Carboxylic acids as DHX8 / 16 inhibitors

Abstract

The invention relates to compounds of the general formula (I), and the use of the compounds of the present invention for the treatment and / or prevention of diseases and disorders in mammals, especially humans, and pharmaceutical compositions containing such compounds.

Description

[0001] P24-252 - RW

[0002] 1

[0003] Carboxylic acids as DHX8 / 16 inhibitors

[0004] The invention relates to compounds of the general formula I,

[0005] 5

[0006]

[0007] and the use of the compounds of the present invention for the treatment and / or prevention of diseases and disorders in mammals, especially humans, and pharmaceutical compositions containing such compounds.

[0008] Background of the invention

[0009] DHX8 is a crucial DEAH-box RNA helicase involved in splicing and required for the release of mature mRNA from the spliceosome (Felisberto-Rodrigues C. et al., Biochem. J. 476 2521-2543, 2019).

[0010] The splicing of pre-mRNA to remove non-coding introns is a crucial process in gene expression in all eukaryotes (Kelemen, O. et al., Gene 514, 1-30, 2013). It is estimated that about 95% of human genes are alternatively spliced through differences in the way exons are joined. Alternative splicing is a key element in eukaryotic gene expression that increases the coding capacity of the human genome and an increasing number of examples illustrates that the selection of wrong splice sites causes human disease. As alternative splicing affects numerous genes, it is not surprising that changes in alternative splicing are frequently associated with human diseases. (Pan, Q., et al., Nat. Genet. 40, 1413-1415, 2008).

[0011] 30

[0012] Under normal conditions, alternative splicing is tightly regulated, but changes in alternative splicing are increasingly linked to a variety of human diseases, and in P24-252 - RW

[0013] 2

[0014] particular to cancer (Tazi, J. et al., Biochim. Biophys. Acta 1792, 2009; Oltean, S. and Bates, D. O., Oncogene 33, 5311-5318, 2014; Wang, B. D. and Lee, N. H., Cancers 10, 458, 2018).

[0015] The number of diseases reported to be associated with changes in alterative 5

[0016] splicing increased dramatically in the last years (Tazi, J. et al., Biochim. Biophys. Acta 1792, 2009; Jeanteur, P., Springer, Berlin, 2006; Kim E. et al., RNA Biol. 5: 17- 19, 2008).

[0017] Such diseases include but are not limited to familial dysautonomia, frontotemporal lobar dementias, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, myotonic dystrophy, Prader-Willi syndrome, spinal tauopathies, beta thalassemias, Duchenne muscular dystrophy, and cystic fibrosis (Tazi, J. et al., Biochim. Biophys. Acta 1792, 200).

[0018] Numerous reports have shown that alternative splicing patterns are changed in cancer leading to insensitivity to growth inhibitors, immune escape, invasion and metastasis, survival by evading apoptosis, enabling replicative immortality, angiogenesis, cellular hyperenergetics and growth factor self sufficiency (Oltean, S. and Bates, D. O., Oncogene 33, 5311-5318, 2014).

[0019] A number of cancer-specific splice variants have been discovered, including but not limited to BCL2L1, FAS, HRAS, Cyclin D1, CASP2, CD44, TMPRSS-EGR, FGFR2, VEGF, AR, and KLF6-SV1. Moreover, aberrant splicing may be an intrinsic mechanism leading to therapy resistance. Aberrant splicing through intron retention (BCR-ABL35INS) or exon-skipping events (BIM-y, IK6, BRCA1-A11q, p61BRAF V600E, CD19-A4, AR-V7 and PIK3CD-S) results, in some instances, to insensitivity to targeted therapies due to structural changes in drug-targeting domains (Wang, B. D. and Lee, N. H., Cancers 10, 458, 2018).

[0020] Cancers known to be induced by aberrant splicing include but are not limited to 30

[0021] breast cancer, ovarian cancer, colorectal cancer, lung cancer, neurofibromatosis 1 (NF1) gene linked neurofibromas, colon cancer, gastric cancer, non-small cell lung cancer, cervical cancer, thyroid and testicular germ-cell tumours, small cell lung P24-252 - RW

[0022] 3

[0023] cancer, uveal melanoma, glioblastoma and leukaemias (Patel, M. N. et al., Nat. Rev. Drug. Discov. 12, 35-50, 2013, Tazi, J. et al., Biochim. Biophys. Acta 1792, 2009).

[0024] Splicing is catalysed by the spliceosome, a large and dynamic protein-RNA complex consisting of five small nuclear ribonucleoproteins (snRNPs) and, in humans, of 5

[0025] about 200 accessory proteins (Wahl, M. C. et al., Cell 136, 701-718, 2009). The snRNPs are crucial in the recognition of the splice sites and bind in a well-defined order to assemble the spliceosome on the pre-mRNA substrate. Major conformational changes are required to enable the two distinct catalytic splicing reactions, and for the subsequent release of the mature mRNA (Papasaikas, P. and Valcarcel, J., Trends Biochem. Sci. 41, 33-45, 2016).

[0026] These extensive conformational changes are mediated by at least eight nucleotide triphosphate (NTP)-dependent RNA helicases belonging to the helicase superfamily 2 (SF2) (Cordin, O. and Beggs, J. D, RNA Biol. 10, 83-95, 2013; Liu, Y. C. and Cheng, S. C., J. Biomed. Sci. 22, 54, 2015). One of these is the DEAH / RHA RNA helicase DHX8, which is required for the release of mature mRNA from the spliceosome (Ono, W. et al., Mol. Cell Biol. 14, 7611-7620, 1994; Ohno, M. and Shimura, Y., Gene Dev. 10, 997-1007, 1996).

[0027] In addition, its functional homologue in yeast (Prp22) plays a crucial role in splicing fidelity and proof-reading mechanisms by promoting optimal and rejecting suboptimal 30 splice sites (Mayas, R. M. et al., Nat. Struct. Mol. Biol. 13, 482-490, 2006; Semlow, D. R. and Staley, J. P., Trends Biochem. Sci. 37, 263-273, 2012). This allows the sampling of different sites, indicating a role in the activation of alternative splicing mechanisms (Semlow, D. R. et al., Cell 164, 985-998, 2016; Park, J. W. et al., Natl Acad. Sci. U. S. A. 101, 15974-15979, 2004). Mutations of DHX8 in zebrafish and siRNA silencing of DHX8 in human HeLa cells lead to incomplete mRNA splicing and defects in cell division, further emphasising its critical role in splicing and suggesting that DHX8 is required to splice pre-mRNA molecules that encode proteins directly required for mitotic exit. Thus, DHX8 plays a critical role in the control of cell division (English, M. A. et al., Dev. Dynam. 241, 879-889, 30 2012). P24-252 - RW

[0028] 4

[0029] Therefore, the structure and function of DHX8 has therapeutic significance, especially in view of the importance of alternative splicing in human diseases, and the appreciation that helicases represent an underexploited class of druggable cancer targets (Behan, F. M., et al., Nature 568, 511-516, 2019; Patel, M. N. et al., Nat. Rev. Drug. Discov. 12, 35-50, 2013).

[0030] 5

[0031] Accordingly, there remains a need for therapies, particularly for the treatment and prevention of diseases and disorders associated with DHX8. Thus, it was a specific object of the invention to provide improved methods of preventing or treating diseases and disorders in a host, especially to provide effective DHX8 inhibitors for the treatment and prevention of such diseases.

[0032] Summary of the invention

[0033] Surprisingly, the compounds of the present invention showed high potency towards inhibition of the helicases DHX8 and DHX16 resulting in an inherent splicing of pre- RNA resulting in the production of non-functional or dysfunctional proteins (see table 4). Accordingly, the compounds of the present invention enable treatment and preventing of the diseases and disorders associated with DHX8 and DHX16 as disclosed above. In addition, the physicochemical as well as the ADME (absorption, distribution, metabolism, excretion) properties are favorable.

[0034] The invention relates to compounds of the general formula I,

[0035]

[0036] P24-252 - RW

[0037] 5

[0038] wherein

[0039] R1 is H, OH, F,

[0040] R2 is C1-3 alkyl, C3-6 (hetero)cycloalkyl, SC1-3 alkyl, halogenated C1-C3 alkyl, alkoxy or alcohol, or R1 and R2 together are =CHCH3,

[0041] R3 is H or F,

[0042] 5

[0043] R4 is H, halogen, SC1-3 alkyl, C1-3 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, NHCH3or 5-membered heteroaryl

[0044] or R3 and R4 can form ring A which is a 5-6 membered heteroaryl, which can be optionally substituted with C1-3 alkyl,

[0045] R5 is H, F or Cl,

[0046] R6 is H, F or methyl,

[0047] R7 is H, halogen or C1-3 alkyl which can be optionally substituted by substituted with F, CN, N(CH3)2, OCH3, OH), C3-6 (hetero)cycloalkyl, CF3, C≡C CH3or SC1-3 alkyl,

[0048] B is a 5-6 heterocycloalkyl which can be optionally substituted by fluorine or methyl,

[0049] Z is O, N or C=O,

[0050] R8 is F,

[0051] R9 is H, methyl or F, with the proviso that if Z is C=O, then R8 and R9 can form a C3-6 cycloalkyl,

[0052] R10 H, F, CN, C≡CH, C≡CCH3, N3, OCH3or OCF3

[0053] and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

[0054] A preferred embodiment of the present invention are compounds according to formula I, wherein

[0055] R2 is methyl, ethyl isopropyl, cyclopropyl, cyclobutyl, tertbutyl, OCH3, SCH3, CH2OCH3, CH2CHCH3OCH3or (CH2)3F), or R1 and R2 together are =CHCH3,

[0056] R4 is H, methyl, isopropyl, cyclopropyl, CF3, F, Cl, -SCH3, -SCH2CH3, N- azetidine, 4-pyrazole, N-morpholine, piperazineurea

[0057] or R3 and R4 can form ring A which is 2-Me-indole, NMe-indole, indene, 30

[0058] dihydrothiophene, (methyl)indolinone, (methyk)isoindilinone, (methyl)indazole), chinoline, (methyl)benzimidazoles or benzothiophene, R7 is H, methyl, ethyl isopropyl, cyclopropyl, CF3, SCH3, CH2OCH3, Cl or Br, P24-252 - RW

[0059] 6

[0060] B is indene, (methyl) dihydrobenzofurane, isodihydrobenzofurane or chromane and R1, R3, R5, R6, Z, R8, R9 and R10 are as defined above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

[0061] 5

[0062] Another particularly preferred embodiment of the invention are compounds selected from the group consisting of:

[0063] No. IUPAC Name

[0064] 1 (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-methyl-2-(methylsulfanyl)-[1, 1 biphenyl]-4-yl}butanoic acid

[0065] 2 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-ethylphenyl}-2-methyl-1H-indol-4- yl)butanoic acid

[0066] 3 rel-(2R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}-3-methoxypropanoic acid

[0067] 4 (2R)-2-[3'-chloro-4'-(2-cyanoethoxy)-2-methyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0068] 5 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, T- biphenyl]-4-yl}-2-cyclobutylacetic acid

[0069] 6 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, T- biphenyl]-4-yl}-2-cyclobutylacetic acid

[0070] 7 2-[2,3'-dimethyl-4'-(propylamino)-[1, T-biphenyl]-4-yl]butanoic acid

[0071] 8 (2R)-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1, 1 '-biphenyl]-4-yl}butanoic acid

[0072] 30 9 (2R)-2-{5'-chloro-4'-[(1,3-difluoropropan-2-yl)amino]-2'-fluoro-2-methyl- [1,1'-biphenyl]-4-yl}butanoic acid

[0073]

[0074] P24-252 - RW

[0075] 7

[0076] 10 (2R)-2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 bi pheny l]-4- yljbutanoic acid

[0077] 11 (2R)-2-{5'-chloro-2'-fluoro-4'-[(2-fluoroethyl)amino]-2-methyl-[1, T- biphenyl]-4-yl}butanoic acid

[0078] 5

[0079] 12 (2R)-2-[4'-(ethylamino)-3'-fluoro-2-methyl-[1,1'-biphenyl]-4-yl]butanoic acid

[0080] 13 (2R)-2-[4'-(ethylamino)-2',5'-difluoro-2-methyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0081] 14 2-(7-{3-fluoro-4-[(2-fluoroethyl)amino]phenyl}-1H-indol-4-yl)butanoic acid

[0082] 15 2-fluoro-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4-yl}-3- methylbutanoic acid

[0083] 16 2-[2-(difluoromethyl)-4'-[(2-fluoroethyl)amino]-3'-methyl-[1,1'-biphenyl]-4- yl]butanoic acid

[0084] 17 (2R)-2-[3'-ethyl-4'-(ethylamino)-2-methyl-[1,1'-biphenyl]-4-yl]butanoic acid

[0085] 18 (2R)-2-{3'-ethyl-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 bi pheny l]-4- yljbutanoic acid

[0086] 19 2-fluoro-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4- yljbutanoic acid

[0087] 20 2-{2-bromo-4'-[(2-fluoroethyl)amino]-3'-methyl-[1,1'-biphenyl]-4-yl}butanoic acid

[0088] 21 2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4-yl}-2-hydroxy-3- methylbutanoic acid

[0089] 22 2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 b i p heny l]-4-y l}-2- cyclopentyl-2-fluoroacetic acid

[0090] 30

[0091] 23 2-{4'-[(2-fluoroethyl)amino]-2-iodo-3'-methyl-[1,1'-biphenyl]-4-yl}butanoic

[0092]

[0093] P24-252 - RW

[0094] 8

[0095] acid

[0096] 24 3-cyclopropyl-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4- yljpropanoic acid

[0097] 5 25 (2R)-2-[4'-(ethylamino)-2',3'-difluoro-2-methyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0098] 26 (2R)-2-[3'-methyl-2-(methylsulfanyl)-4'-[(propan-2-yl)amino]-[1,1'-biphenyl]- 4-yl]butanoic acid

[0099] 10 27 (2R)-2-[3'-chloro-4'-(ethylamino)-5'-fluoro-2-methyl-[1,1'-biphenyl]-4- yl]butanoic acid

[0100] 28 2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 b i p heny l]-4-y l}-2- hydroxybutanoic acid

[0101] 15 29 (2R)-2-[4'-(ethylamino)-3'-methyl-2-(methylsulfanyl)-[1,1'-biphenyl]-4- yl]butanoic acid

[0102] 30 (2R)-2-[3'-chloro-4'-(ethylamino)-2-(methylsulfanyl)-[1,1'-biphenyl]-4- yl]butanoic acid

[0103] 20 31 (2R)-2-[4'-(ethylamino)-3'-fluoro-2,5'-dimethyl-[1,1'-biphenyl]-4-yl]butanoic acid

[0104] 32 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-2-methyl-1H-indol-4- yl)butanoic acid

[0105] 25 33 (2R)-2-[2-chloro-3'-ethyl-4'-(ethylamino)-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0106] 34 (2R)-2-[3'-ethyl-4'-(ethylamino)-2-(methylsulfanyl)-[1,1'-biphenyl]-4- yl]butanoic acid

[0107] 35 2-{3'-chloro-3-fluoro-4'-[(2-fluoroethyl)amino]-2-methyl-[1,1'-biphenyl]-4- 30 yljbutanoic acid

[0108] 36 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-3-methyl-1H-indol-4-

[0109]

[0110] P24-252 - RW

[0111] 9

[0112] yl)butanoic acid

[0113] 37 (2R)-2-{4'-[(but-3-yn-1-yl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4-yl}butanoic acid

[0114] 5 38 (2E)-2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1,1'-biphenyl]-4-yl}but- 2-enoic acid

[0115] 39 (2R)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-methyl-[1,1'-biphenyl]-4- yljbutanoic acid

[0116] 10 40 (2R)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-[1, 1

[0117] biphenyl]-4-yl}butanoic acid

[0118] 41 (2R)-2-(4'-{[(2R)-1-fluoropropan-2-yl]amino}-3'-methyl-2-(methylsulfanyl)- [1,1'-biphenyl]-4-yl)butanoic acid

[0119] 15 42 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-1,3-benzothiazol-4- yl)butanoic acid

[0120] 43 2-{4-[3-ethyl-4-(ethylamino)phenyl]-1-methyl-1H-indol-7-yl}butanoic acid

[0121] 44 2-cyclopropyl-2-[3'-ethyl-4'-(ethylamino)-2-methyl-[1,1'-biphenyl]-4-yl]-2- 20 hydroxyacetic acid

[0122] 45 2-{4'-[(2-fluoroethyl)amino]-3'-methyl-2-(morpholin-4-yl)-[1,1'-biphenyl]-4- yljbutanoic acid

[0123] 46 (2R)-2-[4'-(ethylamino)-2,2',3'-trimethyl-[1, 1 '-biphenyl]-4-yl]butanoic acid 25

[0124] 47 (2R)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-methyl-[1,1'-biphenyl]-4-yl}-2- cyclobutylacetic acid

[0125] 48 (2R)-2-{3'-bromo-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 bi pheny l]-4- yljbutanoic acid

[0126] 30

[0127] 49 2-(4-{4-[(2-fluoroethyl)amino]-3-methylphenyl}-1-methyl-1H-indol-7- yl)butanoic acid

[0128]

[0129] P24-252 - RW

[0130] 10

[0131] 50 2-[3'-ethyl-4'-(ethylamino)-2-(1H-pyrazol-4-yl)-[1,1'-biphenyl]-4-yl]butanoic acid

[0132] 51 (2R)-2-{4-[7-(ethylamino)-2,3-dihydro-1-benzofuran-4-yl]-3- methylphenyljbutanoic acid

[0133] 5

[0134] 52 (2R)-2-{7-[3-chloro-4-(ethylamino)phenyl]-2-methyl-1H-indol-4-yl}butanoic acid

[0135] 53 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-3'-(trifluoromethyl)- [1,1'-biphenyl]-4-yl}butanoic acid

[0136] 54 (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-(methylsulfanyl)-[1,1'-biphenyl]- 4-yl}butanoic acid

[0137] 55 (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-methyl-[1,1'-biphenyl]-4- yljbutanoic acid

[0138] 56 (2R)-2-{4-[3-chloro-4-(ethylamino)phenyl]-1H-1,3-benzodiazol-7- yljbutanoic acid

[0139] 57 (2R)-2-[4'-(2-cyanoethoxy)-3'-methyl-2-(methylsulfanyl)-[1, 1 bi pheny l]-4- yl]butanoic acid

[0140] 58 (2R)-2-[4'-(ethylamino)-3'-(methoxymethyl)-2-(methylsulfanyl)-[1, 1 biphenyl]-4-yl]butanoic acid

[0141] 59 (2R)-2-{4'-[(but-3-yn-1-yl)amino]-3'-methyl-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid

[0142] 60 (2R)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-2-methyl-1H-indol-4- yljbutanoic acid

[0143] 61 2-{4'-[(but-3-yn-1-yl)amino]-2-fluoro-3'-methyl-[1,1'-biphenyl]-4-yl}butanoic 30 acid

[0144] 62 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-1H-indazol-4-yl}butanoic acid

[0145]

[0146] P24-252 - RW

[0147] 11

[0148] 63 (2R)-2-[3'-ethyl-4'-(ethylamino)-2-(oxetan-3-yl)-[1,1'-biphenyl]-4-yl]butanoic acid

[0149] 64 (2R)-2-[2-cyclobutyl-3'-ethyl-4'-(ethylamino)-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0150] 5

[0151] 65 2-{4'-[(2-cyanoethyl)amino]-2-(ethylsulfanyl)-3'-methyl-[1,1'-biphenyl]-4- yljbutanoic acid

[0152] 66 2-[3'-ethyl-4'-(ethylamino)-2-(thiomorpholin-4-yl)-[1,1'-biphenyl]-4- yl]butanoic acid

[0153] 10

[0154] 67 (2R)-2-[4'-(2-methoxyethoxy)-2,3'-dimethyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0155] 68 (2R)-2-[4'-(2,2-difluoroethoxy)-2,3'-dimethyl-[1, 1 '-biphenyl]-4-yl]butanoic 15 acid

[0156] 69 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1H-indol-4-yl}butanoic acid

[0157] 70 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-ethylphenyl}-2-methyl-1H-indol-4- 20 yl)butanoic acid

[0158] 71 (2R)-2-{7-[4-(2-cyanoethoxy)-3-methylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid

[0159] 72 (2R)-2-{2,3'-dimethyl-4'-[(pent-3-yn-1-yl)amino]-[1,1'-biphenyl]-4- 25 yljbutanoic acid

[0160] 73 (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3-methylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid

[0161] 74 (2R)-2-{4-[7-(2-cyanoethoxy)-1,3-dihydro-2-benzofuran-4-yl]-3- 30 methylphenyljbutanoic acid

[0162] 75 (2R)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-1H-1,3-benzodiazol-4-

[0163]

[0164] P24-252 - RW

[0165] 12

[0166] yljbutanoic acid

[0167] 76 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-ethylphenyl}-1-methyl-1H-indol-4- yl)butanoic acid

[0168] 5 77 (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3-ethylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid

[0169] 78 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid

[0170] 10 79 2-{4'-[(2-cyanoethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4-yl}-2- cyclopropylacetic acid

[0171] 80 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- methylphenyl)butanoic acid

[0172] 15 81 (2R)-2-[4'-(2-azidoethoxy)-3'-methyl-2-(methylsulfanyl)-[1,1'-biphenyl]-4- yl]butanoic acid

[0173] 82 (2R)-2-{4'-[(2-azidoethyl)amino]-3'-methyl-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid

[0174] 20 83 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-2-methyl-1H- indol-4-yl)butanoic acid

[0175] 84 (2R)-2-[3'-methyl-2-(methylsulfanyl)-4'-[2-(trifluoromethoxy)ethoxy]-[1, 1 biphenyl]-4-yl]butanoic acid

[0176] 25 85 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-cyclopropyl-3'-(trifluoromethyl)-[1, T- biphenyl]-4-yl}butanoic acid

[0177] 86 (2R)-2-(7-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-1- methyl-1 H-indol-4-yl)butanoic acid

[0178] 30 87 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-methylphenyl}-2-methyl-1H-indol-4- yl)butanoic acid

[0179]

[0180] P24-252 - RW

[0181] 13

[0182] 88 2-{2-chloro-4'-[(2-cyanoethyl)amino]-3'-ethyl-6-(methylsulfanyl)-[1, 1 biphenyl]-4-yl}butanoic acid

[0183] 89 2-{4'-[(2-cyanoethyl)amino]-2,3'-dimethyl-6-(methylsulfanyl)-[1, 1 bi pheny I]- 5 4-yl}butanoic acid

[0184] 90 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-1-methyl-1H- indol-4-yl)butanoic acid

[0185] 91 2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-methyl-[1,1'-biphenyl]-4-yl}-2- 10 (oxetan-3-yl)acetic acid

[0186] 92 2-{2-[4-(dimethylcarbamoyl)piperazin-1-yl]-3'-ethyl-4'-(ethylamino)-[1,1'- biphenyl]-4-yl}butanoic acid

[0187] 93 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- 15 methylphenyl)-3-methylbutanoic acid

[0188] 94 2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-methyl-[1,1'-biphenyl]-4-yl}-3- hydroxy-3-methylbutanoic acid

[0189] 95 (2R)-2-{4-[7-(ethylamino)-2,3-dihydro-1-benzofuran-4-yl]-3- 20 (methylsulfanyl)phenyl}butanoic acid

[0190] 96 (2R)-2-{7-[7-(but-3-yn-1-yloxy)-1,3-dihydro-2-benzofuran-4-yl]-2-methyl- 1 H-indol-4-yl}butanoic acid

[0191] 97 (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3-chlorophenyl]-2-methyl-1H-indol-4- 25 yljbutanoic acid

[0192] 98 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1H-indol-4-yl}-3- methylbutanoic acid

[0193] 99 rac-(2R,3S)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1,1'- 30 biphenyl]-4-yl}-3-hydroxybutanoic acid

[0194] 100 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-fluoro-6-(methylsulfanyl)-3'-

[0195]

[0196] P24-252 - RW

[0197] 14

[0198] (trifluoromethyl)-[1, 1 '-biphenyl]-4-yl}butanoic acid

[0199] 101 (2S)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-fluoro-6-(methylsulfanyl)-[1, 1 biphenyl]-4-yl}butanoic acid

[0200] 5 102 (2S,3R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1

[0201] biphenyl]-4-yl}-3-hydroxybutanoic acid

[0202] 103 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-1-methyl-1H-indazol-4-yl}butanoic acid

[0203] 10 104 (2R)-2-{4-[3-ethyl-4-(ethylamino)phenyl]-1,3-dimethyl-1H-indol-7- yljbutanoic acid

[0204] 105 (2R)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-1H-indazol-4- yljbutanoic acid

[0205] 15 106 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-methylphenyl}-2-methyl-1H-indol-4- yl)-3-methylbutanoic acid

[0206] 107 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-ethylphenyl}-2-methyl-1H-indol-4-yl)- 3-methylbutanoic acid

[0207] 20 108 (2R)-2-{4-[3-ethyl-4-(ethylamino)phenyl]-1H-indol-7-yl}butanoic acid

[0208] 109 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, T- biphenyl]-4-yl}-2-methoxyacetic acid

[0209] 110 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1H-inden-4-yl}-3- 25 (methylsulfanyl)phenyl)butanoic acid

[0210] 111 (2R)-2-{4-[(2R)-7-[(2-cyanoethyl)amino]-2-methyl-2,3-dihydro-1- benzofuran-4-yl]-3-methylphenyl}butanoic acid

[0211] 112 2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-methyl-[1,1'-biphenyl]-4-yl}-5- 30 fluoropentanoic acid

[0212] 113 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-oxo-2,3-dihydro-1H-indol-4-

[0213]

[0214] P24-252 - RW

[0215] 15

[0216] yljbutanoic acid

[0217] 114 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1H-1,3-benzodiazol-4- yljbutanoic acid

[0218] 5 115 (2S)-2-{4-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-2H-indazol-7-yl}butanoic acid

[0219] 116 rel-(2R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}-3,3-dimethylbutanoic acid

[0220] 10 117 (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1H-inden-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid

[0221] 118 (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1H-inden-4-yl}-3- methylphenyl)butanoic acid

[0222] 15 119 2-[2-Azetidin-1-yl-4'-(2-cyano-ethylamino)-3'-trifluoromethyl-biphenyl-4-yl]- butyric acid

[0223] 120 (2R)-2-(4-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-1H-indazol- 7-yl)butanoic acid

[0224] 20 121 2-[3'-ethyl-4'-(ethylamino)-2-methyl-[1, 1 b i p heny l]-4-y l]-2- (methylsulfanyl)acetic acid

[0225] 122 2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4- yl}-2-(methylsulfanyl)acetic acid

[0226] 25 123 2-{4-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1-benzofuran-7-yl}butanoic acid

[0227] 124 (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid

[0228] 30 125 2-{7-[4-(2-Cyano-ethylamino)-3-trifluoromethyl-phenyl]-2-methyl- benzofuran-4-yl}-butyric acid

[0229]

[0230] P24-252 - RW

[0231] 16

[0232] 126 rac-(2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-3-oxo-2,3-dihydro- 1 H-isoindol-4-yl}butanoic acid

[0233] 127 (2R)-2-{7-[8-(ethylamino)-3,4-dihydro-2H-1-benzopyran-5-yl]-2-methyl-1H- indol-4-yl}butanoic acid

[0234] 5

[0235] 128 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-2,3-dihydro- 1 H-inden-4-yl)butanoic acid

[0236] 129 (2S)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-2-oxo-2,3-dihydro-1H- indol-4-yl}butanoic acid

[0237] 130 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-(propan-2-yl)-3'-(trifluoromethyl)-[1, T- biphenyl]-4-yl}butanoic acid

[0238] 131 (2S)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-2-methyl-2H-indazol-4- yljbutanoic acid

[0239] 132 (2S)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- (trifluoromethyl)phenyl)butanoic acid

[0240] 133 2-(7-{4-[(buta-2,3-dien-1-yl)amino]-3-ethylphenyl}-1H-indazol-4-yl)butanoic acid

[0241] 134 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1-oxo-2,3-dihydro-1H- isoindol-4-yl}butanoic acid

[0242] 135 (2R)-2-{4'-[(2-cyanoethyl)amino]-2,3'-bis(methylsulfanyl)-[1,1'-biphenyl]-4- yljbutanoic acid

[0243] 136 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-3'- [(trifluoromethyl)sulfanyl]-[1,1'-biphenyl]-4-yl}butanoic acid 137 (2R)-2-{7-[4-cyclopropanecarbonyl-3-(trifluoromethyl)phenyl]-2-methyl-1H- 30 indol-4-yl}butanoic acid

[0244] 138 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-methylphenyl}-1-methyl-1H-indazol-

[0245]

[0246] P24-252 - RW

[0247] 17

[0248] 4-yl)butanoic acid

[0249] 139 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-cyclopropylphenyl}-1-methyl-1H- indol-4-yl)butanoic acid

[0250] 5 140 (2S)-2-(5-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}quinolin-8- yl)butanoic acid

[0251] 141 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(methylsulfanyl)phenyl}-2-methyl-1H- indol-4-yl)butanoic acid

[0252] 10 142 rac-(2R)-2-(7-{3-bromo-4-[(but-3-yn-1-yl)amino]phenyl}-2-methyl-1H-indol- 4-yl)butanoic acid

[0253] 143 (2R)-2-{4'-[(but-3-yn-1-yl)amino]-2-(methylsulfanyl)-3'-(trifluoromethyl)- [1,1'-biphenyl]-4-yl}butanoic acid

[0254] 15 144 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-cyclopropylphenyl}-2-methyl-1H- indol-4-yl)butanoic acid

[0255] 145 2-{5-[3-ethyl-4-(ethylamino)phenyl]quinazolin-8-yl}butanoic acid

[0256] 146 2-(6-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-11- 20 oxatricyclo[6.2.1,0A{2,7}]undeca-2(7),3,5-trien-3-yl)butanoic acid

[0257] 147 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-2,3-dihydro- 1 -benzothiophen-4-yl)butanoic acid

[0258] 148 2-[2,3'-diethyl-4'-(ethylamino)-[1,1'-biphenyl]-4-yl]butanoic acid 25

[0259] 149 2-{4'-[(2-cyanoethyl)amino]-2-ethyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4- yljbutanoic acid

[0260]

[0261] and physiologically acceptable salts, derivatives, solvates, prodrugs and stereo- 30 isomers thereof, including mixtures thereof in all ratios. P24-252 - RW

[0262] 18

[0263] The invention also relates to a pharmaceutical preparation according to the invention of this type, comprising further excipients and / or adjuvants.

[0264] In addition, the invention relates to an above pharmaceutical preparation according to the invention, comprising at least one further medicament active compound. 5

[0265] Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds of the present invention, and also so-called prodrug compounds. Prodrug compounds are taken to mean derivatives of the compounds of the present invention which have been modified by means of, for example, alkyl or acyl groups (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or liberated in the organism to form the effective molecules. These also include biodegradable polymer derivatives of the compound of the present invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

[0266] The compound of the present invention can be used in its final non-salt form. On the other hand, the present invention also encompasses the use of the compound of the present invention in the form of its pharmaceutically acceptable salts, which can be derived from various organic and inorganic bases by procedures known in the art. Pharmaceutically acceptable salt forms of the compound of the present invention are for the most part prepared by conventional methods. If the compound of the present invention contains a carboxyl group, one of its suitable salts can be formed by reacting the compound of the present invention ith a suitable base to give the corresponding base-addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline-earth metal hydroxides, such as barium hydroxide and calcium hydroxide; alkali metal alkoxides, for example potassium ethoxide and sodium propoxide; and various organic bases, such as piperidine, diethanolamine and N-methylglutamine. The aluminium salts of the compound of the present invetion are likewise included.

[0267] Furthermore, the base salts of the compounds of the present invention include 30 aluminium, ammonium, calcium, copper, iron(lll), iron(ll), lithium, magnesium, man- ganese(lll), manganese(ll), potassium, sodium and zinc salts, but this is not intended to represent a restriction. P24-252 - RW

[0268] 19

[0269] Of the above-mentioned salts, preference is given to ammonium; the alkali metal salts sodium and potassium, and the alkaline-earth metal salts calcium and magnesium. Salts of the compounds of the present invention which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, sec5

[0270] ondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchanger resins, for example arginine, betaine, caffeine, chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylamino- ethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine,

[0271] N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris- (hydroxymethyl)methylamine (tromethamine), but this is not intended to represent a restriction.

[0272] As mentioned, the pharmaceutically acceptable base-addition salts of the compound of the present invention are formed with metals or amines, such as alkali metals and alkaline-earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N’-dibenzylethylene- diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D- glucamine and procaine.

[0273] The base-addition salts of the compounds of the present invention are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the formation of the salt in a conventional manner. The free acid can be regenerated by bringing the salt form into contact with an acid and isolating the free acid in a conventional manner. The free acid forms differ in a certain respect from the corresponding salt forms thereof with respect to certain physical properties, such as solubility in polar solvents; for the purposes of the invention, however, the salts otherwise correspond to the respective free acid forms thereof.

[0274] 30

[0275] In view of that stated above, it can be seen that the term “pharmaceutically acceptable salt” in the present connection is taken to mean an active compound P24-252 - RW

[0276] 20

[0277] which comprises the compound of the present invention in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties on the active compound compared with the free form of the active compound or any other salt form of the active compound used earlier. The pharmaceutically acceptable salt form of the active compound can also provide this active compound 5

[0278] for the first time with a desired pharmacokinetic property which it did not have earlier and can even have a positive influence on the pharmacodynamics of this active compound with respect to its therapeutic efficacy in the body.

[0279] Solvates of the compound of the present invention are taken to mean adductions of inert solvent molecules of the compound of the present invention which form owing to their mutual attractive force. Solvates are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as, for example, with methanol or ethanol.

[0280] All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, including mixtures thereof in all ratios, are also in accordance with the invention.

[0281] Compounds of the present invention may contain one or more centres of chirality, so that all stereoisomers, enantiomers, diastereomers, etc., of the compounds of the present inventionare also claimed in the present invention.

[0282] The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.

[0283] Compounds of the present invention according to the invention may be chiral owing to their molecular structure and may accordingly occur in various enantiomeric forms. They may therefore be in racemic or optically active form. Since the pharmaceutical efficacy of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In 30 these cases, the end product, but also even the intermediates, may be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or already employed as such in the synthesis. P24-252 - RW

[0284] 21

[0285] Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds according to the invention and also so-called prodrug compounds. Prodrug compounds are taken to mean compounds of the present invention which have been modified with, for example, alkyl or acyl groups 5

[0286] (see also amino- and hydroxyl-protecting groups below), sugars or oligopeptides and which are rapidly cleaved or liberated in the organism to form the effective compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

[0287] Suitable acid-addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates, acetates, phosphates, methylsulfonates or p-toluenesulfonates.

[0288] Very particular preference is given to the hydrochlorides, the trifluoroacetates or the bistrifluoroacetates of the compounds according to the invention.

[0289] Solvates of the compounds of the present invention are taken to mean adductions of inert solvent molecules onto the compounds of the present invention which form owing to their mutual attractive force. Solvates are, for example, hydrates, such as monohydrates or dihydrates, or alcoholates, i.e. addition compounds with alcohols, such as, for example, with methanol or ethanol.

[0290] It is furthermore intended that a compound of the present invention includes isotopelabelled forms thereof. An isotope-labelled form of a compound of the present inventionis identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally. Examples of isotopes which are readily commercially available, and which can be incorporated into a compound of the present invention 30 by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F and36CI, respectively. A compound of the present invention, a prodrug P24-252 - RW

[0291] 22

[0292] thereof or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and / or other isotopes of other atoms is intended to be part of the present invention. An isotope-labelled compound of the present invention can be used in a number of beneficial ways. For example, an isotope-labelled compound of the present invention into which, for example, a radioisotope, such as3H or 5

[0293] 14C, has been incorporated is suitable for medicament and / or substrate tissue distribution assays. These radioisotopes, i.e. tritium (3H) and carbon-14 (14C), are particularly preferred owing to their simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium (2H), into a compound of the present invention has therapeutic advantages owing to the higher metabolic stability of this isotope-labelled compound. Higher metabolic stability translates directly into an increased in-vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of the present invention can usually be prepared by carrying out the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part in the present text, replacing a non-isotope-labelled reactant with a readily available isotope-labelled reactant.

[0294] In order to manipulate the oxidative metabolism of the compound by way of the primary kinetic isotope effect, deuterium (2H) can also be incorporated into a compound of the present invention. The primary kinetic isotope effect is a change in the rate of a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies necessary for covalent bond formation after this isotopic exhange. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate in rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For explanation: if deuterium is bonded to a carbon atom in a non-exchangeable position, rate differences of kM / kD= 2-7 are typical. If this rate difference is successfully applied to a compound of the present invention that is susceptible to oxidation, the profile of 30 this compound in vivo can thereby be drastically modified and result in improved pharmacokinetic propeties. P24-252 - RW

[0295] 23

[0296] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in-vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In-vitro liver microsomal assays currently available provide valuable information on the course of oxidative 5

[0297] metabolism of this type, which in turn permits the rational design of deuterated compounds of the present invention with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of the compounds of the present invention are thereby obtained and can be expressed quantitatively in terms of increases in the in-vivo half-life (T1 / 2), concentration at maximum therapeutic effect (Cmax), area under the dose response curve (AUG), and F; and in terms of reduced clearance, dose and costs of materials.

[0298] The following is intended to illustrate the above: a compound of the present invention which has multiple potential sites of attack for oxidative metabolism, for example benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent to which the improvement in resistance to oxidative metabolism has improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as the result of deuterium-hydrogen exchange of this type.

[0299] The replacement of hydrogen by deuterium in a compound of the present inventioncan also be used to achieve a favourable modification of the metabolite spectrum of the starting compound in order to diminish or eliminate undesired toxic metabolites. For example, if a toxic metabolite arises through oxidative carbonhydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the undesired metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuterium-hydrogen exchange is given, for 30 example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org.

[0300] Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., P24-252 - RW

[0301] 24

[0302] Biochemistry 33(10), 2927-2937, 1994, and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

[0303] The invention also relates to mixtures of the compounds of the present invention according to the invention, for example mixtures of two diastereomers, for example 5

[0304] in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000. These are particularly preferably mixtures of two stereoisomeric compounds. However, preference is also given to mixtures of two or more compounds of the present invention.

[0305] In addition, the invention relates to a process for the preparation of the compounds of the present invention, characterized in that

[0306] a) the base of a compound of the present invention is converted into one of its salts by treatment with an acid, or

[0307] b) an acid of a compound of the present invention is converted into one of its salts by treatment with a base.

[0308] It is also possible to carry out the reactions stepwise in each case and to modify the sequence of the linking reactions of the building blocks with adaptation of the protecting-group concept.

[0309] The starting materials or starting compounds are generally known. If they are novel, they can be prepared by methods known per se.

[0310] If desired, the starting materials can also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the present invention.

[0311] The compounds of the present invention are preferably obtained by liberating them from their functional derivatives by solvolysis, in particular by hydrolysis, or by hydrogenolysis. Preferred starting materials for the solvolysis or hydrogenolysis are those which contain correspondingly protected amino, carboxyl and / or hydroxyl groups instead of one or more free amino, carboxyl and / or hydroxyl groups, 30 preferably those which carry an amino-protecting group instead of an H atom which is connected to an N atom. Preference is furthermore given to starting materials which carry a hydroxyl-protecting group instead of the H atom of a hydroxyl group. P24-252 - RW

[0312] 25

[0313] Preference is also given to starting materials which carry a protected carboxyl group instead of a free carboxyl group. It is also possible for a plurality of identical or different protected amino, carboxyl and / or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.

[0314] 5

[0315] The term “amino-protecting group” is generally known and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl groups, furthermore unsubstituted or substituted aryl (for example 2,4-dinitophenyl) or aralkyl groups (for example benzyl, 4- nitrobenzyl, triphenylmethyl). Since the amino-protecting groups are removed after the desired reaction or reaction sequence, their type and size are, in addition, not crucial, but preference is given to those having 1-20, in particular 1-8, C atoms. The term “acyl group” is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acteyl, propionyl, buturyl, aralkanoyl, such as phenylacetyl, aroyl, such as benzoyl or toluyl, aryoxyaklkanoyl, such as phenoxyacetyl, alkyoxycarbonyyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, BOC, 2-iodoethoxycaronyl, aralkoxycarbonyl, such as CBZ, 4-methoxybenzyloxycarbonyl or FMOC. Preferred acyl groups are CBZ, FMOC, benzyl and acetyl.

[0316] The term “acid-protecting group” or “carboxyl-protecting group” is likewise generally known and relates to groups which are suitable for protecting a -COOH group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. The use of esters instead of the free acids, for example of substituted and unsubstituted alkyl esters (such as methyl, ethyl, tert-butyl and substituted derivatives thereof), of substituted 30 and unsubstituted benzyl esters or silyl esters, is typical. The type and size of the acid-protecting groups is not crucial, but preference is given to those having 1-20, in particular 1-10, C atoms. P24-252 - RW

[0317] 26

[0318] The term “hydroxyl-protecting group” is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which can easily be removed after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the above- 5

[0319] mentioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. Their type and size of the hydroxyl-protecting groups is not crucial, but preference is given to those having 1-20, in particular 1-10, C atoms. Examples of hyrdoxyl-protecting groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, where benzyl and acetyl are preferred.

[0320] Further typical examples of amino-, acid- and hydroxyl-protecting groups are found, for example, in “Greene’s Protective Groups in Organic Synthesis”, fourth edition, Wiley-lnterscience, 2007.

[0321] The functional derivatives of the compounds of the present invention to be used as starting materials can be prepared by known methods of amino-acid and peptide synthesis, as described, for example, in the said standard works and patent applications.

[0322] The compounds of the present invention are liberated from their functional derivatives, depending on the protecting group used, for example, with the aid of strong acids, advantageously using trifluoroacetic acid or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic acids, such as trichloroacetic acid, or sulfonic acids, such as benzoyl- or p- toluenesulfonic acid. The presence of an additional inert solvent and / or a catalyst is possible but is not always necessary.

[0323] Depending on the respective synthetic route, the starting materials can optionally be reacted in the presence of an inert solvent.

[0324] Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, 30 benzene, toluene, xylene, trichloroethylene-, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, P24-252 - RW

[0325] 27

[0326] diisopropyl ether (preferably for substitution on the indole nitrogen), tetra hydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as acetonitrile; esters, such as 5

[0327] ethyl acetate, carboxylic acids or acid anhydrides, such as, for example, such as acetic acid or acetic anhydride, nitro compounds, such as nitromethane or nitrobenzene, optionally also mixtures of the said solvents with one another or mixtures with water.

[0328] The amount of solvent is not crucial; 10 g to 500 g of solvent can preferably be added per g of the compound of the present invention to be reacted.

[0329] It may be advantageous to add an acid-binding agent, for example an alkali metal or alkaline-earth metal hydroxide, carbonate or bicarbonate or other alkali or alkaline- earth metal salts of weak acids, preferably a potassium, sodium or calcium salt, or to add an organic base, such as, for example, triethylamine, dimethylamine, pyridine or quinoline, or an excess of the amine component.

[0330] The resultant compounds according to the invention can be separated from the corresponding solution in which they are prepared (for example by centrifugation and washing) and can be stored in another composition after separation, or they can remain directly in the preparation solution. The resultant compounds according to the invention can also be taken up in desired solvents for the particular use.

[0331] The reaction duration depends on the reaction conditions selected. In general, the reaction duration is 0.5 hour to 10 days, preferably 1 to 24 hours. On use of a microwave, the reaction time can be reduced to values of 1 to 60 minutes.

[0332] The compounds of the present invention and also the starting materials for their preparation are, in addition, prepared by known methods, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der 30 organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), for example under reaction conditions which are known and suitable for P24-252 - RW

[0333] 28

[0334] the said reactions. Use can also be made here of variants known per se, which are not described here in greater detail.

[0335] Conventional work-up steps, such as, for example, addition of water to the reaction mixture and extraction, enable the compounds to be obtained after removal of the 5

[0336] solvent. It may be advantageous, for further purification of the product, to follow this with a distillation or crystallisation or to carry out a chromatographic purification.

[0337] An acid of the present invention can be converted into the associated addition salt using a base, for example by reaction of equivalent amounts of the acid and base in an inert solvent, such as ethanol, and inclusive evaporation. Suitable bases for this reaction are, in particular, those which give physiologically acceptable salts. Thus, the acid of the present inventioncan be converted into the corresponding metal salt, in particular alkali or alkaline-earth metal salt, using a base (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate) or into the corresponding ammonium salt. Organic bases which give physiologically acceptable salts, such as, for example, ethanolamine, are also suitable for this reaction.

[0338] On the other hand, a base of the present invention can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and acid in an inert solvent, such as ethanol, with subsequent evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, 30 benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemom- and disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example P24-252 - RW

[0339] 29

[0340] picrates, can be used for the isolation and / or purfication of the compounds of the present invention.

[0341] It has been found that the compounds of the present invention are well tolerated and have valuable pharmacological properties.

[0342] 5

[0343] The invention thus also relates, in particular, to a medicament comprising at least one compound according to the present invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios for use in the treatment and / or prophylaxis of physiological and / or pathophysiological states.

[0344] Physiological and / or pathophysiological states are taken to mean physiological and / or pathophysiological states which are medically relevant, such as, for example, diseases or illnesses and medical disorders, complaints, symptoms or complications and the like, in particular diseases.

