Novel sulfonamide derivatives

Abstract

The invention relates to a compound of formula (I) wherein A1 and A2 and R1 to R7 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: P39770

[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] one of A1and A2is nitrogen and the other one is CR8;

[0009] R1is hydrogen, alkyl or halogen;

[0010] R2is hydrogen, alkyl, halogen, hydroxyalkyl, alkoxy, dialkylamino, cycloalkyl, cycloalkoxy, haloalkoxy, haloalkyl, halocycloalkyl, haloalkoxyalkyl, (halo)(alkyl)azetidinyl, haloalkylpyrrolidinyl, haloazaspiro[3.3]heptan-2-yl, perdeuterioalkoxy or cyano;

[0011] DP / 24.09.25 R3is hydrogen, hydroxyl, alkoxy, haloalkoxy or halogen;

[0012] R4is hydrogen or halogen;

[0013] R5is hydrogen or halogen;

[0014] R6is hydrogen, halogen, alkyl, haloalkyl or cyano;

[0015] or R5an R6together form -OCH2CH2O-;

[0016] R7is halophenyl, alkylphenyl, alkoxyphenyl, dialkylphenyl, dialkoxyphenyl, cycloalkylphenyl, haloalkylphenyl, haloalkoxyphenyl, haloalkoxyalkylphenyl, (halo)(alkyl)phenyl, (haloalkoxyalkyl)(alkyl)phenyl, (alkyl)(halocycloalkylamino)phenyl, (haloalkoxyalkyl)(halo)phenyl, (halocycloalkyl)(alkyl)phenyl, alkinylphenyl, alkenylphenyl, alkylalkinylphenyl, dialkylaminophenyl, halocycloalkylphenyl, halocycloalkylaminophenyl, indolyl, alkylindolyl, haloalkylindolyl, haloazetidinylphenyl, azetidinylphenyl, haloalkylcycloalkylphenyl, alkoxyalkylphenyl, benzofuranyl, cycloalkylindolyl, morpholinylphenyl, haloalkylcycloalkylaminophenyl, halocycloalkylalkylphenyl, halothiophenyl, alkylthiphenyl, haloalkylthiophenyl, oxetanylphenyl, (haloalkoxy)(haloalkyl)phenyl, haloalkylaminophenyl, haloalkylazetidinylphenyl, haloazaspiro [3.3]heptanylphenyl, haloazabicyclo[3.1.0]hexanylphenyl, hydroxyalkylaminophenyl, haloalkylcycloalkyloxyphenyl, (halocycloalkylalkylamino)(halo)phenyl, (N- haloalkyl)(N-alkyl)aminophenyl, (halo)(haloalkylcycloalkylamino)phenyl or haloalkoxycycloalkylaminophenyl, (haloalkoxyalkyl)(haloalkyl)phenyl, halocycloalkylalkylaminophenyl; and

[0017] R8is hydrogen, halogen or alkyl;

[0018] or a pharmaceutically acceptable salt thereof.

[0019] 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:

[0020] 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).

[0021] 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.).

[0022] 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.).

[0023] 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.).

[0024] 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.).

[0025] 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.).

[0026] 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 E, May S, Eohmann K, Grallert H, Eieb W, Strauch K, Miiller-Nurasyid M, Berger K, Schormair B, Winkelmann J, Mollenhauer B, Trenkwalder C, Maetzler W, Berg D, Kasten M, Klein C, Hbglinger GU, Gasser T, Deuschi G, Franke A, Krawczak M, Dempfle A, Kuhlenbaumer G. Rare variants in specific lysosomal genes are associated with Parkinson’s disease. Mov Disord 35: 1245-1248, 2020. doi: 10.1002 / mds.28037), Rapid-eye-movement (REM) sleep behavior disorder (RBD) (Krohn E, 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 Eewy Bodies (Chia R, Sabir MS, Bandres-Ciga S, et al.; American Genome Center. Genome sequencing analysis identifies new loci associated with Eewy 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:

[0027] 10.1073 / pnas.1616332114).

[0028] 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.

[0029] Neurobiol Dis. 2021 Jul;154:105360). Therefore, TMEM175 enhancers may address the underlying disease biology in ALS.

[0030] 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.

[0031] In the present description the term “alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straightchain and branched-chain Ci-Cs alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl more particularly methyl, ethyl, propyl, isopropyl, isobutyl, tert.-butyl and isopentyl. Particular examples of “alkyl” are methyl, ethyl, propyl, particularly n-propyl and isopropyl, butyl, particularly isobutyl.

[0032] The term “cycloalkyl”, alone or in combination, signifies a monocyclic or bicyclic cycloalkyl or spirocycloalkyl ring with 3 to 8 carbon atoms and particularly a mono- or bicyclic cycloalkyl or spirocycloalkyl ring with 3 to 7, in particular 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentanyl, cyclohexyl, spiro[2.3]hexyl, cycloheptyl, spirocyclo[3.3]heptanyl and cyclooctyl.

[0033] Particular “cycloalkyl” are cyclopropyl, cyclobutyl and spirocyclo [3.3] hep tanyl.

[0034] The term “oxy”, alone or in combination, signifies the -O- group.

[0035] 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. Particular examples of “alkyloxy” or “alkoxy” are methoxy and ethoxy, more particularly methoxy.

[0036] The term “cycloalkyloxy” or “cycloalkoxy”, alone or in combination, signifies a group of the formula cycloalkyl-O- in which the term "cycloalkyl" has the previously given significance, such as cyclopropoxy and cyclobutoxy. A particular example of “cycloalkoxy” is cyclopropoxy.

[0037] The terms “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens, i.e. one, two or three halogens. Particular halogens are fluorine, bromine and chlorine, more particularly fluorine and chlorine.

[0038] 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, trifluoroethyl, difluoroethyl, fluoropropyl, trifluoropropyl and fluorobutyl.

[0039] 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, difluorocyclopropyl, difluorocyclobutyl, difluorospiro[2.3]hexyl, difluorocyclohexyl and

[0040] difluoro spirocyclo [3.3 ] hep tanyl. 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. Particular “haloalkoxy” are difluoromethoxy, difluoroethoxy and trifluoroethoxy.

[0041] The term “halophenyl”, alone or in combination, denotes a phenyl group substituted with at least one halogen, particularly substituted with one to three halogens, more particularly one halogen. Particular “halophenyl” are fluorophenyl and difluorophenyl.

[0042] The terms “hydroxyl” and “hydroxy”, alone or in combination, signify the -OH group.

[0043] The term “carbonyl”, alone or in combination, signifies the -C(O)- group.

[0044] The term “amino”, alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

[0045] The term “cyano”, alone or in combination, signifies the -CN group.

[0046] The term “alkenyl”, alone or in combination, signifies a monovalent linear or branched hydrocarbon group of 2 to 7 carbon atoms, in particular 2 to 4 carbon atoms, with at least one double bond. Examples of alkenyl include ethenyl, propenyl, prop-2-enyl, isopropenyl, n-butenyl, i-butenyl, and t-butenyl. A particular examples of “alkenyl” is propenyl, particularly isopropenyl.

[0047] The term “alkynyl”, alone or in combination, signifies a monovalent linear or branched saturated hydrocarbon group of 2 to 7 carbon atoms, in particular from 2 to 4 carbon atoms, and comprising one, two or three triple bonds. Examples of alkynyl include ethynyl, propynyl, prop-2-ynyl, isopropynyl, n-butynyl, and iso-butynyl. A particular example of “alkynyl” is propynyl.

[0048] 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.

[0049] 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).

[0050] 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.

[0051] 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.

[0052] The invention relates in particular to a compound of formula (I) wherein

[0053] one of A1and A2is nitrogen and the other one is CR8;

[0054] R1is hydrogen, alkyl or halogen;

[0055] R2is hydrogen, alkyl, halogen, hydroxyalkyl, alkoxy, dialkylamino, cycloalkyl, cycloalkoxy, haloalkoxy, haloalkyl, halocycloalkyl, haloalkoxyalkyl, (halo)(alkyl)azetidinyl, haloalkylpyrrolidinyl, haloazaspiro[3.3]heptan-2-yl, perdeuterioalkoxy or cyano;

[0056] R3is hydrogen, hydroxyl, alkoxy, haloalkoxy or halogen; R4is hydrogen or halogen;

[0057] R5is hydrogen or halogen;

[0058] R6is hydrogen, halogen, alkyl, haloalkyl or cyano;

[0059] or R5an R6together form -OCH2CH2O-;

[0060] R7is halophenyl, alkylphenyl, alkoxyphenyl, dialkylphenyl, dialkoxyphenyl, cycloalkylphenyl, haloalkylphenyl, haloalkoxyphenyl, haloalkoxyalkylphenyl, (halo)(alkyl)phenyl, (haloalkoxyalkyl)(alkyl)phenyl, (alkyl)(halocycloalkylamino)phenyl, (haloalkoxyalkyl)(halo)phenyl, (halocycloalkyl)(alkyl)phenyl, alkinylphenyl, alkenylphenyl, alkylalkinylphenyl, dialkylaminophenyl, halocycloalkylphenyl, halocycloalkylaminophenyl, indolyl, alkylindolyl, haloalkylindolyl, haloazetidinylphenyl, azetidinylphenyl, haloalkylcycloalkylphenyl, alkoxyalkylphenyl, benzofuranyl, cycloalkylindolyl, morpholinylphenyl, haloalkylcycloalkylaminophenyl, halocycloalkylalkylphenyl, halothiophenyl, alkylthiphenyl, haloalkylthiophenyl or oxetanylphenyl; and

[0061] R8is hydrogen, halogen or alkyl;

[0062] or a pharmaceutically acceptable salt thereof.

[0063] The invention further relates to:

[0064] A compound of formula (I) wherein A1is nitrogen and A2is CR8;

[0065] A compound of formula (I) wherein R1is hydrogen or halogen;

[0066] A compound of formula (I) wherein R1is hydrogen or fluorine;

[0067] A compound of formula (I) wherein R1is hydrogen;

[0068] A compound of formula (I) wherein R2is alkyl, halogen, hydroxyalkyl, alkoxy, dialkylamino, cycloalkyl, cycloalkoxy, haloalkoxy, haloalkyl, halocycloalkyl, haloalkoxyalkyl, (halo)(alkyl)azetidinyl, haloalkylpyrrolidinyl, haloazaspiro[3.3]heptan-2-yl, perdeuterioalkoxy or cyano;

[0069] A compound of formula (I) wherein R2is halogen, alkyl, haloalkyl, alkoxy or haloalkoxy; A compound of formula (I) wherein R2is chlorine, methyl, difluoromethyl, difluoroethyl, trifluoroethyl, methoxy or difluoromethoxy;

[0070] A compound of formula (I) wherein R3is hydrogen, halogen or alkoxy;

[0071] A compound according to any one of claims 1 to 8, wherein R3is hydrogen, fluorine or methoxy;

[0072] A compound of formula (I) wherein R4is hydrogen;

[0073] A compound of formula (I) wherein R5is hydrogen or fluorine;

[0074] A compound of formula (I) wherein R5is hydrogen;

[0075] A compound of formula (I) wherein R6is hydrogen, halogen or alkyl;

[0076] A compound of formula (I) wherein R6is hydrogen, fluoro, chloro or methyl;

[0077] A compound of formula (I) wherein R7is alkylphenyl, halothiophenyl, (halo)(alkyl)phenyl, dialkylaminophenyl, halocycloalkylphenyl, indolyl, alkylindolyl, alkenylphenyl, halocycloalkylaminophenyl, cycloalkylindolyl, haloalkoxyphenyl, morpholinylphenyl, haloalkylcycloalkylaminophenyl, halocycloalkylalkylphenyl, haloalkoxyalkylphenyl, (haloalkoxyalkyl)(alkyl)phenyl, haloalkylaminophenyl, haloalkylazetidinylphenyl, haloalkylcycloalkyloxyphenyl, halocycloalkylalkylaminophenyl, (N-haloalkyl)(N-alkyl)aminophenyl or haloalkoxycycloalkylaminophenyl;

[0078] A compound of formula (I) wherein R7is alkylphenyl, halothiophenyl, (halo)(alkyl)phenyl, dialkylaminophenyl, halocycloalkylphenyl, indolyl, alkylindolyl, alkenylphenyl, halocycloalkylaminophenyl, cycloalkylindolyl, haloalkoxyphenyl, morpholinylphenyl, haloalkylcycloalkylaminophenyl, halocycloalkylalkylphenyl, haloalkoxyalkylphenyl or (haloalkoxyalkyl)(alkyl)phenyl;

[0079] A compound of formula (I) wherein R7is chlorothiophenyl, chlorophenyl, cyclopropylphenyl, trifluoromethylthiophenyl, difluoromethylthiophenyl, ethylphenyl, methylphenyl, fluorophenyl, trifluoromethylphenyl, (chloro)(methyl)phenyl, isopropylphenyl, difluoroethylphenyl, fluoromethylphenyl, difluorophenyl, methylthiophenyl, difluoromethylphenyl, cyanophenyl, dimethylphenyl, difluoromethoxyphenyl, (fluoro)(methyl)phenyl, dimethylaminophenyl, fluorocyclopropylphenyl, cyclopropylphenyl, methoxyphenyl, isopropenylphenyl, methylindolyl, difluoroazetidinylphenyl, azetidinylphenyl, trifluoromethylcyclopropylphenyl, difluoropropylphenyl, methoxyethylphenyl, fluoropropylphenyl, fluorobutylphenyl, propinylphenyl, isopropenylphenyl, fluorocyclobutylaminophenyl, (difluoro)(isopropyl)phenyl, trifluoropropylphenyl, benzofuranyl, difluorocyclopropylphenyl, dimethoxyphenyl, cyclopropylindolyl, difluoroethoxyphenyl, trifluoroethoxyphenyl, morpholinylphenyl, indolyl, trifluoromethylcyclobutylaminophenyl, difluorocyclopropylmethylphenyl, difluorocyclobutylaminophenyl, phenylmehtylthiophenyl, difluoromethoxymethylphenyl, (methyl)(difluoromethoxymethyl)phenyl, oxetanylphenyl, difluoromethylcyclobutylaminophenyl, hydroxyethylazetidinylphenyl, (difhioromethylcyclobutylamino)(methyl)phenyl, (chloro)(difluoromethoxymethyl)phenyl, (fhioro)(difhioromethoxymethyl)phenyl, (fluorocyclopropyl)(methyl)phenyl, (fluorocyclobutylamino)(methyl)phenyl, (difhioromethoxymthyl)(difluoromethyl)phenyl, difluorospiro[3.3]heptanylaminophenyl, difluoroethylaminophenyl, trifluoromethylazetidinylphenyl, difluoroazaspiro[3.3]heptanylphenyl, difluoroazabicyclo [3.1.0]hexanylphenyl,

[0080] trifluoromethylbicyclo [1.1. l]pentanylaminophenyl, difluorospiro[2.3]hexanylaminophenyl, hydroxethylaminophenyl, difluoromethylcyclobutyloxyphenyl, (difhioromethylcyclobutylamino)(fluoro)phenyl, difluorocyclohexylaminophenyl, trifluoropropylaminophenyl, trifluoroethylaminophenyl, difluoromethylbicyclo [1.1. l]pentanylaminophenyl, difluorocyclobutylaminophenyl, trifluoroethylazetidinylphenyl, trifluoroethylcyclobutylaminophenyl, trifluoromethylcyclopropylaminophenyl, (N-trifluoroethyl)(N-methyl)aminophenyl, difluorocyclopropylaminophenyl, difluoromethoxycyclobutylaminophenyl, (trifluoromethylcyclobutylamino)(fluoro)phenyl, trifluoromethylcyclobutyloxyphenyl, trifluoromethylcyclopropyloxyphenyl or trifluoromethylcyclobutyloxyphenyl;

[0081] A compound of formula (I) wherein R7is chlorothiophenyl, chlorophenyl, cyclopropylphenyl, trifluoromethylthiophenyl, difluoromethylthiophenyl, ethylphenyl, methylphenyl, fluorophenyl, trifluoromethylphenyl, (chloro)(methyl)phenyl, isopropylphenyl, difluoroethylphenyl, fluoromethylphenyl, difluorophenyl, methylthiophenyl, difluoromethylphenyl, cyanophenyl, dimethylphenyl, difluoromethoxyphenyl, (fluoro)(methyl)phenyl, dimethylaminophenyl, fluorocyclopropylphenyl, cyclopropylphenyl, methoxyphenyl, isopropenylphenyl, methylindolyl, difluoroazetidinylphenyl, azetidinylphenyl, trifluoromethylcyclopropylphenyl, difluoropropylphenyl, methoxyethylphenyl, fluoropropylphenyl, fluorobutylphenyl, propinylphenyl, isopropenylphenyl, fluorocyclobutylaminophenyl, (difluoro)(isopropyl)phenyl, trifluoropropylphenyl, benzofuranyl, difluorocyclopropylphenyl, dimethoxyphenyl, cyclopropylindolyl, difluoroethoxyphenyl, trifluoroethoxyphenyl, morpholinylphenyl, indolyl, trifluoromethylcyclobutylaminophenyl, difluorocyclopropylmethylphenyl, difluorocyclobutylaminophenyl, phenylmehtylthiophenyl, difluoromethoxymethylphenyl, (methyl)(difluoromethoxymethyl)phenyl, oxetanylphenyl, difluoromethylcyclobutylaminophenyl, hydroxyethylazetidinylphenyl, (difhioromethylcyclobutylamino)(methyl)phenyl, (chloro)(difluoromethoxymethyl)phenyl, or (fluoro) (difluoromethoxymethyl)phenyl;

[0082] A compound of formula (I) wherein R7is methylphenyl, ethylphenyl, chlorothiophenyl, methylthiophenyl, (fluoro)(methyl)phenyl, dimethylaminophenyl, fluorocyclopropylphenyl, indolyl, N-methyl-indolyl, propenylphenyl, fluorocyclobutylaminophenyl, difluorocyclobutylaminophenyl, N-cyclopropyl-indolyl, difluoroethoxyphenyl, difluorocyclopropylphenyl, morpholinylphenyl, difluoromethoxymethylphenyl, trifluoromethylcyclobutylaminophenyl, difluorocyclopropylmethylphenyl, (difluoromethoxymethyl)(methyl)phenyl, difluoromethylcyclobutylaminophenyl, difluorospiro[3.3]heptanylaminophenyl, difluoroethylaminophenyl, trifluoromethylazetidinylphenyl, difluoromethylcyclobutyloxyphenyl, difluorocyclobutylmethylaminophenyl, (N-trifluoroethyl)(N-methyl)aminophenyl, difluoromethoxycyclobutylaminophenyl, trifluoromethylcyclopropyloxyphenyl or trifluoromethylcyclobutyloxyphenyl;

[0083] A compound of formula (I) wherein R7is methylphenyl, ethylphenyl, chlorothiophenyl, methylthiophenyl, (fluoro)(methyl)phenyl, dimethylaminophenyl, fluorocyclopropylphenyl, indolyl, N-methyl-indolyl, propenylphenyl, fluorocyclobutylaminophenyl, difluorocyclobutylaminophenyl, N-cyclopropyl-indolyl, difluoroethoxyphenyl, difluorocyclopropylphenyl, morpholinylphenyl, difluoromethoxymethylphenyl, trifluoromethylcyclobutylaminophenyl, difluorocyclopropylmethylphenyl, (difluoromethoxymethyl) (methyl)phenyl or difluoromethylcyclobutylaminophenyl; and

[0084] A compound of formula (I) wherein R8is hydrogen.

[0085] In the definition of R2, a particular example of perdeuterioalkoxy is d3-methoxy. In the definition of R7, it is particularly advantageous that at least one of the substituents of the phenyl group is in para position to the sulfur atom of the compound of Formula (I).

[0086] The invention relates in particular to a compound of formula (I) which is of formula (I-R)

[0087]

[0088] wherein A1and A2and R1to R7are as defined above;

[0089] or a pharmaceutically acceptable salt thereof.

[0090] The asymmetric carbon atom bearing the R3substituent is thus advantageously of the (R) absolute configuration.

[0091] The invention further relates to a compound selected from:

[0092] 5-chloro-N-[2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide;

[0093] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide;

[0094] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3-fluoro-benzenesulfonamide;

[0095] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-chloro-thiophene-2-sulfonamide;

[0096] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-cyclopropyl-benzenesulfonamide;

[0097] 5-chloro-N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide;

[0098] N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-(trifluoromethyl)thiophene-2-sulfonamide;

[0099] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-(difluoromethyl)thiophene-2-sulfonamide;

[0100] 5-chloro-N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide;

[0101] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-ethyl-benzenesulfonamide; N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide; N-(2-benzyl-8-chloro-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3-fluoro-benzenesulfonamide; N-(2-benzyl-5-fluoro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-chloro-thiophene-2-sulfonamide;

[0102] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(trifluoromethyl)benzenesulfonamide;

[0103] 2-chloro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0104] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0105] 2-chloro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0106] 5-(difluoromethyl)-N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin- 3 -yl] thiophene-2- sulfonamide;

[0107] 5-chloro-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide;

[0108] 4-isopropyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0109] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-(1,1-difluoroethyl)benzenesulfonamide;

[0110] 4-(fluoromethyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0111] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3,5-difluoro-benzenesulfonamide;

[0112] N-(2-benzyl-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-chloro-benzenesulfonamide;

[0113] 5-chloro-N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide; 5-chloro-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide;

[0114] N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2- sulfonamide;

[0115] N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0116] N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0117] N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0118] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-(difluoromethyl)benzenesulfonamide;

[0119] N-(2-benzyl-5-chloro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide;

[0120] N-(2-benzyl-5-fluoro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide;

[0121] 4-methyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0122] N-(2-benzyl-8-methyl-4-oxo-pyrido[4,3-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide; N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide;

[0123] N-(2-benzyl-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide;

[0124] 4-ethynyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0125] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-2,4-dimethyl-benzenesulfonamide;

[0126] N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide; N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0127] N-[8-methoxy-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0128] N-[2-[methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0129] 4-(difluoromethoxy)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0130] 3-fluoro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0131] 4-(dimethylamino)-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin- 3-yl]benzenesulfonamide;

[0132] N-[2-[fluoro(phenyl)methyl]-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0133] 4-(2,2-difluoroethyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0134] 4-(difluoromethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0135] 4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0136] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-methyl-benzenesulfonamide;

[0137] N-[5-fluoro-2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0138] N-[2-[(3-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0139] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-2-methyl-benzenesulfonamide; 4-(1-fluorocyclopropyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0140] N-(2-((2-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide;

[0141] 3-cyclopropyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0142] 3-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0143] N-(2-(methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide;

[0144] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-methoxy-benzenesulfonamide;

[0145] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methoxy-benzenesulfonamide;

[0146] 4-(1,1-difluoroethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0147] 4-isopropyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0148] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropenyl-benzenesulfonamide;

[0149] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-1-methyl-indole-5-sulfonamide;

[0150] 4-(3,3-difluoroazetidin-l-yl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0151] 4-(3,3-difluorocyclobutyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0152] 4-(difluoromethoxy)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; N-[8-(dimethylamino)-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0153] N-[2-[methoxy(phenyl)methyl]-6,8-dimethyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0154] 4-(azetidin-l-yl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0155] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[1-(trifluoromethyl)cyclopropyl]benzenesulfonamide;

[0156] N-[2-[methoxy-[4-(trifluoromethyl)phenyl]methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0157] N-[8-cyclopropyl-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0158] 4-(2,2-difluoro-1-methyl-ethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0159] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(1-methoxyethyl)benzenesulfonamide;

[0160] N-[2-[(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0161] (R)-4-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0162] 4-(2-fluoropropyl)-N-(2-(methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0163] N-[8-(difluoromethoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0164] 4-(1-fluoro-2-methyl-propyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0165] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-prop- 1-ynyl-benzenesulfonamide; 4-isopropenyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0166] N-[8-(difluoromethoxy)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0167] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0168] N-[8-(3-fluoro-3-methyl-azetidin-l-yl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0169] 4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0170] 4-(1-fluorocyclopropyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0171] N-[2-[(4-cyanophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-fluoro-benzenesulfonamide;

[0172] N-[6-chloro-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropyl-benzenesulfonamide;

[0173] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3,4-difluoro-benzenesulfonamide;

[0174] 4-(difluoromethyl)-N- [2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0175] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-(trifluoromethyl)benzenesulfonamide;

[0176] 4-methyl-N-[8-methyl-4-oxo-2-[(S)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide;

[0177] N-[2-[hydroxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0178] 4-(difluoromethoxy)-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-isopropyl-N-[8-methyl-4-oxo-2-[(S)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-y 1] benzenesulfonamide;

[0179] 3,5-difluoro-N- [2- [(4-fluorophenyl)-methoxy-methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-isopropyl-benzenesulfonamide;

[0180] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoro-1-methyl-ethyl)benzenesulfonamide;

[0181] N-[8-(difluoromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0182] N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzofuran-3-sulfonamide;

[0183] N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0184] 4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0185] 4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0186] (S)-4-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0187] 3,4-dimethoxy-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0188] 4-isopropenyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0189] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-[rel-(3R)-3-(trifluoromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0190] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-[rel-(3S)-3-(trifluoromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0191] 1-cyclopropyl-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]indole-5-sulfonamide; N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-y 1 ] benzofuran- 5 - sulfonamide;

[0192] N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0193] N- [2- [(4-fluorophenyl) -methoxy-methyl] - 8 - (hydroxymethyl) -4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0194] N-[8-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] -4-methyl-benzenesulfonamide;

[0195] 4-(1-fluorocyclopropyl)-N-[4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0196] 4-(2,2-difluoroethoxy)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0197] 4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0198] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethoxy)benzenesulfonamide;

[0199] 4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0200] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;

[0201] N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0202] 4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0203] N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-1H-indole- 6- sulfonamide;

[0204] 4-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;

[0205] 4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0206] 4-(2,2-difluorocyclopropyl)-N-(2-((R)-methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0207] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0208] N-(2-((4-fluorophenyl)(methoxy)methyl)-8-(methoxy-d3)-4-oxopyrido[3,4-d]pyrimidin- 3 (4H) -yl) -4-methylbenzenesulfonamide;

[0209] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[(1s,3s)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0210] 4-[(2,2-difluorocyclopropyl)methyl]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0211] N-(8-cyano-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide;

[0212] N-(8-ethoxy-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide;

[0213] N-[8-(cyclopropoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0214] (R)-N-(8-(2,2-difluoroethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;

[0215] N-(2-((4-fluorophenyl)(methoxy)methyl)-4-oxo-8-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;

[0216] (R)-4-(1-fluorocyclopropyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methoxy-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0217] (R)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide; (S)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;

[0218] (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;

[0219] (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-((difluoromethoxy)methyl)benzenesulfonamide;

[0220] N-[8-(difluoromethoxy)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;

[0221] (S)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido [3,4-d] pyrimidin- 3 (4H)-yl)benzene sulfonamide;

[0222] (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-5-(fluoromethyl)thiophene-2-sulfonamide;

[0223] (R)-4-(difluoromethoxy)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0224] (R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido [3,4-d] pyrimidin- 3 (4H)-yl)benzene sulfonamide;

[0225] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide;

[0226] 4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0227] 4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0228] N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(oxetan-2-yl)benzenesulfonamide;

[0229] 4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0230] 4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide; N-[8-(2,2-difluoroethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide;

[0231] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0232] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0233] 4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0234] N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3 -yl] - 5 - (fluoromethyl) thiophene-2- sulfonamide;

[0235] 4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0236] N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;

[0237] N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;

[0238] 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0239] N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-[( 1 S)- 1 -hydroxyethyl] azetidin- 1 -yl]benzenesulfonamide;

[0240] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide; and 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0241] 4-[[(ls,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0242] 1-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3 -yl] indole- 5 - sulfonamide;

[0243] 1-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3 -yl] indole- 5 - sulfonamide;

[0244] (R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl- 4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-3-methylbenzenesulfonamide;

[0245] (S)-3-chloro-4-((difluoromethoxy)methyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0246] (S)-4-((difluoromethoxy)methyl)-3-fluoro-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0247] (R)-3-chloro-4-((difluoromethoxy)methyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0248] (R)-4-((difluoromethoxy)methyl)-3-fluoro-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0249] N- [2- [difluoromethoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl] -4-methyl-benzenesulfonamide;

[0250] 4-(l-fluorocyclopropyl)-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0251] 4-[((1s,3s)-3-fluorocyclobutyl)amino]-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0252] 4-(l-fluorocyclopropyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0253] 4-[((1s,3s)-3-fluorocyclobutyl)amino]-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-(difluoromethoxymethyl)-3-(difluoromethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0254] (S)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-3-methylbenzenesulfonamide;

[0255] 4-[(2,2-difluorospiro[3.3]heptan-6-yl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0256] 4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0257] 4-(3,3-difluoroazetidin-1-yl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0258] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)azetidin-1-yl]benzenesulfonamide;

[0259] 4-[(2,2-difluorospiro[3.3]heptan-6-yl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0260] 4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0261] 4-(3,3-difluoroazetidin-1-yl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0262] N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)azetidin-1-yl]benzenesulfonamide;

[0263] 4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0264] 4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0265] 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0266] 4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-[8-methyl-4-oxo-2-[rel-(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-chlorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0267] 4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0268] 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0269] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]benzenesulfonamide;

[0270] 4-[(2,2-difluorospiro[2.3]hexan-5-yl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0271] 4-(2-hydroxyethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0272] N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]benzenesulfonamide;

[0273] 4-[(2,2-difluorospiro[2.3]hexan-5-yl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0274] 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-[4- (difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide;

[0275] 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0276] N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;

[0277] N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;

[0278] 4-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0279] 4-[(lr,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide; 4-(((lr,3R)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0280] 4-(((ls,3R)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((S)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0281] 4-(((ls,3S)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0282] 4-(((lr,3s)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((S)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0283] 4-[(4,4-difluorocyclohexyl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0284] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[(2,2,2-trifluoro-l-methyl-ethyl)amino]benzenesulfonamide;

[0285] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethylamino)benzenesulfonamide;

[0286] 4-[[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0287] 4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0288] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]benzenesulfonamide;

[0289] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(2,2,2-trifluoroethyl)cyclobutyl]amino]benzenesulfonamide;

[0290] 4-[(4,4-difluorocyclohexyl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0291] N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[(2,2,2-trifluoro-l-methyl-ethyl)amino]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(2,2,2-trifluoroethyl)cyclobutyl]amino]benzenesulfonamide;

[0292] N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethylamino)benzenesulfonamide;

[0293] 4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0294] 4-[[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0295] N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]benzenesulfonamide;

[0296] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[2-(trifluoromethyl)cyclopropyl]amino]benzenesulfonamide;

[0297] N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide;

[0298] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide;

[0299] 4-[(2,2-difluorocyclopropyl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0300] N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[2-(trifluoromethyl)cyclopropyl]amino]benzenesulfonamide;

[0301] 4-[[3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0302] 4-[[3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[rel-(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0303] 3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(((1r,3R)-3-(trifluoromethyl)cyclobutyl)amino)benzenesulfonamide;

[0304] N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin- 3(4H)-yl)-4-(((lr,3R)-3-(trifluoromethyl)cyclobutyl)amino)benzenesulfonamide; N-[8-(2,2-difluoroethyl)-2-[(R*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0305] N-[8-(difluoromethyl)-2-[(S*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0306] N-[8-(2,2-difluoroethyl)-2-[(S*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0307] N-[8-(difluoromethyl)-2-[(R*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0308] N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)cyclobutoxy]benzenesulfonamide;

[0309] N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1S,2S)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide;

[0310] N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3-yl]-4-[rel-(1R,2R)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide;

[0311] N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)cyclobutoxy]benzenesulfonamide;

[0312] N-[2-[(S*)-(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0313] N-[2-[(R*)-methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0314] N-[2-[(S*)-methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0315] N-[2-[(R*)-(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0316] N-[2-[(R*)-[4- (difluoromethyl)phenyl] -methoxy-methyl] - 8 -methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide; and N- [2- [(S *)- [4-(difluoromethyl)phenyl] -methoxy-methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0317] or a pharmaceutically acceptable salt thereof. The invention further relates to a compound selected from:

[0318] 5-chloro-N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide;

[0319] N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-ethyl-benzenesulfonamide; N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide; N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2- sulfonamide;

[0320] N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0321] N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0322] N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0323] 4-methyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0324] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0325] N-[8-methoxy-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0326] N-[2-[methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0327] 3-fhioro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0328] 4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0329] N-[5-fluoro-2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide; N-[2-[(3-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0330] 4-(1-fluorocyclopropyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0331] N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-1-methyl-indole-5-sulfonamide;

[0332] N-[2-[(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0333] N-[8-(difluoromethoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0334] 4-isopropenyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0335] N-[8-(difluoromethoxy)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0336] 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0337] 4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0338] 1-cyclopropyl-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]indole-5-sulfonamide;

[0339] N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;

[0340] 4-(2,2-difluoroethoxy)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0341] 4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0342] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide; 4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0343] N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-1H-indole- 6- sulfonamide;

[0344] 4-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0345] 4-(2,2-difluorocyclopropyl)-N-(2-((R)-methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;

[0346] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[(1s,3s)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;

[0347] 4-[(2,2-difluorocyclopropyl)methyl]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0348] (R)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;

[0349] (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-((difluoromethoxy)methyl)benzenesulfonamide;

[0350] N-[8-(difluoromethoxy)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;

[0351] (R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido [3,4-d] pyrimidin- 3 (4H)-yl)benzene sulfonamide;

[0352] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide;

[0353] 4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0354] 4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0355] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide; 4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0356] N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;

[0357] 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0358] 4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0359] 4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0360] 4-[(2,2-difluorospiro[3.3]heptan-6-yl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0361] 4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide;

[0362] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)azetidin-1-yl]benzenesulfonamide;

[0363] 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0364] 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-chlorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;

[0365] 4-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0366] 4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;

[0367] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide;

[0368] 4-[[3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1S,2S)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide;

[0369] N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1R,2R)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide; and

[0370] N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)cyclobutoxy]benzenesulfonamide;

[0371] or a pharmaceutically acceptable salt thereof.

[0372] The following abbreviations are use in the present description:

[0373] AcOH is acetic acid;

[0374] ACN / MeCN is acetonitrile;

[0375] EtOAc / EA is ethyl acetate;

[0376] DAST is diethylamino sulfur trifluoride;

[0377] DCM is dichloromethane;

[0378] DIPEA is N, N-diisopropylethylamine;

[0379] DMA is Dimethylacetamide;

[0380] DMF is N, N-dimethylformamide;

[0381] DMAP is dimethylaminopyridine;

[0382] DMSO is dimethyl sulfoxide;

[0383] FA is formic acid;

[0384] HATU is Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium;

[0385] 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;

[0386] LED is light emitting diode;

[0387] LiHMDS is lithium Bis(trimethylsilyl)amide; NMI is N-Methylimidazole;

[0388] PE is petroleum ether;

[0389] Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0);

[0390] Pd(dppf)Cl2 is 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride;

[0391] PYBROP is bromo tripyrrolidinophosphonium hexafluorophosphate;

[0392] o / n is overnight;

[0393] RT is room temperature;

[0394] SFC is supercritical fluid chromatography;

[0395] TCFH is tetramethylchloroformamidinium hexafluorophosphate;

[0396] THF is tetrahydrofuran;

[0397] CLint is intrinsic clearance;

[0398] CMV is cytomegalovirus;

[0399] FBS is fetal bovine serum;

[0400] HEPES is 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid;

[0401] NMDG is N-methyl-D-glucamine diatrizoate;

[0402] EGTA is ethylene glycol-bis(beta- aminoethyl ether)-N, N, N’, N’ -tetraacetic acid;

[0403] DPBS is Dulbecco’s phosphate-buffered saline;

[0404] mV is millivolt;

[0405] DCPIB is 4-[(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro- 1-oxo- lH-inden-5-yl)oxy]butanoic acid; and

[0406] 4-AP is 4- aminopyridine.

[0407] 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 an enantiomerically pure compound, however with longer synthesis.

[0408] For more information on the general procedures, please refer to the embodiments relating to the process of making the compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein.

[0409] o R7-S(=O)-Cl H2N-NHBoc pyridine, AcN, 40C o R7-S-NH 4 NHBoc

[0410] PCI3 80-100C

[0411]

[0412] Scheme 1: Synthesis of the compound of formula (I)

[0413] Amino(iso)nicotinic acid 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 ACN 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 to yield 2-amido-(iso)nicotinic acid intermediate 3 (scheme 1). Subsequent reaction with sulfonyl Boc-hydrazide 4 (or with the unprotected sulfonyl hydrazide) and phosphorus trichloride in Me-THF, 1,4-dioxane or 2,2-dimethyloxolane at 80 to 100°C affords desired cyclized sulfonamide of Formula I. NH2NH2. H2O EtOH, 80C

[0414] o R7-S-CI 4 O LiHMDS THF, -78C

[0415]

[0416] Scheme 2: Synthesis of the compound of formula (I)

[0417] Treatment of methyl amino(iso)nicotinate 5 with either an acid using TCFH, NMI in DMA or HATU, DIPEA in DMF, DCM or DMSO, or with an acyl chloride using a suitable base (DIPEA, NEta) in DCM or DMF affords amide intermediate 6 (scheme 2), which can then be cyclized by reaction with hydrazine in EtOH at 80°C to form the 3-aminopyrido[3,4-d]pyrimidin-4(3H)-one intermediate 7. Subsequent reaction with sulfonyl chlorides in the presence of LiHMDS in THF at -78°C affords the desired sulfonamide of formula I.

