

[0424]

[0425] a) ethyl 5-[(4-fluorophenyl)(methoxy)methyl]-6-(4-methylbenzenesulfonamido)-7-oxo-[1,2] thiazolo [4, 5 -d\ pyrimidine- 3 -c arboxylate

[0426] The title compound was obtained in analogy to Example 4 as a yellow solid (40.4% yield) using 3-(ethoxycarbonyl)-4-[2-(4-fluorophenyl)-2-methoxyacetamido]-l,2-thiazole-5-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 533.0

[0427] b) N- { 5 - [(4-fluorophenyl)(methoxy)methyl] -3-(hydroxymethyl)-7 -oxo- [ 1,2] thiazolo [4,5-<7| pyri m idi n-6-yl } -4-methylbenzenesulfonamide

[0428] To a stirred solution of ethyl 5-[(4-fluorophenyl)(methoxy)methyl]-6-(4-methylbenzenesulfonamido)-7-oxo-[l,2]thiazolo[4,5-6?]pyrimidine-3-carboxylate (900 mg, 1.690 mmol, 1.0 equiv) in THF (20 mL) was added DIBAL-H (480.70 mg, 3.380 mmol, 2 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for additional 2 h. 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 mL). The combined organic layers were washed 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 (1:1) to afford A-{5-[(4-fhiorophenyl)(methoxy)methyl]-3-(hydroxymethyl)-7-oxo-[l,2]thiazolo[4,5-d]pyrimidin-6-yl] -4-methylbenzenesulfonamide (600 mg, 72.38% yield) as a white solid. LCMS (ESI) [M + H]+: 491.0

[0429] c) N- [3-(fluoromethyl)-5 - [(4-fluorophenyl)-methoxy-methyl] -7 -oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide

[0430] To a stirred solution of A-{5-[(4-fluorophenyl)(methoxy)methyl]-3-(hydroxymethyl)-7-oxo-[l,2]thiazolo[4,5-d]pyrimidin-6-yl}-4-methylbenzenesulfonamide (100 mg, 0.204 mmol, 1.0 equiv) in DCM (5 mL) was added DAST (131.4 mg, 0.816 mmol, 4 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 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 (Column: Xselect CSH Prep C18, 30*150mm 5pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 30% to 50% B in 13 min; Wave Length: 254 / 220 nm; RT=13.07 min) to afford N-[3-(fhioromethyl)-5-[(4-fhiorophenyl)-methoxy-methyl]-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide (22.2 mg, 22.11% yield) as a light yellow solid. LCMS (ESI) [M + H]+: 493.05. ’H NMR (400 MHz, Acetonitrile-d3) δ 7.74 – 7.68 (m, 2H), 7.51 - 7.44 (m, 2H), 7.39 (d, J= 7.8 Hz, 2H), 7.13 (t, J= 8.9 Hz, 2H), 5.94 (s, 1H), 5.77 (s, 1H), 5.65 (s, 1H), 3.45 (s, 3H), 2.47 (s, 3H).

[0431] Example 37: 4- (2,2-difluoroethyl) -N- [4-oxo-2- [(R) - (4-fluorophenyl) -methoxy -methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl] benzenesulfonamide

[0432] F

[0433] o=s=o o

[0434]

[0435] F

[0436] a) A-{2'-[(4-fhiorophenyl)(methoxy)methyl]-4'-oxo-5',6'-dihydrospiro[cyclobutane-l,8'-pyrano[3,4-t / ]pyrimidin]-3'-yl}-4-iodobenzenesulfonamide

[0437] The title compound was obtained in analogy to Example 9 as a white solid (24.8% yield) using 9-[2-(4-fluorophenyl)-2-methoxyacetamido]-5-oxaspiro[3.5]non-8-ene-8-carboxylic acid and A'-(4-iodobenzenesulfonyl)tert-butoxycarbohydrazide. LC-MS (ES, m / z):

