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] Foreignfiling text P25-116-SEC-WO01

[0002] 1

[0003] DHX8 / 16 inhibitors

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

[0005] 5

[0006] 10

[0007]

[0008] 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.

[0009] Background of the invention

[0010] 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., 20 Biochem. J. 4762521-2543, 2019).

[0011] 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).

[0012] 30

[0013] Under normal conditions, alternative splicing is tightly regulated, but changes in alternative splicing are increasingly linked to a variety of human diseases, and inForeignfiling text P25-116-SEC-WO01

[0014] 2

[0015] 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).

[0016] The number of diseases reported to be associated with changes in alterative 5

[0017] 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).

[0018] Such diseases include but are not limited to familial dysautonomia, frontotemporal 10 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).

[0019] 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).

[0020] 20

[0021] 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).

[0022] Cancers known to be induced by aberrant splicing include but are not limited to 30

[0023] 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 lungForeignfiling text P25-116-SEC-WO01

[0024] 3

[0025] 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).

[0026] 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

[0027] 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 10 Valcarcel, J., Trends Biochem. Sci. 41, 33-45, 2016).

[0028] 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).

[0029] In addition, its functional homologue in yeast (Prp22) plays a crucial role in splicing 20 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).Foreignfiling text P25-116-SEC-WO01

[0030] 4

[0031] 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).

[0032] 5

[0033] 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 10 the treatment and prevention of such diseases.

[0034] Summary of the invention

[0035] 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, 20 distribution, metabolism, excretion) properties are favorable.

[0036] The invention relates to compounds of the general formula I,

[0037]

[0038] whereinForeignfiling text P25-116-SEC-WO01

[0039] 5

[0040]

[0041] R2 is C1-3 alkyl, C3-6 (hetero)cycloalkyl, SC1-3 alkyl, halogenated C1-C3 alkyl, 5

[0042] alkoxy or alcohol, or R1 and R2 together are =CHCH3,

[0043] R3 is H or F,

[0044] R4 is H, halogen, SC1-3 alkyl, C1-3 alkyl, C3-6 cycloalkyl, C4-6 heterocyclyl, NHCH3 or 5-membered heteroaryl

[0045] or R3 and R4 can form ring A which is a 5-6 membered heteroaryl, which can be optionally substituted with C1-3 alkyl,

[0046] R5 is H, F or Cl,

[0047] R6 is H, F or methyl,

[0048] 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 15 SC1-3 alkyl,

[0049] B is a 5-6 heterocycloalkyl which can be optionally substituted by fluorine or methyl,

[0050] Z is O, N or C=O,

[0051] R8 is F,

[0052] R9 is H, methyl or F, with the proviso that if Z is C=O, then R8 and R9 can form 20 a C3-6 cycloalkyl,

[0053] R10 H, F, CN, C=CH, C=CCH3, N3, OCH3or OCF3

[0054] and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

[0055] A preferred embodiment of the present invention are compounds according to formula I, wherein

[0056] R2 is methyl, ethyl isopropyl, cyclopropyl, cyclobutyl, tertbutyl, OCH3, SCH3, CH2OCH3, CH2CHCH3OCH3 or (CH2)3F), or R1 and R2 together are =CHCH3,

[0057] R4 is H, methyl, isopropyl, cyclopropyl, CF3, F, Cl, -SCH3, -SCH2CH3, N- 30

[0058] azetidine, 4-pyrazole, N-morpholine, piperazineureaForeignfiling text P25-116-SEC-WO01

[0059] 6

[0060] or 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 chromane 5

[0061] 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.

[0062] A further preferred embodiment of the present invention are compounds according 10 to formula I, wherein Z is C=O, then R8 and R9 form a cyclopropyl,

[0063] and R1, R2, R3, R4, R5, R6, R7, B and R10 are as defined above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

[0064] Another particularly preferred embodiment of the invention are compounds selected from the group consisting of:

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[0101] and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.Foreignfiling text P25-116-SEC-WO01

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[0103] The invention also relates to a pharmaceutical preparation according to the invention of this type, comprising further excipients and / or adjuvants.

[0104] In addition, the invention relates to an above pharmaceutical preparation according 5

[0105] to the invention, comprising at least one further medicament active compound.

[0106] 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

[0107] 10 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.

[0108] 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.

[0109] 20 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.

[0110] 30 Furthermore, the base salts of the compounds of the present invention include aluminium, ammonium, calcium, copper, iron(lll), iron(ll), lithium, magnesium, man-Foreignfiling text P25-116-SEC-WO01

[0111] 15

[0112] ganese(lll), manganese(ll), potassium, sodium and zinc salts, but this is not intended to represent a restriction.