[0418] NH2NH2H2O EtOH, 80C COOH

[0419] O R7-S(=O)-Cl 4 O LiHMDS THF, -78C

[0420]

[0421] Scheme 3: Synthesis of the compound of formula (I) Amino(iso)nicotinic acid 1 can be reacted with phenyl acetic acid using HATU and a suitable base (e.g. DIPEA, NEta) in DCM, DMF or DMSO, or using TCFH, NMI in DMA, or using the corresponding acyl chloride in presence of a suitable base (e.g. DIPEA, NEta) in DCM to yield the amide 3 or in some cases cyclized intermediate 8 directly (scheme 3). Amide intermediate 3 can be converted to cyclized intermediate 8 by treatment with acetic anhydride at 120°C, which can then be reacted with hydrazine in EtOH at 80°C to form 3-aminopyrido[3,4-d]pyrimidin-4(3H)-one 7. Final coupling with sulfonyl chloride in the presence of LiHMDS in THF at -78 °C leads to the desired sulfonamide of formula I.

[0422] Pd2(dba)3, xantphos

[0423] DIPEA BnSH

[0424] RrToluene, 100C R7'

[0425]

[0426] 9 10

[0427] NCS, AcOH

[0428] H2O, rt

[0429] i) nBuLi, THF, -78C

[0430]

[0431] R7O-Cl

[0432] ii) SO2CI2

[0433] 11

[0434] Scheme 4: Synthesis of sulfonyl chloride

[0435] Sulfonyl chlorides can be prepared by cross -coupling reaction between (hetero)aryl bromide 9 and benzyl mercaptan to yield thioether intermediates 10 (scheme 4). 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 11. Alternatively, aryl bromide 9 can be reacted with n-BuLi in THF at -78 °C followed by addition of SO2CI2 to yield the desired sulfonyl chlorides 11.

[0436] Buchwald-Hartwig amination

[0437]

[0438] Scheme 5: Late stage functionalization of iodobenzene sulfonamide NR’R” in scheme 5 can be 3,3-difluoroazetidine, azetidine, 3-fluorocyclobutan-l-amine, morpholine, 3-trifluoromethylcyclobutan-l -amine, 3,3-difluorocyclobutan-l-amine, 3 -(difluoromethyl)cyclobutan- 1 - amine.

[0439] Late stage functionalization of iodobenzene sulfonamide 12 can be performed via Buchwald-Hartwig amination (scheme 5) by reaction of an iodo-aryl intermediate with an amine (or its corresponding HC1 salt) in the presence of a Pd catalyst (such as Pd2(dba)3 and a phosphine ligand (such as XPhos) in 1,4-dioxane at 100°C.

[0440] Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography, supercritical fluid chromatography or a combination of these procedures. However, other equivalent separation or isolation procedures could, of course, also be used. Mixtures of chiral compounds of formula (I) or intermediates can be separated using preparative chiral HPLC or SFC purifications. Chiral chromatography purifications were performed using the following conditions:

[0441] A Column: CHIRALPAK IA, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)— HPLC, Mobile Phase B: EtOH; Flow rate: 20 mL / min; Gradient: isocratic 20% B Column: CHIRALPAK IG, 3*25 cm, 5 pm; Mobile Phase A: Hex(10mM NH3- MeOH), Mobile Phase B: EtOH— HPLC; Flow rate: 40 mL / min; Gradient: isocratic 30%

[0442] C Column: NB_CHIRALPAK AD-H, 3*25 cm, 5 pm; Mobile Phase A: Hex(10mM NHa-MeOH), Mobile Phase B: IPA; Flow rate: 35 mL / min; Gradient: isocratic 50%

[0443] D CHIRAL ART Cellulose-SZ, 3*25 cm, 5 pm; Mobile Phase A: Hex (0.1% FA)— HPLC, Mobile Phase B: ETOH; Flow rate: 40 mL / min; Gradient: isocratic 10% E 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 10% F Column: CHIRALPAK IA, 3*25 cm, 5 pm; Mobile Phase A: Hex(0.1% FA)- HPLC, Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30% G Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: MtBE:

[0444] Hex=l: l(0.1%FA), Mobile Phase B: ETOH; Flow rate: 40 mL / min; Gradient: isocratic 5%

[0445]

[0446] H CHIRALPAK IH 3*25 cm, 5 μm; Mobile Phase A: CO₂, Mobile Phase B: IPA; Flow rate: 100 mL / min; Gradient: isocratic 30% B; Column Temperature (°C): 25; Back Pressure(bar): 100

[0447] I Column: NNN-CHIRALCEL OD, 5cm*25cm; Mobile Phase A: CO₂, Mobile Phase B: IPA; Flow rate: 200 mL / min; Gradient: isocratic 40% B; Column Temperature (°C): 35; Back Pressure(bar): 100

[0448] J Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 μm; Mobile Phase A:

[0449] Hex(0.1% FA)— HPLC, Mobile Phase B: EtOH; Flow rate: 40 mL / min; Gradient (B%): isocratic 10%

[0450] K Column: NB_CHIRALPAK AD-H, 3*25 cm, 5 μm; Mobile Phase A: CO₂, Mobile Phase B: IPA(20 mM NH₃); Flow rate: 100 mL / min; Gradient (B%): isocratic 30% B; Column Temperature(°C): 35; Back Pressure(bar): 100

[0451] L Column: CHIRALPAK IC-3, 3*50 cm, 4.6μm; Mobile Phase A:(MtBE:Hex=1:1)(0.1%TFA), Mobile Phase B: ETOH; Flow rate: 1.67mL / min; Gradient: isocratic 10%

[0452] M Column: CHIRALPAK-IK, 3*25mm, 5μm; Mobile Phase A: Hex (0.1% FA)- HPLC, Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30% N Column: CHIRAL ART Amylose-C NEO, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.1% FA)-HPLC, Mobile Phase B: IPA; Flow rate: 40 mL / min; Gradient: isocratic 30%

[0453] O Column: (S, S)-WHELK-O1-Kromasil 2.12*25 cm, 5 μm; Mobile Phase A:

[0454] HEX(0.1% DEA)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 30%

[0455] P Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 μm; Mobile Phase A:

[0456] Hex(0.1% DEA)— HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 40 mL / min; Gradient (B%): isocratic 30%

[0457]

[0458] The invention thus further relates to a process for the preparation of a compound of formula (I) comprising one of the following steps:

[0459] (a) The reaction of a compound of formula (A)

[0460]

[0461] in the presence of R7SO2Cl and a base; or

[0462] (b) The reaction of a compound of formula (B)

[0463]

[0464] in the presence of R7SO2NH-NHRpand PCl3.

[0465] wherein R1to R7are as defined above and wherein Rp is hydrogen or an amine protecting group.

[0466] In step (a), the base is advantageously a non-nucleophilic base, in particular a lithiated organosilicon base, more particularly LiHMDS.

[0467] Step (a) can advantageously be carried out in THF, for example at around -78°C.

[0468] Step (b) can advantageously be carried out in Me-THF, THF, 1,4-dioxane or 2,2-dimethyloxolane.

[0469] Step (b) can be carried out at a temperature comprised between around 80°C and 100°C.

[0470] In step (b), the amine protecting group can be for example a Boc goup.

[0471] The invention further relates to:

[0472] A compound of formula (I), when manufactured according to a process of the invention;

[0473] A compound of formula (I) for use as therapeutically active substance; A pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier;

[0474] 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;

[0475] 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;

[0476] 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

[0477] 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.

[0478] 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.

[0479] 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.

[0480] 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.

[0481] 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.

[0482] 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).

[0483] The invention will now be illustrated by the following examples which have no limiting character. Examples

[0484] Example 1: 5-chloro-N-[2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0485] o=s=o o

[0486]

[0487] a) 3-[2-(2,3-dihydro- 1,4-benzodioxin-6-yl)acetamido]-2-methylpyridine-4-carboxylic acid

[0488] To a stirred solution of 3-amino-2-methylpyridine-4-carboxylic acid (400.0 mg, 2.629 mmol, 1 equiv) and 2,3-dihydro-l,4-benzodioxin-6-ylacetic acid (765.7 mg, 3.944 mmol, 1.5 equiv) in DCM (5 mL) were added DIPEA (1.70 g, 13.145 mmol, 5 equiv) and HATU (1.50 g, 3.944 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 (10mmol / L NH₄HCO₃), 10% to 50% gradient in 10 min; detector, UV 254 nm.) to afford 3-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamido]-2-methylpyridine-4-carboxylic acid (410.0 mg, 47.50% yield) as a light yellow solid. LCMS (ESI) [M + H]+: 329

[0489] b) 5-chloro-N-[2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin- 3 -yl] thiophene-2- sulfonamide

[0490] To a stirred solution of 3-[2-(2,3-dihydro-l,4-benzodioxin-6-yl)acetamido]-2-methylpyridine-4-carboxylic acid (400.0 mg, 1.218 mmol, 1 equiv) and A'-(5-chlorothiophen-2-ylsulfonyl)tert-butoxycarbohydrazide (762.1 mg, 2.436 mmol, 2 equiv) in 2-Methyltetrahydrofuran (5 mL) was added trichloropho sphane (501.9 mg, 3.654 mmol, 3 equiv) dropwise at room temperature. The resulting mixture was stirred for 1 h at 100 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (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 20 min; detector, UV 254 nm.) to afford 5-chloro-N-[2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide (178.0 mg, 28.54% yield) as a white solid. LCMS (ESI) [M + H]+: 504.95. ’H NMR (400 MHz, DMS0-< / 6) 8 12.10 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.64 (d, J = 5.2 Hz, 1H), 7.54 (d, J= 4.1 Hz, 1H), 7.25 (d, J = 4.1 Hz, 1H), 6.84 - 6.78 (m, 2H), 6.78 - 6.72 (m, 1H), 4.21 (s, 6H), 2.73 (s, 3H).

[0491] Example 2: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide

[0492]

[0493] a) methyl 2-methyl-3-[(2-oxo-3-phenylpropyl)amino]pyridine-4-carboxylate

[0494] A solution of methyl 3-amino-2-methylpyridine-4-carboxylate (1.5 g, 9.026 mmol, 1 equiv) in DMF (7 mL, 0.030 mmol) was treated with EtaN (2740.2 mg, 27.078 mmol, 3 equiv) and DMAP (551.3 mg, 4.513 mmol, 0.5 equiv) for 1 min at 25 °C under nitrogen atmosphere followed by the addition of phenylacetyl chloride (2093.0 mg, 13.539 mmol, 1.5 equiv) at 0 °C. The resulting mixture was stirred for additional overnight at room temperature. The reaction was quenched with H2O at 0 °C. 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 (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 2-methyl-3-[(2-oxo-3-phenylpropyl)amino]pyridine-4-carboxylate (250 mg, 9.28% yield) as a green oil. LC-MS (ES, m / z): [M+l] = 285.12.

[0495] b) 3-amino-2-benzyl-8-methylpyrido[3,4-d]pyrimidin-4-one

[0496] A solution of methyl 2-methyl-3-[(2-oxo-3-phenylpropyl)amino]pyridine-4-carboxylate (300 mg, 1.006 mmol, 1 equiv) in EtOH (2 mL) and hydrazine hydrate (2 mL) was stirred for at 2 h under nitrogen atmosphere. 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 (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in 3-amino-2-benzyl-8-methylpyrido[3,4-t / ]pyrimidin-4-one (200 mg, 74.69% yield) as a white solid. LC-MS (ES, m / z): [M+l] = 267.12 c) N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide

[0497] To a stirred mixture of 3-amino-2-benzyl-8-methylpyrido[3,4-7]pyrimidin-4-one (100 mg, 0.376 mmol, 1 equiv) and 2-chlorobenzenesulfonyl chloride (118.8 mg, 0.564 mmol, 1.5 equiv) in THF (2 mL) was added LiHMDS (125.6 mg, 0.752 mmol, 2 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for additional 2 h at -78 °C. The reaction was quenched with H2O at 0 °C. 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 (10 mmol / L NH4HCO3), 40% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide (51.1 mg, 30.49% yield) as a white solid. LC-MS (ES, m / z):

[0498] [M+l] = 441.10. ’H NMR (400 MHz, Methanol-^) 68.26 (d, J= 5.4 Hz, 1H), 7.90 (dd, J = 7.9, 1.7 Hz, 1H), 7.64 (dd, 7= 5.4, 0.7 Hz, 1H), 7.51 (dd, 7 = 7.9, 1.3 Hz, 1H), 7.47 -7.39 (m, 1H), 7.36 - 7.27 (m, 4H), 7.27 - 7.15 (m, 2H), 4.39 (s, 2H), 2.63 (s, 3H).

[0499] Example 3: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3-fluoro-benzenesulfonamide

[0500]

[0501] The title compound was obtained in analogy to Example 2 as a white solid (19% yield) using 3-amino-2-benzyl-8-methylpyrido[3,4-d]pyrimidin-4-one and 3-fluorobenzenesulfonyl chloride. LC-MS (ES, m / z): [M+l] = 425.10. ’H NMR (400 MHz, Methanol-^) 88.28 (d, 7= 5.4 Hz, 1H), 7.62 (d, 7= 5.4 Hz, 1H), 7.56 (dd, 7= 17.6, 8.4 Hz, 2H), 7.48 - 7.38 (m, 1H), 7.38 - 7.16 (m, 6H), 4.44 (s, 2H), 2.68 (s, 3H).

[0502] Example 4: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-chloro-thiophene-2-sulfonamide

[0503]

[0504] The title compound was obtained in analogy to Example 2 as a white solid (19% yield) using 3-amino-2-benzyl-8-methylpyrido[3,4-d]pyrimidin-4-one and 5-chlorothiophene-2-sulfonyl chloride. LC-MS (ES, m / z): [M+l] = 447.03. 1H NMR (400 MHz, Methanol-d4) 5 8.33 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 5.4 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.31 - 7.24 (m, 3H), 7.24 - 7.16 (m, 1H), 6.93 (d, J = 4.0 Hz, 1H), 4.42 (s, 2H), 2.70 (s, 3H).

[0505] Example 5: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-cyclopropyl-benzenesulfonamide

[0506]

[0507] a) N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-bromobenzenesulfonamide

[0508] The title compound was obtained in analogy to Example 2 as a white solid (34.3% yield) using 3-amino-2-benzyl-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-bromobenzenesulfonyl chloride. LC-MS (ES, m / z): [M+l] = 485.02.

[0509] b) N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-cyclopropyl-benzenesulfonamide

[0510] To a stirred solution of N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-bromobenzenesulfonamide (100 mg, 0.206 mmol, 1 equiv) in anhydrous dioxane (2 mL) was added cyclopropylboronic acid (26.5 mg, 0.309 mmol, 1.5 equiv), Pd(dppf)Ch (30.1 mg, 0.041 mmol, 0.2 equiv) and K2CO3 (85.4 mg, 0.618 mmol, 3 equiv). The reaction mixture was stirred at 100 °C for a period of 2 h. 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 (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-cyclopropyl-benzenesulfonamide (31.2 mg, 33.34% yield) as a white solid. LC-MS (ES, m / z): [M+l] = 447.15. ’H NMR (300 MHz, Methanol-^) 88.30 (d, J= 5.4 Hz, 1H), 7.69 - 7.59 (m, 3H), 7.27 (d, J= 4.3 Hz, 4H), 7.21 - 7.09 (m, 3H), 4.31 (s, 2H), 2.68 (s, 3H), 2.06 - 1.90 (m, 1H), 1.11 - 0.99 (m, 2H), 0.82 - 0.70 (m, 2H).

[0511] Example 6: 5-chloro-N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0512] A

[0513]

[0514] The title compound was obtained in analogy to Example 1 as a white solid (16.3% yield) using 3-[2-(4-fluorophenyl)acetamido]-2-methylpyridine-4-carboxylic acid and 7V-(5-chlorothiophen-2-ylsulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 464.95. ’H NMR (300 MHz, DMSO-6) δ 12.12 (s, 1H), 8.50 (d, J= 5.3 Hz, 1H), 7.67 - 7.63 (m, 1H), 7.55 (d, J= 4.1 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.26 (d, J= 4.1 Hz, 1H), 7.22 - 7.13 (m, 2H), 4.35 (s, 2H), 2.66 (s, 3H).

[0515] Example 7: N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-(trifluoromethyl)thiophene-2-sulfonamide

[0516]

[0517] The title compound was obtained in analogy to Example 2 as a white solid (8.9% yield) using 3-amino-2-[(4-fluorophenyl)methyl]-8-methylpyrido[3,4-7]pyrimidin-4-one and 5- (trifluoromethyl)thiophene-2-sulfonyl chloride. LCMS (ESI) [M + H]+: 499.25.!H NMR (400 MHz, DMSO-6) δ 8.49 (d, J= 5.2 Hz, 1H), 7.82 (dd, J= 4.0, 1.2 Hz, 1H), 7.76 (dt, J = 4.0, 1.4 Hz, 1H), 7.60 (d, J = 5.3 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.23 - 7.13 (m, 2H), 4.34 (s, 2H), 2.66 (s, 3H).

[0518] Example 8: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-(difluoromethyl)thiophene-2-sulfonamide

[0519]

[0520] F

[0521] The title compound was obtained in analogy to Example 1 as a white solid (44.2% yield) using 2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N′-[5-(difluoromethyl)thiophen-2-ylsulfonyl]tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 462.95. ‘H NMR (400 MHz, DMSO-6) δ 12.22 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.81 -7.45 (m, 3H), 7.41 - 7.24 (m, 6H), 4.34 (m, 2H), 2.68 (s, 3H).

[0522] Example 9: 5-chloro-N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0523]

[0524] The title compound was obtained in analogy to Example 1 as a white solid (13.5% yield) using 2-chloro-3-(2-(4-fluorophenyl) acetamido) isonicotinic acid and tert-butyl 2-((5-chlorothiophen-2-yl) sulfonyl) hydrazine- 1 -carboxylate. LC-MS: (ES, m / z): [M+l] = 485.00. ‘H NMR (400 MHz, DMSO-6) δ 12.19 (s, 1H), 8.42 (d, J= 5.1 Hz, 1H), 7.82 (d, J= 5.1 Hz, 1H), 7.56 (d, J= 4.1 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.24 (d, J= 4.1 Hz, 1H), 7.21 - 7.12 (m, 2H), 4.35 (s, 2H). Example 10: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-ethyl-benzenesulfonamide

[0525] 0-S-0 0

[0526]

[0527] The title compound was obtained in analogy to Example 1 as a white solid (8.1% yield) using 2-methyl-3-(2-phenylacetamido)isonicotinic acid and tert-butyl 2-((4-ethylphenyl)sulfonyl)hydrazine-1-carboxylate. LC-MS: (ES, m / z): [M+l] =435. H NMR (400 MHz, Methanol-^) 68.37 (d, J= 5.3 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.53 (d, J= 5.4 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.32 - 7.23 (m, 4H), 7.26 - 7.19 (m, 1H), 4.37 (s, 2H), 2.79 -2.68 (m, 5H), 1.26 (q, 7= 7.3 Hz, 3H).

[0528] Example 11: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide

[0529] o=s=o o

[0530]

[0531] The title compound was obtained in analogy to Example 1 as a white solid (17.9% yield) using 2-methyl-3-(2-phenylacetamido)isonicotinic acid and tert- butyl 2-tosylhydrazine-l-carboxylate. LC-MS: (ES, m / z): [M+l] =421. ’H NMR (400 MHz, Methanol-^) 88.37 (d, J= 5.3 Hz, 1H), 7.67 (d, J= 8.3 Hz, 2H), 7.55 (d, J= 5.3 Hz, 1H), 7.35 -7.19 (m, 7H), 4.71 - 4.11 (m, 2H), 2.77 (s, 3H), 2.43 (s, 3H).

[0532] Example 12: N-(2-benzyl-8-chloro-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3-fluoro-benzenesulfonamide

[0533]

[0534] The title compound was obtained in analogy to Example 1 as a white solid (12.2% yield) using 2-chloro-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'-(3-fluorobenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 444.95.1H NMR (400 MHz, DMSO-d6) 6 11.96 (s, 1H), 8.39 (d, 7= 5.1 Hz, 1H), 7.73 (d, 7= 5.1 Hz, 1H), 7.69 - 7.54 (m, 4H), 7.39 - 7.28 (m, 4H), 7.31 - 7.23 (m, 1H), 4.31 (s, 2H).

[0535] Example 13: N-(2-benzyl-5-fluoro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-chloro-thiophene-2-sulfonamide

[0536]

[0537] The title compound was obtained in analogy to Example 1 as a white solid (48.4% yield) using 5-fluoro-2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'-(5-chlorothiophen-2-ylsulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 465.00. ’H NMR (400 MHz, DMSO-d6) 612.20 - 12.00 (s, 1H), 8.44 (d, J= 1.8 Hz, 1H), 7.52 (d, J = 4.1 Hz, 1H), 7.44 - 7.08 (m, 6H), 4.32 (s, 2H), 2.59 (d, J= 1.5 Hz, 3H).

[0538] Example 14: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(trifluoromethyl)benzenesulfonamide

[0539]

[0540] The title compound was obtained in analogy to Example 1 as a white solid (42.0% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and tertbutyl 2-((4-(trifluoromethyl)phenyl)sulfonyl)hydrazine-l-carboxylate. MS (ESIpos): m / z = 505.00 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d₃) 59.16 - 8.82 (m, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.00 - 7.95 (m, 2H), 7.86 - 7.80 (m, 2H), 7.49 - 7.41 (m, 3H), 7.40 - 7.32 (m, 3H), 5.91 (s, 1H), 3.49 (s, 3H), 2.78 (s, 3H).

[0541] Example 15: 2-chloro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0542]

[0543] The title compound was obtained in analogy to Example 1 as a white solid (50.2% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(2-chloro-4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 485.00. ’H NMR (400 MHz, Acetonitrile-d₃) 58.91 (s, 1H), 8.47 (d, J= 5.3 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J= 5.2 Hz, 1H), 7.51 (d, J= 1.4 Hz, 1H), 7.45 (dd, J= 7.4, 2.2 Hz, 2H), 7.36 (s, 3H), 7.22 (d, J= 8.4 Hz, 1H), 5.79 (s, 1H), 3.40 (s, 3H), 2.57 (s, 3H), 2.42 (s, 3H).

[0544] Example 16: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0545]

[0546] The title compound was obtained in analogy to Example 1 as a white solid (34.6% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N 'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z = 451.00 [M+H]+.

[0547] 1H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J = 5.2 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.48 (d, J = 5.2 Hz, 1H), 7.44 (dd, J = 7.5, 2.2 Hz, 2H), 7.40 - 7.32 (m, 5H), 5.85 (s, 1H), 3.44 (s, 3H), 2.78 (s, 3H), 2.43 (s, 3H).

[0548] Example 17: 2-chloro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0549]

[0550] The title compound was obtained in analogy to Example 1 as a white solid (61.0% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and A'-(2-chlorobenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z = 471.00 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d₃) 58.41 (d, J= 5.3 Hz, 1H), 7.85 (dd, J= 7.9, 1.6 Hz, 1H), 7.61 (dd, J = 8.0, 1.5 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.53 (d, J= 5.3 Hz, 1H), 7.48 (dd, J = 7.7, 1.9 Hz, 2H), 7.39 - 7.30 (m, 4H), 5.91 (s, 1H), 3.37 (s, 3H), 2.77 (s, 3H).

[0551] Example 18: 5-(difluoromethyl)-N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0552]

[0553] The title compound was obtained in analogy to Example 1 as a white solid (27.0% yield) using 3-[2-(4-fluorophenyl)acetamido]-2-methylpyridine-4-carboxylic acid and N'-[5-(difluoromethyl)thiophen-2-ylsulfonyl]tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 481.00. ‘H NMR (400 MHz, DMSO-d6) 6 12.22- 11.12 (m, 1H),8.49 (d, J = 5.3 Hz, 1H), 7.66 (dd, J= 3.8, 1.8 Hz, 1H), 7.59 (d, J= 5.2 Hz, 1H), 7.52 (dt, J= 3.8, 1.7 Hz, 1H), 7.41 - 7.29 (m, 3H), 7.22 - 7.12 (m, 2H), 4.32 (s, 2H), 2.66 (s, 3H).

[0554] Example 19: 5-chloro-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0555]

[0556] The title compound was obtained in analogy to Example 1 as a white solid (18.3% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and A7-(5-chlorothiophen-2-ylsulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 495.05. ’H NMR (400 MHz, DMSO-d6) 88.52 (d, J= 5.2 Hz, 1H), 7.65 (d, J= 5.2 Hz, 1H), 7.50 (q, J= 5.7 Hz, 3H), 7.22 (t, J= 5.4 Hz, 3H), 5.92 (s, 1H), 3.41 (s, 3H), 2.75 (s, 3H).

[0557] Example 20: 4-isopropyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide o=s=o o

[0558]

[0559] The title compound was obtained in analogy to Example 1 as a white solid (37.1% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(4-isopropylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 479.10.1H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J = 5.2 Hz, 1H), 7.72 – 7.68 (m, 2H), 7.46 (d, J = 5.2 Hz, 1H), 7.44 – 7.33 (m, 7H), 5.81 (s, 1H), 3.43 (s, 3H), 3.02 (p, J = 6.9 Hz, 1H), 2.78 (s, 3H), 1.25 (d, J = 6.9 Hz, 6H).

[0560] Example 21: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-(l,l-difluoroethyl)benzenesulfonamide

[0561] O=S=O o

[0562]

[0563] The title compound was obtained in analogy to Example 1 as a white solid (15.1% yield) using 2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and A'-[4-( 1, 1 -difluoroethyl)benzenesulfonyl]tert-butoxycarbohydrazide. LC-MS: (ES, m / z): [M+l] = 471.12. ’H NMR (400 MHz, DMSO-*) 5 11.87 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 5.2 Hz, 1H), 7.39 - 7.23 (m, 5H), 4.49 (d, J= 15.5 Hz, 1H), 4.18 (d, J= 15.5 Hz, 1H), 2.68 (s, 3H), 2.09 - 1.89 (m, 3H).

[0564] Example 22: 4-(fluoromethyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0565]

[0566] The title compound was obtained in analogy to Example 1 as a white solid (36.8% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-[4-(fluoromethyl)benzenesulfonyl]tert-butoxycarbohydrazide.

[0567] LC-MS(ES, m / z): LCMS (ESI) [M + H]+: 469.10. ’H NMR (400 MHz, Acetonitrile-d₃) 6 8.46 (d, J= 5.2 Hz, 1H), 7.86 - 7.79 (m, 2H), 7.53 (dd, J= 8.4, 1.5 Hz, 2H), 7.49 - 7.42 (m, 3H), 7.40 - 7.33 (m, 3H), 5.88 (s, 1H), 5.57 (s, 1H), 5.45 (s, 1H), 3.46 (s, 3H), 2.78 (s, 3H).

[0568] Example 23: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3,5-difluoro-benzenesulfonamide

[0569]

[0570] The title compound was obtained in analogy to Example 1 as a white solid (17.3% yield) using 2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'-(3,5-difluorobenzenesulfonyl)tert-butoxycarbohydrazide. LC-MS (ES, m / z): [M+l] = 442.09.

[0571] 1H NMR (400 MHz, DMSO-*) 5 12.05 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.79 - 7.66 (m, 1H), 7.62 - 7.50 (m, 3H), 7.40 - 7.23 (m, 5H), 4.37 (s, 2H), 2.68 (s, 3H).

[0572] Example 24: N-(2-benzyl-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-chloro-benzenesulfonamide

[0573]

[0574] The title compound was obtained in analogy to Example 1 as a white solid (11.8% yield) using 2-methoxy-3-(2-phenylacetamido)pyridine-4-carboxylic acid and A'-(4-chlorobenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z =457.00 [M+H]+.1H NMR (400 MHz, Acetonitrile-d₃) 68.08 (d, J = 5.4 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.54 -7.48 (m, 2H), 7.35 - 7.23 (m, 5H), 7.19 (d, J= 5.4 Hz, 1H), 4.36 (s, 2H), 4.02 (s, 3H).

[0575] Example 25: 5-chloro-N-[8-chloro-2- [(4-fluorophenyl)-methoxy-methyl] -4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0576]

[0577] The title compound was obtained in analogy to Example 1 as a white solid (19.0% yield) using 2-chloro-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and A'-(5-chlorothiophen-2-ylsulfonyl) tert-butoxycarbohydrazide. LC-MS(ES, m / z): LCMS (ESI) [M + H]+: 514.90. ’H NMR (400 MHz, DMSO-*) 5 12.31 (s, 1H),8.45 (d, J= 5.2 Hz, 1H), 7.83 (d, J= 5.2 Hz, 1H), 7.52 (d, J= 16.8 Hz, 3H), 7.22 (q, J= 8.8, 6.7 Hz, 3H), 5.92 (s, 1H), 3.38 - 3.26 (m, 3H).

[0578] Example 26: 5-chloro-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide

[0579]

[0580] The title compound was obtained in analogy to Example 1 as a white solid (47.6% yield) using methyl 3-(2-fluoro-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(5-chlorothiophen-2-ylsulfonyl)tert-butoxycarbohydrazide. LC-MS: (ES, m / z): [M+l] = 464.02.1H NMR (400 MHz, DMSO-*) 5 12.12 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.54 (dd, J = 6.6, 3.1 Hz, 3H), 7.52 - 7.43 (m, 3H), 7.24 (d, J = 4.2 Hz, 1H), 6.94 (d, J= 46.0 Hz, 1H), 2.87 - 2.74 (m, 3H).

[0581] Example 27: N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide

[0582]

[0583] The title compound was obtained in analogy to Example 1 as a white solid (34.9% yield) using 2-chloro-3-[2-(4-fluorophenyl)acetamido]pyridine-4-carboxylic acid and N' -(5-methylthiophen-2-ylsulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z =465.00 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d₃) 68.34 (d, J= 5.2 Hz, 1H), 7.69 (d, J= 5.1 Hz, 1H), 7.37 - 7.30 (m, 3H), 7.11 - 7.02 (m, 2H), 6.80 - 6.75 (m, 1H), 4.34 (s, 2H), 2.51 (s, 3H).

[0584] Example 28: N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] -4-methyl-benzenesulfonamide

[0585]

[0586] The title compound was obtained in analogy to Example 1 as a white solid (36.3% yield) using 3-(2-fluoro-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N 'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LC-MS: (ES, m / z): [M+l] = 438.12.

[0587] 1H NMR (300 MHz, DMSO-d6) 8 12.50 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 7.72 - 7.62 (m, 2H), 7.58 (d, J= 5.2 Hz, 1H), 7.53 - 7.40 (m, 5H), 7.36 (d, J= 8.1 Hz, 2H), 6.89 (d, J = 46.2 Hz, 1H), 2.79 (s, 3H), 2.40 (s, 3H).

[0588] Example 29: N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0589]

[0590] The title compound was obtained in analogy to Example 1 as a white solid (7.5% yield) using 2-chloro-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+:489.10. ’H NMR (400 MHz, DMSO-d6) 6 11.59 (s, 1H), 8.42 (d, J= 5.2 Hz, 1H), 7.75 (d, J= 5.1 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.47 (s, 2H), 7.35 (d, 7= 7.9 Hz, 2H), 7.21 (t, J = 8.9 Hz, 2H), 5.91 (s, 1H), 3.37 (s, 3H), 2.40 (s, 3H).

[0591] Example 30: N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide F

[0592]

[0593] The title compound was obtained in analogy to Example 1 as a white solid (18.8% yield) using 3-[2-(4-fluorophenyl)acetamido]-2-methylpyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 439.05.!H NMR (400 MHz, DMSO-d6) 6 11.59 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.55 (d, J = 5.2 Hz, 1H), 7.41 -7.27 (m, 4H), 7.22 - 7.11 (m, 2H), 4.29 (s, 2H), 2.65 (s, 3H), 2.40 (s, 3H).

[0594] Example 31: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-(difluoromethyl)benzenesulfonamide

[0595] O=s=o o

[0596]

[0597] The title compound was obtained in analogy to Example 1 as a white solid (34.4% yield) using 2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'-[4-(difluoromethyl)benzenesulfonyl]tert-butoxycarbohydrazide. LC-MS (ES, m / z): [M+l] = 457.00. ’H NMR (400 MHz, DMSO-d6) 6 11.90 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 5.2 Hz, 1H), 7.39 - 7.24 (m, 5H), 7.11 (d, J= 55.3 Hz, 1H), 4.35 (s, 2H), 2.68 (s, 3H).

[0598] Example 32: N-(2-benzyl-5-chloro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide

[0599]

[0600] The title compound was obtained in analogy to Example 1 as a white solid (7.0% yield) using 5-chloro-2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'-(2-chlorobenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+:474.90.!H NMR (400 MHz, DMSO-d6) 5 11.81 (s, 1H), 8.46 (s, 1H), 7.94 - 7.88 (m, 1H), 7.71 (q, J = 4.8, 4.1 Hz, 2H), 7.50 (ddd, J = 8.3, 6.1, 2.5 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.30 - 7.22 (m, 3H), 4.19 (s, 2H), 2.56 (s, 3H).

[0601] Example 33: N-(2-benzyl-5-fluoro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide

[0602]

[0603] The title compound was obtained in analogy to Example 1 as a white solid (19.2% yield) using 5-fluoro-2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and 2-chlorobenzenesulfonohydrazide. LCMS (ESI) [M+H]+: 458.95.1H NMR (400 MHz, DMSO-d6) 6 11.82 (s, 1H), 8.44 (d, J= 1.6 Hz, 1H), 7.92 (dd, J= 7.6, 1.3 Hz, 1H), 7.76 -7.67 (m, 2H), 7.51 (ddd, J = 8.3, 6.3, 2.2 Hz, 1H), 7.39 - 7.18 (m, 5H), 4.40 - 4.10(s,2H), 2.55 (d, J= 1.4 Hz, 3H).

[0604] Example 34: 4-methyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide o=s=o o

[0605]

[0606] 4-methyl-N-[8-methyl-4-oxo-2-[methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 1 as a white solid (23.8% yield) using (R)-3-(2-methoxy-2-phenylacetamido)-2-methylisonicotinic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. Chiral separation using conditions A afforded 4-methyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (38.1% yield, RT=7.0min, first peak). LCMS(ESI) [M + H]+: 451.10. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.85 - 8.56 (m, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.48 - 7.39 (m, 3H), 7.39 - 7.30 (m, 5H), 5.85 (s, 1H), 3.44 (s, 3H), 2.78 (s, 3H), 2.43 (s, 3H).

[0607] Example 35: N-(2-benzyl-8-methyl-4-oxo-pyrido[4,3-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide

[0608]

[0609] The title compound was obtained in analogy to Example 1 as a white solid (2.5% yield) using 5-methyl-4-(2-phenylacetamido)pyridine-3-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 421.05. ’H NMR (400 MHz, Acetonitrile-d₃) 58.83 (s, 1H), 8.66 (d, J= 1.0 Hz, 1H), 7.69 - 7.65 (m, 2H), 7.36 - 7.25 (m, 7H), 4.36 (s, 2H), 2.41 (d, J= 10.9 Hz, 6H).

[0610] Example 36: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide

[0611]

[0612] The title compound was obtained in analogy to Example 1 as a white solid (33.6% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(5-methylthiophen-2-ylsulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 457.00. ’H NMR (400 MHz, Acetonitrile-d₃) 58.91 (s, 1H), 8.49 (d, J= 5.2 Hz, 1H), 7.56 (d, J = 5.2 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.41 - 7.31 (m, 4H), 6.83 (dd, J = 3.8, 1.2 Hz, 1H), 5.88 (s, 1H), 3.46 (s, 3H), 2.79 (s, 3H), 2.52 (d, J= 1.0 Hz, 3H).

[0613] Example 37: N-(2-benzyl-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide

[0614]

[0615] The title compound was obtained in analogy to Example 1 as a white solid (8.3% yield) using 2-methoxy-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 437.00.!H NMR (400 MHz, Acetonitrile-d₃) 68.08 (d, J= 5.4 Hz, 1H), 7.68 - 7.63 (m, 2H), 7.34 -7.29 (m, 4H), 7.28 - 7.22 (m, 3H), 7.18 (d, J = 5.4 Hz, 1H), 4.32 (s, 2H), 4.02 (s, 3H), 2.42 (s, 3H).

[0616] Example 38: 4-ethynyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide o=s=o o

[0617]

[0618] The title compound was obtained in analogy to Example 1 as a white solid (28.7% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(4-ethynylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 461.05.!H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J = 5.2 Hz, 1H), 7.79 - 7.75 (m, 2H), 7.62 -7.57 (m, 2H), 7.50 - 7.44 (m, 3H), 7.40 - 7.34 (m, 3H), 5.92 (s, 1H), 3.67 (s, 1H), 3.47 (s, 3H), 2.79 (s, 3H).