[0438] [M+H]+= 612.0

[0439] b) 4-(2,2-difhioroethyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide A solution of A-{2'-[(4-fluorophenyl)(methoxy)methyl]-4'-oxo-5',6'-dihydrospiro[cyclobutane-l,8'-pyrano[3,4-6?]pyrimidin]-3'-yl}-4-iodobenzenesulfonamide (300 mg, 0.491 mmol, 1 equiv), l,l-difluoro-2-iodoethane (470.9 mg, 2.455 mmol, 5 equiv), 2,6-dimethylpyridine (115.7 mg, 1.080 mmol, 2.2 equiv), 1,1, 1,3,3, 3-hexamethyl-2-(trimethylsilyl)trisilane (124.6 mg, 0.501 mmol, 1.02 equiv), [4,4'-Bis(tert-butyl)-2,2'-bipyridine] nickel dibromide (11.9 mg, 0.025 mmol, 0.05 equiv) and Ir[dF(CF3)ppy]2(dtbpy))PF6(5.5 mg, 0.005 mmol, 0.01 equiv) in DME (6 mL) was stirred at 1500 rpm stir rate and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate for 2 hours. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (5 x 3 mL). The resulting mixture was concentrated under vacuum. 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), 30% to 70% gradient in 30 min, UV 254 nm. This resulted in 4-(2,2-difhioroethyl)-N-[4-oxo-2-[(4-fhiorophenyl)-methoxy-methyl] spiro [5,6-dihydropyrano [3,4-d]pyrimidine- 8, 1 "-cyclobutane] -3-yl]benzenesulfonamide (110 mg, 40.79% yield) as a white solid. Chiral separation using conditions F afforded 4-(2,2-difluoroethyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] spiro [5,6-dihydropyrano [3,4-d]pyrimidine- 8, 1 "-cyclobutane] -3-yl]benzenesulfonamide (23.5% yield, RT=8.86min, first peak) as a white solid. LC-MS (ES, m / z): [M+H]+= 550.1H NMR (300 MHz, Chloroform- ) 58.01 - 7.80 (m, 1H), 7.74 (d, J= 8.1 Hz, 2H), 7.53 (d, J= 7.9 Hz, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.06 (t, J= 8.5 Hz, 2H), 6.19 - 5.76 (m, 2H), 3.68 (s, 2H), 3.57 (s, 3H), 3.23 (td, J= 17.3, 4.2 Hz, 2H), 8.01 – 7.80 (d, J = 60.6 Hz, 8H).

[0440] Example 38: 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide

[0441]

[0442] 4-methyl-N-[4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide was obtained in analogy to Example 9 as a white solid (70.0% yield) using 9-[2-(4-fluorophenyl)-2- methoxyacetamido]-5-oxaspiro[3.5]non-8-ene-8-carboxylic acid and A'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. Chiral separation using conditions F afforded 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano [3,4-d]pyrimidine-8, 1 "-cyclobutane] -3-yl]benzenesulfonamide (27.0% yield, RT=10.60min, first peak) as a white solid. LC-MS (ESI, m / z): [M+H]+= 500.0.1H NMR (400 MHz, DMSO-tfe) 5 11.80 - 11.26 (m, 1H), 7.66 (d, J= 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 4H), 7.22 (d, J = 8.8 Hz, 2H), 5.90-5.74 (m, 1H), 3.70 (s, 1H), 3.64 (dt, J= 11.4, 5.6 Hz, 1H),3.4O (s, 3H), 2.60 (s, 1H), 2.40 (s, 3H), 2.21 - 2.14 (m, 6H), 1.98 (s, 1H).

[0443] Example 39: N-[5-[(4-fluorophenyl)-methoxy-methyl]-3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide

[0444] F

[0445] o=s=o o

[0446]

[0447] a) N-[3-(bromomethyl)-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]-4-methylbenzenesulfonamide

[0448] To a stirred solution of N-{5-[(4-fluorophenyl)(methoxy)methyl]-3-(hydroxymethyl)-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl}-4-methylbenzenesulfonamide (Example 36, 200 mg, 0.408 mmol, 1.0 equiv) in DCM (5 mL) was added PBr3 (132.4 mg, 0.490 mmol, 1.2 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by the addition of sat. NaHCOa (aq.) (5 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were 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 (1:1) to afford N-[3-(bromomethyl)-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]-4-methylbenzenesulfonamide (150 mg, 63.75% yield) as a white solid. LCMS (ESI) [M + H]+: 553.0

[0449] b) N-[5-[(4-fluorophenyl)-methoxy-methyl]-3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide A solution of N-[3-(bromomethyl)-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]-4-methylbenzenesulfonamide (90 mg, 0.163 mmol, 1.0 equiv) and Zn (77.6 mg, 1.190 mmol, 7.3 equiv), NH4CI (86.9 mg, 1.630 mmol, 10 equiv) in MeOH (2 mL) was stirred at 80 °C for 1 h. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 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 (Column: Xbridge Phenyl OBD Column, 30*150mm 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 43% B to 60% B in 30 min; Wave Length: 254 / 220 nm; RT=10.62 min) to afford N-[5-[(4-fluorophenyl)-methoxy-methyl]-3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide (23.2 mg, 30.06% yield) as a white solid. LCMS (ESI) [M + H]+: 475.10. ’H NMR (400 MHz, Acetonitrile-^) 5 7.75 - 7.67 (m, 2H), 7.48 (dd, J = 8.5, 5.5 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 8.8 Hz, 2H), 5.93 (s, 1H), 3.45 (s, 3H), 2.65 (s, 3H), 2.46 (s, 3H).