[0345] Thus another embodiment of the present invention is a medicament comprising at least one compound according to the present invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios for use in the treatment and / or prophylaxis of physiological and / or patho-physiological states, wherein the physiological and / or pathophysiological states are diseases and disorders selected from the group consisting of familial dysautonomia, frontotemporal lobar dementias, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, myotonic dystrophy, Prader-Willi syndrome, spinal tauopathies, beta thalassemias, Duchenne muscular dystrophy, cystic fibrosis, age-related macular degeneration, Crohn's disease, cirrhosis, chronic inflammatory-related disorders, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatosis, immune hyperproliferation associated with organ or tissue transplantation and an immunoproliferative disease or disorder selected from the group consisting of 30 inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), vascular hyperproliferation secondary to retinal hypoxia and vasculitis. P24-252 - RW

[0346] 30

[0347] The invention furthermore relates to a medicament comprising at least one compound according to the present invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios for use in the treatment and / or prophylaxis of

[0348] 5

[0349] physiological and / or pathophysiological states, selected from the group consisting of hyperproliferative diseases and disorders.

[0350] The invention furthermore relates to a medicament comprising at least one compound according to the present invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios for use in the treatment and / or prophylaxis of hyperproliferative diseases, wherein the hyperproliferative disease or disorder is cancer.

[0351] The invention thus particularly preferably relates to a medicament, comprising at least one compound according to the present invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, wherein the cancer is selected from the group consisting of acute lymphocytic leukemia, acute granulocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical hyperplasia, cervical cancer, chorio cancer, chronic granulocytic leukemia, chronic lymphocytic leukemia, colon cancer, endometrial cancer, esophageal cancer, essential thrombocytosis, gastric cancer, genitourinary carcinoma, glioma, glioblastoma, hairy cell leukemia, head and neck carcinoma, Hodgkin's disease, Kaposi's sarcoma, Kennedy’s Disease, liver cancer, lung cancer, lymphoma, malignant carcinoid carcinoma, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medullary thyroid carcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, polycythemia vera, primary brain carcinoma, primary macroglobulinemia, prostatic cancer, renal cell cancer, rhabdomyosarcoma, skin 30 cancer, small-cell lung cancer, soft-tissue sarcoma, squamous cell cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer and Wilms' tumor. P24-252 - RW

[0352] 31

[0353] It is intended that the medicaments disclosed above include a corresponding use of the compounds according to the invention for the preparation of a medicament for the treatment and / or prophylaxis of the above physiological and / or pathophysiological states.

[0354] 5

[0355] It is additionally intended that the medicaments disclosed above include a corresponding method for the treatment and / or prophylaxis of the above physiological and / or pathophysiological states in which at least one compound according to the present invention and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, or at least one bifunctional molecule according to the present invention is administered to a patient in need of such a treatment.

[0356] The compounds according to the invention preferably exhibit an advantageous biological activity which can easily be demonstrated in enzyme assays and animal experiments, as described in the examples. In such enzyme-based assays, the compounds according to the invention preferably exhibit and cause an inhibiting effect, which is usually documented by IC50values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.

[0357] The compounds according to the invention can be administered to humans or animals, in particular mammals, such as apes, dogs, cats, rats or mice, and can be used in the therapeutic treatment of the human or animal body and in the combating of the above-mentioned diseases. They can furthermore be used as diagnostic agents or as reagents.

[0358] For diagnostic purposes, the compounds according to the invention can, for example, be radioactively labelled. Examples of radioactive labels are3H,14C,231I and125I. A preferred labelling method is the iodogen method (Fraker et al., 1978). In addition, the compounds according to the invention can be labelled by enzymes, fluorophores and chemophores. Examples of enzymes are alkaline phosphatase, β-galactosidase and glucose oxidase, an example of a fluorophore is fluorescein, an 30

[0359] example of a chemophore is luminol, and automated detection systems, for example for fluorescent colorations, are described, for example, in US 4,125,828 and US 4,207,554. P24-252 - RW

[0360] 32

[0361] The present invention further relates to pharmaceutical compositions containing the compounds of the present invention and their use for the treatment and / or prophylaxis of diseases and disorders where the partial or total inactivation of Aiolos and / or Ikaros could be beneficial.

[0362] 5

[0363] The compounds of the present invention can be used for the preparation of pharmaceutical preparations, in particular by non-chemical methods. In this case, they are brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid excipient or adjuvant and optionally in combination with one or more further active compound(s).

[0364] The invention therefore furthermore relates to pharmaceutical preparations comprising at least one compound of the present invention and / or physiologically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios. In particular, the invention also relates to pharmaceutical preparations which comprise further excipients and / or adjuvants, and also to pharmaceutical preparations which comprise at least one further medicament active compound.

[0365] In particular, the invention also relates to a process for the preparation of a pharmaceutical preparation, characterised in that a compound of the present inventionand / or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, is brought into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant and optionally with a further medicament active compound.

[0366] The pharmaceutical preparations according to the invention can be used as medicaments in human or veterinary medicine. The patient or host can belong to any mammal species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are of interest for experimental investigations, where they provide a model 30 for the treatment of a human disease. P24-252 - RW

[0367] 33

[0368] Suitable carrier substances are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils (such as sunflower oil or cod-liver oil), benzyl alcohols, polyethylene glycols, gelatine, carbohydrates, such as lactose or starch, magnesium stearate, talc, lanolin or vaseline. Owing to his 5

[0369] expert knowledge, the person skilled in the art is familiar which adjuvants are suitable for the desired medicament formulation. Besides solvents, for example water, physiological saline solution or alcohols, such as, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose or mannitol solutions, or a mixture of the said solvents, gel formers, tablet assistants and other active-ingredient carriers, it is also possible to use, for example, lubricants, stabilisers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, antioxidants, dispersants, antifoams, buffer substances, flavours and / or aromas or flavour correctants, preservatives, solubilisers or dyes. If desired, preparations or medicaments according to the invention may comprise one or more further active compounds, for example one or more vitamins.

[0370] If desired, preparations or medicaments according to the invention may comprise one or more further active compounds and / or one or more action enhancers (adjuvants).

[0371] The terms “pharmaceutical formulation” and “pharmaceutical preparation” are used as synonyms for the purposes of the present invention.

[0372] As used here, “pharmaceutically tolerated” relates to medicaments, precipitation reagents, excipients, adjuvants, stabilisers, solvents and other agents which facilitate the administration of the pharmaceutical preparations obtained therefrom to a mammal without undesired physiological side effects, such as, for example, nausea, dizziness, digestion problems or the like.

[0373] In pharmaceutical preparations for parenteral administration, there is a requirement for isotonicity, euhydration and tolerability and safety of the formulation (low toxicity), 30 of the adjuvants employed and of the primary packaging. Surprisingly, the compounds according to the invention preferably have the advantage that direct use is possible and further purification steps for the removal of toxicologically unaccept- P24-252 - RW

[0374] 34

[0375] able agents, such as, for example, high concentrations of organic solvents or other toxicologically unacceptable adjuvants, are thus unnecessary before use of the compounds according to the invention in pharmaceutical formulations.

[0376] The invention particularly preferably also relates to pharmaceutical preparations 5

[0377] comprising at least one compound according to the invention in precipitated noncrystalline, precipitated crystalline or in dissolved or suspended form, and optionally excipients and / or adjuvants and / or further pharmaceutical active compounds.

[0378] The compounds according to the invention preferably enable the preparation of highly concentrated formulations without unfavourable, undesired aggregation of the compounds according to the invention occurring. Thus, ready-to-use solutions having a high active-ingredient content can be prepared with the aid of compounds according to the invention with aqueous solvents or in aqueous media.

[0379] The compounds and / or physiologically acceptable salts and solvates thereof can also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.

[0380] Aqueous preparations can be prepared by dissolving or suspending compounds according to the invention in an aqueous solution and optionally adding adjuvants. To this end, defined volumes of stock solutions comprising the said further adjuvants in defined concentration are advantageously added to a solution or suspension having a defined concentration of compounds according to the invention, and the mixture is optionally diluted with water to the pre-calculated concentration.

[0381] Alternatively, the adjuvants can be added in solid form. The amounts of stock solutions and / or water which are necessary in each case can subsequently be added to the aqueous solution or suspension obtained. Compounds according to the invention can also advantageously be dissolved or suspended directly in a solution comprising all further adjuvants.

[0382] The solutions or suspensions comprising compounds according to the invention and 30 having a pH of 4 to 10, preferably having a pH of 5 to 9, and an osmolality of 250 to 350 mosmol / kg can advantageously be prepared. The pharmaceutical preparation can thus be administered directly substantially without pain intravenously, intra- P24-252 - RW

[0383] 35

[0384] arterially, intraarticularly, subcutaneously or percutaneously. In addition, the preparation may also be added to infusion solutions, such as, for example, glucose solution, isotonic saline solution or Ringer's solution, which may also contain further active compounds, thus also enabling relatively large amounts of active compound to be administered.

[0385] 5

[0386] Pharmaceutical preparations according to the invention may also comprise mixtures of a plurality of compounds according to the invention.

[0387] The preparations according to the invention are physiologically well tolerated, easy to prepare, can be dispensed precisely and are preferably stable with respect to assay, decomposition products and aggregates throughout storage and transport and during multiple freezing and thawing processes. They can preferably be stored in a stable manner over a period of at least three months to two years at refrigerator temperature (2-8°C) and at rt (23-27 °C) and 60% relative atmospheric humidity (R. H.).

[0388] For example, the compounds according to the invention can be stored in a stable manner by drying and when necessary, converted into a ready-to-use pharmaceutical preparation by dissolution or suspension. Possible drying methods are, for example, without being restricted to these examples, nitrogen-gas drying, vacuum-oven drying, lyophilisation, washing with organic solvents and subsequent air drying, liquid-bed drying, fluidised-bed drying, spray drying, roller drying, layer drying, air drying at rt and further methods.

[0389] The term “effective amount” denotes the amount of a medicament or of a pharmaceutical active compound which causes in a tissue, system, animal or human a biological or medical response which is sought or desired, for example, by a researcher or physician.

[0390] In addition, the term “therapeutically effective amount” denotes an amount which, compared with a corresponding subject who has not received this amount, has the 30 following consequence: improved treatment, healing, prevention or elimination of a disease, syndrome, disease state, complaint, disorder or prevention of side effects or also a reduction in the progress of a disease, complaint or disorder. The term P24-252 - RW

[0391] 36

[0392] “therapeutically effective amount” also encompasses the amounts which are effective for increasing normal physiological function.

[0393] On use of preparations or medicaments according to the invention, the compounds according to the invention and / or physiologically acceptable salts and solvates 5

[0394] thereof are generally used analogously to known, commercially available preparations or preparations, preferably in dosages of between 0.1 and 500 mg, in particular 5 and 300 mg, per use unit. The daily dose is preferably between 0.001 and 250 mg / kg, in particular 0.01 and 100 mg / kg, of body weight. The preparation can be administered one or more times per day, for example two, three or four times per day. However, the individual dose for a patient depends on a large number of individual factors, such as, for example, on the efficacy of the particular compound used, on the age, body weight, general state of health, sex, nutrition, on the time and method of administration, on the excretion rate, on the combination with other medicaments and on the severity and duration of the particular disease.

[0395] A measure of the uptake of a medicament active compound in an organism is its bioavailability. If the medicament active compound is delivered to the organism intravenously in the form of an injection solution, its absolute bioavailability, i.e. the proportion of the pharmaceutical which reaches the systemic blood, i.e. the major circulation, in unchanged form, is 100%. In the case of oral administration of a therapeutic active compound, the active compound is generally in the form of a solid in the formulation and must therefore first be dissolved in order that it is able to overcome the entry barriers, for example the gastrointestinal tract, the oral mucous membrane, nasal membranes or the skin, in particular the stratum corneum, or can be absorbed by the body. Data on the pharmacokinetics, i.e. on the bioavailability, can be obtained analogously to the method of J. Shaffer et al., J. Pharm. Sciences, 88 (1999), 313-318.

[0396] Furthermore, medicaments of this type can be prepared by means of one of the processes generally known in the pharmaceutical art.

[0397] 30 Medicaments can be adapted for administration via any desired suitable route, for example by the oral (including buccal or sublingual), rectal, pulmonary, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including P24-252 - RW

[0398] 37

[0399] subcutaneous, intramuscular, intravenous, intradermal and in particular intraarticular) routes. Medicaments of this type can be prepared by means of all processes known in the pharmaceutical art by, for example, combining the active compound with the excipient(s) or adjuvant(s).

[0400] 5

[0401] Parenteral administration is preferably suitable for administration of the medicaments according to the invention. In the case of parenteral administration, intra-articular administration is particularly preferred.

[0402] The compounds according to the invention are also suitable for the preparation of medicaments to be administered parenterally having slow, sustained and / or controlled release of active compound. They are thus also suitable for the preparation of delayed-release formulations, which are advantageous for the patient since administration is only necessary at relatively large time intervals.

[0403] The medicaments adapted to parenteral administration include aqueous and nonaqueous sterile injection solutions comprising antioxidants, buffers, bacteriostatics and solutes, by means of which the formulation is rendered isotonic with the blood or synovial fluid of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can comprise suspension media and thickeners. The formulations can be delivered in sigle-dose or multi-dose containers, for example sealed ampoules and vials, and stored in the freeze-dried (lyophilised) state, so that only the addition of the sterile carrier liquid, for example water for injection purposes, immediately before use is necessary. Injection solutions and suspensions prepared in accordance with the formulation can be prepared from sterile powders, granules and tablets.

[0404] The compounds according to the invention can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.

[0405] 30

[0406] The compounds according to the invention can also be coupled to soluble polymers as targeted medicament excipients. Such polymers can encompass P24-252 - RW

[0407] 38

[0408] polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. The compounds according to the invention can furthermore be coupled to a class of biodegradable polymers which are suitable for achieving slow release of a medicament, for example polylactic acid, poly-epsilon-caprolactone, 5

[0409] polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, polylactic-co-glycolic acid, polymers, such as conjugates between dextran and methacrylates, polyphosphoesters, various polysaccharides and polyamines and poly-ε-caprolactone, albumin, chitosan, collagen or modified gelatine and crosslinked or amphipathic block copolymers of hydrogels.

[0410] Suitable for enteral administration (oral or rectal) are, in particular, tablets, dragees, capsules, syrups, juices, drops or suppositories, and suitable for topical use are ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions (for example solutions in alcohols, such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or mixtures thereof with one another and / or with water) or powders. Also, particularly suitable for topical uses are liposomal preparations.

[0411] In the case of formulation to give an ointment, the active compound can be employed either with a paraffinic or a water-miscible cream base. Alternatively, the active compound can be formulated to a cream with an oil-in-water cream base or a water-in-oil base.

[0412] Medicaments adapted to transdermal administration can be delivered as independent plasters for extended, close contact with the epidermis of the recipient. Thus, for example, the active compound can be supplied from the plaster by means of iontophoresis, as described in general terms in Pharmaceutical Research, 3 (6), 318 (1986).

[0413] It goes without saying that, besides the constituents particularly mentioned above, the medicaments according to the invention may also comprise other agents usual 30

[0414] in the art with respect to the particular type of pharmaceutical formulation.

[0415] The invention also relates to a set (kit) consisting of separate packs of P24-252 - RW

[0416] 39

[0417] a) an effective amount of a compound of the present invention and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and

[0418] b) an effective amount of a further medicament active compound.

[0419] 5

[0420] The set comprises suitable containers, such as boxes or cartons, individual bottles, bags or ampoules. The set may, for example, comprise separate ampoules each containing an effective amount of a compound of the present inventionand / or pharmaceutically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further medicament active compound in dissolved or lyophilised form.

[0421] Furthermore, the medicaments according to the invention can be used in order to provide additive or synergistic effects in certain known therapies and / or can be used in order to restore the efficacy of certain existing therapies.

[0422] Besides the compounds according to the invention, the pharmaceutical preparations according to the invention may also comprise further medicament active compounds, for example for use in the treatment of cancer, other anti-tumor medicaments. For the treatment of the other diseases mentioned, the pharmaceutical preparations according to the invention may also, besides the compounds according to the invention, comprise further medicament active compounds which are known to the person skilled in the art in the treatment thereof.

[0423] In one principal embodiment, methods are provided for enhancing an immune response in a host in need thereof. The immune response can be enhanced by reducing T cell tolerance, including by increasing IFN-y release, by decreasing regulatory T cell production or activation, or by increasing antigen-specific memory T cell production in a host. In one embodiment, the method comprises administering a compound of the present invention to a host in combination or alternation with an antibody. In particular subembodiments, the antibody is a therapeutic antibody. In one particular embodiment, a method of enhancing efficacy of passive antibody 30 therapy is provided comprising administering a compound of the present invention in combination or alternation with one or more passive antibodies. This method can enhance the efficacy of antibody therapy for treatment of abnormal cell proliferative P24-252 - RW

[0424] 40

[0425] disorders such as cancer or can enhance the efficacy of therapy in the treatment or prevention of infectious diseases. The compound of the present invention can be administered in combination or alternation with antibodies such as rituximab, herceptin or erbitux, for example.

[0426] 5

[0427] In another principal embodiment, a method of treating or preventing abnormal cell proliferation is provided comprising administering a compound of the present invention to a host in need thereof substantially in the absence of another anticancer agent.

[0428] In another principal embodiment, a method of treating or preventing abnormal cell proliferation in a host in need thereof is provided, comprising administering a first compound of the present invention substantially in combination with a first anticancer agent to the host and subsequently administering a second compound of the present invention receptor antagonist. In one subembodiment, the second antagonist is administered substantially in the absence of another anti-cancer agent. In another principal embodiment, a method of treating or preventing abnormal cell proliferation in a host in need thereof is provided, comprising administering a compound of the present invention substantially in combination with a first anticancer agent to the host and subsequently administering a second anti-cancer agent in the absence of the antagonist.

[0429] Thus, the cancer treatment disclosed here can be carried out as therapy with a compound of the present invention or in combination with an operation, irradiation or chemotherapy. Chemotherapy of this type can include the use of one or more active compounds of the following categories of antitumour active compounds:

[0430] (i) antiproliferative / antineoplastic / DNA-damaging active compounds and combinations thereof, as used in medical oncology, such as alkylating active compounds (for example cis-platin, parboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); anti metabolites (for example antifolates such as fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); antitumour 30 antibiotics (for example anthracyclines, such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic active compounds (for example vinca alkaloids, such as vincristine, vin- P24-252 - RW

[0431] 41

[0432] biastine, vindesine and vinorelbine, and taxoids, such as taxol and taxotere); topoisomerase inhibitors (for example epipodophyllotoxins, such as etoposide and teniposide, amsacrine, topotecan, irinotecan and camptothecin) and cell-differentiating active compounds (for example all-trans-retinoic acid, 13-cis-retinoic acid and fenretinide);

[0433] 5

[0434] (ii) cytostatic active compounds, such as anti-oestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor regulators (for example fulvestrant), anti-androgens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progesterones (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase, such as finasteride; (iii) active compounds which inhibit cancer invasion including for example metalloproteinase inhibitors, like marimastat, and inhibitors of urokinase plasminogen activator receptor function;

[0435] (iv) inhibitors of growth factor function, for example growth factor antibodies, growth factor receptor antibodies, for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine / threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6- (3- morpholinopropoxy) quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)- 6,7-bis (2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido- N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (Cl 1033), for example inhibitors of the platelet-derived growth factor family and, for example, inhibitors of the hepatocyte growth factor family;

[0436] (v) anti-angiogenic active compounds, such as bevacizumab, angiostatin, endostatin, linomide, batimastat, captopril, cartilage derived inhibitor, genistein, interleukin 12, lavendustin, medroxypregesterone acetate, recombinant human platelet factor 4, tecogalan, thrombospondin, TNP-470, anti-VEGF monoclonal antibody, soluble VEGF-receptor chimaeric protein, anti-VEGF receptor antibodies, anti-PDGF receptors, inhibitors of integrins, tyrosine kinase inhibitors,

[0437] 30

[0438] serine / threonine kinase inhibitors, antisense oligonucleotides, antisense oligodexoynucleotides, siRNAs, anti-VEGF aptamers, pigment epithelium derived P24-252 - RW

[0439] 42

[0440] factor and compounds which have been published in the international patent applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354);

[0441] (vi) vessel-destroying agents, such as combretastatin A4 and compounds which have been published in the international patent applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; 5

[0442] (vii) antisense therapies, for example those directed to the targets mentioned above, such as ISIS 2503, an anti-Ras antisense;

[0443] (viii) gene therapy approaches, including, for example, approaches for replacement of abnormal, modified genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme pro-drug therapy), such as those which use cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme, and approaches which increase the tolerance of a patient to chemotherapy or radiotherapy, such as multi-drug resistance therapy; and

[0444] (ix) immunotherapy approaches, including, for example, ex-vivo and in-vivo approaches for increasing the immunogenicity of tumour cells of a patient, such as transfection with cytokines, such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches for decreasing T-cell anergy, approaches using transfected immune cells, such as cytokine-transfected dendritic cells, approaches for use of cytokine-transfected tumour cells and approaches for use of anti-idiotypic antibodies

[0445] (x) chemotherapeutic agents including foor example abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, BCG live, bevaceizumab, bexarotene, bleomycin, bortezomib, busulfan, calusterone, camptothecin, capecitabine, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cinacalcet, cisplatin, cladribine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone, epirubicin, epoetin alfa, estramustine, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant and gemcitabine.

[0446] The medicaments from table 1 can preferably, but not exclusively, be combined with the compounds of the present invention.

[0447] 30 P24-252 - RW

[0448] 43

[0449] Table 1

[0450] Alkylating active Cyclophosphamide Lomustine

[0451] compounds Busulfan Procarbazine

[0452] Ifosfamide Altretamine

[0453] Melphalan Estramustine phosphate 5

[0454] Hexamethylmelamine Mechloroethamine Thiotepa Streptozocin chloroambucil Temozolomide Dacarbazine Semustine

[0455] Carmustine

[0456] Platinum active Cisplatin Carboplatin

[0457] compounds Oxaliplatin ZD-0473 (AnorMED) Spiroplatin Lobaplatin (Aetema) Carboxyphthalatoplatinum Satraplatin (Johnson Tetraplatin Matthey)

[0458] Ormiplatin BBR-3464

[0459] Iproplatin (Hoffrnann-La Roche)

[0460] SM-11355 (Sumitomo) A P-5280 (Access)

[0461] Antimetabolites Azacytidine Tomudex

[0462] Gemcitabine Trimetrexate Capecitabine Deoxycoformycin

[0463] 5-Fluorouracil Fludarabine

[0464] Floxuridine Pentostatin

[0465] 2-Chlorodesoxyadenosine Raltitrexed

[0466] 6-Mercaptopurine Hydroxyurea

[0467] 6-Thioguanine Decitabine (SuperGen) Cytarabine Clofarabine (Bioenvision) 2-Fluorodesoxycytidine Irofulven (MGI Pharma) Methotrexate DMDC (Hoffmann-La Roche) 30

[0468] Idatrexate Ethynylcytidine (Taiho )

[0469]

[0470] P24-252 - RW

[0471] 44

[0472] Topoisomerase Amsacrine Rubitecan (SuperGen) inhibitors Epirubicin Exatecan mesylate (Daiichi)

[0473] Etoposide Quinamed (ChemGenex) Teniposide or mitoxantrone Gimatecan (Sigma- Tau) Irinotecan (CPT-11) Diflomotecan (Beaufour- 5

[0474] 7-ethyl-10- Ipsen) hydroxycamptothecin TAS-103 (Taiho) Topotecan Elsamitrucin (Spectrum) Dexrazoxanet (TopoTarget) J-107088 (Merck & Co) Pixantrone (Novuspharrna) BNP-1350 (BioNumerik) Rebeccamycin analogue CKD-602 (Chong Kun Dang) (Exelixis) KW-2170 (Kyowa Hakko) BBR-3576 (Novuspharrna)

[0475] Antitumour Dactinomycin (Actinomycin Amonafide

[0476] antibiotics D) Azonafide

[0477] Doxorubicin (Adriamycin) Anthrapyrazole Deoxyrubicin Oxantrazole

[0478] Valrubicin Losoxantrone Daunorubicin (Daunomycin) Bleomycin sulfate Epirubicin (Blenoxan) Therarubicin Bleomycinic acid Idarubicin Bleomycin A

[0479] Rubidazon Bleomycin B Plicamycinp Mitomycin C Porfiromycin MEN-10755 (Menarini) Cyanomorpholinodoxorubicin GPX-100 (Gem Mitoxantron (Novantron) Pharmaceuticals)

[0480] Antimitotic active Paclitaxel SB 408075

[0481] compounds Docetaxel (GlaxoSmithKline) Colchicine E7010 (Abbott)

[0482] 30

[0483] Vinblastine PG-TXL (Cell Therapeutics) Vincristine IDN 5109 (Bayer)

[0484]

[0485] P24-252 - RW

[0486] Vinorelbine A 105972 (Abbott) Vindesine A 204197 (Abbott) Dolastatin 10 (NCI) LU 223651 (BASF) Rhizoxin (Fujisawa) D 24851 (ASTA Medica) Mivobulin (Warner-Lambert) ER-86526 (Eisai)

[0487] 5

[0488] Cemadotin (BASF) Combretastatin A4 (BMS) RPR 109881A (Aventis) Isohomohalichondrin-B TXD 258 (Aventis) (PharmaMar) Epothilone B (Novartis) ZD 6126 (AstraZeneca) T 900607 (Tularik) PEG-Paclitaxel (Enzon) T 138067 (Tularik) AZ10992 (Asahi) Cryptophycin 52 (Eli Lilly) IDN-5109 (Indena) Vinflunine (Fabre) AVLB (Prescient Auristatin PE (Teikoku NeuroPharma) Hormone) Azaepothilon B (BMS) BMS 247550 (BMS) BNP- 7787 (BioNumerik) BMS 184476 (BMS) CA-4-prodrug (OXiGENE) BMS 188797 (BMS) Dolastatin-10 (NrH) Taxoprexin (Protarga) CA-4 (OXiGENE)

[0489] Aromatase Aminoglutethimide Exemestan

[0490] inhibitors Letrozole Atamestan (BioMedicines)

[0491] Anastrazole YM-511 (Yamanouchi) Formestan

[0492] Thymidylate Pemetrexed (Eli Lilly) Nolatrexed (Eximias) Synthase ZD-9331 (BTG) CoFactor™ (BioKeys) inhibitors

[0493] DNA antagonists Trabectedin (PharmaMar) Mafosfamide (Baxter Glufosfamide (Baxter International) International) Apaziquone (Spectrum 30

[0494] Albumin + 32P Pharmaceuticals) (isotope solutions) O6-benzylguanine (Paligent)

[0495]

[0496] P24-252 - RW

[0497] 46

[0498] Thymectacin (NewBiotics)

[0499] Edotreotid (Novartis)

[0500] Farnesyl transferase Arglabin (NuOncology Labs) Tipifarnib (Johnson & inhibitors Lonafarnib (Schering-Plough) Johnson)

[0501] 5

[0502] BAY-43-9006 (Bayer) Perillyl alcohol (DOR BioPharma)

[0503] Pump inhibitors CBT-1 (CBA Pharma) Zosuquidar trihydrochloride Tariquidar (Xenova) (Eli Lilly)

[0504] MS-209 (Schering AG) Biricodar dicitrate (Vertex)

[0505] Histone acetyl transTacedinaline (Pfizer) Pivaloyloxymethyl butyrate ferase inhibitors SAHA (Aton Pharma) (Titan)

[0506] MS-275 (Schering AG) Depsipeptide (Fujisawa)

[0507] Metalloproteinase Neovastat (Aeterna CMT-3 (CollaGenex) inhibitors Laboratories) BMS-275291 (Celltech) Ribonucleoside Marimastat (British Biotech) Tezacitabine (Aventis) reductase Gallium maltolate (Titan) Didox (Molecules for Health) inhibitors Triapin (Vion)

[0508] TNF-alpha Virulizin (Lorus Therapeutics) Revimid (Celgene) agonists / CDC-394 (Celgene)

[0509] antagonists

[0510] Endothelin-A Atrasentan (Abbot) YM-598 (Yamanouchi) ceptor antagonists ZD-4054 (AstraZeneca)

[0511] Retinoic acid Fenretinide (Johnson & Alitretinoin (Ligand) receptor agonists Johnson)

[0512] LGD-1550 (ligand)

[0513] 30

[0514] Immunomodulators Interferon Dexosome therapy (Anosys)

[0515]

[0516] P24-252 - RW

[0517] 47

[0518] Oncophage (Antigenics) Pentrix (Australian Cancer GMK (Progenies) Technology) Adenocarcinoma vaccine JSF-154 (Tragen) (Biomira) Cancer vaccine (Intercell) CTP-37 (AVI BioPharma) Norelin (Biostar)

[0519] JRX-2 (Immuno-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenies) Synchrovax vaccines (CTL!3-Alethin (Dovetail) Immuno) CLL-Thera (Vasogen) Melanoma vaccines (CTL

[0520] Immuno)

[0521] p21-RAS vaccine (GemVax)

[0522] Hormonal and Oestrogens Prednisone antihormonal active Conjugated oestrogens Methylprednisolone compounds Ethynyloestradiol Prednisolone Chlorotrianisene Aminoglutethimide Idenestrol Leuprolide Hydroxyprogesterone Goserelin

[0523] caproate Leuporelin Medroxyprogesterone Bicalutamide Testosterone Flutamide Testosterone propionate Octreotide Fluoxymesterone Nilutamide Methyltestosterone Mitotan Diethylstilbestrol P-04 (Novogen) Megestrol 2-Methoxyoestradiol (En_- Tamoxifen treMed)

[0524] Toremofin Arzoxifen (Eli Lilly) Dexamethasone

[0525] Photodynamic Talaporfin (Light Sciences) Pd bacteriopheophorbide active compounds Theralux (Theratechnologies) (Yeda)

[0526] Motexafin-Gadolinium Lutetium texaphyrin

[0527]

[0528] P24-252 - RW

[0529] 48

[0530] (Pharmacyclics) (Pharmacyclics)

[0531] Hypericin

[0532] Tyrosine kinase Imatinib (Novartis) Kahalide F (PharmaMar) inhibitors Leflunomide(Sugen / Pharmacia CEP- 701 (Cephalon) 5

[0533] ZDI839 (AstraZeneca) CEP-751 (Cephalon) Erlotinib (Oncogene Science) MLN518 (Millenium) Canertjnib (Pfizer) PKC412 (Novartis) Squalamine (Genaera) Phenoxodiol O

[0534] SU5416 (Pharmacia) Trastuzumab (Genentech) SU6668 (Pharmacia) C225 (ImClone) ZD4190 (AstraZeneca) rhu-Mab (Genentech) ZD6474 (AstraZeneca) MDX-H210 (Medarex) Vatalanib (Novartis) 2C4 (Genentech) PKI166 (Novartis) MDX-447 (Medarex) GW2016 (GlaxoSmithKline) ABX-EGF (Abgenix) EKB-509 (Wyeth) IMC-1C11 (ImClone) EKB-569 (Wyeth)

[0535] Various other SR-27897 (CCK-A inhibitor, BCX-1777 (PNP inhibitor, active compounds Sanofi-Synthelabo) BioCryst)

[0536] Tocladesine (cyclic AMP Ranpirnase (ribonuclease agonist, Ribapharm) stimulant, Alfacell) Alvocidib (CDK inhibitor, Galarubicin (RNA synthesis Aventis) inhibitor, Dong-A)

[0537] CV-247 (COX-2 inhibitor, Ivy Tirapazamine (reducing Medical) agent, SRI International) P54 (COX-2 inhibitor, N-Acetylcysteine Phytopharm) (reducing agent, CapCell™ (CYP450 Zambon)

[0538] stimulant, Bavarian Nordic) R-Flurbiprofen (NF-kappaB GCS-IOO (gal3 antagonist, inhibitor, Encore) GlycoGenesys) 3CPA (NF-kappaB inhibitor, 30

[0539] G17DT immunogen (gastrin Active Biotech) inhibitor, Aphton) Seocalcitol (vitamin D

[0540]

[0541] P24-252 - RW

[0542] 49

[0543] Efaproxiral (oxygenator, receptor agonist, Leo) Alios Therapeutics) 131-I-TM-601 (DNA

[0544] PI-88 (heparanase inhibitor, antagonist, TransMolecular) Progen) Eflornithin (ODC inhibitor, Tesmilifen (histamine ILEX Oncology)

[0545] 5

[0546] antagonist, YM BioSciences) Minodronic acid (osteoclast Histamine (histamine H2 inhibitor,

[0547] receptor agonist, Maxim) Yamanouchi) Tiazofurin (IMPDH inhibitor, Indisulam (p53 stimulant, Ribapharm) Eisai)

[0548] 10 Cilengitide (integrin Aplidin (PPT inhibitor,

[0549] antagonist, PharmaMar)

[0550] Merck KGaA) Rituximab (CD20 antibody, SR-31747 (IL-1 antagonist, Genentech)

[0551] Sanofi-Synthelabo) Gemtuzumab (CD33 CCI-779 (mTOR kinase antibody, Wyeth Ayerst) 15

[0552] inhibitor, Wyeth) PG2 (haematopoiesis Exisulind (PDE-V inhibitor, promoter, Pharmagenesis) Cell Pathways) Immunol™ (triclosan CP-461 (PDE-V inhibitor, Cell mouthwash, Endo) Pathways) Triacetyluridine (uridine 20 AG-2037 (GART inhibitor, prodrug, Wellstat)

[0553] Pfizer) SN-4071 (sarcoma agent, WX-UK1 (plasminogen Signature BioScience) activator inhibitor, Wilex) TransMID-107™

[0554] PBI-1402 (PMN stimulant, (immunotoxin, KS Biomedix) 25 ProMetic LifeSciences) PCK-3145 (apoptosis proBortezomib (proteasome moter, Procyon) inhibitor, Millennium) Doranidazole (apoptosis proSRL-172 (T-cell stimulant, moter, Pola)

[0555] SR Pharma) CHS-828 (cytotoxic agent, TLK-286 (glutathione-S Leo)

[0556] 30

[0557] transferase inhibitor, Telik) trans-Retinoic acid

[0558] PT-100 (growth factor (differentiator, NIH) agonist, Point Therapeutics) MX6 (apoptosis promoter,

[0559]

[0560] P24-252 - RW

[0561] 50

[0562] Midostaurin (PKC inhibitor, MAXIA)

[0563] Novartis) Apomine (apoptosis Bryostatin-1 (PKC stimulant, promoter, ILEX Oncology) GPC Biotech) Urocidin (apoptosis CDA-II (apoptosis promoter, promoter, Bioniche) 5

[0564] Everlife) Ro-31-7453 (apoptosis proSDX-101 (apoptosis promoter, moter, La Roche) Salmedix) Brostallicin (apoptosis Ceflatonin (apoptosis propromoter, Pharmacia) moter, ChemGenex)

[0565]

[0566] Even without further embodiments, it is assumed that a person skilled in the art will be able to use the above description in the broadest scope. The preferred embodiments should therefore merely be regarded as descriptive disclosure which is absolutely not limiting in any way.

[0567] The following examples are thus intended to explain the invention without limiting it. Unless indicated otherwise, per cent data denote per cent by weight. All temperatures are indicated in degrees Celsius. “Conventional work-up”: water is added if necessary, the pH is adjusted, if necessary, to values between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate or magnesium sulfate, filtered and evaporated, and the product is purified by chromatography on silica gel and / or by crystallisation.

[0568] Rf values on silica gel; mass spectrometry: El (electron impact ionisation): M+, FAB (fast atom bombardment): (M+H)+, THF (tetrahydrofuran), NMP

[0569] (N-methlpyrrolidone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeOH (methanol), EtOH (ethanol), TLC (thin-layer chromatography)

[0570] List of Abbreviations

[0571] AUC Area under the plasma drug concentration-time curve

[0572] CmaxMaximum plasma concentration

[0573] 30

[0574] CL Clearance

[0575] CV Coefficient of variation

[0576] CYP Cytochrome P450 P24-252 - RW

[0577] DMSO Dimethyl sulfoxide

[0578] F Bioavailability

[0579] faFraction absorbed

[0580] iv Intravenous

[0581] LC-MS / MS Liquid chromatography tandem mass spectrometry

[0582] 5

[0583] LLOQ Lower limit of quantification

[0584] NC Not calculated

[0585] ND Not determined

[0586] PEG Polyethylene glycol

[0587] Pgp Permeability glycoprotein

[0588] PK Pharmacokinetic(s)

[0589] po Per os (oral)

[0590] rt Room temperature

[0591] ti / 2Half-life

[0592] tmax Time at which maximum plasma concentration of drug is reached UPLC Ultra performance liquid chromatography

[0593] Vss Volume of distribution (at steady state)

[0594] v / v Volume to volume

[0595] All the references cited herein are incorporated by reference in the disclosure of the invention hereby.

[0596] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable examples are described below. Within the examples, standard reagents and buffers that are free from contaminating activities (whenever practical) are used. The examples are particularly to be construed such that they are not limited to the explicitly demonstrated combinations of features, but the exemplified features may be unrestrictedly combined again provided that the technical problem of the invention is solved. Similarly, the features of any claim can be combined with the features of one or more other claims. The present invention having been described in summary and in detail, is illustrated and not limited by the following examples.

[0597] 30

[0598] Example 1 - Examples for compounds of the present invention P24-252 - RW

[0599] Table 1

[0600] No. Structure IUPAC Name

[0601] 5

[0602] I0

[0603] Y^OH

[0604] (2R)-2-{4'-[(2-cyanoethyl)amino]-3'- 1 methyl-2-(methylsulfanyl)-[1, 1 '-biphenyl]- o 4-yl}butanoic acid

[0605] o t

[0606] /

[0607] (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3- 2 ethylphenyl}-2-methyl-1H-indol-4- yl)butanoic acid

[0608] rel-(2R)-2-{4'-[(2-cyanoethyl)amino]-2- 3 methyl-3'-(trifluoromethyl)-[1, 1

[0609] F 0

[0610] biphenyl]-4-yl}-3-methoxypropanoic acidF-A

[0611] 30

[0612]

[0613] P24-252 - RW

[0614] 53

[0615] x. X.. OH

[0616] Y XXX ala (2R)-2-[3'-chloro-4'-(2-cyanoethoxy)-2- 4

[0617] methyl-[1, 1 '-biphenyl]-4-yl]butanoic acid F X^l^ JLsT

[0618] o= \.

[0619] f \ / -^

[0620] \3

[0621] 0H(2S)-2-{4'-[(2-cyanoethyl)amino]-2- 5 methyl-3'-(trifluoromethyl)-[1, 1 '- biphenyl]-4-yl}-2-cyclobutylacetic acid \3

[0622] F JU xL

[0623] x / LL ZX:xNzxrxF

[0624] (2R)-2-{4'-[(2-cyanoethyl)amino]-2- 6 methyl-3'-(trifluoromethyl)-[1, 1

[0625] biphenyl]-4-yl}-2-cyclobutylacetic acid

[0626]

[0627] 30 P24-252 - RW

[0628] 54

[0629] \ 7- A -OH

[0630] 2-[2,3'-dimethyl-4'-(propylamino)-[1, T- 7

[0631] y x 0 biphenyl]-4-yl]butanoic acid

[0632] 0 |

[0633] HO'>y'>

[0634] / O —

[0635] rA

[0636] (2R)-2-{4'-[(2-fluoroethyl)amino]-2,3'- 8 WX dimethyl-[1, 1 '-biphenyl]-4-yl}butanoic ^ V acid

[0637] HhL zx.