[0619] Example 39: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-2,4-dimethyl-benzenesulfonamide

[0620]

[0621] The title compound was obtained in analogy to Example 1 as a white solid (21.3% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(2,4-dimethylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 465.05.1H NMR (400 MHz, Acetonitrile-d₃) 58.70 (s, 1H), 8.47 (d, J= 5.2 Hz, 1H), 7.60 (d, J= 8.1 Hz, 1H), 7.51 (d, J= 5.1 Hz, 1H), 7.36 (s, 5H), 7.29 (s, 1H), 7.06 (dd, J= 7.9, 1.6 Hz, 1H), 5.68 (s, 1H), 3.36 (s, 3H), 2.78 (s, 3H), 2.63 (s, 3H), 2.37 (s, 3H).

[0622] Example 40: N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide

[0623]

[0624] The title compound was obtained in analogy to Example 1 as a white solid (26.8% yield) using 3-(2-fluoro-2-phenylacetamido)-2-methylisonicotinic acid and tert-butyl 2-((5-methylthiophen-2-yl) sulfonyl) hydrazine- 1 -carboxylate. LC-MS (ES, m / z): [M+l] = 444.95.1H NMR (400 MHz, Methanol-^) 68.48 (d, J = 5.3 Hz, 1H), 7.66 (d, J = 5.3 Hz, 1H), 7.58 - 7.51 (m, 2H), 7.44 - 7.37 (m, 3H), 7.32 (m, 1H), 7.10 -6.90 (dd, 1H), 6.82 (dd, J = 3.8, 1.1 Hz, 1H), 2.87 (s, 3H), 2.52 (d, J = 1.0 Hz, 3H).

[0625] Example 41: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0626]

[0627] The title compound was obtained in analogy to Example 1 as a white solid (9.1% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 468.95. ’H NMR (400 MHz, Methanol-^) 68.41 (d, J= 5.3 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.56 (d, J= 5.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.32 (d, J= 8.1 Hz, 2H), 7.11 (t, J = 8.7 Hz, 2H), 6.07 (s, 1H), 3.54 (s, 3H), 2.82 (s, 3H), 2.43 (s, 3H).

[0628] Example 42: N-[8-methoxy-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0629]

[0630] a) 8-methoxy-2-[methoxy(phenyl)methyl]pyrido[3,4-d][1,3]oxazin-4-one

[0631] A solution of 3-amino-2-methoxypyridine-4-carboxylic acid (1 g, 5.947 mmol, 1 equivalent) in DMF (30 mL) was treated with methoxy (phenyl) acetic acid (1.09 g, 6.542 mmol, 1.1 equivalent) and DIEA (2.31 g, 17.841 mmol, 3.0 equivalent) for 5 min at room temperature under nitrogen atmosphere followed by the addition of HATU (2.71 g, 7.136 mmol, 1.2 equivalent) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C under nitrogen atmosphere. After completion, the organic solvent was removed under reduced pressure to obtain the residue. The residue was dissolved in water (15 mL) extracted with EtOAc (3 x 25 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 to afford 8-methoxy-2-[methoxy(phenyl)methyl]pyrido[3,4-d][1,3]oxazin-4-one (200 mg, 11.27% yield) as a yellow solid without further purification. LCMS(ECI) [M + H]+: 299.

[0632] b) 3-amino-8-methoxy-2-[methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-4-one

[0633] A solution of 8-methoxy-2-[methoxy(phenyl)methyl]pyrido[3,4-d][1,3]oxazin-4-one (100 mg, 0.335 mmol, 1.0 equivalent) and NHiNHi’fLO (2 mL) in EtOH (4 mL) was stirred for 4 h at 80 °C under nitrogen atmosphere. After completion, the organic solvent was removed under reduced pressure to obtain the residue. The residue was dissolved in water (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 xlO mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-amino-8-methoxy-2-[methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-4-one (45 mg, 42.98% yield) as yellow oil without further purification. LCMS(ECI) [M + H]+: 313.

[0634] c) N-[8-methoxy-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0635] A solution of 3-amino-8-methoxy-2-[methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-4-one (40 mg, 0.128 mmol, 1.0 equivalent) in THF (5 mL) was treated with p-toluene sulfonyl chloride (29.30 mg, 0.154 mmol, 1.2 equivalent) for 1 h at -78 °C under nitrogen atmosphere followed by the addition of LiHMDS (42.86 mg, 0.256 mmol, 2.0 equivalent) drop wise. The resulting mixture was stirred for 2 h at -78 °C under nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 37% B in 7 min; Wave Length: 254nm / 220nm; RT=6.95min) to afford N-{8-methoxy-2-[methoxy(phenyl)methyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide (16.7 mg, 27.36% yield) as a white solid. LCMS(ECI) [M - H]’: 467.05. ’H NMR (400 MHz, DMSO-d6) 3 11.56 (s, 1H), 8.13 (d, 7= 5.4 Hz, 1H), 7.65 (d, J= 8.1 Hz, 2H), 7.35 (p, J= 8.2, 7.8 Hz, 7H), 7.27 (d, J= 5.4 Hz, 1H), 5.91 (s, 1H), 4.03 (s, 3H), 3.33 (s, 3H), 2.39 (s, 3H).

[0636] Example 43: N- [2- [methoxy(p-tolyl)methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin- 3-yl]-4-methyl-benzenesulfonamide

[0637] o=s=o o

[0638] The title compound was obtained in analogy to Example 1 as a white solid (48.6% yield) using 3- [2-methoxy-2-(4-methylphenyl)acetamido] -2-methylpyridine-4-carboxylic acid and N (4-methylbenzene sulfonyl)tert-butoxyc arbohydrazide. MS (ESIpos): m / z = 465.00 [M+H]+.1H NMR (400 MHz, Acetonitrile-^) 58.73 (s, 1H),

[0639]

[0640] 8.45 (d, J = 5.3 Hz, 1H), 7.70 - 7.63 (m, 2H), 7.48 (d, J = 5.2 Hz, 1H), 7.37 - 7.25 (m, 4H), 7.17 (d, J = 7.7 Hz, 2H), 5.80 (s, 1H), 3.42 (s, 3H), 2.92 - 2.68 (m, 3H), 2.43 (s, 3H), 2.31 (s, 3H).

[0641] Example 44: 4-(difluoromethoxy)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo- pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0642]

[0643] The title compound was obtained in analogy to Example 1 as a white solid (14.0% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-[4-(difluoromethoxy)benzenesulfonyl]tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 503.05.1H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J = 5.2 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.49 - 7.44 (m, 3H), 7.40 - 7.34 (m, 3H), 7.25 - 7.20 (m, 2H), 6.91 (t, J = 73.1 Hz, 1H), 5.92 (s, 1H), 3.48 (s, 3H), 2.78 (s, 3H).

[0644] Example 45: 3-fluoro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0645]

[0646] The title compound was obtained in analogy to Example 1 as a white solid (11.7% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(3-fluoro-4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 469.05. ’H NMR (400 MHz, Acetonitrile-d₃) 58.47 (d, J= 5.2 Hz, 1H), 7.52 - 7.44 (m, 5H), 7.42 - 7.34 (m, 4H), 5.89 (s, 1H), 3.47 (s, 3H), 2.79 (s, 3H), 2.35 (d, J = 2.1 Hz, 3H).

[0647] Example 46: 4-(dimethylamino)-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0648]

[0649] The title compound was obtained in analogy to Example 2 as a white solid (5.5% yield) using 3-amino-2-[fluoro(phenyl)methyl]-8-methylpyrido[3,4-6?]pyrimidin-4-one and 4-(dimethylamino)benzenesulfonyl chloride. LCMS (ESI) [M + H]+: 468.00.!H NMR (400 MHz, DMSO-d6) 88.57 (s, 1H), 7.72 - 7.65 (m, 8H), 7.18 - 6.97 (m, 1H), 6.65 (m, 1H), 3.08 (s, 6H), 2.74 (s, 3H).

[0650] Example 47: N-[2-[fluoro(phenyl)methyl]-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0651]

[0652] The title compound was obtained in analogy to Example 1 as a white solid (8.7% yield) using 3-(2-fluoro-2-phenylacetamido)-2-methoxypyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS(ECI) [M + H]+: 455.15. ’H NMR (400 MHz, DMSO-d6) 3 11.60 (s, 1H), 8.21 (d, J= 5.3 Hz, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.45 (s, 5H), 7.36 (d, J= 8.0 Hz, 1H), 7.27 (d, J= 5.3 Hz, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 4.06 (s, 3H), 2.40 (s, 3H).

[0653] Example 48: 4- (2,2-difluoroethyl) -N- [2- [methoxy (phenyl)methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0654]

[0655] The title compound was obtained in analogy to Example 1 as a white solid (50.4% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and A'-[4-(2,2-difluoroethyl)benzenesulfonyl]tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 501.05. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J= 5.2 Hz, 1H), 7.81 - 7.73 (m, 2H), 7.48 - 7.40 (m, 5H), 7.40 - 7.31 (m, 3H), 6.28 - 5.95 (m, 1H), 5.85 (s, 1H), 3.45 (s, 3H), 3.35 - 3.23 (m, 2H), 2.78 (s, 3H).

[0656] Example 49: 4-(difluoromethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0657] F

[0658] o=s=oo

[0659]

[0660] a) 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid

[0661] To a stirred solution of (4-fluorophenyl) methoxy) acetic acid (500 mg, 2.715 mmol, 1 equiv), 3-amino-2-methylpyridine-4-carboxylic acid (413 mg, 2.715 mmol, 1.0 equiv) and DIEA (530 mg 4.072 mmol, 1.5 equiv) in DMF (10 mL) was added HATU (5.16 g, 13.575 mmol, 5 equiv) drop wise at room temperature. The resulting mixture was stirred for 30 min at room temperature. 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), 10% to 50% gradient in 30 min; detector, UV 254 nm to afford 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid (200 mg, 23.14% yield) as a white solid. LCMS (ESI): m / z = 319.10 [M + H]+ b) 2- [(4-fluorophenyl)(methoxy)methyl] - 8-methylpyrido [3,4-t ] [ 1,3] oxazin-4-one

[0662] A mixture of 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid (170 mg, 0.534 mmol, 1 equiv) in acetic anhydride (10 mL) was stirred for 1 h at 120 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2-[(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d][l,3]oxazin-4-one (150 mg, 93.53% yield) as a white solid. LCMS (ESI): m / z = 301.09 [M + H]+

[0663] c) 3-amino-2-[(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one

[0664] A solution of 2-[(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d][1,3]oxazin-4-one (150 mg, 0.500 mmol, 1 equiv) and hydrazine hydrate (5 mL, 0.750 mmol) in ethyl alcohol (5 mL) was stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 20 min; detector, UV 254 nm to afford 3-amino-2-[(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one (100 mg, 63.69% yield) as a white solid. LCMS (ESI): m / z = 315.12[M + H]+

[0665] d) 4-(difluoromethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0666] To a stirred solution of 3-amino-2-[(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one (60 mg, 0.191 mmol, 1 equiv) and 4-(difluoromethyl)benzene sulfonyl chloride (64.8 mg, 0.286 mmol, 1.5 equiv) in THF (5 mL) was added LiHMDS (47.9 mg, 0.286 mmol, 1.5 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at -78 °C under nitrogen atmosphere. The reaction was quenched with water at -78 °C. The resulting mixture was extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions [MeCN in Water (0.1% FA)] to afford 4-(difluoromethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (30.5 mg, 31.51% yield) as a white solid. LCMS (ESI): m / z = 505.15 [M + H]+. ’H NMR (400 MHz, DMSO-d6) 5 11.77 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.95 (d, J= 8.1 Hz, 2H), 7.77 (d, J= 8.2 Hz, 2H), 7.55 (d, J= 5.2 Hz, 1H), 7.48 (s, 2H), 7.20 (d, J= 19.8 Hz, 3H), 5.88 (s, 1H), 3.41 (s, 3H), 2.85 (s, 3H). Example 50: 4- (dimethylamino) -N- [2- [(4-fluorophenyl) -methoxy-methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0667]

[0668] The title compound was obtained in analogy to Example 49 as a white solid (1.4% yield) using 3-amino-2-[(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(dimethylamino)benzenesulfonyl chloride. LCMS (ESI) [M + H]+: 498.05.!H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.61 - 7.43 (m, 5H), 7.18 (t, J = 8.7 Hz, 2H), 6.79 - 6.70 (m, 2H), 5.90 (s, 1H), 3.42 (s, 3H), 3.02 (s, 6H), 2.96 - 2.53 (m, 3H).

[0669] Example 51: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-methyl-benzenesulfonamide

[0670] o=s=oo

[0671]

[0672] The title compound was obtained in analogy to Example 1 as a white solid (26.2% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(3-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 451.20. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.47 (d, J= 5.2 Hz, 1H), 7.63 - 7.58 (m, 2H), 7.53 (d, Hz, 1H), 7.48 (d, J= 5.2 Hz, 1H), 7.46 - 7.40 (m, 3H), 7.39 - 7.31 (m, 3H), 5.82 (s, 1H), 3.44 (s, 3H), 2.78 (s, 3H), 2.32 (s, 3H).

[0673] Example 52: N-[5-fluoro-2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0674]

[0675] The title compound was obtained in analogy to Example 1 as a white solid (16.0% yield) using 5-fluoro-3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and A7-(4-methylbenzenesulfonyl) tert-butoxycarbohydrazide. LC-MS (ESI, m / z): [M+ H]+: 469.1. ’H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.42 (d, J= 1.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.48 - 7.41 (m, 2H), 7.41 - 7.29 (m, 5H), 5.92 (s, 1H), 3.36 (s, 3H), 2.68 (s, 3H), 2.39 (s, 3H).

[0676] Example 53: N- [2- [(3-fluorophenyl)-methoxy-methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0677]

[0678] The title compound was obtained in analogy to Example 1 as a white solid (3.5% yield) using 3-[2-(3-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 469.00. ’H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J= 5.2 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.59 (d, J = 5.2 Hz, 1H), 7.48 - 7.35 (m, 3H), 7.30 - 7.02 (m, 3H), 5.88 (s, 1H), 3.42 (s, 3H), 2.71 (s, 3H), 2.43 (s, 3H).

[0679] Example 54: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-2-methyl-benzenesulfonamide o=s=oo

[0680]

[0681] The title compound was obtained in analogy to Example 1 as a white solid (30.5% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(2-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 451.15.!H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.73 (d, J= 7.8 Hz, 1H), 7.58 (d, J= 6.1 Hz, 2H), 7.48 (d, J= 7.4 Hz, 1H), 7.36 (s, 6H), 5.71 (s, 1H), 3.31 (s, 3H), 2.70 (s, 6H).

[0682] Example 55: 4-(1-fluorocyclopropyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0683] o=s=oo

[0684]

[0685] The title compound was obtained in analogy to Example 1 as a white solid (17.0% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and A'-[4-(l-fluorocyclopropyl)benzenesulfonyl]tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 494.95. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.80 (s, 1H), 8.47 (d, J= 5.2 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.49 - 7.43 (m, 3H), 7.39 - 7.33 (m, 5H), 5.87 (s, 1H), 3.46 (s, 3H), 2.78 (s, 3H), 1.66 - 1.55 (m, 2H), 1.30- 1.17 (m, 2H).

[0686] Example 56: N-(2-((2-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide o=s=o o

[0687]

[0688] The title compound was obtained in analogy to Example 1 as a white solid (2.4% yield) using 3-(2-(2-fluorophenyl)-2-methoxyacetamido)-2-methylisonicotinic acid and tert-butyl 2-tosylhydrazine-1-carboxylate. LC-MS (ES, m / z): [M+l] = 469.05. ’H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 5.1 Hz, 1H), 7.38 (t, J = 8.9 Hz, 4H), 7.22 (dd, J = 10.2, 8.2 Hz, 2H), 6.14 (s, 1H), 3.43 (s, 3H), 2.73 (s, 3H), 2.42 (s, 3H).

[0689] Example 57: 3-cyclopropyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0690]

[0691] The title compound was obtained in analogy to Example 49 as a white solid (18.2% yield) using 3-amino-2-[methoxy(phenyl)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 3-cyclopropylbenzenesulfonyl chloride. LCMS (ESI): m / z = 477.16 [M + H]+. ’H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J = 5.2 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.52 (s, 1H), 7.47 - 7.35 (m, 7H), 5.86 (s, 1H), 3.41 (s, 3H), 2.74 (s, 3H), 2.09 - 1.96 (m, 1H), 1.04 - 0.94 (m, 2H), 0.66 (dt, 7= 5.7, 4.2 Hz, 2H).

[0692] Example 58: 3-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide o=s=oo

[0693]

[0694] The title compound was obtained in analogy to Example 1 as a white solid (20.2% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and A'-[3-(dimethylamino)benzenesulfonyl]tert-butoxycarbohydrazide. MS (ESIpos): m / z = 498.15 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.48 (d, J= 5.3 Hz, 1H), 7.55 -7.28 (m, 4H), 7.20 - 6.97 (m, 4H), 6.93 (d, J= 2.5 Hz, 1H), 5.75 (s, 1H), 3.42 (s, 3H), 2.84 (s, 8H).

[0695] Example 59: N-(2-(methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide

[0696]

[0697] The title compound was obtained in analogy to Example 1 as a white solid (5.6% yield) using 4-(2-methoxy-2-phenylacetamido)-5-methylpyridine-3-carboxylic acid and A'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z = 451.00 [M+H]+. ‘HNMR (300 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.91 (s, 1H), 8.77 (s, 1H), 7.71 (d, 7= 8.3 Hz, 2H), 7.44 - 7.36 (m, 7H), 5.87 (s, 1H), 3.40 (s, 3H), 2.54 - 2.52 (m, 3H), 2.43 (s, 3H).

[0698] Example 60: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-methoxy-benzenesulfonamide

[0699]

[0700] The title compound was obtained in analogy to Example 1 as a white solid (32.5% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'-(3-methoxybenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+:

[0701] 485.10.XH NMR (300 MHz, DMSO-d6) δ 12 – 11(s, J = 5.3 Hz, 1H), 8.52 (d, J = 5.3 Hz, 1H), 7.60 (d, J= 5.2 Hz, 1H), 7.52 - 7.37 (m, 4H), 7.41 - 7.25 (m, 2H), 7.20 (t, J= 8.7 Hz, 2H), 5.84 (s, 1H), 3.80 (s, 3H), 3.40 (s, 3H), 2.76 (s, 3H).

[0702] Example 61: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methoxy-benzenesulfonamide

[0703]

[0704] The title compound was obtained in analogy to Example 1 as a white solid (26.2% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'-(4-methoxybenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): m / z = 485.13 [M + H]+. ’H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 5.2 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.22 (t, J = 8.7 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 5.91 (s, 1H), 3.85 (s, 3H), 3.40 (s, 3H), 2.74 (s, 3H).

[0705] Example 62: 4-(l,l-difluoroethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[0706] o=s=oo

[0707]

[0708] The title compound was obtained in analogy to Example 1 as a white solid (9.6% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'- [4-( 1, 1 -difluoroethyl)benzenesulfonyl] tert-butoxycarbohydrazide.

[0709] LCMS (ESI) [M + H]+: 519.251H NMR (400 MHz, Methanol-d4) δ 8.41 (d, J = 5.3 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.72 - 7.65 (m, 2H), 7.57 - 7.49 (m, 3H), 7.12 (t, J= 8.5 Hz, 2H), 6.08 (s, 1H), 3.56 (s, 3H), 2.90 (s, 3H), 1.95 (t, J= 18.4 Hz, 3H).

[0710] Example 63: 4-isopropyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0711]

[0712] The title compound was obtained by chiral separation of 4-isopropyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 20) using conditions B (15.6% yield, RT=11.0min, first peak). LCMS (ESI) [M + H]+: 479.20. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.45 (d, J = 5.2 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.47 (d, J= 5.2 Hz, 1H), 7.44 - 7.31 (m, 7H), 5.82 (s, 1H), 3.41 (s, 3H), 3.01 (p, J= 6.9 Hz, 1H), 2.78 (s, 3H), 1.25 (d, J = 6.9 Hz, 6H).

[0713] Example 64: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropenyl-benzenesulfonamide

[0714]

[0715] The title compound was obtained in analogy to Example 1 as a white solid (2.3% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'- [4-(2-hydroxypropan-2-yl)benzenesulfonyl] tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 495.20. ’H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.50 (d, J= 5.3 Hz, 1H), 7.76 (d, J= 8.5 Hz, 2H), 7.69 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 5.2 Hz, 1H), 7.46 (s, 2H), 7.22 (s, 2H), 5.85 (s, 1H), 5.62 (s, 1H), 5.33 - 5.28 (m, 1H), 3.30 (s, 3H), 2.85 (s, 3H), 2.14 (dd, J= 1.5, 0.8 Hz, 3H).

[0716] Example 65: N- [2- [(4-fluorophenyl)-methoxy-methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-l-methyl-indole-5-sulfonamide

[0717]

[0718] The title compound was obtained in analogy to Example 1 as a white solid (28.8% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'-(1-methylindol-5-ylsulfonyl)tert-butoxycarbohydrazide. LC-MS: (ES, m / z): [M+l] = 508.14. ’H NMR (400 MHz, Acetonitrile-d3) δ 9.00 – 8.44 (m, 1H), 8.40 (d, J= 5.3 Hz, 1H), 8.05 (d, J= 1.9 Hz, 1H), 7.58 (dd, J = 8.8, 1.9 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.43 (s, 2H), 7.38 - 7.32 (m, 2H), 7.08 (s, 2H), 6.55 (dd, J= 3.2, 0.9 Hz, 1H), 5.88 (d, J = 54.2 Hz, 1H), 3.84 (s, 3H), 3.39 (s, 3H), 2.87 (s, 3H).

[0719] Example 66: 4-(3,3-difluoroazetidin-l-yl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0720]

[0721] a) A^-{2-[(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-6?]pyrimidin-3-yl}-4-iodobenzenesulfonamide

[0722] The title compound was obtained in analogy to Example 1 as a white solid (41.2% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and M-(4-iodobcnzcncsulfonyl) / e / 7-butoxycarbohydrazidc. LCMS(ECI) [M + H]+: 581. b) 4-(3,3-difluoroazctidin- l-yl)-N-[2-[(4-fluorophcnyl)-mcthoxy-mcthyl|-8-mcthyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0723] A solution of A-{2-[(4-fluorophenyl)(methoxy)methyl ]-8-methyl-4-oxopyrido[3,4-6?]pyrimidin-3-yl}-4-iodobenzenesulfonamide (100 mg, 0.172 mmol, 1 equiv), Xphos (32.86 mg, 0.069 mmol, 0.4 equiv) and DIPEA (66.81 mg, 0.516 mmol, 3 equiv) in dioxane (10 mL) was treated with 3,3-difluoroazetidine (24.06 mg, 0.258 mmol, 1.5 equiv) followed by the addition of Pd2(dba)3(31.56 mg, 0.034 mmol, 0.2 equiv) in portions at room temperature. The resulting mixture was stirred for 1 hour at 100 °C under nitrogen atmosphere. After completion, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions (NH4HCO3 System) to afford 4-(3,3-difluorocyclobutyl)- N- { 2- [(4-fluorophenyl)(methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-6?]pyrimidin-3-yl}benzenesulfonamide (42.3 mg, 44.95% yield) as a white solid.

[0724] LCMS(ECI) [M + H]+: 546.10. ’H NMR (400 MHz, DMSO-d6) 611.20 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 7.63 - 7.55 (m, 3H), 7.46 (s, 2H), 7.24 - 7.16 (m, 2H), 6.64 - 6.56 (m, 2H), 5.89 (s, 1H), 4.45 - 4.41 (d, J = 12.2 Hz, 4H), 3.39 (s, 3H), 2.81 (s, 3H).

[0725] Example 67: 4-(3,3-difluorocyclobutyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide o=s=o o

[0726]

[0727] F F

[0728] The title compound was obtained in analogy to Example 1 as a white solid (20.0% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and 7V'-[4-(3,3-difluorocyclobutyl)benzenesulfonyl]tert-butoxycarbohydrazide. MS (ESIpos): m / z =527.15 [M+H]+.XH NMR (400 MHz, DMSO-d6) 8 11.61 (s, 1H), 8.51 (d, 7= 5.3 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.59 - 7.50 (m, 3H), 7.45 - 7.31 (m, 5H), 5.83 (s, 1H), 3.63 -3.49 (m, 1H), 3.14 - 2.98 (m, 2H), 2.95 - 2.59 (m, 5H).

[0729] Example 68: 4- (difluoromethoxy) -N - [2- [(4-fluorophenyl) -methoxy-methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0730]

[0731] The title compound was obtained in analogy to Example 1 as a white solid (80.8% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and M-[4-(difluoromethoxy)benzenesulfonyl]tert-butoxycarbohydrazide. LCMS(ECI) [M + H]+: 521.20. ’H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 8.52 (d, J= 5.2 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.55 (dd, 7= 17.8, 6.3 Hz, 2H), 7.46 (d, J = 7.3 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.28 - 7.20 (t, J= 8.6 Hz, 2H), 5.88 (s, 1H), 3.37 (m, 3H), 2.86 (s, 3H).

[0732] Example 69: N-[8-(dimethylamino)-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0733]

[0734] The title compound was obtained in analogy to Example 1 as a white solid (54.3% yield) using 2-(dimethylamino)-3-(2-methoxy-2-phenylacetamido)pyridine-4-carboxylic acid and MN'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LC-MS: (ES, m / z): [M+l] = 480. ’H NMR (400 MHz, DMSO-*) 5 12.0 - 11.31 (m, 1H), 8.06 (d, J= 5.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.45 - 7.28 (m, 7H), 6.88 (d, J = 5.1 Hz, 1H), 5.83 (s, 1H), 3.50 -3.35 (m, 6H), 2.98 - 2.68 (s, 3H), 2.40 (s, 3H).

[0735] Example 70: N-[2-[methoxy(phenyl)methyl]-6,8-dimethyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0736]

[0737] The title compound was obtained in analogy to Example 1 as a white solid (50.9% yield) using 3-(2-methoxy-2-phenylacetamido)-2,6-dimethylpyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z = 465.00 [M+H]+.1H NMR (400 MHz, Acetonitrile-d₃) 68.61 (s, 1H), 7.72 - 7.62 (m, 2H), 7.53 -7.20 (m, 8H), 5.82 (s, 1H), 3.43 (s, 3H), 2.69 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H).

[0738] Example 71: 4-(azetidin-l-yl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[0739] o=s=oo

[0740]

[0741] The title compound was obtained in analogy to Example 66 as a white solid (23.2% yield) using N- { 2- [(4-fluorophenyl)(methoxy)methyl] - 8- mcthy l-4-oxopy rido 13,4-d | py ri m idi n-3-yl}-4-iodobenzenesulfonamide and azetidine. LCMS(ECI) [M + H]+: 510. ’H NMR (400 MHz, DMSO-*) 5 11.14 (s, 1H), 8.51 (d, 7= 5.2 Hz, 1H), 7.60 (d, 7= 5.2 Hz, 1H), 7.47 (dd, 7= 21.2, 7.0 Hz, 4H), 7.21 (t, 7= 8.7 Hz, 2H), 6.39 (d, 7= 8.5 Hz, 2H), 5.88 (s, 1H), 3.93 (t, 7 = 7.3 Hz, 4H), 3.37 (m, 3H), 2.73 (s, 3H), 2.36 (p, 7= 7.3 Hz, 2H).

[0742] Example 72: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin- 3-yl]-4-[l-(trifluoromethyl)cyclopropyl]benzenesulfonamide

[0743]

[0744] The title compound was obtained in analogy to Example 1 as a white solid (10.1% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and 7V-{4-[l-(trifluoromethyl)cyclopropyl]benzenesulfonyl } tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 545.10. ’H NMR (400 MHz, Acetonitrile-d₃) 68.81 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.82- 7.74 (m, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 5.5 Hz, 3H), 7.44 - 7.33 (m, 3H), 5.84 (s, 1H), 3.44 (s, 3H), 2.14 (s, 3H), 1.48 - 1.41 (m, 2H), 1.14 (q, J= 4.2, 2.9 Hz, 2H).

[0745] Example 73: N- [2- [methoxy- [4-(trifluoromethyl)phenyl]methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide o=s=o o

[0746]

[0747] The title compound was obtained in analogy to Example 1 as a white solid (33.3% yield) using 3- [( { 2-methoxy-2- [4-(trifluoromethyl)phenyl] acetyl } oxy)amino] -2-methylpyridine-4-carboxylic acid and A'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z = 519.12 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d₃) 68.77 (s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 7.72 - 7.62 (m, 6H), 7.59 (d, J = 5.4 Hz, 1H), 7.28 (dd, J = 54.4, 7.9 Hz, 2H), 6.00 (s, 1H), 3.49 (s, 3H), 2.59 (s, 3H), 2.43 (s, 3H).

[0748] Example 74: N-[8-cyclopropyl-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0749]

[0750] The title compound was obtained in analogy to Example 1 as a white solid (3.4% yield) using 2-cyclopropyl-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and MN'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 495.05. ’H NMR (300 MHz, Acetonitrile-d₃) 58.73 (s, 1H), 8.40 (d, J= 5.2 Hz, 1H), 7.72 -7.63 (m, 2H), 7.48 (t, J= 7.1 Hz, 2H), 7.40- 7.29 (m, 3H), 7.11 (t, J = 8.8 Hz, 2H), 5.89 (s, 1H), 3.45 (s, 3H), 3.25 (s, 1H), 2.43 (s, 3H), 1.11 (d, J= 5.1 Hz, 4H).

[0751] Example 75: 4-(2,2-difluoro-l-methyl-ethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[0752] o=s=o o

[0753]

[0754] F

[0755] a) 4-( 1, 1 - difluoroprop- 1 -en-2-yl)-A- { 2- [(4-fluorophenyl)(methoxy)methyl] -8-methyl-4-oxopyrido[3,4-*pyrimidin-3 -yljbenzenesulfonamide

[0756] The title compound was obtained in analogy to Example 1 as a white solid (32.8% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'- [4-( 1, 1 -difluoroprop- 1 -en-2-yl)benzenesulfonyl] tert-butoxycarbohydrazide.

[0757] LCMS (ESI) [M + H]+: 531

[0758] b) 4-(2,2-difhioro-l-methyl-ethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0759] A solution of 4-( 1,1 -difluoroprop- 1 -en-2-yl)-A-{ 2- [(4-fluorophenyl)(methoxy)methyl] -8-methyl-4- oxopyrido[3,4-*pyrimidin-3-yl}benzenesulfonamide (60 mg, 0.113 mmol, 1 equiv) and Pd / C (20 mg, 0.188 mmol, 1.66 equiv) in ethanol (10 mL) was stirred for 1 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with ethanol (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, MeCN in Water (0.1% FA), 10% to 90% gradient in 60 min; detector, UV 254 nm. This resulted in 4-(2,2-difluoro-l-methyl-ethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (11.1 mg, 18.13% yield) as a white solid. LCMS (ESI) [M + H]+: 533.15. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.80 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.79 - 7.73 (m, 2H), 7.46 (dt, J= 9.0, 2.8 Hz, 5H), 7.11 (t, J = 8.7 Hz, 2H), 5.85 (d, J= 2.0 Hz, 2H), 3.44 (d, J = 1.4 Hz, 3H), 3.37 (tdd, J = 15.1, 7.6, 4.3 Hz, 1H), 2.14 (s, 3H), 1.38 (d, J= 7.1 Hz, 3H).

[0760] Example 76: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(l-methoxyethyl)benzenesulfonamide F

[0761] o=s=o o

[0762]

[0763] I

[0764] The title compound was obtained in analogy to Example 1 as a white solid (20.6% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and M-|4-( l-mcthoxycthyl)bcnzcncsulfonyl| / e / -butoxycarbohydrazidc. LCMS (ESI) [M + H]+: 513.10.XH NMR (400 MHz, Acetonitrile-d₃) 68.84 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 7.79 - 7.71 (m, 2H), 7.51 - 7.39 (m, 5H), 7.10 (t, J= 8.5 Hz, 2H), 5.89 (s, 1H), 4.41 (q, J = 6.4 Hz, 1H), 3.48 - 3.43 (m, 3H), 3.19 (d, J= 1.0 Hz, 3H), 2.78 (s, 3H), 1.36 (dd, J = 6.5, 0.8 Hz, 3H).

[0765] Example 77: N-[2-[(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0766]

[0767] The title compound was obtained in analogy to Example 1 as a white solid (25.8% yield) using 3-[2-(4-chlorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): m / z = 485.10 [M + H]+. ’H NMR (400 MHz, DMSO-*) 5 11.52 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.69 -7.65 (m, 2H), 7.57 (dd, J= 5.2, 0.8 Hz, 1H), 7.44 (s, 4H), 7.38 (d, J= 8.1 Hz, 2H), 5.85 (s, 1H), 3.35 (s, 3H), 2.85 (s, 3H), 2.41 (s, 3H). Example 78: (R)-4-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0768]

[0769] The title compound was obtained by chiral separation of 4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 50) using conditions C (34.4% yield, RT=12.0 min, first peak). LCMS (ESI) [M + H]+: 498.20.1H NMR (400 MHz, DMSO-d6) 8 10.9 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.53 - 7.41 (m, 4H), 7.19 (s, 2H), 6.72 (d, J = 8.7 Hz, 2H), 5.89 (s, 1H), 3.36 (s, 3H), 3.00 (s, 6H), 2.84 (s, 2H), 2.51 (s, 1H).

[0770] Example 79: 4-(2-fluoropropyl)-N-(2-(methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0771]

[0772] The title compound was obtained in analogy to Example 1 as a white solid (22.4% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and / V'-[4-(2-fluoropropyl)benzenesulfonyl]tert-butoxycarbohydrazide. MS (ESIpos): m / z = 497.00 [M+H]+. ‘H NMR (400 MHz, DMSO-d6) 6 11.71 (d, J = 164.2 Hz, 1H), 8.51 (d, 7= 5.2 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.54 (d, J= 5.2 Hz, 1H), 7.50 - 7.29 (m, 7H), 5.81 (s, 1H), 5.04 - 4.84 (m, 1H), 3.42 - 3.35 (m, 3H), 3.11 - 2.96 (m, 2H), 2.86 (s, 2H), 2.46 (s, 1H), 1.30 (dd, 7 = 23.8, 6.1 Hz, 3H). Example 80: N- [8- (difluoromethoxy) -2- [(4-fluorophenyl) -methoxy-methyl] -4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0773]

[0774] The title compound was obtained in analogy to Example 1 as a white solid (4.6% yield) using 2-(difluoromethoxy)-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z = 521.15 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 6 11.75 (d, J= 155.5 Hz, 1H), 8.25 (d, J= 5.3 Hz, 1H), 7.98 (d, J = 72.2 Hz, 1H), 7.62 (dd, J = 44.8, 6.7 Hz, 3H), 7.38 (d, J= 8.1 Hz, 4H), 7.25 - 7.16 (m, 2H), 5.82 (s, 1H), 3.34 - 3.35 (m, 3H), 2.41 (s, 3H).

[0775] Example 81: 4-(l-fluoro-2-methyl-propyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0776] N

[0777] 'O

[0778] HN'N

[0779] o=s=o o

[0780]

[0781] The title compound was obtained in analogy to Example 1 as a white solid (14.8% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and / V'-[4-(l-fluoro-2-methylpropyl)benzenesulfonyl]tert-butoxycarbohydrazide. LC-MS (ESI, m / z): [M+ H]+: 511.35. ’H NMR (400 MHz, DMSO-d6) 8 11.82 (d, J= 161.3 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.60 - 7.25 (m, 8H), 5.87 (s, 1H), 5.55 - 5.32 (m, 1H), 3.43 (s, 3H), 2.86 (s, 2H), 2.46 (s, 1H), 2.17 - 1.96 (m, 1H), 1.06 - 0.77 (m, 6H).

[0782] Example 82: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-prop-l-ynyl-benzenesulfonamide

[0783]

[0784] a) A-{2-[(4-fluorophenyl) (mcthoxy)mcthyl|-8-mcthyl-4-oxopyrido|3,4-d| pyrimidin-3-yl } -4-iodobenzenesulfonamide

[0785] The title compound was obtained in analogy to Example 1 as a white solid (57.6% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and M-(4-iodobenzenesulfonyl) tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 581.2.

[0786] b) N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-prop- 1 -ynyl-benzenesulfonamide

[0787] A solution of A-{2-[(4-fluorophenyl) (mcthoxy)mcthyl|-8-mcthyl-4-oxopyrido|3,4-<7| pyrimidin-3-yl} -4-iodobenzenesulfonamide (110 mg, 0.190 mmol, 1 equiv) and tributyl(prop-l-yn-l-yl) stannane (74.8 mg, 0.228 mmol, 1.2 equiv) in Toluene (2 mL) was treated with Pd(PPh3)4 (10.95 mg, 0.010 mmol, 0.05 equiv). The mixture was stirred 3 hours at 100 °C under N2 atmosphere. The resulting mixture was extracted with EtOAc (3 x 3 mL). The combined organic layers were washed with water (3 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-{2-[(4-fluorophenyl) (mcthoxy)mcthyl | -8-mcthyl-4-oxopyrido| 3,4-<7| pyrimidin-3-yl } -4-(prop- 1 -yn- 1 -yl) benzenesulfonamide (20.2 mg, 21.64% yield) as a yellow solid. LCMS (ESI): [M+H]+: 493.25. ‘H NMR (400 MHz, DMSO-d6) <5 11.65 (s, 1H), 8.51 (d, J= 5.3 Hz, 1H), 7.73 (d, J= 8.4 Hz, 2H), 7.56 (t, J = 7.2 Hz, 2H), 7.46 (s, 3H), 7.22 (s, 2H), 5.89 (s, 1H), 3.40 (s, 3H), 2.85 (s, 3H), 2.10 (s, 3H).