[0450] Example 40: 4- (difluoromethoxymethyl) -N - [7-(difluoromethyl) -2- [(4-fluorophenyl) -methoxy-methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide

[0451]

[0452] a) 3-amino-2-[(4-fluorophenyl)(methoxy)methyl]-7-{[(4-methoxyphenyl)methoxy]methyl}thieno[3,2-d]pyrimidin-4-one

[0453] The title compound was obtained in analogy to Example 1 as a yellow oil (28.1% yield) using methyl 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-4-{[(4-methoxyphenyl)methoxy]methyl}thiophene-2-carboxylate and hydrazine monohydrate. LCMS (ESI) [M + H]+: 456.2.

[0454] b) 3-amino-2- [(4-fluorophenyl) (methoxy)methyl] -7 -(hydroxymethyl) thieno[3,2-d] pyrimidin-4-one A solution of 3-amino-2-[(4-fluorophenyl) (methoxy)methyl]-7-{[(4-methoxyphenyl) methoxy] methyl] thieno[3,2-d] pyrimidin-4-one (240 mg, 0.527 mmol, 1 equiv) in DCM (3 mL) was added TFA (0.8 mL) at 0°C. The mixture was stirred for 2 hours at 60°C. The resulting mixture was concentrated under reduced pressure. The crude was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, H2O (FA) in ACN, 20% to 60% gradient in 20 min, UV 254 nm to afford 3-amino-2-[(4-fluorophenyl) (methoxy)methyl]-7-(hydroxymethyl) thieno[3,2-d] pyrimidin-4-one (120 mg, 67.91% yield) as a yellow oil. LCMS (ESI) [M + H] +: 336.2.

[0455] c) 3-amino-2-[(4-fluorophenyl) (methoxy)methyl]-4-oxothieno[3,2-d] pyrimidine-7-carbaldehyde

[0456] A solution of 3-amino-2-[(4-fluorophenyl) (methoxy)methyl]-7-(hydroxymethyl) thieno[3,2-d] pyrimidin-4-one (120 mg, 0.358 mmol, 1 equiv) in DCM (50 mL) was added Mn02 (622.1 mg, 7.160 mmol, 20 equiv) at rt. The mixture was stirred for overnight at rt. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 10 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, H2O (FA) in ACN, 20% to 60% gradient in 20 min, UV 254 nm to afford 3-amino-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxothieno[3,2-d]pyrimidine-7-carbaldehyde (40 mg, 33.53% yield) as a white solid. LCMS (ESI) [M + H] +: 334.2

[0457] d) 3-amino-7-(difhioromethyl)-2-[(4-fluorophenyl) (methoxy)methyl] thicno|3,2-<7| pyrimidin-4-one

[0458] A solution of 3-amino-2-[(4-fluorophenyl) (mcthoxy)mcthyl|-4-oxothicno|3,2-<7| pyrimidine-7-carbaldehyde (40 mg, 0.120 mmol, 1 equiv) in DCM (1.5 mL) was added DAST (96.7 mg, 0.60 mmol, 5 equiv) at 0 °C under nitrogen atmosphere. The mixture was stirred for 2 hours at rt. The reaction was quenched with H2O (3 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with H2O (1 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase separation column [Mobile Phase A: Water (0.3% EA), Mobile Phase B: acetonitrile; Gradient: 0% B to 70% B in 30 min] to give 3-amino-7-(difhioromethyl)-2-[(4-fluorophenyl) (methoxy)methyl] thicno|3,2-<7| pyrimidin-4-one (30 mg, 52.96% yield) as a white solid. LCMS (ESI) [M + H]+: 483.2.