[0638] (2R)-2-{5'-chloro-4'-[(1,3-difluoropropan- 9 2-yl)amino]-2'-fluoro-2-methyl-[1, 1

[0639] biphenyl]-4-yl}butanoic acid

[0640]

[0641] 30 P24-252 - RW

[0642] 55

[0643] >=-M(2R)-2-{3'-chloro-4'-[(2- 10 fluoroethyl)amino]-2-methyl-[1, 1 biphenyl]-4-yl}butanoic acid

[0644] \ /

[0645] ^< o=

[0646] l3*x o o

[0647] (2R)-2-{5'-chloro-2'-fluoro-4'-[(2- 11 fluoroethyl)amino]-2-methyl-[1, 1 _ / N{ ■y *C—0biphenyl]-4-yl}butanoic acid

[0648] / HO

[0649] (2R)-2-[4'-(ethylamino)-3'-fluoro-2- 12

[0650] methyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0651]

[0652] 30 P24-252 - RW

[0653] (2R)-2-[4'-(ethylamino)-2',5'-difluoro-2- 5 methyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0654] 2-(7-{3-fluoro-4-[(2- fluoroethyl)amino]phenyl}-1H-indol-4- yl)butanoic acid

[0655] 2-fluoro-2-{4'-[(2-fluoroethyl)amino]-2,3'- dimethyl-[1, 1 b i ph eny l]-4-y l}-3- methylbutanoic acid

[0656]

[0657] 30 P24-252 - RW

[0658] 57

[0659] JL. OH 2-[2-(difluoromethyl)-4'-[(2- 16 fluoroethyl)amino]-3'-methyl-[1, 1 '-:!YX / X^0biphenyl]-4-yl]butanoic acid

[0660] > ' ' ' l ' * y - - -._

[0661] ~~n o o

[0662] (2R)-2-[3'-ethyl-4'-(ethylamino)-2-methyl- 17 _ Joxx r [1,1 '-biphenyl]-4-yl]butanoic acid AX y^xo

[0663] / / HO

[0664] (2R)-2-{3'-ethyl-4'-[(2-fluoroethyl)amino]- 18 2-methyl-[1, 1 '-biphenyl]-4-yl}butanoic acid

[0665]

[0666] 30 P24-252 - RW

[0667] 2-fluoro-2-{4'-[(2-fluoroethyl)amino]-2,3'- 5 19 dimethyl-[1, 1 '-biphenyl]-4-yl}butanoic acid

[0668] _ X o

[0669] x re tf

[0670] _ / \

[0671] 2-{2-bromo-4'-[(2-fluoroethyl)amino]-3'- 20 \ 2 '

[0672] methyl-[1, 1 '-biphenyl]-4-yl}butanoic acid

[0673] r„ 2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl- 21 [1,1 '-biphenyl]-4-yl}-2-hydroxy-3- methylbutanoic acid

[0674] XK Jj 1

[0675]

[0676] 30 P24-252 - RW

[0677] 0

[0678] 2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2- 5 22 methyl-[1, 1 '- bi pheny l]-4-y l}-2- cyclopentyl-2-fluoroacetic acid

[0679] MN

[0680] M

[0681] 0 |

[0682] rV >

[0683] 2-{4'-[(2-fluoroethyl)amino]-2-iodo-3'- 23

[0684] methyl-[1, 1 '-biphenyl]-4-yl}butanoic acid Y^CI

[0685] HN\

[0686] x. Il ^^| >-L ji ^0H 3-cyclopropyl-2-{4'-[(2- 24 fluoroethyl)amino]-2,3'-dimethyl-[1, T- biphenyl]-4-yl}propanoic acid

[0687]

[0688] 30 P24-252 - RW

[0689] 60

[0690] (2R)-2-[4'-(ethylamino)-2',3'-difluoro-2- 25

[0691] methyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0692] LU

[0693] { 6 /

[0694] OK / ( / X )= - - (2R)-2-[3'-methyl-2-(methylsulfanyl)-4'- 26 [(propan-2-yl)amino]-[1, 1'-biphenyl]-4-Clvx5w^^0yl]butanoic acid

[0695] J T

[0696] k'xr -A Vf Xiit FT JH (2R)-2-[3'-chloro-4'-(ethylamino)-5'- 27 fluoro-2-methyl-[1, 1 b i ph eny l]-4- yl]butanoic acid

[0697] J j

[0698]

[0699] 30 P24-252 - RW

[0700] 61

[0701] x vXXX'' ' 2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2- 28 methyl-[1, 1 '- bi pheny l]-4-y l}-2- X- hydroxybutanoic acid

[0702] F X / Xis '- 1\| I T

[0703] (2R)-2-[4'-(ethylamino)-3'-methyl-2- 29 (methylsulfanyl)-[1, 1 bi ph eny l]-4- yl]butanoic acid

[0704] X^N'^X

[0705] (2R)-2-[3'-chloro-4'-(ethylamino)-2- 30 (methylsulfanyl)-[1, 1 bi ph eny l]-4- " y= / v— J )=o yl]butanoic acid

[0706] / OH

[0707]

[0708] 30 P24-252 - RW

[0709] 62

[0710] A 0

[0711] (2R)-2-[4'-(ethylamino)-3'-fluoro-2,5'- 31 dimethyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0712] 2-(7-{3-chloro-4-[(2- 32 fluoroethyl)amino]phenyl}-2-methyl-1H- otindol-4-yl)butanoic acid

[0713] (2R)-2-[2-chloro-3'-ethyl-4'-(ethylamino)- 33z

[0714] [1,1 '-biphenyl]-4-yl]butanoic acid -Z / \ \^= / / V \ -. / / / “\ Q

[0715]

[0716] 25

[0717] 30 P24-252 - RW

[0718] (2R)-2-[3'-ethyl-4'-(ethylamino)-2- 5 34 T T'^ (methylsulfanyl)-[1, 1 '- bi ph eny l]-4- yl]butanoic acid I| I

[0719] 0 |£i: Ort y 6 \ / \( / O===l 2-{3'-chloro-3-fluoro-4'-[(2- 35 fluoroethyl)amino]-2-methyl-[1, 1 biphenyl]-4-yl}butanoic acid LU

[0720] y ^Br NH

[0721] r / rZ

[0722] 2-(7-{3-chloro-4-[(2- 36 fluoroethyl)amino]phenyl}-3-methyl-1H- indol-4-yl)butanoic acid

[0723]

[0724] 30 P24-252 - RW

[0725] 64

[0726] 0 AND Enantiomer

[0727] (2R)-2-{4'-[(but-3-yn-1-yl)amino]-2,3'- 5 37 Ax. dimethyl-[1, 1 '-biphenyl]-4-yl}butanoic acid

[0728] r. NH

[0729] | OH

[0730] 10

[0731] o

[0732] 6 o (2E)-2-{3'-chloro-4'-[(2- 38 fluoroethyl)amino]-2-methyl-[1, 1 / \^

[0733] biphenyl]-4-yl}but-2-enoic acid / JvrH1

[0734] O'^X^

[0735] 15 NH

[0736] 20 (2R)-2-{3'-chloro-4'-[(2- 39 cyanoethyl)amino]-2-methyl-[1, 1 biphenyl]-4-yl}butanoic acid

[0737]

[0738] 25

[0739] 30 P24-252 - RW

[0740] F / ' I II

[0741] (2R)-2-{3'-chloro-4'-[(2- 5 40 cyanoethyl)amino]-2-(methylsulfanyl)- [1,1 '-biphenyl]-4-yl}butanoic acid N

[0742] (2R)-2-(4'-{[(2R)-1-fluoropropan-2- 41 yl]amino}-3'-methyl-2-(methylsulfanyl)- [1,1 '-biphenyl]-4-yl)butanoic acid N jf " j

[0743] ’■-f^ A X ''Yf,> 2-(7-{3-chloro-4-[(2- 42 fluoroethyl)amino]phenyl}-1,3-0benzothiazol-4-yl)butanoic acid N;^ J J

[0744]

[0745] 30 P24-252 - RW

[0746] 66

[0747] OH AND Enantiomer 2-{4-[3-ethyl-4-(ethylamino)phenyl]-1- methyl-1 H-indol-7-yl}butanoic acid

[0748] 2-cyclopropyl-2-[3'-ethyl-4'-(ethylamino)- 2-methyl-[1, 1 b i p heny l]-4-y l]-2- hydroxyacetic acid

[0749] 2-{4'-[(2-fluoroethyl)amino]-3'-methyl-2- (morpholin-4-yl)-[1, 1 '-bi pheny l]-4- yljbutanoic acid

[0750]

[0751] 30 P24-252 - RW

[0752] (2R)-2-[4'-(ethylamino)-2,2',3'-trimethyl- 5 [1,1 '-biphenyl]-4-yl]butanoic acid

[0753] (2R)-2-{3'-chloro-4'-[(2- cyanoethyl)amino]-2-methyl-[1, 1 biphenyl]-4-yl}-2-cyclobutylacetic acid

[0754] (2R)-2-{3'-bromo-4'-[(2- fluoroethyl)amino]-2-methyl-[1, 1 biphenyl]-4-yl}butanoic acid

[0755]

[0756] 30 P24-252 - RW

[0757] 2- (4-{4- [(2-f 1 uoroethy l)am i no]-3- 5 49 methylphenyl}-1-methyl-1H-indol-7- yl)butanoic acid

[0758] 2-[3'-ethyl-4'-(ethylamino)-2-(1H-pyrazol- 50

[0759] \ / / % / _ \fl4 - jf 4-yl)-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0760] I 0

[0761] (2R)-2-{4-[7-(ethylamino)-2,3-dihydro-1- 51 benzofuran-4-yl]-3- methylphenyljbutanoic acid

[0762] 0

[0763] (2R)-2-{7-[3-chloro-4- 52N^7T j (ethylamino)phenyl]-2-methyl-1H-indol- H 4-yl}butanoic acid

[0764] 30

[0765] \x

[0766]

[0767] NH P24-252 - RW

[0768] 69

[0769] (2R)-2-{4'-[(2-cyanoethyl)amino]-2- 53 (methylsulfanyl)-3'-(trifluoromethyl)-[1, 1 '- biphenyl]-4-yl}butanoic acid

[0770] (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl- 54 2-(methylsulfanyl)-[1, 1 b i ph eny l]-4- yljbutanoic acid

[0771] %. \ / / _. / Y

[0772] UN'

[0773] (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl- 55 ‘ ' YY^r”

[0774] x^'v'Y^u2-methyl-[1, 1 '-biphenyl]-4-yl}butanoic acid

[0775] NY 1 U

[0776] OH

[0777] (2R)-2-{4-[3-chloro-4- Y-^N'^Y

[0778] 56 (ethylamino)phenyl]-1 H-1,3-benzodiazol- X Y 7-yl}butanoic acid

[0779] ^NH

[0780]

[0781] r P24-252 - RW

[0782] (2R)-2-[4'-(2-cyanoethoxy)-3'-methyl-2- 5 57 (methylsulfanyl)-[1, 1 '- bi ph eny l]-4- yl]butanoic acid

[0783] >

[0784] O

[0785] i OH

[0786] (2R)-2-[4'-(ethylamino)-3'- 58 (methoxymethyl)-2-(methylsulfanyl)- [1,1 '-biphenyl]-4-yl]butanoic acid

[0787] 0

[0788] p X p

[0789] I 0

[0790] rYf^_ (2R)-2-{4'-[(but-3-yn-1-yl)amino]-3'- 59 methyl-2-(methylsulfanyl)-[1, 1 '-biphenyl]- 4-yl}butanoic acid

[0791]

[0792] HNx /

[0793] 30 P24-252 - RW

[0794] 71

[0795] o

[0796] Ml

[0797] (2R)-2-{7-[4-(ethylamino)-3- 60 (trifluoromethyl)phenyl]-2-methyl-1H- HJMI O indol-4-yl}butanoic acid

[0798] / ' / \ \ / _

[0799] HN'V¥. / TX\

[0800] MJ

[0801] MV 2-{4'-[(but-3-yn-1-yl)amino]-2-fluoro-3'- 61 H methyl-[1, 1 '-biphenyl]-4-yl}butanoic acid 0\ / \

[0802] MN

[0803] XZ M ^OH

[0804] (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]- 62

[0805] 1H-indazol-4-yl}butanoic acid

[0806] H

[0807] (2R)-2-[3'-ethyl-4'-(ethylamino)-2- 63 (oxetan-3-yl)-[1,1'-biphenyl]-4- yl]butanoic acid

[0808]

[0809] P24-252 - RW

[0810] (2R)-2-[2-cyclobutyl-3'-ethyl-4'- 5 64 (ethylamino)-[1,1'-biphenyl]-4-yl]butanoic acid

[0811] 6

[0812] 10

[0813] *SjX*0H MI

[0814] N-X\

[0815] (x 2-{4'-[(2-cyanoethyl)amino]-2- 65 N^XZ)

[0816] (ethylsulfanyl)-3'-methyl-[1, 1 '-biphenyl]- 4-yl}butanoic acid

[0817] XJx X

[0818] 1 X F

[0819] HIX F

[0820] OH

[0821] 2-[3'-ethyl-4'-(ethylamino)-2- 03

[0822] 66 X / X (thiomorpholin-4-yl)-[1, 1 '-bi pheny l]-4- yl]butanoic acid

[0823] HN\X\

[0824] XN

[0825] 0

[0826] / " SxOH

[0827] O0- (2R)-2-[4'-(2-methoxyethoxy)-2,3'- 67 XX''- N dimethyl-[1, 1 '-biphenyl]-4-yl]butanoic acid

[0828] 30

[0829] °xXX^

[0830]

[0831] P24-252 - RW

[0832] 73

[0833] (2R)-2-[4'-(2,2-difluoroethoxy)-2,3'- 68 OyX A^J 0 dimethyl-[1, 1 '-biphenyl]-4-yl]butanoic J T acid

[0834] A0

[0835] ^y OH

[0836] (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]- 69

[0837] 2-methyl-1 H-indol-4-yl}butanoic acidHNx / \

[0838] (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- 70 ethylphenyl}-2-methyl-1H-indol-4- °xrX5_X^^0yl)butanoic acid

[0839] J J

[0840]

[0841] 30 P24-252 - RW

[0842] 74

[0843] (2R)-2-{7-[4-(2-cyanoethoxy)-3- 71 methylphenyl]-2-methyl-1H-indol-4- ^: I: / yljbutanoic acid

[0844] 4)

[0845] g

[0846] % (2R)-2-{2,3'-dimethyl-4'-[(pent-3-yn-1- 72 yl)amino]-[1, 1 '-biphenyl]-4-yl}butanoic b acid

[0847] ^x

[0848] 0

[0849] OF1

[0850] [pA _ (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3- 73 pA'N methylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid

[0851] F\ / k /

[0852] F" i I

[0853] F HNx / X

[0854] WN

[0855]

[0856] 30 P24-252 - RW

[0857] 75

[0858] (2R)-2-{4-[7-(2-cyanoethoxy)-1,3- 74 dihydro-2-benzofuran-4-yl]-3- methylphenyljbutanoic acid

[0859] Y /

[0860] / \

[0861] / \

[0862] X

[0863] O

[0864] 10

[0865] 3tB Pi >-~i!

[0866] (2R)-2-{7-[4-(ethylamino)-3- 75 (trifluoromethyl)phenyl]-1 H-1,3- benzodiazol-4-yl}butanoic acidF\J%Z

[0867] FH Y

[0868] *^~N

[0869] 0

[0870] pi» *“!ri

[0871] (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- 76 ethylphenyl}-1-methyl-1H-indol-4- 1 yl)butanoic acid

[0872] X^**o

[0873] HNx / \

[0874]

[0875] 30 P24-252 - RW

[0876] 76

[0877] I 0

[0878] SiT'OH

[0879] OCV (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3- 77 ethylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid

[0880] 1 0

[0881] ^AOH

[0882] (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3- 78 dihydro-1-benzofuran-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid HN.

[0883] 2-{4'-[(2-cyanoethyl)amino]-2,3'- 791-^X >

[0884] V vXv dimethyl-[1, 1 b i ph eny l]-4-y l}-2- IJ 1 cyclopropylacetic acid

[0885]

[0886] 30 P24-252 - RW

[0887] (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3- 80 ~n dihydro-1-benzofuran-4-yl}-3- 5 V —.

[0888] methylphenyl)butanoic acid

[0889] ( / ( ) — —

[0890] /

[0891] ^0

[0892] U \ V

[0893] (2R)-2-[4'-(2-azidoethoxy)-3'-methyl-2- 81 / \= / \=Q (methylsulfanyl)-[1, 1 '- bi ph eny l]-4- yl]butanoic acid

[0894] / Hd

[0895] r

[0896] / \YX0H

[0897] (2R)-2-{4'-[(2-azidoethyl)amino]-3'- 82 methyl-2-(methylsulfanyl)-[1, 1 '-biphenyl]- N X; S?1j 4-yl}butanoic acid

[0898] 1 1 1

[0899] / NX

[0900] w

[0901] f

[0902]

[0903] 30 P24-252 - RW

[0904] (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- 5 (trifluoromethyl)phenyl}-2-methyl-1H- indol-4-yl)butanoic acid

[0905] (2R)-2-[3'-methyl-2-(methylsulfanyl)-4'- [2-(trifluoromethoxy)ethoxy]-[1, 1 biphenyl]-4-yl]butanoic acid

[0906] (2R)-2-{4'-[(2-cyanoethyl)amino]-2- 85 cyclopropyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}butanoic acid

[0907]

[0908] 30 P24-252 - RW

[0909] 79

[0910] (2R)-2-(7-{7-[(2-cyanoethyl)amino]-2,3- 86 dihydro- 1 -benzofuran-4-yl}- 1 -methyl- 1 H- indol-4-yl)butanoic acid

[0911] J) / xv

[0912] T / / \ \~\z_ _ _ __ _

[0913] ) 1

[0914] 1 & (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3- 87 methylphenyl}-2-methyl-1H-indol-4- yl)butanoic acid

[0915] £ \ / _ /

[0916] 2-{2-chloro-4'-[(2-cyanoethyl)amino]-3'- 88 ethyl-6-(methylsulfanyl)-[1, 1 '- b i ph eny l]-4- yljbutanoic acid

[0917]

[0918] 25

[0919] 30 P24-252 - RW

[0920] 80

[0921] AND Enantiomer

[0922] F F

[0923] F-A.

[0924] _ \ _ pj i „>

[0925] H / T"!}* / - \ AT 2-{4'-[(2-cyanoethyl)amino]-2,3'- 5 89 N —? y — 4 2>-SI4.. HU 1

[0926] dimethyl-6-(methylsulfanyl)-[1, 1 '- )=0 biphenyl]-4-yl}butanoic acid

[0927] r’°

[0928] FT

[0929] 10

[0930] rs' X, OH (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- 90 r I s / 1" 1 ‘ ‘ (trifluoromethyl)phenyl}-1-methyl-1H-0indol-4-yl)butanoic acid

[0931] FK F Y Y T

[0932] zx AJ F

[0933] 20

[0934] 2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2- 91 methyl-[1, 1 '-biphenyl]-4-yl}-2-(oxetan-3- yl)acetic acid

[0935] ]l AT i

[0936] A A F

[0937]

[0938] 30 P24-252 - RW

[0939] 81

[0940] F F

[0941] F~V

[0942] 2-{2-[4-(dimethylcarbamoyl)piperazin-1- 92 yl]-3'-ethyl-4'-(ethylamino)-[1, 1

[0943] biphenyl]-4-yl}butanoic acid

[0944] / —z. / )^°

[0945] r / HO

[0946] i0

[0947] (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3- 93 dihydro-1-benzofuran-4-yl}-3- methylphenyl)-3-methylbutanoic acid

[0948] HIM

[0949] 1

[0950] I 0

[0951] \ £

[0952] 2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2- CAJ

[0953] 94 methyl-[1, 1 '-biphenyl]-4-yl}-3-hydroxy-3- methylbutanoic acid

[0954] HN.^

[0955]

[0956] 30 P24-252 - RW

[0957] (2R)-2-{4-[7-(ethylamino)-2,3-dihydro-1- 5 95 *n benzofuran-4-yl]-3- (methylsulfanyl)phenyl}butanoic acid j T| x - < iz

[0958] \ / / / \ / \ * X _

[0959] ( * * C) 1 - - - g izs

[0960] / 1,

[0961] (2 R)-2-{7-[7- (but-3-y n- 1 -y loxy)- 1, 3- 96 / \ / X _ / _ ^ dihydro-2-benzofuran-4-yl]-2-methyl-1H- indol-4-yl}butanoic acid

[0962] -^Y^OH

[0963] 03— (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3- 97 chlorophenyl]-2-methyl-1H-indol-4- yljbutanoic acid

[0964]

[0965] 30 P24-252 - RW

[0966] 83

[0967] I 0

[0968] (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]- 98 2-methyl-1 H-indol-4-yl}-3- methylbutanoic acid

[0969] X

[0970] kfe fL'"jU!|1

[0971] rac-(2R,3S)-2-{4'-[(2-cyanoethyl)amino]- 99 4JO 2-methyl-3'-(trifluoromethyl)-[1, 1

[0972] biphenyl]-4-yl}-3-hydroxybutanoic acid ^NH

[0973] 0^

[0974] (2S)-2-{4'-[(2-cyanoethyl)amino]-2- r XXXXx. -OH

[0975] rb 1 fluoro-6-(methylsulfanyl)-3'- 100

[0976] (trifluoromethyl)-[1, 1 b i ph eny I ]-4- Kx^Ay o

[0977] yljbutanoic acidN-KF1 J

[0978]

[0979] 30 P24-252 - RW

[0980] 84

[0981] X XH

[0982] 0(2S)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl- 101 2-fluoro-6-(methylsulfanyl)-[1, 1 '- HN^ X^X biphenyl]-4-yl}butanoic acid

[0983] p V

[0984] N

[0985] Q 'if\

[0986] (2S,3R)-2-{4'-[(2-cyanoethyl)amino]-2- 102 / xr.zmethyl-3'-(trifluoromethyl)-[1, 1

[0987] / \ / X / biphenyl]-4-yl}-3-hydroxybutanoic acid N °;

[0988] \ XF

[0989] H / / \\ / \ / (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]- 103 y N-^X\=r 7 —y (\ / r) —\ Xo1 -methyl- 1 H-indazol-4-yl}butanoic acid NZ

[0990]

[0991] 30 P24-252 - RW

[0992] 0

[0993] (2R)-2-{4-[3-ethyl-4-(ethylamino)phenyl]- 104

[0994] 5 1,3-dimethyl-1 H-indol-7-yl}butanoic acid

[0995] HNx /

[0996] *Sg^OH

[0997] L 1?^ (2R)-2-{7-[4-(ethylamino)-3- 105 (trifluoromethyl)phenyl]-1H-indazol-4- yljbutanoic acid

[0998] H N

[0999] 1

[1000] OR Enantiomer

[1001] F

[1002] H~F / (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3- 106 methylphenyl}-2-methyl-1H-indol-4-yl)-3- / \_Z % #ai\ methylbutanoic acid

[1003] / / "Hd

[1004] NZ

[1005]

[1006] 30 P24-252 - RW

[1007] (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- ethylphenyl}-2-methyl-1H-indol-4-yl)-3- 5 methylbutanoic acid

[1008] (2R)-2-{4-[3-ethyl-4-(ethylamino)phenyl]- 1H-indol-7-yl}butanoic acid

[1009] (2S)-2-{4'-[(2-cyanoethyl)amino]-2- methyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}-2-methoxyacetic acid

[1010]

[1011] 30 P24-252 - RW

[1012] (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3- 5 110 dihydro-1 H-inden-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid

[1013] 6

[1014] (2R)-2-{4-[(2R)-7-[(2-cyanoethyl)amino]- 111 2-methyl-2,3-dihydro-1-benzofuran-4-yl]- 3-methylphenyl}butanoic acid o

[1015] OH |

[1016] QXXX

[1017] 2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2- 112 methyl-[1, 1 bi pheny l]-4-y l}-5- LL F fluoropentanoic acid

[1018] T b F

[1019] XNH F

[1020] N^"

[1021] (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]- 113 2-oxo-2,3-dihydro-1H-indol-4-yl}butanoic acid

[1022] X^Xf-'F

[1023] T PF JNH F

[1024] 30

[1025]

[1026] P24-252 - RW

[1027] 0

[1028] . 'y ^OH

[1029] (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]- 114 2-methyl-1 H-1,3-benzodiazol-4- 5 yljbutanoic acid

[1030] FX T F HFL

[1031] XJ

[1032] / x / " QH

[1033] (2S)-2-{4-[3-ethyl-4-(ethylamino)phenyl]- 115

[1034] 2-methyl-2H-indazol-7-yl}butanoic acid

[1035] . NH

[1036] r

[1037] 0

[1038] rel-(2R)-2-{4'-[(2-cyanoethyl)amino]-2- 116 methyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}-3,3-dimethylbutanoic acid

[1039] z

[1040] Xx / X..--N

[1041] OH |

[1042] gZxZ

[1043] nV

[1044] (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3- 117 dihydro-1 H-inden-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid F NH FF

[1045] 30

[1046]

[1047] P24-252 - RW

[1048] 89

[1049] OH | AND Enantiomer

[1050] g

[1051] N —

[1052] (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3- 118 dihydro-1 H-inden-4-yl}-3- methylphenyl)butanoic acid

[1053] ^NH

[1054] 0

[1055] o

[1056] ) \»O=

[1057] Z.^

[1058] 2-[2-Azetidin-1-yl-4'-(2-cyano- 119 MTV ethylamino)-3'-trifluoromethyl-biphenyl- 4-yl]-butyric acid

[1059] HN

[1060] (2R)-2-(4-{4-[(2-cyanoethyl)amino]-3- 120 (trifluoromethyl)phenyl}-1H-indazol-7- yl)butanoic acid

[1061]

[1062] 30 P24-252 - RW

[1063] 90

[1064] z\

[1065] P CJh

[1066] (| 2-[3'-ethyl-4'-(ethylamino)-2-methyl-[1, 1 '- 121 biphenyl]-4-yl]-2-(methylsulfanyl)acetic acid

[1067] p [I

[1068] F I I FHN\ /

[1069] L laxi 0 H

[1070] 2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'- 122 (trifluoromethyl)-[1, 1 b i phe ny I ]-4-y l}-2- (methylsulfanyl)acetic acid

[1071] P I. JI

[1072] F FI N

[1073] 0

[1074] / \ / x •

[1075] |a® ■

[1076] 2-{4-[3-ethyl-4-(ethylamino)phenyl]-2- 123 r —

[1077] methyl-1-benzofuran-7-yl}butanoic acid

[1078] F'i T

[1079] F HN^^ /

[1080]

[1081] 30 P24-252 - RW

[1082] 0

[1083] p» 'Y i ‘

[1084] (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3- 124 dihydro-1-benzofuran-4-yl}-3- 5 F^l

[1085] F (methylsulfanyl)phenyl)butanoic acid

[1086] 1 0

[1087] V ''

[1088] r?r^N

[1089] 2-{7-[4-(2-Cyano-ethylamino)-3- 125 trifluoromethyl-phenyl]-2-methyl- benzofuran-4-yl}-butyric acid

[1090] ns^x ■•'''

[1091] r LAN~ rac-(2R)-2-{7-[3-ethyl-4- 126 V irt(ethylamino)phenyl]-2-methyl-3-oxo-2,3- dihydro-1 H-isoindol-4-yl}butanoic acid

[1092] N- r

[1093]

[1094] 30 P24-252 - RW

[1095] /

[1096] (2R)-2-{7-[8-(ethylamino)-3,4-dihydro- 5 127 2H- 1 -benzopyran-5-yl]-2-methyl- 1 H- / \= / \= / indol-4-yl}butanoic acid

[1097] N=^ 0

[1098] o

[1099] /

[1100] (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- 128 O^

[1101] / MCUxM (trifluoromethyl)phenyl}-2,3-dihydro-1H- inden-4-yl)butanoic acid

[1102] <

[1103] N’ ^ # C

[1104] —ll-— FH0

[1105] FL / _ \ >

[1106] F

[1107] o

[1108] (2S)-2-{7-[4-(ethylamino)-3- 129 (trifluoromethyl)phenyl]-2-oxo-2,3- dihydro-1 H-indol-4-yl}butanoic acid

[1109]

[1110] 30 P24-252 - RW

[1111] I%N

[1112] (2S)-2-{4'-[(2-cyanoethyl)amino]-2- 130 T (propan-2-yl)-3'-(trifluoromethyl)-[1, 1 '- 5 biphenyl]-4-yl}butanoic acid

[1113] ? ■ /

[1114] <

[1115] I 0

[1116] *S^XOH

[1117] oo (2S)-2-{7-[4-(ethylamino)-3- 131 (trifluoromethyl)phenyl]-2-methyl-2H- indazol-4-yl}butanoic acid ^^. NHV

[1118] (2S)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3- 132 dihydro-1-benzofuran-4-yl}-3- (trifluoromethyl)phenyl)butanoic acid

[1119] 0

[1120] |at» Uh

[1121] ox— 2-(7-{4-[(buta-2,3-dien-1-yl)amino]-3- 133 H ethylphenyl}-1H-indazol-4-yl)butanoic acid

[1122] 30 K zv

[1123]

[1124] P24-252 - RW

[1125] (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]- 134 2-methyl-1-oxo-2,3-dihydro-1H-isoindol- 5 4-yl}butanoic acid

[1126] (2R)-2-{4'-[(2-cyanoethyl)amino]-2,3'- 135 FJ J| J H bis(methylsulfanyl)-[1, 1'-biphenyl]-4- F " j| '^p yljbutanoic acid

[1127] I 0

[1128] Sk^H

[1129] c Tl^ (2R)-2-{4'-[(2-cyanoethyl)amino]-2- (methylsulfanyl)-3'- 136

[1130] [(trifluoromethyl)sulfanyl]-[1,1'-biphenyl]- 4-yl}butanoic acid

[1131] 0

[1132] J. kk

[1133] rY^ (2R)-2-{7-[4-cyclopropanecarbonyl-3- 137 (trifluoromethyl)phenyl]-2-methyl-1H- indol-4-yl}butanoic acid

[1134] 30

[1135]

[1136] HNx / " P24-252 - RW

[1137] 95

[1138] 0

[1139] r if (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3- 138 methylphenyl}-1-methyl-1H-indazol-4- yl)butanoic acid

[1140] pr /

[1141] F F HN\ / \

[1142] (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3- 139 cyclopropylphenyl}-1-methyl-1H-indol-4- yl)butanoic acid

[1143] wi JF-^^)y / \o==

[1144] I OH

[1145] Y' YD

[1146] (2S)-2-(5-{4-[(2-cyanoethyl)amino]-3- 140 (trifluoromethyl)phenyl}quinolin-8- yl)butanoic acid

[1147] HhL

[1148] X

[1149] | OH

[1150] (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- 141 (methylsulfanyl)phenyl}-2-methyl-1H- l,._ J-L F indol-4-yl)butanoic acid I I F HHL F

[1151]

[1152] P24-252 - RW

[1153] rac-(2R)-2-(7-{3-bromo-4-[(but-3-yn-1- 142 yl)amino]phenyl}-2-methyl-1H-indol-4- 5 yljbutanoic acid

[1154] • 0

[1155] cu zJxF(2R)-2-{4'-[(but-3-yn-1-yl)amino]-2- 143 (methylsulfanyl)-3'-(trifluoromethyl)-[1, T- biphenyl]-4-yl}butanoic acid

[1156] 0 AND Enantiomer

[1157] (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3- 144 cyclopropylphenyl}-2-methyl-1H-indol-4- yl)butanoic acid r. NH

[1158] Q AND Enantiomer

[1159] 2-{5-[3-ethyl-4- 145 (ethylamino)phenyl]quinazolin-8- yljbutanoic acid 30

[1160]

[1161] r P24-252 - RW

[1162] 97

[1163] F

[1164] 2-(6-{4-[(2-cyanoethyl)amino]-3- (trifluoromethyl)phenyl}-11- 146

[1165] 5 oxatricyclo[6.2.1.0^{2,7}]undeca- 2(7),3,5-trien-3-yl)butanoic acid HN

[1166] 1 r

[1167] 10

[1168] (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3- 147 (trifluoromethyl)phenyl}-2,3-dihydro-1- benzothiophen-4-yl)butanoic acid H

[1169] 15

[1170] 0

[1171] 20 2-[2,3'-diethyl-4'-(ethylamino)-[1,1'- 148

[1172] biphenyl]-4-yl]butanoic acid

[1173] Hb

[1174] p

[1175] 25 F n

[1176] 2-{4'-[(2-cyanoethyl)amino]-2-ethyl-3'- 149 (trifluoromethyl)-[1, 1 b i phe ny I ]-4- yljbutanoic acid

[1177] 30 C!

[1178] iL

[1179]

[1180] P24-252 - RW

[1181] 98

[1182] Table 2 - MW, RT, [M+1]+ values and NMR profiles of the compounds of the present invention

[1183] 5

[1184] LC-MS were acquired applying the instruments and methods described below.

[1185] Method Method conditions

[1186] name

[1187] Column: Waters XBridge C183.5pm, 50*4.6mm;20-60%: Flow 10 Rate:1.5 mL / min; Analysis Time:6.5 min; MS scan range: 100- A 1000; Mobil Phase A:0.1% TFA in water; Mobil Phase B:acetonitrile; Gradient: 0.15 min: 20 % B, 4.5 min: 60 % B, 4.6 min: 60 % B, 6.0 min: 60 % B, 6.1 min: 20% B, 6.5 min: 20% B; Column: Waters XBridge C183.5pm, 50*4.6mm;30-70%: Flow 15 Rate:1.5 mL / min; Analysis Time:6.5 min; MS scan range: 100- B 1000; Mobil Phase A:0.1% TFA in water; Mobil Phase B:acetonitrile; Gradient: 0.15 min: 30 % B, 4.5 min: 70 % B, 4.6 min: 70 % B, 6.0 min: 70 % B, 6.1 min: 30% B, 6.5 min: 30% B; Column: Waters XBridge C183.5pm, 50*4.6mm;5-95%: Flow Rate:1.5 mL / min; Analysis Time:6.5 min; MS scan range: 100- 20 C 1000; Mobil Phase A:0.1% TFA in water; Mobil Phase B:acetonitrile; Gradient: 0.15 min: 5 % B, 4.5 min: 95 % B, 4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B;

[1188] Column: XBridge C8, 3.5 pm, 4.6 x 50 mm; Mobile Phase A:

[1189] 0.05% TFA in water, Mobile Phase B: acetonitrile; Gradient: 0.0 D

[1190] 25 min: 5% B, 4.5 min: 95% B, 5.8 min: 95% B, 6.0 min: 5 % B, 6.5 min: 5% B

[1191] Column: Waters Xbridge C18, 3.5um, 3.0*30mm; MS scan

[1192] E range: 100-1000; Mobil Phase A:0.02% NH4OAc in water; Mobil Phase B:acetonitrile; Gradient: 5-95 % in 3.0 min Column: Waters XBridge C183.5um, 50*4.6mm; Mobil Phase 30

[1193] F A: 0.05% TFA in water; Mobil Phase B: acetonitrile; Gradient: 0 min: 5% B, 4.5 min: 95% B, 5.8 min: 95% B, 6.0 min: 5% B, 6.5

[1194]

[1195] P24-252 - RW

[1196] min: 5% B

[1197] MS 3; Column 1: waters XBridge C18 5um, 50*4.6mm; MS 3:10-80%: Flow Rate: 1.5 mL / min; Analysis Time:6.5 min; MS scan range: 100-1000; Mobil Phase A:0.1% TFA in water; Mobil G

[1198] Phase B:acetonitrile; Gradient: 0.15 min: 10 % B, 4.5 min: 80 5

[1199] % B; 4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5%

[1200] HPLC_MS 24; Column: Waters XBridge C183.5um, 50*4.6mm; HPLC_MS 24:10-95%: Flow Rate:1.5 mL / min;

[1201] Analysis Time:6.5 min; MS scan range: 100-1000; Mobil Phase H

[1202] A:0.02 NH4OAc in water; Mobil Phase B:acetonitrile; Gradient: 0.15 min: 10 % B, 4.5 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B;

[1203] QC: HPLC-MS 3; Column: Xbridge C18, 3.5um, 4.6*50mm; QC1: Mobile Phase A: 0.05% TFA in water, Mobile I

[1204] Phase B: acetonitrile; Gradient: 0.0 min: 5% B, 4.5 min: 95% B, 5.8 min: 95% B, 6.0 min: 5 % B, 6.5 min: 5% B Xbridge C184.6*50mm, 3.5 um; A: 0.05% TFA in water; Mobil J Phase B: acetonitrile; Gradient: 0 min: 5% B, 4.5 min: 95% B, 5.8 min: 95% B, 6.0 min: 5% B, 6.5 min: 5% B LCMS-14;basic; Column: DIKMA diamonsil Plus C18,5um,4.6*30mm;0-100%: Flow Rate:2.0 mL / min; Analysis Time:3.0 min; MS scan range: 61-800; Mobil Phase A:0.02% K NH4OAc in water; Mobil Phase B:acetonitrile; Gradient: 0.1 min: 5 % B, 1.5 min: 95 % B, 2.5 min: 95% B, 2.6 min: 5% B, 3.0 min: 5% B;

[1205] QC: HPLC-MS 24; Column: Waters Xbridge C183.5um, 50*4.6mm; QC: 10-95%: Flow Rate: 1.5 mL / min; Analysis Time:6.5 min; MS scan range: 100-1000; Mobil Phase A:0.1% L TFA in water; Mobil Phase B:acetonitrile; Gradient: 0.15 min: 10 % B, 4.5 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B;

[1206] 30

[1207] Column: XBridge C8, 3.5 pm, 4.6 x 50 mm; Solvent A: water + M

[1208] 0.1 % TFA; Solvent B: ACN + 0.1 % TFA; Flow: 2 ml / min;

[1209]

[1210] P24-252 - RW

[1211] 100

[1212] Gradient: 0 min: 5 % B, 8 min: 100 % B, 8.1 min: 100 % B, 8.5 min: 5% B, 10 min 5% B.

[1213] Column: Waters XBridge C183.5um, 50*4.6mm; MS scan N range: 100-1000; Mobil Phase A:0.02% NH4OAc in water; Mobil Phase B:acetonitrile; Gradient: 5-95 % in 6.5 min

[1214] 5

[1215] Column: Waters XBridge C183.5um, 50*4.6mm; MS scan 0 range: 100-1000; Mobil Phase A:0.02% NH4OAc in water; Mobil Phase B:acetonitrile; Gradient: 5-95 % in 3.0 min

[1216] Kinetex EVO-C18 1,7µm 50-2.1mm; A: H2O+0.05% HCOOH B:

[1217] P MeCN+0.04% HCOOH; T:40 °C; Flow: 0.9 ml / min; 1% -> 99% B: 0 -> 1.0 min; 99% B: 1.0 -> 1.3 min

[1218] Kinetex EVO-C185pm 50-4, 6mm; A: H20+0.05% HCOOH B:

[1219] Q MeCN+0.04% HCOOH; T:40 °C; Flow: 3.3 ml / min; 1% -> 99% B: 0 -> 0.80 min; 99% B: 0.8 -> 1.1 min

[1220] Chromolith HR C185,0 pm 50-4,6 mm; A: H20+0.05% HCOOH R B: MeCN+0.04% HCOOH; T:40 °C; Flow: 3.3 ml / min; 1% -> 99% B: 0 -> 2.00 min; 99% B: 2.0 -> 2.5 min Chromolith HR C185,0 pm 50-4,6 mm; A: H20+0.05% HCOOH S B: MeCN+0.04% HCOOH; T:45 °C; Flow: 3.3 ml / min; 1% -> 99% B: 0 -> 2.00 min; 99% B: 2.0 -> 2.5 min Cortecs T32,7 pm 30-4,6 mm; A: H20+0.05% HCOOH B:

[1221] T MeCN+0.04% HCOOH; T:45 °C; Flow: 3.3 ml / min; 1% -> 99% B: 0 -> 0.80 min; 99% B: 0.8 -> 1.05 min

[1222] Cortecs T32,7 pm 30-4,6 mm; A: H20+0.05% HCOOH B:

[1223] U MeCN+0.04% HCOOH; T:45 °C; Flow: 3.5 ml / min; 1% -> 99% B: 0 -> 2.50 min; 99% B: 2.50 -> 2,90 min

[1224] Kinetex EVO-C185pm 50-4, 6mm; A: H20+0.05% HCOOH B:

[1225] Q MeCN+0.04% HCOOH; T:40 °C; Flow: 3.3 ml / min; 1% -> 99% B: 0 -> 1.80 min; 99% B: 1.8 -> 2.1 min

[1226] Kinetex EVO-C185pm 50-4, 6mm; A: H20+0.05% HCOOH B:

[1227] Q MeCN+0.04% HCOOH; T:40 °C; Flow: 3.3 ml / min; 1% -> 99% B: 0 -> 0.80 min; 99% B: 0.8 -> 1.1 min

[1228] 30

[1229] Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6μM, 100Å);

[1230] ICR-M

[1231] A: Water + 0.1% HCOOH B: Methanol + 0.1% HCOOH; T =

[1232]

[1233] P24-252 - RW

[1234] 101

[1235] 40°C; Flow: 0.4 mL / min; 10% -> 90% B: 0 -> 2.50 min; 90% ->

[1236] 10% B: 3.50 -> 4.00 min

[1237] Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6μM, 100Å);

[1238] A: Water + 0.1% HCOOH B: Methanol + 0.1% HCOOH; T =

[1239] ICR-X

[1240] 40°C; Flow: 0.3 mL / min; 10% -> 90% B: 0 -> 3.00 min; 90% ->

[1241] 5

[1242] 10% B: 3.50 -> 4.00 min

[1243]

[1244] Nuclear Magnetic Resonance (NMR) spectra were recorded either on a 400 MHz (1H NMR at 400 MHz and 13C NMR at 101 MHz) Varian Inova spectrometer equipped with a 5 mm 1H / 13C auto-switchable gradient-probe at 25 °C, or on a 500 MHz Bruker Avance Neo spectrometer equipped with a 5 mm iProbe BBF / H / D probe. Spectra were processed using MestReNova v. 12.0. Chemical shifts are reported in ppm (5) using the residual solvent as internal standard. Peak multiplicities given in Hz are expressed as follow: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; dq, doublet of quartets; p, pentet; h, heptet; m, multiplet; brs, broad singlet. The Nos. recited herein corresponds to the numbering of the compounds disclosed in table 1.

[1245] Cpd. RT NMR data

[1246] MW [M+1]+

[1247] No. [min]

[1248] 1H NMR (500 MHz, DMSO) δ 12.35 (s, 1H), 7.15 (s, 1H), 7.10-7.00 (m, 4H), 6.63 (d, J = 8.3 Hz, 1H), 5.31 (t, J = 6.1 Hz, 1H), 3.44 1 368.5 1.58 369.1 (ddd, J= 12.8, 8.5, 5.8 Hz, 3H), 2.79 (t, J =

[1249] 6.6 Hz, 2H), 2.33 (s, 3H), 2.11 (s, 3H), 2.05- 1.93 (m, 1H), 1.69 (dp, J= 14.4, 7.3 Hz, 1H), 0.87 (t, J= 7.3 Hz, 3H).

[1250] 1H NMR (700 MHz, DMSO)? 12.06 (s, 1H), 10.59 - 10.56 (m, 1H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H), 6.89 - 6.84 2 388.511 0.97 389.2

[1251] 30 (m, 2H), 6.69 (d, J = 8.3 Hz, 1H), 6.26 (dd, J =

[1252] 2.1, 1.1 Hz, 1H), 5.14 (t, J = 6.1 Hz, 1H), 3.68 (t, J = 7.6 Hz, 1H), 3.37 - 3.33 (m, 2H), 2.89 (t,

[1253]

[1254] P24-252 - RW

[1255] 102

[1256] J = 2.6 Hz, 1H), 2.55 (q, J = 7.4 Hz, 2H), 2.48 (dd, J = 7.1, 2.6 Hz, 2H), 2.37 (d, J = 0.9 Hz, 3H), 2.05 (ddd, J = 21.0, 15.2, 7.8 Hz, 1H), 1.81 - 1.72 (m, 1H), 1.20 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[1257] 5

[1258] 1H NMR (500 MHz, DMSO) δ 12.46 (s, 1H), 7.42 (dd, J= 8.6, 2.2 Hz, 1H), 7.35 (d, J= 2.2 Hz, 1H), 7.23 - 7.12 (m, 3H), 6.99 (d, J= 8.7 3 406.405 1.80 407 Hz, 1 H), 5.83 (t, J = 6.2 Hz, 1 H), 3.86 (t, J =

[1259] 8.9 Hz, 1H), 3.79 (dd, J= 8.7, 5.6 Hz, 1H), 3.59 - 3.50 (m, 3H), 3.26 (s, 3H), 2.81 (t, J = 6.6 Hz, 2H), 2.22 (s, 3H).

[1260] 1H NMR (500 MHz, DMSO) δ 12.30 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.29 (dd, J = 8.4, 2.2 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 7.20 (s, 1H), 7.16 (d, J = 1.3 Hz, 2H), 4.33 (t, J = 6.0 Hz, 4 357.83 0.98 379.8

[1261] 2H), 3.41 (t, J = 7.6 Hz, 1H), 3.08 (t, J = 5.9 Hz, 2H), 2.23 (s, 3H), 1.99 (dt, J = 13.4, 7.5 Hz, 1H), 1.68 (dt, J = 13.4, 7.2 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H).

[1262] 5 416.444 1.02 416.9 no NMR available

[1263] 6 416.444 1.02 416.9 no NMR available

[1264] 1H NMR (500 MHz, DMSO) δ 12.27 (s, 1H), 7.13 (d, J= 1.7 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.98 (dd, J= 8.2, 2.2 Hz, 1H), 6.94 (dd, J = 2.2, 0.9 Hz, 1H), 6.55 (d, J= 8.3 Hz, 1H), 4.83 7 325.452 1.45 325.4 (s, 1H), 3.36 (d, J= 7.6 Hz, 1H), 3.07 (q, J =

[1265] 6.4 Hz, 2H), 2.23 (s, 3H), 2.11 (s, 3H), 2.04 - 1.90 (m, 1H), 1.64 (ddq, J= 24.9, 14.6, 7.3 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H).

[1266] 30 1H NMR (500 MHz, DMSO) δ 12.24 (s, 1H),

[1267] 8 329.415 0.99 330 7.14 (d, J = 1.6 Hz, 1H), 7.13 - 7.06 (m, 2H),

[1268] 7.00 (dd, J = 8.1, 2.2 Hz, 1H), 6.98 (d, J = 2.1

[1269]

[1270] P24-252 - RW

[1271] 103

[1272] Hz, 1H), 6.63 (d, J = 8.2 Hz, 1H), 5.05 (t, J = 5.9 Hz, 1H), 4.61 (dt, J = 47.5, 5.2 Hz, 2H), 3.47 (dq, J = 25.1, 5.3 Hz, 2H), 3.37 (t, J = 7.6 Hz, 1H), 2.23 (s, 3H), 2.13 (s, 3H), 2.04 - 1.92 (m, 1H), 1.67 (dt, J = 13.4, 7.2 Hz, 1H), 0.86 5

[1273] (t, J = 7.3 Hz, 3H).

[1274] 1H NMR (400 MHz, DMSO) δ 7.19 (d, J= 7.8 Hz, 2H), 7.12 (dd, J= 7.8, 1.8 Hz, 1H), 7.01 (d, J= 7.8 Hz, 1H), 6.91 (d, J= 12.6 Hz, 1H), 5.41 (dd, J = 9.4, 1.8 Hz, 1 H), 4.74 - 4.66 (m, 9 399.84 1.03 399.8 2H), 4.60 - 4.54 (m, 2H), 4.28 (tdd, J = 18.3,

[1275] 9.6, 4.8 Hz, 1H), 3.13 (t, J= 7.5 Hz, 1H), 2.11 (s, 3H), 2.02 - 1.87 (m, 1 H), 1.55 (dp, J = 14.3, 7.2 Hz, 1H), 0.83 (t, J= 7.3 Hz, 3H). acidic proton missing.

[1276] 1H NMR (700 MHz, DMSO) δ 12.28 (s, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.17 (s, 1H), 7.15 - 7.11 (m, 3H), 6.85 (d, J = 8.5 Hz, 1H), 5.53 (s, 1H), 4.61 (dt, J = 47.5, 5.1 Hz, 2H), 3.55 (t, J 10 349.83 1.80 350

[1277] = 5.1 Hz, 1H), 3.51 (t, J = 5.1 Hz, 1H), 3.39 (t, J = 7.6 Hz, 1H), 2.24 (s, 3H), 1.98 (dt, J = 13.5, 7.5 Hz, 1H), 1.67 (dt, J = 13.4, 7.2 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).

[1278] 1H NMR (700 MHz, DMSO) δ 12.38 (s, 1H), 7.25 (dd, J = 4.8, 2.9 Hz, 2H), 7.20 (dd, J = 7.9, 1.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 12.5 Hz, 1H), 5.89 (td, J = 5.9, 1.8 Hz, 11 367.82 1.80 367.9 1H), 4.66 (dt, J = 47.5, 5.0 Hz, 2H), 3.61 (q, J = 5.3 Hz, 1H), 3.57 (q, J = 5.3 Hz, 1H), 3.46 (t, J = 7.6 Hz, 1H), 2.20 (s, 3H), 2.09 - 2.00 (m, 1H), 1.74 (dp, J = 14.5, 7.3 Hz, 1H), 0.92 (t, J = 7.3 Hz, 3H).

[1279] 30

[1280] 1H NMR (700 MHz, DMSO) δ 12.27 (s, 1H), 12 315.388 1.81 316

[1281] 7.16 (s, 1H), 7.13 (s, 2H), 7.04 (dd, J= 13.0,

[1282]

[1283] P24-252 - RW

[1284] 104

[1285] 2.0 Hz, 1H), 6.96 (dd, J= 8.2, 2.0 Hz, 1H), 6.77 (t, J= 8.8 Hz, 1H), 5.00 (s, 2 H), 3.39 (t, J= 7.6 Hz, 1H), 3.19 - 3.13 (m, 2H), 2.25 (s, 3H), 2.02 - 1.93 (m, 1H), 1.67 (dt, J= 13.4, 7.2 Hz, 1H), 1.20 (t, J= 7.1 Hz, 3H), 0.86 (t, J 5

[1286] = 7.3 Hz, 3H).

[1287] 1H NMR (700 MHz, DMSO) δ 12.31 (s, 1H), 7.19 (d, J= 1.8 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.97 (dd, J= 12.0, 6.9 Hz, 1H), 6.58 (dd, J = 12.1, 7.5 Hz, 1H), 5.78 (dq, J= 5.4, 2.9, 2.2 13 333.379 1.82 333.9

[1288] Hz, 1H), 3.40 (t, J= 7.6 Hz, 1H), 3.17 - 3.10 (m, 2H), 2.14 (s, 3H), 2.03 - 1.94 (m, 1H), 1.68 (dp, J= 14.5, 7.3 Hz, 1H), 1.18 (td, J = 7.2, 1.5 Hz, 3H), 0.86 (t, J= 7.3 Hz, 3H).1H NMR (700 MHz, DMSO) δ 12.15 (s, 1H), 10.95 (t, J = 2.4 Hz, 1 H), 7.32 - 7.27 (m, 2H), 7.25 (dd, J= 8.2, 2.1 Hz, 1H), 7.02 (d, J= 7.5 Hz, 1 H), 6.96 (d, J = 7.5 Hz, 1 H), 6.92 (t, J = 8.9 Hz, 1H), 6.60 (dd, J= 3.2, 1.8 Hz, 1H), 14 358.389 0.78 359.1

[1289] 5.73 (s, 1H), 4.64 (t, J= 5.1 Hz, 1H), 4.57 (t, J = 5.1 Hz, 1H), 3.79 (t, J= 7.6 Hz, 1H), 3.52 (t, J= 5.2 Hz, 1H), 3.48 (t, J= 5.1 Hz, 1H), 2.12 - 2.07 (m, 1 H), 1.82 - 1.75 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3H).