[0788] Example 83: 4-isopropenyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0789]

[0790] The title product was obtained by chiral separation of N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropenyl-benzenesulfonamide (Example 64) 4 using conditions J to afford 4-isopropenyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (28.6% yield, RT= 9.55min, first peak) as a white solid. LCMS (ESI): [M+H]+: 494.95.1H NMR (400 MHz, DMSO-d6) 6 11.68 (s, 1H), 8.51 (d, J = 5.3 Hz, 1H), 7.78 - 7.76 (d, J= 8.3 Hz, 2H), 7.71 - 7.69 (d, J= 8.3 Hz, 2H), 7.58 (d, J= 5.2 Hz, 1H), 7.47 (s, 2H), 7.25 (t, J= 8.6 Hz, 2H), 5.86 (s, 1H), 5.62 (s, 1H), 5.30 (s, 1H), 3.390 (s, 3H), 2.75 (s, 3H), 2.14 (s, 3H).

[0791] Example 84: N-[8-(difluoromethoxy)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0792] F

[0793] o=s=o o

[0794]

[0795] The title compound was obtained by chiral separation of N-[8-(difluoromethoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (Example 80) using conditions J (41.1% yield, RT=8.74 min, first peak). LCMS (ESI): [M+H]+: 521.10. ’H NMR (400 MHz, DMSO-d6) 6 11.73 (d, J = 150.6 Hz, 1H), 8.25 (d, J= 5.3 Hz, 1H), 7.97 (d, J= 71.7 Hz, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.57 (d, J = 5.3 Hz, 1H), 7.44 - 7.35 (m, 4H), 7.21 (d, J = 8.8 Hz, 2H), 5.83 (s, 1H), 3.36 (s, 3H), 2.41 (s, 3H).

[0796] Example 85: 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0797]

[0798] 4-methyl-N-[4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 1 as a white solid (70.0% yield) using 3-[2-(4-fluorophenyl)-2-methoxy acetamido] -2-(2, 2, 2-trifluoroethyl)pyridine-4-carboxy lie acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. Chiral separation using conditions J afforded 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifhioroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (35.9% yield, RT= 7.09min, first peak) as a white solid. LCMS (ESI): [M+H]+: 537.10. ’H NMR (400 MHz, DMSO-d6) 6 12.10 - 11.54 (s, 1H), 8.67 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.45 - 7.36 (m, 4H), 7.26 (s, 1H), 7.20 (d, 7= 9.0 Hz, 1H), 5.81 (s, 1H), 4.40 - 4.30 (m, 1H), 3.70 (s, 1H), 3.31 (s, 3H), 2.41 (s, 3H).

[0799] Example 86: N-[8-(3-fluoro-3-methyl-azetidin-l-yl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide F

[0800] o=s=o o

[0801]

[0802] The title compound was obtained in analogy to Example 49 as a white solid (36.4% yield) using 3-amino-8-(3-fluoro-3-methylazetidin- l-yl)-2-[(4-fluorophenyl) (methoxy) methyl]pyrido[3,4-6?]pyrimidin-4-one and p-toluenesulfonyl chloride. LCMS (ESI):

[0803] [M+H]+: 542.20. ’H NMR (400 MHz, DMSO-d6) 611.65 (d, J= 194.9 Hz, 1H), 8.05 (s, 1H), 7.68 (d, J= 8.0 Hz, 2H), 7.38 (t, J= 8.0 Hz, 4H), 7.25 (d, J= 39.5 Hz, 2H), 6.87 (d, J = 5.4 Hz, 1H), 5.80 (s, 1H), 4.46 (s, 2H), 3.82 (s, 2H), 3.39 (s, 3H), 2.41 (s, 3H), 1.77 -1.38 (m, 3H).

[0804] Example 87: 4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0805]

[0806] a) 4-iodo-N-{2-[(R)-methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide

[0807] The title compound was obtained in analogy to Example 49 as a white solid (41.0% yield) using 3-amino-2-[(7?)-methoxy(phenyl)methyl]-8-methylpyrido[3,4-6?]pyrimidin-4-one (obtained by chiral separation) and 4-iodobenzene sulfonyl chloride. LCMS (ESI) [M + H]+: 563.0 b) 4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0808] The title compound was obtained in analogy to Example 66 as a white solid (24.4% yield) using 4-iodo-N-{2-[(R)-methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide and (1s,3s)-3-fluorocyclobutan-1-amine. LCMS (ESI) [M + H]+: 524.20. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J= 5.2 Hz, 1H), 8.25 (s, 1H), 7.50 - 7.41 (m, 5H), 7.35 (d, J = 6.5 Hz, 3H), 6.56 - 6.45 (m, 2H), 5.91 (s, 1H), 5.59 (d, J = 6.6 Hz, 1H), 4.87 (dp, J = 56.0, 6.8 Hz, 1H), 3.52 - 3.46 (m, 1H), 3.45 (s, 3H), 2.97 -2.63 (m, 5H), 2.10 - 2.01 (m, 2H).

[0809] Example 88: 4-(l-fluorocyclopropyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0810] F

[0811]

[0812] 4-(l-fluorocyclopropyl)-N-[4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 1 as a white solid (57.5% yield) using 3-[2-(4-fluorophenyl)-2-methoxy acetamido] -2-(2, 2, 2-trifluoroethyl)pyridine-4-carboxy lie acid and N'-[4-(1-fluorocyclopropyl)benzenesulfonyl]tert-butoxycarbohydrazide. Chiral separation using conditions J afforded 4-(1-fluorocyclopropyl)-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (18.4% yield, RT= 8.25min, first peak) as a white solid. LCMS (ESI) [M + H]+: 581.15.1H NMR (400 MHz, Acetonitrile-d3) δ 8.61 (d, J= 5.2 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.67 (d, J= 5.2 Hz, 1H), 7.52 - 7.43 (m, 2H), 7.40 - 7.32 (m, 2H), 7.16 - 7.06 (m, 2H), 5.89 (s, 1H), 4.15 (q, J= 10.8 Hz, 2H), 3.46 (s, 3H), 1.68 - 1.55 (m, 2H), 1.31 - 1.17 (m, 2H).

[0813] Example 89: N-[2-[(4-cyanophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-fluoro-benzenesulfonamide CN

[0814] 0=S=0 O

[0815]

[0816] The title compound was obtained in analogy to Example 1 as a white solid (12.6% yield) using 3-(2-(4-cyanophenyl)acetamido)-2-methylisonicotinic acid and 3-fluorobenzenesulfonohydrazide. LCMS (ESI) [M+H]+: 450.0.1H NMR (300 MHz, DMSO-d6) 5 11.90 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.94 - 7.76 (m, 2H), 7.70 - 7.45 (m, 7H), 4.46 (s, 2H), 2.61 (s, 3H).

[0817] Example 90: N-[6-chloro-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropyl-benzenesulfonamide

[0818]

[0819] The title compound was obtained in analogy to Example 2 as a white solid (28.3% yield) using 3-amino-6-chloro-2-[methoxy(phenyl)methyl] pyrido[3,4-d] pyrimidin-4-one and 4-isopropylbenzenesulfonyl chloride. LCMS (ESI): [M+H]+: 499.15. ’H NMR (400 MHz, DMSO-d6) d 11.55 (s, 1H), 9.08 (s, 1H), 7.78 -7.69 (m, 3H), 7.47 (d, J= 8.2 Hz, 2H), 7.36 (s, 5H), 5.76 (s, 1H), 3.32 – 3.31 (m, 3H), 3.01 (p, J= 6.8 Hz, 1H), 1.23 (d, J= 6.9 Hz, 6H).

[0820] Example 91: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3,4-difluoro-benzenesulfonamide o=s=o o

[0821]

[0822] F

[0823] The title compound was obtained in analogy to Example 1 as a white solid (24.8% yield) using 2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'-(3,4-difluorobenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 442.09.1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.97 - 7.88 (m, 1H), 7.72 - 7.64 (m, 2H), 7.58 (d, J = 5.2 Hz, 1H), 7.40 - 7.30 (m, 4H), 7.30 - 7.24 (m, 1H), 4.38 (s, 2H), 2.68 (s, 3H).

[0824] Example 92: 4-(difluoromethyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0825] o=s=o o

[0826]

[0827] The title compound was obtained in analogy to Example 1 as a white solid (27.8% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-[4-(difluoromethyl)benzenesulfonyl]tert-butoxycarbohydrazide. LCMS (ESIpos): [M+H]+: 487.00. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.95 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.41 (dd, J = 36.8, 5.8 Hz, 6H), 6.89 (t, J = 55.5 Hz, 1H), 5.89 (s, 1H), 3.47 (s, 3H), 2.84 (s, 3H).

[0828] Example 93: N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-(trifluoromethyl)benzenesulfonamide

[0829]

[0830] The title compound was obtained in analogy to Example 1 as a white solid (17.8% yield) using 2-methyl-3-(2-phenylacetamido)pyridine-4-carboxylic acid and N'-[2-(trifluoromethyl)benzenesulfonyl]tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 474.10.1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.46 (d, J = 5.2 Hz, 1H), 8.15 -7.99 (m, 2H), 7.95 - 7.81 (m, 2H), 7.54 (d, J = 5.2 Hz, 1H), 7.38 - 7.23 (m, 5H), 4.27 (d, J = 90.7 Hz, 2H), 2.66 (s, 3H).

[0831] Example 94: 4-methyl-N-[8-methyl-4-oxo-2-[(S)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0832]

[0833] The title compound is the second peak obtained in the chiral separation of 4-methyl-N-[8-methyl-4-oxo-2-[methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 34) using conditions A (40.5% yield, RT=9.0min, second peak). LCMS(ESI) [M + H]+: 451.10. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.85 - 8.56 (m, 1H), 8.46 (d, J = 5.2 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.49 - 7.40 (m, 3H), 7.37 - 7.31 (m, 5H), 5.85 (s, 1H), 3.44 (s, 3H), 2.78 (s, 3H), 2.43 (s, 3H).

[0834] Example 95: N-[2-[hydroxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide o=s=o o

[0835]

[0836] a) W(2-{[(tert-butyldiphenylsilyl)oxy](phenyl)methyl}-8-methyl-4-oxopyrido[3,4-t / ]pyrimidin-3-yl)-4-methylbenzenesulfonamide

[0837] The title compound was obtained in analogy to Example 1 as a light yellowish oil (44.4% yield) using 3- { 2- [(tert-butyldiphenylsilyl)oxy] -2-phenylacetamido } -2-methylpyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 675

[0838] b) N-[2-[hydroxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0839] To a stirred solution of W(2-{[(tert-butyldiphenylsilyl)oxy](phenyl)methyl}-8-methyl-4-oxopyrido[3,4-t / ]pyrimidin-3-yl)-4-methylbenzenesulfonamide (200.0 mg, 0.29 mmol, 1 equiv) in DMF (5 mL) was added triethylamine trihydrofluoride (238.8 mg, 1.48 mmol, 5 equiv) dropwise at room temperature. The resulting mixture was stirred for overnight 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 10 min; detector, UV 254 nm, to afford N-[2-[hydroxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (19.4 mg, 14.84% yield) as a white solid. LCMS (ESI): [M+H]+: 437.15. ’H NMR (300 MHz, DMSO-d6) 611.29 (s, 1H), 8.51 (d, J= 5.3 Hz, 1H), 7.74 - 7.63 (m, 2H), 7.58 (dd, J= 5.2, 0.7 Hz, 1H), 7.45 - 7.24 (m, 7H), 6.15 (s, 1H), 2.78 (s, 3H), 2.42 (s, 3H).

[0840] Example 96: 4- (difluoromethoxy) -N- [2- [fluoro(phenyl)methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0841]

[0842] F

[0843] The title compound was obtained in analogy to Example 1 as a white solid (22.8% yield) using 3-(2-fluoro-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-[4-(difluoromethoxy)benzenesulfonyl]tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 491.05. ’H NMR (400 MHz, Methanol-d4) δ 8.45 (d, J= 5.4 Hz, 1H), 7.88 - 7.80 (m, 2H), 7.62 - 7.53 (m, 3H), 7.43 (dd, J = 5.0, 2.0 Hz, 3H), 7.26 - 7.21 (m, 2H), 7.20 - 6.84 (m, 2H), 2.87 (s, 3H).

[0844] Example 97: 4-isopropyl-N-[8-methyl-4-oxo-2-[(S)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0845]

[0846] The title compound was obtained by chiral separation of 4-isopropyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 20) using conditions B (21.2% yield, RT=13.74min, second peak). LCMS (ESI) [M + H]+: 479.20.1H NMR (400 MHz, Acetonitrile-d3) δ 8.45 (d, 7= 5.2 Hz, 1H), 7.70 (d, 7= 8.3 Hz, 2H), 7.47 (d, 7= 5.3 Hz, 1H), 7.44 - 7.31 (m, 7H), 5.82 (s, 1H), 3.41 (s, 3H), 3.01 (p, 7= 6.9 Hz, 1H), 2.78 (s, 3H), 1.25 (d, 7= 6.9 Hz, 6H).

[0847] Example 98: 3,5-difluoro-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropyl-benzenesulfonamide F

[0848] 0=S=0 O

[0849]

[0850] The title compound was obtained in analogy to Example 1 as a white solid (9.6% yield) using 3 3-(2-(4-fluorophenyl)-2-methoxyacetamido)-2-methylisonicotinic acid and N'-(3,5-difluoro-4-isopropylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 533.15. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.48 (d, J= 5.2 Hz, 1H), 7.50 (dd, J= 8.6, 5.6 Hz, 3H), 7.37 (d, J= 7.2 Hz, 2H), 7.12 (t, J= 8.7 Hz, 2H), 5.88 (s, 1H), 3.47 (s, 3H), 3.41 (p, J= 7.1 Hz, 1H), 2.14 (s, 3H), 1.38 - 1.31 (m, 6H).

[0851] Example 99: N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoro-l-methyl-ethyl)benzenesulfonamide

[0852] o=s=o o

[0853]

[0854] The title compound was obtained in analogy to Example 1 as a white solid (40.9% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-[4-(1,1,1-trifluoropropan-2-yl)benzenesulfonyl]tert-butoxycarbohydrazide.

[0855] LCMS (ESI) [M + H]+: 533.0. ’H NMR (300 MHz, DMSO-d6) δ 11.30 (s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.62 (d, J= 8.2 Hz, 2H), 7.55 (d, J= 5.2 Hz, 1H), 7.47 - 7.33 (m, 6H), 5.84 (s, 1H), 4.01 - 3.89 (m, 1H), 3.02 (s, 3H), 2.76 - 2.70 (m, 3H), 1.51 (d, 7 = 7.1 Hz, 3H). Example 100: N- [8- (difluoromethyl) -2- [(4-fluorophenyl) -methoxy-methyl] -4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0856]

[0857] a) N-{8-[(benzyloxy)methyl]-2-[(4-fluorophenyl) (methoxy) methyl] -4-oxopyrido [3, 4-d] pyrimidin-3-yl } -4-methylbenzenesulfonamide

[0858] A solution of 2-[(benzyloxy)methyl]-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylic acid (500 mg, 1.178 mmol, 1 equiv) and 2V-(4-me thy Ibenzene sulfonyl) tert-butoxycarbohydrazide (404.8 mg, 1.414 mmol, 1.2 equiv) in dioxane (3 mL) was treated with trichloropho sphane (485.3 mg, 3.534 mmol, 3 equiv) at RT. The mixture was stirred 1.5 hours at 100 °C. The reaction was quenched with water at 0 °C. The mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2 / 3) to afford N-{8-[(benzyloxy)methyl]-2-[(4-fluorophenyl) (methoxy) methyl]-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-methylbenzenesulfonamide (400 mg, 59.09% yield) as a yellow oil. LCMS (ESI) [M + H]+: 575.2.

[0859] b) N-{2-[(4-fluorophenyl) (methoxy)methyl]-8-(hydroxymethyl)-4-oxopyrido[3,4-d] pyrimidin-3-yl } -4-methylbenzenesulfonamide

[0860] A solution of N-{8-[(benzyloxy)methyl]-2-[(4-fluorophenyl) (methoxy)methyl]-4-oxopyrido[3,4-d] pyrimidin-3-yl]-4-methylbenzenesulfonamide (200 mg, 0.348 mmol, 1 equiv) in DCM (2 mL) was treated with TiC14 (33.0 mg, 0.174 mmol, 0.5 equiv) at 0 °C under nitrogen atmosphere. The mixture was stirred overnight at RT. The reaction was quenched with water at 0 °C. The resulting mixture was extracted with DCM (3 x 3 mL). The combined organic layers were washed with water (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 60% gradient in 30 min; detector, UV 254 nm. This resulted in N-{2-[(4-fluorophenyl) (methoxy)methyl]-8-(hydroxymethyl)-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-methylbenzenesulfonamide (110 mg, 65.23% yield) as a white solid. LCMS (ESI) [M + H] +: 485.2.

[0861] c) N- { 2- [(4-fluorophenyl(methoxy)methyl] - 8-formyl-4-oxopyrido [3,4-d] pyrimidin-3-yl } -4-methylbenzenesulfonamide

[0862] A solution of N-{2-[(4-fluorophenyl) (methoxy)methyl]-8-(hydroxymethyl)-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-methylbenzenesulfonamide (100 mg, 0.206 mmol, 1 equiv) in DCM (3 mL) was treated with manganese dioxide (179.4 mg, 2.060 mmol, 10 equiv) at RT. The mixture was stirred overnight at RT. 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-{2-[(4-fluorophenyl(methoxy)methyl]-8-formyl-4-oxopyrido[3,4-d] pyrimidin-3-yl} -4-methylbenzenesulfonamide (80 mg, 80.33% yield) as white solid. LCMS (ESI) [M + H] +: 483.2.

[0863] d) N-[8-(difhioromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0864] A solution of A-{2-[(4-fluorophenyl) (mcthoxy)mcthyl|-8-formyl-4-oxopyrido|3,4-<7| pyrimidin-3-yl} -4-methylbenzenesulfonamide (90 mg, 0.187 mmol, 1 equiv) in DCM (2 mL) was treated with DAST (60.1 mg, 0.374 mmol, 2 equiv) at -78 °C under nitrogen atmosphere. The mixture was stirred for 2 hours at RT. The reaction was quenched with H2O at 0 °C. The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with H2O (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-[8-(difhioromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (1.5 mg, 2.32% yield) as a white solid. LCMS (ESI) [M + H]+:

[0865] 505.2. ‘H NMR (400 MHz, DMSO-d6) d 11.9 -11.4 (s, 1H), 8.72 (d, J= 5.1 Hz, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.66 (d, J= 7.9 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 7.32 (s, 2H), 7.19 (t, J= 8.7 Hz, 3H), 5.97 (s, 1H), 3.36 (s, 3H), 2.39 (s, 3H).

[0866] Example 101: N- [2- [methoxy(phenyl)methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzofuran-3-sulfonamide

[0867]

[0868] The title compound was obtained in analogy to Example 1 as a white solid (15.7% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-(1-benzofuran-3-sulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): m / z = 477.12 [M + H]+. ’H NMR (400 MHz, DMSO-d6) 8 11.97 (s, 1H), 8.70 (s, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.75 (t, J= 8.1 Hz, 2H), 7.50- 7.46 (m, 2H), 7.44- 7.32 (m, 6H), 5.91 (s, 1H), 3.31 (s, 3H), 2.86 (s, 3H).

[0869] Example 102: N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0870]

[0871] The title compound was obtained in analogy to Example 1 as a white solid (4.4% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-(2,2,2-trifluoroethyl)pyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LC-MS (ES, m / z): [M+l] =537.XH NMR (300 MHz, DMSO-d6) 611.8 - 11.2 (m, 1H), 8.67 (d, 7= 5.2 Hz, 1H), 7.79 (d, 7= 5.2 Hz, 1H), 7.71 (d, 7= 8.1 Hz, 2H), 7.51 - 7.35 (m, 4H), 7.18 (t, 7 = 8.7 Hz, 2H), 5.87 (s, 1H), 4.1 - 4.3 (m, 2H), 3.40 (s, 3H), 2.43 (s, 3H).

[0872] Example 103: 4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0873]

[0874] The title compound was obtained in analogy to Example 66 as a white solid (18.4% yield) using 4-iodo-N-{2-[methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and (ls,3s)-3-fluorocyclobutan-l-amine. LCMS (ESI) [M + H]+: 524.20.1H NMR (400 MHz, Acetonitrile-d3) δ8.60 - 8.40 (m, 2H), 7.52 - 7.28 (m, 8H), 6.53 - 6.46 (m, 2H), 5.90 (s, 1H), 5.60 (d, J= 6.5 Hz, 1H), 4.87 (dp, J= 56.0, 6.8 Hz, 1H), 3.51 - 3.41 (m, 4H), 3.08 - 2.79 (m, 5H), 2.12 - 2.03 (m, 2H).

[0875] Example 104: 4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0876] o=s=o o

[0877]

[0878] F

[0879] The title compound was obtained in analogy to Example 1 as a white solid (98.7% yield) using 3-(2-methoxy-2-phenylacetamido)-2-methylpyridine-4-carboxylic acid and N'-[4-(2,2-difluorocyclopropyl)benzenesulfonyl]tert-butoxycarbohydrazide. LC-MS (ES, m / z):

[0880] [M+l] =513. ’H NMR (400 MHz, DMSO-d6) δ 12.05 - 11.50 (m, 1H), 8.51 (d, J= 5.2 Hz, 1H), 7.76 (dd, J= 8.6, 2.3 Hz, 2H), 7.55 (t, J= 6.1 Hz, 1H), 7.49 (d, J= 8.3 Hz, 1H), 7.44 (s, 1H), 7.38 (s, 4H), 7.35 (d, J= 6.7 Hz, 1H), 5.81 (d, J = 7.2 Hz, 1H), 3.39 (d, J= 4.6 Hz, 3H), 3.25 - 3.12 (m, 1H), 2.86 (s, 2H), 2.47 (s, 1H), 2.16 - 2.04 (m, 2H). Example 105: (S)-4-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0881]

[0882] The title compound was obtained by chiral separation of 4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 50) using conditions C (29.8% yield, RT=33.1 min, second peak). LCMS (ESI) [M + H]+: 498.15. ’H NMR (400 MHz, DMSO-d6) 8 10.9 (s, 1H), 8.50 (d, J= 5.3 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.52 - 7.38 (m, 4H), 7.19 (s, 2H), 6.72 (d, J= 8.7 Hz, 2H), 5.86 (s, 1H), 3.37 (s, 3H), 3.01 (s, 6H), 2.85 (s, 2H), 2.51 (d, J = 2.4 Hz, 1H).

[0883] Example 106: 3,4-dimethoxy-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0884]

[0885] 3,4-dimethoxy-N-[8-methyl-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 1 as a white solid (9.9% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'-(3,4-dimethoxybenzenesulfonyl) tert-butoxycarbohydrazide. Chiral separation using conditions J afforded 3,4-dimethoxy-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (35.7% yield, RT= 8.50min, first peak) as a white solid. LCMS (ESI): [M+H]+: 515.25. ’H NMR (300 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.58 (d, J= 5.2 Hz, 1H), 7.47 (s, 2H), 7.33 (dd, J = 8.5, 2.2 Hz, 1H), 7.25 (d, J= 2.2 Hz, 1H), 7.22 (s, 2H), 7.07 (d, J = 8.6 Hz, 1H), 5.90 (s, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 3.40 (s, 3H), 2.84 (s, 2H), 2.49 (s, 1H).

[0886] Example 107: 4-isopropenyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0887]

[0888] The title compound is the second peak from the chiral separation of 4-isopropenyl-N-[8-methyl-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 83) using conditions J (27.6% yield, RT=12.09 min, second peak). LCMS (ESI): [M+H]+: 495.05.1H NMR (400 MHz, DMSO-d6) 6 11.64 (s, 1H), 8.43 (d, J= 5.3 Hz, 1H), 7.77 - 7.61 (m, 4H), 7.50 (s, 1H), 7.39 (s, 2H), 7.15 (s, 2H), 5.79 (s, 1H), 5.54 (s, 1H), 5.23 (s, 1H), 3.49 (s, 3H), 2.67 (s, 3H), 2.07 (s, 3H).

[0889] Example 108: 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-[rel- (3R)-3-(trifluoromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[0890]

[0891] 4-methyl-N-[4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]-8-[3-(trifluoromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 1 as a yellow solid (21.4% yield) using 3-[2-(4- fluorophenyl)-2-methoxyacetamido]-2-[3-(trifluoromethyl)pyrrolidin-l-yl]pyridine-4-carboxylic acid and N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. Chiral separation using conditions K afforded 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-[rel-(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (6.63% yield, RT= 3.55min, first peak) as a white solid. LCMS (ESI): [M+H]+: 592.20. ’H NMR (400 MHz, DMSO-d6) 311.66 (d, J= 195.9 Hz, 1H), 8.09 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.2 Hz, 4H), 7.20 (s, 2H), 6.87 (d, J = 5.2 Hz, 1H), 5.81 (d, J= 23.4 Hz, 1H), 4.28 - 3.46 (m, 4H), 3.37 (s, 3H), 3.08 (s, 1H), 2.50 (s, 3H), 2.24 (s, 2H).

[0892] Example 109: 4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-[rel- (3S)-3-(trifluoromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[0893]

[0894] The title compound is the fourth peak obtained by chiral separation of 4-methyl-N-[4-oxo-2-[(4-fluorophenyl)-rnethoxy-rnethyl]-8-[3-(trifhioromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 108) using conditions K (6.51% yield, RT=5.65min, fourth peak). LCMS (ESI) [M+H]+: 592.20.1H NMR (400 MHz, DMSO-d6) δ11.66 (d, J = 195.9 Hz, 1H), 8.09 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.2 Hz, 4H), 7.20 (s, 2), 6.87 (d, J = 5.2 Hz, 1H), 5.81 (d, J = 23.4 Hz, 1H), 4.28 - 3.46 (m, 4H), 3.37 (s, 3H), 3.08 (s, 1H), 2.50 (s, 3H), 2.24 (s, 2H).

[0895] Example 110: l-cyclopropyl-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]indole-5-sulfonamide F

[0896] o=s=o o

[0897]

[0898] The title compound was obtained in analogy to Example 1 as a white solid (20.7% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'-(1-cyclopropylindol-5-ylsulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 534.16. ’H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 8.04 (s, 1H), 7.71 (d, J= 8.7 Hz, 1H), 7.58 (dd, J= 8.7, 1.9 Hz, 1H), 7.53 (d, J= 3.3 Hz, 1H), 7.50 (dd, J= 5.2, 0.7 Hz, 1H), 7.43 -7.37 (m, 2H), 7.20 (d, J= 8.6 Hz, 2H), 6.58 (d, J= 3.3 Hz, 1H), 5.77 (s, 1H), 3.54 (tt, J = 7.0, 3.6 Hz, 1H), 3.35 (s, 3H), 2.85 (s, 2H), 2.51 (s, 1H), 1.14 - 1.08 (m, 2H), 1.01 - 0.94 (m, 2H).

[0899] Example 111: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzofuran-5-sulfonamide

[0900] F

[0901] o=s=o o

[0902]

[0903] The title compound was obtained in analogy to Example 1 as a white solid (27.6% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-methylpyridine-4-carboxylic acid and N'-(1-benzofuran-5-sulfonyl)tert-butoxycarbohydrazide. LCMS (ESI): [M+H]+: 495.11. ’H NMR (300 MHz, DMSO-d6) δ 11.52 (s, 1H),8.48 (d, J= 5.2 Hz, 1H), 8.18 - 8.14 (m, 2H), 7.79 (d, J= 1.3 Hz, 2H), 7.52- 7.45 (m, 3H), 7.19 (t, J= 8.8 Hz, 2H), 7.09 (d, J= 2.3 Hz, 1H), 5.90 (s, 1H), 3.35 (s, 3H), 2.75 (s, 3H). Example 112: N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0904]

[0905] The title compound was obtained by chiral separation of N-[8-(difluoromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (Example 100) using conditions G (37.8% yield, RT=15.7 min, first peak). LCMS (ESI): [M+H]+: 505.15. ’H NMR (400 MHz, DMSO-d6) 8 12.20 - 11.39 (m, 1H), 8.76 (d, J= 5.1 Hz, 1H), 7.95 (d, J= 5.1 Hz, 1H), 7.76 - 7.13 (m, 9H), 5.87 (s, 1H), 3.38 (s, 3H), 2.41 (s, 3H).

[0906] Example 113: N- [2- [(4-fluorophenyl)-methoxy-methyl] -8-(hydroxymethyl)-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0907] F

[0908] o=s=o o

[0909]

[0910] a) N-{8-[(benzyloxy)methyl]-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-methylbenzenesulfonamide

[0911] The title compound was obtained in analogy to Example 1 as a yellow solid (52.8% yield) using 2-[(benzyloxy)methyl]-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4- carboxylic acid and MN'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M + H]+: 575.1

[0912] b) N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-(hydroxymethyl)-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0913] To a stirred solution of A-{8-[(benzyloxy)methyl]-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxo-pyrido[3,4-6?]pyrimidin-3-yl}-4-methylbenzenesulfonamide (200.0 mg, 0.348 mmol, 1 equiv) in DCM (5 mL) was added Titanium tetrachloride (66.01 mg, 0.348 mmol, 1 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 diluted with DCM (300 mL). The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The combined organic layers were washed with water (3x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B:

[0914] ACN; Flow rate: 60 mL / min; Gradient: 25% B to 41 % B in 10 min; Wave Length:

[0915] 254nm / 220nm; RT=11.82min) to afford N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-(hydroxymethyl)-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (37.6 mg, 22.30% yield, 97.757% purity) as a white solid. LCMS (ESI): [M+H]+: 485.15. ’H NMR (300 MHz, DMSO-d6) 6 11.74 (d, J= 142.5 Hz, 1H), 8.63 (d, J= 5.2 Hz, 1H), 7.76 - 7.64 (m, 3H), 7.55 - 7.44 (m, 1H), 7.40 (d, J = 8.2 Hz, 3H), 7.33 - 7.12 (m, 2H), 5.85 (d, J = 26.5 Hz, 1H), 5.11 (s, 1H), 4.70 (d, J = 22.6 Hz, 1H), 3.38 (d, J = 13.6 Hz, 3H), 2.42 (s, 3H).

[0916] Example 114: N-[8-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0917]

[0918] - Ill - N-[8-(6,6-difhioro-2-azaspiro[3.3]heptan-2-yl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide was obtained in analogy to Example 49 as a yellow solid (88.4% yield) using 3-amino-8-{6,6-difluoro-2-azaspiro [3.3] heptan-2-yl]-2-[(4-fluorophenyl) (methoxy) methyl] pyrid |3,4-<7| pyrimidin-4-one and p-toluenesulfonyl chloride. Chiral separation using conditions K afforded N-[8-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (35.7% yield, RT= 15.64min, second peak) as a white solid. LCMS(ESI) [M + H]+: 586.2.!H NMR (400 MHz, DMSO-d6) δ 11.87 – 11.36 (m, J = 5.3 Hz, 1H), 8.02 (d, J = 5.3 Hz, 1H), 7.67 (d, J= 8.0 Hz, 2H), 7.37 (d, J= 7.8 Hz, 4H), 7.23 (s, 2H), 6.81 (d, J= 5.3 Hz, 1H), 5.80 (s, 1H), 4.1 - 3.7 (s, 2H), 4.45 (s, 2H), 3.38 (s, 3H), 2.91 (s, 4H), 2.40 (s, 3H).

[0919] Example 115: 4-(l-fluorocyclopropyl)-N-[4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0920]

[0921] The title compound is the second peak obtained in the chiral separation of 4-(l-fluorocyclopropyl)-N-[4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifhioroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 88) using conditions J (24.2% yield, RT=11.23min, second peak). LCMS (ESI) [M + H]+: 581.20. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.61 (d, J = 5.1 Hz, 1H), 7.83 - 7.75 (m, 2H), 7.67 (d, J = 5.2 Hz, 1H), 7.47 (ddd, J = 8.5, 5.4, 2.6 Hz, 2H), 7.40 - 7.32 (m, 2H), 7.16 - 7.06 (m, 2H), 5.89 (s, 1H), 4.17 (s, 2H), 3.46 (s, 3H), 1.68 - 1.54 (m, 2H), 1.31 - 1.15 (m, 2H).

[0922] Example 116: 4-(2,2-difluoroethoxy)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0923]

[0924] a) 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-6?]pyrimidin-4-one

[0925] 3-amino-2-[(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one was obtained in analogy to Example 49 as a white solid (42.3% yield) using 2-[(4-fluorophenyl)(methoxy)methyl] - 8-methylpyrido [3,4-d] [ 1,3] oxazin-4-one and hydrazine hydrate. Chiral separation using conditions I afforded 3-amino-2-[( / ?)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-6?]pyrimidin-4-one (100% ee, 48.6% yield, RT=4.62min, first peak) and 3-amino-2-|(. S')-(4-fluorophcnyl)(mcthoxy)mcthyl |-8-methylpyrido[3,4-6?]pyrimidin-4-one (98.64% ee, 42.3% yield, RT=6.24min, second peak). MS (ESIpos): m / z = 315.00 [M+H]+

[0926] b) 4-(2,2-difhioroethoxy)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-rnethoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzenesulfonamide

[0927] The title compound was obtained in analogy to Example 49 as a white solid (18.5% yield) using 3-amino-2-[(R)-(4-fluorophenyl) (methoxy)methyl] -8-methylpyrido[3,4-<7|pyrimidin-4-onc and 4-(2,2-difluoroethoxy)benzenesulfonyl chloride. LCMS (ESI): [M+H]+: 535.15. ’H NMR (400 MHz, DMSO-d6) 8 11.66 (d, J= 186.9 Hz, 1H), 8.50 (d, J = 5.2 Hz, 1H), 7.83 - 7.66 (m, 2H), 7.60 - 7.54 (m, 1H), 7.54 - 7.36 (m, 2H), 7.17 (d, J = 8.9 Hz, 4H), 6.60 - 6.26 (m, 1H), 5.90 (s, 1H), 4.54 - 4.36 (m, 2H), 3.41 (s, 3H), 2.86 (s, 2H), 2.56 (s, 1H).

[0928] Example 117: 4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[0929]

[0930] F

[0931] The title compound was obtained in analogy to Example 116 as a white solid (64.6% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(2,2-difluorocyclopropyl)benzenesulfonyl chloride. MS (ESIpos): m / z = 531.12 [M+H]+. ’H NMR (300 MHz, DMSO-d6) 55 12.1 - 11.4 (m, 1H), 8.52 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.60 - 7.20 (m, 5H), 7.17 (s, 2H), 5.80 (d, 7= 5.8 Hz, 1H), 3.41 (s, 3H), 3.21 (s, 1H), 2.86 (s, 2H), 2.55 - 2.52 (m, 1H), 2.17 -2.05 (m, 2H).

[0932] Example 118: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethoxy)benzenesulfonamide

[0933]

[0934] The title compound was obtained in analogy to Example 116 as a white solid (43.0% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(2,2,2-trifluoroethoxy)benzenesulfonyl chloride. MS (ESIpos): m / z = 553.11 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 6 11.40 (s, 1H), 8.49 (d, J= 5.2 Hz, 1H), 7.77 (d, J= 8.8 Hz, 2H), 7.56 (d, J= 5.2 Hz, 1H), 7.46 (d, J= 6.7 Hz, 2H), 7.30 -7.03 (m, 4H), 5.90 (s, 1H), 4.95 - 4.78 (m, 2H), 3.40 (s, 3H), 2.72 (s, 3H). Example 119: 4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0935] F

[0936] o=s=o o

[0937]

[0938] The title compound was obtained in analogy to Example 116 as a white solid (63.5% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(2,2-difluorocyclopropyl)benzenesulfonyl chloride. MS (ESIpos): m / z = 531.12 [M+H]+. ’H NMR (300 MHz, DMSO-d6) 5 12.1 - 11.4 (m, 1H), 8.52 (d, J= 5.3 Hz, 1H), 7.77 (d, J= 8.3 Hz, 2H), 7.57 (d, J= 5.1 Hz, 1H), 7.49 (d, J= 8.3 Hz, 4H), 7.22 (s, 2H), 5.83 (s, 1H), 3.45 - 3.35 (m, 3H), 3.28 - 3.11 (m, 1H), 2.86 (s, 2H), 2.55 - 2.52 (m, 1H), 2.19 - 2.03 (m, 2H).

[0939] Example 120: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide

[0940] F

[0941] o=s=o o

[0942]

[0943] a) A^-{2-[(7?)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-6?]pyrimidin-3-yl}-4-iodobenzenesulfonamide

[0944] The title compound was obtained in analogy to Example 116 as a white solid (88.5% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4- d]pyrimidin-4-one and 4-iodobenzenesulfonyl chloride. MS (ESIpos): m / z = 581.00 [M+H]+

[0945] b) N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide

[0946] The title compound was obtained in analogy to Example 66 as a white solid (49.7% yield) using A-{2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-*pyrimidin-3-yl]-4-iodobenzenesulfonamide and morpholine. MS (ESIpos): m / z = 540.00 [M+H]+.1H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J = 5.2 Hz, 2H), 7.61 -7.40 (m, 5H), 7.09 (s, 2H), 6.92 - 6.83 (m, 2H), 5.91 (s, 1H), 3.80 - 3.73 (m, 4H), 3.45 (s, 3H), 3.34 - 3.21 (m, 4H), 2.96 - 2.52 (m, 3H).