[0459] e) 4-(difluoromethoxymethyl)-N-[7-(difluoromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide A solution of 3-amino-7-(difluoromethyl)-2-[(4-fluorophenyl) (methoxy)methyl] thieno[3,2-t7] pyrimidin-4-one (70 mg, 0.197 mmol, 1 equiv) and 4-[(difluoromethoxy)methyl] benzenesulfonyl chloride (60.6 mg, 0.236 mmol, 1.2 equiv) in THF (2 mL) was added LiHMDS (65.9 mg, 0.394 mmol, 2 equiv) at -78 °C under nitrogen atmosphere. The mixture was stirred for 1 hour at -78 °C. The reaction was quenched by the addition of NH4CI (3 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 3 mL). The combined organic layers were washed with H2O (3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by re versed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, H2O (LA) in ACN, 20% to 70% gradient in 20 min, UV 254 nm to afford 4-[(difhioromethoxy)methyl ]-A-[7-(difhioromethyl)-2-[(4-fluorophenyl) (methoxy)methyl |-4-oxothicno|3,2-<7| pyrimidin-3-yl] benzenesulfonamide (16.1 mg, 14.20% yield) as a white solid. LCMS (ESI) [M + H]+: 576.2. ’H NMR (400 MHz, CD3CN) <58.32 (s, 1H), 7.84 (d, J= 8.2 Hz, 2H), 7.56 (d, J= 8.1 Hz, 2H), 7.48 (dd, J = 8.4, 5.5 Hz, 2H), 7.17 - 7.04 (m, 3H), 6.72 - 6.32 (m, 1H) 5.94 (s, 1H), 5.04 (s, 2H), 3.44 (s, 3H).

[0460] Example 41: 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(R)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide

[0461]

[0462] a) ethyl 6-{4-[(difluoromethoxy)methyl]benzenesulfonamido}-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[1,2]thiazolo[4,5-d]pyrimidine-3-carboxylate The title compound was obtained in analogy to Example 4 as a yellow oil (24.8% yield) using 3-(ethoxycarbonyl)-4-[2-(4-fluorophenyl)-2-methoxyacetamido]-1,2-thiazole-5-carboxylic acid and N'-{4-[(difluoromethoxy)methyl]benzenesulfonyl}tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 599.0 b) 4-[(difluoromethoxy)methyl]-N-{5-[(4-fluorophenyl)(methoxy)methyl]-3-(hydroxymethyl)-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl}benzenesulfonamide

[0463] To a stirred solution of ethyl 6-{4-[(difluoromethoxy)methyl]benzenesulfonamido}-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[l,2]thiazolo[4,5-6?]pyrimidine-3-carboxylate (660 mg, 1.103 mmol, 1 equiv) in THF (10 mL) was added DIBAL-H (313.6 mg, 2.206 mmol, 2 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for additional 1 h. The reaction was quenched by the addition of sat. NH4CI (aq.) (10 mL) at -78 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were 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 (1:1) to afford 4-[(difhioromethoxy)methyl]-A-{5-[(4-fhiorophenyl)(methoxy)methyl]-3-(hydroxymethyl)-7-oxo-[l,2]thiazolo[4,5-t / ]pyrimidin-6-yl}benzenesulfonamide (340 mg, 55.41% yield) as a white solid. LCMS (ESI) [M + H]+: 557.0

[0464] c) N-[3-(bromomethyl)-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]-4-[(difluoromethoxy)methyl]benzenesulfonamide

[0465] To a stirred solution of 4-[(difluoromethoxy)methyl]-N-{5-[(4-fluorophenyl)(methoxy)methyl]-3-(hydroxymethyl)-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl}benzenesulfonamide (340 mg, 0.611 mmol, 1 equiv) in DCM (5 mL) was added PBr3 (198.4 mg, 0.733 mmol, 1.2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (2 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were 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 (1:1) to afford N-[3-(bromomethyl)-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]-4-[(difluoromethoxy)methyl]benzenesulfonamide (170 mg, 44.92% yield) as a yellow solid. LCMS (ESI) [M + H]+: 619.0

[0466] d) 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(R)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide

[0467] A solution of N-[3-(bromomethyl)-5-[(4-fluorophenyl)(methoxy)methyl]-7-oxo-[1,2]thiazolo[4,5-d]pyrimidin-6-yl]-4-[(difluoromethoxy)methyl]benzenesulfonamide (150 mg, 0.242 mmol, 1 equiv) and Zn (115.58 mg, 1.767 mmol, 7.3 equiv), NH4CI (129.53 mg, 2.420 mmol, 10 equiv) in MeOH (2 mL) was stirred at 80 °C for 1 h. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). 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%): 38% B to 55% B in 30 min; Wave Length: 254 / 220 nm; RT1= 12.92 min) to afford 4- (difhioromethoxymethyl)-N-[3-methyl-7-oxo-5-[(4-fluorophenyl)-methoxy- methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide (90 mg, 68.76% yield) as a yellow solid. Chiral separation using conditions F afforded 4-(difhioromethoxymethyl)-N- [3-methyl-7-oxo-5-[(R)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6- yl]benzenesulfonamide (21.4% yield, RT=13.17min, second peak) as a white solid. LCMS (ESI) [M+H]+: 541.05. ’H NMR (400 MHz, Acetonitrile-^) 57.83 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H), 7.49 (dd, J= 8.6, 5.6 Hz, 2H), 7.19 - 7.06 (m, 2H), 6.76 - 6.31 (m, 1H), 5.95 (s, 1H), 5.04 (s, 2H), 3.45 (s, 3H), 2.65 (s, 3H).