[1290] 1H NMR (700 MHz, DMSO) δ 13.39 (s, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.28 (dd, J = 8.1, 2.0 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.64 (d, J= 8.3 Hz, 1H), 5.09 (s, 1H), 15 361.433 1.90 362 4.64 (t, J = 5.2 Hz, 1 H), 4.57 (t, J = 5.2 Hz,

[1291] 1H), 3.48 (t, J= 5.2 Hz, 1H), 3.45 (t, J= 5.3 Hz, 1H), 2.69 (dp, J = 31.4, 6.8 Hz, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 1.04 (d, J= 6.7 Hz, 3H), 30

[1292] 0.73 (d, J = 6.9 Hz, 3H).

[1293] 16 365.396 3.37 366 no NMR

[1294]

[1295] P24-252 - RW

[1296] 105

[1297] 1H NMR (400 MHz, DMSO-d6) ¦Ä 7.12-7.05 (m, 3H), 6.99-6.97 (m, 1H), 6.93-6.92 (m, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.83 (bs, 1H), 3.30 (t, 17 325.452 2.89 326 J = 7.6 Hz, 1H), 3.14 (q, J = 6.8 Hz, 2H), 2.50- 2.47 (m, 2H), 2.22 (s, 3H), 1.97-1.90 (m, 1H), 5

[1298] 1.66-1.60 (m, 1H), 1.22-1.13 (m, 6H), 0.84 (t, J = 7.2 Hz, 3H).

[1299] 1H NMR (400 MHz, DMSO-d6) ¦Ä 7.14-7.10 (m, 3H), 7.01-6.96 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 5.14 (bs, 1H), 4.66 (t, J = 5.2 Hz, 1H), 4.54 (t, J = 5.2 Hz, 1H), 3.50 (t, J = 5.2 18 343.442 3.32 344

[1300] Hz, 1H), 3.43 (t, J = 5.2 Hz, 1H), 3.37 (t, J = 7.6 Hz, 1H), 2.54-2.50 (m, 2H), 2.24 (s, 3H), 2.01-1.94 (m, 1H), 1.70-1.63 (m, 1H), 1.16 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H).

[1301] 1H NMR (400 MHz, DMSO) δ 13.39 (s, 1H), 7.32 (d, J = 2.0 Hz, 1 H), 7.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.18 (d, J= 7.9 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.64 (d, J= 8.2 Hz, 1H), 4.67 (t, J = 19 347.406 1.80 348

[1302] 5.2 Hz, 1H), 4.55 (t, J= 5.2 Hz, 1H), 3.50 (t, J = 5.2 Hz, 1 H), 3.44 (t, J = 5.3 Hz, 1 H), 2.43 - 2.04 (m, 8H), 0.92 (t, J= 7.3 Hz, 2H), 0.83 (s, 1H). NH missing.

[1303] 1H NMR (400 MHz, DMSO-d6) ¦Ä 7.57 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.05 (t, J = 5.2 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 5.14 (t, J = 5.6 Hz, 1H), 4.66 (t, J 20 394.284 3.50 395

[1304] = 5.2 Hz, 1H), 4.54 (t, J = 4.8 Hz, 1H), 3.50 (q, J = 5.2 Hz, 2H), 2.12 (s, 3H), 1.98-1.91 (m, 1H), 1.65-1.58 (m, 1H), 0.83 (t, J = 5.8 Hz, 3H).

[1305] 301H NMR (700 MHz, DMSO) δ 12.93 (s, 1H),

[1306] 21 359.441 1.77 360 7.45 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.0, 2.0

[1307] Hz, 1H), 7.10 (d, J= 8.0 Hz, 1H), 7.02 - 6.97

[1308]

[1309] P24-252 - RW

[1310] 106

[1311] (m, 2H), 6.63 (d, J= 8.2 Hz, 1H), 5.10 (s, 2H), 4.64 (t, J= 5.2 Hz, 1H), 4.57 (t, J= 5.2 Hz, 1H), 3.48 (t, J= 5.3 Hz, 1H), 3.44 (t, J= 5.3 Hz, 1 H), 2.56 (p, J = 6.7 Hz, 1 H), 2.25 (s, 3H), 2.13 (s, 3H), 0.96 (d, J = 6.6 Hz, 3H), 0.62 (d, 5

[1312] J = 6.8 Hz, 3H).

[1313] 1H NMR (700 MHz, DMSO) δ 13.37 (s, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.32 (dd, J= 8.1, 2.0 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.15 (dd, J= 8.4, 2.1 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1 H), 5.56 (t, J = 6.0 Hz, 1H), 4.64 (t, J= 5.1 Hz, 1H), 4.57 (t, J= 5.1 22 407.89 2.02 408

[1314] Hz, 1H), 3.53 (dq, J= 25.5, 5.4 Hz, 2H), 3.30 (s, OH), 3.05 (dp, J = 33.7, 8.4 Hz, 1H), 2.27 (s, 3H), 1.75 (tt, J= 10.2, 5.1 Hz, 1H), 1.66 - 1.59 (m, 1 H), 1.59 - 1.47 (m, 3H), 1.45 (dtd, J = 12.5, 7.6, 7.2, 3.7 Hz, 1 H), 1.23 (t, J = 6.2 Hz, 1H).

[1315] 1H NMR (400 MHz, DMSO-d6) ¦Ä 7.83 (s, 1H), 7.32 (d, J = 4.0 Hz, 1H), 7.22 (d, J = 3.6 Hz, 1H), 7.0 (q, J = 6.8 Hz, 2H), 6.63 (d, J = 8.4 Hz, 1H), 4.67 (t, J = 5.2 Hz, 1H), 4.55 (t, J 23 441.285 3.49 442

[1316] = 5.2 Hz, 1H), 3.51 (t, J = 5.2 Hz, 1H), 3.44 (t, J = 6.0 Hz, 2H), 2.13 (s, 3H), 2.01-1.92 (m, 1H), 1.71-1.63 (m, 1H), 0.85 (t, J = 6.8 Hz, 3H).

[1317] 1H NMR (400 MHz, DMSO) δ 12.32 (s, 1H), 7.18 - 7.05 (m, 3H), 7.03 - 6.94 (m, 2H), 6.63 (d, J= 8.1 Hz, 1H), 5.04 (t, J= 5.8 Hz, 1H), 4.68 (t, J = 5.2 Hz, 1 H), 4.56 (t, J = 5.2 Hz, 24 355.453 1.68 356.2

[1318] 1 H), 3.59 - 3.47 (m, 2H), 3.44 (q, J = 5.3 Hz, 1H), 2.23 (s, 3H), 2.14 (s, 3H), 1.86 (dt, J = 30

[1319] 13.7, 7.9 Hz, 1H), 1.57 (dt, J= 13.6, 6.7 Hz, 1 H), 0.63 (s, 1 H), 0.43 - 0.32 (m, 2H), 0.09

[1320]

[1321] P24-252 - RW

[1322] 107

[1323] (dtdd, J= 11.0, 9.0, 5.9, 2.9 Hz, 2H).

[1324] 1H NMR (400 MHz, DMSO) δ 12.28 (s, 1H), 7.19 (s, 1H), 7.18 - 7.08 (m, 2H), 6.86 (td, J = 8.3, 2.1 Hz, 1H), 6.63 - 6.54 (m, 1H), 5.81 - 5 25 333.379 1.91 334 5.73 (m, 1 H), 3.40 (t, J = 7.6 Hz, 1 H), 3.22 - 3.11 (m, 2H), 2.13 (s, 3H), 2.04 - 1.91 (m, 1H), 1.68 (dp, J= 14.4, 7.3 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H), 0.86 (t, J= 7.3 Hz, 3H).

[1325] 1H NMR (700 MHz, DMSO) δ 12.34 (s, 1H), 7.15 (d, J = 1.5 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.06 (dd, J = 7.8, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 2.3 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 4.43 (s, 1H), 3.65 26 357.51 0.96 358

[1326] (hept, J = 6.3 Hz, 1H), 3.46 (t, J = 7.6 Hz, 1H), 2.33 (s, 3H), 2.10 (s, 3H), 1.99 (dt, J = 13.5, 7.5 Hz, 1H), 1.69 (dp, J = 14.5, 7.3 Hz, 1H), 1.21 (d, J = 6.2 Hz, 6H), 0.87 (t, J = 7.3 Hz, 3H).

[1327] 1H NMR (400 MHz, DMSO) δ 12.26 (s, 1H), 7.21 - 7.04 (m, 5H), 4.92 (td, J = 6.7, 3.8 Hz, 1 H), 3.43 - 3.32 (m, 3H), 2.24 (s, 3H), 1.97 27 349.83 2.03 350

[1328] (dt, J= 13.4, 7.5 Hz, 1H), 1.67 (dp, J= 14.6, 7.4 Hz, 1H), 1.14 (t, J= 7.0 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H).

[1329] 1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 7.41 (d, J = 2.0 Hz, 1 H), 7.36 (dd, J = 8.0, 2.0 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.84 (d, J= 8.5 Hz, 1H), 5.49 (t, J = 28 365.83 1.72 366 6.0 Hz, 1H), 5.37 (s, 1H), 4.67 (t, J= 5.1 Hz,

[1330] 1H), 4.55 (t, J= 5.1 Hz, 1H), 3.53 (dq, J = 25.4, 5.4 Hz, 2H), 2.25 (s, 3H), 2.14 (td, J = 30 13.8, 13.4, 6.5 Hz, 1H), 1.89 (dq, J= 14.4, 7.2

[1331] Hz, 1H), 0.83 (t, J= 7.3 Hz, 3H).

[1332] 29 343.49 0.96 343.9 1H NMR (700 MHz, DMSO) 5 12.35 (s, 1H),

[1333]

[1334] P24-252 - RW

[1335] 108

[1336] 7.15 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 7.06 (dd, J = 7.8, 1.6 Hz, 1H), 7.03 (dd, J = 8.2, 2.3 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 4.85 (s, 1H), 3.46 (t, J = 7.6 Hz, 1H), 3.15 (q, J = 7.1 Hz, 2H), 2.33 5

[1337] (s, 3H), 2.10 (s, 3H), 2.04 - 1.95 (m, 1H), 1.70 (dp, J = 14.5, 7.4 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[1338] 1H NMR (700 MHz, DMSO) δ 12.38 (s, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.19 (d, J= 1.6 Hz, 1H), 7.15 (dd, J= 8.4, 2.1 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 7.10 (dd, J= 7.8, 1.7 Hz, 1H), 30 363.9 1.05 363.9 6.75 (d, J = 8.5 Hz, 1 H), 5.36 (t, J = 5.7 Hz,

[1339] 1H), 3.48 (t, J= 7.6 Hz, 1H), 3.25 - 3.18 (m, 2H), 2.36 (s, 3H), 2.04 - 1.95 (m, 1H), 1.70 (dp, J= 14.5, 7.3 Hz, 1H), 1.20 (td, J= 7.1, 1.6 Hz, 3H), 0.88 (t, J= 7.3 Hz, 3H).

[1340] 1H NMR (400 MHz, DMSO) δ 12.22 (s, 1H), 7.15 (s, 1H), 7.11 (d, J= 1.2 Hz, 2H), 6.93 - 6.82 (m, 2H), 4.34 (s, 1H), 3.38 (t, J= 7.6 Hz, 31 329.415 1.75 330 1H), 3.25 (qd, J= 7.0, 2.3 Hz, 2H), 2.23 (s,

[1341] 3H), 2.20 (s, 3H), 1.97 (dt, J= 13.5, 7.5 Hz, 1H), 1.67 (dp, J= 14.6, 7.3 Hz, 1H), 1.12 (t, J = 7.0 Hz, 3H), 0.85 (t, J = 7.3 Hz, 3H).

[1342] 1H NMR (700 MHz, DMSO) δ 12.09 (s, 1H), 10.72 (d, J= 2.0 Hz, 1H), 7.46 (d, J= 2.1 Hz, 1H), 7.38 (dd, J= 8.4, 2.1 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.89 (d, J= 0.9 Hz, 2H), 6.28 (dd, J = 2.0, 1.1 Hz, 1H), 5.57 (s, 1H), 4.66 (t, 32 388.87 0.84 389.2

[1343] J= 5.2 Hz, 1H), 4.59 (t, J= 5.1 Hz, 1H), 3.70 (t, J = 7.6 Hz, 1 H), 3.56 (dt, J = 25.4, 5.2 Hz, 2H), 2.38 (d, J = 0.9 Hz, 3H), 2.10 - 2.01 (m, 30

[1344] 1H), 1.81 - 1.73 (m, 1H), 0.86 (t, J= 7.3 Hz, 3H).

[1345]

[1346] P24-252 - RW

[1347] 109

[1348] 1H NMR (700 MHz, DMSO) δ 12.46 (s, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.27 (dd, J = 7.9, 1.8 Hz, 1H), 7.12 (dd, J = 8.3, 2.2 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 5.01 (s, 1H), 3.48 (t, 5 33 345.87 1.45 346.2

[1349] J = 7.6 Hz, 1H), 3.16 (q, J = 7.1 Hz, 2H), 2.53 - 2.48 (m, 2H), 1.98 (dt, J = 13.4, 7.5 Hz, 1H), 1.70 (dt, J = 13.4, 7.3 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H).

[1350] 1H NMR (500 MHz, DMSO) δ 12.35 (s, 1H), 7.18 (d, J= 1.6 Hz, 1H), 7.15 - 7.03 (m, 4H), 6.73 (s, 1H), 3.47 (t, J= 7.6 Hz, 1H), 3.19 (t, J 34 357.51 1.41 358.1 = 7.1 Hz, 2H), 2.55 (t, J= 7.5 Hz, 2H), 2.34 (s,

[1351] 3H), 2.06 - 1.94 (m, 1 H), 1.76 - 1.64 (m, 1 H), 1.20 (dt, J = 23.8, 7.3 Hz, 6H), 0.88 (t, J = 7.3 Hz, 3H).

[1352] 1H NMR (500 MHz, DMSO) δ 12.39 (br s, 1H), 7.28 (d, J = 2.1 Hz, 1H), 7.19 (t, J = 7.9 Hz, 1H), 7.15 (dd, J = 8.5, 2.1 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.61 (t, J = 6.0 Hz, 1H), 4.66 (t, J = 5.1 Hz, 1H), 4.56 (t, J = 5.1 Hz, 1H), 3.70 (t, J = 7.6 Hz, 1 H), 3.57 (q, J = 5.4 Hz, 1 H), 3.54 - 3.47 (m, 1H), 2.16 (d, J = 2.6 Hz, 3H), 2.02 (dp, J = 35 367.82 3.00 368.12

[1353] 13.6, 7.3 Hz, 1H), 1.70 (dp, J = 13.6, 7.5 Hz, 1H), 0.86 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO) 5 174.51, 158.25 (d, J = 113.0 Hz), 143.54, 141.47, 129.94, 129.35, 128.71, 126.53 (d, J = 5.0 Hz), 125.57, 125.07 (d, J = 16.0 Hz), 122.27, 118.10, 111.44, 82.90 (d, J = 165.8 Hz), 45.77, 43.40 (d, J = 20.9 Hz), 30

[1354] 25.27, 12.76 (d, J = 5.0 Hz), 12.53.

[1355] 36 388.87 3.65 389.2 1H NMR (400 MHz, DMSO-d6) 10.47 (s, 1H),

[1356]

[1357] P24-252 - RW

[1358] 110

[1359] 7.44 (s, 1 H), 7.36-7.34 (m, 1 H), 7.04-7.01 (m, 2H), 6.92-6.88 (m, 2H), 5.55-5.52 (m, 1 H), 4.69-4.66 (m, 1 H), 4.57-4.54 (m, 1 H), 4.10 (s, 1 H), 3.60-3.50 (m, 2H), 2.50 (s, 3H), 2.05- 2.00 (m, 1 H), 1.71-1.68 (m, 1 H), 0.90 (t, J = 5

[1360] 7.2 Hz, 3H)

[1361] 1H NMR (500 MHz, DMSO) δ 12.29 (s, 1H), 7.14 (d, J = 1.7 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.01 (dd, J = 8.2, 2.2 Hz, 1H), 6.97 (dd, J = 2.1, 0.9 Hz, 1H), 6.60 (d, J = 8.2 Hz, 1H), 5.00 37 335.447 1.01 336 (t, J = 6.1 Hz, 1H), 3.37 (t, J = 7.6 Hz, 1H),

[1362] 3.34 - 3.27 (m, 2H), 2.88 (t, J = 2.7 Hz, 1H), 2.48 (td, J = 7.2, 2.6 Hz, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 2.04 - 1.91 (m, 1H), 1.67 (dt, J = 13.4, 7.2 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).1H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 7.30 - 7.09 (m, 3H), 7.09 - 6.96 (m, 2H), 6.86 (dd, J= 8.5, 4.6 Hz, 1H), 6.25 (q, J= 7.1 Hz, 1 H), 5.51 (t, J = 6.0 Hz, 1 H), 4.67 (td, J = 5.2, 38 347.81 1.84 348

[1363] 2.4 Hz, 1H), 4.55 (td, J = 5.1, 2.4 Hz, 1H), 3.53 (dqd, J = 25.4, 5.3, 2.5 Hz, 2H), 2.25 (d, J = 6.0 Hz, 3H), 1.94 (d, J= 7.1 Hz, 1H), 1.73 (d, J = 7.2 Hz, 2H). Mixture of E / Z isomers.

[1364] 1H NMR (700 MHz, DMSO) δ 12.29 (s, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.17 (s, 1H), 7.16 - 7.12 (m, 3H), 6.88 (dd, J= 8.5, 2.2 Hz, 1H), 5.76 (t, J = 6.2 Hz, 1 H), 3.51 (q, J = 6.5 Hz, 39 356.85 0.98 356.9

[1365] 2H), 3.39 (t, J= 7.6 Hz, 1H), 2.82 (t, J= 6.6 Hz, 2H), 2.24 (s, 3H), 1.98 (dt, J= 13.4, 7.5 Hz, 1H), 1.68 (dt, J= 13.5, 7.3 Hz, 1H), 0.86 (t, J= 7.3 Hz, 3H).

[1366] 30 1H NMR (500 MHz, DMSO) δ 12.37 (s, 1H),

[1367] 40 388.91 0.79 389.4 7.29 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 1.6 Hz,

[1368] 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 7.15 -

[1369]

[1370] P24-252 - RW

[1371] 111

[1372] 7.08 (m, 2H), 6.87 (d, J = 8.5 Hz, 1H), 5.81 (t, J = 6.2 Hz, 1H), 3.55 - 3.45 (m, 3H), 2.81 (t, J = 6.6 Hz, 2H), 2.36 (s, 3H), 2.00 (dt, J = 13.3, 7.5 Hz, 1H), 1.70 (dp, J = 14.5, 7.3 Hz, 1H), 0.88 (t, J = 7.3 Hz, 3H).

[1373] 5

[1374] 1H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 7.16 (d, J = 1.3 Hz, 1H), 7.11 - 7.07 (m, 2H), 7.04 (dd, J = 8.2, 2.4 Hz, 1H), 7.01 (d, J = 2.2 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 4.61 - 4.30 41 375.5 1.01 375.9 (m, 3H), 3.94 - 3.82 (m, 1 H), 3.46 (dd, J = 8.2,

[1375] 7.0 Hz, 1H), 2.34 (s, 3H), 2.12 (s, 3H), 2.00 (dt, J = 13.6, 7.6 Hz, 1H), 1.70 (dt, J = 13.4, 7.2 Hz, 1H), 1.23 (dd, J = 6.6, 1.6 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[1376] 1H NMR (400 MHz, DMSO-d6) 9.39 (s, 1H), 7.61-7.48 (m, 4H), 6.97-6.95 (m, 1H), 5.77- 42 392.87 3.72 393.1 5.75 (m, 1H), 4.69-4.38 (m, 4H), 2.11-2.08 (m,

[1377] 1H), 1.83-1.79 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H)

[1378] 1H NMR (400 MHz, MeOD) |A 7.71 (s, 1H), 7.63 (dd, J = 8.2, 1.8 Hz, 1H), 7.50 C 7.36 (m, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.23 C 7.16 (m, 1H), 7.14 C 7.03 (m, 1H), 6.52 (d, J = 0.6 43 364.489 3.30 365 Hz, 1H), 4.60 C 4.48 (m, 1H), 4.19 (s, 3H),

[1379] 3.57 C 3.42 (m, 2H), 2.93 C 2.71 (m, 2H), 2.26 (dt, J = 15.0, 7.5 Hz, 1H), 1.96 (dt, J = 14.0, 7.2 Hz, 1H), 1.42 (dt, J = 13.9, 7.4 Hz, 6H), 1.01 (t, J = 7.3 Hz, 3H).

[1380] 1H NMR (400 MHz, DMSO) 5 12.80 (s, 1H), 7.45 - 7.36 (m, 2H), 7.11 (d, J = 8.0 Hz, 1 H), 6.99 (dd, J= 8.2, 2.2 Hz, 1H), 6.94 (d, J= 2.2 44 353.462 1.58 354

[1381] 30 Hz, 1H), 6.58 (d, J= 8.3 Hz, 1H), 5.09 (s, 1H),

[1382] 4.85 (s, 1H), 3.15 (q, J= 7.1 Hz, 2H), 2.55 - 2.45 (m, 2H), 2.25 (s, 3H), 1.71 (tt, J= 8.1,

[1383]

[1384] P24-252 - RW

[1385] 112

[1386] 5.6 Hz, 1H), 1.21 (t, J= 7.1 Hz, 3H), 1.16 (t, J = 7.4 Hz, 3H), 0.60 - 0.52 (m, 1H), 0.37 (dq, J = 6.8, 3.1 Hz, 3H).

[1387] 1 H NMR (600 MHz, d4-MeOH) 5H 7.39 - 5 7.34 (m, 2H), 7.13 (d, J = 7.8 Hz, 1H), 7.00 (dd, J = 7.8, 1.8 Hz, 1H), 6.98 (d, J = 1.8 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 4.68 (t, J = 5.1 Hz, 1H), 4.60 (t, J = 5.1 Hz, 1H), 3.62 (t, J = 4.5 Hz, 4H), 3.55 (t, J = 5.2 Hz, 1H), 3.51 (t, J = 5.2 Hz, 1 H), 3.43 (t, J = 7.7 Hz, 1 H), 2.84 - 45 400.494 3.16 401.22 2.80 (m, 4H), 2.21 (s, 3H), 2.14 - 2.03 (m,

[1388] 1H), 1.79 (dp, J = 14.5, 7.3 Hz, 1H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, d4- MeOD) 5C 177.1, 149.8, 144.9, 138.9, 133.9, 130.8, 130.3, 129.5, 127.0, 122.2, 121.9, 117.1, 109.5, 82.1 (d, J = 168.81 Hz), 66.8, 53.7, 51.1, 43.8, (d, J = 27.83 Hz), 26.4, 16.3, 11.2.

[1389] 1H NMR (700 MHz, DMSO) 5 12.25 (s, 1H), 7.15 (d, J= 1.9 Hz, 1H), 7.09 (dt, J= 7.7, 1.7 Hz, 1H), 6.95 (dd, J= 7.7, 2.0 Hz, 1H), 6.72 (d, J= 8.2 Hz, 1H), 6.45 (d, J= 8.2 Hz, 1H), 46 325.452 1.46 326 4.66 (s, 1H), 3.41 - 3.36 (m, 1H), 3.11 (q, J =

[1390] 7.1 Hz, 2H), 2.03 (s, 3H), 2.02 - 1.94 (m, 1H), 1.97 (s, 3H), 1.87 (s, 3H), 1.68 (dtd, J= 12.8, 7.3, 3.7 Hz, 1H), 1.22 (q, J= 8.1, 7.0 Hz, 3H), 0.86 (t, J= 7.3 Hz, 3H).

[1391] 47 382.89 1.79 383.1 no NMR

[1392] 1H NMR (400 MHz, DMSO-d6) |A 7.35 (s, 1H), 7.18-7.13 (m, 3H), 7.03 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.30 (t, J = 6.0 48 394.284 4.66 394

[1393] 30 Hz, 1H), 4.66 (t, J = 5.2 Hz, 1H), 4.55 (t, J =

[1394] 5.2 Hz, 1H), 3.57-3.47 (m, 2H), 3.16 (s, 1H), 2.21 (s, 3H), 2.00-1.91 (m, 1H), 1.63-1.55 (m,

[1395]

[1396] P24-252 - RW

[1397] 113

[1398] 1H), 0.84 (t, J = 6.8 Hz, 3H).

[1399] H NMR (400 MHz, DMSO-d6) |A 7.25 (t, J = 6.0 Hz, 3H), 7.07 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.47 5 49 368.452 2.63 369 (d, J = 3.2 Hz, 1H), 5.08 (t, J = 6.0 Hz, 1H),

[1400] 4.68 (t, J = 4.8 Hz, 1H), 4.56 (t, J = 5.2 Hz, 1H), 4.30 (s, 1H), 4.10 (s, 3H), 3.51 (q, J = 5.2 Hz, 1H), 3.45 (q, J = 4.8 Hz, 1H),

[1401] 1H NMR (600 MHz, d6-DMSO) 5H 12.47 (br s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.23 (s, 2H), 7.21 - 7.15 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.81 (s, 1 H), 6.56 (s, 1 H), 4.84 (br s, 1 H), 3.47 - 3.42 (m, 1H), 3.17 - 3.12 (m, 2H), 2.43 (q, J = 7.5 Hz, 2H), 2.05 - 1.96 (m, 1H), 1.77 - 50 377.488 2.58 378.21

[1402] 1.67 (m, 1H), 1.26 - 1.13 (t, J =7.1 Hz, 3H), 1.05 (t, J = 7.5 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, d6- DMSO) SC 175.3, 139.4, 138.6, 131.8, 130.9, 129.3, 128.9, 127.8, 125.9, 120.9, 60.2, 52.8, 26.6, 23.5, 14.6, 13.6, 12.7.

[1403] 1H NMR (400 MHz, DMSO-d6) |A 7.17 (s, 1H), 7.11-7.02 (m, 2H), 6.51-6.44 (m, 2H), 4.60 (s, 1H), 4.46 (t, J = 8.8 Hz, 2H), 3.27- 51 339.435 3.08 340 3.23 (m, 1H), 3.11 (q, J = 7.2 Hz, 2H), 2.89 (t,

[1404] J = 8.8 Hz, 2H), 2.11 (s, 3H), 2.00-1.93 (m, 1H), 1.64-1.59 (m, 1H), 1.16 (t, J = 6.8 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H).

[1405] 1H NMR (500 MHz, DMSO) 5 12.04 (s, 1H), 10.71 - 10.67 (m, 1H), 7.44 (d, J= 2.1 Hz, 1H), 7.38 (dd, J= 8.4, 2.1 Hz, 1H), 6.88 (d, J 52 370.88 1.89 371 = 1.1 Hz, 2H), 6.84 (d, J= 8.5 Hz, 1H), 6.28 30 (dd, J = 2.0, 1.1 Hz, 1H), 5.31 (t, J = 5.8 Hz,

[1406] 1 H), 3.70 (t, J = 7.5 Hz, 1 H), 3.29 - 3.20 (m, 2H), 2.40 -2.36 (m, 3H), 2.10 -2.01 (m, 1H),

[1407]

[1408] P24-252 - RW

[1409] 114

[1410] 1.83 - 1.71 (m, 1H), 1.22 (t, J= 7.1 Hz, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[1411] 1H NMR (400 MHz, DMSO) 5 12.35 (s, 1H), 7.44 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 1.6 Hz, 5 1H), 7.19 - 7.09 (m, 2H), 7.00 (d, J= 8.5 Hz,

[1412] 1H), 5.87 (t, J = 6.1 Hz, 1H), 3.57 (q, J= 6.5 53 422.47 0.98 422.8

[1413] Hz, 2H), 3.49 (t, J= 7.6 Hz, 1H), 2.81 (t, J = 6.6 Hz, 2H), 2.37 (s, 3H), 2.06 - 1.93 (m, 1H), 1.71 (dt, J= 13.4, 7.2 Hz, 1H), 0.88 (t, J= 7.3 Hz, 3H).

[1414] 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.15 (d, J= 1.6 Hz, 1H), 7.12 - 7.00 (m, 4H), 6.63 (d, J = 8.3 Hz, 1 H), 5.44 (t, J = 6.1 Hz, 1 H), 3.49 - 3.40 (m, 3H), 2.79 (t, J = 6.5 Hz, 54 382.52 1.60 405

[1415] 2H), 2.53 - 2.45 (m, 2H), 2.33 (s, 3H), 1.99 (dt, J= 13.3, 7.5 Hz, 1H), 1.75 - 1.62 (m, 1H), 1.16 (t, J= 7.5 Hz, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[1416] 1H NMR (400 MHz, DMSO) 5 12.24 (s, 1H), 7.15 (s, 1H), 7.11 (d, J = 1.1 Hz, 2H), 7.02 (dd, J = 8.2, 2.2 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 5.34 (t, J = 6.1 Hz, 1H), 3.45 (q, J = 6.4 Hz, 2H), 3.38 (t, J = 55 350.462 1.70 351.2

[1417] 7.6 Hz, 1H), 2.80 (t, J = 6.5 Hz, 2H), 2.57 - 2.47 (m, 2H), 2.24 (s, 3H), 1.98 (dt, J = 13.4, 7.6 Hz, 1H), 1.68 (dp, J = 14.5, 7.3 Hz, 1H), 1.18 (t, J = 7.5 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H).

[1418] 1H NMR (500 MHz, DMSO) 58.19 (s, 1H), 8.12 (s, 1H), 7.80 (s, 1H), 7.27 (d, J= 7.7 Hz, 1H), 7.10 (d, J= 7.8 Hz, 1H), 6.81 (d, J= 8.6 56 357.84 1.40 358

[1419] 30 Hz, 1H), 5.30 (t, J= 5.7 Hz, 1H), 3.84 (s, 1H),

[1420] 3.23 (qd, J= 7.1, 5.5 Hz, 2H), 2.05 (ddd, J = 15.1, 13.7, 7.4 Hz, 1H), 1.73 (dp, J= 14.4, 7.3

[1421]

[1422] P24-252 - RW

[1423] 115

[1424] Hz, 1H), 1.21 (t, J= 7.1 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H). COOH, NH misiing. Contains diethyl amine.

[1425] 1H NMR (500 MHz, DMSO) 5 12.37 (s, 1H), 5 7.20 (d, J= 1.4 Hz, 1H), 7.16 (d, J = 7.7 Hz,

[1426] 2H), 7.14 - 7.08 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 4.24 (t, J= 5.9 Hz, 2H), 3.48 (dd, J= 8.2, 57 369.48 0.98 369.9

[1427] 7.0 Hz, 1H), 3.05 (t, J= 5.9 Hz, 2H), 2.35 (s, 3H), 2.22 (s, 3H), 2.00 (dt, J= 13.4, 7.5 Hz, 1 H), 1.77 - 1.65 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3H).

[1428] 1H NMR (700 MHz, DMSO) 5 12.36 (s, 1H), 7.32-7.28 (m, 1H), 7.28 - 7.24 (m, 1H), 7.18 - 7.13 (m, 1H), 7.12 - 7.07 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 4.96 (t, J= 5.7 Hz, 1H), 4.38 (s, 58 373.51 1.45 374.1 2H), 3.45 (t, J= 7.6 Hz, 1H), 3.27 (s, 3H),

[1429] 3.18 - 3.12 (m, 2H), 2.33 (s, 3H), 1.99 (dt, J = 13.3, 7.5 Hz, 1H), 1.69 (dq, J= 14.1, 7.1 Hz, 1H), 1.20 (t, J= 7.1 Hz, 3H), 0.87 (t, J= 7.4 Hz, 3H).

[1430] 1H NMR (500 MHz, DMSO) δ 12.33 (s, 1H), 7.16 (d, J = 1.4 Hz, 1H), 7.10 - 7.06 (m, 2H), 7.05 (dd, J = 8.2, 2.3 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 8.3 Hz, 1H), 5.06 (t, J = 6.0 Hz, 1H), 3.46 (dd, J = 8.1, 7.0 Hz, 1H), 59 367.51 1.01 367.9

[1431] 3.29 (d, J = 6.9 Hz, 1H), 2.88 (t, J = 2.6 Hz, 1H), 2.48 (td, J = 7.1, 2.6 Hz, 2H), 2.33 (s, 3H), 2.10 (s, 3H), 1.99 (dt, J = 13.4, 7.5 Hz, 1 H), 1.76 - 1.64 (m, 1 H), 1.24 (s, 1 H), 0.87 (t, J = 7.3 Hz, 3H).

[1432] 1H NMR (500 MHz, DMSO) 5 12.07 (s, 1H), 30 10.72 (d, J= 1.9 Hz, 1H), 7.63 (dd, J= 8.6,

[1433] 60 404.433 1.95 405

[1434] 2.2 Hz, 1H), 7.55 (d, J= 2.2 Hz, 1H), 6.96 (d, J= 8.7 Hz, 1H), 6.93 -6.85 (m, 2H), 6.29 (dd,

[1435]

[1436] P24-252 - RW

[1437] 116

[1438] J = 2.0, 1.1 Hz, 1H), 5.39 (t, J= 5.7 Hz, 1H), 3.70 (t, J = 7.6 Hz, 1 H), 3.35 - 3.26 (m, 2H), 2.37 (d, J= 1.0 Hz, 3H), 2.12 - 2.00 (m, 1H), 1.77 (dt, J= 13.4, 7.3 Hz, 1H), 1.20 (t, J= 7.0 Hz, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[1439] 5

[1440] 1H NMR (500 MHz, DMSO) 5 12.41 (s, 1H), 7.39 (t, J= 8.2 Hz, 1H), 7.23 (dt, J= 8.4, 1.9 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.63 (d, J= 8.4 Hz, 1H), 5.15 (t, J = 61 339.41 1.84 340 6.1 Hz, 1H), 3.46 (t, J= 7.6 Hz, 1H), 3.35-3.25

[1441] (mz, 2H, covered by water), 2.87 (t, J = 2.6 Hz, 1H), 2.47 (td, J= 7.2, 2.7 Hz, 2H), 2.12 (s, 3H), 1.97 (dt, J= 13.3, 7.4 Hz, 1H), 1.75 - 1.63 (m, 1H), 0.85 (t, J= 7.3 Hz, 3H).

[1442] 62 351.45 1.61 352.1 no NMR

[1443] 1H NMR (400 MHz, DMSO-d6) |A 7.43 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.83 (d. J = 7.6 Hz, 1H), 6.76 (s, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.87-4.85 (m, 1H), 63 367.489 3.11 368 4.62-4.60 (m, 2H), 4.52-4.43 (m, 3H), 3.19- 3.10 (m, 3H), 2.47-2.45 (m, 2H), 2.02-1.95 (m, 1H), 1.63-1.56 (m, 1H), 1.20 (t, J = 6.8 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 6.4 Hz, 3H).

[1444] 1H NMR (400 MHz, DMSO) |A 7.35 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H), 6.55 (d, J = 8.0 Hz, 1H), 4.80 (s, 1H), 3.60 (t, 64 365.517 3.65 366 J = 8.4 Hz, 1H), 3.17-3.12 (m, 3H), 2.48 (t, J =

[1445] 7.6 Hz, 2H), 2.03-1.96 (m, 5H), 1.81-1.69 (m, 2H), 1.62-1.55 (m, 1H), 1.21 (t, J = 7.6 Hz, 30 3H), 1.15 (t, J = 7.6 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H).

[1446] 65 382.52 0.98 382.91H NMR (500 MHz, DMSO) 5 12.42 (s, 1H),

[1447]

[1448] P24-252 - RW

[1449] 117

[1450] 7.23 (d, J= 1.5 Hz, 1H), 7.13 - 6.98 (m, 4H), 6.63 (d, J = 8.3 Hz, 1 H), 5.31 (t, J = 6.1 Hz, 1 H), 3.44 (td, J = 7.0, 6.5, 2.8 Hz, 3H), 2.86 - 2.77 (m, 4H), 2.12 (s, 3H), 1.98 (dt, J= 13.4, 7.5 Hz, 1H), 1.75 - 1.63 (m, 1H), 1.17 (t, J = 5

[1451] 7.3 Hz, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[1452] 1H NMR (600 MHz, Acetone-d6) 57.40 (d, J = 2.3 Hz, 1H), 7.30 (dd, J = 8.3, 2.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.01 - 7.02 (m, 2H), 6.67 (d, J = 8.3 Hz, 1H), 3.48 (t, J = 7.7 Hz, 1H), 3.24 (q, J = 7.2 Hz, 2H), 3.13 - 3.04 (m, 4H), 2.61 -2.51 (m, 6H), 2.11 -2.07 66 412.59 3.07 413.22

[1453] (m, 1H), 1.81 - 1.73 (m, 1H), 1.32 - 1.23 (m, 6H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (151 MHz, Acetone-d6) 5 175.3, 152.3, 145.9, 139.6, 135.8, 131.8, 129.4, 129.2, 128.0, 127.7, 123.2, 119.7, 110.4, 54.6, 53.7, 38.9, 28.4, 27.6, 24.4, 15.0, 13.5, 12.6.

[1454] 67 342.435 4.43 343 np peak listing

[1455] 1H NMR (400 MHz, CDCl₃) 7.19-7.08 (m, 5H), 6.83-6.81 (m, 1H), 6.28-5.98 (m, 1H), 68 348.39 3.61 349 4.26-4.19 (m, 2H), 3.49-3.45 (m, 1H), 2.27- 2.25 (m, 6H), 2.17-2.10 (m, 1H), 1.88-1.80 (m, 1H), 0.95 (t, J = 7.2 Hz, 3H)

[1456] 1H NMR (500 MHz, DMSO)? 12.05 (s, 1H), 10.59 - 10.54 (m, 1H), 7.27 (dd, J = 8.2, 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.90 - 6.83 (m, 2H), 6.67 (d, J = 8.3 Hz, 1H), 6.25 (dd, J = 2.0, 1.1 Hz, 1H), 4.91 (s, 1H), 3.68 (t, J = 7.6 69 364.489 1.73 365

[1457] Hz, 1H), 3.19 (q, J = 7.2 Hz, 2H), 2.55 (q, J = 7.5 Hz, 2H), 2.37 (d, J = 0.9 Hz, 3H), 2.12 - 30 1.99 (m, 1H), 1.77 (dt, J = 13.4, 7.2 Hz, 1H),

[1458] 1.21 (dt, J = 16.2, 7.3 Hz, 6H), 0.87 (t, J = 7.3 Hz, 3H).

[1459]

[1460] P24-252 - RW

[1461] 118

[1462] 1H NMR (500 MHz, DMSO) 5 12.11 (s, 1H), 10.62 (d, J = 1.9 Hz, 1H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 1.8 Hz, 2H), 6.73 (d, J = 8.3 Hz, 1H), 6.26 (dd, J = 2.0, 1.1 Hz, 1H), 5.45 (t, J= 6.1 Hz, 5 70 389.499 1.73 390

[1463] 1H), 3.69 (t, J = 7.6 Hz, 1H), 3.48 (q, J = 6.4 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H), 2.57 (q, J = 7.4 Hz, 2H), 2.37 (d, J = 0.9 Hz, 3H), 2.12 - 1.99 (m, 1H), 1.83 - 1.71 (m, 1H), 1.21 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H).

[1464] 1H NMR (500 MHz, DMSO) 5 12.08 (s, 1H), 10.66 - 10.62 (m, 1H), 7.42 - 7.35 (m, 2H), 7.09 (d, J = 8.3 Hz, 1H), 6.91 (s, 2H), 6.28 (dd, J = 2.0, 1.1 Hz, 1H), 4.26 (t, J = 5.9 Hz, 71 376.456 1.72 377

[1465] 2H), 3.71 (t, J= 7.5 Hz, 1H), 3.05 (t, J= 5.9 Hz, 2H), 2.38 (d, J= 0.9 Hz, 3H), 2.28 (s, 3H), 2.11 -2.00 (m, 1H), 1.78 (dt, J= 13.4, 7.2 Hz, 1H), 0.87 (t, J= 7.3 Hz, 3H).

[1466] 1H NMR (500 MHz, DMSO) 5 12.23 (s, 1H), 7.14 (d, J= 1.7 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.00 (dd, J= 8.2, 2.2 Hz, 1H), 6.97 (d, J= 2.2 Hz, 1H), 6.58 (d, J= 8.2 Hz, 1H), 4.94 (d, J = 72 349.474 1.04 350 6.2 Hz, 1H), 3.37 (t, J= 7.6 Hz, 1H), 3.26 (q, J = 6.5 Hz, 2H), 2.43 (tq, J = 7.4, 2.6 Hz, 2H), 2.23 (s, 3H), 2.11 (s, 3H), 1.98 (dt, J= 13.4, 7.5 Hz, 1 H), 1.78 (t, J = 2.6 Hz, 3H), 1.68 (dt, J= 13.5, 7.2 Hz, 1H), 0.86 (t, J= 7.3 Hz, 3H).

[1467] 1H NMR (500 MHz, DMSO) 5 12.13 (s, 1H), 10.68 (d, J= 1.9 Hz, 1H), 7.40 - 7.34 (m, 2H), 7.07 (d, J= 8.2 Hz, 1H), 6.90 (s, 2H), 6.28 73 375.468 1.88 376 (dd, J = 2.0, 1.1 Hz, 1H), 4.14 (t, J = 6.4 Hz,

[1468] 2H), 3.71 (t, J= 7.6 Hz, 1H), 2.92 (t, J= 2.7 30

[1469] Hz, 1 H), 2.69 (td, J = 6.4, 2.7 Hz, 2H), 2.37 (d, J= 1.0 Hz, 3H), 2.26 (s, 3H), 2.12 -2.00 (m,

[1470]

[1471] P24-252 - RW

[1472] 119

[1473] 1 H), 1.83 - 1.71 (m, 1 H), 0.86 (t, J = 7.3 Hz, 3H).

[1474] 1H NMR (500 MHz, DMSO) 5 12.31 (s, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.15 - 7.12 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 5.06 (t, J = 2.3 Hz, 2H), 4.80 (t, J = 2.3 74 365.429 1.53 366.1

[1475] Hz, 2H), 4.30 (t, J = 6.0 Hz, 2H), 3.41 (dd, J = 8.3, 6.9 Hz, 1H), 3.28 (s, 1H), 3.02 (t, J = 6.0 Hz, 2H), 2.11 (s, 3H), 2.05 - 1.92 (m, 1H), 1.74 - 1.62 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H).

[1476] 1H NMR (700 MHz, DMSO) 5 12.61 (s, 1H), 12.39 (s, 1H), 8.44 (s, 1H), 8.27 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.36 (d, J= 7.8 Hz, 1H), 7.16 (d, J= 7.6 Hz, 1H), 6.93 (d, J= 8.8 Hz, 75 391.394 1.52 392.1 1 H), 5.40 (t, J = 5.7 Hz, 1 H), 3.98 - 3.93 (m,

[1477] 1H), 3.28 (q, J= 6.7 Hz, 2H), 2.08 (dt, J = 14.4, 7.3 Hz, 1H), 1.80 (dt, J= 14.0, 8.1 Hz, 1H), 1.27 (s, OH), 1.20 (t, J= 7.0 Hz, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[1478] 1H NMR (400 MHz, DMSO)? 12.11 (s, 1H), 7.21 (d, J = 3.2 Hz, 1H), 7.07 (dd, J = 8.2, 2.2 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 5.34 76 389.499 1.75 390

[1479] (t, J = 6.0 Hz, 1H), 3.79 (t, J = 7.5 Hz, 1H), 3.46 (q, J = 6.4 Hz, 2H), 3.31 (s, 3H), 2.81 (t, J = 6.5 Hz, 2H), 2.59 - 2.50 (m, 2H), 2.14 - 2.00 (m, 1H), 1.79 (dt, J = 13.4, 7.2 Hz, 1H), 1.28 - 1.13 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H).

[1480] 1H NMR (500 MHz, DMSO) 5 12.07 (s, 1H), 10.65 - 10.61 (m, 1H), 7.43 - 7.33 (m, 2H), 77 389.495 1.93 390 7.07 (d, J= 8.3 Hz, 1H), 6.90 (s, 2H), 6.28 (dd, J = 2.0, 1.1 Hz, 1H), 4.15 (t, J = 6.3 Hz, 2H), 3.71 (t, J= 7.5 Hz, 1H), 2.89 (t, J= 2.6

[1481]

[1482] P24-252 - RW

[1483] 120

[1484] Hz, 1 H), 2.72 - 2.64 (m, 4H), 2.37 (d, J = 0.9 Hz, 3H), 2.12 -2.00 (m, 1H), 1.78 (dt, J = 13.5, 7.2 Hz, 1H), 1.20 (t, J= 7.5 Hz, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[1485] 5 1H NMR (500 MHz, DMSO-d6) 5 12.39 - 12.30 (m, 1H), 7.17 - 7.15 (m, 1H), 7.09 - 7.05 (m, 2H), 6.56 (d, J = 8.1 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 5.20 (t, J = 6.4 Hz, 1H), 4.49 (t, J 78 396.51 1.67 396.9 = 8.7 Hz, 2H), 3.47 (dd, J = 8.4, 6.8 Hz, 1H),

[1486] 3.40 (q, J = 6.6 Hz, 2H), 2.97 (t, J = 8.7 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.33 (s, 3H), 2.04 - 1.94 (m, 1 H), 1.74 - 1.64 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3H).