[0947] Example 121: N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0948]

[0949] The title compound was obtained in analogy to Example 1 as a white solid (61.5% yield) using 3- [2-(4-fluorophenyl)-2-methoxyacetamido] -2-(trifluoromethyl)pyridine-4-carboxylic acid and MN'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. MS (ESIpos): m / z = 523.00 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.67 (d, J = 5.1 Hz, 1H), 7.92 (d, J= 5.0 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.51 - 7.43 (m, 2H), 7.38 - 7.32 (m, 2H), 7.16 - 7.05 (m, 2H), 5.89 (s, 1H), 3.44 (s, 3H), 2.44 (s, 3H).

[0950] Example 122: 4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0951]

[0952] The title compound was obtained in analogy to Example 120 as a white solid (88.5% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one (obtained by chiral separation in example 116) and 4-[(difluoromethoxy)methyl]benzenesulfonyl chloride. LC-MS (ESI, m / z): [M+ H]+:

[0953] 535.15. ’H NMR (400 MHz, DMSO-d6) 8 11.82 (d, J= 186.0 Hz, 1H), 8.51 (d, J= 5.2 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.63 - 7.50 (m, 3H), 7.43 (s, 2H), 7.34 - 7.12 (m, 2H), 7.06 -6.64 (m, 1H), 5.82 (s, 1H), 5.05 (s, 2H), 3.40 (s, 3H), 2.98 - 2.79 (m, 2H), 2.52 (s, 1H).

[0954] Example 123: N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-lH-indole-6-sulfonamide

[0955] o=s=o o

[0956]

[0957] a) 3-amino-2-[(R)-methoxy(phenyl)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one

[0958] 3-amino-2-[methoxy(phenyl)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one was obtained in analogy to Example 49 using 2-[methoxy(phenyl)methyl]-8-methylpyrido[3,4-d][l,3]oxazin-4-one and hydrazine monohydrate (69.7% yield) as a light yellow solid. Chiral separation using conditions H afforded 3-amino-2-[(R)-methoxy(phenyl)methyl]-8-methylpyrido [3,4-t7]pyrimidin-4-one (99.3%ee, 50% yield, RT=3.68min, first peak) and 3-amino- 2-|(. S')-mcthoxy(phcnyl)mcthyl|-8-mcthylpyrido|3,4-d|pyrimidin-4-onc (98.9% ee, 43.3% yield, 5.05min, second peak), both as light yellow solid. b) N- { 2- [(R)-methoxy(phenyl)methyl] -8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl } -3-nitro-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide

[0959] The title compound was obtained in analogy to Example 49 as a white solid (56.4% yield) using 3-amino-2-[(R)-methoxy(phenyl)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 3-nitro-4-[2-(trimethylsilyl)ethynyl]benzenesulfonyl chloride. MS (ESIpos): m / z = 578.00 [M+H]+

[0960] c) 3-amino-N-{2-[(R)-methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl } -4- [2-(trimethylsilyl)ethynyl]benzenesulfonamide

[0961] A solution of N-{2-[(R)-methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}-3-nitro-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide (100 mg, 0.173 mmol, 1 equiv) and Tin(II) chloride dihydrate (200.0 mg, 0.886 mmol, 5.12 equiv) in EtOAc (5 mL) was stirred at 30°C overnight under nitrogen atmosphere. The reaction was quenched with Water / Ice at 0°C. The mixture was basified to pH 5 with saturated Na2CO3 (aq.). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-amino-N-{2-[(R)-methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide (90 mg, crude) as a yellow solid. MS (ESIpos): m / z = 548.00 [M+H]+

[0962] d) N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-lH-indole- 6- sulfonamide

[0963] A solution of 3-amino-A-{2-[(R)-methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[2-(trimethylsilyl)ethynyl]benzenesulfonamide (90 mg, 0.164 mmol, 1 equiv) and Cui (12.5 mg, 0.066 mmol, 0.40 equiv) in DMF (2 mL) was stirred at 120 °C for 2 h under nitrogen atmosphere. 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: 5% B to 5% B in 1.5 min, 5% B to 28% B in 2 min, 28% to 46% B in 15 min; Wave Length: 254nm / 220 nm; RT=13.37 min) to afford N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-lH-indole-6-sulfonamide (36.9 mg, 47.22% yield, 99.5% purity) as a white solid. MS (ESIpos): m / z = 476.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 11.65 (d, J = 43.9 Hz, 1H), 11.28 (s, 1H), 8.47 (d, J= 5.3 Hz, 1H), 7.85 (s, 1H), 7.76 - 7.66 (m, 2H), 7.49 (d, J= 5.2 Hz, 1H), 7.44 - 7.27 (m, 6H), 6.63 - 6.59 (m, 1H), 5.72 (s, 1H), 3.31 - 3.24 (m, 3H), 2.86 (s, 2H), 2.46 (s, 1H). Example 124: 4-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0964]

[0965] The title compound was obtained in analogy to Example 116 as a white solid (54.3% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and tosyl chloride. LCMS (ESI): [M+H]+: 469.15. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.78 (s, 1H), 8.48 - 8.42 (m, 1H), 7.69 - 7.64 (m, 2H), 7.57 - 7.43 (m, 3H), 7.36 - 7.30 (m, 2H), 7.13 (d, J= 28.5 Hz, 2H), 5.86 (s, 1H), 3.44 (s, 3H), 2.89 (s, 3H), 2.43 (s, 3H).

[0966] Example 125: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide

[0967]

[0968] The title compound was obtained in analogy to Example 120 as a white solid (38.5% yield) using N-{2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-iodobenzenesulfonamide and morpholine. MS (ESIpos): m / z = 540.00 [M+H]+.1H NMR (400 MHz, Acetonitrile-d3) δ 8.65 – 8.42 (m, 2H), 7.59 - 7.53 (m, 2H), 7.48 (t, J= 6.1 Hz, 3H), 7.10 (t, J = 8.8 Hz, 2H), 6.90 - 6.82 (m, 2H), 5.92 (s, 1H), 3.78 - 3.72 (m, 4H), 3.45 (s, 3H), 3.31 - 3.23 (m, 4H), 2.77 (s, 3H).

[0969] Example 126: 4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0970] F

[0971]

[0972] The title compound was obtained in analogy to Example 122 as a white solid (23.8% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl] -8-methylpyrido[3,4-<7|pyrimidin-4-onc (obtained by chiral separation in example 116) and 4-[(difluoromethoxy)methyl]benzenesulfonyl chloride. LC-MS (ESI, m / z): [M+ H]+:

[0973] 535.15. ’H NMR (400 MHz, DMSO-d6) 8 11.82 (d, J= 186.3 Hz, 1H), 8.51 (d, J= 5.2 Hz, 1H), 7.89 - 7.76 (m, 2H), 7.68 - 7.54 (m, 3H), 7.46 (d, J = 22.1 Hz, 2H), 7.23 (d, J = 25.7 Hz, 2H), 7.08 - 6.62 (m, 1H), 5.84 (d, J= 21.6 Hz, 1H), 5.05 (s, 2H), 3.36 (s, 3H), 2.86 (s, 2H), 2.52 (s, 1H).

[0974] Example 127: 4-(2,2-difluorocyclopropyl)-N-(2-((R)-methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[0975] o=s=o o

[0976]

[0977] F The title compound was obtained in analogy to Example 123 as a white solid (51.6% yield) using 3-amino-2-[(R)-methoxy(phenyl)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(2,2-difluorocyclopropyl) benzenesulfonyl chloride. LCMS (ESI) [M + H]+: 513.1. ’H NMR (400 MHz, DMSO-d6) d 11.57 (s, 1H), 8.51 (d, J= 5.3 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.55 (dd, 7= 8.9, 5.1 Hz, 1H), 7.47 (dd, J= 18.7, 6.0 Hz, 2H), 7.36 (d, J = 13.1 Hz, 5H), 5.81 (d, J = 7.3 Hz, 1H), 3.39 (d, J = 4.4 Hz, 3H), 3.18 (q, J = 10.9 Hz, 1H), 2.86 (s, 2H), 2.47 (s, 1H), 2.10 (q, J = 10.1 Hz, 2H).

[0978] Example 128: N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[0979]

[0980] A solution of N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (example 29, 100 mg, 0.205 mmol, 1 equiv) in MeOH (3 mL) was added with MeONa (33.1 mg, 0.615 mmol, 3 equiv) at 0 °C. The mixture was stirred for 48 hours at 40 °C. The resulting mixture was extracted with EtOAc (3 x 5 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, H2O (FA) in ACN, 20% to 70% gradient in 20 min; detector, UV 254 nm to afford N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (48.8 mg, 49.25% yield) as a white solid. LCMS (ESI) [M + H]+: 485.1. ’H NMR (400 MHz, DMSO-d6) d 11.47 (s, 1H), 8.17 (d, J= 5.4 Hz, 1H), 7.66 (d, J= 7.9 Hz, 2H), 7.38 (d, J = 8.0 Hz, 4H), 7.27 (d, J = 5.3 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 5.82 (s, 1H), 4.06 (s, 2H), 3.94 (s, 1H), 3.34 (s, 3H), 2.41 (s, 3H).

[0981] Example 129: N-(2-((4-fluorophenyl)(methoxy)methyl)-8-(methoxy-d3)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide

[0982]

[0983] A solution of N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (example 29, 100 mg, 0.205 mmol, 1 equiv) and t-BuOK (45.9 mg, 0.409 mmol, 2.00 equiv) in CD3OD (5 mL) was stirred at 50 °C overnight under nitrogen atmosphere. The reaction was quenched with water 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 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: 33% B to 48% B in 10 min; Wave Length: 254nm / 220nm; RT= 10.41 min to afford N-(2-((4-fluorophenyl)(methoxy)methyl)-8-(methoxy-d3)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide (25.9 mg, 25.97% yield) as a white solid. LCMS (ESI): m / z = 488.00 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 6 11.48 (s, 1H), 8.17 (d, J= 5.4 Hz, 1H), 7.70- 7.63 (m, 2H), 7.38 (d, J= 8.1 Hz, 4H), 7.27 (d, J= 5.3 Hz, 1H), 7.20 (t, J= 8.7 Hz, 2H), 5.83 (s, 1H), 3.34 (s, 3H), 2.41 (s, 3H).

[0984] Example 130: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[(ls,3s)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide

[0985]

[0986] The title compound was obtained in analogy to Example 120 as a white solid (20.6% yield) using N- { 2- [(R)-(4-fluorophenyl)(methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-d]pyrimidin-3-yl}-4-iodobenzenesulfonamide and (ls,3s)-3-(trifluoromethyl)cyclobutan-l-amine hydrochloride. LCMS (ESIpos): m / z = 592.00 [M+H]+.1H NMR (400 MHz, Acetonitrile-d₃) 58.48 - 8.43 (m, 1H), 7.51 - 7.43 (m, 5H), 7.09 (t, J = 8.8 Hz, 2H), 6.56 -6.48 (m, 2H), 5.92 (s, 1H), 5.61 (d, J = 6.9 Hz, 1H), 4.00 - 3.88 (m, 1H), 3.44 (s, 3H), 2.92 - 2.82 (m, 1H), 2.77 (s, 3H), 2.67 - 2.58 (m, 2H), 2.00 (d, J= 11.3 Hz, 2H).

[0987] Example 131: 4-[(2,2-difluorocyclopropyl)methyl]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[0988]

[0989] The title compound was obtained in analogy to Example 123 as a white solid (51.6% yield) using 3-amino-2-[(R)-methoxy(phenyl)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-[(2,2-difluorocyclopropyl)methyl]benzenesulfonyl chloride. LC-MS (ES, m / z):

[0990] [M+l] = 527.15. ’H NMR (400 MHz, Acetonitrile-d₃) 58.85-8.55 (m, 1H), 8.46 (d, J= 5.2 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.44 (td, J = 8.5, 5.8 Hz, 5H), 7.40 - 7.30 (m, 3H), 5.85 (s, 1H), 3.44 (s, 3H), 2.92 - 2.88 (m, 2H), 2.84 - 2.70 (s, 3H), 1.91 - 1.82 (m, 1H), 1.63 -1.49 (m, 1H), 1.30 - 1.14 (m, 1H).

[0991] Example 132: N-(8-cyano-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide F

[0992] o=s=o o

[0993]

[0994] A solution of N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (100 mg, 0.205 mmol, 1 equiv) and zincdicarbonitrile (24.0 mg, 0.205 mmol, 1 equiv) in DMF (2 mL) was added with Pd(PPh3)4 (11.82 mg, 0.010 mmol, 0.05 equiv) at rt. The mixture was stirred for 2 hours at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 3 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 organic layers were purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, H2O (FA) in ACN, 20% to 75% gradient in 20 min; detector, UV 254 nm to afford N-(8-cyano-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide (8.6 mg, 8.77% yield) as a white solid. LCMS(ESI) [M + H]+: 480.2. ’H NMR (400 MHz, Acetonitrile-d₃) d 8.71 (d, J= 5.1 Hz, 2H), 7.90 (d, J= 5.0 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.48 (s, 2H), 7.35 (d, J= 8.1 Hz, 2H), 7.13 (d, J= 8.6 Hz, 2H), 5.87 (s, 1H), 3.45 (s, 3H), 2.44 (s, 3H).

[0995] Example 133: N-(8-ethoxy-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide

[0996]

[0997] The title compound was obtained in analogy to Example 128 as a white solid (13.0% yield) using N - [8-chloro-2- [(4-fluorophenyl)-methoxy-methyl] -4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide and EtONa in EtOH.

[0998] LCMS (ESI): m / z = 499.00 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 88.08 (d, J= 49.5 Hz, 1H), 7.59 (d, J = 7.9 Hz, 2H), 7.49 (s, 2H), 7.24 (d, J= 5.4 Hz, 3H), 7.14 (t, J= 8.8 Hz, 2H), 6.13 (s, 1H), 4.49 (t, J= 7.2 Hz, 2H), 3.31 (s, 3H), 2.35 (s, 3H), 1.39 (t, J= 7.0 Hz, 3H).

[0999] Example 134: N-[8-(cyclopropoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[1000]

[1001] The title compound was obtained in analogy to Example 128 as a light yellow solid (7.3% yield) using N - [8-chloro-2- [(4-fluorophenyl)-methoxy-methyl] -4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide and cyclopropanol. LCMS (ESI): m / z = 511.00 [M+H]+. ’H NMR (400 MHz, DMSO-d6) 6 11.44 (s, 1H), 8.20 (d, J= 5.4 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.37 (d, J= 8.1 Hz, 4H), 7.31 (d, J= 5.3 Hz, 1H), 7.19 (t, J= 8.5 Hz, 2H), 5.81 (s, 1H), 4.37 (s, 1H), 3.30 (s, 3H), 2.40 (s, 3H), 0.84 (s, 4H).

[1002] Example 135: (R)-N-(8-(2,2-difluoroethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide

[1003] F

[1004]

[1005] N-(8-(2,2-difluoroethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide was obtained in analogy to Example 1 as a white solid (38.3% yield) using 2-(2,2-difluoroethoxy)-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylic acid and A'-[4-(l-fluorocyclopropyl) benzenesulfonyl] tert-butoxycarbohydrazide. Chiral separation using conditions D afforded (R)-N-(8-(2,2-difluoroethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide (39.7% yield, RT= 9.9min, first peak) as a white solid. LCMS(ESI) [M + H]+: 579.15. ’H NMR (400 MHz, Acetonitrile-d₃) 38.11 (d, J = 5.3 Hz, 1H), 7.81 - 7.74 (m, 2H), 7.49 - 7.41 (m, 2H), 7.39 - 7.31 (m, 2H), 7.28 (d, J = 5.4 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.31 (t, J= 3.8 Hz, 1H), 5.87 (s, 1H), 4.74 (tdd, J = 14.3, 7.6, 3.7 Hz, 2H), 3.41 (s, 3H), 1.67 - 1.54 (m, 2H), 1.29 - 1.17 (m, 2H)

[1006] Example 136: N-(2-((4-fluorophenyl)(methoxy)methyl)-4-oxo-8-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide

[1007]

[1008] The title compound was obtained in analogy to Example 1 as a white solid (35.6% yield) using 3-[2-(4-fluorophenyl)-2-methoxyacetamido]-2-(2,2,2-trifluoroethoxy)pyridine-4-carboxylic acid and N'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide.

[1009] LCMS (ESIpos): m / z = 553.00 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d₃) 68.11 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.50 - 7.39 (m, 2H), 7.34 (d, J = 7.8 Hz, 3H), 7.09 (t, 7= 8.9 Hz, 2H), 5.85 (s, 1H), 5.14- 4.93 (m, 2H), 3.39 (s, 3H), 2.43 (s, 3H).

[1010] Example 137: (R)-4-(l-fluorocyclopropyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methoxy-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1011]

[1012] a) N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]- 4— (1 -fluorocyclopropyl) benzenesulfonamide

[1013] The title compound was obtained in analogy to Example 1 as a white solid (50.2% yield) using 2-chloro-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylic acid and A^'-[4-(l-fluorocyclopropyl) benzenesulfonyl] tert-butoxycarbohydrazide. LCMS(ESI) [M + H]+: 533.2

[1014] b)(R)-4-(l-fluorocyclopropyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methoxy-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1015] 4-(l-fluorocyclopropyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methoxy-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide was obtained in analogy to Example 135 as a white solid (30.3% yield) using N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4— (1 -fluorocyclopropyl) benzenesulfonamide and MeONa in MeOH. Chiral separation using conditions D afforded (R)-4-(l-fluorocyclopropyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methoxy-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide (30.2% yield, RT= 5.21min, first peak) as a white solid. LCMS(ESI) [M + H]+: 529.15. ’H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 8.17 (dd, J = 5.5, 2.4 Hz, 1H), 7.77 (d, J= 8.2 Hz, 2H), 7.42 (d, J= 7.9 Hz, 4H), 7.27 - 7.20 (t, 3H), 5.84 (s, 1H), 4.05 (s, 3H), 3.36 (s, 3H), 1.67 - 1.56 (m, 2H), 1.28 (s, 2H).

[1016] Example 138: (R)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide

[1017]

[1018] The title compound was obtained in analogy to Example 100 as a white solid (27.8% yield) using 4-(l-fluorocyclopropyl)-N-{2-[(4-fluorophenyl)(methoxy)methyl]-8-formyl- 4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and DAST. Chiral separation using conditions F afforded (R)-N-(8-(difhioromethyl)-2-((4- fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(l- fluorocyclopropyl)benzenesulfonamide (36.7% yield, RT= 8.17min, first peak) as a white solid. LC-MS (ES, m / z): LCMS (ESI) [M + H]+: 549.15. ’H NMR (400 MHz, Acetonitrile-d₃) 68.76 - 8.66 (m, 1H), 7.87 - 7.76 (m, 3H), 7.68 - 7.31 (m, 5H), 7.18 - 7.06 (m, 2H), 5.96 - 5.85 (m, 1H), 3.45 (s, 3H), 1.66 - 1.61 (m, 1H), 1.61 - 1.55 (m, 1H), 1.31 - 1.16 (m, 2H).

[1019] Example 139: (S)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4- oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide

[1020] F

[1021]

[1022] The title compound was obtained in analogy to Example 107 as a white solid (27.8% yield) using 4-(l-fhiorocyclopropyl)-N-{2-[(4-fluorophenyl)(methoxy)methyl]-8-formyl- 4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and DAST. Chiral separation using conditions F afforded (S)-N-(8-(difhioromethyl)-2-((4- fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(l- fluorocyclopropyl)benzenesulfonamide (40.4% yield, RT=12.64min, second peak) as a white solid. LC-MS (ES, m / z): LCMS (ESI) [M + H]+: 549.15. ’H NMR (400 MHz, Acetonitrile-d₃) 58.75 - 8.60 (m, 1H), 7.86 - 7.72 (m, 3H), 7.68 - 7.27 (m, 5H), 7.18 - 7.04 (m, 2H), 5.99 - 5.85 (m, 1H), 3.45 (d, J = 1.3 Hz, 3H), 1.67 - 1.60 (m, 1H), 1.60 -1.55 (m, 1H), 1.29 - 1.17 (m, 2H).

[1023] Example 140: (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide

[1024]

[1025] N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide was obtained in analogy to Example 1 as a white solid (32.8% yield) using 2-(difluoromethoxy)-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and 7V'-[4-(l-fluorocyclopropyl)benzenesulfonyl]tert-butoxycarbohydrazide. Chiral separation using conditions D afforded (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide (35.4% yield, RT=14.5min, first peak) as a white solid. LCMS (ESI) [M+H]+: 565.11.!H NMR (400 MHz, DMSO-d6) 6 11.67 (s, 1H), 8.24 (d, J= 5.3 Hz, 1H), 7.79 (d, J= 8.2 Hz, 3H), 7.57 (d, J= 5.3 Hz, 1H), 7.47 - 7.39 (m, 4H), 7.25 - 7.17 (m, 2H), 5.87 (s, 1H), 3.37 (s, 3H), 1.62 (dd, J = 19.5, 1.9 Hz, 2H), 1.29 - 1.25 (m, 2H).

[1026] Example 141: (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4- ((difluoromethoxy)methyl)benzenesulfonamide

[1027]

[1028] N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-((difluoromethoxy)methyl)benzenesulfonamide was obtained in analogy to Example 1 as a white solid (50.5% yield) using 2-(difluoromethoxy)-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and TV'- { 4-[(difluoromethoxy)methyl]benzenesulfonyl } tert-butoxycarbohydrazide. Chiral separation using conditions E afforded (R)-N-(8-(difhioromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-((difluoromethoxy)methyl)benzenesulfonamide (40.0% yield, RT=26.5min, second peak) as a white solid. LCMS (ESI) [M+H]+: 587.09. ’H NMR (400 MHz, DMSO-d6) 8 11.69 (s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 8.08 - 7.69 (m, 3H), 7.61 - 7.53 (m, 3H), 7.42 (s, 2H), 7.25 - 7.17 (m, 2H), 7.07 - 6.64 (m, 1H), 5.84 (s, 1H), 5.05 (s, 2H), 3.37 (s, 3H).

[1029] Example 142: N-[8-(difluoromethoxy)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide

[1030] O'

[1031] N. A

[1032] o'

[1033] HN'N

[1034]

[1035] a) N-[8-(difluoromethoxy)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-iodobenzenesulfonamide

[1036] The title compound was obtained in analogy to Example 1 as a white solid (72.3% yield) using 2-(difluoromethoxy)-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and 2V'-(4-iodobenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M+H]+: 632.35

[1037] b) N-[8-(difhioromethoxy)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide

[1038] The title compound was obtained in analogy to Example 66 as a white solid (24.4% yield) using H8-(difhioromethoxy)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-6?]pyrimidin-3-yl]-4-iodobenzenesulfonamide and (ls,3s)-3-fhiorocyclobutan-l-amine. Chiral separation using conditions L afforded N-[8-(difhioromethoxy)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide (35.9% yield, RT=5.3min, first peak) as a white solid. LCMS (ESI) [M+H]+: 594.15. ’H NMR (400 MHz, Acetonitrile-d₃) 58.19 -7.77 (m, 2H), 7.74 - 7.36 (m, 6H), 7.18 - 6.95 (m, 2H), 6.58 - 6.37 (m, 2H), 5.90 (s, 1H), 5.61 (d, J = 6.5 Hz, 1H), 4.87 (dp, J = 56.0, 6.8 Hz, 1H), 3.49 (dt, J = 8.7, 6.9 Hz, 1H), 3.41 (s, 3H), 2.90 (ddd, J = 13.0, 6.6, 1.9 Hz, 2H), 2.06 (dd, J = 8.1, 4.4 Hz, 2H).

[1039] Example 143: (S)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1040]

[1041] The title compound was obtained in analogy to Example 120 as a white solid (8.9% yield) using N- { 2- [ (. S’ - ( 4- fl uorophcny 1 )( methoxy ) methyl ] - 8-methyl-4-oxopyrido [3,4-*pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3,3-difhiorocyclobutan-l-amine. LCMS (ESI) [M + H]+: 560.20. ’H NMR (400 MHz, Acetonitrile-d₃) 58.46 (d, J= 5.2 Hz, 1H), 7.56 - 7.42 (m, 5H), 7.09 (d, J= 8.9 Hz, 2H), 6.57 - 6.50 (m, 2H), 5.92 (s, 1H), 5.71 (d, J = 5.8 Hz, 1H), 3.91 - 3.79 (m, 1H), 3.45 (s, 3H), 3.04 (hept, J = 7.5 Hz, 2H), 2.80 (s, 3H), 2.48 (qd, J= 15.1, 6.3 Hz, 2H).

[1042] Example 144: (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-5-(fluoromethyl)thiophene-2-sulfonamide

[1043]

[1044] F

[1045] a) (5-{[8-(difluoromethoxy)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-6?]pyrimidin-3-yl]sulfamoyl}thiophen-2-yl)methyl acetate

[1046] The title compound was obtained in analogy to Example 1 as a brown oil (63.4% yield) using 2-(difluoromethoxy)-3-[2-(4-fluorophenyl)-2-methoxyacetamido]pyridine-4-carboxylic acid and {5-[(Z)-A'-[(tert-butoxycarbonyl)imino]hydrazinesulfonyl]thiophen-2-yljmethyl acetate. LCMS (ESI) [M+H]+: 585.06.

[1047] b) W|8-(difluoromcthoxy)-2-|(4-fluorophcnyl)(mcthoxy)mcthyl|-4-oxopyrido|3,4- | py r i m id i n - 3 -yl] - 5 - (hydroxymethyl)thiophene-2- sulfonamide.

[1048] To a stirred solution of (5-{[8-(difhioromethoxy)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-6?]pyrimidin-3-yl]sulfamoyl}thiophen-2-yl)methyl acetate (300 mg, 0.513 mmol, 1 equiv) in THF (4 mL), H2O (1 mL) and MeOH (1 mL) was added LiOH (36.8 mg, 1.539 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for additional 1 h at 25 °C. The residue was acidified to pH 5 with 2 M HC1. 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), 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in A-[8-(difhioromethoxy)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-6?]pyrimidin-3-yl]-5-(hydroxymethyl)thiophene-2-sulfonamide (230 mg, 82.61% yield) as a brown oil. LCMS (ESI) [M+H]+: 542.05.

[1049] c) (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d)pyrimidin-3(4H)-yl)-5-(fluoromethyl)thiophene-2-sulfonamide

[1050] To a stirred solution of A-[8-(difhioromethoxy)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-6?]pyrimidin-3-yl]-5-(hydroxymethyl)thiophene-2-sulfonamide (100 mg, 0.184 mmol, 1 equiv) in DCM (3 mL) was added DAST (59.4 mg, 0.368 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred for additional 1 h at 25 °C. The reaction was quenched with H2O at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: Column: 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: 31% B to 48% B in 30 min; Wave Length: 254 / 220 nm; RT= 14.097. This resulted in N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-5-(fluoromethyl)thiophene-2-sulfonamide (56 mg, 55.79% yield) as a white solid. Chiral separation using conditions E afforded (R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-5-(fluoromethyl)thiophene-2-sulfonamide (37.9% yield, RT=25.09 min, second peak) as a white solid. LCMS (ESI) [M+H]+: 545.05. ’H NMR (400 MHz, DMSO-d6) 8 11.99 (s, 1H), 8.27 (d, J= 5.3 Hz, 1H), 7.95 (d, J= 71.6 Hz, 1H), 7.62 (d, J = 5.4 Hz, 2H), 7.44 (d, J= 7.4 Hz, 2H), 7.33 - 7.26 (m, 1H), 7.26 - 7.17 (m, 2H), 5.84 (s, 1H), 5.71 (s, 1H), 5.59 (s, 1H), 3.38 (s, 3H).

[1051] Example 145: (R)-4-(difluoromethoxy)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1052]

[1053] 4-(difluoromethoxy ) -N- ( 8 -(difluoromethyl) -2- ((4-fluorophenyl) (methoxy )methyl) -4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide was obtained in analogy to Example 100 as a white solid (42.4% yield) using 4- (difluoromethoxy) -A- {2- [(4-fluorophenyl)(methoxy)methyl]-8-formyl-4-oxopyrido |3,4- |pyrimidin-3-yl} benzenesulfonamide and DAST. Chiral separation using conditions C afforded (R)-4-(difluoromethoxy)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide (33.0% yield, RT=9.82min, first peak) as a white solid. LCMS (ESI) [M + H]+: 557.10.!H NMR (400 MHz, Acetonitrile- di) 58.72 (d, J = 5.1 Hz, 1H), 7.86-7.76 (m, 3H), 7.67 - 7.33 (m, 3H), 7.27 - 7.22 (m, 2H), 7.13 - 6.70 (m, 3H), 5.95 (s, 1H), 3.48 (s, 3H).

[1054] Example 146: (R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1055] o=s=o o

[1056] F^AJ

[1057]

[1058] F

[1059] The title compound was obtained in analogy to Example 120 as a white solid (8.3% yield) using A-{2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-*pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3,3-difluorocyclobutan-l-amine. LCMS (ESI) [M + H]+: 560.20.1H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J = 5.2 Hz, 1H), 7.56 - 7.42 (m, 5H), 7.09 (d, J= 8.9 Hz, 2H), 6.57 - 6.50 (m, 2H), 5.92 (s, 1H), 5.71 (d, J = 5.8 Hz, 1H), 3.91 - 3.79 (m, 1H), 3.45 (s, 3H), 3.04 (hept, J = 7.5 Hz, 2H), 2.80 (s, 3H), 2.48 (qd, J= 15.1, 6.3 Hz, 2H).

[1060] Example 147: N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide

[1061] o=s=o o

[1062] o

[1063] F

[1064]

[1065] ^F a) A-{8-chloro-2-[(4-fluorophenyl(methoxy)methyl]-4-oxopyrido[3,4-6?] pyrimidin-3-yl}-4-[(difluoromethoxy)methyl] benzenesulfonamide

[1066] The title compound was obtained in analogy to Example 1 as a yellow solid (31% yield) using 2-chloro-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylic acid and N'- { 4- [(difluoromethoxy)methyl] benzenesulfonyl } tert-butoxycarbohydrazide. LCMS (ESI) [M+H]+: 555.09

[1067] b) N-[8-(2,2-difhioroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide

[1068] A solution of A-{8-chloro-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-[(difhioromethoxy)methyl]benzenesulfonamide (300 mg, 0.541 mmol, 1 equiv), l,l-difluoro-2-iodoethane (311.3 mg, 1.623 mmol, 3.00 equiv), [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide (13.1 mg, 0.027 mmol, 0.05 equiv), Ir[dF(CF3)ppy]2(dtbpy))PF6(6.0 mg, 0.005 mmol, 0.01 equiv), l,l,l,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane( 137.1 mg, 0.552 mmol, 1.02 equiv), 2,6-dimethylpyridine (127.4 mg, 1.190 mmol, 2.2 equiv) in 1,2-dimethoxyethane (15 mL). The reaction mixture was purged with nitrogen and then exposed to blue LEDs for 16 hours. Desired product could be detected by LCMS. The reaction was quenched by the addition of H2O (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with H2O (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc=40% to afford A-[8-(2,2-difluoroethyl)-2-[(4-fluorophenyl) (methoxy)methyl]-4-oxopyrido[3,4-d] pyrimidin-3-yl]-4-[(difluoromethoxy)methyl] benzene sulfonamide (80 mg, 25.32%yield) as a white solid. Chiral separation using conditions E afforded N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difhioromethoxymethyl)benzenesulfonamide (22.9% yield, RT=12.72min, second peak) as a white solid. LCMS (ESI) [M+H]+: 585.09.1H NMR (400 MHz, Acetonitrile-d₃) d 8.57 (d, J= 5.2 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.62 (d, J= 5.2 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.55 - 7.46 (m, 2H), 7.20 - 7.10 (m, 2H), 6.74 - 6.26 (m, 2H), 5.92 (s, 1H), 5.04 (s, 2H), 3.78 (td, J = 16.6, 4.9 Hz, 2H), 3.49 (s, 3H)

[1069] Example 148: 4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[1070]

[1071] The title compound was obtained in analogy to Example 116 as a white solid (20.8% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-* pyrimidin-4-one and 4-[(difluoromethoxy)methyl]-2-methylbenzenesulfonyl chloride. LCMS (ESI) [M + H]+: 549.10. ’H NMR (400 MHz, DMSO-6) δ 11.70 (d, J= 191.8 Hz, 1H), 8.51 (d, J= 5.2 Hz, 1H), 7.80 – 7.63 (m, 1H), 7.58 (d, J = 5.2 Hz, 1H), 7.49 (s, 1H), 7.42 – 7.32 (m, 2H), 7.31 – 7.13 (m, 3H), 7.06 – 6.59 (m, 1H), 5.64 (s, 1H), 4.99 (s, 2H), 3.30 (d, J= 11.7 Hz, 3H), 2.80 (d, J= 38.6 Hz, 3H), 2.68 (s, 2H), 2.54– 2.51 (m, 1H).

[1072] Example 149: 4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1073]

[1074] The title compound was obtained in analogy to Example 116 as a white solid (33.5% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-[(difluoromethoxy)methyl]-3-methylbenzenesulfonyl chloride. LCMS (ESI) [M+H]+: 549.15. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.47 (d, J= 5.2 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.52 (d, J= 8.1 Hz, 1H), 7.50 - 7.42 (m, 3H), 7.16 - 7.05 (m, 2H), 6.51 (t, J= 75.1 Hz, 1H), 5.83 (s, 1H), 5.00 (s, 2H), 3.44 (s, 3H), 2.78 (s, 3H), 2.28 (s, 3H).

[1075] Example 150: N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(oxetan-2-yl)benzenesulfonamide

[1076]

[1077] The title compound was obtained in analogy to Example 123 as a white solid (5.2% yield) using 3-amino-2-[(7?)-methoxy(phenyl)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(oxetan-2-yl)benzenesulfonyl chloride. LCMS (ESI) [M + H]+: 493.20.1H NMR (400 MHz, Acetonitrile-d3) δ 8.45 (dd, J= 5.2, 1.8 Hz, 1H), 7.83 - 7.78 (m, 2H), 7.57 - 7.53 (m, 2H), 7.49 - 7.43 (m, 3H), 7.39 - 7.33 (m, 3H), 5.88 (s, 1H), 5.84 (t, J = 7.6 Hz, 1H), 4.81 - 4.74 (m, 1H), 4.64- 4.57 (m, 1H), 3.45 (d, J= 1.0 Hz, 3H), 3.13 - 3.03 (m, 1H), 2.78 (s, 3H), 2.57 - 2.49 (m, 1H).

[1078] Example 151: 4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1079]

[1080] The title compound was obtained in analogy to Example 116 as a white solid (15.4% yield) using 3-amino-2-[(7?)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-[(difluoromethoxy)methyl]-3-methylbenzenesulfonyl chloride. LCMS (ESI) [M+H]+: 549.15. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J= 5.2 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.55 - 7.40 (m, 4H), 7.15 - 7.03 (m, 2H), 6.51 (t, J = 75.1 Hz, 1H), 5.83 (s, 1H), 4.99 (s, 2H), 3.43 (s, 3H), 2.78 (s, 3H), 2.28 (s, 3H).

[1081] Example 152: 4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[1082]

[1083] F F

[1084] The title compound was obtained in analogy to Example 116 as a white solid (22.8% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-6?] pyrimidin-4-one and 4-[(difluoromethoxy)methyl]-2-methylbenzenesulfonyl chloride. LC-MS (ESI, m / z): [M+H]+: 549.10. ’H NMR (400 MHz, DMSO-6) δ 11.70 (d, J = 191.8 Hz, 1H), 8.52 (d, J = 5.2 Hz, 1H), 7.75 – 7.65 (m, 1H), 7.61 – 7.47 (m, 2H), 7.44 –7.34 (m, 2H), 7.32 – 7.12 (m, 3H), 6.84 (t, J = 75.2 Hz, 1H), 5.69 (d, J = 34.2 Hz, 1H), 4.99 (s, 2H), 3.30 (d, J= 11.8 Hz, 3H), 2.80 (d, J= 38.8 Hz, 3H), 2.68 (s, 2H), 2.53 (s, 1H).

[1085] Example 153: N-[8-(2,2-difluoroethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide

[1086]

[1087] The title compound is the first peak obtained in the chiral separation of N-[8-(2,2-difhioroethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide (Example 147) using conditions E (22.9% yield, RT=10.04min, first peak). LCMS (ESI) [M+H]+: 585.09. ’H NMR (400 MHz, Acetonitrile-d₃) 38.57 (d, J= 5.2 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.62 (d, J= 5.2 Hz, 1H), 7.59 - 7.46 (m, 4H), 7.20 - 7.09 (m, 2H), 6.73 - 6.28(m, 2H), 5.92 (s, 1H), 5.04 (s, 2H), 3.78 (td, J= 16.6, 5.0 Hz, 2H), 3.48 (s, 3H).