[0468] Example 42: 4-methyl-N-[7-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy- methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide

[0469] The title compound was obtained by chiral separation of N-[2-[(4-fluorophenyl)-methoxy- methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (Example 6) as a white solid using conditions A (42.6% yield, 12.50min, second peak). LCMS(ESI) [M + H]+: 474.10. ’H NMR (400 MHz, DMSO-tfe) 8 11.44 (s, 1H), 7.91 -

[0470]

[0471] 7.85 (m, 1H), 7.70 - 7.63 (m, 2H), 7.39 (dd, J= 19.2, 7.2 Hz, 4H), 7.20 (t, J= 8.9 Hz, 2H), 5.89 (s, 1H), 3.35 (s, 3H), 2.40 (s, 3H), 2.30 (s, 3H).

[0472] Example 43: 4-methyl-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy- methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide

[0473]

[0474] The title compound was obtained by chiral separation of N-[2-[(4-fluorophenyl)-methoxy-methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (Example 6) as a white solid using conditions A (45.9% yield, 8.99min, first peak).

[0475] LCMS(ESI) [M + H]+: 474.05. ’H NMR (400 MHz, DMSO-tfe) 611.36 (s, 1H), 7.94 -7.82 (m, 1H), 7.66 (d, J= 7.7 Hz, 2H), 7.39 (t, J= 10.7 Hz, 4H), 7.20 (t, J= 8.7 Hz, 2H), 5.88 (s, 1H), 3.34 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H).

[0476] Example 44: 4-(2,2-difluoroethyl)-N-[4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl] benzenesulfonamide

[0477]

[0478] F

[0479] The title compound was obtained by chiral separation of 4-(2,2-difluoroethyl)-N-[4-oxo-2-[(4-fhiorophenyl)-methoxy-methyl] spiro [5,6-dihydropyrano [3,4-d]pyrimidine- 8,1"-cyclobutane]-3-yl]benzenesulfonamide (Example 37) as a white solid using conditions F (25.9% yield, 13.7min, second peak). LC-MS (ES, m / z): [M+H]+: 550.1H NMR (300 MHz, Chloroform- d) 58.01 - 7.80 (m, 1H), 7.79 - 7.70 (m, 2H), 7.52 (t, J = 7.1 Hz, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.06 (t, J= 8.5 Hz, 2H), 6.21 - 5.74 (m, 2H), 3.67 (t, J= 5.0 Hz, 2H), 3.57 (s, 3H), 3.23 (td, J = 17.3, 4.2 Hz, 2H), 2.79 - 1.82 (m, 8H). Example 45: 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(S)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide

[0480]

[0481] The title compound was obtained by chiral separation of 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide (Example 41) as a white solid using conditions F (29.6% yield, 8.2min, first peak). LCMS (ESI) [M+H]+: 541.05. ’H NMR (400 MHz, Acetonitrile-d3) 6 7.84 (d, J= 8.2 Hz, 2H), 7.56 (d, J= 8.2 Hz, 2H), 7.49 (dd, J= 8.6, 5.6 Hz, 2H), 7.17 -7.05 (m, 2H), 6.73 - 6.33 (m, 1H), 5.95 (s, 1H), 5.04 (s, 2H), 3.46 (s, 3H), 2.65 (s, 3H).

[0482] Example 46: Biological experiments

[0483] a) The potency of exemplary compounds of formula (I) was determined using thallium fluorescence.

[0484] Cell Culture

[0485] 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.

[0486] Assay solution and compound preparation

[0487] 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.

[0488] Assay Protocol

[0489] 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.

[0490] 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.

[0491] Data Analysis

[0492] Percent activation was calculated from changes in fluorescent response using the following equation:

[0493] % activation = ((RFU test agent - RFU buffer) / (RFU positive control - RFU buffer))* 100

[0494] 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).

[0495] b) The potency of exemplary compounds of formula (I) was determined using the SyncroPatch 384 (Nanion) high throughput electrophysiology platform.

[0496] Cell Culture

[0497] 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.

[0498] Solutions

[0499] Solutions were of the following composition:

[0500] 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.

[0501] Cell Preparation

[0502] 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.

[0503] SyncroPatch Recording

[0504] 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.

[0505] Data Analysis 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:

[0506] % Activation = ((Test compoundCorr -ControlCorr) / (DCPIBCorr - ControlCorr))*100

[0507] 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).