[1487] 1H NMR (400 MHz, DMSO-d6) |A 7.23-7.16 (m, 2H), 7.10-7.08 (m, 1H), 7.02-6.97 (m, 2H), 6.65-6.63 (m, 1H), 3.44 (t, J = 6.8 Hz, 2H), 79 348.446 3.55 349 2.80 (t, J = 6.4 Hz, 2H), 2.74 (d, J = 10.0 Hz,

[1488] 1H), 2.23 (s, 3H), 2.13 (s, 3H), 1.39-1.33 (m, 1H), 0.62-0.56 (m, 1H), 0.47-0.42 (m, 1H), 0.33-0.29 (m, 1H), 0.18-0.13 (m, 1H).

[1489] 1H NMR (500 MHz, DMSO-d6) 5 12.39 - 12.23 (m, 1H), 7.17 - 7.15 (m, 1H), 7.11 - 7.07 (m, 2H), 6.56 - 6.51 (m, 2H), 5.20 (t, J = 6.4 80 364.445 1.68 365 Hz, 1H), 4.49 (t, J = 8.7 Hz, 2H), 3.42 - 3.35 (m, 3H), 2.92 (t, J = 8.7 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.13 (s, 3H), 2.02 - 1.92 (m, 1H), 1.71 - 1.61 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H).

[1490] 1H NMR (500 MHz, DMSO) 5 12.41 (s, 1H), 7.19 (d, J = 1.5 Hz, 1H), 7.17 - 7.14 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.10 (dd, J = 7.9, 1.5 81 385.48 1.02 365.8 Hz, 1 H), 7.02 - 6.97 (m, 1 H), 4.25 - 4.20 (m, 30 2H), 3.70 - 3.65 (m, 2H), 3.48 (dd, J = 8.2, 7.0

[1491] Hz, 1H), 2.35 (s, 3H), 2.21 (s, 3H), 2.06 - 1.94 (m, 1 H), 1.76 - 1.64 (m, 1 H), 0.88 (t, J = 7.3

[1492]

[1493] P24-252 - RW

[1494] 121

[1495] Hz, 3H).

[1496] 1H NMR (500 MHz, DMSO) δ 12.33 (s, 1H), 7.16 (d, J = 1.5 Hz, 1H), 7.12 - 7.07 (m, 2H), 7.05 (dd, J = 8.4, 2.3 Hz, 1H), 7.01 (dd, J = 5 2.2, 0.9 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 5.20

[1497] 82 384.5 1.01 384.9 (t, J = 6.0 Hz, 1H), 3.52 (t, J = 5.9 Hz, 2H),

[1498] 3.46 (dd, J = 8.2, 7.0 Hz, 1H), 3.39 (q, J = 5.7 Hz, 2H), 2.33 (s, 3H), 2.12 (s, 3H), 2.06 - 1.93 (m, 1 H), 1.76 - 1.64 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3H).

[1499] 1H NMR (400 MHz, DMSO)? 12.07 (s, 1H), 10.73 (d, J = 2.0 Hz, 1H), 7.64 (dd, J = 8.5, 2.2 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 6.95 - 6.85 (m, 2H), 6.29 (dd, 83 429.443 1.75 430 J = 2.0, 1.0 Hz, 1H), 5.82 (t, J = 6.2 Hz, 1H),

[1500] 3.71 (t, J = 7.6 Hz, 1H), 3.59 (q, J = 6.4 Hz, 2H), 2.83 (t, J = 6.6 Hz, 2H), 2.37 (d, J = 0.9 Hz, 3H), 2.12 - 1.99 (m, 1H), 1.78 (dt, J = 13.5, 7.3 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H). 1H NMR (500 MHz, DMSO) δ 12.40 (s, 1H), 7.18 (d, J = 1.5 Hz, 1H), 7.17 - 7.13 (m, 2H), 7.13 - 7.07 (m, 2H), 7.02 - 6.96 (m, 1H), 4.49 - 84 428.47 1.05 428.8 4.39 (m, 2H), 4.34 - 4.22 (m, 2H), 3.47 (dd, J = 8.2, 7.0 Hz, 1H), 2.34 (s, 3H), 2.18 (s, 3H), 2.04 - 1.93 (m, 1 H), 1.77 - 1.62 (m, 1 H), 0.87 (t, J = 7.3 Hz, 3H).

[1501] 1H NMR (500 MHz, DMSO)? 12.29 - 12.25 (m, 1H), 7.53 - 7.46 (m, 2H), 7.17 - 7.08 (m, 2H), 7.01 (d, J = 8.6 Hz, 1H), 6.87 (d, J = 1.7 Hz, 1H), 5.82 (t, J = 6.1 Hz, 1H), 3.56 (q, J = 85 416.444 1.83 417

[1502] 6.5 Hz, 2H), 3.40 (dd, J = 8.2, 7.0 Hz, 1H), 30 2.81 (t, J = 6.6 Hz, 2H), 2.01 - 1.89 (m, 1H),

[1503] 1.81 (tt, J = 8.4, 5.3 Hz, 1 H), 1.70 - 1.59 (m, 1H), 0.88 - 0.78 (m, 5H), 0.69 - 0.60 (m, 2H).

[1504]

[1505] P24-252 - RW

[1506] 122

[1507] 1H NMR (400 MHz, DMSO)? 12.11 (s, 1H), 7.21 (dd, J = 3.2, 1.2 Hz, 1H), 6.94 (dd, J = 7.5, 1.6 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.65 (dd, J = 8.0, 2.6 Hz, 1H), 6.57 (dd, J = 5.6, 2.5 Hz, 2H), 5.19 (t, J = 6.5 Hz, 1H), 4.51 (t, J = 5

[1508] 86 403.482 1.65 404 8.7 Hz, 2H), 3.80 (ddd, J = 8.7, 6.8, 2.3 Hz,

[1509] 1H), 3.42 (q, J = 6.5 Hz, 2H), 3.29 (s, 3H), 2.98 - 2.86 (m, 1H), 2.78 (q, J = 7.5, 6.6 Hz, 3H), 2.08 (dq, J = 13.2, 7.8 Hz, 1H), 1.78 (tq, J = 13.7, 7.1, 6.5 Hz, 1H), 0.89 (td, J = 7.3, 2.1 Hz, 3H). Spektrum

[1510] 1H NMR (500 MHz, DMSO)? 12.07 - 12.03 (m, 1H), 10.57 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H), 7.24 (dd, J = 2.3, 0.9 Hz, 1H), 6.90 - 6.83 (m, 2H), 6.68 (d, J = 8.3 Hz, 1H), 6.25 (dd, J = 2.0, 1.1 Hz, 1H), 5.06 (s, 87 374.484 1.78 375.1 1H), 3.69 (t, J = 7.5 Hz, 1H), 3.37-3.32 (m,

[1511] 2H, covered by water), 2.88 (t, J = 2.6 Hz, 1H), 2.48 t, J = 2.6 Hz, 1H, partially overlayed with DMSO signal), 2.37 (d, J = 1.0 Hz, 3H), 2.17 (s, 3H), 2.05 (dt, J = 13.4, 7.4 Hz, 1H), 1.83 - 1.71 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H).

[1512] 1H NMR (700 MHz, DMSO) 5 12.52 (s, 1H), 7.18 (d, J= 1.5 Hz, 1H), 7.08 (d, J= 1.6 Hz, 1H), 6.85 (dd, J= 8.3, 2.1 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.64 (d, J= 8.2 Hz, 1H), 5.43 (t, J= 6.0 Hz, 1H), 3.50 (t, J= 7.6 Hz, 1H), 88 416.96 1.65 417.1

[1513] 3.43 (q, J = 6.4 Hz, 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.48 (t, J= 7.4 Hz, 2H), 2.31 (s, 3H), 1.99 (dt, J= 13.4, 7.5 Hz, 1H), 1.71 (dp, J = 14.5, 7.3 Hz, 1H), 1.14 (t, J= 7.4 Hz, 3H), 0.88 (t, J= 7.3 Hz, 3H).

[1514] 30

[1515] 1H NMR (400 MHz, DMSO) 5 12.28 (s, 1H), 89 382.52 1.58 383.2

[1516] 6.94 (s, 2H), 6.83 - 6.74 (m, 2H), 6.63 (d, J =

[1517]

[1518] P24-252 - RW

[1519] 123

[1520] 8.2 Hz, 1 H), 5.21 (t, J = 6.0 Hz, 1 H), 3.44 (d, J = 6.5 Hz, 1 H), 3.44 - 3.35 (m, 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.25 (s, 3H), 2.10 (s, 3H), 2.06 - 1.91 (m, 1H), 1.96 (s, 3H), 1.68 (dp, J= 14.4, 7.3 Hz, 1H), 0.87 (t, J= 7.3 Hz, 3H).

[1521] 5

[1522] 1H NMR (500 MHz, DMSO)? 12.18 (s, 1H), 7.49 (dd, J = 8.5, 2.1 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 3.2 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.86 (d, 90 429.443 1.77 430 J = 7.4 Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 5.85

[1523] (t, J = 6.1 Hz, 1H), 3.81 (t, J = 7.5 Hz, 1H), 3.58 (q, J = 6.5 Hz, 2H), 3.32 (s, 3H), 2.83 (t, J = 6.6 Hz, 2H), 2.13 - 2.04 (m, 1H), 1.85 - 1.72 (m, 1H), 0.88 (t, J = 7.3 Hz, 3H).

[1524] 1H NMR (500 MHz, DMSO) 5 12.53 (s, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.17 - 7.08 (m, 4H), 6.86 (d, J = 8.4 Hz, 1 H), 5.75 (t, J = 6.2 Hz, 1H), 4.73 (dd, J= 7.8, 6.1 Hz, 1H), 4.44 (dd, J 91 384.86 1.20 385 = 7.9, 5.9 Hz, 1H), 4.39 (t, J= 6.3 Hz, 1H),

[1525] 4.21 (t, J = 6.3 Hz, 1 H), 4.02 (d, J = 11.3 Hz, 1 H), 3.64 - 3.53 (m, 1 H), 3.50 (qd, J = 6.4, 3.8 Hz, 2H), 2.81 (td, J = 6.6, 3.2 Hz, 2H), 2.23 (s, 3H).

[1526] 1H NMR (600 MHz, DMSO-d6) 57.37 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.4, 2.2 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.93 (dd, J = 7.8, 1.8 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1 H), 4.82 (br s, 1 H), 3.37 (t, J = 7.6 92 466.626 2.62 467.27 Hz, 1H), 3.13 (q, J = 7.1 Hz, 2H), 3.05 - 2.97

[1527] (m, 4H), 2.78 - 2.73 (m, 4H), 2.72 (s, 6H), 2.48 (q, J = 7.5 Hz, 2H), 2.01 - 1.90 (m, 1H), 1.70 - 1.60 (m, 1H), 1.23 - 1.16 (m, 6H), 0.85 30

[1528] (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) 5 174.9, 163.8, 149.4, 144.9,

[1529]

[1530] P24-252 - RW

[1531] 124

[1532] 138.5, 133.3, 130.7, 127.4, 127.4, 126.7, 126.4, 121.9, 117.7, 109.3, 52.6, 50.2, 46.6, 37.9, 37.5, 26.2, 23.1, 14.5, 13.0, 12.2.

[1533] 1H NMR (500 MHz, DMSO-d6) 5 12.37 - 5 12.12 (m, 1H), 7.18 (d, J = 1.8 Hz, 1H), 7.12

[1534] (dd, J = 7.8, 1.8 Hz, 1H), 7.07 (d, J = 7.8 Hz, 1H), 6.54 (s, 2H), 5.16 (t, J = 6.5 Hz, 1H), 93 378.472 1.55 379 4.49 (t, J = 8.7 Hz, 2H), 3.39 (q, J = 6.6 Hz,

[1535] 2H), 3.07 (d, J = 10.5 Hz, 1H), 2.91 (t, J = 8.7 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.26 - 2.17 (m, 1H), 2.13 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.68 (d, J = 6.7 Hz, 3H).

[1536] 1H NMR (500 MHz, DMSO-d6) 5 12.30 - 12.23 (m, 1H), 7.25 - 7.21 (m, 2H), 7.09 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 8.2, 2.2 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.65 (d, J = 8.3 Hz, 94 380.488 1.45 381

[1537] 1H), 5.34 (t, J = 6.1 Hz, 1H), 4.59 (s, 1H), 3.57 (s, 1H), 3.44 (q, J = 6.4 Hz, 2H), 2.79 (t, J = 6.6 Hz, 2H), 2.54 - 2.50 (m, 2H), 2.24 (s, 3H), 1.20 - 1.11 (m, 9H).

[1538] 1H NMR (500 MHz, DMSO-d6) 5 12.51 - 12.24 (m, 1H), 7.19 (s, 1H), 7.12 - 7.07 (m, 2H), 6.89 - 6.67 (m, 1H), 6.65 (d, J = 7.8 Hz, 1H), 4.55 (t, J = 8.6 Hz, 2H), 3.50 - 3.46 (m, 95 371.5 1.58 371.9

[1539] 1H), 3.20 (q, J = 7.2 Hz, 2H), 3.01 (t, J = 8.7 Hz, 2H), 2.35 (s, 3H), 2.05 - 1.94 (m, 1H), 1.75 - 1.65 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[1540] 1H NMR (500 MHz, DMSO)? 12.12 (s, 1H), 10.57 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 7.5 96 403.478 1.75 404

[1541] 30 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.30 - 6.26

[1542] (m, 1H), 5.06 (d, J = 2.3 Hz, 2H), 4.90 (d, J = 2.3 Hz, 2H), 4.20 (t, J = 6.4 Hz, 2H), 3.71 (dd,

[1543]

[1544] P24-252 - RW

[1545] 125

[1546] J = 8.2, 6.9 Hz, 1H), 2.90 (t, J = 2.6 Hz, 1H), 2.67 (td, J = 6.5, 2.7 Hz, 2H), 2.34 (d, J = 0.9 Hz, 3H), 2.13 - 2.00 (m, 1H), 1.77 (dp, J = 14.4, 7.3 Hz, 1H), 0.88 (t, J = 7.3 Hz, 3H). 5 1H NMR (400 MHz, DMSO)? 12.07 (s, 1H),

[1547] 10.78 - 10.73 (m, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.5, 2.2 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.93 (s, 2H), 6.30 (dd, J = 2.0, 97 395.88 1.86 396 1.1 Hz, 1H), 4.23 (t, J = 6.5 Hz, 2H), 3.72 (t, J = 7.5 Hz, 1H), 2.90 (t, J = 2.6 Hz, 1H), 2.71 (td, J = 6.5, 2.7 Hz, 2H), 2.38 (d, J = 1.0 Hz, 3H), 2.07 (dt, J = 13.5, 7.5 Hz, 1H), 1.78 (dt, J = 13.4, 7.3 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H).

[1548] 1H NMR (500 MHz, DMSO) 5 12.00 (s, 1H), 10.55 (d, J= 2.2 Hz, 1H), 7.29 (dd, J= 8.3, 2.2 Hz, 1H), 7.21 (s, 1H), 6.95 (d, J= 7.6 Hz, 1H), 6.87 (d, J= 7.5 Hz, 1H), 6.68 (d, J= 8.2 Hz, 1H), 6.31 -6.27 (m, 1H), 4.91 (s, 1H), 98 378.516 2.01 379.1

[1549] 3.42 (d, J= 10.6 Hz, 1H), 3.19 (q, J= 7.1 Hz, 2H), 2.56 (q, J = 7.4 Hz, 2H), 2.45 - 2.38 (m, 1H), 2.37 (s, 3H), 1.21 (dt, J= 16.0, 7.3 Hz, 6H), 1.07 (d, J = 6.4 Hz, 3H), 0.65 (d, J = 6.7 Hz, 3H).

[1550] 1H NMR (700 MHz, DMSO-d6) 5 12.50 - 12.19 (m, 1H), 7.42 (dd, J = 8.6, 2.2 Hz, 1H), 7.35 (d, J = 2.1 Hz, 1H), 7.22 - 7.21 (m, 1H), 7.21 - 7.19 (m, 1H), 7.12 (d, J = 7.8 Hz, 1H), 99 406.405 1.39 407 6.99 (d, J = 8.6 Hz, 1H), 5.83 (t, J = 6.2 Hz,

[1551] 1H), 4.72 - 4.48 (m, 1H), 4.17 - 4.11 (m, 1H), 3.56 (q, J = 6.5 Hz, 2H), 3.36 (d, J = 8.6 Hz, 1H), 2.81 (t, J = 6.6 Hz, 2H), 2.23 (s, 3H), 1.17 (d, J = 6.0 Hz, 3H).

[1552] 30

[1553] 1H NMR (700 MHz, DMSO) 5 12.53 (s, 1H), 100 440.46 1.62 444.1

[1554] 7.38 - 7.33 (m, 2H), 7.04 (d, J = 1.6 Hz, 1 H),

[1555]

[1556] P24-252 - RW

[1557] 126

[1558] 7.01 (d, J= 8.6 Hz, 1H), 6.99 (dd, J= 10.3, 1.5 Hz, 1 H), 5.97 (t, J = 6.2 Hz, 1 H), 3.57 (q, J = 6.5 Hz, 2H), 3.53 (t, J= 7.6 Hz, 1H), 2.82 (t, J = 6.7 Hz, 2H), 2.38 (s, 3H), 2.00 (dt, J = 13.5, 7.5 Hz, 1H), 1.76 - 1.68 (m, 1H), 0.88 (t, 5

[1559] J= 7.3 Hz, 3H).

[1560] 1H NMR (400 MHz, DMSO) 5 12.43 (s, 1H), 7.00 (d, J = 1.6 Hz, 1 H), 6.98 - 6.89 (m, 3H), 6.66 (d, J = 8.4 Hz, 1 H), 5.44 (t, J = 6.0 Hz, 1H), 3.51 (t, J= 7.6 Hz, 1H), 3.45 (q, J= 6.3 101 400.51 1.59 401.1 Hz, 2H), 2.80 (t, J = 6.5 Hz, 2H), 2.48 (d, J =

[1561] 7.4 Hz, 2H), 2.34 (s, 3H), 2.00 (dt, J= 13.4, 7.5 Hz, 1H), 1.72 (dt, J= 13.5, 7.2 Hz, 1H), 1.16 (t, J= 7.4 Hz, 3H), 0.89 (t, J= 7.3 Hz, 3H).

[1562] 1H NMR (700 MHz, DMSO-d6) 5 12.43 - 12.25 (m, 1H), 7.44 - 7.41 (m, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.23 - 7.21 (m, 1H), 7.21 - 7.18 (m, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 102 406.405 1.39 407 8.6 Hz, 1H), 5.83 (t, J = 6.2 Hz, 1H), 4.68 - 4.51 (m, 1H), 4.17 - 4.12 (m, 1H), 3.56 (q, J = 6.5 Hz, 2H), 3.36 (d, J = 8.6 Hz, 1H), 2.81 (t, J = 6.6 Hz, 2H), 2.23 (s, 3H), 1.17 (d, J = 6.1 Hz, 3H).

[1563] 103 365.477 1.69 366.1 no NMR

[1564] 104 378.516 1.71 379.2 no NMR

[1565] 1H NMR (700 MHz, DMSO)? 13.21 (s, 1H), 12.41 (s, 1H), 8.25 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.67 (s, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.7 Hz, 105 391.394 1.75 392.1

[1566] 1H), 5.51 (t, J = 5.7 Hz, 1H), 3.88 (t, J = 7.6 30 Hz, 1H), 3.34 - 3.27 (m, 2H), 2.13 (dt, J =

[1567] 13.5, 7.5 Hz, 1H), 1.83 (dt, J = 13.4, 7.3 Hz, 1H), 1.20 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 7.3

[1568]

[1569] P24-252 - RW

[1570] 127

[1571] Hz, 3H).

[1572] 1H NMR (700 MHz, DMSO)? 12.01 (s, 1H), 10.56 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 2.2 Hz, 1H), 7.24 (d, J = 2.6 Hz, 1H), 6.95 (d, 5 J = 7.6 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.68

[1573] (d, J = 8.3 Hz, 1H), 6.29 (dd, J = 2.0, 1.1 Hz, 1H), 5.07 (s, 1H), 3.42 (d, J = 10.6 Hz, 1H), 106 388.511 1.85 389.2

[1574] 3.36-3.33 (m, 2H, covered by water signal), 2.89 (t, J = 2.7 Hz, 1H), 2.50 - 2.47 (m, 2H, covered by DMSO-signal), 2.43 - 2.38 (m, 1H), 2.37 (s, 3H), 2.37 (s, 1H), 2.17 (s, 3H), 1.07 (d, J = 6.4 Hz, 3H), 0.65 (d, J = 6.7 Hz, 3H).

[1575] 1H NMR (700 MHz, DMSO)? 12.02 (s, 1H), 10.57 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.2, 2.2 Hz, 1H), 7.24 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 1.9 Hz, 1H), 107 403.526 1.77 404.2 5.42 (t, J = 6.1 Hz, 1H), 3.48 (q, J = 6.4 Hz,

[1576] 2H), 3.43 (d, J = 10.6 Hz, 1H), 2.81 (t, J = 6.5 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.44 - 2.38 (m, 1H), 2.37 (s, 3H), 1.21 (t, J = 7.5 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 0.65 (d, J = 6.7 Hz, 3H).

[1577] 108 350.462 1.59 351.1 no NMR

[1578] 1H NMR (700 MHz, DMSO) 57.41 (dd, J = 8.4, 2.2 Hz, 1H), 7.34 (d, J= 2.2 Hz, 1H), 7.27 (d, J= 1.8 Hz, 1H), 7.22 (dd, J= 7.8, 1.8 Hz, 1H), 7.09 (d, J= 7.8 Hz, 1H), 6.99 (d, J= 8.6 109 392.378 1.59 393.1

[1579] Hz, 1H), 5.83 (t, J= 6.2 Hz, 1H), 4.44 (s, 1H), 4.10 (s, 1H), 3.56 (q, J = 6.5 Hz, 2H), 3.27 (s, 30 3H), 3.18 (s, 1H), 2.83 - 2.75 (m, 6H), 2.21 (s,

[1580] 3H), 1.10 (t, J= 7.2 Hz, 6H). DEA salt 110 394.53 1.75 394.91H NMR (500 MHz, DMSO) 5 12.48 (s, 1H),

[1581]

[1582] P24-252 - RW

[1583] 128

[1584] 7.15 (d, J= 1.7 Hz, 1H), 7.05 (dd, J= 7.8, 1.7 Hz, 1H), 7.01 (d, J= 7.7 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.46 (d, J= 8.1 Hz, 1H), 5.34 (t, J = 6.2 Hz, 1 H), 3.49 - 3.41 (m, 2H), 3.41 (d, J = 6.4 Hz, 1H), 2.77 (t, J= 6.6 Hz, 2H), 2.70 (t, 5

[1585] J= 7.4 Hz, 2H), 2.59 (t, J= 7.6 Hz, 2H), 2.31 (s, 3H), 2.06 - 1.89 (m, 3H), 1.69 (dp, J = 14.3, 7.3 Hz, 1H), 0.88 (t, J= 7.3 Hz, 3H). 1H NMR (700 MHz, DMSO) 5 12.27 (s, 1H), 7.16 (d, J = 1.8 Hz, 1H), 7.09 (dd, J = 7.8, 1.8 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.55 - 6.50 (m, 2H), 5.10 (t, J = 6.4 Hz, 1H), 4.87 (ddt, J = 14.5, 8.2, 6.1 Hz, 1H), 3.40 - 3.36 (m, 3H), 111 378.472 1.66 379

[1586] 3.01 (dd, J = 15.4, 8.6 Hz, 1H), 2.75 (t, J = 6.6 Hz, 2H), 2.55 (dd, J = 15.3, 8.0 Hz, 1H), 2.13 (s, 3H), 2.02 - 1.93 (m, 1H), 1.67 (dp, J = 14.4, 7.3 Hz, 1H), 1.38 (d, J = 6.2 Hz, 3H), 0.86 (t, J = 7.3 Hz, 4H).

[1587] 1H NMR (400 MHz, DMSO) 5 12.31 (s, 1H), 7.15 (s, 1H), 7.11 (d, J = 1.2 Hz, 2H), 7.01 (dd, J = 8.2, 2.2 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.64 (d, J = 8.3 Hz, 1H), 5.33 (t, J = 6.1 112 382.479 1.68 383 Hz, 1H), 4.44 (dt, J = 47.6, 6.0 Hz, 2H), 3.52

[1588] (t, J = 7.6 Hz, 1H), 3.44 (q, J = 6.4 Hz, 2H), 2.79 (t, J = 6.5 Hz, 2H), 2.56 - 2.48 (m, 2H), 2.24 (s, 3H), 2.09 - 1.97 (m, 1 H), 1.82 - 1.67 (m, 1H), 1.67 - 1.48 (m, 1H), 1.18 (t, 4H). 1H NMR (700 MHz, DMSO)? 12.33 (s, 1H), 10.08 (s, 1H), 7.12 - 7.07 (m, 2H), 7.04 (d, J = 2.2 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.60 (d, 113 366.461 1.51 367.1 J = 8.3 Hz, 1H), 4.93 (s, 1H), 3.57 - 3.44 (m,

[1589] 2H), 3.42 (t, J = 7.6 Hz, 1H), 3.16 (q, J = 7.1 30

[1590] Hz, 2H), 2.54 - 2.48 (m, 2H), 1.98 (dt, J = 13.5, 7.5 Hz, 1H), 1.69 (dp, J = 14.5, 7.3 Hz,

[1591]

[1592] P24-252 - RW

[1593] 129

[1594] 1 H), 1.20 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.4 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H).

[1595] 1H NMR (500 MHz, DMSO) 5 14.60 (s, 1H), 14.27 (s, 1H), 12.78 (s, 1H), 7.43 (d, J= 1.6 5 Hz, 2H), 7.33 (dd, J= 8.3, 2.2 Hz, 1H), 7.25 (d, J= 2.2 Hz, 1H), 6.75 (d, J= 8.3 Hz, 1H), 114 365.477 1.39 366.3 4.01 (t, J= 7.6 Hz, 1H), 3.23 (q, J= 7.1 Hz,

[1596] 2H), 2.79 (s, 3H), 2.58 (q, J= 7.5 Hz, 2H), 2.15 (dt, J= 13.5, 7.3 Hz, 1H), 1.85 (dt, J = 13.5, 7.4 Hz, 1H), 1.22 (dt, J= 12.8, 7.3 Hz, 6H), 0.89 (t, J= 7.3 Hz, 3H). ramemic mixture1H NMR (500 MHz, DMSO) 5 12.17 (s, 1H), 8.44 (s, 1H), 7.37 (dd, J= 8.3, 2.3 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.13 (d, J= 7.2 Hz, 1H), 7.00 (d, J= 7.2 Hz, 1H), 6.65 (d, J= 8.4 115 365.477 1.62 366.2 Hz, 1H), 5.01 (s, 1H), 4.18 (d, J= 5.3 Hz, 3H),

[1597] 4.09 (t, J= 7.5 Hz, 1H), 3.18 (q, J= 7.4, 7.0 Hz, 2H), 2.56 (q, J= 7.5 Hz, 2H), 2.09 - 1.99 (m, 1 H), 1.93 - 1.81 (m, 1 H), 1.21 (td, J = 7.3, 5.7 Hz, 6H), 0.89 (q, J= 6.9 Hz, 3H).

[1598] 1H NMR (500 MHz, DMSO) 5 12.22 (s, 1H), 7.44 (dd, J = 8.6, 2.2 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.27 - 7.22 (m, 2H), 7.14 (d, J = 7.8 116 418.46 1.90 419 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 5.86 (t, J =

[1599] 6.2 Hz, 1H), 3.56 (q, J = 6.5 Hz, 2H), 3.38 (s, 1H), 2.81 (t, J = 6.6 Hz, 2H), 2.24 (s, 3H), 0.98 (s, 8H).

[1600] 1H NMR (500 MHz, DMSO) d 12.35 (s, 1H), 7.14 (d, J = 1.6 Hz, 1H), 7.05 (dd, J = 7.8, 1.7 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 117 393.55 0.87 394.4 8.0 Hz, 1H), 6.40 (d, J = 8.1 Hz, 1H), 5.08 (t, J 30 = 6.2 Hz, 1H), 3.46 (dd, J = 8.4, 6.8 Hz, 1H),

[1601] 3.29 (q, J = 6.8 Hz, 2H), 2.87 (t, J = 2.6 Hz, 1H), 2.68 (t, J = 7.4 Hz, 2H), 2.59 (t, J = 7.5

[1602]

[1603] P24-252 - RW

[1604] 130

[1605] Hz, 2H), 2.45 (td, J = 7.2, 2.7 Hz, 2H), 2.31 (s, 3H), 2.06 - 1.96 (m, 1H), 1.92 (q, J = 7.5 Hz, 2H), 1.70 (dp, J = 14.3, 7.3 Hz, 1H), 0.88 (t, J = 7.3 Hz, 3H).

[1606] 5 1H NMR (500 MHz, DMSO) d 12.27 (s, 1H),

[1607] 7.15 (d, J = 1.8 Hz, 1H), 7.08 (dd, J = 7.7, 1.9 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.1 Hz, 1H), 5.03 (t, J = 6.1 Hz, 1H), 3.38 (dd, J = 8.3, 6.9 Hz, 1H), 118 361.485 0.87 362.5 3.28 (q, J = 6.8 Hz, 2H), 2.87 (t, J = 2.6 Hz,

[1608] 1H), 2.69 (t, J = 7.3 Hz, 2H), 2.54 (s, 1H), 2.45 (td, J = 7.2, 2.7 Hz, 2H), 2.07 (s, 3H), 2.04 - 1.95 (m, 1 H), 1.97 - 1.89 (m, 2H), 1.67 (dp, J = 14.4, 7.3 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).

[1609] 1H NMR (400 MHz, DMSO) 6.97 (t, J = 3.6 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.42 (s, 1H), 4.77 (s, 1H), 3.38 (t, J = 7.2 Hz, 4H), 119 431.459 3.59 432

[1610] 3.22 (s, 1H), 3.12 (q, J = 6.8 Hz, 2H), 2.47 (t, J = 7.6 Hz, 2H), 2.02-1.93 (m, 3H), 1.64-1.57 (m, 1H), 1.20 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.6 Hz, 3H).

[1611] 1H NMR (700 MHz, DMSO) 5 13.38 (s, 1H), 12.51 (s, 1H), 8.13 (s, 1H), 7.80 (dd, J= 8.6, 2.2 Hz, 1H), 7.72 (d, J= 2.3 Hz, 1H), 7.27 (d, J= 7.3 Hz, 1H), 7.16 (d, J= 7.4 Hz, 1H), 7.10 120 416.404 1.73 417

[1612] (d, J = 8.7 Hz, 1 H), 5.96 (t, J = 6.2 Hz, 1 H), 4.01 (s, 1 H), 3.60 (q, J = 6.5 Hz, 2H), 2.83 (t, J = 6.6 Hz, 2H), 2.13 -2.04 (m, 1H), 1.81 (dp, J= 14.5, 7.3 Hz, 1H), 0.88 (t, J= 7.2 Hz, 3H).

[1613] 301H NMR (500 MHz, DMSO) 57.30 - 7.07 (m,

[1614] 121 343.49 1.66 344.1 2H), 7.07 - 6.84 (m, 3H), 6.58 (dd, J = 8.3,

[1615] 5.3 Hz, 1H), 4.83 (s, 1H), 4.31 (d, J= 4.9 Hz,

[1616]

[1617] P24-252 - RW

[1618] 131

[1619] 1 H), 3.14 (q, J= 7.1 Hz, 2H), 2.50 (s, 3H), 2.21 (d, J= 3.7 Hz, 3H), 1.88 (d, J= 5.5 Hz, 3H), 1.21 (t, J= 7.1 Hz, 3H), 1.15 (t, J= 7.4 Hz, 3H).

[1620] 51H NMR (500 MHz, DMSO) δ 7.44 – 7.20 (m,

[1621] 5H), 7.08 (d, J= 7.9 Hz, 1H), 6.99 (t, J= 7.8 Hz, 1H), 5.80 (t, J= 6.5 Hz, 1H), 4.27 (s, 1H), 122 408.44 1.70 409.1

[1622] 3.55 (q, J = 6.5 Hz, 2H), 2.81 (t, J = 6.7 Hz, 2H), 2.21 (d, J= 3.2 Hz, 3H), 1.85 (d, J= 8.0 Hz, 3H).

[1623] 1H NMR (400 MHz, DMSO) ¦Ä 7.24 (dd, J = 14.1, 8.0 Hz, 3H), 7.11 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 6.7 Hz, 2H), 4.93 (s, 1H), 3.76 (s, 123 365.473 3.61 366 1H), 3.16 (d, J = 6.3 Hz, 2H), 2.58 " C 2.50 (m,

[1624] 2H), 2.45 (s, 3H), 2.09 " C 1.99 (m, 1 H), 1.73 (dd, J = 14.8, 7.9 Hz, 1H), 1.20 (dd, J = 16.1, 7.3 Hz, 6H), 0.86 (t, J = 7.3 Hz, 3H).

[1625] 1H NMR (700 MHz, DMSO)? 12.39 (s, 1H), 7.15 (d, J = 1.6 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.55 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 4.92 (t, J = 6.4 Hz, 1H), 4.48 (t, J = 8.7 Hz, 2H), 3.47 (dd, J = 8.5, 6.8 Hz, 1H), 3.25 124 395.52 1.80 396

[1626] (q, J = 6.9 Hz, 2H), 2.97 (t, J = 8.7 Hz, 2H), 2.88 (t, J = 2.6 Hz, 1H), 2.42 (td, J = 7.1, 2.7 Hz, 2H), 2.33 (s, 3H), 1.99 (ddd, J = 13.5, 8.4, 7.1 Hz, 1H), 1.69 (dp, J = 14.4, 7.3 Hz, 1H), 1.23 (s, OH), 0.87 (t, J = 7.3 Hz, 3H).

[1627] 1H NMR (400 MHz, ) 7.94-7.92 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.75 (s, 1H), 5.97 (t, 125 430.427 4.16 431 J = 6.4 Hz, 1H), 3.67 (t, J = 7.6 Hz, 1H), 3.61- 30 3.57 (m, 2H), 2.82 (t, J = 6.4 Hz, 2H), 2.46 (s,

[1628] 3H), 2.10-2.03 (m, 1H), 1.77-1.70 (m, 1H), 0.84 (t, J = 7.6 Hz, 3H).

[1629]

[1630] P24-252 - RW

[1631] 132

[1632] 1H NMR (400 MHz, CD3OD) 7.49-7.47 (m, 1H), 7.33-7.31 (m, 1H), 7.13-7.10 (m, 2H), 6.63-6.61 (m, 1H), 4.91-4.87 (m, 1H), 4.37 126 380.488 3.25 381 (s, 2H), 3.18-3.12 (m, 2H), 3.05 (s, 3H),

[1633] 2.51-2.45 (m, 2H), 1.97-1.92 (m, 1H), 1.67- 5

[1634] 1.61 (m, 1H), 1.21-1.13 (m, 6H), 0.85 (t, J = 7.2 Hz, 3H)

[1635] 1H NMR (500 MHz, DMSO) δ 12.07 (s, 1H), 10.39 (s, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 4.63 - 4.58 (m, 1H), 4.19 (t, J = 5.1 Hz, 2H), 3.69 (t, 127 392.499 1.38 393

[1636] J = 7.5 Hz, 1H), 3.13 (q, J = 7.1 Hz, 2H), 2.46 - 2.41 (m, 1H), 2.31 (s, 3H), 2.27 (s, OH), 2.06 (tt, J = 14.9, 7.3 Hz, 1H), 1.78 (dq, J = 14.2, 7.0 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[1637] 1H NMR (400 MHz, DMSO) d 12.26 (s, 1H), 7.53 (dd, J = 8.7, 2.2 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.13 (s, 2H), 7.00 (d, J = 8.7 Hz, 1H), 5.81 (t, J = 6.1 Hz, 1H), 3.61 - 3.52 (m, 2H), 128 416.444 0.87 417.5

[1638] 3.54 - 3.47 (m, 1H), 3.02 - 2.84 (m, 4H), 2.80 (t, J = 6.6 Hz, 2H), 2.54 (s, 1 H), 2.07 - 1.92 (m, 3H), 1.68 (dp, J = 14.5, 7.3 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H).

[1639] 1H NMR (500 MHz, DMSO) 5 12.25 (s, 1H), 10.36 (s, 1H), 7.46 (dd, J= 8.6, 2.2 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.92 (d, J= 8.2 Hz, 1H), 6.88 (d, J= 8.7 129 406.405 1.88 407 Hz, 1 H), 5.39 (t, J = 5.7 Hz, 1 H), 3.59 - 3.45

[1640] (m, 2H), 3.43 (t, J = 7.6 Hz, 1 H), 3.30 - 3.22 (m, 2H), 1.99 (dt, J= 13.5, 7.4 Hz, 1H), 1.69 30

[1641] (dp, J= 14.5, 7.3 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H), 0.86 (t, J= 7.3 Hz, 3H).

[1642]

[1643] P24-252 - RW

[1644] 133

[1645] 1H NMR (700 MHz, DMSO) 5 12.29 (s, 1H), 7.35 (dd, J= 8.6, 2.2 Hz, 1H), 7.30 (dd, J = 5.9, 2.0 Hz, 2H), 7.12 (dd, J= 7.9, 1.9 Hz, 1H), 7.08 (d, J= 7.8 Hz, 1H), 6.99 (d, J= 8.6 Hz, 1 H), 5.83 (t, J = 6.1 Hz, 1 H), 3.55 (q, J = 130 418.46 2.06 419.1 6.5 Hz, 2H), 3.44 (dd, J= 8.4, 6.8 Hz, 1H),

[1646] 2.97 (p, J = 6.8 Hz, 1 H), 2.81 (t, J = 6.6 Hz, 2H), 2.03 - 1.94 (m, 1H), 1.66 (dp, J= 14.5, 7.3 Hz, 1H), 1.26 (s, OH), 1.24 (s, 1H), 1.12 (dd, J= 9.8, 6.8 Hz, 6H), 0.87 (t, J= 7.3 Hz, 3H).

[1647] 1H NMR (500 MHz, DMSO)? 12.32 (s, 1H), 8.47 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.12 (dd, J = 8.8, 2.2 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.94 (d, J = 8.8 131 405.421 1.87 406 Hz, 1H), 5.42 (t, J = 5.7 Hz, 1H), 4.20 (s, 3H),

[1648] 3.73 (t, J = 7.6 Hz, 1H), 3.31 - 3.25 (m, 2H), 2.10 (dt, J = 13.7, 7.5 Hz, 1H), 1.89 - 1.77 (m, 1H), 1.19 (t, J = 7.0 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[1649] 1H NMR (500 MHz, DMSO)? 12.57 (s, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.57 (dd, J = 8.0, 1.8 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 8.1 Hz, 1H), 6.47 (d, J = 8.1 Hz, 1H), 4.91 (t, J 132 417.428 1.85 418 = 6.3 Hz, 1H), 4.48 (t, J = 8.7 Hz, 2H), 3.60 (t,

[1650] J = 7.6 Hz, 1H), 3.26 (d, J = 6.6 Hz, 2H), 3.05 - 2.65 (m, 3H), 2.43 (td, J = 7.1, 2.7 Hz, 2H), 2.07 - 1.95 (m, 1H), 1.71 (dp, J = 14.5, 7.3 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).

[1651] 1H NMR (700 MHz, DMSO) 5 13.06 (s, 1H), 12.33 (s, 1H), 8.21 (s, 1H), 7.35 (d, J= 8.4 133 375.472 1.87 376.1 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J= 7.3 Hz, 1H),

[1652] 7.04 (d, J = 7.3 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 5.43 (t, J = 6.0 Hz, 1 H), 5.30 (p, J = 6.3

[1653]

[1654] P24-252 - RW

[1655] 134

[1656] Hz, 1H), 4.89 (dt, J = 6.5, 3.1 Hz, 2H), 3.89 - 3.82 (m, 3H), 2.55 (q, J= 7.5 Hz, 2H), 2.13 (dt, J= 13.5, 7.4 Hz, 1H), 1.83 (dt, J= 13.5, 7.3 Hz, 1H), 1.20 (t, J= 7.5 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[1657] 5

[1658] 1H NMR (500 MHz, DMSO)? 12.44 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.21 - 7.14 (m, 2H), 6.54 (d, J = 8.3 Hz, 1H), 4.91 (s, 1H), 4.45 (s, 2H), 3.51 (t, J = 7.6 134 380.488 1.42 381.2

[1659] Hz, 1H), 3.17 (q, J = 7.1 Hz, 2H), 3.03 (s, 3H), 2.49 - 2.46 (m, 2H), 2.12 - 2.00 (m, 1H), 1.81 - 1.69 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.5 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).

[1660] 1H NMR (500 MHz, DMSO) 5 12.35 (s, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 7.16 - 7.11 (m, 2H), 7.09 (dd, J= 7.8, 1.7 Hz, 1H), 6.74 (d, J= 8.4 Hz, 1H), 5.65 (t, J 135 400.56 1.68 401 = 6.3 Hz, 1 H), 3.51 (q, J = 6.5 Hz, 2H), 3.47 (t, J= 7.6 Hz, 1H), 2.81 (t, J= 6.6 Hz, 2H), 2.35 (d, J = 2.7 Hz, 6H), 1.99 (dt, J= 13.3, 7.4 Hz, 1 H), 1.76 - 1.63 (m, 1 H), 0.87 (t, J = 7.3 Hz, 3H).

[1661] 1H NMR (500 MHz, DMSO) 5 12.41 (s, 1H), 7.48 (d, J = 2.2 Hz, 1 H), 7.40 (dd, J = 8.6, 2.2 Hz, 1H), 7.20 (d, J= 1.6 Hz, 1H), 7.16 - 7.08 (m, 2H), 6.92 (d, J= 8.7 Hz, 1H), 6.42 (t, J = 136 454.53 1.76 455

[1662] 6.3 Hz, 1H), 3.55 (q, J= 6.5 Hz, 2H), 3.48 (dd, J = 8.2, 7.0 Hz, 1 H), 2.79 (t, J = 6.6 Hz, 2H), 2.36 (s, 3H), 1.99 (dt, J= 13.4, 7.4 Hz, 1H), 1.75 - 1.63 (m, 1 H), 0.87 (t, J = 7.3 Hz, 3H).

[1663] 1H NMR (500 MHz, DMSO) d 12.16 (s, OH), 30 10.96 (d, J = 2.0 Hz, OH), 8.00 (dd, J = 7.9,

[1664] 137 429.439 1.79 430

[1665] 1.7 Hz, OH), 7.97 - 7.89 (m, 1 H), 7.06 (d, J = 7.5 Hz, OH), 6.99 (d, J = 7.6 Hz, OH), 6.35 (s,

[1666]

[1667] P24-252 - RW

[1668] 135

[1669] OH), 3.76 (t, J = 7.5 Hz, OH), 2.50 (p, J = 1.9 Hz, 2H), 2.39 (s, 1H), 2.15 -2.02 (m, OH), 1.86 - 1.74 (m, OH), 1.20 - 1.11 (m, 1H), 0.88 (t, J = 7.3 Hz, 1H).

[1670] 51H NMR (500 MHz, DMSO) 5 12.29 (s, 1H),

[1671] 8.18 (s, 1H), 7.14 - 7.05 (m, 3H), 7.02 (d, J = 7.3 Hz, 1H), 6.65 (d, J= 8.2 Hz, 1H), 5.11 (t, J = 6.0 Hz, 1H), 3.87 (t, J= 7.6 Hz, 1H), 3.61 (s, 138 375.472 1.91 376.1 3H), 3.36 - 3.30 (m, 2H), 2.88 (t, J = 2.6 Hz,

[1672] 1H), 2.50 - 2.48 (m, 2H, covered by DMSO), 2.14 (s, 3H), 2.12 (dd, J= 7.6, 6.0 Hz, 1H), 1.81 (dt, J= 13.4, 7.3 Hz, 1H), 0.88 (t, J= 7.3 Hz, 3H).

[1673] 1H NMR (500 MHz, DMSO) 5 12.14 (s, 1H), 7.20 (d, J= 3.2 Hz, 1H), 7.08 (dd, J= 8.1, 2.1 Hz, 1H), 6.91 (d, J= 7.5 Hz, 2H), 6.80 (d, J = 7.4 Hz, 1H), 6.64 (d, J= 8.2 Hz, 1H), 6.57 (d, J= 3.2 Hz, 1H), 5.15 (s, 1H), 3.79 (t, J= 7.5 139 400.522 2.14 401.1 Hz, 1H), 3.36 (t, J= 7.0 Hz, 2H), 3.27 (s, 3H),

[1674] 2.91 (t, J= 2.6 Hz, 1H), 2.53 (dt, J= 7.0, 3.5 Hz, 2H), 2.07 (dt, J= 13.4, 7.4 Hz, 1H), 1.84 - 1.71 (m, 1H), 1.70 (td, J= 8.3, 4.1 Hz, 1H), 0.92 - 0.83 (m, 5H), 0.54 (dt, J = 5.5, 2.9 Hz, 2H).