[0113] 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 5

[0114] magnesium. Salts of the compounds of the present invention which are derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary 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 10 (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylamino- ethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine,

[0115] 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.

[0116] 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 20 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.

[0117] 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 30 as solubility in polar solvents; for the purposes of the invention, however, the salts otherwise correspond to the respective free acid forms thereof.Foreignfiling text P25-116-SEC-WO01

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[0119] 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 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 5

[0120] other salt form of the active compound used earlier. The pharmaceutically acceptable salt form of the active compound can also provide this active compound 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.

[0121] 10

[0122] 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.

[0123] All physiologically acceptable salts, derivatives, solvates and stereoisomers of these compounds, including mixtures thereof in all ratios, are also in accordance with the invention.

[0124] 20 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.

[0125] The invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.

[0126] 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

[0127] 30 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 these cases, the end product, but also even the intermediates, may be separatedForeignfiling text P25-116-SEC-WO01

[0128] 17

[0129] into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or already employed as such in the synthesis.

[0130] Pharmaceutically or physiologically acceptable derivatives are taken to mean, for example, salts of the compounds according to the invention and also so-called 5

[0131] prodrug compounds. Prodrug compounds are taken to mean compounds of the present invention which have been modified with, 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 compounds according to the invention. These also include biodegradable polymer 10 derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115 (1995), 61-67.

[0132] 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.

[0133] Very particular preference is given to the hydrochlorides, the trifluoroacetates or the bistrifluoroacetates of the compounds according to the invention.

[0134] 20 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.

[0135] 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 30 usually occurs naturally. Examples of isotopes which are readily commercially available, and which can be incorporated into a compound of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen,Foreignfiling text P25-116-SEC-WO01

[0136] 18

[0137] 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 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 5

[0138] 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 or14C, 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.

[0139] 10 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.

[0140] 20 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 30 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 ofForeignfiling text P25-116-SEC-WO01

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[0142] this compound in vivo can thereby be drastically modified and result in improved pharmacokinetic propeties.

[0143] When discovering and developing therapeutic agents, the person skilled in the art attempts to optimise pharmacokinetic parameters while retaining desirable in-vitro 5

[0144] 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 metabolism of this type, which in turn permits the rational design of deuterated compounds of the present invention with improved stability through resistance to 10 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 (AUC), and F; and in terms of reduced clearance, dose and costs of materials.

[0145] 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 20 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.

[0146] 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 30 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, forForeignfiling text P25-116-SEC-WO01

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[0148] example in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33(10), 2927-2937, 1994, and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

[0149] 5

[0150] 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 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.

[0151] 10

[0152] In addition, the invention relates to a process for the preparation of the compounds of the present invention, characterized in that

[0153] a) the base of a compound of the present invention is converted into one of its salts by treatment with an acid, or

[0154] b) an acid of a compound of the present invention is converted into one of its salts by treatment with a base.

[0155] 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.

[0156] 20

[0157] The starting materials or starting compounds are generally known. If they are novel, they can be prepared by methods known per se.

[0158] 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.

[0159] 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 30 those which contain correspondingly protected amino, carboxyl and / or hydroxyl groups instead of one or more free amino, carboxyl and / or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom whichForeignfiling text P25-116-SEC-WO01

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[0161] 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. 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 5

[0162] molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.

[0163] 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 10 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 20 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.

[0164] 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 30 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 and unsubstituted benzyl esters or silyl esters, is typical. The type and size of theForeignfiling text P25-116-SEC-WO01

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[0166] acid-protecting groups is not crucial, but preference is given to those having 1-20, in particular 1-10, C atoms.

[0167] The term “hydroxyl-protecting group” is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical 5

[0168] 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- 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 10 hyrdoxyl-protecting groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, where benzyl and acetyl are preferred.

[0169] 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.

[0170] 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.

[0171] 20

[0172] 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.

[0173] Depending on the respective synthetic route, the starting materials can optionally be reacted in the presence of an inert solvent.

[0174] 30

[0175] Suitable inert solvents are, for example, heptane, hexane, petroleum ether, DMSO, benzene, toluene, xylene, trichloroethylene-, 1,2-dichloroethane, carbonForeignfiling text P25-116-SEC-WO01

[0176] 23

[0177] tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether (preferably for substitution on the indole nitrogen), tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or 5

[0178] butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as acetonitrile; esters, such as 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 10 with water.

[0179] 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.

[0180] 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.

[0181] 20 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.

[0182] 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.