[0508] TMEM175

[0509] TMEM175 EP

[0510] FLIPR

[0511] Example HUMAN EC50

[0512] HUMAN EC50

[0513] (uM)

[0514] (uM)

[0515] 1 0.219 0.115

[0516] 2 0.312 0.131

[0517] 3 0.151 0.075

[0518] 4 0.442 0.546

[0519] 5 0.398 0.653

[0520] 6 0.075 0.136

[0521] 7 0.961 0.674

[0522] 8 0.099 0.283

[0523] 9 0.104 0.217

[0524] 10 0.154 0.307

[0525] 11 1.001 0.921

[0526] 12 0.185 0.333

[0527] 13 1.407 0.743

[0528] 14 0.146 0.145

[0529] 15 0.289 0.692

[0530] 16 0.068 0.090

[0531] 17 0.081 0.106

[0532] 18 2.912 0.904

[0533] 19 0.132 0.483

[0534] 20 0.152 0.304

[0535] 21 0.419 0.171

[0536] 22 1.321 0.301

[0537] 23 0.177 0.085

[0538] 24 0.140 0.240

[0539] 25 0.111 0.151

[0540] 26 5.285 0.918

[0541] 27 0.120 0.094

[0542] 28 0.150 0.040

[0543] 29 0.200 0.235

[0544]

[0545] 30 2.760 0.776 31 3.25 0.7558

[0546] 32 0.1647 0.1626

[0547] 33 0.4691 0.2636

[0548] 34 0.1043 0.1029

[0549] 35 0.2015 0.1836

[0550] 36 0.17 0.2287

[0551] 37 0.180 0.073

[0552] 38 0.19 0.16

[0553] 39 0.31 0.29

[0554] 40 0.16 0.07

[0555] 41 0.19 0.10

[0556] 42 3.06 0.51

[0557] 43 0.05 0.06

[0558] 44 3.59 1.12

[0559]

[0560] 45 4.57 1.49

[0561] Table 1

[0562] Example A

[0563] Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

[0564] Ingredients Per tablet

[0565] Kernel:

[0566] Compound of formula (I) 10.0 mg 200.0 mg

[0567] Microcrystalline cellulose 23.5 mg 43.5 mg

[0568] Lactose hydrous 60.0 mg 70.0 mg

[0569] Povidone K30 12.5 mg 15.0 mg

[0570] Sodium starch glycolate 12.5 mg 17.0 mg

[0571] Magnesium stearate 1.5 mg 4.5 mg

[0572] (Kernel Weight) 120.0 mg 350.0 mg

[0573] Film Coat:

[0574] Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg

[0575] Polyethylene glycol 6000 0.8 mg 1.6 mg

[0576]

[0577] Talc 1.3 mg 2.6 mg

[0578] Iron oxide (yellow) 0.8 mg 1.6 mg

[0579] Titan dioxide 0.8 mg 1.6 mg

[0580]

[0581] 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.

[0582] Example B

[0583] Capsules containing the following ingredients can be manufactured in a conventional manner:

[0584] Ingredients Per capsule

[0585] Compound of formula (I) 25.0 mg

[0586] Lactose 150.0 mg

[0587] Maize starch 20.0 mg

[0588] Talc 5.0 mg

[0589]

[0590] The components are sieved and mixed and filled into capsules of size 2.

[0591] Example C

[0592] Injection solutions can have the following composition:

[0593] Compound of formula (I) 3.0 mg

[0594] Polyethylene glycol 400 150.0 mg

[0595] Acetic acid q.s. ad pH 5.0

[0596] Water for injection solutions ad 1.0 ml

[0597]

[0598] 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

Claims1. A compound of formula (I)whereinR1and R2together with the carbon atoms to which they are attached form alkylthiophenyl, perdeuterioalyklthiophenyl, haloalkylthiophenyl, hydroxyalkylthiophenyl, cycloalkylthiophenyl, alkylisothiazolyl, haloalkylisothiazolyl, haloalkoxyisothiazolyl, dialkylpyrazolyl, dihydrospiro- cycloalkylpyranyl, halocycloalkyl-dihydro-2H -pyranyl or haloalkyl-dihydro- 2H-pyranyl;R3is hydrogen or alkoxy;R4is hydrogen or halogen;R5is alkyl, haloalkyl, dialkylamino, halocycloalkyl, haloalkoxyalkyl or halocycloalkylamino; andR6is hydrogen;or R5and R6, together with the carbon atom to which they are attached, form haloalkylthiazolyl, pyrrolyl, dihydro-1H-imidazolyl;or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein R1and R2together with the carbon atoms to which they are attached form alkylthiophenyl, perdeuterioalyklthiophenyl, haloalkylthiophenyl, cycloalkylthiophenyl, alkylisothiazolyl or dihydrospiro- cycloalkylpyranyl.