[1088] Example 154: N-[8-(2,2-difluoroethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[1089]

[1090] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide was obtained in analogy to Example 147 as a yellow oil (4.7% yield) using A-{8-chloro-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido [3,4-d]pyrimidin-3-yl } -4-methylbenzenesulfonamide and 1, 1 -difluoro-2-iodoethane. Chiral separation using conditions G afforded N-[8-(2,2-difluoroethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (31.8% yield, RT=11.34min, second peak) as a white solid. LCMS (ESI) [M+H]+: 519.09. ’H NMR (400 MHz, Acetonitrile-d₃) 38.57 (d, J= 5.2 Hz, 1H), 7.75 - 7.68 (m, 2H), 7.63 (d, J= 5.2 Hz, 1H), 7.54 - 7.45 (m, 2H), 7.37 (d, J= 8.0 Hz, 2H), 7.19 - 7.09 (m, 2H), 6.43 (t, J= 5.1 Hz, 1H), 5.91 (s, 1H), 3.78 (td, J= 16.5, 4.9 Hz, 2H), 3.47 (d, J= 0.9 Hz, 3H), 2.46 (s, 3H).

[1091] Example 155: N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[1092]

[1093] The title compound is the first peak obtained in the chiral separation of N-[8-(2,2-difhioroethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide (Example 154) using conditions G (29.6% yield, RT=8.80min, first peak). LCMS (ESI) [M+H]+: 519.09.1H NMR (400 MHz, Acetonitrile-3) δ 8.57 (d, J= 5.2 Hz, 1H), 7.75 – 7.68 (m, 2H), 7.63 (d, J= 5.2 Hz, 1H), 7.54 – 7.45 (m, 2H), 7.37 (d, J= 8.0 Hz, 2H), 7.19 – 7.09 (m, 2H), 6.43 (t, J= 5.1 Hz, 1H), 5.91 (s, 1H), 3.78 (td, J = 16.5, 4.9 Hz, 2H), 3.47 (d, J= 0.9 Hz, 3H), 2.45 (s, 3H).

[1094] Example 156: 4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1095]

[1096] 4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 100 as a pink oil (40.1% yield) using 4-[(difhioromethoxy)methyl]-A-{2-[(4-fluorophenyl)(methoxy)methyl]-8-formyl-4- oxopyrido|3,4-<7|pyrimidin-3-yl} benzenesulfonamide and DAST. Chiral separation using conditions E afforded (R)-4-(difhioromethoxy)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide (39.3% yield, RT=11.77min, first peak) as a white solid. LCMS (ESI) [M + H]+: 571.15. ’H NMR (400 MHz, Acetonitrile-d₃) 68.74 (d, J= 5.1 Hz, 1H), 7.89 -7.81 (m, 3H), 7.71 -7.37 (m, 5H), 7.20 - 7.06 (m, 2H), 6.54 (t, J = 75.0 Hz, 1H), 5.93 (s, 1H), 5.05 (s, 2H), 3.49 (s, 3H).

[1097] Example 157: N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-5-(fluoromethyl)thiophene-2-sulfonamide

[1098]

[1099] a) (5-{[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4- *pyrimidin-3-yl]sulfamoyl}thiophen-2-yl)methyl acetate

[1100] The title compound was obtained in analogy to Example 100 as a white solid (74.0% yield) using [5-( { 2- [(4-fluorophenyl)(methoxy)methyl] - 8-formyl-4-oxopyrido [3,4-*pyrimidin-3-yl}sulfamoyl)thiophen-2-yl]methyl acetate and DAST. LCMS (ESI) [M + H]+: 569

[1101] b) A-[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4- *pyrimidin-3-yl]-5-(hydroxymethyl)thiophene-2-sulfonamide

[1102] To a stirred solution of (5-{[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-*pyrimidin-3-yl]sulfamoyl}thiophen-2-yl)methyl acetate (195.0 mg, 0.343 mmol, 1.0 equiv) in THF (2 mL) / H2O (1 mL) was added LiOH (16.4 mg, 0.686 mmol, 2.0 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The mixture was acidified to pH 6 with citric acid. 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, MeOH in Water (0.1% FA), 0% to 60% gradient in 20 min; UV 254 nm. to afford A-[8-(difhioromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-*pyrimidin-3-yl]-5-(hydroxymethyl)thiophene-2- sulfonamide (125 mg, 69.22% yield) as a white solid. LCMS (ESI) [M + H]+: 527. c) N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-5-(fluoromethyl)thiophene-2-sulfonamide

[1103] To a stirred solution of A-[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-t / ]pyrimidin-3-yl]-5-(hydroxymethyl)thiophene-2-sulfonamide (120.0 mg, 0.228 mmol, 1.0 equiv) and Triethylamine trihydrofluoride (36.74 mg, 0.228 mmol, 1.0 equiv) in DCM (10 mL) was added DAST (146.9 mg, 0.912 mmol, 4.0 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (10 mL) at 0 °C. The aqueous layer was extracted with CH2CI2 (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (mg) 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 (B%): isocratic 37% to 58% B in 12 min; Wave Length: 254 / 220 nm; RT=11.67 min) to afford A-[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-t / ]pyrimidin-3-yl]-5-(fhioromethyl)thiophene-2-sulfonamide (80 mg, 66.42% yield) as a white solid. Chiral separation using conditions N afforded N-[8-(difhioromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-5-(fluoromethyl)thiophene-2-sulfonamide (28.0% yield, RT=7.44min, first peak) as a white solid. LCMS (ESI) [M + H]+: 529.10. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.65 (d, J= 5.1 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.63 - 7.24 (m, 4H), 7.12 - 7.07 (m, 1H), 7.06 - 7.00 (m, 2H), 5.81 (s, 1H), 5.53 (d, J= 0.8 Hz, 1H), 5.41 (d, J= 0.7 Hz, 1H), 3.39 (s, 3H).

[1104] Example 158: 4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1105]

[1106] The title compound is the second peak obtained in the chiral separation of 4-(difhioromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 156) using conditions E (38.6% yield, RT=16.38min, second peak). LCMS (ESI) [M + H]+: 571.15. ’H NMR (400 MHz, Acetonitrile-d₃) 68.74 (d, J= 5.1 Hz, 1H), 7.88 - 7.78 (m, 3H), 7.70 - 7.36 (m, 5H), 7.19 - 7.09 (m, 2H), 6.54 (t, J = 75.0 Hz, 1H), 5.92 (s, 1H), 5.05 (s, 2H), 3.49 (s, 3H).

[1107] Example 159: N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide

[1108]

[1109] a) A-[8-(difhioromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4- *pyrimidin-3-yl]-4-iodobenzenesulfonamide

[1110] The title compound was obtained in analogy to Example 100 as a yellow solid (48.2% yield) using N-{2-[(4-fluorophenyl)(methoxy)methyl]-8-formyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-iodobenzenesulfonamide and DAST. LCMS (ESI) [M + H]+: 617 b) N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide

[1111] N-[8-(difluoromethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide was obtained in analogy to Example 87 as a yellow solid (26.7% yield) using A-[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-6?]pyrimidin-3-yl]-4-iodobenzenesulfonamide and (ls,3s)-3-fluorocyclobutan-l-amine hydrochloride. Chiral separation using conditions M afforded N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide (39.2% yield, RT=14.59min, first peak) as a white solid. LCMS (ESI) [M + H]+: 578.20.1H NMR (400 MHz, Acetonitrile-d₃) 68.77 -8.34 (m, 2H), 7.88 - 7.77 (m, 1H), 7.73 - 7.24 (m, 5H), 7.10 (s, 2H), 6.60 - 6.43 (m, 2H), 5.93 (s, 1H), 5.62 (d, J = 6.6 Hz, 1H), 5.00 - 4.71 (m, 1H), 3.58 - 3.35 (m, 4H), 3.01 -2.81 (m, 2H), 2.11 - 1.98 (m, 2H).

[1112] Example 160: N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide

[1113]

[1114] The title compound is the second peak obtained in the chiral separation of N-[8-(difluoromethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide (Example 159) using conditions M (33.4% yield, RT=20.71min, second peak). LCMS (ESI) [M + H]+: 578.20.

[1115] 1H NMR (400 MHz, Acetonitrile-d₃) 58.76 - 8.66 (m, 1H), 7.87 - 7.79 (m, 1H), 7.73 -7.22 (m, 5H), 7.17 - 7.04 (m, 2H), 6.57 - 6.45 (m, 2H), 5.93 (s, 1H), 5.61 (d, J = 6.6 Hz, 1H), 4.99 - 4.74 (m, 1H), 3.55 - 3.40 (m, 4H), 2.96 - 2.84 (m, 2H), 2.11 - 1.98 (m, 2H).

[1116] Example 161: 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide F

[1117] o=s=o o

[1118]

[1119] F

[1120] The title compound was obtained in analogy to Example 120 as a white solid (27.1% yield) using AA-{2-|( / ?)-(4-fluorophcnyl)(mcthoxy)mcthyl|-8-mcthyl-4-oxopyrido|3,4-<r / |pyrimidin-3-yl }-4-iodobcnzcncsulfonamidc and (lr,3r)-3-(difluoromethyl)cyclobutan-l-amine. LCMS (ESI) [M+H]+: 574.17. ’H NMR (400 MHz, DMSO-d6) 3 11.17 (d, J = 181.5 Hz, 1H), 8.50 (d, J= 5.3 Hz, 1H), 7.58 (dd, J= 5.2, 0.8 Hz, 1H), 7.43 (d, J= 8.6 Hz, 4H), 7.20 (s, 2H), 7.09 (d, J = 6.0 Hz, 1H), 6.51 (d, J = 8.8 Hz, 2H), 6.39 - 6.08 (m, 1H), 5.85 (s, 1H), 4.06 - 3.93 (m, 1H), 3.36 (s, 3H), 2.91 - 2.54 (m, 4H), 2.46 - 2.35 (m, 2H), 2.12- 2.00 (m, 2H).

[1121] Example 162: N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-[(lS)-l-hydroxyethyl]azetidin-l-yl]benzenesulfonamide

[1122]

[1123] The title compound was obtained in analogy to Example 120 as a white solid (12.7% yield) using 4-iodo-A^-{2-[(R)-methoxy(phenyl)methyl]-8-methyl-4-oxopyrido[3,4-<7|pyrimidin-3-yl } benzenesulfonamide and ( IS)- l-(azctidin-3-yl)cthanol. LCMS (ESI) [M + H]+: 536.20. ’H NMR (400 MHz, DMSO-d6) 6 11.02 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.50 - 7.25 (m, 7H), 6.38 (d, 7= 8.6 Hz, 2H), 5.89 (s, 1H), 4.79 (d, J= 4.9 Hz, 1H), 3.91 (t, J= 8.3 Hz, 2H), 3.78 (q, J= 5.8 Hz, 2H), 3.65 (t, J = 6.9 Hz, 1H), 3.40- 3.35 (m, 3H), 2.75 (d, J = 78.9 Hz, 4H), 1.04 (d, J = 6.2 Hz, 3H).

[1124] Example 163: N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide

[1125]

[1126] N-[8-(2,2-difluoroethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide was obtained in analogy to Example 66 as a yellow solid (21.3% yield) using A-[8-(2,2-difluoroethyl)-2-[(4-fluorophenyl) (mcthoxy)mcthyl|-4-oxopyrido|3,4-d| pyrimidin-3-yl]-4-iodobenzenesulfonamide and cis-3-fluorocyclobutanamine hydrochloride. Chiral separation using conditions E afforded N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide (34.8% yield, RT=24.5min, second peak) as a white solid. LCMS(ESI) [M + H]+: 592.2.1H NMR (400 MHz, Acetonitrile-d₃) d 8.58 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 5.2 Hz, 1H), 7.55 - 7.44 (m, 4H), 7.19 - 7.09 (m, 2H), 6.60 - 6.28 (m, 3H), 5.95 (s, 1H), 5.64 (d, J = 6.6 Hz, 1H), 4.97 – (m, 1H), 3.82 (m, 2H), 3.58 - 3.48 (m, 4H), 2.99 - 2.86 (m, 2H), 2.11 - 1.91 (m, 2H).

[1127] Example 164: 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide F

[1128] o=s=oo

[1129]

[1130] F

[1131] The title compound was obtained in analogy to Example 120 as a white solid (23.7% yield) using A-{2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-*pyrimidin-3-yl}-4-iodobenzenesulfonamide and (lr,3r)-3-(difluoromethyl)cyclobutan-l-amine. LCMS (ESI) [M+H]+: 574.17. ’H NMR (400 MHz, DMSO-d6) δ 11.17 (d, J = 181.0 Hz, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.58 (d, J= 5.2 Hz, 1H), 7.43 (d, J= 8.7 Hz, 4H), 7.14 (d, J= 44.4 Hz, 3H), 6.51 (d, J= 8.7 Hz, 2H), 6.39 - 6.07 (m, 1H), 5.86 (s, 1H), 4.05 - 3.95 (m, 1H), 3.36 (s, 3H), 2.92 - 2.53 (m, 4H), 2.46 - 2.35 (m, 2H), 2.12 - 2.00 (m, 2H).

[1132] Example 165: 4-[[(ls,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1133] F

[1134]

[1135] The title compound was obtained in analogy to Example 120 as a white solid (20.5% yield) using A-{2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-*pyrimidin-3-yl}-4-iodobenzenesulfonamide and (ls,3s)-3-(difluoromethyl)cyclobutan-1 -amine. LCMS (ESI) [M + H]+: 574.05.1H NMR (400 MHz, Acetonitrile-d₃) 68.37 (d, J = 5.2 Hz, 1H), 7.44 - 7.31 (m, 5H), 7.01 (t, J= 8.7 Hz, 2H), 6.46 - 6.39 (m, 2H), 5.94 -5.61 (m, 2H), 5.48 (d, J= 6.7 Hz, 1H), 3.83 (p, J = 7.5, 7.0 Hz, 1H), 3.35 (s, 3H), 2.68 (s, 3H), 2.49 - 2.35 (m, 3H), 1.82 - 1.75 (m, 2H).

[1136] Example 166: 4-[[(ls,3s)-3-(difhioromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1137] F

[1138] o=s=o o

[1139]

[1140] The title compound was obtained in analogy to Example 120 as a white solid (21.9% yield) using N- { 2- [(S)-(4-fluorophenyl)(methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-*pyrimidin-3-yl}-4-iodobenzenesulfonamide and (ls,3s)-3-(difluoromethyl)cyclobutan-1 -amine. LCMS (ESI) [M + H]+: 574.10. ’H NMR (400 MHz, Acetonitrile-d₃) 68.37 (d, J = 5.2 Hz, 1H), 7.43 - 7.31 (m, 5H), 7.01 (t, J= 8.8 Hz, 2H), 6.45 - 6.39 (m, 2H), 5.94 -5.63 (m, 2H), 5.48 (d, J= 6.6 Hz, 1H), 3.82 (q, J= 7.4 Hz, 1H), 3.35 (s, 3H), 2.68 (s, 3H), 2.50 - 2.35 (m, 3H), 1.82 - 1.73 (m, 2H).

[1141] Example 167: 4-[[(ls,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1142]

[1143] The title compound was obtained in analogy to Example 159 as a yellow solid (22.9% yield) using A-[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-*pyrimidin-3-yl]-4-iodobenzenesulfonamide and (ls,3s)-3-(difluoromethyl)cyclobutan-l-amine hydrochloride. Chiral separation using conditions M afforded 4-[[(ls,3s)-3-(difhioromethyl)cyclobutyl]amino]-N-[8-(difhioromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (37.7% yield, RT=11.62min, first peak) as a white solid. LCMS (ESI) [M + H]+: 610.25.!H NMR (400 MHz, Acetonitrile-d₃) 68.74 (d, J= 5.0 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.76 - 7.45 (m, 5H), 7.13 (t, J= 8.7 Hz, 2H), 6.59 - 6.51 (m, 2H), 6.08 - 5.74 (m, 2H), 5.62 (d, J= 6.7 Hz, 1H), 4.02 - 3.87 (m, 1H), 3.47 (s, 3H), 2.65 - 2.46 (m, 3H), 1.94 - 1.84 (m, 2H).

[1144] Example 168: 4-[[(ls,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1145]

[1146] The title compound is the second peak obtained in the chiral separation of 4-[[(ls,3s)-3-(difhioromethyl)cyclobutyl]amino]-N-[8-(difhioromethyl)-4-oxo-2-[(4-fluorophenyl)- methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 167) using conditions M as a white solid (39.6% yield, RT=17.54min, second peak). LCMS (ESI) [M + H]+: 610.25. ’H NMR (400 MHz, Acetonitrile-d₃) 68.74 (d, J= 5.1 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.75 - 7.39 (m, 5H), 7.20 - 7.07 (m, 2H), 6.60 - 6.51 (m, 2H), 6.11 - 5.72 (m, 2H), 5.62 (d, J= 6.7 Hz, 1H), 4.02 - 3.87 (m, 1H), 3.47 (s, 3H), 2.64 - 2.47 (m, 3H), 1.94 - 1.86 (m, 2H).

[1147] Example 169: l-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]indole-5-sulfonamide

[1148]

[1149] The title compound was obtained by chiral separation of N-[2-[(4-fluorophenyl)-methoxy-methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl] - 1 -methyl-indole-5- sulfonamide (Example 65) using conditions J as a yellow solid (28.0% yield, RT=6.72min, first peak). LCMS(ESI) [M + H]+: 508.5.1H NMR (400 MHz, CD3CN) δ 8.6 – 8.4 (s, 1H), 8.32 (m, 1H), 7.96 (s, 1H), 7.57 - 7.25 (m, 6H), 6.99 (s, 2H), 6.37 (s, 1H), 5.74 (s, 1H), 3.76 (s, 3H), 3.30 (s, 3H), 2.80 (s, 2H), 2.49 (s, 1H)

[1150] Example 170: l-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]indole-5-sulfonamide

[1151]

[1152] The title compound is the second peak obtained in the chiral separation of N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-l-methyl-indole- 5 -sulfonamide (Example 65) using conditions J as a yellow solid (28.6% yield, RT=8.35min, second peak). LCMS(ESI) [M + H]+: 508.5.1H NMR (400 MHz, CD3CN) δ 8.54 – 8.4 (s, 1H), 8.32 (m, 1H), 7.95 (s, 1H), 7.57 - 7.47 (m, 1H), 7.48 - 7.25 (m, 5H), 6.99 (s, 2H), 6.47 (s, 1H), 5.71 (s, 1H) 3.76 (s, 3H), 3.33 (s, 3H), 2.81 (s, 2H), 2.47 (s, 1H)

[1153] Example 171: (R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-3-methylbenzenesulfonamide

[1154]

[1155] The title compound was obtained in analogy to Example 120 as a white solid (31.7% yield ) using 4-bromo- A- { 2- 1 ( / ?)-(4-fl uorophcny I )( methoxy ) methyl | - 8-methyl-4-oxopyrido [3,4-*pyrimidin-3-yl}-3-methylbenzenesulfonamide and 3,3-difhiorocyclobutan-l-amine hydr ochloride. LCMS (ESI) [M+H]+: 574.25. ’H NMR (400 MHz, Acetonitrile-d₃) 68.51 (s, 1 H), 8.36 (d, J = 5.2 Hz, 1H), 7.50 - 7.22 (m, 5H), 7.00 (t, J = 8.7 Hz, 2H), 6.38 (d, J = 8.6 Hz, 1H), 5.77 (s, 1H), 4.97 (d, J = 5.6 Hz, 1H), 3.94 – 3.74 (m, 1H), 3.34 (s, 3H), 3.11 – 2.89 (m, 2H), 2.68 (s, 3H), 2.59 - 2.39 (m, 2H), 1.94 (s, 3H).

[1156] Example 172: (S)-3-chloro-4-((difluoromethoxy)methyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1157]

[1158] The title compound was obtained in analogy to Example 116 as a white solid (8.5% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 3-chloro-4-[(difluoromethoxy)methyl]benzenesulfonyl chloride. LCMS (ESI) [M + H]+: 569.09.1H NMR (400 MHz, Acetonitrile-d₃) 58.36 (d, J = 5.2 Hz, 1H), 7.76 (d, J= 1.9 Hz, 1H), 7.66 (dd, J = 8.2, 1.9 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.40 (dd, J= 8.6, 5.5 Hz, 3H), 7.07 - 6.97 (m, 2H), 6.47 (t, J = 74.7 Hz, 1H), 5.81 (s, 1H), 4.99 (s, 2H), 3.39 (s, 3H), 2.68 (s, 3H).

[1159] Example 173: (S)-4-((difluoromethoxy)methyl)-3-fluoro-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1160]

[1161] The title compound was obtained in analogy to Example 116 as a white solid (29.8% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-[(difluoromethoxy)methyl]-3-fluorobenzenesulfonyl chloride. LCMS (ESI) [M + H]+: 553.20.1H NMR (400 MHz, Acetonitrile-d₃) 68.33 (d, J = 5.3 Hz, 1H), 7.61 - 7.48 (m, 3H), 7.40 (m, J = 13.4, 6.7, 3.7 Hz, 3H), 7.12 - 6.91 (m, 2H), 6.42 (t, J = 74.7 Hz, 1H), 5.84 (s, 1H), 4.95 (s, 2H), 3.36 (s, 3H), 2.66 (s, 3H).

[1162] Example 174: (R)-3-chloro-4-((difluoromethoxy)methyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1163] F

[1164]

[1165] F F

[1166] The title compound was obtained in analogy to Example 116 as a white solid (11.1% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 3-chloro-4-[(difluoromethoxy)methyl]benzenesulfonyl chloride. LCMS (ESI) [M + H]+: 569.09.1H NMR (400 MHz, Acetonitrile-d₃) 58.38 (d, J = 5.3 Hz, 1H), 7.76 (d, J= 1.9 Hz, 1H), 7.67 (dd, J = 8.2, 1.9 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.40 (t, J= 6.4 Hz, 3H), 7.03 (s, 2H), 6.47 (t, J = 74.7 Hz, 1H), 5.81 (s, 1H), 4.99 (s, 2H), 3.39 (s, 3H), 2.75 (s, 2H)2.51 (s, 1H).

[1167] Example 175: (R)-4-((difluoromethoxy)methyl)-3-fluoro-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1168]

[1169] The title compound was obtained in analogy to Example 116 as a white solid (20.7% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-[(difluoromethoxy)methyl]-3-fluorobenzenesulfonyl chloride. LCMS (ESI) [M + H]+: 553.20. ’H NMR (400 MHz, Acetonitrile-d₃) 68.36 (d, J= 5.2 Hz, 1H), 7.66 - 7.44 (m, 3H), 7.44 - 7.31 (m, 3H), 7.12 - 6.89 (m, 2H), 6.43 (t, J = 74.7 Hz, 1H), 5.83 (s, 1H), 4.96 (s, 2H), 3.38 (s, 3H), 1.85 (h, J= 2.4 Hz, 3H).

[1170] Example 176: N-[2-[difluoromethoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide

[1171]

[1172] The title compound was obtained in analogy to Example 1 as a white solid (39.8% yield) using 3-[2-(difluoromethoxy)-2-phenylacetamido]-2-methylpyridine-4-carboxylic acid and A'N'-(4-methylbenzenesulfonyl)tert-butoxycarbohydrazide. LCMS(ESI) [M + H]+: 487.05. ’H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.53 (d, J= 5.2 Hz, 1H), 7.61 (dd, J = 40.7, 6.6 Hz, 3H), 7.40 (d, J = 24.2 Hz, 7H), 6.93 (t, J = 74.6 Hz, 1H), 6.65 (s, 1H), 2.85 (s, 3H), 2.40 (s, 3H).

[1173] Example 177: 4-(l-fluorocyclopropyl)-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1174]

[1175] The title compound was obtained in analogy to Example 116 as a white solid (76.1% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(l-fluorocyclopropyl)-3-methylbenzenesulfonyl chloride. LCMS (ESI) [M + H]+: 527.15. ’H NMR (400 MHz, Acetonitrile-d₃) 68.92 (s, 1H), 8.57 - 8.43 (m, 1H), 7.75 - 7.63 (m, 2H), 7.60 - 7.43 (m, 4H), 7.24 - 7.06 (m, 2H), 5.85 (s, 1H), 3.46 (s, 3H), 2.81 (s, 3H), 2.50 (s, 3H), 1.57 - 1.41 (m, 2H), 1.20 - 1.03 (m, 2H)..

[1176] Example 178: 4-[((1s,3s)-3-fluorocyclobutyl)amino]-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1177]

[1178] The title compound was obtained in analogy to Example 66 as a white solid (39.4% yield) using 4-bromo-A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d\ pyrimidin-3-yl}-3-methylbenzenesulfonamide and f / .s,3.s)-3-fluorocyclobutan- l-aminc hydrochloride. LCMS (ESI) [M + H]+: 556.1. ’H NMR (400 MHz, Acetonitrile-d₃) d 8.35 (dd, J= 5.5, 1.6 Hz, 1H), 7.40 - 7.27 (m, 4H), 7.24 (d, J= 2.4 Hz, 1H), 7.00 (d, J = 9.4 Hz, 2H), 6.35 (d, J= 8.7 Hz, 1H), 5.76 (s, 1H), 4.91 - 4.82 (m, 1H), 4.72 (p, J= 6.8 Hz, 1H), 3.51 - 3.37 (m, 1H), 3.33 (s, 3H), 2.90 - 2.77 (m, 2H), 2.68 (s, 3H), 2.08 (ddt, J = 20.2, 15.2, 8.1 Hz, 2H), 1.93 (s, 3H).

[1179] Example 179: 4-(l-fluorocyclopropyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[1180] o=s=o o

[1181]

[1182] The title compound was obtained in analogy to Example 116 as a white solid (65.5% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-(l-fluorocyclopropyl)-3-methylbenzenesulfonyl chloride. LCMS (ESI) [M + H]+: 527.15. ’H NMR (400 MHz, Acetonitrile-d₃) 68.97 (s, 1H), 8.54 - 8.43 (m, 1H), 7.72 - 7.63 (m, 2H), 7.60 - 7.43 (m, 4H), 7.19 - 7.07 (m, 2H), 5.85 (s, 1H), 3.46 (s, 3H), 2.81 (s, 3H), 2.55 - 2.47 (m, 3H), 1.54 - 1.41 (m, 2H), 1.16 - 1.04 (m, 2H).

[1183] Example 180: 4-[((1s,3s)-3-fluorocyclobutyl)amino]-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1184]

[1185] The title compound was obtained in analogy to Example 66 as a white solid (33.4% yield) using 4-bromo-A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d\ pyrimidin-3-yl}-3-methylbenzenesulfonamide and f / .s,3.s)-3-fluorocyclobutan- l-aminc hydrochloride. LCMS (ESI) [M + H]+: 556.1. ’H NMR (400 MHz, Acetonitrile-d₃) 38.35 (dd, J= 5.5, 1.6 Hz, 1H), 7.40 - 7.27 (m, 4H), 7.24 (d, J= 2.4 Hz, 1H), 7.00 (d, J = 9.4 Hz, 2H), 6.35 (d, J= 8.7 Hz, 1H), 5.76 (s, 1H), 4.91 - 4.82 (m, 1H), 4.72 (p, J= 6.8 Hz, 1H), 3.51 - 3.37 (m, 1H), 3.33 (s, 3H), 2.90 - 2.77 (m, 2H), 2.68 (s, 3H), 2.08 (ddt, J = 20.2, 15.2, 8.1 Hz, 2H), 1.93 (s, 3H).

[1186] Example 181: 4-(difluoromethoxymethyl)-3-(difluoromethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide F

[1187] o=s=oo

[1188]

[1189] The title compound was obtained in analogy to Example 116 as a white solid (39.8% yield) using 3-amino-2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4- [(difluoromethoxy)methyl] -3-(difluoromethyl)benzenesulfonyl chloride. LCMS (ESI) [M + H]+: 585.10. ’H NMR (400 MHz, Acetonitrile-d₃) 68.91 (s, 1H), 8.49 (d, J= 5.2 Hz, 1H), 8.02 - 7.93 (m, 2H), 7.76 (d, J= 8.1 Hz, 1H), 7.55 - 7.45 (m, 3H), 7.21 - 6.83 (m, 3H), 6.66 (d, J= 74.5 Hz, 1H), 5.94 (s, 1H), 5.18 (s, 2H), 3.51 (s, 3H), 2.80 (s, 3H).

[1190] Example 182: (S)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-3-methylbenzenesulfonamide

[1191]

[1192] The title compound was obtained in analogy to Example 120 as a white solid (33.0% yield) using 4-bromo-A-{2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-*pyrimidin-3-yl}-3-methylbenzenesulfonamide and 3,3-difluorocyclobutan- 1 -amine hydrochloride. LCMS (ESI) [M+H]+: 574.25.!H NMR (400 MHz, Acetonitrile-d₃) 58.59 (s, 1H), 8.48 (d, J= 5.2 Hz, 1H), 7.65 - 7.31 (m, 5H), 7.11 (s, 2H), 6.50 (d, J= 8.6 Hz, 1H), 5.88 (s, 1H), 5.09 (d, J= 5.6 Hz, 1H), 4.07 - 3.85 (m, 1H), 3.46 (s, 3H), 3.18 - 3.01 (m, 2H), 2.90 (s, 2H), 2.73 - 2.47 (m, 3H), 2.06 (s, 3H).

[1193] Example 183: 4- [(2,2-difluorospiro[3.3]heptan-6-yl)amino] -N- [8-methyl-4-oxo-2- [(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1194]

[1195] The title compound was obtained in analogy to Example 120 as a white solid (40.3% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 6,6-difluorospiro [3.3] hep tan-2- amine hydrochloride. LCMS (ESI) [M + H]+: 600.2.1H NMR (400 MHz, Acetonitrile-d₃) 38.48 (dd, J= 5.3, 2.0 Hz, 2H), 7.54 - 7.42 (m, 5H), 7.12 (t, J= 8.7 Hz, 2H), 6.55 - 6.47 (m, 2H), 5.94 (s, 1H), 5.59 (d, J= 6.1 Hz, 1H), 3.90 (h, J= 7.5 Hz, 1H), 3.47 (s, 3H), 2.80 (s, 3H), 2.75 - 2.53 (m, 6H), 2.11 - 2.01 (m, 2H).

[1196] Example 184: 4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1197]

[1198] The title compound was obtained in analogy to Example 120 as a white solid (43.0% yield) using A-{2-[(7?)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 2,2-difluoroethanamine. LCMS (ESIpos):

[1199] [M+H]+: 534.10.1H NMR (400 MHz, Acetonitrile-d₃) 58.54 - 8.15 (m, 2H), 7.53 - 7.28 (m, 5H), 7.01 (t, J= 8.7 Hz, 2H), 6.65 - 6.55 (m, 2H), 6.06 - 5.71 (m, 2H), 5.44 (t, J= 6.7 Hz, 1H), 3.57 - 3.42 (m, 2H), 3.36 (s, 3H), 2.69 (s, 3H).

[1200] Example 185: 4-(3,3-difluoroazetidin-l-yl)-N-[8-methyl-4-oxo-2-[(R)-(4- fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1201] F

[1202] o=s=oo

[1203]

[1204] F F

[1205] The title compound was obtained in analogy to Example 120 as a white solid (32.0% yield) using A-{2-[(7?)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3,3-difluoroazetidine. LCMS (ESI) [M + H]+: 546.05. ’H NMR (400 MHz, Acetonitrile-d₃) 68.37 (d, J= 5.1 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.40 (m, 3H), 7.01 (m, 2H), 6.41 (dd, J = 9.3, 2.4 Hz, 2H), 5.84 (d, J= 2.2 Hz, 1H), 4.26 (m, 4H), 3.36 (d, J= 2.0 Hz, 3H), 2.68 (s, 3H).

[1206] Example 186: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)azetidin-l-yl] benzenesulfonamide

[1207] F - F

[1208]

[1209] F

[1210] The title compound was obtained in analogy to Example 120 as a white solid (20.2% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(trifluoromethyl) azetidine hydrochloride. LCMS (ESI) [M + H]+: 578.3.1H NMR (400 MHz, Acetonitrile-d₃) 38.56 - 8.40(m, 2H), 7.61 - 7.45 (m, 5H), 7.12 (s, 2H), 6.44 (d, J = 8.8 Hz, 2H), 5.94 (s, 1H), 4.20 (td, J= 8.1, 2.9 Hz, 2H), 4.06 (dt, J = 8.6, 4.1 Hz, 2H), 3.68 - 3.53 (m, 1H), 3.48 (s, 3H), 2.93 (s, 2H), 2.58 (s, 1H).

[1211] Example 187: 4-[(2,2-difluorospiro[3.3]heptan-6-yl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1212]

[1213] The title compound was obtained in analogy to Example 120 as a white solid (30.0% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 6,6-difluorospiro [3.3] hep tan-2- amine hydrochloride. LCMS (ESI) [M + H]+: 600.3.1H NMR (400 MHz, Acetonitrile-d₃) d 8.37 (d, J = 5.2 Hz, 2H), 7.39 (dd, J= 9.0, 5.3 Hz, 3H), 7.38 - 7.30 (m, 2H), 7.01 (t, J= 8.6 Hz, 2H), 6.44- 6.36 (m, 2H), 5.82 (s, 1H), 5.47 (d, J= 6.1 Hz, 1H), 3.78 (td, J= 7.6, 6.3 Hz, 1H), 3.35 (s, 3H), 2.7 (s,3H), 2.63 - 2.55 (m, 1H), 2.57 - 2.49 (m, 1H), 2.53 - 2.45 (m, 2H), 2.48 - 2.41 (m, 2H), 1.94 (ddt, J = 9.7, 7.9, 1.7 Hz, 2H).

[1214] Example 188: 4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1215]

[1216] F F The title compound was obtained in analogy to Example 120 as a white solid (57.2% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 2,2-difluoroethanamine. LCMS (ESIpos):

[1217] [M+H]+: 534.10. ’H NMR (400 MHz, Acetonitrile-d₃) 68.37 (d, J= 5.2 Hz, 2H), 7.45 -7.32 (m, 5H), 7.07 - 6.95 (m, 2H), 6.63 - 6.55 (m, 2H), 6.04 - 5.70 (m, 2H), 5.44 (t, J = 6.7 Hz, 1H), 3.57 - 3.42 (m, 2H), 3.35 (s, 3H), 2.78 - 2.59 (m, 3H).

[1218] Example 189: 4-(3,3-difluoroazetidin-l-yl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1219]

[1220] F F

[1221] The title compound was obtained in analogy to Example 120 as a white solid (26.5% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3,3-difluoroazetidine. LCMS (ESI) [M + H]+: 546.05. ’H NMR (400 MHz, Acetonitrile-d₃) 58.40 (d, J= 5.2 Hz, 2H), 7.56 - 7.48 (m, 2H), 7.42 (t, J= 5.6 Hz, 3H), 7.04 (t, J= 8.6 Hz, 2H), 6.50 - 6.36 (m, 2H), 5.87 (s, 1H), 4.29 (t, J = 12.0 Hz, 4H), 3.40 (s, 3H), 2.68 (d, J= 31.0 Hz, 3H).

[1222] Example 190: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)azetidin-l-yl]benzenesulfonamide

[1223]

[1224] The title compound was obtained in analogy to Example 120 as a white solid (17.2% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(trifluoromethyl) azetidine hydrochloride. LCMS (ESI) [M + H]+: 578.3.1H NMR (400 MHz, Acetonitrile-d₃) d 8.56 - 8.40(s, 1H), 7.61 - 7.45 (m, 5H), 7.12 (s, 2H), 6.44 (d, J= 8.8 Hz, 2H), 5.94 (s, 1H), 4.20 (td, J= 8.1, 2.9 Hz, 2H), 4.06 (dt, J = 8.6, 4.1 Hz, 2H), 3.68 - 3.53 (m, 1H), 3.48 (s, 3H), 2.93 - 2.58 (s, 3H).

[1225] Example 191: 4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1226] o=s=o o

[1227]

[1228] The title compound was obtained in analogy to Example 120 as a white solid (37.8% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 6,6-difluoro-2-azaspiro[3.3] heptane. LCMS (ESI) [M + H]+: 586.10. ’H NMR (400 MHz, Acetonitrile-d₃) 68.35 (d, J= 5.2 Hz, 1H), 7.48 - 7.32 (m, 5H), 7.09 - 6.94 (m, 2H), 6.37 - 6.15 (m, 2H), 5.85 (s, 1H), 3.94 (s, 4H), 3.36 (s, 3H), 2.78 (s, 1H), 2.75 (s, 2H), 2.72 (s, 1H), 2.67 (s, 3H).

[1229] Example 192: 4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1230] F

[1231]

[1232] The title compound was obtained in analogy to Example 120 as a white solid (20.8% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride. LCMS (ESI) [M+H]+: 572.15. ’H NMR (400 MHz, DMSO-*) 5 11.29 (s, 1H), 8.50 (d, J= 5.3 Hz, 1H), 7.59 (d, J= 5.2 Hz, 1H), 7.55 - 7.34 (m, 4H), 7.18 (s, 2H), 6.60 (d, J= 8.8 Hz, 2H), 5.87 (d, J= 28.8 Hz, 1H), 3.66 (s, 4H), 3.37 (s, 3H), 2.85 (s, 2H), 2.76 (d, J= 11.8 Hz, 2H), 2.51 (s, 1H).