[0183] The compounds of the present invention and also the starting materials for their 30 preparation are, in addition, prepared by known methods, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag,Foreignfiling text P25-116-SEC-WO01

[0184] 24

[0185] Stuttgart), for example under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants known per se, which are not described here in greater detail.

[0186] Conventional work-up steps, such as, for example, addition of water to the reaction 5

[0187] mixture and extraction, enable the compounds to be obtained after removal of the 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.

[0188] An acid of the present invention can be converted into the associated addition salt 10 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.

[0189] On the other hand, a base of the present invention can be converted into the 20 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, 30 methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxysulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemom- and disulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for exampleForeignfiling text P25-116-SEC-WO01

[0190] 25

[0191] picrates, can be used for the isolation and / or purfication of the compounds of the present invention.

[0192] It has been found that the compounds of the present invention are well tolerated and have valuable pharmacological properties.

[0193] 5

[0194] 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

[0195] 10 physiological and / or pathophysiological states.

[0196] 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.

[0197] 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 20 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.Foreignfiling text P25-116-SEC-WO01

[0198] 26

[0199] 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

[0200] 5

[0201] physiological and / or pathophysiological states, selected from the group consisting of hyperproliferative diseases and disorders.

[0202] The invention furthermore relates to a medicament comprising at least one compound according to the present invention and / or one of its physiologically 10 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.

[0203] 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, 20 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.Foreignfiling text P25-116-SEC-WO01

[0204] 27

[0205] 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.

[0206] 5

[0207] 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 10 ratios, or at least one bifunctional molecule according to the present invention is administered to a patient in need of such a treatment.

[0208] 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 IC50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.

[0209] The compounds according to the invention can be administered to humans or 20 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.

[0210] For diagnostic purposes, the compounds according to the invention can, for example, be radioactively labelled. Examples of radioactive labels are3H,14C,231l and125l. 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, [3- galactosidase and glucose oxidase, an example of a fluorophore is fluorescein, an 30

[0211] 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.Foreignfiling text P25-116-SEC-WO01

[0212] 28

[0213] 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.

[0214] 5

[0215] 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 10 further active compound(s).

[0216] 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.

[0217] In particular, the invention also relates to a process for the preparation of a

[0218] 20 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.

[0219] 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.Foreignfiling text P25-116-SEC-WO01

[0220] 29

[0221] 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

[0222] 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 active10 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.

[0223] 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).

[0224] 20 The terms “pharmaceutical formulation” and “pharmaceutical preparation” are used as synonyms for the purposes of the present invention.

[0225] 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.

[0226] 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-Foreignfiling text P25-116-SEC-WO01

[0227] 30

[0228] 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.

[0229] The invention particularly preferably also relates to pharmaceutical preparations 5

[0230] 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.

[0231] The compounds according to the invention preferably enable the preparation of 10 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.

[0232] 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.

[0233] Aqueous preparations can be prepared by dissolving or suspending compounds according to the invention in an aqueous solution and optionally adding adjuvants.

[0234] 20 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.

[0235] 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.

[0236] 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-Foreignfiling text P25-116-SEC-WO01

[0237] 31

[0238] 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.

[0239] 5

[0240] Pharmaceutical preparations according to the invention may also comprise mixtures of a plurality of compounds according to the invention.

[0241] The preparations according to the invention are physiologically well tolerated, easy 10 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.).

[0242] 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, 20 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.

[0243] 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.

[0244] 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 termForeignfiling text P25-116-SEC-WO01

[0245] 32

[0246] “therapeutically effective amount” also encompasses the amounts which are effective for increasing normal physiological function.

[0247] On use of preparations or medicaments according to the invention, the compounds according to the invention and / or physiologically acceptable salts and solvates 5

[0248] 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 10 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.

[0249] 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 20 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.

[0250] Furthermore, medicaments of this type can be prepared by means of one of the processes generally known in the pharmaceutical art.

[0251] 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 (includingForeignfiling text P25-116-SEC-WO01

[0252] 33

[0253] 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).

[0254] 5

[0255] 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.

[0256] The compounds according to the invention are also suitable for the preparation of 10 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.

[0257] 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 20 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.

[0258] 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.

[0259] 30

[0260] The compounds according to the invention can also be coupled to soluble polymers as targeted medicament excipients. Such polymers can encompassForeignfiling text P25-116-SEC-WO01

[0261] 34

[0262] 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

[0263] 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-s-caprolactone, albumin, chitosan, collagen or modified gelatine and crosslinked or amphipathic block copolymers of hydrogels.

[0264] 10

[0265] 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.

[0266] 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 20 active compound can be formulated to a cream with an oil-in-water cream base or a water-in-oil base.