3. A compound according to claim 1 or 2, wherein R1and R2together with the carbon atoms to which they are attached form methylthiophenyl, trifluoromethylthiophenyl, cyclopropythiophenyl, trideuteriomethylthiophenyl, difluoromethylthiophenyl, difluoroethylthiophenyl, methylisothiazolyl, dihydrospiro-cyclopropylpyranyl or dihydrospiro-cyclobutylpyranyl.

4. A compound according to any one of claims 1 to 3, wherein R3is alkoxy.

5. A compound according to any one of claims 1 to 4, wherein R3is methoxy.

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

7. A compound according to any one of claims 1 to 6, wherein R5is alkyl, haloalkyl, haloalkoxyalkyl, halocycloalkylamino or halocycloalkyl.

8. A compound according to any one of claims 1 to 7, wherein R5is methyl, difluoroethyl, difluoromethoxymethyl, fluorocyclobutylamino or fluorocyclopropyl.

9. A compound according to any one of claims 1 to 6, wherein R5and R6, together with the carbon atom to which they are attached, form pyrrolyl.

10. A compound according to any one of claims 1 to 9 selected fromN-(2-benzyl-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl)-4-methyl- benzenesulfonamide;N-(2-benzyl-5-methyl-4-oxo-thieno[2,3-d]pyrimidin-3-yl)-4-methyl- benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4- methyl-benzenesulfonamide;N-[6-[methoxy(phenyl)methyl]-3-methyl-4-oxo-isothiazolo[5,4-d]pyrimidin-5-yl]-4- methyl-benzenesulfonamide;N-[5-[methoxy(phenyl)methyl]-3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4- methyl-benzenesulfonamide;N-[2-[(4-fhiorophenyl)-methoxy-methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3- yl]-4-methyl-benzenesulfonamide;N-(6-(methoxy(phenyl)methyl)- 1,3-dimethyl-4-oxo- 1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)-4-methylbenzenesulfonamide;N-[5-(difluoromethyl)-2-[methoxy(phenyl)methyl]-4-oxo-thieno[2,3-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,r-cyclopropane]-3-yl]-4-methyl-benzenesulfonamide;4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,r-cyclopropane]-3-yl]benzenesulfonamide;N-[5-[methoxy(phenyl)methyl]-1,3-dimethyl-7-oxo-pyrazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide;N-[7-(difluoromethyl)-2-[methoxy(phenyl)methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-methyl-N- [6-methyl-4-oxo-2- [(R)-methoxy(phenyl)methyl] thieno [3,2-d]pyrimidin-3-yl]benzenesulfonamide;N- [2- [methoxy(phenyl)methyl] -4-oxo-5- (trifluoromethyl)thieno [2, 3 -d] pyrimidin-3 -yl]-4-methyl-benzenesulfonamide;(R)-4-(l-fluorocyclopropyl)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydro spiro [cyclopropane- 1, 8 '-pyrano [3,4-d] pyrimidin] - 3 '(4'H) -yl)benzenesulfonamide;N- [7 -cyclopropyl-4-oxo-2- [(R)-(4-fluorophenyl)-methoxy-methyl] thieno [3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7-(trideuteriomethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;N-[7-cyclopropyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-methyl-N-[5-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[2,3-d]pyrimidin-3-yl]benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7-(2,2,2-trifluoroethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;(R)-4-(l-fluorocyclopropyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(R)-4-(l,l-difluoroethyl)-N-(2-(methoxy(phenyl)methyl)-7-methyl-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(R)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;(R)-4-(dimethylamino)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydro spiro [cyclopropane- 1, 8 '-pyrano [3,4-d] pyrimidin] - 3 '(4'H) -yl)benzenesulfonamide;(R)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'-dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)-4-methylbenzenesulfonamide;(S)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;4-(difluoromethoxymethyl)-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,1-cyclopropane]-3-yl]benzenesulfonamide;N-[7-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxothieno[3,2-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;4-[(3-fluorocyclobutyl)amino]-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,1-cyclopropane]-3-yl]benzenesulfonamide;4-(difluoromethoxymethyl)-N-[2-[(S)-(4-fluorophenyl)-methoxymethyl]-4-oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,1-cyclopropane]-3-yl]benzenesulfonamide;4-( 1 -fluorocyclopropyl) -N- (7 - (hydroxymethyl) -2- (methoxy (phenyl) methyl) -4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-[7-(difluoromethyl)-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2-d]pyrimidin-3-yl]-4-(l-fluorocyclopropyl)benzenesulfonamide;2-(difluoromethyl)-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] thieno [3,2-d]pyrimidin-3-yl] - 1 -benzothiazole-6- sulfonamide;N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]-lH-indole-6-sulfonamide;N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8, l-cyclopropane]-3-yl]- lH-indole-6-sulfonamide;N-[3-(fluoromethyl)-5-[(4-fluorophenyl)-methoxy-methyl]-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide;4-(2,2-difluoroethyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide; N-[7-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin- 3 -yl] - 5 - (fluoromethyl) thiophene-2- sulfonamide;N-[5-[(4-fluorophenyl)-methoxy-methyl]-3-methyl-7-oxo-isothiazolo[4,5-d]pyrimidin-6-yl]-4-methyl-benzenesulfonamide;4-(difluoromethoxymethyl)-N- [7-(difluoromethyl)-2- [(4-fluorophenyl)-methoxy-methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(R)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide;4-methyl-N-[7-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;4-methyl-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluoroethyl)-N-[4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,r-cyclobutane]-3-yl]benzenesulfonamide; and 4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(S)-(4-fluorophenyl)-methoxy-methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide;or a pharmaceutically acceptable salt thereof.