[1233] Example 193: 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide HN

[1234]

[1235] F

[1236] a) 4-iodo-iV- { 2- [methoxy(4-methylphenyl)methyl] - 8-methyl-4-oxopyrido [3,4-d]pyrimidin- 3 -yl } benzenesulfonamide

[1237] The title compound was obtained in analogy to Example 1 as a light yellow oil (79.2% yield) using 3- [2-methoxy-2-(4-methylphenyl)acetamido] -2-methylpyridine-4-carboxylic acid and -(4-iodobenzenesulfonyl)tert-butoxycarbohydrazide. LCMS (ESI) [M+H]+: 577.0.

[1238] b) 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide.

[1239] 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 66 as a yellow solid (15.2% yield) using 4-iodo-2V-{2-[methoxy(4-methylphenyl)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and (lr,3r)-3-(difluoromethyl)cyclobutan-1-amine hydrochloride. Chiral separation using conditions O afforded 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2- [(R)-methoxy(p-tolyl)methyl]pyrido [3,4-d]pyrimidin-3-yl]benzenesulfonamide (13.5% yield, RT=18.9min, first peak) as awhite solid. LCMS (ESI) [M+H]+: 570.15.1HNMR(400 MHz, DMSO-d6) 6 11.14 (d, J = 173.6 Hz, 1H), 8.49 (d, J= 5.1 Hz, 1H), 7.58 (d, J= 5.2 Hz, 1H), 7.43 (d, J= 8.5 Hz, 2H), 7.26 (s, 2H), 7.14 (s, 3H), 6.51 (d, J= 8.6 Hz, 2H), 6.23 (td, J= 57.2, 4.9 Hz, 1H), 5.80 (s, 1H), 3.99 (t, J= 7.4 Hz, 1H), 3.32 (s, 3H), 2.85 (s, 2H), 2.67 (s, 1H), 2.40 (s, 3H), 2.30 (d, J= 26.4 Hz, 3H), 2.06 (s, 2H). Example 194: 4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1240]

[1241] The title compound was obtained in analogy to Example 120 as a white solid (31.1% yield) using N-{2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-iodobenzenesulfonamide and 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride. LCMS (ESI) [M+H]+: 572.10. ’H NMR (400 MHz, DMSO-d6) 6 11.04 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.55 - 7.37 (m, 4H), 7.19 (s, 2H), 6.59 (d, J = 8.8 Hz, 2H), 5.84 (s, 1H), 3.66 (s, 4H), 3.37 (s, 3H), 2.85 (s, 2H), 2.76 (d, J = 11.9 Hz, 2H), 2.52 (d, J= 1.7 Hz, 1H).

[1242] Example 195: 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-chlorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1243]

[1244] 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(4-chlorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 193 as a yellow solid (15.2% yield) using 7V-{2-[(4-chlorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl} -4-iodobenzenesulfonamide and (lr,3r)-3-(difluoromethyl)cyclobutan-1-amine hydrochloride. Chiral separation using conditions O afforded 4-[[(lr,3r)-3- (difhioromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-chlorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (34.4% yield, RT=19.2min, first peak) as a white solid. LCMS (ESI) [M+H]+: 590.05.!H NMR (400 MHz, Acetonitrile-d3) δ 8.31 (d, J= 5.2 Hz, 1H), 7.38 - 7.27 (m, 5H), 7.25 - 7.19 (m, 2H), 6.38 - 6.30 (m, 2H), 6.03 - 5.74 (m, 2H), 5.50 - 5.45 (m, 1H), 3.91 - 3.79 (m, 1H), 3.29 (s, 3H), 2.65 - 2.55 (m, 4H), 2.33 (ddd, J= 12.6, 7.9, 4.3 Hz, 2H), 1.94 - 1.90 (m, 2H).

[1245] Example 196: 4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[1246] o=s=o o

[1247]

[1248] F F

[1249] The title compound was obtained in analogy to Example 120 as a white solid (33.0% yield) using A-{2-[(7?)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 6,6-difluoro-2-azaspiro[3.3] heptane. LCMS (ESI) [M + H]+: 586.05.1H NMR (400 MHz, Acetonitrile-d₃) 68.35 (d, J = 5.2 Hz, 1H), 7.48 - 7.33 (m, 5H), 7.05 - 6.93 (m, 2H), 6.34 - 6.18 (m, 2H), 5.85 (s, 1H), 3.94 (s, 4H), 3.36 (s, 3H), 2.78 (s, 1H), 2.75 (s, 2H), 2.72 (s, 1H), 2.67 (s, 3H).

[1250] Example 197: 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1251] HN

[1252]

[1253] F

[1254] The title compound is the second peak obtained in the chiral separation of 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 193) using conditions O (14.2% yield, RT=29.4min, second peak). LCMS (ESI) [M+H]+: 570.15. ’H NMR (400 MHz, DMSO-d6) 6 11.14 (d, J = 175.3 Hz, 1H), 8.49 (d, J= 5.0 Hz, 1H), 7.58 (d, J= 5.3 Hz, 1H), 7.42 (d, J= 8.6 Hz, 2H), 7.37 - 7.21 (m, 2H), 7.14 (s, 3H), 6.51 (d, J = 8.5 Hz, 2H), 6.23 (td, J = 57.2, 4.9 Hz, 1H), 5.79 (s, 1H), 3.99 (q, J= 7.2 Hz, 1H), 3.32 (s, 3H), 2.92 - 2.73 (m, 3H), 2.40 (s, 3H), 2.37 - 2.22 (m, 3H), 2.08 (d, J = 13.8 Hz, 2H).

[1255] Example 198: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)-l-bicyclo[ 1.1.1] pentanyl] amino] benzenesulfonamide

[1256] F

[1257]

[1258] The title compound was obtained in analogy to Example 120 as a white solid (4.2% yield) using N-{2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride. LCMS (ESI) [M+H]+: 604.20.1H NMR (400 MHz, Acetonitrile-d3) d 8.49 (d, J= 5.3 Hz, 1H), 7.55 - 7.46 (m, 5H), 7.17 - 7.10 (m, 2H), 6.76 - 6.72 (m, 2H), 6.01 (d, J= 35.3 Hz, 1H), 3.48 (d, J= 1.7 Hz, 3H), 2.81 (s, 3H), 2.37 (d, J= 1.6 Hz, 6H).

[1259] Example 199: 4-[(2,2-difluorospiro[2.3]hexan-5-yl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1260]

[1261] The title compound was obtained in analogy to Example 120 as a white solid (13.3% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 1,1-difluorospiro[2.3]hexan-5-amine hydrochloride. LCMS (ESI) [M + H] +: 586.2.1H NMR (300 MHz, Acetonitrile-d₃) d 8.48 (d, J= 5.2 Hz, 1H), 7.56 - 7.44 (m, 5H), 7.12 (t, J = 8.9 Hz, 2H), 6.59 - 6.50 (m, 2H), 5.95 (s, 1H), 5.71 (d, J = 6.0 Hz, 1H), 4.25 - 4.12 (m, 1H), 3.47 (s, 3H), 2.80 (s, 3H), 2.53 (t, J = 10.1 Hz, 2H), 2.31 - 2.20 (m, 2H), 1.40 (t, J= 8.5 Hz, 2H).

[1262] Example 200: 4-(2-hydroxyethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1263] F

[1264]

[1265] The title compound was obtained in analogy to Example 120 as a white solid (13.2% yield) using A-{2-[(7?)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and ethanolamine. LCMS (ESIpos) [M+H] +: 514.20. ‘H NMR (400 MHz, DMSO-d6) d 10.92 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.60 (d, J= 5.2 Hz, 1H), 7.41 (d, J= 8.7 Hz, 4H), 7.20 (s, 2H), 6.70 (s, 1H), 6.60 (d, J= 8.7 Hz, 2H), 5.88 (s, 1H), 4.76 (t, J= 5.4 Hz, 1H), 3.55 (q, J= 5.7 Hz, 2H), 3.36 (s, 3H), 3.15 (q, J = 5.8 Hz, 2H), 2.83 (s, 2H), 2.53 (s, 1H).

[1266] Example 201: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d] pyrimidin-3-yl] -4- [ [3- (trifluoromethyl) - 1 -bicyclo[ 1.1.1] pentanyl] amino] benzenesulfonamide

[1267]

[1268] The title compound was obtained in analogy to Example 120 as a white solid (5.9% yield) using N- { 2- [ (. S’) - (4- fl uorophcny 1 ) (methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-d] pyrimidin-3-yl]-4-iodobenzenesulfonamide and 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-amine hydrochloride. LCMS (ESI) [M+H]+: 604.20.1H NMR (400 MHz, Acetonitrile-d3) δ 8.33 (d, J= 5.2 Hz, 1H), 7.33 (dd, J= 7.7, 5.9 Hz, 5H), 7.00 - 6.91 (m, 2H), 6.61 -6.53 (m, 2H), 5.83 (d, J= 36.4 Hz, 1H), 3.31 (s, 3H), 2.63 (s, 3H), 2.20 (s, 6H).

[1269] Example 202: 4-[(2,2-difluorospiro[2.3]hexan-5-yl)amino]-N-[8-methyl-4-oxo-2-[(R)- (4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pynmidin-3-yl]benzenesulionamide

[1270]

[1271] The title compound was obtained in analogy to Example 120 as a white solid (4.2% yield) using N- { 2- [ ( / ?) - ( 4- f 1 uorophcny 1 ) (methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 1,1-difluorospiro[2.3]hexan-5-amine hydrochloride. LCMS (ESI) [M + H] +: 586.2.1H NMR (300 MHz, Acetonitrile-d₃) 38.48 (d, J= 5.2 Hz, 1H), 7.56 - 7.44 (m, 5H), 7.12 (t, J = 8.9 Hz, 2H), 6.59 - 6.50 (m, 2H), 5.95 (s, 1H), 5.71 (d, J = 6.0 Hz, 1H), 4.25 - 4.12 (m, 1H), 3.47 (s, 3H), 2.80 (s, 3H), 2.53 (t, J = 10.1 Hz, 2H), 2.31 - 2.20 (m, 2H), 1.40 (t, J= 8.5 Hz, 2H).

[1272] Example 203: 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)- [4-(difluoromethyl)phenyl] -methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1273]

[1274] F a) A-(2-{[4-(difluoromethyl) phenyl] (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3 -yl) -4-iodobenzene sulfonamide.

[1275] The title compound was obtained in analogy to Example 49 as a white solid (40.1% yield) using 3-amino-2-{[4-(difluoromethyl) phenyl] (methoxy)methyl]-8-methylpyrido[3,4-d] pyrimidin-4-one and 4-iodobenzenesulfonyl chloride. LCMS (ESI) [M + H]+: 613.02.

[1276] b) 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-[4- (difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide.

[1277] 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide was obtained in analogy to Example 66 as a white solid (20.2% yield) using A-(2-{[4-(difhioromethyl) phenyl] (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl)-4-iodobenzenesulfonamide and (lr,3r)-3-(difluoromethyl) cyclobutan-1 -amine hydrochloride. Chiral separation using conditions B afforded 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (27.5% yield, RT=19.2min, second peak) as a white solid. LCMS (ESI) [M + H]+: 606.18. ’H NMR (400 MHz, DMSO-d6) d 11.03 (s, 1H), 8.49 (d, J= 5.2 Hz, 1H), 7.65 -7.49 (m, 5H), 7.47 -7.39 (m, 2H), 7.19 -6.89 (m, 2H), 6.51 (d, J= 8.8 Hz, 2H), 6.39 - 6.07 (m, 1H), 6.00 - 5.89 (m, 1H), 4.00 (q, J= 7.1 Hz, 1H), 3.32 (s, 3H); 2.69 (d, J = 4.9 Hz, 4H), 2.46 - 2.35 (m, 2H), 2.12 - 2.00 (m, 2H).

[1278] Example 204: 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1279]

[1280] The title compound is the first peak obtained in the chiral separation of 4-[[(lr,3r)-3-(difhiorornethyl)cyclobutyl]arnino]-N-[8-rnethyl-4-oxo-2-[[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (Example 203) using conditions B (27.5% yield, RT=15.2min, first peak). LCMS (ESI) [M + H]+: 606.18.!H NMR (400 MHz, DMSO-d6) d 10.97 (s, 1H), 8.50 (d, J= 5.3 Hz, 1H), 7.68 - 7.50 (m, 5H), 7.44 (d, J= 8.7 Hz, 2H), 7.19 - 6.89 (m, 2H), 6.51 (d, J= 8.8 Hz, 2H), 6.23 (td, J= 57.2, 4.9 Hz, 1H), 5.94 (s, 1H), 4.26 - 3.95 (m, 1H), 3.34 (s, 3H), 2.93 - 2.58 (m, 4H), 2.44 - 2.36 (m, 2H), 2.11 -2.01 (m, 2H).

[1281] Example 205: N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide

[1282]

[1283] N-[8-(difluoromethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide was obtained in analogy to Example 159 as a yellow oil (57.4% yield) using A^-[8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-iodobenzene sulfonamide and morpholine. Chiral separation using conditions P afforded 4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide (31.1% yield, RT=23.2min, second peak) as a white solid. LCMS (ESI) [M + H]+: 576.10. ’H NMR (400 MHz, DMSO-d6) 6 11.43 (s, 1H), 8.72 (d, J= 5.1 Hz, 1H), 7.95 (d, J = 5.1 Hz, 1H), 7.73 -7.41 (m, 5H), 7.25 - 7.13 (m, 2H), 6.97 (d, J = 9.1 Hz, 2H), 5.99 (s, 1H), 3.80 - 3.69 (m, 4H), 3.35 (s, 3H), 3.29 - 3.22 (m, 4H).

[1284] Example 206: N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide

[1285]

[1286] The title compound is the first peak obtained in the chiral separation of N-[8-(difluoromethyl)-4-oxo-2-[(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide (Example 205) using conditions P (26.5% yield, RT=18.1min, first peak). LCMS (ESI) [M + H]+: 576.10. ’H NMR (400 MHz, DMSO-d6) 5 8.72 (d, J= 5.1 Hz, 1H), 7.95 (d, J= 5.1 Hz, 1H), 7.65 - 7.42 (m, 5H), 7.24 - 7.12 (m, 2H), 6.97 (d, J= 8.8 Hz, 2H), 6.00 (s, 1H), 3.79 - 3.68 (m, 4H), 3.37 - 3.35 (m, 3H), 3.28 -3.22 (m, 4H). Example 207: 4-[(lr,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1287] F

[1288]

[1289] F

[1290] The title compound was obtained in analogy to Example 116 as a white solid (47.3% yield) using 3-amino-2-[(7?)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-[(lr,3r)-3-(difluoromethyl)cyclobutoxy]benzenesulfonyl chloride. LCMS (ESI) [M+H]+: 575.25.1H NMR (400 MHz, Acetonitrile-d₃) 68.72 (s, 1H), 8.49 (d, J= 5.3 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.60 - 7.44 (m, 3H), 7.23 - 7.05 (m, 2H), 6.96 - 6.88 (m, 2H), 6.12 - 5.78 (m, 2H), 4.82 - 4.71 (m, 1H), 3.49 (s, 3H), 2.98 -2.44 (m, 6H), 2.15 - 2.08 (m, 2H).

[1291] Example 208: 4-[(lr,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1292]

[1293] The title compound was obtained in analogy to Example 116 as a white solid (57.8% yield) using 3-amino-2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methylpyrido[3,4-d]pyrimidin-4-one and 4-[(lr,3r)-3-(difluoromethyl)cyclobutoxy]benzenesulfonyl chloride. LCMS (ESI) [M+H]+: 575.25.1H NMR (400 MHz, Acetonitrile-d₃) 68.68 (s, 1H), 8.49 (d, J= 5.2 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.54 - 7.46 (m, 3H), 7.22 - 7.05 (m, 2H), 6.96 - 6.88 (m, 2H), 6.11 - 5.78 (m, 2H), 4.82 - 4.71 (m, 1H), 3.49 (s, 3H), 2.96 -2.44 (m, 6H), 2.15 - 2.10 (m, 2H).

[1294] Example 209: 4-(((lr,3r)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1295]

[1296] The title compound was obtained in analogy to Example 120 as a white solid (3.8% yield) using 4-bromo-3-fluoro-N-{2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and (lr,3r)-3-(difluoromethyl)cyclobutan- 1 -amine. LCMS (ESI) [M + H]+: 592.10. ’H NMR (400 MHz, Acetonitrile-d₃) 58.37 (d, J= 5.2 Hz, 1H), 7.41 (dd, J= 7.5, 5.2 Hz, 3H), 7.28 (dd, J = 11.3, 2.1 Hz, 1H), 7.21 (dd, J= 8.6, 2.2 Hz, 1H), 7.07 - 6.96 (m, 2H), 6.42 (t, J= 8.5 Hz, 1H), 6.12 - 5.78 (m, 2H), 5.44 (d, J = 5.6 Hz, 1H), 3.98 (m, 1H), 3.37 (s, 3H), 2.73 - 2.56 (m, 4H), 2.40 (m, 2H), 2.11 (d, J = 8.8 Hz, 2H).

[1297] Example 210: 4-(((ls,3s)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((S)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1298] HN

[1299]

[1300] F

[1301] The title compound was obtained in analogy to Example 120 as a white solid (25.2% yield) using 4-bromo-3-fluoro-A-{2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and ( 1.s,3.s)-3-(difluoromethyl)cyclobutan- 1 -amine hydrochloride. LCMS (ESI) [M + H]+: 592.15.!H NMR (400 MHz, Acetonitrile-d3) δ 8.47 (d, J= 5.2 Hz, 1H), 7.51 (dd, J= 8.2, 5.3 Hz, 3H), 7.40 - 7.30 (m, 2H), 7.12 (t, J= 8.8 Hz, 2H), 6.59 (t, J= 8.5 Hz, 1H), 6.06 - 5.72 (m, 2H), 4.03 - 3.89 (m, 1H), 3.48 (s, 3H), 2.78 (s, 3H), 2.63 - 2.45 (m, 3H), 2.00 (s, 2H). Example 211: 4-(((ls,3s)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1302]

[1303] The title compound was obtained in analogy to Example 120 as a white solid (18.9% yield) using 4-bromo-3-fluoro-A-{2-[(R)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and ( 1.s,3.s)-3-(difluoromethyl)cyclobutan- 1 -amine hydrochloride. LCMS (ESI) [M + H]+: 592.10.!H NMR (400 MHz, Acetonitrile-d₃) 58.48 (d, J= 5.2 Hz, 1H), 7.52 (dd, J= 8.2, 5.3 Hz, 3H), 7.42- 7.31 (m, 2H), 7.13 (t, J= 8.8 Hz, 2H), 6.60 (t, J= 8.5 Hz, 1H), 6.08 - 5.74 (m, 2H), 4.05 - 3.90 (m, 1H), 3.49 (s, 3H), 2.80 (s, 3H), 2.64 - 2.46 (m, 3H), 2.01 (s, 2H).

[1304] Example 212: 4-(((lr,3s)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((S)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide

[1305]

[1306] The title compound was obtained in analogy to Example 120 as a white solid (23.0% yield) using 4-bromo-3-fluoro-N-{2-[(S)-(4-fluorophenyl)(methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3-yl}benzenesulfonamide and (lr,3r)-3-(difluoromethyl)cyclobutan- 1 -amine. LCMS (ESI) [M + H]+: 592.10. LCMS (ESI) [M + H]+: 592.15. ’H NMR (400 MHz, Acetonitrile-d₃) 68.37 (d, J= 5.2 Hz, 1H), 7.41 (dd, J = 7.5, 5.2 Hz, 3H), 7.28 (dd, J= 11.3, 2.1 Hz, 1H), 7.21 (dd, J = 8.6, 2.2 Hz, 1H), 7.07 -6.96 (m, 2H), 6.42 (t, J= 8.5 Hz, 1H), 6.12 - 5.78 (m, 2H), 5.44 (d, J= 5.6 Hz, 1H), 3.98 (m, 1H), 3.37 (s, 3H), 2.73 -2.56 (m, 4H), 2.40 (m, 2H), 2.11 (d, J = 8.8 Hz, 2H).

[1307] Example 213: 4-[(4,4-difluorocyclohexyl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1308]

[1309] The title compound was obtained in analogy to Example 120 as a white solid (26.2% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 4,4-difluorocyclohexan- 1 -amine. LCMS (ESI) [M+H]+: 588.05. ’H NMR (400 MHz, Acetonitrile-d₃) 68.35 (dd, J= 5.2, 1.6 Hz, 1H), 7.42 - 7.29 (m, 5H), 7.00 (t, J = 8.7 Hz, 2H), 6.51 - 6.44 (m, 2H), 5.84 (s, 1H), 5.21 (d, J= 7.9 Hz, 1H), 3.48 - 3.32 (m, 4H), 3.36 (d, J= 1.6 Hz, 3H), 2.05 - 1.96 (m, 2H), 1.93 - 1.87 (m, 2H), 1.83 - 1.74 (m, 2H), 1.47 (t, J = 11.8 Hz, 2H).

[1310] Example 214: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[(2,2,2-trifluoro-l-methyl-ethyl)amino]benzenesulfonamide

[1311]

[1312] The title compound was obtained in analogy to Example 120 as a white solid (8.4% yield) using N- { 2- [ ( / ?) - ( 4- f 1 uorophcny 1 ) (methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and l,l,l-trifluoropropan-2- amine hydrochloride. LC-MS (ESI, m / z): [M+ H]+: 566.00.1H NMR (400 MHz, DMSO-d6) δ 11.26 (d, J= 181.1 Hz, 1H), 8.51 (dd, J = 5.2, 1.6 Hz, 1H), 7.64 - 7.39 (m, 5H), 7.20 (s, 2H), 7.02 (d, J= 9.0 Hz, 1H), 6.86 - 6.76 (m, 2H), 5.86 (s, 1H), 4.65 - 4.33 (m, 1H), 3.37 (s, 3H), 2.84 (s, 3H), 1.33 (d, J= 6.7 Hz, 3H).

[1313] Example 215: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethylamino)benzenesulfonamide F

[1314] F - F

[1315]

[1316] F

[1317] The title compound was obtained in analogy to Example 120 as a white solid (37.7% yield) using A-{2-[(7?)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 2,2,2-trifluoroethylamine hydrochloride. LCMS (ESIpos) [M+H]+: 552.05.1H NMR (400 MHz, Acetonitrile-d₃) 68.37 (d, J = 5.2 Hz, 1H), 7.48 - 7.34 (m, 5H), 7.01 (t, J= 8.8 Hz, 2H), 6.68 - 6.60 (m, 2H), 5.82 (s, 1H), 5.64 - 5.57 (m, 1H), 3.89 - 3.77 (m, 2H), 3.36 (s, 3H), 2.69 (s, 3H).

[1318] Example 216: 4-[[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1319]

[1320] The title compound was obtained in analogy to Example 120 as a white solid (3.5% yield) using N- { 2- [ ( / ?) - ( 4- f 1 uorophcny 1 ) (methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(difluoromethyl)bicyclo[l.1. l]pentan- 1-amine hydrochloride. LCMS (ESI) [M+H]+: 586.25.1H NMR (300 MHz, Acetonitrile-d3) δ 8.49 (d, J= 5.2 Hz, 1H), 7.58 - 7.48 (m, 4H), 7.47 (s, 1H), 7.13 (t, J= 8.8 Hz, 2H), 6.73 (d, J= 9.0 Hz, 2H), 6.15 - 5.88 (m, 3H), 3.48 (s, 3H), 2.81 (s, 3H), 2.21 (d, J= 0.8 Hz, 6H).

[1321] Example 217: 4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1322]

[1323] The title compound was obtained in analogy to Example 120 as a white solid (23.7% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and l-(3,3-difluorocyclobutyl) methanamine hydrochloride. LC-MS (ESI, m / z): [M+ H]+: 574.10. ’H NMR (400 MHz, DMSO-d6) 8 11.16 (d, 7 = 185.3 Hz, 1H), 8.49 (d, 7= 5.2 Hz, 1H), 7.58 (d, 7= 5.2 Hz, 1H), 7.42 (d, 7 = 8.7 Hz, 4H), 7.20 (s, 2H), 6.86 (s, 1H), 6.60 (d, 7= 8.8 Hz, 2H), 5.88 (s, 1H), 3.37 (s, 3H), 3.25 - 3.14 (m, 2H), 2.85 (s, 2H), 2.73 - 2.56 (m, 2H), 2.51 (s, 1H), 2.44 - 2.21 (m, 3H).

[1324] Example 218: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(2,2,2-trifluoroethyl)azetidin-l-yl] benzenesulfonamide

[1325]

[1326] The title compound was obtained in analogy to Example 120 as a white solid (45.0% yield) using A-{2-[(7?)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(2,2,2-trifluoroethyl)azetidine. LCMS (ESI) [M + H]+: 592.05. ’H NMR (400 MHz, Acetonitrile-d₃) 68.74 (d, J= 153.1 Hz, 1H), 8.34 (d, J= 5.2 Hz, 1H), 7.39 (dd, J= 7.0, 4.8 Hz, 5H), 6.97 (s, 2H), 6.24 (d, J= 8.6 Hz, 2H), 5.84 (s, 1H), 4.04 (m, 2H), 3.62 (dd, J= 8.3, 5.5 Hz, 2H), 3.36 (s, 3H), 3.00 (m, 1H), 2.84 (s, 2H) 2.49 (m, 3H).

[1327] Example 219: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(2,2,2-trifluoroethyl)cyclobutyl]amino]benzenesulfonamide

[1328]

[1329] The title compound was obtained in analogy to Example 120 as a white solid (45.0% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(2,2,2-trifluoroethyl)cyclobutan- 1-amine. LCMS (ESI) [M + H]+: 606.05. ’H NMR (300 MHz, Acetonitrile-d3) δ 8.48 (d, J = 5.2 Hz, 1H), 8.30 - 8.20 (m, 1H), 7.57 -7.41 (m, 5H), 7.12 (t, J = 8.7 Hz, 2H), 6.51 (dd, J = 8.9, 7.1 Hz, 2H), 5.94 (s, 1H), 5.63 (dd, J = 33.7, 6.3 Hz, 1H), 4.07 - 3.73 (m, 1H), 3.47 (s, 3H), 2.80 (s, 3H), 2.72 - 2.57 (m, 2H), 2.52 - 2.22 (m, 4H), 1.68 (d, J = 9.4 Hz, 1H).

[1330] Example 220: 4-[(4,4-difluorocyclohexyl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1331]

[1332] The title compound was obtained in analogy to Example 120 as a white solid (19.2% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 4,4-difluorocyclohexan- 1 -amine. LCMS (ESI) [M+H]+: 588.10. ’H NMR (400 MHz, Acetonitrile-d₃) 58.34 (d, J= 5.2 Hz, 2H), 7.37 (m, 5H), 6.99 (t, J = 8.7 Hz, 2H), 6.53 - 6.42 (m, 2H), 5.84 (s, 1H), 5.21 (d, J = 7.9 Hz, 1H), 3.44 - 3.34 (m, 4H), 2.50 - 2.94 (m, 3H), 2.05 - 1.94 (m, 2H), 1.93 - 1.87 (m, 2H), 1.79 (m, 2H), 1.53 - 1.36 (m, 2H).

[1333] Example 221: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[(2,2,2-trifluoro-l-methyl-ethyl)amino]benzenesulfonamide

[1334]

[1335] The title compound was obtained in analogy to Example 120 as a white solid (6.4% yield) using N- { 2- [ (. S')-(4-fl uorophcny 1 ) (methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-d] pyrimidin-3-yl } -4-iodobenzenesulfonamide and 1,1,1 -trifluoropropan-2-amine hydrochloride. LC-MS (ESI, m / z): [M+H]+: 566.00.1H NMR (400 MHz, DMSO-d6) 6 11.26 (d, J= 189.6 Hz, 1H), 8.50 (dd, J = 5.2, 1.8 Hz, 1H), 7.67 - 7.35 (m, 5H), 7.20 (s, 2H), 7.01 (d, J= 9.0 Hz, 1H), 6.81 (d, J = 8.9 Hz, 2H), 5.86 (s, 1H), 4.62 - 4.49 (m, 1H), 3.36 (d, J= 8.2 Hz, 3H), 2.84 (s, 3H), 1.33 (d, J = 6.7 Hz, 3H).

[1336] Example 222: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(2,2,2-trifluoroethyl)cyclobutyl]amino]benzenesulfonamide

[1337]

[1338] The title compound was obtained in analogy to Example 120 as a white solid (28.1% yield) using A^-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(2,2,2-trifluoroethyl)cyclobutan- 1-amine. LCMS (ESI) [M + H]+:606.05. ’H NMR (300 MHz, Acetonitrile-d3) δ 8.48 (d, J = 5.2 Hz, 1H), 7.55 - 7.42 (m, 5H), 7.12 (t, J = 8.9 Hz, 2H), 6.51 (dd, J= 9.0, 7.1 Hz, 2H), 5.95 (s, 1H), 5.62 (dd, J = 33.9, 6.2 Hz, 1H), 4.09 - 3.77 (m, 1H), 3.47 (s, 3H), 2.80 (s, 3H), 2.65 (d, J= 11.7 Hz, 2H), 2.49 -2.24 (m, 4H), 1.68 (d, J = 9.9 Hz, 1H).

[1339] Example 223: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethylamino)benzenesulfonamide

[1340] F - F

[1341]

[1342] F

[1343] The title compound was obtained in analogy to Example 120 as a white solid (41.8% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(2,2,2-trifluoroethyl)cyclobutan- 1-amine. LCMS (ESIpos) [M+H]+: 552.00.1H NMR (400 MHz, Acetonitrile-d₃) 58.32 (d, J = 5.2 Hz, 1H), 7.43 - 7.29 (m, 5H), 6.96 (t, J= 8.9 Hz, 2H), 6.64 - 6.55 (m, 2H), 5.77 (s, 1H), 5.59 - 5.52 (m, 1H), 3.84 - 3.69 (m, 2H), 3.30 (s, 3H), 2.63 (s, 3H).

[1344] Example 224: 4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide

[1345]

[1346] The title compound was obtained in analogy to Example 120 as a white solid (25.9% yield) using A^-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and l-(3,3-difluorocyclobutyl) methanamine hydrochloride. LC-MS (ESI, m / z): [M+ H]+: 574.05.1H NMR (400 MHz, DMSO-d6) 8 11.17 (d, J= 193.9 Hz, 1H), 8.50 (dd, J= 5.1, 2.0 Hz, 1H), 7.58 (d, J= 5.2 Hz, 1H), 7.55 -7.32 (m, 4H), 7.19 (s, 2H), 6.86 (s, 1H), 6.61 (dd, J= 9.1, 2.5 Hz, 2H), 5.86 (s, 1H), 3.37 (s, 3H), 3.26 - 3.15 (m, 2H), 2.85 (s, 2H), 2.74 - 2.59 (m, 2H), 2.51 (s, 1H), 2.43 - 2.24 (m, 3H).

[1347] Example 225: 4-[[3-(difluoromethyl)-l-bicyclo[l.l.l]pentanyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1348]

[1349] The title compound was obtained in analogy to Example 120 as a white solid (4.1% yield) using N- { 2- [ (. S')-(4-fl uorophcny 1 ) (methoxy)methyl] - 8-methyl-4-oxopyrido [3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(difluoromethyl)bicyclo[l.1. l]pentan- 1-amine hydrochloride. LCMS (ESI) [M+H]+: 586.25.!H NMR (300 MHz, Acetonitrile-d₃) 58.49 (d, J= 5.3 Hz, 1H), 7.61 - 7.47 (m, 5H), 7.13 (t, J= 8.8 Hz, 2H), 6.73 (d, J= 8.9 Hz, 2H), 6.07 - 5.91 (m, 3H), 3.48 (s, 3H), 2.81 (s, 3H), 2.21 (s, 6H).

[1350] Example 226: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(2,2,2-trifluoroethyl)azetidin-l-yl]benzenesulfonamide

[1351]

[1352] The title compound was obtained in analogy to Example 120 as a white solid (34.4% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 3-(2,2,2-trifluoroethyl)azetidine. LCMS (ESI) [M + H]+: 592.15. ’H NMR (400 MHz, Acetonitrile-d₃) 68.49 (d, J= 5.3 Hz, 1H), 7.52 (dd, J= 9.3, 6.5 Hz, 5H), 7.12 (t, J= 8.8 Hz, 2H), 6.38 (d, J= 8.6 Hz, 2H), 5.97 (s, 1H), 4.18 (m, 2H), 3.76 (m, 2H), 3.48 (s, 3H), 3.13 (m, 1H), 2.80 (s, 3H), 2.70 - 2.59 (m, 2H).

[1353] Example 227: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[2- (trifluoromethyl)cyclopropyl] amino] benzenesulfonamide

[1354]

[1355] The title compound was obtained in analogy to Example 120 as a white solid (23.4% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 2-(trifluoromethyl) cyclopropan-1 -amine hydrochloride. LCMS (ESIpos): m / z = 578.10 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d3) 88.43 (d, J= 5.2 Hz, 1H), 7.54 - 7.38 (m, 5H), 7.07 (t, J= 8.8 Hz, 2H), 6.78 - 6.68 (m, 2H), 5.90 (d, J= 6.5 Hz, 1H), 3.41 (d, J= 1.7 Hz, 3H), 2.84 (s, 1H), 2.79 -2.71 (m, 3H), 1.87 - 1.80 (m, 1H), 1.38 - 1.29 (m, 1H), 1.18 - 1.13 (m, 1H).

[1356] Example 228: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide

[1357]

[1358] The title compound was obtained in analogy to Example 120 as a white solid (22.9% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and methyl(2,2,2-trifluoroethyl) amine hydrochloride. LC-MS (ESI, m / z): [M+ H]+: 566.25.!H NMR (400 MHz, Acetonitrile-d3) 3 8.52 - 8.41 (m, 1H), 7.67 - 7.55 (m, 2H), 7.54 - 7.46 (m, 3H), 7.17 - 7.07 (m, 2H), 6.94 - 6.82 (m, 2H), 5.93 (s, 1H), 4.15 (q, J = 9.1 Hz, 2H), 3.47 (s, 3H), 3.13 (s, 3H), 2.80 (s, 3H).

[1359] Example 229: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide

[1360]

[1361] The title compound was obtained in analogy to Example 120 as a white solid (22.9% yield) using AA-{2-|( / ?)-(4-fluorophcnyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and methyl(2,2,2-trifluoroethyl) amine hydrochloride. LC-MS (ESI, m / z): [M+ H]+: 566.25.1H NMR (400 MHz, Acetonitrile-d3) 38.49 (d, J= 5.2 Hz, 1H), 7.66 - 7.56 (m, 2H), 7.50 (q, J= 5.5, 4.5 Hz, 3H), 7.13 (t, J = 8.9 Hz, 2H), 6.91 - 6.79 (m, 2H), 5.93 (s, 1H), 4.15 (q, J = 9.0 Hz, 2H), 3.47 (s, 3H), 3.13 (s, 3H), 2.80 (s, 3H).

[1362] Example 230: 4-[(2,2-difluorocyclopropyl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide F

[1363] 0=S=0 o

[1364]

[1365] a) tert-butyl (2,2-difluorocyclopropyl)(4-(N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)sulfamoyl)phenyl)carbamate.

[1366] The title compound was obtained in analogy to Example 116 as a white solid (48.7% yield) using 3-amino-2-[(R)-(4-fluorophenyl) (methoxy) methyl |-8-mcthylpyrido| 3, 4-d| pyrimidin-4-one and tert-butyl A-[4-(chlorosulfonyl) phenyl ]-A-(2,2-difluorocyclopropyl) carbamate. LC-MS (ES, m / z): [M+H]+= 646.

[1367] b) 4-[(2,2-difluorocyclopropyl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide.

[1368] A stirred solution of tert-butyl A-(2,2-difhiorocyclopropyl)-A-[4-({2-[(R)-(4-fluorophenyl) (methoxy) methyl |-8-mcthyl-4-oxopyrido|3,4- | pyrimidin-3-yl} sulfamoyl) phenyl] carbamate (100 mg, 0.15 mmol, 1 equiv) in HCOOH (1 mL) was stirred at room temperature for 8 h. 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), 20% to 70% gradient in 30 min; detector, UV 254 nm. This resulted 4-[(2,2-difluorocyclopropyl) amino]-A-{2-[(R)-(4-fluorophenyl) (methoxy) methyl]-8-methyl-4-oxopyrido|3,4-<7| pyrimidin- 3 -yl] benzene sulfonamide (17.3 mg, 20.47% yield, 94.3% purity) as a white solid. LC-MS (ES, m / z): [M+H] + = 546.0.!H NMR (400 MHz, Acetonitrile-d₃) d 8.50 (d, J= 5.3 Hz, 1H), 7.60 - 7.52 (m, 4H), 7.50 (s, 1H), 7.12 (s, 2H), 6.76 (d, J= 8.6 Hz, 2H), 5.95 (s, 1H), 5.78 (s, 1H), 3.48 (s, 3H), 3.20 - 3.10 (m, 1H) 2.93 (s, 3H), 1.89 (dd, J = 14.8, 8.3 Hz, 1H), 1.46 (s, 1H). Example 231: N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[2-(trifluoromethyl)cyclopropyl]amino]benzenesulfonamide

[1369]

[1370] The title compound was obtained in analogy to Example 120 as a white solid (28.3% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and 2-(trifluoromethyl) cyclopropan-1 -amine hydrochloride. LCMS (ESIpos): m / z = 578.15 [M+H]+. ’H NMR (400 MHz, Acetonitrile-d3) 88.43 (d, J = 5.2 Hz, 1H), 7.57 - 7.35 (m, 5H), 7.07 (t, J = 8.8 Hz, 2H), 6.78 - 6.66 (m, 2H), 5.89 (d, J = 6.6 Hz, 1H), 3.41 (d, J = 1.7 Hz, 3H), 2.90 - 2.80 (m, 1H), 2.75 (d, J = 4.5 Hz, 3H), 1.86 - 1.80 (m, 1H), 1.33 (dt, J = 8.8, 6.7 Hz, 1H), 1.20- 1.13 (m, 1H).