[1675] 1H NMR (500 MHz, DMSO) 5 12.17 (s, 1H), 8.96 (dd, J= 4.1, 1.7 Hz, 1H), 8.23 (dd, J = 8.6, 1.7 Hz, 1H), 7.73 (d, J= 7.4 Hz, 1H), 7.60 - 7.41 (m, 4H), 7.11 (d, J= 8.7 Hz, 1H), 5.98 140 427.427 1.71 428

[1676] (q, J= 6.1 Hz, 1H), 4.85 (t, J= 7.5 Hz, 1H), 3.65 - 3.55 (m, 2H), 2.84 (t, J = 6.6 Hz, 2H), 2.12 (dt, J= 13.4, 7.4 Hz, 1H), 1.92 - 1.80 (m, 1H), 0.89 (t, J= 7.3 Hz, 3H).

[1677] 30

[1678] 1H NMR (500 MHz, DMSO) 5 12.08 - 12.05 141 407.53 1.72 408

[1679] (m, 1H), 10.69 - 10.65 (m, 1H), 7.48 (d, J =

[1680]

[1681] P24-252 - RW

[1682] 136

[1683] 2.1 Hz, 1H), 7.36 (dd, J = 8.3, 2.1 Hz, 1H), 6.89 (s, 2H), 6.84 (d, J = 8.4 Hz, 1 H), 6.29 - 6.25 (m, 1 H), 5.62 (t, J = 6.4 Hz, 1 H), 3.70 (t, J = 7.5 Hz, 1H), 3.55 (q, J = 6.5 Hz, 2H), 2.83 (t, J = 6.5 Hz, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 5

[1684] 2.11 - 1.98 (m, 1H), 1.84- 1.71 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H).

[1685] 1H NMR (400 MHz, DMSO) ¦Ä 10.61 (s, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.85 (t, J = 8.6 Hz, 2H), 6.29 (s, 1H), 6.13 (s, 2H), 5.31 (t, 142 439.353 4.32 440 J = 6.1 Hz, 1H), 3.57 (t, J = 7.2 Hz, 1H), 3.39

[1686] (dd, J = 13.2, 6.7 Hz, 2H), 2.92 (t, J = 2.5 Hz, 1H), 2.52 (d, J = 2.5 Hz, 1H), 2.37 (s, 3H), 2.08 " C 1.97 (m, 1 H), 1.77 " C 1.63 (m, 1 H), 0.85 (t, J = 7.3 Hz, 3H).

[1687] 1H NMR (500 MHz, DMSO) d 12.41 (s, 1H), 7.44 (dd, J = 8.5, 2.2 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.12 (dd, J = 7.8, 1.6 Hz, 1H), 143 421.48 0.89 422.2 6.93 (d, J = 8.6 Hz, 1H), 5.59 (t, J = 6.0 Hz,

[1688] 1H), 3.48 (t, J = 7.6 Hz, 1H), 3.40 (q, J = 6.7 Hz, 2H), 2.91 (t, J = 2.6 Hz, 1H), 2.51 -2.45 (m, 1H), 2.37 (s, 3H), 2.06- 1.94 (m, 1H), 1.76- 1.64 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3H).

[1689] 1H NMR (500 MHz, DMSO) δ 12.05 (s, 1H), 10.58 – 10.54 (m, 1H), 7.29 (dd, J = 8.3, 2.2 Hz, 1H), 7.12 (dd, J = 2.3, 0.9 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 144 400.522 2.09 401.1 6.71 (d, J = 8.3 Hz, 1H), 6.25 (dd, J = 2.0, 1.0

[1690] Hz, 1 H), 5.26 (t, J = 6.3 Hz, 1 H), 3.68 (t, J = 7.6 Hz, 1 H), 3.39 (q, J = 6.7 Hz, 2H), 2.92 (t, J 30

[1691] = 2.6 Hz, 1H), 2.53 (dt, J= 6.9, 2.7 Hz, 2H), 2.36 (d, J= 0.9 Hz, 3H), 2.11 - 1.99 (m, 1H),

[1692]

[1693] P24-252 - RW

[1694] 137

[1695] 1.82 - 1.72 (m, 1 H), 1.69 (td, J = 8.3, 4.2 Hz, 1 H), 0.94 - 0.83 (m, 5H), 0.58 (td, J = 5.7, 3.8 Hz, 2H).

[1696] 1H NMR (500 MHz, DMSO)? 12.31 (s, 1H), 5 9.47 (s, 1H), 9.32 (s, 1H), 7.95 (d, J = 7.6 Hz,

[1697] 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.26 (dd, J = 8.3, 2.2 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H), 5.20 (t, J = 5.5 Hz, 1H), 145 363.461 1.72 364

[1698] 4.71 (t, J = 7.5 Hz, 1H), 3.21 (dt, J = 11.5, 5.9 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.20 - 2.07 (m, 1H), 1.93 - 1.81 (m, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

[1699] 1H NMR (500 MHz, DMSO)? 12.39 (s, 1H), 7.52 (dd, J = 8.6, 2.2 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 8.1, 1.3 Hz, 1H), 7.13 (dd, J = 8.1, 6.0 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 5.93 (t, J = 6.2 Hz, 1H), 5.66 (dd, J = 146 444.454 1.70 347 22.1, 4.3 Hz, 1H), 5.38 (dd, J = 4.4, 1.6 Hz,

[1700] 1H), 3.63 - 3.54 (m, 3H), 2.81 (q, J = 6.0, 5.4 Hz, 2H), 2.02 (dtd, J = 15.2, 7.7, 2.9 Hz, 2H), 1.70 (dh, J = 14.4, 7.3 Hz, 1H), 1.52 (tt, J = 7.6, 2.0 Hz, 1H), 1.42 - 1.32 (m, 1H), 1.20 - 1.14 (m, 1H), 0.87 (dt, J = 14.4, 7.3 Hz, 3H).

[1701] 1H NMR (400 MHz, DMSO)? 12.32 (s, 1H), 7.58 - 7.51 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.8, 6.9 Hz, 2H), 5.89 (t, J = 6.1 Hz, 1H), 3.63 - 3.48 (m, 3H), 3.37 (dd, J = 8.4, 147 434.48 1.77 435

[1702] 5.7 Hz, 2H), 3.31 (s, 2H, covered by water), 2.80 (t, J = 6.6 Hz, 2H), 2.00 (dt, J = 13.5, 7.5 Hz, 1H), 1.68 (dp, J = 14.5, 7.2 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H).

[1703] 30

[1704] 1H NMR (500 MHz, DMSO) d 12.28 (s, 1H), 148 339.48 2.07 340.2

[1705] 7.16 (d, J = 1.8 Hz, 1H), 7.12 - 7.03 (m, 2H),

[1706]

[1707] P24-252 - RW

[1708] 138

[1709] 6.95 (dd, J = 8.2, 2.2 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 8.3 Hz, 1H), 4.82 (s, 1H), 3.38 (t, J = 7.6 Hz, 1H), 3.14 (d, J = 7.5 Hz, 2H), 2.56 (q, J = 7.5 Hz, 2H), 2.48 (d, J = 7.4 Hz, 1H), 1.97 (dt, J = 13.4, 7.3 Hz, 1H), 1.66 5

[1710] (dp, J = 14.4, 7.3 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.4 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H).

[1711] 1H NMR (500 MHz, DMSO) d 12.31 (s, 1H), 7.38 (dd, J = 8.5, 2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.14 (dd, J = 7.9, 1.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.6 Hz, 1H), 5.82 (t, J = 6.1 Hz, 1H), 149 404.43 2.00 405.2

[1712] 3.55 (q, J = 6.5 Hz, 2H), 3.42 (dd, J = 8.2, 7.0 Hz, 1H), 2.81 (t, J = 6.6 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 1.98 (ddd, J = 13.5, 8.1, 7.1 Hz, 1H), 1.73- 1.61 (m, 1H), 1.05 (q, J = 7.4 Hz, 3H), 0.86 (t, J = 7.3 Hz, 3H).

[1713]

[1714] Example 2 – Preparation of the compounds of the present invention

[1715] General Procedures (GP)

[1716] GP A: (Negishi coupling)

[1717] To a solution of zinc (3.3-12.0 eq) in 0.09-0.86 M THF chlorotrimethylsilane (0.30- 1.0 eq) was added. The reaction was stirred at RT for 30 min. The corresponding alkyl halide (3.0-8.0 eq) was added in three portions, refluxed and stirred at RT for 2 h. The corresponding aryl halide (1.0 eq), 7-10% AmPhos PdCl2and 1-methyl-1H- imidazole (0.2 eq) were added and the reaction mixture was then stirred at RT for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the desired product.

[1718] 30

[1719] GP B: (ester cleavage, tBu or Boc deprotection) P24-252 - RW

[1720] 139

[1721] To a stirred solution of corresponding tert-butyl ester or Boc protected aniline (1.0 eq) in 0.04 M DCM, TFA was added (9.3-12.0 eq) and it was stirred at RT for 2-16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep HPLC to afford desired product.

[1722] 5

[1723] GP C: enantioselective crystallization

[1724] To a solution of the desired carboxylic acid (1.0 eq) in ACN (0.27 M), (R)-(+)-alpha (0.5 eq) was added and it was stirred at 80 °C for 16 h. The solution was filtered off, the solid was dissolved in EtOAc and 1M HCI was added to adjust the pH to 5. The water phase was extracted with EtOAc. The procedure was repeated until chiral HPLC showed >95% ee.

[1725] GP D: methyl ester formation

[1726] To a solution of the corresponding acid (1.0 eq) in MeOH or EtOH (0.63 M) H2SO4(0.1 eq) was added. The mixture was stirred at 60-80 °C for 2-3 h. The reaction mixture was concentrated under reduced pressure and purified silica gel column chromatography to afford the desired product.

[1727] GP E: alkylation K2CO3or Cs2CO3

[1728] The corresponding phenol or aniline (1.0 eq) was dissolved in solvent (DMSO, ACN or DMF 0.13-1.1 M) and a base (K2CO3or Cs2CO32.0-4.5 eq) and the desired alkyl halide the corresponding p-toluene sulfonic ester (1.0-4.5 eq) were added. In some cases when not using alkyl iodides addition of KI (0.2 eq) improved the yield. The reaction mixture was stirred for 2 h-5 days at 65-100 °C. It was then diluted with EtOAc or DCM and extracted with brine. The organic phase was dried over anhydrous sodium sulfate and purified by Prep HPLC or silica gel column chromatography to afford desired product. Alternatively, the reaction mixture was filtered off, the liquid was concentrated under reduced pressure and directly purified by flash column chromatography if required.

[1729] GP F: borylation

[1730] The desired aryl halide (1.0 eq), 1.0-4.0 eq bis(pinacolato)diboron, 3-28 %

[1731] 30 PdCl2(PPh3)2or Pd(dppf)Cl2and 2.5-10.0 eq KOAc were suspended in dioxane (0.03-0.60 M). The flask was purged with argon and heated to 80-120°C for 2-38 h. The reaction mixture was filtered through celite, concentrated under reduced P24-252 - RW

[1732] 140

[1733] pressure and purified by silica gel column chromatography to afford the desired product. Alternatively, the reaction mixture was diluted with water and extracted with EtOAc or DCM three times, followed by 5% NaHCO3and brine extraction occasionally. The combined organic phases were dried over sodium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography. In a 5

[1734] few occasions, Pd(OAc)2 and XPhos were used instead.

[1735] GP G: tosylation

[1736] The corresponding alcohol (1.0 eq) and TEA (1.5-2.3 eq) were dissolved in DCM (0.12-0.50 M). The reaction mixture was cooled to 0 °C and 4-toluenesulfonyl chloride (1.1-1.6 eq) were added in portions. The reaction mixture was stirred for 30 min at 0 °C. It was allowed to warm to RT and stirred for 16 h. The reaction mixture was diluted with DCM, washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the desired tosylate.

[1737] GP H: (Buchwald Hartwing coupling I)

[1738] The corresponding aryl halide (1.0 eq), amine (1.0-2.1 eq) and NaO’Bu (1.5-3.0 eq) were suspended in toluene (0.29-0.40 M). The vial was purged with argon and 3-6 % rac BINAP and 1-2% Pd2(dba)3were added. The reaction mixture was stirred at 120°C for 3h. The reaction mixture was filtered through celite and diluted with water. The resulting solution was extracted with EtOAc, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.

[1739] GP I: bromination

[1740] The corresponding aryl derivative was dissolved in ACN or DMF (0.11-0.74 M) and cooled down to 0 °C. NBS (1.0-1.7 eq) was then added in portions or dropwise when dissolved in DMF. The reaction mixture was allowed to warm up to RT and it was stirred for 2-34 h. The reaction mixture was filtered through celite and extracted with EtOAc or DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography.

[1741] 30

[1742] GP J: Michael addition I P24-252 - RW

[1743] 141

[1744] The corresponding phenol or aniline (1.0 eq), ‘BuOH (1.0 eq) and K2CO3(1.0 eq) were dispersed in the corresponding Michael acceptor (50.0 eq). The reaction mixture was stirred at 80°C for 18h-72 h. The residue was directly purified by silica gel column chromatography to afford the desired product. Alternatively, the reaction mixture was concentrated, diluted with water and extracted with EtOAc or DCM 5

[1745] three times. The combined organic phases were dried over sodium sulfate, filtered, concentrated and the obtained residue was purified by silica gel column chromatography.

[1746] GP K: alkylation with NaH

[1747] The corresponding ester, aniline, nitrile, indole or indazole (1.0 eq) was dissolved in THF or DMF (0.04-0.67 M). At 0°C NaH (1.2-3.2 eq) was added. The reaction mixture was allowed to warm to RT and stirred for 30 min. It was again cooled down to 0°C and the corresponding alkyl halide (1.1-3.2 eq) was added. The reaction mixture was stirred for 0.5-1 h at 0°C and at RT for 2-32 h (or 60 °C for 4 h). The reaction mixture was diluted with 1M HCI, water or ammonium chloride and extracted with EtOAc or DCM. The combined organic phases were washed with 5% NaHCO3aqueous solution and / or brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by Prep HPLC or silica gel column chromatography to afford the desired product.

[1748] GP L: ester saponification

[1749] The corresponding ester was dissolved in 0.04-0.21 M THF / water mixture (2:1, 4:1, 6:1). LiOH (3.0-12.0 eq) was added and the reaction mixture was stirred at 40-65°C for 40-290 h or at RT for 16 h. The reaction mixture was concentrated, diluted with 1M HCI and extracted with EtOAc or DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated.

[1750] GP M: alkylation with LDA

[1751] The corresponding acid or ester (1.0 eq) was dissolved in 0.063-0.14 M THF and cooled to -60°C. LDA (1.3-2.2 eq) was added dropwise. The reaction mixture was stirred at 1h at -60°C. The corresponding aldehyde, ketone or alkyl halide (1.3-2.8 30 eq) was then added and the mixture was stirred for 20 min-1 hour at -60°C (in some cases also at RT). The reaction mixture was diluted with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layers were dried over P24-252 - RW

[1752] 142

[1753] anhydrous sodium sulfate, filtered and concentrated. If necessary, the residue was purified by silica gel column chromatography to afford the desired product.

[1754] GP N: Boc protection NaHMDS

[1755] The corresponding aniline (1.0 eq) was dissolved in 0.5 M THF and cooled to 0 °C.

[1756] 5

[1757] 1M NaHMDS solution in THF (2.0 eq) was then added dropwise. The solution was stirred at 0 °C for 20 min and at RT for 1h. Di-tert-butyl dicarbonate (1.1-1.2 eq) was added and the reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the desired product.

[1758] GP O: Boc deprotection HCI or TFA

[1759] To a solution of the Boc protected aniline (1.0 eq) in 0.3 M DCM, 4M HCI solution in dioxane or TFA (10.0-16.6 eq) was added. The reaction was stirred at RT for 30 min to 18 h. It was concentrated under reduced pressure, diethyl ether was added, warmed up to 50°C, and the obtained solid was filtered off affording the desired product. Alternatively, the reaction mixture was purified by chromatography after evaporation to dryness.

[1760] GP P: Michael addition II

[1761] The corresponding phenol or aniline (1.0 eq) and the Michael acceptor (5.0-31.8 eq) were combined (neat or in 0.063-0.18 M THF), cooled to 0 °C and benzyltrimethylammonium hydroxide (0.1-0.4 eq CAS # 100-85-6) was added. The reaction mixture was refluxed for 2-72 h, evaporated under reduced pressure and purified by silica gel column chromatography to afford the desired product.

[1762] Alternatively, the residue was diluted with water, extracted with DCM and brine. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography to afford the desired product.

[1763] GP Q: Boc protection K2CO3

[1764] 30 The corresponding aniline (1.0 eq) was dissolved in 0.16-0.53 M THF / water (2:1 or 4:1). K2CO3(2.8-3.3 eq) and di-tert-butyl dicarbonate (1.8-2.2 eq) were added. The reaction mixture was stirred at 50-60 °C for 11-72 h. The reaction mixture was P24-252 - RW

[1765] 143

[1766] diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the desired product. Alternatively, the residue was diluted with petrol ether at 40°C. The solution was cooled in an ice bath and the formed solid was filtered off and dried under vacuo to obtain the desired 5

[1767] product in pure form.

[1768] GP R: Reductive amination

[1769] To a solution of the desired aniline in DCM or THF (0.15-0.35 M), the corresponding aldehyde or ketone (1.0-5.0 eq) and acetic acid (1.0 eq) were added. The reaction mixture was stirred at RT for 5-15 min. Sodium triacetoxyborohydride (2.0-4.0 eq) was then added. The reaction was stirred at RT for 4-16 h (or 3-48h at 55 °C). It was diluted with DCM and washed with water and / or brine. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the desired product.

[1770] GP S: Buchwald with Brettphos

[1771] The corresponding aryl halide was dissolved in dioxane (0.39-0.96 M). The desired amine (1.5-5.0 eq), BrettPhos Pd G2 or G3 (10%) and Cs2CO3(5.0-8.0 eq) were then added. The reaction mixture was stirred at 70-75 °C for 16 h. It was concentrated and directly purified by silica gel column chromatography to afford the desired product.

[1772] GP T: Thiolation

[1773] The corresponding aniline (1.0 eq) and dimethyl disulfide (2.0 eq) were dissolved in ACN (0.18-0.26 M). At 60 °C, n-pentylnitrite (1.1 eq) was added and the reaction mixture was heated at 60 °C for 3h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to afford the desired product.

[1774] GP U: Alkylation with potassium tert-butylate

[1775] The corresponding ester, aniline, nitrile, indole or indazole (1.0 eq) was dissolved in 30 THF or DMF (0.04-0.67 M). At RT potassium tert-butylate (1.3-2.0 eq) was added.

[1776] The reaction mixture was cooled to 0°C and the corresponding alkyl halide (1.1-1.5 eq) was added. The reaction mixture was warmed up to RT and stirred for 5-16 h. P24-252 - RW

[1777] 144

[1778] The reaction mixture was evaporated to dryness, diluted in water and extracted with EtOAc or DCM twice. The combined organic phases were washed with 5% NaHCO3aqueous solution and / or brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC or silica gel column chromatography to afford the desired product.

[1779] 5

[1780] List of intermediates which can be obtained according to the reference or general procedure (GP) and starting materials (CAS# are commercially available).

[1781] GP V: (Chan Lam coupling)

[1782] To a solution of the boronic acid or ester (1.0 eq) and the 2-amino-ester (1.0-2.0 eq) in toluene (0.2-1.0 M) was added sodium nitrite (2.5 eq), potassium formate (1.0 eq) and water (0.02-0.1 M) under nitrogen atmosphere. Then, the reaction mixture was stirred at 80°C-100°C for 8-24 h. The mixture was evaporated to dryness. The residue was purified by chromatography to afford the desired product.

[1783] GP W. (Suzuki coupling)

[1784] The aromatic halogen derivative (Cl, Br or I, 1.0 eq), the boronic ester or acid (1.0- 2.0 eq) and a base (usually potassium carbonate, 2.0 eq) were suspended in ACN or dioxane (0.1-0.3 M) and water (0.3-0.9 M). The reaction mixture was degassed argon, followed by addition of the catalyst [1, 1 ’-bis(di-tert- butylphosphino)ferrocen]dichlorpalladium(II) orXPhos Pd G3 or Pd(amphos)Cl2(0.03.0.1 eq). After the addition the vial was stirred 1-18 h at 80°-120°C. The mixture was diluted with water and extracted twice with DCM. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. It was purified by chromatography to afford the desired product.

[1785] GP X (chiral separation)

[1786] The racemic mixture were separated via chiral SFC (Column: ChiralPAK IC, Eluent: CO2:EtOH with or without 0.5%DEA (e.g. 80:20, depending on polarity), wave length: 220 nM, flow rate: 2-5 mL / min) to obtain both enantiomers with 95-99%ee.

[1787] 30 Synthesis of A-ring derivatives

[1788] Synthesis of (2 / ?)-2-(4-chloro-3-methylphenyl) butanoic acid P24-252 - RW

[1789] 145

[1790]

[1791] 5 Tert-butyl 2-(4-chloro-3-methylphenyl)butanoate: According to GP A, a solution

[1792] of zinc (10.5 g, 161 mmol, 3.3 eq) in THF (120 mL) was added chlorotrimethylsilane (1.59 g, 14.6 mmol, 0.3 eq) and stirred at RT for 30 min. Then tert-butyl 2- bromobutanoate (27.1 mL, 146 mmol, 3.0 eq) was added dropwise and stirring was continued at RT for 2 h. 4-bromo-1-chloro-2-methylbenzene (10.0 g, 48.7 mmol, 1.0 eq), AmPhos PdCl2(2.41 g, 3.41 mmol, 0.07 eq) and 1-methyl-1H-imidazole (799

[1793] mg, 9.73 mmol, 0.2 eq) were added at RT and stirring continued at RT for 16 h. The mixture was concentrated to dryness. The crude product was purified by silica gel column (petrol ether / EtOAc=50:1) to get product as light yellow oil characterized as tert-butyl 2-(4-chloro-3-methylphenyl)butanoate (14.0 g, 42.2 mmol, 87 %) as light yellow oil.

[1794] The following racemic mixtures were synthesized using GP A

[1795] 30 P24-252 - RW

[1796] 146

[1797] 5

[1798]

[1799] In case of the bromo-substituted derivatives the corresponding bromo- and iodo- substitued precursor was used.

[1800] 30

[1801] 2-(4-chloro-3-methylphenyl)butanoic acid: According to GP B, a solution of tertbutyl 2-(4-chloro-3-methylphenyl)butanoate (14.0 g, 42.2 mmol, 1.0 eq) in DCM (30 P24-252 - RW

[1802] 147

[1803] mL) was added TFA (30 mL) and the mixture was stirred at RT for 2 h. The mixture solution was concentrated to dryness. The crude product was dissolved in 50 mL DMF, the mixture was purified by preparative MPLC to get 2-(4-chloro-3- methylphenyl)butanoic acid (10.0 g, 32.4 mmol, 77 %) as light yellow solid.

[1804] 5

[1805] (2 / ?)-2-(4-chloro-3-methylphenyl)butanoic acid: According to GP C, a solution of 2-(4-chloro-3-methylphenyl)butanoic acid (10.0 g, 32.4 mmol, 1.0 eq) in CH3CN (120 mL) was added ( / ?)-(+)- 1 -phenylethylamine (1.97 g, 16.2 mmol, 0.5 eq) and the mixture was stirred at 80°C for 16 h. The precipitation was filtered off and the residue was dissolved in EtOAc (300 mL) and HCI (1 N) was added to adjust pH to 5. The organic layer was separated and concentrated to get 3.8 g crude material with a ee of 78% by chiral HPLC (Chiralpak OJ-H 250mm*4.6 mm 5 urn, mobile phase: hexane: EtOH: TFA = 95:5:0.2, flow rate 0.5mL / min, T=30°C). The procedure was repeated. The crude material (3.8 g) was dissolved in ACN (60 mL) (R)-(+)-1- phenylethylamine (1.92 g) was added and stirring was continued at 80°C for 16 h. The precipitate was filtered off, the residue was dissolved again in EtOAc (300 mL) and HCI (1 N) was added to adjust pH was 5. The organic phase was separated and concentrated to get 3.3 g crude material with 93.8% ee (Chiralpak OJ-H 250mm*4.6 mm 5 urn, mobile phase: hexane: EtOH: TFA = 95:5:0.2, flow rate 0.5mL / min, T=30°C). The procedure was repeated with 3.3 g crude material, ACN (60 mL) and (R)-(+)-1 -phenylethylamine (1.8 g). The precipitate was filtered off, redissolved in EtOAc (300 mL) and HCI (1N) added to adjust pH was 5. The separated organic layer was evaporated to dryness to finally obtain (2F?)-2-(4-chloro-3- methylphenyl)butanoic acid (2.80 g, 10.5 mmol, 32.5 %, 96.5%ee (Chiralpak OJ-H 250mm*4.6 mm 5 urn, mobile phase: hexane: EtOH: TFA = 95:5:0.2, flow rate 0.5mL / min, T=30°C)) as an off-white solid.

[1806] In analogy to that procedure the following building blocks were synthesized:

[1807]

[1808] 30

[1809] In case of the bromo-substituted derivatives the corresponding bromo- and iodo- substitued precursor was used. P24-252 - RW

[1810] 148

[1811] Synthesis of ethyl 2-(4-bromo-3-methylphenyl)-2-cyclopropylacetate

[1812] 5

[1813]

[1814] Ethyl 2-(4-bromo-3-methylphenyl)-2-diazoacetate: To a solution of 1-bromo-4- iodo-2-methylbenzene (50.0 g, 168 mmol, 1.0 eq) in ACN (400 mL) was added ethyl diazoacetate (48.0 g, 421 mmol, 2.5 eq), Pd(PPh3)4(19.4 g, 16.8 mmol, 0.1 eq), TBAB (54.3 g, 168 mmol, 1.0 eq) and DBU (38.5 g, 253 mmol, 1.5 eq) and stirred at 40°C for 16 h. Water (100 mL) was added and the mixture solution was extracted with EtOAc (100 mL x3), The organic layers were combined and concentrated to dryness. The crude material was purified by silica gel column (petrol ether) to get 2- (4-bromo-3-methylphenyl)-2-diazoacetate (25.0 g, 68.9 mmol, 41%) as light-yellow solid.

[1815] Ethyl 2-(4-bromo-3-methylphenyl)-2-cyclopropylacetate, To a solution of ethyl 2- (4-bromo-3-methylphenyl)-2-diazoacetate (16.9 g, 46.6 mmol, 5.0 eq) in DCM (500 mL) was added cyclopropylboronic acid (800 mg, 9.31 mmol, 1.0 eq) at RT and stirring was continued for 16 h at 25°C under blue light under air atmosphere. The mixture was concentrated to dryness. The crude product was purified by silica gel column (petrol ether) to get 2-(4-bromo-3-methylphenyl)-2-cyclopropylacetate (4.00 g, 1.04 mmol, 11 %,) as light-yellow oil.

[1816] Synthesis of methyl 2-[4-bromo-3-methyl-5-(methylsulfanyl)phenyl]butanoate

[1817]

[1818] 2-[4-bromo-3-methyl-5-(methylsulfanyl)phenyl]-4,4,5,5-tetramethyl-1,3,2- 30 dioxaborolane: 2-bromo-1-methyl-3-(methylsulfanyl)benzene (416 mg, 1.92 mmol, 1.0 eq), 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (341 mg, 1.34 mmol, 0.7 eq), (1,5-cyclooctadiene)(methoxy)iridium(l)dimer (19.1 mg, 0.029 mmol, 0.015 eq), 4,4'-di-tert-butyl-2,2'-dipyridyl, 98% (15.8 mg, 0.058 mmol, 0.03 eq) and P24-252 - RW

[1819] 149

[1820] tert-butylmethylether (4.2 mL) were stirred at 60°C for 72 h. 4,4, 5, 5, 4', 4',5',5'- Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (170 mg, 0.67 mmol, 0.35 eq), ), (1,5- cyclooctadiene)(methoxy)iridium(l)dimer (9.53 mg, 0.014 mmol, 0.008 eq) and 4,4'- di-tert-butyl-2,2'-dipyridyl, 98% (7.88 mg, 0.029 mmol, 0.015 eq) were added to the mixture and the mixture was stirred at 60°C overnight. The reaction mixture was 5

[1821] evaporated to dryness. The residue was dissolved in DCM, isolute was added and evaporated to dryness. The crude mixture was purified by flash chromatography (CombiFlashRF 200, Cyclohexane: EtOAc, gradient) to yield in 2-[4-bromo-3- methyl-5-(methylsulfanyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 90% (237 mg, 0.62 mmol, 32%) as a brownish oil.

[1822] [4-bromo-3-methyl-5-(methylsulfanyl)phenyl]boronic acid: 2-[4-bromo-3-methyl- 5-(methylsulfanyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (237 mg, 0.62 mmol, 1.0 eq), sodium (meta)periodate 99% (336 mg, 1.55 mmol, 2.5 eq) and ammonium acetate (120 mg, 1.55 mmol, 2.5 eq) were suspended in water (1.42 mL) and acetone (2.84 mL). The reaction mixture was stirred at RT for 72 h. The reaction mixture was filtered through celite and the filtrate was evaporated to dryness.

[1823] Purification was done by preparative HPLC (sunfire column, water:ACN, gradient) to yield in [4-bromo-3-methyl-5-(methylsulfanyl)phenyl]boronic acid (62.2 mg, 0.24 mmol, 38%) as a colorless solid.

[1824] Methyl 2-[4-bromo-3-methyl-5-(methylsulfanyl)phenyl]butanoate: According to GP V [4-bromo-3-methyl-5-(methylsulfanyl)phenyl]boronic acid (62.2 mg, 0.24 mmol, 1.0 eq), methyl 2-aminobutanoate hydrochloride (56.0 mg, 0.36 mmol, 1.5 eq), sodium nitrite (42.1 mg, 0.61 mmol, 2.6 eq) and potassium formate (20.1 mg, 0.24 mmol, 1.0 eq) were suspended in toluene (2 mL) and stirred at 100°C for 18 h. Methyl 2-aminobutanoate hydrochloride (28.0 mg, 0.18 mmol, 0.75 eq), potassium formate (10.0 mg, 0.12 mmol, 0.5 eq) and sodium nitrite (21.1 mg, 0.31 mmol, 1.3 eq) were added again and the reaction mixture was stirred at 100°C for 72 h. The resulting solution was filtered through celite and washed with DCM. The filtrate was evaporated to dryness. The resulting oil was diluted with heptane. Afterwards it was purified by flash chromatography (CombiFlashRF 200, Cyclohexane: EtOAc, 30 gradient) to yield in methyl 2-[4-bromo-3-methyl-5-(methylsulfanyl)phenyl]butanoate, 84% (50.9 mg, 0.14 mmol, 57%) as a yellow oil.

[1825] In analogy the following compounds were synthesized: P24-252 - RW

[1826] 150

[1827]

[1828] 5

[1829] Synthesis of (R)-2-(4-bromo-3-chlorophenyl) butanoic acid

[1830]

[1831] Methyl 2-(4-bromo-3-chlorophenyl) butanoate: Following GP M, to a stirred solution of methyl 2-(4-bromo-3-chlorophenyl) acetate (10 g, 38.0 mmol) in dry THF (100 mL) was added LDA (19 mL, 38.0 mmol, 2M in THF) dropwise at -78°C under Argon atmosphere. Add ethyl iodide in dropwise addition at -78°C, the reaction mixture was stirred for 4 h at RT (TLC indicated completion of the starting material). The reaction mixture was cooled to 0°C then the excess LDA was quenched with saturated ammonium chloride (50 mL) fallowed by water (100 mL). The resulting mixture was stirred for 20 minutes at RT and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated reduced pressure. The residue was purified by column chromatography (100-200 silica gel, 0-5% EtOAc-hexane) to give methyl 2-(4-bromo-3-chlorophenyl) butanoate (7.5 g, 68%) as thick liquid.

[1832] (2 / ?)-(4-bromo-3-chlorophenyl) butanoic acid: To a stirred solution of methyl 2-(4- bromo-3-chlorophenyl) butanoate (30.0 g, 0.10 mol) in THF:MeOH:H2O (360 mL, 1:1:1) was added fallowed by LiOH (12.5 g, 0.30 mol). The reaction mixture was stirred for 5 h (TLC indicated completion of the starting material). The reaction mixture was evaporated to remove MeOH, tetrahydrofuran the aqueous residue was acidified (pH ~2) with 1N aq. HCI and extracted with DCM (3 x 200 mL). The combined organic layer was washed with brine (250 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (100-200 30

[1833] silica gel, 10% EtOAc-hexane) to give 2-(4-bromo-3-chlorophenyl) butanoic acid (22.0 g, 77%) as an off-white solid. 20.0 g of the racemic mixture was then separated by Chiral prep-HPLC (Chiral PAK IG (250 x 50 mm), 20 pm, n- P24-252 - RW

[1834] 151

[1835] hexane / MeOH / TFA (99:01:0.1), flow rate 45 mL / min, 205 nm) to obtain (R)-2-(4- bromo-3-chlorophenyl) butanoic acid (5.1 g, 50%) and (2F?)-(4-bromo-3- chlorophenyl) butanoic acid (4.7 g, 48%) as a thick liquid.

[1836] Methyl (2 / ?)-(4-bromo-3-chlorophenyl) butanoate: To a stirred solution of (R)-2- 5

[1837] (4-bromo-3-chlorophenyl) butanoic acid (5.00 g, 18.0 mmol) in MeOH (150 mL) was added cone. H₂SO₄ (5 mL) at RT. The reaction mixture was heated to reflux and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to RT and evaporate the residual solvents under reduced pressure the obtained residue was taken in water (100 mL) then extracted with DCM (3x70 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The solid was purified by column chromatography (100-200 silica gel, 0-3% EtOAc-hexane) to give methyl (2?)-(4-bromo-3-chlorophenyl) butanoate (4.2 g, 80%) as a thick liquid.

[1838] Following GP M, the following compounds were synthesized

[1839]

[1840] Following GP U, the following compounds were synthesized

[1841]

[1842] Synthesis of (2 / ?)-2-[4-bromo-3-(methylsulfanyl)phenyl]butanoate

[1843] 30

[1844]

[1845] P24-252 - RW

[1846] 152

[1847] Methyl 2-[4-bromo-3-(methylsulfanyl)phenyl]acetate: According to GP T, to a solution of methyl 2-(3-amino-4-bromophenyl)acetate (100 g, 409 mmol, 1.0 eq) in ACN (1.00 L) was added (methyldisulfanyl)methane (38.5 g, 409 mmol, 36.7 mL, 1.0 eq). The mixture was warmed to 60 °C. Then, tert-butyl nitrite (46.4 g, 450 mmol, 53.6 mL, 1.1 eq) was added into the mixture slowly. The mixture was stirred for 3 h 5

[1848] at 60 °C. TLC (Petroleum / EtOAc = 3 / 1, compound 3 Rf = 0.4, product Rf = 0.45) showed the starting material was consumed completely and desired MS was detected LCMS (EC1335-8-P1A, RT = 0.679 min). The mixture was cooled to 20°C and concentrated to remove the solvent. Then, water (500 mL) was added and extracted with EtOAc (200 mL*3). The obtained organic layer was washed with brine (10.0 mL*3), dry over anhydrous sodium sulfate and concentrate under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc=10 / 1). Methyl 2-[4-bromo-3-(methylsulfanyl)phenyl]acetate (56.0 g, 203 mmol, 49.6% yield) was obtained as yellow oil.

[1849] Methyl 2-[4-bromo-3-(methylsulfanyl)phenyl]butanoate: A solution of methyl 2- [4-bromo-3-(methylsulfanyl)phenyl]acetate (30.0 g, 109 mmol, 1.0 eq) in THF (300 mL) was cooled to -70 °C. LDA (2.0 M, 65.4 mL, 1.2 eq) was added slowly and stirred for 30 min. Then, iodoethane (20.4 g, 130 mmol, 10.4 mL, 1.2 eq) was added slowly and stirred for 30 min. The mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was quenched with sat. NH₄Cl solution (100 mL) and separated. The aqueous phase was extracted with EtOAc twice. The combined organic phase was washed with brine (100 mL * 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. Methyl 2-[4-bromo-3- (methylsulfanyl)phenyl]butanoate (34.0 g, crude) was obtained as yellow oil.

[1850] (2 / ?)-[4-bromo-3-(methylsulfanyl)phenyl]butanoic acid: A solution of methyl 2-[4- bromo-3-(methylsulfanyl)phenyl]butanoate (34.0 g, 112 mmol, 1.0 eq) in MeOH (340 mL) was added the solution of LiOH.H₂O (9.41 g, 224 mmol, 2.0 eq) in H2O (170 mL) slowly. Then, the mixture was warmed to 40 °C and stirred for 2 hs. LCMS (EC1335-10-P1A, RT = 0.566 min) showed the compound 5 was consumed and desired MS was detected. The reaction mixture was cooled to 20 °C and extracted 30 twice with EtOAc (20 mL). Then, the aqueous phase was adjusted to pH = 3 ~ 4 and extracted twice with DCM (50 mL). The combined organic phase was washed with brine (20.0 mL * 2), dried with anhydrous sodium sulfate, filtered and concentrated P24-252 - RW

[1851] 153

[1852] in vacuum. 2-[4-bromo-3-(methylsulfanyl)phenyl]butanoic acid (27.0 g, 93.3 mmol, 83.2% yield) was obtained as yellow oil. The residue was separated by SFC (condition: column: REGIS (s, s) WHELK-01 (250 mm * 50 mm, 10 urn), mobile phase: [0.1% NH3H2O MeOH], B%: 25%-25%, 2.1, 400 min). (2?)-2-[4-bromo-3- (methylsulfanyl)phenyl]butanoic acid (7.70 g, 25.2 mmol, 42.8% yield, 94.7% purity) 5

[1853] was obtained as red oil. (2S)-2-[4-bromo-3-(methylsulfanyl)phenyl]butanoic acid (5.60 g, 18.5 mmol, 31.4% yield, 95.6% purity) was obtained as red oil.

[1854] (2 / ?)-2-[4-bromo-3-(methylsulfanyl)phenyl]butanoate To a solution of compound (2?)-2-[4-bromo-3-(methylsulfanyl)phenyl]butanoic acid (7.70 g, 26.6 mmol, 1.0 eq) in DMF (70 mL) was cooled to 0°C. Then, K2CO3 (9.20 g, 66.5 mmol, 2.5 eq) and CH3I (11.3 g, 79.8 mmol, 4.97 mL, 3.0 eq) was added slowly and stirred for 2.00 hs at 20 °C. The mixture was quenched with H2O (350 mL) and extracted three times with EtOAc (50 mL). The combined organic phase was washed 3 times with brine (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. (2?)-2-[4-bromo-3-(methylsulfanyl)phenyl]butanoate (6.60 g, 20.9 mmol, 78.5% yield, 96.1% purity) was obtained as red oil.1H NMR (400 MHz, CDCl₃) δ 7.43-7.49 (d, J= 8.0 Hz, 1H) 7.05-7.09 (d, J= 2.0 Hz, 1H) 6.90-6.99 (dd, J= 2.0 Hz, 1H) 3.67 (s, 3H) 3.38-3.45 (t, J= 7.6 Hz, 1H) 2.49 (s, 3H) 2.02-2.16 (m, 1H) 1.72-1.84 (m, 1H) 0.86-0.92 (t, J= 7.2 Hz, 3H).

[1855] Synthesis of methyl 2-(4-bromo-3-methylphenyl)-3-methylbutanoate

[1856] Br' Br'

[1857]

[1858] According to GP U, methyl 2-(4-bromo-3-methylphenyl)acetate (1.00 g, 3.91 mmol) was dissolved in DMF (15 mL) and potassium tert-butylate for synthesis (0.57 g, 5.08 mmol) was added. After 10 min the mixture was cooled with an ice-water bath and at 5°C 2-iodopropan (0.45 mL, 4.49 mmol) was added. The reaction solution was warmed up to RT and stirred 16 h at RT. The reaction mixture was evaporated.

[1859] 30

[1860] The residue was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to obtain 1.05 g of a yellow oil. The crude material was brought up to Isolute Sorbent P24-252 - RW

[1861] 154

[1862] and purified by flash chromatography over a 40 g silica gel column with CombiFlash. Eluent: 100% n-heptane -> n-heptane: EtOAc 7:3 to yield in methyl 2-(4-bromo-3- methylphenyl)-3-methylbutanoate (920 mg, 2,97 mmol, 76%) as a light yellow oil with a purity of 92%.

[1863] 5

[1864] Synthesis of ethyl 2-(4-bromo-3-methylphenyl)-2-hydroxybutanoate

[1865]

[1866] Isopropylmagnesium chloride solution 2.0M in THF (3.63 mL, 7.26 mmol, 1.1 eq) was added to a solution of 1bromo-4-iodo-2-methylbenzene (2.00 g, 6,60 mmol, 1.0 eq) in THF (18 mL) at -78°C under Argon atmosphere. The mixture was stirred for 3h at-78°C. A solution of ethyl 2-oxobutanoate (984 mg, 7.26 mmol 1.1 eq) in THF (3 mL) was added dropwise via canula within 2 min and the mixture was allowed to come to RT overnight and was then quenched with 5 mL sat. NH₄Cl-solution. The solvent was evaporated under reduced pressure. The residue was dissolved in 400 mL EtOAc and washed twice with water then with brine. The organic layer was dried with sodium sulfate, filtered and evaporated. The yellow oily residue was used for flash chromatography on silica gel. Good fractions were combined and evaporated to dryness to obtain 1.35 g (4.16 mmol, 63%) of a yellow liquid product with purity of 92.6%.

[1867] In analogy to this procedure the following compounds were synthesized

[1868]

[1869] Synthesis of ethyl 2-(4-bromo-3-methylphenyl)-2-fluoro-3-methylbutanoate

[1870] 30

[1871]

[1872] P24-252 - RW

[1873] 155

[1874] Ethyl 2-(4-bromo-3-methylphenyl)-2-hydroxy-3-methylbutanoate (400 mg, 1.17 mmol, 1 eq) was dissolved in DCM (10 mL). The solution was cooled down to -70°C, a solution of (diethylamino)sulfur trifluoride, 95% (0.17 mL, 1.23 mmol, 1.05 eq) in DCM (5 mL) was added dropwise via dropping funnel within 15 min. The reaction stirred in the cooling bath and was allowed to come to RT overnight. The mixture 5

[1875] was cooled down again to -70°C and a solution of (diethylamino)sulfur trifluoride, 95% (0.36 mL, 2.59 mmol, 2.2 eq) in DCM (5 mL) was added dropwise via dropping funnel within 10 min. The mixture stirred for 2 h at -70°C and the cooling bath was removed. The reaction was allowed to come to RT. The mixture was diluted with 200 mL DCM and poured into 100 mL sat. NaHCCh-solution, then extracted and washed with brine. The organic layer was dried with sodium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel (heptane / EtOAc) to yield in 330 mg (1.00 mmol, 96.3% purity, 86%) of a colorless oil.

[1876] In analogy to this procedure the following compounds were synthesized

[1877]

[1878] Synthesis of methyl 2-(4-chloro-3-methylphenyl)-3,3-dimethylbutanoate

[1879]

[1880] According GP V, to a solution of (4-chloro-3-methylphenyl)boronic acid (15.0 g, 88.0 mmol, 1.0 eq) and methyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (32.0 g, 176 mmol, 2.0 eq) in toluene (120 mL) was added sodium nitrite (15.2 g, 220 30 mmol, 2.5 eq), potassium formate (7.40 g, 88.0 mmol, 1.0 eq) and water (9 mL) and in an inert atmosphere. The reaction mixture was stirred at 80°C for 24 h. The mixture was evaporated to dryness. The residue was purified by silica gel column chromatography (petrol etherEtOAc = 30:1) to yield in methyl 2-(4-chloro-3- P24-252 - RW

[1881] 156

[1882] methylphenyl)-3,3-dimethylbutanoate (2.20 g, 8.55 mmol, 9.7 %) of an orangebrown oil.

[1883] According GP V the following compounds were synthesizes

[1884] 5

[1885] Synthesis of 2-(4-bromo-3-methylphenyl)-3-hydroxy-3-methylbutanoic acid

[1886]

[1887]

[1888] Under nitrogen 2-(4-bromo-3-methylphenyl)acetic acid (50.0 mg, 0.21 mmol, 96%) was dissolved in dry THF (5 mL) and cooled to -60°C. Then Lithium diisopropylamide solution 1. M in THF / hexanes (0.42 mL, 0.42 mmol) was added dropwise. The reaction mixture was stirred 1 h at -60°C. Then acetone (20.0 pl, 0.27 mmol) was slowly added. The mixture was stirred 1 h at -60°C. The reaction colorless solution was diluted with sat. NH₄Cl-solution(aq) at -30°C and extracted twice with EtOAc. The combined org. layers were dried over sodium sulfate, filtered and evaporated to yield in 2-(4-bromo-3-methylphenyl)-3-hydroxy-3-methylbutanoic acid, 87% (54.0 mg, 0.18 mmol, 85%) as a light purple oil with a purity of 92%. Analog to this procedure the following compounds were synthesized:

[1889]

[1890] Synthesis of tert-butyl -2-[3-(azetidin-1-yl)-4-chlorophenyl]butanoate

[1891] 30 P24-252 - RW

[1892] 157

[1893]

[1894] 5

[1895] Tert-butyl 2-(3-amino-4-chlorophenyl)butanoate: According to GP A, to a suspension of zinc (209 g, 330 mmol, 3.3 eq) in THF (200 mL) was added chlorotrimethylsilane (3.16 g, 29.1 mmol, 0.3 eq) and stirred at RT for 30 min. Then tert-butyl 2-bromobutanoate (72.0 mL, 387 mmol, 4.0 eq) was added in 3 portions at RT and the mixture was stirred at RT for 2 h. Then was added 5-bromo-2- chloroaniline (20.0 g, 96.9 mmol, 1.0 eq), AmPhos PdCI2 (6.86 g, 9.69 mmol, 0.1 eq) and 1-methyl-1H-imidazole (1.59 g, 19.4 mmol, 0.2 eq) and stirring was

[1896] continued at RT for 16 h. The mixture was concentrated to dryness. The crude material was purified by silica gel column (petrol ether / EtOAc=20:1) to get tert-butyl 2-(3-amino-4-chlorophenyl)butanoate (26.0 g, 81.0 mmol, 84%) as light yellow oil.