11. A compound according to any one of claims 1 to 10 selected fromN-[2-[methoxy(phenyl)methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3-yl]-4- methyl-benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-7-methyl-4-oxo-thieno[3,2-d]pyrimidin-3- yl]-4-methyl-benzenesulfonamide;N- [2- [methoxy(phenyl)methyl] -4-oxo-5- (trifluoromethyl)thieno [2, 3 -d] pyrimidin-3 - yl]-4-methyl-benzenesulfonamide;N- [7 -cyclopropyl-4-oxo-2- [(R)-(4-fluorophenyl)-methoxy-methyl] thieno [3,2- d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-7- (trideuteriomethyl)thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;(R)-N-(7-(2,2-difluoroethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxothieno[3,2- d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;(R)-N-(2'-((4-fluorophenyl)(methoxy)methyl)-4'-oxo-5',6'- dihydrospiro[cyclopropane-1,8'-pyrano[3,4-d]pyrimidin]-3'(4'H)-yl)-4-methylbenzenesulfonamide;4-(difluoromethoxymethyl)-N-[2-[(R)-(4-fluorophenyl)-methoxymethyl]-4- oxospiro[5,6-dihydropyrano[3,4-d]pyrimidine-8,l-cyclopropane]-3- yl] benzenesulfonamide;N-[7-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxothieno[3,2- d]pyrimidin-3-yl]-4-[((ls,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;N-[7-(difluoromethyl)-4-oxo-2-[(R)-methoxy(phenyl)methyl]thieno[3,2- d]pyrimidin-3-yl]-4-(l-fluorocyclopropyl)benzenesulfonamide;N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2- d]pyrimidin-3-yl]-lH-indole-6-sulfonamide;4-(2,2-difluoroethyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6- dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]spiro[5,6- dihydropyrano[3,4-d]pyrimidine-8,l"-cyclobutane]-3-yl]benzenesulfonamide;4-(difluoromethoxymethyl)-N- [7-(difluoromethyl)-2- [(4-fluorophenyl)-methoxy- methyl]-4-oxo-thieno[3,2-d]pyrimidin-3-yl]benzenesulfonamide;4-(difluoromethoxymethyl)-N-[3-methyl-7-oxo-5-[(R)-(4-fluorophenyl)-methoxy- methyl]isothiazolo[4,5-d]pyrimidin-6-yl]benzenesulfonamide; and4-methyl-N-[7-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]thieno[3,2- d]pyrimidin-3-yl]benzenesulfonamide;or a pharmaceutically acceptable salt thereof.

12. A process for the preparation of a compound according to any one of claims 1 to 11 comprising one of the following steps:(a) The reaction of a compound of formula (A)in the presence of a compound of formula (B)and a base; or(b) The reaction of a compound of formula (C)R40 H(C)in the presence of a compound of formula (D)and PCl3;wherein R1to R6are as defined in any one of claims 1 to 9 and wherein R is hydrogen or an amine protecting group.

13. A compound according to any one of claims 1 to 11, when manufactured according to a process of claim 12.

14. A compound according to any one of claims 1 to 11 for use as therapeutically active substance.

15. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 11 and a therapeutically inert carrier.

16. The use of a compound according to any one of claims 1 to 11 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.

17. The use of a compound according to any one of claims 1 to 11 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.

18. A compound according to any one of claims 1 to 11 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.

19. 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 comprisesadministering an effective amount of a compound as defined in any one of claims 1 to 11 to a patient in need thereof.

20. The invention as hereinbefore described.***

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