[1371] Example 232: 4-[[(ls,3s)-3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1372]

[1373] The title compound was obtained in analogy to Example 120 as a white solid (24.2% yield) using A-{2-[(R)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and (ls,3s)-3-(difluoromethoxy)cyclobutan-l-amine. LCMS (ESI) [M + H]+: 590.16. ’H NMR (400 MHz, Acetonitrile-d₃) 58.49 (d, J = 5.2 Hz, 1H), 8.20 (s, 1H), 7.59 - 7.40 (m, 5H), 7.12 (s, 2H), 6.57 - 6.12 (m, 3H), 5.94 (s, 1H), 5.62 (d, J= 6.7 Hz, 1H), 4.43 (p, J= 7.3 Hz, 1H), 3.61 (h, J = 7.1 Hz, 1H), 3.47 (s, 3H), 2.70 - 3.00 (m, 5H), 2.03 (dt, J = 12.5, 8.3 Hz, 2H).

[1374] Example 233: 4-[[(ls,3s)-3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide

[1375]

[1376] The title compound was obtained in analogy to Example 120 as a white solid (21.7% yield) using A-{2-[(S)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and ( I,s,3.s )-3-(difluoromcthoxy)cyclobutan- 1 -amine. LCMS (ESI) [M + H]+: 590.05. ’H NMR (400 MHz, Acetonitrile-d3) δ 8.48 (d, J = 5.2 Hz, 1H), 7.58 - 7.39 (m, 5H), 7.13 (s, 2H), 6.58 - 6.12 (m, 3H), 5.93 (s, 1H), 5.63 (d, J = 6.7 Hz, 1H), 4.42 (p, J= 7.3 Hz, 1H), 3.60 (h, J= 7.1 Hz, 1H), 3.48 (s, 3H), 2.70 - 3.00 (m, 5H), 2.02 (dt, J= 12.5, 8.3 Hz, 2H).

[1377] Example 234: 3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(((lr,3r)-3- (trifluoromethyl)cyclobutyl)amino)benzenesulfonamide

[1378]

[1379] The title compound was obtained in analogy to Example 120 as a white solid (27.1% yield) using 4-bromo-3-fluoro-N-{2-[(R)-(4-fluorophenyl) (methoxy) methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl} benzenesulfonamide and (lr,3r)-3-(trifluoromethyl) cyclobutan-1 -amine hydrochloride. LCMS (ESI) [M + H]+: 610.15.!H NMR (400 MHz, Acetonitrile-d₃) d 8.48 (d, J= 5.2 Hz, 1H), 7.55 - 7.49 (m, 3H), 7.41 (dd, J= 11.3, 2.1 Hz, 1H), 7.34 (ddd, J= 8.6, 2.2, 0.9 Hz, 1H), 7.13 (t, J= 8.9 Hz, 2H), 6.55 (td, J = 8.5, 1.1 Hz, 1H), 5.98 (s, 1H), 4.15 (q, J= 7.3 Hz, 1H), 3.49 (s, 3H), 3.11 (td, J = 15.6, 5.3 Hz, 1H), 2.85 - 2.73 (m, 3H), 2.63 (ddd, J = 13.0, 8.4, 4.7 Hz, 2H), 2.38 - 2.31 (m, 2H).

[1380] Example 235: N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(((lr,3r)-3-(trifluoromethyl)cyclobutyl)amino)benzenesulfonamide

[1381]

[1382] The title compound was obtained in analogy to Example 120 as a white solid (29.3% yield) using A-{2-[(7?)-(4-fluorophenyl) (methoxy)methyl]-8-methyl-4-oxopyrido[3,4-d] pyrimidin-3-yl}-4-iodobenzenesulfonamide and (lr,3r)-3-(trifluoromethyl) cyclobutan-1-amine hydrochloride. LCMS (ESI) [M + H]+: 592.2.1H NMR (400 MHz, Acetonitrile-d3) d 8.47 - 8.40 (m, 1H), 7.51 - 7.42 (m, 5H), 7.09 (s, 2H), 6.49 (d, J = 8.4 Hz, 2H), 5.92 (s, 1H), 5.69 (d, 7= 6.1 Hz, 1H), 4.08 (d, J = 7.5 Hz, 1H), 3.44 (s, 3H), 3.08 (ddq, J = 15.4, 10.4, 5.0 Hz, 1H), 2.82 - 2.54 (m, 5H), 2.21 (m, 2H).

[1383] Example 236: N-[8-(2,2-difluoroethyl)-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide

[1384] F

[1385]

[1386] a) 2-(2,2-difhioroethyl)-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylate

[1387] A solution of methyl 2-chloro-3-[2-(4-fLuorophenyl)-2-methoxyacetamido]pyridine-4-carboxylate (1g, 2.834 mmol, 1 equiv), l,l-difluoro-2-iodoethane (1.63 g, 8.502 mmol, 3 equiv), [4,4'-Bis(tert-butyl)-2,2'-bipyridine] nickel dibromide (69.0 mg, 0.142 mmol, 0.05 equiv), Ir[dF(CF3)ppy]2(dtbpy))PF6 (31.8 mg, 0.028 mmol, 0.01 equiv), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl) trisilane (719.0 mg, 2.890 mmol, 1.02 equiv), 2,6-dimethylpyridine (668.3 mg, 6.234 mmol, 2.2 equiv) in 1,2-dimethoxyethane (40 mL) was stirred for 16 hours at 450 nm LED under nitrogen atmosphere. The reaction was quenched by the addition of H2O (30 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with H2O (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The organic layers were purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 2-(2,2-difluoroethyl)-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylate (300 mg, 27.65%yield) as a yellow oil.

[1388] LCMS(ESI) [M + H]+:383.2.

[1389] b) 2-(2,2-difluoroethyl)-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylic acid.

[1390] A solution of methyl 2-(2,2-difhioroethyl)-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylate (300 mg, 0.784 mmol, 1 equiv) in THF (5 mL) was added with LiOH’EhO (98.8 mg, 2.352mmol, 3 equiv) in H2O (1 mL) at 0 °C. The mixture was stirred for 1 hour at RT. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, H2O (FA) in ACN, 10% to 50% gradient in 18 min to afford 2-(2,2-difluoroethyl)-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylic acid (270 mg, 93.42%yield) as a white solid. LCMS(ESI) [M + H]+: 369.2.

[1391] c) A-[8-(2,2-difluoroethyl)-2-[(4-fluorophenyl) (methoxy)methyl]-4-oxopyrido[3,4-d] pyrimidin-3-yl]-4-iodobenzenesulfonamide

[1392] A solution of 2-(2,2-difluoroethyl)-3-[2-(4-fluorophenyl)-2-methoxyacetamido] pyridine-4-carboxylic acid (270 mg, 0.734 mmol, 1 equiv) and A'-(4-iodobenzenesulfonyl) tertbutoxycarbohydrazide (350.3 mg, 0.880 mmol, 1.2 equiv) in dioxane (5 mL) was added trichloropho sphane (301.9 mg, 2.199 mmol, 3 equiv) at RT. The mixture was stirred for 1 hour at 100 °C. The reaction was quenched by the addition of H2O (5 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with H2O (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=1;1) to afford A-[8-(2,2-difhioroethyl)-2-[(4-fluorophenyl) (methoxy)methyl]-4-oxopyrido[3,4-d) pyrimidin-3-yl]-4-iodobenzenesulfonamide (270 mg, 58.44%yield) as a yellow solid. LCMS(ESI) [M + H]+: 631.2.

[1393] d) N-[8-(2,2-difhioroethyl)-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifhioromethyl)cyclobutyl]amino]benzenesulfonamide. N-[8-(2,2-difluoroethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide was obtained in analogy to Example 120 as a brown oil (49.1% yield) using A-[8-(2,2-difluoroethyl)-2-[(4-fluorophenyl) (methoxy)methyl]-4-oxopyrido[3,4-d] pyrimidin-3-yl] -4- iodobenzenesulfonamide and ( I / ',3 / ')-3-(trifluoromcthyl) cyclobutan-1 -amine hydrochloride. Chiral separation using conditions J afforded N-[8-(2,2-difluoroethyl)-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide (33.3% yield, RT=8.3min, first peak) as a white solid. LCMS(ESI) [M + H]+: 642.2.1H NMR (300 MHz, Acetonitrile-d3) 38.57 (d, J= 5.2 Hz, 1H), 7.64 (d, J= 5.2 Hz, 1H), 7.50 (dt, J= 8.9, 2.8 Hz, 4H), 7.13 (t, J = 8.8 Hz, 2H), 6.71 - 6.38 (m, 3H), 5.95 (s, 1H), 5.74 (d, J= 6.1 Hz, 1H), 4.16 - 4.05 (m, 1H), 3.78 (s, 2H), 3.48 (s, 3H), 3.19 - 3.03 (m, 1H), 2.61 (q, J = 6.7, 6.2 Hz, 2H), 2.30 -2.19 (m, 2H).

[1394] Example 237: N-[8-(difluoromethyl)-2-[(S)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide

[1395]

[1396] N-[8-(difluoromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide was obtained in analogy to Example 159 as a yellow oil (42.9% yield) using TV- [ 8-(difluoromethyl)-2-[(4-fluorophenyl)(methoxy)methyl]-4-oxopyrido[3,4-d] pyrimidin-3-yl]-4-iodobenzenesulfonamide and ( 1 r,3r)-3-(trifluoromethyl) cyclobutan-1 -amine hydrochloride. Chiral separation using conditions J afforded N-[8-(difluoromethyl)-2-[(S)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide (26.8% yield, RT=ll.lmin, second peak) as a white solid. LCMS (ESI) [M + H]+: 628.10. ’H NMR (400 MHz, Acetonitrile-d₃) 58.71 (d, 7= 5.1 Hz, 1H), 7.82 (dt, 7= 5.0, 0.9 Hz, 1H), 7.62 - 7.31 (m, 5H), 7.10 (t, 7= 8.7 Hz, 2H), 6.55 - 6.48 (m, 2H), 5.93 (s, 1H), 5.72 - 5.68 (m, 1H), 4.08 (q, 7 = 7.0 Hz, 1H), 3.45 (s, 3H), 3.14 - 3.01 (m, 1H), 2.60 (ddd, 7= 12.8, 8.5, 4.6 Hz, 2H), 2.22 (ddd, 7= 14.7, 9.9, 6.4 Hz, 2H).

[1397] Example 238: N-[8-(2,2-difluoroethyl)-2-[(S)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide

[1398]

[1399] The title compound is the second peak obtained in the chiral separation of N-[8-(2,2-difluoroethyl)-2-[(4-fluorophenyl)-rnethoxy-rnethyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide (Example 236) using conditions J (31.7% yield, RT=10.9min, second peak). LCMS(ESI) [M + H]+: 642.2. ’H NMR (300 MHz, Acetonitrile-d₃) d 8.58 (dd, J= 5.3, 2.3 Hz, 1H), 7.64 (dd, J= 5.2, 2.3 Hz, 1H), 7.50 (dq, J= 8.6, 2.7 Hz, 4H), 7.14 (td, J= 9.0, 2.4 Hz, 2H), 6.65 - 6.23(m, 3H), 5.95 (d, 7 = 2.3 Hz, 1H), 5.74 (s, 1H), 4.11 (d, 7= 7.0 Hz, 1H), 3.75 (d, 7 = 16.6 Hz, 2H), 3.48 (d, 7 = 2.4 Hz, 3H), 3.11 (m,lH), 2.63 (m, 2H), 2.26 (m, 2H). Example 239: N-[8-(difluoromethyl)-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide

[1400]

[1401] The title compound is the first peak obtained in the chiral separation of N-[8-(difhioromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[(lr,3r)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide (Example 237) using conditions J (32.0% yield, RT=9.3min, first peak). LCMS (ESI) [M + H]+: 628.10. ’H NMR (400 MHz, Acetonitrile-d₃) 68.71 (d, J= 5.1 Hz, 1H), 7.82 (dt, J= 5.1, 1.0 Hz, 1H), 7.67 - 7.30 (m, 5H), 7.10 (t, J= 8.7 Hz, 2H), 6.55 - 6.46 (m, 2H), 5.93 (s, 1H), 5.71 - 5.67 (m, 1H), 4.08 (q, J= 7.1 Hz, 1H), 3.45 (s, 3H), 3.16 - 3.00 (m, 1H), 2.60 (ddd, J = 13.0, 8.6, 4.7 Hz, 2H), 2.22 (td, J= 9.6, 4.9 Hz, 2H).

[1402] Example 240: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[(lr,3r)-3-(trifluoromethyl)cyclobutoxy ] benzenesulfonamide

[1403]

[1404] The title compound was obtained in analogy to Example 116 as a white solid (11.2% yield) using 3-amino-2- |( / ?)-(4- fluorophenyl) (methoxy) methyl]-8 -mcthylpyrido|3,4-d| pyrimidin-4-one and 4-[(lr,3r)-3-(trifluoromethyl) cyclobutoxy] benzene sulfonyl chloride. LCMS (ESI) [M + H]+: 593.10.1H NMR (400 MHz, Acetonitrile-d₃) d 8.45 (d, J = 5.2 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.54 - 7.44 (m, 3H), 7.15 - 7.05 (m, 2H), 6.92 - 6.83 (m, 2H), 5.93 (s, 1H), 4.92 (p, J= 6.5 Hz, 1H), 3.45 (s, 3H), 3.23 - 3.07 (m, 1H), 2.80 - 2.74 (s, 3H), 2.73 - 2.62 (m, 2H), 2.50 - 2.40 (m, 2H).

[1405] Example 241: N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1S,2S)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide

[1406]

[1407] N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide was obtained in analogy to Example 116 as a white solid (43.4% yield) using 3-amino-2- |( / ?)-(4- fluorophenyl) (methoxy) methyl]-8 -mcthylpyrido|3,4-<7| pyrimidin-4-one and 4- [2- (trifluoromethyl) cyclopropoxy] benzene sulfonyl...

Claims

Claims1. A compound of formula (I)whereinone of A1and A2is nitrogen and the other one is CR8;R1is hydrogen, alkyl or halogen;R2is hydrogen, alkyl, halogen, hydroxyalkyl, alkoxy, dialkylamino, cycloalkyl, cycloalkoxy, haloalkoxy, haloalkyl, halocycloalkyl, haloalkoxyalkyl, (halo)(alkyl)azetidinyl, haloalkylpyrrolidinyl, haloazaspiro[3.3]heptan-2-yl, perdeuterioalkoxy or cyano;R3is hydrogen, hydroxyl, alkoxy, haloalkoxy or halogen;R4is hydrogen or halogen;R5is hydrogen or halogen;R6is hydrogen, halogen, alkyl, haloalkyl or cyano;or R5an R6together form -OCH2CH2O-;R7is halophenyl, alkylphenyl, alkoxyphenyl, dialkylphenyl, dialkoxyphenyl, cycloalkylphenyl, haloalkylphenyl, haloalkoxyphenyl, haloalkoxyalkylphenyl, (halo)(alkyl)phenyl, (haloalkoxyalkyl)(alkyl)phenyl, (alkyl)(halocycloalkylamino)phenyl, (haloalkoxyalkyl)(halo)phenyl, (halocycloalkyl)(alkyl)phenyl, alkinylphenyl, alkenylphenyl, alkylalkinylphenyl, dialkylaminophenyl, halocycloalkylphenyl, halocycloalkylaminophenyl, indolyl, alkylindolyl, haloalkylindolyl, haloazetidinylphenyl, azetidinylphenyl, haloalkylcycloalkylphenyl, alkoxyalkylphenyl, benzofuranyl, cycloalkylindolyl, morpholinylphenyl,haloalkylcycloalkylaminophenyl, halocycloalkylalkylphenyl, halothiophenyl, alkylthiphenyl, haloalkylthiophenyl, oxetanylphenyl, (haloalkoxy)(haloalkyl)phenyl, haloalkylaminophenyl, haloalkylazetidinylphenyl, haloazaspiro [3.3]heptanylphenyl, haloazabicyclo[3.1.0]hexanylphenyl, hydroxyalkylaminophenyl, haloalkylcycloalkyloxyphenyl, halocycloalkylalkylaminophenyl, (halocycloalkylalkylamino)(halo)phenyl, (N-haloalkyl)(N-alkyl)aminophenyl, (halo)(haloalkylcycloalkylamino)phenyl or haloalkoxycycloalkylaminophenyl, (haloalkoxyalkyl)(haloalkyl)phenyl, halocycloalkylalkylaminophenyl; and R8is hydrogen, halogen or alkyl;or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein A1is nitrogen and A2is CR8.

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

4. A compound according to any one of claims 1 to 3, wherein R1is hydrogen or fluorine.

5. A compound according to any one of claims 1 to 4, wherein R1is hydrogen.

6. A compound according to any one of claims 1 to 5, wherein R2is halogen, alkyl, haloalkyl, alkoxy or haloalkoxy.

7. A compound according to any one of claims 1 to 6, wherein R2is chlorine, methyl, difluoromethyl, difluoroethyl, trifluoroethyl, methoxy or difluoromethoxy.

8. A compound according to any one of claims 1 to 7, wherein R3is hydrogen, halogen or alkoxy.

9. A compound according to any one of claims 1 to 8, wherein R3is hydrogen, fluorine or methoxy.

10. A compound according to any one of claims 1 to 9, wherein R4is hydrogen.

11. A compound according to any one of claims 1 to 10, wherein R5is hydrogen or fluorine.

12. A compound according to any one of claims 1 to 11, wherein R5is hydrogen.

13. A compound according to any one of claims 1 to 12, wherein R6is hydrogen, halogen or alkyl.

14. A compound according to any one of claims 1 to 13, wherein R6is hydrogen, fluoro, chloro or methyl.

15. A compound according to any one of claims 1 to 14, wherein R7is alkylphenyl, halothiophenyl, (halo)(alkyl)phenyl, dialkylaminophenyl, halocycloalkylphenyl, indolyl, alkylindolyl, alkenylphenyl, halocycloalkylaminophenyl, cycloalkylindolyl, haloalkoxyphenyl, morpholinylphenyl, haloalkylcycloalkylaminophenyl, halocycloalkylalkylphenyl, haloalkoxyalkylphenyl, (haloalkoxyalkyl)(alkyl)phenyl, haloalkylaminophenyl, haloalkylazetidinylphenyl, haloalkylcycloalkyloxyphenyl, halocycloalkylalkylaminophenyl, (N-haloalkyl)(N-alkyl)aminophenyl or haloalkoxycycloalkylaminophenyl.

16. A compound according to any one of claims 1 to 15, wherein R7is methylphenyl, ethylphenyl, chlorothiophenyl, methylthiophenyl, (fluoro)(methyl)phenyl, dimethylaminophenyl, fluorocyclopropylphenyl, indolyl, N-methyl-indolyl, propenylphenyl, fluorocyclobutylaminophenyl, difluorocyclobutylaminophenyl, N- cyclopropyl-indolyl, difluoroethoxyphenyl, difluorocyclopropylphenyl, morpholinylphenyl, difluoromethoxymethylphenyl, trifluoromethylcyclobutylaminophenyl, difluorocyclopropylmethylphenyl, (difluoromethoxymethyl)(methyl)phenyl, difluoromethylcyclobutylaminophenyl, difluorospiro[3.3]heptanylaminophenyl, difluoroethylaminophenyl, trifluoromethylazetidinylphenyl, difluoromethylcyclobutyloxyphenyl, difluorocyclobutylmethylaminophenyl, (N-trifluoroethyl)(N-methyl)aminophenyl, difluoromethoxycyclobutylaminophenyl, trifluoromethylcyclopropyloxyphenyl or trifluoromethylcyclobutyloxyphenyl.

17. A compound according to any one of claims 1 to 16, wherein R8is hydrogen.

18. A compound according to any one of claims 1 to 17 selected from5-chloro-N-[2-(2,3-dihydro-l,4-benzodioxin-6-ylmethyl)-8-methyl-4-oxo- pyrido [3,4-d]pyrimidin-3-yl] thiophene-2- sulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro- benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3-fluoro- benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-chloro-thiophene-2-sulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-cyclopropyl-benzenesulfonamide;5 -chloro-N- [2- [(4-fluorophenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-y 1] thiophene-2- sulfonamide;N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-(trifluoromethyl)thiophene-2-sulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-(difluoromethyl)thiophene-2-sulfonamide;5-chloro-N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] thiophene-2- sulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-ethyl-benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide;N-(2-benzyl-8-chloro-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3-fluoro-benzenesulfonamide;N-(2-benzyl-5-fluoro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-5-chloro-thiophene-2-sulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(trifluoromethyl)benzenesulfonamide;2-chloro-N- [2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;2-chloro-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;5-(difluoromethyl)-N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin- 3 -yl] thiophene-2- sulfonamide;5-chloro-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin- 3 -yl] thiophene-2- sulfonamide;4-isopropyl-N- [2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3 -yl] benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-(1,1-difluoroethyl)benzenesulfonamide;4-(fluoromethyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3,5-difluoro-benzenesulfonamide;N-(2-benzyl-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-chloro-benzenesulfonamide;5-chloro-N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]thiophene-2-sulfonamide;5-chloro-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] thiophene-2- sulfonamide;N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide;N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-(difluoromethyl)benzenesulfonamide;N-(2-benzyl-5-chloro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide;N-(2-benzyl-5-fluoro-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2-chloro-benzenesulfonamide;4-methyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[4,3-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide;N-(2-benzyl-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide;4-ethynyl-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-y 1] benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-2,4-dimethyl-benzenesulfonamide;N- [2- [fluoro(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl] -5-methyl-thiophene-2-sulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N- [8-methoxy-2- [methoxy(phenyl)methyl] -4-oxo-pyrido [3,4-d]pyrimidin-3 -yl] -4-methyl-benzenesulfonamide;N-[2-[methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(difluoromethoxy)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;3-fluoro-N- [2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(dimethylamino)-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[fluoro(phenyl)methyl]-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(2,2-difluoroethyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(difluoromethyl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-methyl-benzenesulfonamide;N- [5-fluoro-2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[(3-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-2-methyl-benzenesulfonamide;4-(1-fluorocyclopropyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-(2-((2-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin- 3 (4H) -yl) -4-methylbenzenesulfonamide;3-cyclopropyl-N- [2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]benzenesulfonamide;3-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-(2-(methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[4,3-d]pyrimidin-3(4H)-yl)-4-methylbenzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-y 1] - 3 -methoxy-benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methoxy-benzenesulfonamide;4-( 1, 1 -difluoroethyl)-N- [2-[(4-fluorophenyl)-methoxy-methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-isopropyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropenyl-benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-1-methyl-indole-5-sulfonamide;4-(3,3-difluoroazetidin-l-yl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(3,3-difluorocyclobutyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(difluoromethoxy)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-(dimethylamino)-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-6,8-dimethyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(azetidin-l-yl)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[1-(trifluoromethyl)cyclopropyl]benzenesulfonamide;N-[2-[methoxy-[4-(trifluoromethyl)phenyl]methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[8-cyclopropyl-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(2,2-difluoro- 1 -methyl-ethyl)-N - [2- [(4-fluorophenyl)-methoxy-methyl] - 8-methyl-4-oxo-pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] -4-( 1 -methoxyethyl)benzenesulfonamide;N-[2-[(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;(R)-4-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;4-(2-fluoropropyl)-N-(2-(methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-[8-(difluoromethoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-( 1 -fluoro-2-methyl-propyl)-N- [2- [methoxy(phenyl)methyl] -8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] -4-prop- 1 -ynyl-benzene sulfonamide;4-isopropenyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-(difluoromethoxy)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-(3-fluoro-3-methyl-azetidin-l-yl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-( 1 -fluorocyclopropyl)-N- [4-oxo-2- [(R)-(4-fluorophenyl)-methoxy-methyl] -8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[(4-cyanophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-3-fluoro-benzenesulfonamide;N-[6-chloro-2-[methoxy(phenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-isopropyl-benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-3,4-difluoro-benzenesulfonamide;4-(difluoromethyl)-N- [2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-2- (trifluoromethyl)benzenesulfonamide;4-methyl-N-[8-methyl-4-oxo-2-[(S)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[hydroxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(difluoromethoxy)-N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-isopropyl-N-[8-methyl-4-oxo-2-[(S)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;3,5-difluoro-N- [2- [(4-fluorophenyl)-methoxy-methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-isopropyl-benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoro-1-methyl-ethyl)benzenesulfonamide;N-[8-(difluoromethyl)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-y 1 ] benzofuran- 3 - sulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2- [methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;(S)-4-(dimethylamino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;3,4-dimethoxy-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-isopropenyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-[rel-(3R)-3-(trifluoromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-[rel-(3S)-3-(trifluoromethyl)pyrrolidin-l-yl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;1-cyclopropyl-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]indole-5-sulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl] benzofuran- 5 - sulfonamide;N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N- [2- [(4-fluorophenyl) -methoxy-methyl] - 8 - (hydroxymethyl) -4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[8-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(l-fhiorocyclopropyl)-N-[4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]-8- (2,2,2-trifhioroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluoroethoxy)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethoxy)benzenesulfonamide;4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]- 1 H-indole- 6- sulfonamide;4-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluorocyclopropyl)-N-(2-((R)-methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methoxy-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-(2-((4-fluorophenyl)(methoxy)methyl)-8-(methoxy-d3)-4-oxopyrido[3,4-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[(1s,3s)-3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;4-[(2,2-difluorocyclopropyl)methyl]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-(8-cyano-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin- 3 (4H) -yl) -4-methylbenzenesulfonamide;N-(8-ethoxy-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin- 3 (4H) -yl) -4-methylbenzenesulfonamide;N-[8-(cyclopropoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;(R)-N-(8-(2,2-difluoroethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;N-(2-((4-fluorophenyl)(methoxy)methyl)-4-oxo-8-(2,2,2-trifluoroethoxy)pyrido[3,4-d]pyrimidin- 3 (4H)-yl) -4-methylbenzene sulfonamide;(R)-4-(1-fluorocyclopropyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methoxy-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(R)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;(S)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;(R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;(R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-((difluoromethoxy)methyl)benzenesulfonamide;N-[8-(difhioromethoxy)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;(S)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-5-(fluoromethyl)thiophene-2-sulfonamide;(R)-4-(difluoromethoxy)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide;4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(oxetan-2-yl)benzenesulfonamide;4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-(2,2-difluoroethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide;N-[8-(2,2-difluoroethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[8-(2,2-difhioroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-(difhioromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3 -yl] - 5 - (fluoromethyl) thiophene-2- sulfonamide;4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3 - [( 1 S) - 1 -hy droxy ethyl] azetidin- 1 -yl]benzenesulfonamide;N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;4-[[(lr,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(ls,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(ls,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2- [(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl] benzenesulfonamide;4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;l-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3 -yl] indole- 5 - sulfonamide;l-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3 -yl] indole- 5 - sulfonamide;(R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-3-methylbenzenesulfonamide;(S)-3-chloro-4-((difluoromethoxy)methyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)- 8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(S)-4-((difluoromethoxy)methyl)-3-fluoro-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(R)-3-chloro-4-((difluoromethoxy)methyl)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;(R)-4-((difluoromethoxy)methyl)-3-fluoro-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-[2-[difluoromethoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(1-fluorocyclopropyl)-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-[((1s,3s)-3-fluorocyclobutyl)amino]-3-methyl-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(1-fluorocyclopropyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-[((1s,3s)-3-fluorocyclobutyl)amino]-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(difluoromethoxymethyl)-3-(difluoromethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;(S)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-3-methylbenzenesulfonamide;4-[(2,2-difluorospiro[3.3]heptan-6-yl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(3,3-difluoroazetidin-1-yl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3-yl] -4- [3- (trifluoromethyl) azetidin- 1 -yl] benzene sulfonamide;4-[(2,2-difluorospiro[3.3]heptan-6-yl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(3,3-difluoroazetidin-1-yl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3-yl] -4- [3- (trifluoromethyl) azetidin- 1 -yl] benzene sulfonamide;4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-[8-methyl-4-oxo-2-[rel-(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-chlorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)-l-bicyclo[ 1.

1. l]pentanyl]amino]benzenesulfonamide;4-[(2,2-difluorospiro[2.3]hexan-5-yl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2-hydroxyethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]benzenesulfonamide;4-[(2,2-difluorospiro[2.3]hexan-5-yl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(S)-[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-[4-(difluoromethyl)phenyl]-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-(difluoromethyl)-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;4-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[(1r,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-(((lr,3R)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;4-(((ls,3R)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((S)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;4-(((ls,3S)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;4-(((lr,3s)-3-(difluoromethyl)cyclobutyl)amino)-3-fluoro-N-(2-((S)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;4-[(4,4-difluorocyclohexyl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[(2,2,2-trifluoro-l-methyl-ethyl)amino]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethylamino)benzenesulfonamide;4-[[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(2,2,2-trifluoroethyl)azetidin-l-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(2,2,2-trifluoroethyl)cyclobutyl]amino]benzenesulfonamide; 4-[(4,4-difluorocyclohexyl)amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[(2,2,2-trifluoro-1-methyl-ethyl)amino]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(2,2,2-trifluoroethyl)cyclobutyl]amino]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(2,2,2-trifluoroethylamino)benzenesulfonamide;4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-[[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]-N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[2-(trifluoromethyl)cyclopropyl]amino]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide;4-[(2,2-difluorocyclopropyl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-methyl-4-oxo-2-[(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[2-(trifluoromethyl)cyclopropyl]amino]benzenesulfonamide; 4-[[3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[rel-(S)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 3-fluoro-N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(((1r,3R)-3-(trifluoromethyl)cyclobutyl)amino)benzenesulfonamide;N-(2-((R)-(4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(((1r,3R)-3-(trifluoromethyl)cyclobutyl)amino)benzenesulfonamide;N-[8-(2,2-difluoroethyl)-2-[(R*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;N-[8-(difluoromethyl)-2-[(S*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;N-[8-(2,2-difluoroethyl)-2-[(S*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-[[3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;N-[8-(difluoromethyl)-2-[(R*)-(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4- d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide; N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4- d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)cyclobutoxy]benzenesulfonamide;N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1S,2S)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide;N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1R,2R)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide;N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4- d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)cyclobutoxy]benzenesulfonamide;N-[2-[(S*)-(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4- d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;N-[2-[(R*)-methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]- 4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;N-[2-[(S*)-methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]- 4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;N-[2-[(R*)-(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4- d]pyrimidin-3-yl]-4-[[3-(trifluoromethyl)cyclobutyl]amino]benzenesulfonamide; N-[2-[(R*)-[4- (difluoromethyl)phenyl] -methoxy-methyl] - 8 -methyl-4-oxo- pyrido[3,4-d]pyrimidin-3-yl]-4-[[3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide; andN-[2-[(S*)-[4-(difluoromethyl)phenyl]-methoxy-methyl]-8-methyl-4-oxo- pyrido[3,4-d]pyrimidin-3-yl]-4-[[3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;or a pharmaceutically acceptable salt thereof.

19. A compound according to any one of claims 1 to 18 selected from5 -chloro-N- [2- [(4-fluorophenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3- yl] thiophene-2- sulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-ethyl-benzenesulfonamide;N-(2-benzyl-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl)-4-methyl-benzenesulfonamide;N-[8-chloro-2-[(4-fluorophenyl)methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-5-methyl-thiophene-2-sulfonamide;N-[2-[fluoro(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[8-chloro-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[(4-fluorophenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-methyl-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N- [8-methoxy-2- [methoxy(phenyl)methyl] -4-oxo-pyrido [3,4-d]pyrimidin-3 -yl] -4-methyl-benzenesulfonamide;N-[2-[methoxy(p-tolyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;3-fluoro-N- [2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(dimethylamino)-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N- [5-fluoro-2- [methoxy(phenyl)methyl] - 8-methyl-4-oxo-pyrido [3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[2-[(3-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(1-fluorocyclopropyl)-N-[2-[methoxy(phenyl)methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-1-methyl-indole-5-sulfonamide;N-[2-[(4-chlorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;N-[8-(difluoromethoxy)-2-[(4-fluorophenyl)-methoxy-methyl]-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-isopropenyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-(difluoromethoxy)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-methyl-N-[4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]-8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-[((1s,3s)-3-fluorocyclobutyl)amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;1-cyclopropyl-N-[2-[(4-fluorophenyl)-methoxy-methyl]-8-methyl-4-oxo-pyrido[3,4-d]pyrimidin-3-yl]indole-5-sulfonamide;N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(2,2-difluoroethoxy)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluorocyclopropyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-morpholino-benzenesulfonamide;4-(difluoromethoxymethyl)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]-1 H-indole- 6- sulfonamide;4-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-(2,2-difluorocyclopropyl)-N-(2-((R)-methoxy(phenyl)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[[(ls,3s)-3- (trifluoromethyl)cyclobutyl]amino]benzenesulfonamide;4-[(2,2-difluorocyclopropyl)methyl]-N-[8-methyl-4-oxo-2-[(R)-methoxy(phenyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;(R)-N-(8-(difluoromethyl)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-(1-fluorocyclopropyl)benzenesulfonamide;(R)-N-(8-(difluoromethoxy)-2-((4-fluorophenyl)(methoxy)methyl)-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)-4-((difluoromethoxy)methyl)benzenesulfonamide;N-[8-(difluoromethoxy)-2-[(R)-(4-fluorophenyl)-methoxymethyl]-4-oxopyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide;(R)-4-((3,3-difluorocyclobutyl)amino)-N-(2-((4-fluorophenyl)(methoxy)methyl)-8-methyl-4-oxopyrido[3,4-d]pyrimidin-3(4H)-yl)benzenesulfonamide;N-[8-(2,2-difluoroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-(difluoromethoxymethyl)benzenesulfonamide;4-(difluoromethoxymethyl)-2-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;4-(difluoromethoxymethyl)-3-methyl-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-(2,2-difhioroethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-methyl-benzenesulfonamide;4-(difluoromethoxymethyl)-N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl] pyrido [3,4-d] pyrimidin- 3 -yl] benzene sulfonamide;N-[8-(difluoromethyl)-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[((1s,3s)-3-fluorocyclobutyl)amino]benzenesulfonamide; 4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(1s,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[[(ls,3s)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-(difluoromethyl)-4-oxo-2- [(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-y 1] benzenesulfonamide;4-[(2,2-difluorospiro[3.3]heptan-6-yl)amino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-(2,2-difluoroethylamino)-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin- 3-yl] -4- [3- (trifluoromethyl) azetidin- 1 -yl] benzene sulfonamide;4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-methoxy(p-tolyl)methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide;4-[[(1r,3r)-3-(difluoromethyl)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[(R)-(4-chlorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[(lr,3r)-3-(difluoromethyl)cyclobutoxy]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; 4-[(3,3-difluorocyclobutyl)methylamino]-N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[methyl(2,2,2-trifluoroethyl)amino]benzenesulfonamide; 4-[[3-(difluoromethoxy)cyclobutyl]amino]-N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]benzenesulfonamide; N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1S,2S)-2- (trifluoromethyl)cyclopropoxy]benzenesulfonamide;N-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4-d]pyrimidin-3-yl]-4-[rel-(1R,2R)-2-(trifluoromethyl)cyclopropoxy]benzenesulfonamide; andN-[8-methyl-4-oxo-2-[rel-(R)-(4-fluorophenyl)-methoxy-methyl]pyrido[3,4- d]pyrimidin-3-yl]-4-[3-(trifluoromethyl)cyclobutoxy]benzenesulfonamide.or a pharmaceutically acceptable salt thereof.

20. A process for the preparation of a compound according to any one of claims 1 to 19 comprising one of the following steps:(a) The reaction of a compound of formula (A)(A)in the presence of R7SO2Cl and a base; or(b) The reaction of a compound of formula (B)in the presence of R7SO2NH-NHRpand PCl3.wherein R1to R7are as defined in any one of claims 1 to 17 and wherein Rp is hydrogen or an amine protecting group.

21. A compound according to any one of claims 1 to 19, when manufactured according to a process of claim 20.

22. A compound according to any one of claims 1 to 19 for use as therapeutically active substance.

23. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 19 and a therapeutically inert carrier.

24. The use of a compound according to any one of claims 1 to 19 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.

25. The use of a compound according to any one of claims 1 to 19 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.

26. A compound according to any one of claims 1 to 19 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.

27. A method for the treatment or prophylaxis of synucleinopathies, Parkinson’s disease, Dementia with Lewy body disease, REM-sleep behavior disorder, amyotrophic lateral sclerosis or lysosomal storage disorders, which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 19 to a patient in need thereof.

28. The invention as hereinbefore described.***

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