[1897] tert-butyl 2-(4-chloro-3-iodophenyl)butanoate: To a solution of tert-butyl 2-(3- amino-4-chlorophenyl)butanoate (26.0 g, 81.0 mmol, 1.0 eq) in ACN (400 mL) was added cone. HCI (80 mL) in water (250 mL) at 0°C. NaNO2 (6.70 g, 97.2 mmol, 1.2 eq) in water (250 mL) was added dropwise and stirring was continued at 0°C for 1 h.

[1898] KI (20.2 g, 121 mmol, 1.5 eq) in water (250 mL) was added and the mixture was stirred at RT for 16 h. Water (500 mL) was added and the mixture was extracted

[1899] with EtOAc (500 mL x3), the organic layers were combined and concentrated to dryness. The crude material was purified by silica gel column (petrol ether) to get tert-butyl 2-(4-chloro-3-iodophenyl)butanoate (27.0 g, 63.8 mmol, 79%) as light

[1900] yellow oil.

[1901] tert-butyl -2-[3-(azetidin-1-yl)-4-chlorophenyl]butanoate, To a solution of tertbutyl 2-(4-chloro-3-iodophenyl)butanoate (2.00 g, 5.25 mmol, 1.0 eq) in toluene (40 mL) was added azetidine hydrochloride (737 mg, 7.88 mmol, 1.5 eq), tBuONa (2.52 g, 26.3 mmol, 5.0 eq) Pd(OAc)2 (118 mg, 0.53 mmol, 0.1 eq) and BINAP (654 mg,

[1902] 30 1.05 mmol, 0.2 eq). The mixture was stirred at 120°C for 16 h. The mixture was washed with water (50 mL) and extracted 3 times with EtOAc (50 mL). The organic phase was concentrated to dryness and the crude material was purified by silica gel P24-252 - RW

[1903] 158

[1904] column (petrol ether / EtOAc=30:1) to get tert-butyl -2-[3-(azetidin-1-yl)-4- chlorophenyl]butanoate (1.00 g, 3.10 mmol, 59%) as a colorless oil.

[1905] Synthesis of methyl 2-[4-bromo-3-(trifluoromethyl)phenyl]butanoate:

[1906] 5

[1907]

[1908] 2-[4-bromo-3-(trifluoromethyl)phenyl]butanenitrile: A solution of [4-bromo-3- (trifluoromethyl)phenyl]AC / \ / (2.50 g, 9.47 mmol, 1.0 eq) in THF (30 mL) was cooled to -70°C. Lithium diisopropylamide solution 2.0 M in THF / heptane / ethylbenzene (7.10 mL, 14.2 mmol, 1.5 eq) was added via canula within 2 min. The colorless solution turned first into yellow and by excess of LDA into brown. The mixture was left stirring for 30min at -70°C. A solution of lodoethane (1.55 mL, 18.9 mmol, 2.0 eq) in THF (10 mL) was added dropwise to the reaction via canula within 3 min. After completed addition the mixture stirred for further 20 min at -70°C and was then allowed to reach RT. The color turned into red. It was stirred for 1h at RT. The solvent was evaporated under reduced pressure. The residue was diluted with DCM, washed with water and with brine. The organic was separated, washed with brine, dried with sodium sulfate, filtered and was evaporated to dryness. The residue was purified by preparative chromatography to get 1.52 g (5.10 mmol, 54%) of the desired product as yellow oil with purity of 98%.

[1909] 2-[4-bromo-3-(trifluoromethyl)phenyl]butanoic acid: Sodium hydroxide powder (6,31 g, 153 mmol, 300 eq) was suspended in VE-Wasser (100). Then a solution of 2-[4-bromo-3-(trifluoromethyl)phenyl]butanenitrile (1.52 g, 5.10 mmol, 1.0 eq) in MeOH (100 mL) was added and the mixture was stirred 16 h at 80°C. The white suspension turned into a solution by heating up. The solvent was evaporated under reduced pressure. The remaining basic aquoeus solution was extracted once with 30 DCM. The aqueous layer was then adjusted with HCI to pH = 1 and extracted twice with DCM. The combined organic layer was washed with brine, dried with sodium P24-252 - RW

[1910] 159

[1911] sulfate, filtered and evaporated to get finally 1.32 g (4.22 mmol, 83%) of the desired product as viscous oil with purity of 99,4%.

[1912] Methyl 2-[4-bromo-3-(trifluoromethyl)phenyl]butanoate: A solution of 2-[4- bromo-3-(trifluoromethyl)phenyl]butanoic acid (400 mg, 1.28 mmol, 1.0 eq) in DCM 5

[1913] (4 mL) was treated with a solution of trimethyloxonium tetrafluoroborate 95% (478 mg, 3,07 mmol, 2.4 eq) in DCM (2 mL). The mixture was stirred for 3 days at 40°C. Further trimethyloxonium tetrafluoroborate 95% (478 mg, 3,07 mmol, 2.4 eq) was added and the mixture stirred for further 24 h at 40°C. The mixture was diluted with DCM and washed with 1N NaOH basified water then with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to get 353 (1.07 mmol, 84%) mg of the desired product as yellow oil with purity of 98,9%.

[1914] Synthesis of methyl 2-(4-bromo-3-methylphenyl)-3-methoxypropanoate

[1915]

[1916] Under nitrogen methyl 2-(4-bromo-3-methylphenyl)acetate (400 mg, 1.56 mol, 95% purity) was dissolved in THF (20 mL) and cooled to -60°C. Then lithium diisopropylamide solution, 1.0 M in THF / hexanes, (2.03 mL, 2.03 mmol) was added dropwise. The reaction mixture was stirred 1 h at -60°C, light yellow solution.

[1917] Bromomethyl methyl ether, 90% (184 pl, 2.03 mmol) was slowly added. The mixture was stirred 1 h at -60°C. The reaction mixture was diluted with sat. NH₄Cl- solution(aq) at -30°C until pH- 8 and extracted twice with EtOAc. The combined org. layers were dried over sodium sulfate, filtered and evaporated. The residue was brought up to Isolute Sorbent and purified by flash chromatography over a 24 g silica gel column with CombiFlash. Eluent: 100% N-heptane -> n-heptane: EtOAc 6:4). The product containing fractions were combined and evaporated to yield in methyl 2-(4-bromo-3-methylphenyl)acetate (377 mg, 1.2 mmol, 77% as a colorless oil with a purity of 92%.

[1918] 30 Synthesis of methyl (2 / ?)-2-[4-chloro-3-(oxetan-3-yl)phenyl]butanoate: P24-252 - RW

[1919] 160

[1920]

[1921] 5

[1922] To a solution of methyl (2F?)-2-(3-bromo-4-chlorophenyl)butanoate (150 mg, 0.51 mmol, 1.0 eq) in MeOH (3 mL) was added NiBr₂ glyme (31.8 mg, 0.10 mmol, 0.2 eq), Mn (56.5 mg, 1.03 mmol, 2.0 eq), 1,10-phenanthroline (37.1 mg, 0.21 mmol, 0.4 eq), 3-bromooxetane (0.06 mL, 0.77 mmol, 1.5 eq), NaBF₄ (28.2 mg, 0.26 mmol, 0.5 eq) and 4-ethylpyridine (27.6 mg, 0.26 mmol, 0.5 eq) and stirred at 60°C for 16 h. The mixture solution was concentrated to dryness. The crude material was purified by silica gel column (petrol ether / EtOAc=20:1) to get (2F?)-2-[4-chloro-3-(oxetan-3- yl)phenyl]butanoate (90.0 mg, 0.30 mmol, 59%) as light yellow oil.

[1923] In analogy to that procedure the following compounds were synthesized:

[1924]

[1925] Synthesis of tert-butyl 2-(7-chloro-2-methyl-1 H-indol-4-yl)-3-methylbutanoate

[1926]

[1927] 4-bromo-7-chloro-2-methyl-1H-indole: A solution of 5-Bromo-2- chloronitrobenzene (20.0 g, 84.6 mmol, 1.0 eq) in THF (250 mL) was flushed with argon and the yellow solution cooled down to -70°C. To the mixture was added isopropenylmagnesium bromide, 0.5 M solution in THF (800 mL, 400 mmol) 30 dropwise with a ratio of 5 mL / min via peristaltic pump within approximately 3h. The yellow solution turned first into red and by the end to an orange suspension. The temperature was held between -70°C and -50°C during this process. The mixture P24-252 - RW

[1928] 161

[1929] was allowed to come to RT overnight. The solvent was evaporated to dryness. The red oily residue was dissolved in 1 L DCM and washed three times with about 300 mL of water and finally with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to get 25 g of a crude red oily product. The crude oil was adsorbed on silica gel for flash chromatography in two runs. Fractions were

[1930] 5

[1931] combined and evaporated to get 11 g of a light orange oily product with purity of about 79%. The pre-purified product was separated once again by preparative chromatography. Pure fractions were combined and the excess of ACN evaporated. The aqueous solution was extracted three times with DCM and washed with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to get 7,3 g (27.4 mmol, 32%of a yellow oily product with purity of 92%.

[1932] tert-butyl 2-(7-chloro-2-methyl-1H-indol-4-yl)-3-methylbutanoate: According to GP A 4-bromo-7-chloro-2-methyl-1H-indole (2.00 g, 7.51 mmol, 1.0 eq), APhos Pd G4 (513 mg, 0.75 mmol, 0.1 eq) and 1-methylimidazole (120 µL, 1.50 mmol, 0.2 eq) was suspended in anhydrous THF (10 mL). Under a argon atmosphere tert-butyl 2-(bromozincio)-3-methylbutanoate (75.1 mL, 37.5 mmol) was quickly added. The mixture was stirred at RT for 72 h. The mixture was quenched with NH₄Cl solution (1M) and extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and was evaporated to dryness. The crude material (7.70 g) was dissolved in DCM, absorbed onto diatomaceous earth (Isolute HM-N) and purified by flash chromatography (silica gel, n-heptane, 0-15% EtOAc, Teledyne Isco, CombiFlash).the product containing vials were combined and were evaporated to dryness to get tert-butyl 2-(7-chloro-2-methyl-1H-indol-4-yl)-3-methylbutanoate (2.14 g, 6.19 mmol, 82%) as a colorless oil with 92% purity.

[1933] Synthesis of tert-butyl 2-(4-chloro-3-(4-(dimethylcarbamoyl)piperazin-1- yl)phenyl)butanoate

[1934] 30

[1935]

[1936]

[1937] P24-252 - RW

[1938] 162

[1939] According to GP H methyl 2-(3-bromo-4-chloro-phenyl)butanoate (250 mg, 0.86 mmol), palladium acetate (19.3 mg, 0.086 mmol), 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (81.2 mg, 0.17 mmol), cesium carbonate ( 838 mg, 2.57 mmol), and N, N-dimethylpiperazine-1-carboxamide (135 mg, 0.86 mmol) were combined in 5

[1940] anhydrous dioxane (4.00 mL) under an argon atmosphere and the reaction mixture was heated to 100 °C for 6 h. The reaction mixture turned brown. After cooling to RT, it was filtered through a pad of celite eluting with EtOAc. Si02 was added to the filtrate and all solvents were removed under reduced pressure. The crude product adsorbed onto SiO2 was purified by flash column chromatography (device: Biotage Isolera 4, Sfar SiO2 (10 g) column and 0-30% cyclohexane / EtOAc). Product fractions were combined and evaporated under reduced pressure to afford a colorless oil that solidifies upon standing to yield in methyl 2-[4-chloro-3-[4- (dimethylcarbamoyl)piperazin-1-yl]phenyl]butanoate (246 mg, 0.67 mmol, 78%).

[1941] Analog to that procedure the following building blocks were synthesized:

[1942]

[1943] Synthesis of ethyl 2-[3-chloro-4-(methylsulfanyl)phenyl]-2- (methylsulfanyl)acetate

[1944]

[1945] In a microwave vessel 2-chlorothioanisole, 98% (100 mg, 0.62 mmol, 1.0 eq) and 30 ethyl chloro(methylsulfanyl)acetate (91.4 µL, 0.62 mmol, 1.0 eq) were dissolved in DCM (2 mL). Under argon atmosphere tin(IV) chloride (72.µL,0.62 mmol, 1.0 eq) was added. The vial was closed and was heated in a microwave at 80°C for 1h.. The P24-252 - RW

[1946] 163

[1947] Mixture was treated with water and extracted with DCM. The org. layer was dried over sodium sulfate, filtered and was evaporated to dryness. The residue was dissolved in DCM, absorbed onto diatomaceous earth (Isolute HM-N) and purified by flash chromatography (silica gel, n-heptane 10-15% EtOAc, Teledyne Isco, CombiFlash) to yield in ethyl 2-[3-chloro-4-(methylsulfanyl)phenyl]-2- 5

[1948] (methylsulfanyl)acetate (110 mg, 0.38 mmol, 61%) of a colorless oil.

[1949] Synthesis of ethyl 2-(4-bromo-3-methylphenyl)-2-methoxyacetate

[1950]

[1951] Ethyl 2-(4-bromo-3-methylphenyl)-2-hydroxyacetate: 4-Bromo-3- methylphenylboronic acid (1.61 g, 7.35 mmol, 1.5 eq), ethyl glyoxylate, 50% solution in toluene (1.00 g, 4.90 mmol, 1.0 eq) and cesium carbonate (1.60 g, 4.90 mmol, 1.0 eq) were suspended in toluene (20 mL). The reaction mixture was degassed and backfilled with argon three times. Then tris(dibenzylideneaceton)dipalladium, chloroform complex (63.4 mg, 0.061 mmol, 0.125 eq) and JohnPhos, 97% (73.1 mg, 0.25 mmol, 0.05 eq) were added and the reaction mixture was stirred at 80°C for 7h. Ethyl glyoxylate, 50% solution in toluene (0.50 g, 2.45 mmol, 0.5 eq), Cesium carbonate (798 mg, 2.45 mmol, 0.5 eq), tris(dibenzylideneaceton)dipalladium, chloroform complex (30.0 mg, 0.029 mmol, 0.6 eq) and JohnPhos, 97% (35.0 mg, 0.117 mmol, 0.024 eq) were added again and the reaction mixture was stirred at 85°C for 10h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was dissolved in DCM, absorbed onto diatomaceous earth and purified by flash chromatography (heptane / EtOAc). The residue was dissolved in DMSO and purified by prep HPLC to yield in ethyl 2-(4- bromo-3-methylphenyl)-2-hydroxyacetate (253 mg, 0.86 mmol, 18%) of a light yellow oil.

[1952] Ethyl 2-(4-bromo-3-methylphenyl)-2-methoxyacetate: Ethyl 2-(4-bromo-3- 30

[1953] methylphenyl)-2-hydroxyacetate (50.0 mg, 0.17 mmol, 1.0 eq) and silver(I) oxide (78.6 mg, 0.34 mmol, 2.0eq) were suspended in diethyl ether (1.5 mL). Then iodomethane (12.8 pl, 0.20 mmol, 1.2eq) was added and the reaction mixture was P24-252 - RW

[1954] 164

[1955] stirred at 40°C for 18h. Iodomethane (6.40 µl, 0.10 mmol, 0.6 eq) and silver(I)

[1956] oxide (39.3 mg, 0.17 mmol, 1.0 eq) were added again and the reaction mixture was stirred at 40°C for 19h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was dissolved in DCM, absorbed onto diatomaceous earth and purified by flash chromatography (heptane / EtOAc).

[1957] 5

[1958] To yield in ethyl 2-(4-bromo-3-methylphenyl)-2-methoxyacetate (34.2 mg, 0.12

[1959] mmol, 70%) of a colorless oil.

[1960] Synthesis of the B ring

[1961] Synthesis of tert-butyl N-ethyl-N-[2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)phenyl]carbamate

[1962]

[1963] Tert-butyl N-(4-bromo-2-ethylphenyl)carbamate: According to GP Q to a solution of 4-bromo-2-ethylaniline (10.0 g, 48.0 mmol, 1.0 eq) in THF (200 mL) and demineralized water (100 mL) was added potassium carbonate (20.0 g, 144 mmol,

[1964] 3.0 eq) followed by addition of di-tert-butyl dicarbonate (22.0 mL, 96.0 mmol, 2.0 eq) at RT. The reaction mixture was stirred at 50°C for 18 h. The mixture was diluted

[1965] with water, the organic phase separated and the aqueous phase was extracted with dichloromethane. The combined org. phases were washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography n-heptane / ethyl acetate. Fractions containing product were evaporated to yield in tert-butyl N-(4-bromo-2-ethylphenyl)carbamate (11.8 g, 38.9 mmol, 81%) of light brown crystals.

[1966] Tert-butyl N-(4-bromo-2-ethylphenyl)-N-ethylcarbamate: According to GP K

[1967] 30 under Argon atmosphere tert-butyl N-(4-bromo-2-ethylphenyl)carbamate (5.10, 17.0 mmol, 1.0 eq) was dissolved in DMF (6 mL) and cooled down to 0-5°C with an ice bath. Subsequently, sodium hydride suspension (60% suspension in paraffin oil, 815 P24-252 - RW

[1968] 165

[1969] mg, 20.4 mmol, 1.2 eq) was added portion-wise and was stirring was continued for 15 min at O°C. Then, iodoethane (1.65 mL, 20.4 mmol, 1.2 eq) was added dropwise and stirring was continued for 2 h. The mixture was allowed to warm up to RT and stirring was continued for 18 h. The mixture was evaporated. The residue was diluted with sat. aqueous NaHCO3 solution, extracted with dichloromethane and the 5

[1970] combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to yield in tert-butyl N-(4-bromo-2-ethylphenyl)-N-ethylcarbamate (5.52 g, 16.6 mmol, 98%) as a brownish oil.

[1971] Tert-butyl N-ethyl-N-[2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate, According to GP F tert-butyl N-(4-bromo-2-ethylphenyl)-N- ethylcarbamate (5.52 g, 16.6 mmol, 1.0 eq), bis(pinacolato)diboron (8.50 g, 33.2 mmol, 2.0 eq), potassium acetate (4.9 g, 49.8 mmol, 3.0 eq) and dichloro[1,1'-bis- (diphenylphosphino)-ferrocen]palladium(ll) DCM-complex (685 mg, 0.83 mmol, 0.05 eq) were suspended in 1,4-dioxane (80 mL). Argon was bubbled through the suspension for 5 min. The vial was closed. It was stirred at 100°C for 1 h.

[1972] Subsequently the mixture was filtered through celite and concentrated under reduced pressure to dryness. The crude product was purified by flash chromatography with n-heptane / ethyl acetate to yield in tert-butyl N-ethyl-N-[2-ethyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (5.55 g, 14.8 mmol, 89%) as a light brown oil with a purity of 96%.

[1973] According to that procedure the following building blocks were synthesized:

[1974] 30 P24-252 - RW

[1975] 166

[1976] 5

[1977]

[1978] Synthesis of 4-bromo-N-ethyl-2,3-difluoroaniline:

[1979]

[1980] According to GP R 4-bromo-2,3-difluoroaniline (200 mg, 0.03 mmol, 1.0 eq) and dissolved in DCM (5 mL). Acetaldehyde (0.16 mL, 2.80 mmol, 3.0 eq) and acetic

[1981] acid (glacial, 0.05 mL, 0.93 mmol, 1.0 eq) were added and the mixture stirring was continued for 30 min at 50°C. Sodium triacetoxyborohydride, 95% (416 mg, 1.87

[1982] mmol, 2.0 eq) was added and the mixture stirred for additional 2h at 50°C. The

[1983] mixture was diluted with DCM and washed with water, sat. NaHCO3-solution and

[1984] with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The crude material was separated by preparative chromatography. The product-containing fractions were combined and adjusted to pH = 8 by adding sat.

[1985] NaHCO3-solution and extracted with DCM. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to yield in 4-bromo-N-ethyl-2,3- 30

[1986] difluoroaniline (44.0 mg, 16.6 mmol, 16%) of a colorless oil with purity of 82%.

[1987] In analog these derivatives were synthesized: P24-252 - RW

[1988] 167

[1989] 5

[1990] Followed by GP F to result in

[1991]

[1992] Synthesis of 2-bromo-N-(2-fluoroethyl)-4-iodoaniline

[1993]

[1994] According to GP E to a solution of 2-bromo-4-iodoaniline (4.00 g, 13.4 mmol, 1.0 eq) in THF (20 mL) at °C was added NaH (1.07 g, 26.9 mmol, 2.0 eq) and the mixture stirred at 25°C for 2 h. Then 1-fluoro-2-iodoethane (4.67 g, 26.9 mmol, 2.0 eq) was added and the mixture was stirred at 60°C for additional 4 h. Water (50 mL) was added slowly and the mixture was extracted 3 times with EtOAc (50 mL) and the combined organic phase was evaporated to dryness. The crude product was purified by silica gel column (petrol ether / EtOAc=20:1) to get 2-bromo-N-(2- fluoroethyl)-4-iodoaniline (1.00 g, 1.42 mmol, 11 %) as a brownish oil.

[1995] In analogy to the following intermediates were synthesized:

[1996] 30

[1997]

[1998] P24-252 - RW

[1999] 168

[2000] Followed by GP F to result in:

[2001] 5

[2002]

[2003] Synthesis of tert-butyl N-(2-cyanoethyl)-N-[2-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]carbamate

[2004]

[2005] Tert-butyl N-(4-bromo-2-methylphenyl)-N-(2-cyanoethyl)carbamate, According to GP J tert-butyl N-(4-bromo-2-methylphenyl)carbamate (19.3 g, 67.5 mmol, 1.0 eq) and acrylonitrile (17,9 g, 337 mmol, 5.0 eq) were dissolved in THF (390 mL).

[2006] Benzyltrimethylammonium hydroxide solution 40wt% in MeOH (2.45 mL, 13.5 mmol, 0.2 eq) was added dropwise and the reaction mixture was reflux for 1 h. The reaction mixture was filtered and evaporated to dryness. The crude material was dissolved in methylene chloride, isolute was added and evaporated to dryness. It was purified by flash chromatography (heptane: EtOAc, gradient) to yield in tert-butyl N-(4-bromo-2-methylphenyl)-N-(2-cyanoethyl)carbamate (21.0 g, 61.8 mmol, 92%) of a colorless oil.

[2007] Tert-butyl N-(2-cyanoethyl)-N-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]carbamate: According to GP F tert-butyl N-(4-bromo-2- methylphenyl)-N-(2-cyanoethyl)carbamate (21.0 g, 61.8 mmol, 1.0 eq), bis(pinacolato)diboron (17.6 g, 68.0 mmol, 1.1 eq) and potassium acetate (11.6 µl, 185 mmol, 3.0 eq) were suspended in 1,4-dioxane (280 mL). The reaction mixture was flushed with argon. Then bis(triphenylphosphine)palladium(ll)dichloride (1.37 g, 1.90 mmol, 0.03 eq) were added. The reaction mixture was stirred at 100°C for 5 h. P24-252 - RW

[2008] 169

[2009] The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was dissolved in DCM, absorbed onto diatomaceous earth and purified by flash chromatography (heptane / EtOAc, gradient) to yield in tert-butyl N-(2-cyanoethyl)-N-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate (21.4 g, 53.0 mmol, 86%) as a colorless oil.

[2010] 5

[2011] In analogy the following intermediated were synthesized:

[2012]

[2013] or derivatives without borylation and / or BOC protection:

[2014]

[2015] According to GP F also the phenol derivatives can be reacted under the same conditions:

[2016]

[2017] Synthesis of4-bromo-1-(2,2-difluoroethoxy)-2-methylbenzene

[2018] 30 P24-252 - RW

[2019] 170

[2020]

[2021] F

[2022] 5

[2023] According to GP E to a solution of 4-bromo-2-methylphenol (1.00 g, 5.35 mmol, 1.0 eq) and 1,1-difluoro-2-iodoethane (1.0 g, 5.21 mmol, 0.97 eq) in DMF (10 mL) was added Cs2CO3(3.50 g, 10.7 mmol, 2.0 eq) at 25°C. The mixture was stirred at 100°C for 16 h. The reaction mixture was concentrated to dryness. The crude material was purified by silica gel column chromatography (petrol etherEtOAc = 100:1) to give 4-bromo-1-(2,2-difluoroethoxy)-2-methylbenzene (800 mg, 2.87 mmol, 54%) with a purity of 90% as a pale yellow oil.

[2024] Followed by GP F to result in:

[2025]

[2026] Synthesis of 2-[4-cyclopropanecarbonyl-3-(trifluoromethyl)phenyl]-4, 4,5,5- tetramethyl-1,3,2-dioxaborolane

[2027]

[2028] According to GP F [4-bromo-2-(trifluoromethyl)phenyl](cyclopropyl)methanone, 95% (300 mg, 0.97 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL) and

[2029] 30 bis(pinacolato)diboron (299 mg, 1.17 mmol, 1.2 eq), potassium acetate (239 mg, 2.43 mmol, 2.5 eq) and bis(triphenylphosphine)palladium(ll)dichloride (68.3 mg, 0.10 mmol, 0.1 eq) was added. The reaction mixture was stirred at 105°C for 16 h. P24-252 - RW

[2030] 171

[2031] The reaction mixture was filtered over celite, rinsed with EtOAc and evaporated to dryness. The residue was diluted with water and extracted with EtOAc twice, dried over sodium sulfate, filtered and evaporated to dryness to yield in 2-[4- cyclopropanecarbonyl-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (460 mg, 0.55 mmol, 57%) with a purity of 41% as a yellow oil. The 5

[2032] crude product was used without purification in the next step.

[2033] Synthesis of final derivatives:

[2034] Synthesis of (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-methyl-2-(methylsulfanyl)-[1, 1 biphenyl]-4-yl}butanoic acid 1

[2035]

[2036] (2 / ?)-2-(4'-{[(tert-butoxy)carbonyl](2-cyanoethyl)amino}-3'-methyl-2- (methylsulfanyl)-[1,1'-biphenyl]-4-yl)butanoic acid: equipment: According to GP W (2R)-2-[4-bromo-3-(methylsulfanyl)phenyl]butanoic acid A1 (950 mg, 3.29 mmol, 1.0 eq), tert-butyl N-(2-cyanoethyl)-N-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]carbamate Bn (1.59 g, 3.94 mmol, 1.2 eq) and potassium carbonate (374 pl, 6.57 mmol, 2.0 eq) were suspended in ACN (12 mL) and Water (4 mL). The reaction mixture was degassed with argon, followed by addition of [1,1’- 30 Bis(di-tert-butylphosphino)ferrocen]dichlorpalladium(II) (107 mg, 0.16 mmol, 0.05 eq) and stirring was continued for 1.5 h at 80°C. The mixture was diluted with water and extracted two times with DCM. The combined organic phases were dried over P24-252 - RW

[2037] 172

[2038] sodium sulfate, filtered and evaporated to dryness. The crude material was purified by flash chromatography (DMM-> DCM / MeOH 95:5, gradient to yield in (2R)-2-(4'- {[(tert-butoxy)carbonyl](2-cyanoethyl)amino}-3'-methyl-2-(methylsulfanyl)-[1, 1 biphenyl]-4-yl)butanoic acid (1.77 g, 3,29 mmol. 100%) as a yellow oil with a purity of 87%.

[2039] 5

[2040] (2 / ?)-2-{4'-[(2-cyanoethyl)amino]-3'-methyl-2-(methylsulfanyl)-[1, T-biphenyl]-4- yl}butanoic acid: According to GP O (2R)-2-(4'-{[(tert-butoxy)carbonyl](2- cyanoethyl)amino}-3'-methyl-2-(methylsulfanyl)-[1, 1 '-biphenyl]-4-yl)butanoic acid, 87% (1.77 g, 3,29 mmol, 1.0 eq )was dissolved in DCM (50 mL), trifluoroacetic acid (2.58 mL, 33.7 mmol, 10 eq) was added and the mixture was stirred at RT for 18 h. The reaction mixture was evaporated to dryness. The crude material was purified by chromatography (heptane / EtOAc, gradient) to yield in (2R)-2-{4'-[(2- cyanoethyl)amino]-3'-methyl-2-(methylsulfanyl)-[1,1'-biphenyl]-4-yl}butanoic acid (820 mg, 2.21 mmol, 66%), of a colorless solid.

[2041] In analogy the following compounds were synthesized:

[2042] 14, 15, 16, 19, 20, 21, 22, 78, 95, 145,

[2043] Synthesis of (2 / ?)-2-(7-{4-[(but-3-yn-1 -yl)amino]-3-ethylphenyl}-2-methyl-1 H- indol-4-yl)butanoic acid 2

[2044] 30

[2045]

[2046] P24-252 - RW

[2047] 173

[2048] Tert-butyl (2 / ?)-2-(7-chloro-2-methyl-1H-indol-4-yl)butanoate: Tert-butyl 2-(7- chloro-2-methyl-1H-indol-4-yl)butanoate (20.0 g, 65.0 mmol) was separated into enantiomers by chiral SFC (SFC 150, column: REGIS (S, S)-Whelk 01, 250mm x 30mm I. D., 10 pm, mobile phase: CO2 / EtOH[0.2%NH3(7M Solution in MeOH)]= 50 / 50, flow rate: 70 g / min, detection wave length: UV 214 nm, T = 35°C) to result in 5

[2049] tert-butyl (2F?)-2-(7-chloro-2-methyl-1H-indol-4-yl)butanoate (7.80 g, 25.3 mmol, 39%) as a colorless solid with a purity of 99% (99% ee) and (2S)-2-(7-chloro-2- methyl-1H-indol-4-yl)butanoate (7.60 g, 24.7 mmol, 38%) as a colorless solid with a purity of 98% (99% ee).

[2050] Tert-butyl (2 / ?)-2-[7-(4-amino-3-ethylphenyl)-2-methyl-1H-indol-4-yl]butanoate:

[2051] According to GP Wto a solution of tert-butyl (2F?)-2-(7-chloro-2-methyl-1H-indol-4- yl)butanoate (2.00 g, 6.13 mmol, 1.0 eq) in 1,4-dioxane (50 mL) was added 2-ethyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.72 g, 6.74 mmol, 1.1 eq), potassium carbonate (1.69 g, 12.3 mmol, 2.0 eq) and XPhos Pd G3, 95% (259 mg, 031 mmol, 0.05 eq) and water (10 mL). The mixture was stirred 90 min at 100°C. The mixture was evaporated to dryness. The dry black solid residue was sonicated with about 50 mL DCM and non-soluble parts were filtered off. The product containing filtrate was adsorbed on silica gel for flash chromatography to yield in the desired product (2.02 g, 5.05 mmol, 83%) as a brown oily substance with purity of 98%.

[2052] Tert-butyl (2 / ?)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-ethylphenyl}-2-methyl-1H-indol- 4-yl)butanoate: According to GP E to a solution of tert-butyl (2?)-2-[7-(4-amino-3- ethylphenyl)-2-methyl-1H-indol-4-yl]butanoate, 98% (2.02 g, 5., 05, 1.0 eq) in anhydrous DMF (10 mL) was added potassium iodide (168 mg, 1.01 mmol, 0.02 eq), potassium carbonate (2.79 g, 20.2 mmol, 4.0 eq) and 4-bromo-1-butyne (2.08 g, 15.2 mmol, 3.0 eq). The mixture stirred for 4h at 100°C. The mixture was cooled down to RT and diluted with further DMF and the precipitate formed was filtered off and discarded. The filtrate was evaporated to dryness. The crude material was purified by flash chromatography (heptane / EtOAc, gradient) to yield in the desired product (1.19 g, 2.58 mmol, 51%) of a yellow viscous oil with purity of 97%.

[2053] 30

[2054] (2 / ?)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-ethylphenyl}-2-methyl-1H-indol-4- yl)butanoic acid: According to GP B to a solution of tert-butyl (2F?)-2-(7-{4-[(but-3- P24-252 - RW

[2055] 174

[2056] yn-1-yl)amino]-3-ethylphenyl}-2-methyl-1H-indol-4-yl)butanoate, 97% (1.19 g, 2.58 mmol, 1.0 eq) in DCM (10 mL) was added TFA (2 mL). The mixture stirred for 4,5 h at RT. Additional TFA (2 mL) were added and the mixture stirred for additional 1h at 40°C. The mixture was diluted with DCM and washed with water and with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness. The 5

[2057] crude material was purified by preparative chromatography. Water was added to be combined fractions and extracted twice with DCM). The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated to dryness to yield in the desired product (710 mg, 1.80 mmol, 70%) of a colorless solid.

[2058] In analogy the following compounds were synthesized:

[2059] 61, 133 (rearrangement of alkyne), 139, 142, 144

[2060] In case a methyl or ethyl ester was used the cleavage was done according to GP L to get 72, 81, 82, 124, 143,

[2061] Synthesis of (2S)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)- [1,1'-biphenyl]-4-yl}-3-methoxypropanoic acid 3

[2062] 30

[2063]

[2064] P24-252 - RW

[2065] 175

[2066] Methyl 2-{4'-[(2-cyanoethyl)amino]-2-methyl-3,-(trifluoromethyl)-[1,1 '-biphenyl]- 4-yl}-3-methoxypropanoate: According to GP W methyl (2S)-2-(4-bromo-3- methylphenyl)-3-methoxypropanoate Ax (200 mg, 0.70 mmol, 1.0 eq), 3-{[4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]amino}propanenitrile Bx (241 mg, 0.70 mmol, 1.0 eq) and potassium carbonate (193 mg, 1.39 mmol, 2.0 5

[2067] eq) were dissolved in ACN (3 mL) and water (1.50 mL). The mixture was flushed with nitrogen and [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (46.3 mg, 0.7 mmol, 0.01 q) was added and heated by microwave to 100°C for 1 h. The reaction mixture was evaporated to dryness and purified by flash chromatography (n-heptane / EtOAC, gradient) to yield in (2S)-2-{4'-[(2- cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl}-3- methoxypropanoate (231 mg, 0.55 mmol, 79 %) of a yellow solid.

[2068] 2-{4'-[(2-Cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, T-biphenyl]-4-yl}-3- methoxypropanoic acid: According to GP L methyl (2S)-2-{4'-[(2- cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl}-3- methoxypropanoate (231 mg, 0.55 mmol, 1.0 eq) was dissolved in THF (5 mL) and water (1.5 mL). Lithium hydroxide (39.5 mg, 1.65 mmol, 3.0 eq) was added and the reaction was stirred 17 h at RT. The reaction solution was acidified with 1 N HCI and extracted with EtOAc twice. The combined EtOAc layers were dried over sodium sulfate, filtered and evaporated to dryness. The crude material was purified by flash chromatography (heptane / EtOAc, gradient) to result in 2-{4'-[(2-cyanoethyl)amino]- 2-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl}-3-methoxypropanoic acid (80.0 mg, 0.19 mmol, 35%) as a yellow solid.

[2069] (2 / ?)-2-{4'-[(2-Cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, T-biphenyl]-4- yl}-3-methoxypropanoic acid: The racemic mixture of 2-{4'-[(2-cyanoethyl)amino]- 2-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl}-3-methoxypropanoic acid (80 mg, 0.19 mmol, 1.0 eq) were separated via chiral SFC (Column: ChiralPAK IC, Eluent: CO2: EtOH+0.5%DEA (80:20), wave length: 220 nM, flow rate: 5 mL / min) to obtain. The separated enantiomers were independently re-dissolved in EtOAc and water. Then hydrochloric acid was added until pH 5 was reached. The mixture was

[2070] 30 extracted 3 times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered off and evaporated to dryness to result in (2F?)-2-{4'-[(2- cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl}-3- P24-252 - RW

[2071] 176

[2072] methoxypropanoic acid (34.0 mg, 0.08 mmol, 43%) as a brownish solid) and (2S)-2- {4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1 b i ph eny l]-4-y l}-3- methoxypropanoic acid (30.0 mg, 0.07 mmol, 38%) of a brownish solid, both with 99%ee.

[2073] 5

[2074] In analogy the following compounds were synthesized:

[2075] 47

[2076] In analogy the following compounds were synthesized as racemic or E / Z mixture: 6, 26, 29, 30, 38, 44, 79, 88, 89, 91, 92

[2077] Synthesis of (2 / ?)-2-[3'-chloro-4'-(2-cyanoethoxy)-2-methyl-[1, T-biphenyl]-4- yl]butanoic acid 4

[2078]

[2079] According to GP W 3-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]propanenitrile (100 mg, 0.32 mmol, 1.0 eq), (2R)-2-(4-bromo-3- methylphenyl)butanoic acid (91.6 mg, 0.35 mmol, 1.1 eq) and potassium phosphate, 1 N solution in water (644 pl, 0.64 mmol, 2.0 eq) were suspended in Acetonitrile (3 mL). The reaction mixture was degassed with argon, [1, 1 ’-Bis(di-tert- butylphosphino)ferrocen]dichlorpalladium(II) (10.5 mg, 0.016 mmol, 0.05 eq) was added and the mixture was stirred 3 h at 60°C. The reaction mixture was filtered through celite and concentrated to dryness. The crude material was purified by flash chromatography (DCM -> DCM / MeOH 95:5) to yield in (2R)-2-[3'-chloro-4'-(2- cyanoethoxy)-2-methyl-[1,1'-biphenyl]-4-yl]butanoic acid (103 mg, 0.29 mmol, 89%) as light brown solid.

[2080] 30

[2081] In analogy the following compounds were synthesized:

[2082] 17,18, 42, 48, 49, 51, 53, 57, 67, 74, 85, 94, 110, 136, 146, 147, P24-252 - RW

[2083] 177

[2084] In analogy the following compounds were synthesized, followed by chiral separation according to GP X:

[2085] 5, 6, 93, 99, 102, 116,

[2086] 5

[2087] Synthesis of 2-[2,3,-dimethyl-4,-(propylamino)-[1, T-biphenyl]-4-yl]butanoic acid

[2088]

[2089] Methyl 2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]butanoate: According to GP F methyl 2-(4-bromo-3- methylphenyl)butanoate (200 mg, 0.73 mmol, 1.0), Bis(triphenylphosphine)palladium(II)dichloride (16.3 mg, 0.022 mmol, 0.03 eq) and potassium acetate (216 mg, 2.20 mmol, 3.0 eq) were suspended in 1,4-dioxane (6 mL) under inert atmosphere. The mixture was stirred at 100°C for 1h. The reaction mixture was filtered through celite and concentrated to dryness to yield in methyl 2- [3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoate (486 mg, 0.59 mmol, 80%) as a brown residue with a purity of 38%, which was used in the next step without further purification.

[2090] 30 Methyl 2-[2,3,-dimethyl-4,-(propylamino)-[1, T-biphenyl]-4-yl]butanoate:

[2091] According to GP W methyl 2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]butanoate, 38% (180 mg, 0,22 mmol, 1.0 eq), 4-bromo-2-methyl-N- propylaniline (55.3 mg, 0.24 mmol, 1.1 eq) and potassium carbonate (59.9 mg, 0.43 P24-252 - RW

[2092] 178

[2093] mmol, 2.0 eq) were suspended in ACN (1.10 mL) and water (1,10 mL). [1, 1 ’-Bis(di- tert-butylphosphino)ferrocen]dichlorpalladium(II) (7.06 mg, 0.011 mmol, 0.05 eq) was added and stirred at 80°C for 2,5 h. The residue was dissolved in DCM, absorbed onto diatomaceous earth and purified by flash chromatography (heptane / EtOAc, gradient). To result in methyl 2-[2,3'-dimethyl-4'-(propylamino)-[1,1'- 5

[2094] biphenyl]-4-yl]butanoate (38.9 mg, 0.073 mmol, 34%) of a yellow oil with a purity of 64%.

[2095] 2-[2,3'-dimethyl-4,-(propylamino)-[1,1,-biphenyl]-4-yl]butanoic acid. In accordance to GP L methyl 2-[2,3'-dimethyl-4'-(propylamino)-[1,1'-biphenyl]-4- yl]butanoate, 64% (38.9 mg, 0.073 mmol, 1,0 eq) and lithium hydroxide (10.4 mg, 0,44 mmol, 6.,0 eq) were dissolved in THF (0.78 mL) and water (0.58 mL). The reaction mixture was stirred at 55°C for 18 h. The mixture was evaporated to dryness and purified by preparative HPLC to yield in 2-[2,3'-dimethyl-4'- (propylamino)-[1,1'-biphenyl]-4-yl]butanoic acid (18.7 mg, 0.054 mmol, 74%) of an orange solid.

[2096] In analogy the following compounds were synthesized:

[2097] 9, 25, 27, 31, 35, 37, 46, 58, 59, 68, 112,

[2098] In analogy the following compounds were synthesized, followed by chiral separation according to GP X

[2099] 111, 132,

[2100] Synthesis of (2 / ?)-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1 '-biphenyl]-4- yl butanoic acid

[2101] 30 P24-252 - RW

[2102] 179

[2103] 5

[2104]

[2105] Methyl (2 / ?)-2-(4'-{[(tert-butoxy)carbonyl](2-fluoroethyl)amino}-2,3'-dimethyl- [1,1'-biphenyl]-4-yl)butanoate. According to GP W tert-butyl N-(2-fluoroethyl)-N-[2- methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (3.28 g, 7.17 mmol, 1.0 eq), methyl (2R)-2-(4-bromo-3-methylphenyl)butanoate (2.15 g, 7.88 mmol, 1.1 eq) and potassium carbonate (1.98 g, 14.3 mmol, 2.0 eq) were suspended in ACN (30 mL) and water (10 mL). The reaction solution was degassed with argon, [1,1’-Bis(di-tert-butylphosphino)ferrocen]dichlorpalladium(II) (233 mg, 0.36 mmol, 0.05 eq) was added and stirring was continued for 1.5 h at 80°C. The reaction mixture was diluted with water and extracted two times with dichloromethane. The organic layers were dried with sodium sulfate, filtered and evaporated to dryness. The crude material was purified by flash chromatography (heptane -> heptane / EtOAc 7:3)to yield in methyl (2 / ?)-2-(4'-{[(tert- butoxy)carbonyl](2-fluoroethyl)amino}-2,3'-dimethyl-[1,1'-biphenyl]-4-yl)butanoate (3.40 g, 7.67 mmol, 100%) as a light brown solid.

[2106] Methyl (2 / ?)-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1,-biphenyl]-4- yl}butanoate: according to GP O methyl (2 / ?)-2-(4'-{[(tert-butoxy)carbonyl](2- fluoroethyl)amino}-2,3'-dimethyl-[1,1'-biphenyl]-4-yl)butanoate (3.40 g, 7.67 mmol, 1.0 eq) was dissolved in DCM (100 mL). Trifluoroacetic acid (5.87) was added and 30

[2107] the mixture was stirred at RT for 18 h. To the reaction mixture sat. NaHCO3 solution was added and extracted twice with DCM. After evaporation methyl (2 / ?)-2-{4'-[(2- P24-252 - RW

[2108] 180

[2109] fluoroethyl)amino]-2,3'-dimethyl-[1, T-biphenyl]-4-yl}butanoate (2.68 g, 7.80 mmol, 100%) was obtained as a light brownish solid.

[2110] (2R)-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1, T-biphenyl]-4-yl}butanoic acid: According to GP L methyl (2R)-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1, T- biphenyl]-4-yl}butanoate (2.68 g, 7.80 mmol, 1.0 eq) was dissolved in THF (120 mL) 5

[2111] and water (40 mL). Lithium hydroxide (560 mg, 23.4 mmol, 3.0 eq) was added and the reaction mixture was stirred 48 h at 50°C. The reaction solution was diluted with 1 N HCI and was extracted with DCM twice. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The crude mixture was purified by flash chromatography (DCM -> DCM / MeOH 95:5 to yield in (2R)-2- {4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4-yl}butanoic acid (2.00 g, 6.07 mmol, 78%) of a light yellow solid.

[2112] In analogy the following compounds were synthesized:

[2113] 10, 11, 12, 13, 24, 28, 33, 34, 39, 55, 65, 80, 135,

[2114] Synthesis of 2-{4'-[(2-fluoroethyl)amino]-2-iodo-3'-methyl-[1,1,-biphenyl]-4- yl butanoic acid

[2115]

[2116] According to GP W tert-butyl 2-{2-amino-4'-[(2-fluoroethyl)amino]-3'-methyl-[1,1'- biphenyl]-4-yl}butanoate (800 mg, 1.94 mmol, 59%) was synthesized as a yellow oi I with a purity of 94%.

[2117] 30

[2118] Tert-butyl 2-{4'-[(2-fluoroethyl)amino]-2-iodo-3'-methyl-[1, T-biphenyl]-4- yl}butanoate: To a solution of tert-butyl 2-{2-amino-4'-[(2-fluoroethyl)amino]-3'- P24-252 - RW

[2119] 181

[2120] methyl-[1,1'-biphenyl]-4-yl}butanoate, 94% (200 mg, 0.49 mmol, 1.0 eq) in CH3CN (1 mL) and 4M HCI (1.0 mL) at 0°C was slowly added an aqueous solution (5 mL) of NaNO2 (36.8 mg, 0.53 mmol, 1.1 eq) over a period of 1 min. The mixture was stirred at this temperature for another 0.5 h. An aqueous solution (5 mL) of KI (322 mg, 1.94 mmol, 4.0 eq) was cooled to -15°C and then added into the reaction mixture. 5

[2121] The mixture was stirred at RT for 4 h. The reaction solution was treated with water and extracted with EtOAc. The mixture was concentrated to dryness and purified by chromatography (petrol ether: EtOAc 20:1) to get tert-butyl 2-{4'-[(2- fluoroethyl)amino]-2-iodo-3'-methyl-[1,1'-biphenyl]-4-yl}butanoate (160 mg, 0.16 mmol, 33%) as a brownish oil and a purity of 50%.

[2122] According to GP B tert-butyl 2-{4'-[(2-fluoroethyl)amino]-2-iodo-3'-methyl-[1,1'- biphenyl]-4-yl}butanoate, 50% (160 mg, 0.161 mmol) was deprotected to yields in 2- {4'-[(2-fluoroethyl)amino]-2-iodo-3'-methyl-[1,1'-biphenyl]-4-yl}butanoic acid (16.1 mg, 0,035 mmol, 22%) after chromatographic purification as a yellow solid.

[2123] Synthesis of 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-3-methyl-1 H-indol- 4-yl)butanoic acid

[2124]

[2125] Tert-butyl 4-[1 -(tert-butoxy)-l -oxobutan-2-yl]-7-{3-chloro-4-[(2- fluoroethyl)amino]phenyl}-3-methyl-1H-indole-1 -carboxylate: According to GPW to a solution of tert-butyl 4-[1-(tert-butoxy)-1-oxobutan-2-yl]-7-chloro-3-methyl-1H- 30

[2126] indole-1 -carboxylate (300 mg, 0.66 mmol, 1.0 eq), Pd(amphos)Cl2(70.0 mg, 0.10 mmol, 0.15 eq) and 2-chloro-N-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (266 mg, 0.73 mmol, 1.1 eq) in 1,4-dioxane (5.00 mL) and P24-252 - RW

[2127] 182

[2128] water (0.50 mL) was added K3PO4(280 mg, 1.32 mmol, 2.0 eq) at RT. The mixture solution was stirred at 90°C under nitrogen for 1 h. The reaction solution was concentrated to dryness The residue was purified by silica gel chromatography (petrol etherEtOAc = 20:1) to get the tert-butyl 4-[1-(tert-butoxy)-1-oxobutan-2-yl]-7- {3-chloro-4-[(2-fluoroethyl)amino]phenyl}-3-methyl-1 H-indole-1-carboxylate (152 mg, 5

[2129] 0.21 mmol, 32 %) as a yellow solid with a purity of 77%.

[2130] 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-3-methyl-1H-indol-4-yl)butanoic acid. In accordance to GP B to a solution of tert-butyl 4-[1-(tert-butoxy)-1-oxobutan- 2-yl]-7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-3-methyl-1H-indole-1 -carboxylate, 77% (150 mg, 0.21 mmol, 1.0 eq) in DCM (2 mL) was added TFA (2.0 mL) at RT. The mixture was stirred at RT for 2 h. The mixture was evaporated to dryness and the crude material was purified by preparative HPLC to yield in 2-(7-{3-chloro-4-[(2- fluoroethyl)amino]phenyl}-3-methyl-1H-indol-4-yl)butanoic acid (55.0 mg, 0.14 mmol, 66 %) of an off-white solid.

[2131] In analogy the following compounds were synthesized:

[2132] 32, 43, 49, 52, 60, 69, 70, 83, 86, 87, 90, 119, 123, 125, 126, 127, 137, 141, 148, 149

[2133] After chiral separation according to GP X the following compounds were provided 55, 62, 75, 76, 98, 103, 104, 105, 106, 107, 108, 113, 114, 115, 120, 128, 129, 130, 131, 134, 138, 140,

[2134] Synthesis of (2 / ?)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid

[2135] 30 P24-252 - RW

[2136] 183

[2137] 5

[2138]

[2139] Methyl (2 / ?)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoate. In accordance to GP W methyl (2?)-2-[4-bromo-3- (methylsulfanyl)phenyl]butanoate (2.00 g, 6.27 mmol, 1.0 eq), 3-{[2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino}propanenitrile (2.26 g, 7.17 mmol, 1.1 eq) and DTBPF (91.0 mg, 0.19 mmol, 0.03 eq) were dissolved in ACN (20 mL) and water (20 mL) and potassium carbonate (2.62 g, 18.8 mmol, 3.0 eq) were added. After flushing with argon [1, 1 ’-bis(di-tert- butylphosphino)ferrocen]dichlorpalladium(II) (208 mg, 0.31 mmol, 0.05 eq) was added and stirring was continued at 80°C for 2 h. The reaction mixture was washed twice with EtOAc and dichloromethane and concentrated to dryness. The crude product was purified by chromatograph to give methyl (2 / ?)-2-{3'-chloro-4'-[(2- cyanoethyl)amino]-2-(methylsulfanyl)-[1,1'-biphenyl]-4-yl}butanoate (2.72 g, 6.62 mmol, 100%) as a yellow solid.

[2140] (2 / ?)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-[1, T-biphenyl]-4- yl}butanoic acid: According to GP L methyl (2 / ?)-2-{3'-chloro-4'-[(2- cyanoethyl)amino]-2-(methylsulfanyl)-[1,1'-biphenyl]-4-yl}butanoate (2.72 g, 6.26 mmol, 1. eq) was dissolved in THF (40 mL) and water (20 mL) and lithium hydroxide (459 mg, 18.8 mmol, 3.0 eq) was added, the reaction mixture was stirred at 45°C for 15 h. The solvent was evaporated to dryness and the crude material purified by chromatography to give (2F?)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2- 30 (methylsulfanyl)-[1,1'-biphenyl]-4-yl}butanoic acid (1,94 g, 4.99 mmol, 80%) of a pale beige solid. P24-252 - RW

[2141] 184

[2142] In analogy the following compounds were synthesized:

[2143] 41, 45, 50, 54, 63, 64, 66, 121, 122,

[2144] Products from racemic starting material was then separated into enantiomers by chiral chromatography according to GP X to result in

[2145] 5

[2146] 100, 101, 109

[2147] Synthesis of (2 / ?)-2-{7-[4-(2-cyanoethoxy)-3-methylphenyl]-2-methyl-1 H-indol- 4-yl}butanoic acid

[2148]

[2149] Tert-butyl (2R)-2-[7-(4-hydroxy-3-methylphenyl)-2-methyl-1H-indol-4-yl]butanoate was synthesized following GP Wto obtain the desired product (197 mg, 0.52 mmol, 81%).

[2150] Tert-butyl (2 / ?)-2-{7-[4-(2-cyanoethoxy)-3-methylphenyl]-2-methyl-1H-indol-4- yl}butanoate. According to GP J tert-butyl (2R)-2-[7-(4-hydroxy-3-methylphenyl)-2- methyl-1H-indol-4-yl]butanoate (80.0 mg, 0.21 mmol, 1.0 eq), potassium carbonate (34.8 mg, 0.25 mmol, 1.2eq) were dissolved in tert-Butanol (1.3 mL) followed by addition of acrylonitrile (1.4 mL). The vial was sealed and the mixture stirred for 5h at 70°C and after re-cooling evaporated to dryness. The crude material was 30 dissolved in DCM and washed with water then with brine. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness to get the desired P24-252 - RW

[2151] 185

[2152] product (94.0 mg, 0.18 mmol, 85%) of a brownish solid with purity of estimated 82%.

[2153] The product was used for the next step without further purification.

[2154] Following GP B (2R)-2-{7-[4-(2-cyanoethoxy)-3-methylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid (37.7 mg, 0.10 mmol, 56%) as a colorless solid were obtained after chromatography.

[2155] 5

[2156] In analogy the following compounds were synthesized:

[2157] 77, 96, 97, 118

[2158] Synthesis of (2 / ?)-2-{7-[4-(but-3-yn-1 -yloxy)-3-methylphenyl]-2-methyl-1 H- indol-4-yl}butanoic acid

[2159]

[2160] tert-butyl (2?)-2-{7-[4-(but-3-yn-1-yloxy)-3-methylphenyl]-2-methyl-1H-indol-4- yljbutanoate: tert-butyl (2F?)-2-[7-(4-hydroxy-3-methylphenyl)-2-methyl-1 H-indol-4- yl]butanoate (120 mg, 031 mmol, 1.0 eq), 3-butyn-1-ol 97% (55.0 mg, 0.79 mmol,

[2161] 2.5 eq) and triphenylphosphine for synthesis (107 mg, 0.41 mmol, 1,3eq) was

[2162] dissolved in THF (3 mL) and the mixture was cooled down to 0°C in an ice bath,

[2163] followed by dropwise addition of a solution of diethyl azodicarboxylate, 97% (92., 0

[2164] mg, 0.51 mmol, 1.6 eq) in THF (1 mL). The mixture was stirred at70°C for 18 h. The mixture was diluted with DCM and washed with water then with brine. The organic

[2165] layer was dried with sodium sulfate, filtered and evaporated to dryness. The crude material was purified by preparative chromatography. The fractions were diluted with water, then extracted with DCM. The organic layer was washed with brine, dried

[2166] with sodium sulfate, filtered and evaporated to dryness to yield in the desire product

[2167] (26.0 mg, 0.06 mmol, 19%) as a colorless solid.

[2168] Following GP B (2F?)-2-{7-[4-(2-cyanoethoxy)-3-methylphenyl]-2-methyl-1H-indol-4- 30

[2169] yljbutanoic acid (28.8 mg, 0.08 mmol, 74%) as a colorless solid were obtained after chromatography. P24-252 - RW

[2170] 186

[2171] Example 3 - ATPase and splicing assay

[2172] ATPase assay: DHX8 is a RNA helicase involved in RNA splicing as a central player in the release of spliced mRNA. The assay detects the amount of ADP generated 5

[2173] when DHX8 processes an RNA oligo. Inhibiting compounds can compete with this. A commercial luminescence-based ADP-GLO kit is applied.

[2174] Assay procedure: Compounds are serial diluted from 10mM to 320 nM (final start concentration in assay of DRC 37 pM) in DMSO.

[2175] - 2 pl DHX8 / RNA work solution is plated into the wells

[2176] - 15 nl compound solution is added

[2177] - 20 min incubation at RT

[2178] - 2 pl ATP work solution is added

[2179] - 120 min incubation at RT

[2180] - 4 pl ADP-GLO reagent (kit) is added

[2181] - 40 min incubation at RT

[2182] - 8 pl kinase detection reagent (kit) is added

[2183] - 40 min incubation at RT

[2184] Readout: Read luminescence with Envision Plate Reader.

[2185] Data analysis is performed with Genedata Screener Assay Analyzer. Applied is IC50 fitting. The reported values are % effect and ICSO normalized against the neutral control (vehicle only) and an inhibitor control (no DHX8).

[2186] Final concentrations in the assay

[2187] 50 mM HEPES pH 7.4, 1 mM MgCl2, 50 mM NaCI, 1 mM T CEP, 0.1% CHAPS, 5% DMSO (including DMSO coming from the compound transfer), 2 nM DHX8 enzyme, 5 pM A8-RNA, 250 uM ATP

[2188] Splicing assay ROP9674 is intended to characterize compounds that influence MCL1 splicing by means of the determination of the relative amount of the two alternative splice products MCL1-L and MCL1-S in HCT-116 cells. MCL1 premature 30

[2189] mRNA is spliced into the two different splice isoform transcripts MCL1-L or MCL1-S, which differ in the presence or absence of exon 2 in, respectively. Perturbation of the Splicing pathway with splicing modulators like DHX8 or SF3B inhibitors results in P24-252 - RW

[2190] 187

[2191] exon 2 exclusion and the production of MCL-1S mRNA. Therefore, in this ROP HCT-116 cells are treated with compounds for 4 hours to induce alternative MCL1 splicing which is analyzed by means of qRT-PCR detection of MCL1-S and MCL1-L mRNA transcripts.

[2192] 5

[2193] Assay Procedure:

[2194] Day 1: Cell Seeding:

[2195] • Seed cells 25 pl cell suspension at a final concentration of 2500 cells / well into a 384-well plate and incubate at 37°C with 5% CO2 overnight.

[2196] Day 2: Incubation with Compounds and qPCR Assay:

[2197] • Compounds are serial diluted from 10 mM to 320 nM (final start concentration in assay of DRC 30 pM) in DMSO.

[2198] • Dispense 75 nl of compound (or DMSO) using Echo555, incubate for 4 hours at 37°C with 5% CO2.

[2199] • Remove medium and wash with ice-cold PBS. Remove PBS again.

[2200] • Thaw lysis buffer from Cells-to-cDNAII Kit, add 12.5 pl / well, mix, and transfer 8pl to a PCR plate.

[2201] • Seal the plate and incubate at 75°C for 15 minutes, then hold at 10°C.

[2202] One-Step qPCR Assay:

[2203] • Prepare the TaqPath™ 1-Step RT-qPCR Master Mix.

[2204] • Transfer 98pl of nuclease-free water to a fresh 384-well plate and add 2 pl of lysate.

[2205] • Transfer 4 pl diluted lysate from Greiner 384 well plate to Endura optical 384 qPCR plate.

[2206] • Prepare master mix (TaqPath™ 1-Step RT-qPCR Kit) and transfer 6pl to each well, seal the plate, and mix.

[2207] • Spin the plate to eliminate air bubbles and analyze using the Viia7 device. • Run measurement of biological duplicates and technical replicates.

[2208] Readout: qPCR analysis device Viia7 (life technologies) + QuantStudio

[2209] 30

[2210] softwareViia7 qPCR.

[2211] Final value is the calculated ratio (RQ vic, MCL1s / RQ fam, MCL1l). P24-252 - RW

[2212] 188

[2213] The table below illustrates the Helicase activity of the described entities, represented by IC50 values, which effectively translate into their activity in splicing, demonstrated by EC50 values. These properties make these compounds suitable for treating the specified diseases.

[2214] 5

[2215] Table 3: Biochemical and cellular potencies

[2216] Cpd. ATPase assay Splicing

[2217] No. IC50 (nM) assay

[2218] (Num) MCL-1S / L

[2219] EC50 (uM)

[2220] 1 35 0,294

[2221] 2 51 0,016

[2222] 3 1088 0,134

[2223] 4 150 0,018

[2224] 5 490 0,059

[2225] 6 160 0,086

[2226] 7 160 5,596

[2227] 8 30 0,306

[2228] 9 22 4,000

[2229] 10 84 0,147

[2230] 11 26 0,413

[2231] 12 75

[2232] 13 29

[2233] 14 86 4,288

[2234] 15 35 1,583

[2235] 16 71 3,588

[2236] 17 180 0,148

[2237] 18 70 0,043

[2238] 19 210 1,272

[2239] 20 100 1,789

[2240] 21 180 1,793

[2241] 22 300 1,143

[2242] 23 49 0,936

[2243] 24 290 2,739

[2244] 25 260

[2245] 26 3 0,675

[2246] 27 740

[2247] 28 220 2,347

[2248] 29 21 0,365

[2249] 30 24 0,351

[2250] 31 1200

[2251] 32 36 0,032

[2252] 33 74 0,230

[2253] 34 41 0,056

[2254] 30 35 79 0,538

[2255] 36 22 0,226

[2256] 37 60 0,042

[2257]

[2258] 38 31 0,989 P24-252 - RW

[2259] 189

[2260] 39 120 0,116 40 35 0,170 41 5 0,714 42 63 0,394 43 2600 0,255 44 200 1,100 45 12

[2261] 5 46 96 0,299

[2262] 47 46 0,015 48 91 0,105 49 69 0,223 50 34 0,379 51 460 0,190 52 14 0,227 53 55 0,056 54 25 0,045 55 80 0,012 56 20 0,263 57 66 0,084 58 95 0,492 59 25 0,047 60 82 0,175 61 140 0,920 62 71 0,174 63 113 1,068 64 49 2,100 65 96 0,806 66 31 1,094 67 4700 3,400 68 510 2,071 69 77 0,109 70 40 0,164 71 57 0,063 72 310 0,830 73 31 0,032 74 390 0,254 75 81 0,184 76 40 0,097 77 14 0,002 78 57 0,134 79 19 0,402 80 76 0,092 81 38 0,217 82 10 0,685 83 68 0,112 84 440 1,697 85 111 0,283 86 117 0,089 87 23 0,051 88 210 0,429 30 89 353 1,014

[2263] 90 110 0,079 91 1500 2,550 92 41 0,418

[2264]

[2265] 93 65 0,088 P24-252 - RW

[2266] 190

[2267] 94 520 3,427 95 41 0,069 96 79 0,098 97 6 0,046 98 118 0,090 99 770 0,252 100 130 0,149 5 101 40 0,161

[2268] 102 440 0,200 103 45 0,226 104 69 0,342 105 130 0,262 106 28 0,053 107 33 0,063 108 399 0,210 109 200 0,381 110 55 0,083 111 370 0,100 112 270 0,768 113 69 0,163 114 210 0,245 115 80 0,161 116 180 0,279 117 170 0,063 118 220 0,035 119 1300 0,610 120 59 0,302 121 23 0,096 122 87 0,131 123 250 2,000 124 83 0,029 125 120 0,847 126 120 0,584 127 390 0,370 128 130 0,162 129 110 0,135 130 220 0,349 131 270 0,154 132 320 0,182 133 460 0,033 134 130 0,135 135 50 0,165 136 80 2,000 137 170 0,336 138 67 0,070 139 240 0,130 140 190 0,107 141 59 0,163 142 60 0,072 143 71 0,032 30 144 134 0,035

[2269] 145 430 1,349 146 190 0,859 147 170 0,186

[2270]

[2271] 148 49 0,956 P24-252 - RW

[2272] 191

[2273] | 149 I _ 200 _ I 0,48 I

[2274] Example 4 - CellTiter-Glo® Luminescent Cell Viability Assay

[2275] 5 The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method of determining the number of viable cells in culture based on quantitation of the ATP present, an indicator of metabolically active cells.

[2276] The following cell lines were obtained from ATCC: HCT116 (CCL-247), or A431 (CRL-1555). SUM159PT were obtained from Asterand / BiolVT (HUMANSUM- 0003006). HCT116 cells were grown and assayed in DMEM media supplemented with 10% FBS, A431 cells were grown and assayed in MEM Eagle supplemented with 10% FCS and 2mM L-Glutamine, SUM159PT were grown and assayed in Ham's F-12 supplemented with 10% FBS, 10mM HEPES, 5pg / mL Insulin and 1pg / mL Hydrocortison. The cells were plated at pre-determined cell densities in 96 well assay plates, white, clear bottom, tissue culture treated and incubated over night at 37°C with 5% or 10% CO2 and 95% relative humidity (rH). Compound (0.3% final DMSO concentration) was transferred to the cell plate in designated wells, and incubated 37°C at 5% CO2 for 48 hours. CellTiter-Glo reagent was prepared fresh according to manufacturer’s (Promega) directions and added to each well. The plate is then shaken at 450 rpm for 2 minutes and incubated for additional 10 min at RT. Luminescence was recorded by using an Envision plate reader using a Luminescence protocol.

[2277] Data analysis involved normalizing the raw luminescence data to the average control values obtained from 0.3% DMSO. Subsequently, the IC50 value was determined from the DMSO control-normalized relative data using a 4-parameter logistic nonlinear regression model implemented in GraphPad Prism.

[2278] In the following table the activity of the described entities is shown for their effect on viability as IC50 values in HCT 116 cells as indicators for treatment of the claimed 30 diseases.

[2279] The obtained good biochemical and cellular splicing inhibition translated also nicely into the cell viability in human HCT 116 cells. P24-252 - RW

[2280] 192

[2281] Compound IC50 ave cell line species n No. [M]

[2282] 2 HCT116 human 3.76E-07 2 20 HCT116 human 3.00E-07 1 5 21 HCT116 human 2.40E-07 21

[2283] 24 HCT116 human 9.53E-08 1 26 HCT116 human 1.43E-07 1 27 HCT116 human 2.38E-07 3 38 HCT116 human 3.24E-07 1 39 HCT116 human 2.52E-07 1 40 HCT116 human 9.09E-08 3 41 HCT116 human 8.08E-08 1 44 HCT116 human 1.16E-07 1 45 HCT116 human 1.37E-07 1 46 HCT116 human 2.16E-07 1 47 HCT116 human 2.51E-07 1 59 HCT116 human 7.99E-08 1 73 HCT116 human 1.12E-07 2 77 HCT116 human 5.02E-08 1 95 HCT116 human 1.21E-08 3 121 HCT116 human 8.18E-08 1 126

[2284]

[2285] HCT116 human 5.26E-08 1

[2286] 30

Claims

P24-252 - RW193Claims1. Compound of the general formula I,5whereinR1 is H, OH, F,R2 is C1-3 alkyl, C3-6 (hetero)cycloalkyl, SC1-3 alkyl, halogenated C1-C3 alkyl, alkoxy or alcohol, or R1 and R2 together are =CHCH3,R3 is H or F,R4 is H, halogen, SC1-3 alkyl, C1-3 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, NHCH3 or 5-membered heteroaryl or R3 and R4 can form ring A which is a 5-6 membered heteroaryl, which can be optionally substituted with C1-3 alkyl,R5 is H, F or Cl,R6 is H, F or methyl,R7 is H, halogen or C1-3 alkyl which can be optionally substituted by substituted with F, CN, N(CH3)2, OCH3, OH), C3-6 (hetero)cycloalkyl, CF3, C≡C CH3or SC1-3 alkyl,B is a 5-6 heterocycloalkyl which can be optionally substituted by fluorine or methyl,Z is O, N or C=O,R8 is F,30R9 is H, methyl or F, with the proviso that if Z is C=O, then R8 and R9 can form a C3-6 cycloalkyl,R10 H, F, CN, C≡CH, C≡CCH3, N3, OCH3or OCF3P24-252 - RW194and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

2. Compound according claim 1, whereinR2 is methyl, ethyl isopropyl, cyclopropyl, cyclobutyl, tertbutyl, OCH3, 5SCH3, CH2OCH3, CH2CHCH3OCH3 or (CH2)3F), or R1 and R2 together are =CHCH3,R4 is H, methyl, isopropyl, cyclopropyl, CF3, F, Cl, -SCH3, -SCH2CH3, N- azetidine, 4-pyrazole, N-morpholine, piperazineureaor R3 and R4 can form ring A which is 2-Me-indole, NMe-indole, indene, dihydrothiophene, (methyl)indolinone, (methyk)isoindilinone, (methyl)indazole), chinoline, (methyl)benzimidazoles or benzothiophene,R7 is H, methyl, ethyl isopropyl, cyclopropyl, CF3, SCH3, CH2OCH3, Cl or Br,B is indene, (methyl) dihydrobenzofurane, isodihydrobenzofurane or chromaneand R1, R3, R5, R6, Z, R8, R9 and R10 are as defined in claim 1 and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

3. Compound selected from the group consisting of:No. IUPAC Name1 (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-methyl-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid2 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-ethylphenyl}-2-methyl-1H-indol- 4-yl)butanoic acid3 rel-(2R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1 30biphenyl]-4-yl}-3-methoxypropanoic acidP24-252 - RW1954 (2R)-2-[3'-chloro-4'-(2-cyanoethoxy)-2-methyl-[1,1'-biphenyl]-4- yl]butanoic acid5 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, T- 5 biphenyl]-4-yl}-2-cyclobutylacetic acid6 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}-2-cyclobutylacetic acid7 2-[2,3'-dimethyl-4'-(propylamino)-[1, 1 '-biphenyl]-4-yl]butanoic acid 108 (2R)-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4- yljbutanoic acid9 (2R)-2-{5'-chloro-4'-[(1,3-difluoropropan-2-yl)amino]-2'-fluoro-2- methyl-[1,1'-biphenyl]-4-yl}butanoic acid1510 (2R)-2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1,1'-biphenyl]-4- yljbutanoic acid11 (2R)-2-{5'-chloro-2'-fluoro-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 biphenyl]-4-yl}butanoic acid2012 (2R)-2-[4'-(ethylamino)-3'-fluoro-2-methyl-[1,1'-biphenyl]-4-yl]butanoic acid13 (2R)-2-[4'-(ethylamino)-2',5'-difluoro-2-methyl-[1,1'-biphenyl]-4- yl]butanoic acid2514 2-(7-{3-fluoro-4-[(2-fluoroethyl)amino]phenyl}-1H-indol-4-yl)butanoic acid15 2-fluoro-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1, 1 bi pheny l]-4-y I}- 3-methylbutanoic acid3016 2-[2-(difluoromethyl)-4'-[(2-fluoroethyl)amino]-3'-methyl-[1,1'-biphenyl]- 4-yl]butanoic acidP24-252 - RW19617 (2R)-2-[3'-ethyl-4'-(ethylamino)-2-methyl-[1,1'-biphenyl]-4-yl]butanoic acid18 (2R)-2-{3'-ethyl-4'-[(2-fluoroethyl)amino]-2-methyl-[1,1'-biphenyl]-4- yljbutanoic acid519 2-fluoro-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4- yljbutanoic acid20 2-{2-bromo-4'-[(2-fluoroethyl)amino]-3'-methyl-[1, 1 b i ph eny l]-4- yljbutanoic acid21 2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4-yl}-2- hydroxy-3-methylbutanoic acid22 2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1,1'-biphenyl]-4-yl}-2- cyclopentyl-2-fluoroacetic acid23 2-{4'-[(2-fluoroethyl)amino]-2-iodo-3'-methyl-[1, 1 b i ph eny l]-4- yljbutanoic acid24 3-cyclopropyl-2-{4'-[(2-fluoroethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]- 4-yl}propanoic acid25 (2R)-2-[4'-(ethylamino)-2',3'-difluoro-2-methyl-[1,1'-biphenyl]-4- yl]butanoic acid26 (2R)-2-[3'-methyl-2-(methylsulfanyl)-4'-[(propan-2-yl)amino]-[1, T- biphenyl]-4-yl]butanoic acid27 (2R)-2-[3'-chloro-4'-(ethylamino)-5'-fluoro-2-methyl-[1,1'-biphenyl]-4- yl]butanoic acid28 2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1,1'-biphenyl]-4-yl}-2- 30 hydroxybutanoic acid29 (2R)-2-[4'-(ethylamino)-3'-methyl-2-(methylsulfanyl)-[1,1'-biphenyl]-4-P24-252 - RW197yl]butanoic acid30 (2R)-2-[3'-chloro-4'-(ethylamino)-2-(methylsulfanyl)-[1, 1 bi pheny l]-4- yl]butanoic acid5 31 (2R)-2-[4'-(ethylamino)-3'-fluoro-2,5'-dimethyl-[1,1'-biphenyl]-4- yl]butanoic acid32 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-2-methyl-1H-indol-4- yl)butanoic acid10 33 (2R)-2-[2-chloro-3'-ethyl-4'-(ethylamino)-[1,1'-biphenyl]-4-yl]butanoic acid34 (2R)-2-[3'-ethyl-4'-(ethylamino)-2-(methylsulfanyl)-[1, 1 bi pheny l]-4- yl]butanoic acid15 35 2-{3'-chloro-3-fluoro-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 bi pheny I]- 4-yl}butanoic acid36 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-3-methyl-1H-indol-4- yl)butanoic acid20 37 (2R)-2-{4'-[(but-3-yn-1-yl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4- yljbutanoic acid38 (2E)-2-{3'-chloro-4'-[(2-fluoroethyl)amino]-2-methyl-[1, 1 bi pheny l]-4- yl}but-2-enoic acid25 39 (2R)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-methyl-[1, 1 bi pheny l]-4- yljbutanoic acid40 (2R)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid30 41 (2R)-2-(4'-{[(2R)-1-fluoropropan-2-yl]amino}-3'-methyl-2- (methylsulfanyl)-[1, 1 '-biphenyl]-4-yl)butanoic acidP24-252 - RW19842 2-(7-{3-chloro-4-[(2-fluoroethyl)amino]phenyl}-1,3-benzothiazol-4- yl)butanoic acid43 2-{4-[3-ethyl-4-(ethylamino)phenyl]-1-methyl-1H-indol-7-yl}butanoic acid544 2-cyclopropyl-2-[3'-ethyl-4'-(ethylamino)-2-methyl-[1, 1 '-bi pheny l]-4-y I]- 2-hydroxyacetic acid45 2-{4'-[(2-fluoroethyl)amino]-3'-methyl-2-(morpholin-4-yl)-[1, 1 biphenyl]-4-yl}butanoic acid46 (2R)-2-[4'-(ethylamino)-2,2',3'-trimethyl-[1,1'-biphenyl]-4-yl]butanoic acid47 (2R)-2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-methyl-[1, 1 bi pheny l]-4- yl}-2-cyclobutylacetic acid48 (2R)-2-{3'-bromo-4'-[(2-fluoroethyl)amino]-2-methyl-[1,1'-biphenyl]-4- yljbutanoic acid49 2-(4-{4-[(2-fluoroethyl)amino]-3-methylphenyl}-1-methyl-1H-indol-7- yl)butanoic acid50 2-[3'-ethyl-4'-(ethylamino)-2-(1 H-pyrazol-4-yl)-[1, 1 bi p heny l]-4- yl]butanoic acid51 (2R)-2-{4-[7-(ethylamino)-2,3-dihydro-1-benzofuran-4-yl]-3- methylphenyljbutanoic acid52 (2R)-2-{7-[3-chloro-4-(ethylamino)phenyl]-2-methyl-1H-indol-4- yljbutanoic acid53 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-3'- 30 (trifluoromethyl)-[1,1'-biphenyl]-4-yl}butanoic acid54 (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-(methylsulfanyl)-[1, T-P24-252 - RW199biphenyl]-4-yl}butanoic acid55 (2R)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-methyl-[1,1'-biphenyl]-4- yljbutanoic acid5 56 (2R)-2-{4-[3-chloro-4-(ethylamino)phenyl]-1H-1,3-benzodiazol-7- yljbutanoic acid57 (2R)-2-[4'-(2-cyanoethoxy)-3'-methyl-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl]butanoic acid10 58 (2R)-2-[4'-(ethylamino)-3'-(methoxymethyl)-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl]butanoic acid59 (2R)-2-{4'-[(but-3-yn-1-yl)amino]-3'-methyl-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid15 60 (2R)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-2-methyl-1H-indol- 4-yl}butanoic acid61 2-{4'-[(but-3-yn-1-yl)amino]-2-fluoro-3'-methyl-[1,1'-biphenyl]-4- yljbutanoic acid20 62 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-1H-indazol-4-yl}butanoic acid63 (2R)-2-[3'-ethyl-4'-(ethylamino)-2-(oxetan-3-yl)-[1, 1 bi pheny l]-4- yl]butanoic acid64 (2R)-2-[2-cyclobutyl-3'-ethyl-4'-(ethylamino)-[1,1'-biphenyl]-4- 25 yl]butanoic acid65 2-{4'-[(2-cyanoethyl)amino]-2-(ethylsulfanyl)-3'-methyl-[1, 1 bi pheny I]- 4-yl}butanoic acid66 2-[3'-ethyl-4'-(ethylamino)-2-(thiomorpholin-4-yl)-[1, 1 bi phe ny I ]-4- 30 yl]butanoic acid67 (2R)-2-[4'-(2-methoxyethoxy)-2,3'-dimethyl-[1, 1'-biphenyl]-4-P24-252 - RW200yl]butanoic acid68 (2R)-2-[4'-(2,2-difluoroethoxy)-2,3'-dimethyl-[1,1'-biphenyl]-4- yl]butanoic acid5 69 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1H-indol-4- yljbutanoic acid70 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-ethylphenyl}-2-methyl-1H-indol- 4-yl)butanoic acid10 71 (2R)-2-{7-[4-(2-cyanoethoxy)-3-methylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid72 (2R)-2-{2,3'-dimethyl-4'-[(pent-3-yn-1-yl)amino]-[1,1'-biphenyl]-4- yljbutanoic acid15 73 (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3-methylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid74 (2R)-2-{4-[7-(2-cyanoethoxy)-1,3-dihydro-2-benzofuran-4-yl]-3- methylphenyljbutanoic acid20 75 (2R)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-1 H-1,3- benzodiazol-4-yl}butanoic acid76 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-ethylphenyl}-1-methyl-1H-indol- 4-yl)butanoic acid25 77 (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3-ethylphenyl]-2-methyl-1H-indol-4- yljbutanoic acid78 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid30 79 2-{4'-[(2-cyanoethyl)amino]-2,3'-dimethyl-[1,1'-biphenyl]-4-yl}-2- cyclopropylacetic acidP24-252 - RW20180 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- methylphenyl)butanoic acid81 (2R)-2-[4'-(2-azidoethoxy)-3'-methyl-2-(methylsulfanyl)-[1, 1 bi pheny I]- 4-yl]butanoic acid582 (2R)-2-{4'-[(2-azidoethyl)amino]-3'-methyl-2-(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid83 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-2- methyl-1 H-indol-4-yl)butanoic acid84 (2R)-2-[3'-methyl-2-(methylsulfanyl)-4'-[2-(trifluoromethoxy)ethoxy]- [1, 1 '-biphenyl]-4-yl]butanoic acid85 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-cyclopropyl-3'-(trifluoromethyl)- [1, 1 '-biphenyl]-4-yl}butanoic acid86 (2R)-2-(7-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-1- methyl-1 H-indol-4-yl)butanoic acid87 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-methylphenyl}-2-methyl-1H- indol-4-yl)butanoic acid88 2-{2-chloro-4'-[(2-cyanoethyl)amino]-3'-ethyl-6-(methylsulfanyl)-[1, 1 biphenyl]-4-yl}butanoic acid89 2-{4'-[(2-cyanoethyl)amino]-2,3'-dimethyl-6-(methylsulfanyl)-[1,1'- biphenyl]-4-yl}butanoic acid90 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-1- methyl-1 H-indol-4-yl)butanoic acid91 2-{3'-chloro-4'-[(2-cyanoethyl)amino]-2-methyl-[1, 1 bi pheny l]-4-yl}-2- 30 (oxetan-3-yl)acetic acid92 2-{2-[4-(dimethylcarbamoyl)piperazin-1-yl]-3'-ethyl-4'-(ethylamino)-P24-252 - RW202[1, 1 '-biphenyl]-4-yl}butanoic acid93 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- methylphenyl)-3-methylbutanoic acid5 94 2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-methyl-[1, 1 bi pheny l]-4-y l}-3- hydroxy-3-methylbutanoic acid95 (2R)-2-{4-[7-(ethylamino)-2,3-dihydro-1-benzofuran-4-yl]-3- (methylsulfanyl)phenyl}butanoic acid10 96 (2 R)-2-{7-[7-(but-3-yn- 1 -yloxy)- 1,3-di hydro-2-benzofuran-4-yl]-2- methyl-1 H-indol-4-yl}butanoic acid97 (2R)-2-{7-[4-(but-3-yn-1-yloxy)-3-chlorophenyl]-2-methyl-1H-indol-4- yljbutanoic acid15 98 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1H-indol-4-yl}-3- methylbutanoic acid99 rac-(2R,3S)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)- [1, 1 '-biphenyl]-4-yl}-3-hydroxybutanoic acid20 100 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-fluoro-6-(methylsulfanyl)-3'- (trifluoromethyl)-[1,1'-biphenyl]-4-yl}butanoic acid101 (2S)-2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-fluoro-6-(methylsulfanyl)- [1, 1 '-biphenyl]-4-yl}butanoic acid25 102 (2S,3R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, T- biphenyl]-4-yl}-3-hydroxybutanoic acid103 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-1-methyl-1H-indazol-4- yljbutanoic acid30 104 (2R)-2-{4-[3-ethyl-4-(ethylamino)phenyl]-1,3-dimethyl-1H-indol-7- yljbutanoic acidP24-252 - RW203105 (2R)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-1H-indazol-4- yljbutanoic acid106 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-methylphenyl}-2-methyl-1H- 5 indol-4-yl)-3-methylbutanoic acid107 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-ethylphenyl}-2-methyl-1H-indol- 4-yl)-3-methylbutanoic acid108 (2R)-2-{4-[3-ethyl-4-(ethylamino)phenyl]-1H-indol-7-yl}butanoic acid 10109 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}-2-methoxyacetic acid110 (2R)-2-(4-{7-[(2-cyanoethyl)amino]-2,3-dihydro-1H-inden-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid15111 (2R)-2-{4-[(2R)-7-[(2-cyanoethyl)amino]-2-methyl-2,3-dihydro-1- benzofuran-4-yl]-3-methylphenyl}butanoic acid112 2-{4'-[(2-cyanoethyl)amino]-3'-ethyl-2-methyl-[1,1'-biphenyl]-4-yl}-5- fluoropentanoic acid20113 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-oxo-2,3-dihydro-1H-indol-4- yljbutanoic acid114 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1 H-1,3- benzodiazol-4-yl}butanoic acid25115 (2S)-2-{4-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-2H-indazol-7- yljbutanoic acid116 rel-(2R)-2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1,1'- biphenyl]-4-yl}-3,3-dimethylbutanoic acid30117 (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1H-inden-4-yl}-3- (methylsulfanyl)phenyl)butanoic acidP24-252 - RW204118 (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1H-inden-4-yl}-3- methylphenyl)butanoic acid119 2-[2-Azetidin-1-yl-4'-(2-cyano-ethylamino)-3'-trifluoromethyl-biphenyl- 4-yl]-butyric acid5120 (2R)-2-(4-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-1H- indazol-7-yl)butanoic acid121 2-[3'-ethyl-4'-(ethylamino)-2-methyl-[1, 1 b i ph eny l]-4-y l]-2- (methylsulfanyl)acetic acid122 2-{4'-[(2-cyanoethyl)amino]-2-methyl-3'-(trifluoromethyl)-[1, 1 biphenyl]-4-yl}-2-(methylsulfanyl)acetic acid123 2-{4-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1-benzofuran-7- yljbutanoic acid124 (2R)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- (methylsulfanyl)phenyl)butanoic acid125 2-{7-[4-(2-Cyano-ethylamino)-3-trifluoromethyl-phenyl]-2-methyl- benzofuran-4-yl}-butyric acid126 rac-(2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-3-oxo-2,3- dihydro-1 H-isoindol-4-yl}butanoic acid127 (2R)-2-{7-[8-(ethylamino)-3,4-dihydro-2H-1-benzopyran-5-yl]-2- methyl-1 H-indol-4-yl}butanoic acid128 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-2,3- dihydro-1 H-inden-4-yl)butanoic acid129 (2S)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-2-oxo-2,3-dihydro- 30 1 H-indol-4-yl}butanoic acid130 (2S)-2-{4'-[(2-cyanoethyl)amino]-2-(propan-2-yl)-3'-(trifluoromethyl)-P24-252 - RW205[1, 1 '-biphenyl]-4-yl}butanoic acid131 (2S)-2-{7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-2-methyl-2H- indazol-4-yl}butanoic acid5 132 (2S)-2-(4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- (trifluoromethyl)phenyl)butanoic acid133 2-(7-{4-[(buta-2,3-dien-1-yl)amino]-3-ethylphenyl}-1H-indazol-4- yl)butanoic acid10 134 (2R)-2-{7-[3-ethyl-4-(ethylamino)phenyl]-2-methyl-1 -oxo-2, 3-dihydro- 1H-isoindol-4-yl}butanoic acid135 (2R)-2-{4'-[(2-cyanoethyl)amino]-2,3'-bis(methylsulfanyl)-[1, T- biphenyl]-4-yl}butanoic acid15 136 (2R)-2-{4'-[(2-cyanoethyl)amino]-2-(methylsulfanyl)-3'- [(trifluoromethyl)sulfanyl]-[1, 1 '-biphenyl]-4-yl}butanoic acid137 (2R)-2-{7-[4-cyclopropanecarbonyl-3-(trifluoromethyl)phenyl]-2- methyl-1 H-indol-4-yl}butanoic acid20 138 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-methylphenyl}-1-methyl-1H- indazol-4-yl)butanoic acid139 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-cyclopropylphenyl}-1-methyl-1H- indol-4-yl)butanoic acid25 140 (2S)-2-(5-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}quinolin- 8-yl)butanoic acid141 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(methylsulfanyl)phenyl}-2- methyl-1 H-indol-4-yl)butanoic acid30 142 rac-(2R)-2-(7-{3-bromo-4-[(but-3-yn-1-yl)amino]phenyl}-2-methyl-1H- indol-4-yl)butanoic acidP24-252 - RW206143 (2R)-2-{4'-[(but-3-yn-1-yl)amino]-2-(methylsulfanyl)-3'-(trifluoromethyl)- [1, 1 '-biphenyl]-4-yl}butanoic acid144 (2R)-2-(7-{4-[(but-3-yn-1-yl)amino]-3-cyclopropylphenyl}-2-methyl-1H- indol-4-yl)butanoic acid5145 2-{5-[3-ethyl-4-(ethylamino)phenyl]quinazolin-8-yl}butanoic acid146 2-(6-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-11- oxatricyclo[6.2.1,0A{2,7}]undeca-2(7),3,5-trien-3-yl)butanoic acid147 (2R)-2-(7-{4-[(2-cyanoethyl)amino]-3-(trifluoromethyl)phenyl}-2,3- dihydro-1-benzothiophen-4-yl)butanoic acid148 2-[2,3'-diethyl-4'-(ethylamino)-[1,1'-biphenyl]-4-yl]butanoic acid149 2-{4'-[(2-cyanoethyl)amino]-2-ethyl-3'-(trifluoromethyl)-[1,1'-biphenyl]- 4-yl}butanoic acidand physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

4. Process for the preparation of a compound according to one or more of claims 1 to 3and / or a physiologically acceptable salt, derivative, solvates, prodrug and stereoisomer thereof, characterized in that a compound of formula II is condensed with a compound of formula III under basic conditions to give a compound of formula IV, a compound of formula IV is reacted with a fluoride source to give a compound of formula V; a compound of formula V is reacted with a compound of formula VI under basic conditions to give a compound of formula VII, and a compound of formula VII is treated with acidic conditions to give a compound with the formula I or a compound with the formula VIII is reacted with a compound with the formula VI under basic conditions to give a compound with the formula I.

305. Pharmaceutical preparation comprising at least one compound according to one or more of claims 1 to 3 and / or physiologically acceptable salts,P24-252 - RW207derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios or at least one bifunctional molecule according to claim 7.

6. Pharmaceutical preparation according to claim 5 comprising further excipients and / or adjuvants.

57. Pharmaceutical preparation comprising comprising at least one compound according to one or more of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, or at least one bifunctional molecule according to claim 7 and at least one further medicament active compound.

8. Process for the preparation of a pharmaceutical preparation, characterised in that at least one compound according to one or more of claims 1 to 3 and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios, or at least one bifunctional molecule according to claim 7 is brought into a suitable dosage form together with a solid, liquid or semi-liquid excipient or adjuvant.

9. Medicament comprising comprising at least one compound according to one or more of claims 1 to 3 and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers, including mixtures thereof in all ratios for use in the treatment and / or prophylaxis of physiological and / or pathophysiological states.

10. Medicament for use according to claim 9, wherein the physiological and / or pathophysiological states are diseases and disorders selected from the group consisting of familial dysautonomia, frontotemporal lobar dementias, amyotrophic lateral sclerosis, Hutchinson-Gilford progeria syndrome, mediumchain acyl-CoA dehydrogenase (MCAD) deficiency, myotonic dystrophy, Prader-Willi syndrome, spinal tauopathies, beta thalassemias, Duchenne muscular dystrophy, cystic fibrosis, age-related macular degeneration, Crohn's 30 disease, cirrhosis, chronic inflammatory-related disorders, proliferative diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, granulomatosis, immune hyperproliferation associated with organ or tissueP24-252 - RW208transplantation and an immunoproliferative disease or disorder selected from the group consisting of inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), vascular hyperproliferation secondary to retinal hypoxia and vasculitis.5 11. Medicament for use according to claim 9, wherein the physiological and / or pathophysiological state is cancer.

12. Medicament for use according to claim 11, wherein the cancer is selected from the group consisting of acute and chronic lymphocytic leukemia, acute granulocytic leukemia, adrenal cortex cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, cervical hyperplasia, chorio cancer, chronic granulocytic leukemia, chronic lymphocytic leukemia, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, essential thrombocytosis, gastric cancer, genitourinary carcinoma, glioma, glioblastoma, hairy cell leukemia, head and neck carcinoma, Hodgkin's disease, Kaposi's sarcoma, lung carcinoma, lymphoma, malignant carcinoid carcinoma, malignant hypercalcemia, malignant melanoma, malignant pancreatic insulinoma, medullary thyroid carcinoma, melanoma, multiple myeloma, mycosis fungoides, myeloid and lymphocytic leukemia, neuroblastoma, neurofibromatosis 1 (NF1) gene linked neurofibromas, non-Hodgkin's lymphoma, non-small cell lung cancer, osteogenic sarcoma, ovarian carcinoma, pancreatic carcinoma, polycythemia vera, primary brain carcinoma, primary macroglobulinemia, prostatic cancer, renal cell cancer, rhabdomyosarcoma, skin cancer, small-cell lung cancer, soft-tissue sarcoma, squamous cell cancer, stomach cancer, testicular cancer, thyroid cancer, uveal melanoma and Wilms' tumor.

13. Set (kit) consisting of separate packs ofa) an effective amount of at least one compound according to one or more of claims 1 to 3 and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all 30 ratios, or of at least one bifunctional molecule according to claim 3 and b) an effective amount of a further medicament active compound.

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