[0267] 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).

[0268] It goes without saying that, besides the constituents particularly mentioned above, the medicaments according to the invention may also comprise other agents usual 30

[0269] in the art with respect to the particular type of pharmaceutical formulation.

[0270] The invention also relates to a set (kit) consisting of separate packs ofForeignfiling text P25-116-SEC-WO01

[0271] 35

[0272] 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

[0273] b)an effective amount of a further medicament active compound.

[0274] 5

[0275] 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 10 further medicament active compound in dissolved or lyophilised form.

[0276] 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.

[0277] 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 20 compounds according to the invention, comprise further medicament active compounds which are known to the person skilled in the art in the treatment thereof.

[0278] 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 proliferativeForeignfiling text P25-116-SEC-WO01

[0279] 36

[0280] 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.

[0281] 5

[0282] 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.

[0283] 10 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.

[0284] 20

[0285] 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:

[0286] (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); antimetabolites (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-Foreignfiling text P25-116-SEC-WO01

[0287] 37

[0288] 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 celldifferentiating active compounds (for example all-trans-retinoic acid, 13-cis-retinoic acid and fenretinide);

[0289] 5

[0290] (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

[0291] 10 megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-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;

[0292] (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- 20 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;

[0293] (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,

[0294] 30

[0295] serine / threonine kinase inhibitors, antisense oligonucleotides, antisense oligodexoynucleotides, siRNAs, anti-VEGF aptamers, pigment epithelium derivedForeignfiling text P25-116-SEC-WO01

[0296] 38

[0297] 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);

[0298] (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

[0299] (vii) antisense therapies, for example those directed to the targets mentioned above, such as ISIS 2503, an anti-Ras antisense;

[0300] (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 10 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

[0301] (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

[0302] (x) chemotherapeutic agents including foor example abarelix, aldesleukin, 20 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.

[0303] The medicaments from table 1 can preferably, but not exclusively, be combined with the compounds of the present invention.

[0304] 30Foreignfiling text P25-116-SEC-WO01

[0305] 39

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[0342] 30

[0343]

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[0345]

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[0347] 46

[0348] 5

[0349]

[0350] 10

[0351] 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.

[0352] 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 20 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.

[0353] Rf values on silica gel; mass spectrometry: El (electron impact ionisation): M+, FAB (fast atom bombardment): (M+H)+, THF (tetrahydrofuran), NMP

[0354] (N-methlpyrrolidone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeOH (methanol), EtOH (ethanol), TLC (thin-layer chromatography)

[0355] List of Abbreviations

[0356] AUC Area under the plasma drug concentration-time curve

[0357] Cmax Maximum plasma concentration

[0358] 30

[0359] CL Clearance

[0360] CV Coefficient of variation

[0361] CYP Cytochrome P450Foreignfiling text P25-116-SEC-WO01

[0362] DMSO Dimethyl sulfoxide

[0363] F Bioavailability

[0364] faFraction absorbed

[0365] iv Intravenous

[0366] LC-MS / MS Liquid chromatography tandem mass spectrometry

[0367] 5

[0368] LLOQ Lower limit of quantification

[0369] NC Not calculated

[0370] ND Not determined

[0371] PEG Polyethylene glycol

[0372] Pgp Permeability glycoprotein

[0373] 10 PK Pharmacokinetic(s)

[0374] po Per os (oral)

[0375] rt Room temperature

[0376] ti / 2 Half-life

[0377] tmax Time at which maximum plasma concentration of drug is reached UPLC Ultra performance liquid chromatography

[0378] VssVolume of distribution (at steady state)

[0379] v / v Volume to volume

[0380] All the references cited herein are incorporated by reference in the disclosure of the invention hereby.

[0381] 20

[0382] 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.

[0383] 30

[0384] Example 1 - Examples for compounds of the present inventionForeignfilingjext P25-116-SEC-WO01

[0385] 48

[0386] Table 1

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[0390]

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[0412] 30

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[0416] 5

[0417] 15

[0418]

[0419] Table 2 - MW, RT, [M+1 ]+ values and NMR profiles of the compounds of the present invention

[0420] 20

[0421] LC-MS were acquired applying the instruments and methods described below.

[0422] 30

[0423]

[0424] Foreignfiling text P25-116-SEC-WO01

[0425] 56

[0426] 5

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[0428] 20

[0429]

[0430] 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 30

[0431] 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, doubletForeignfiling text P25-116-SEC-WO01

[0432] 57

[0433] 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; br s, broad singlet.

[0434] The Nos. recited herein corresponds to the numbering of the compounds disclosed in table 1.

[0435] 5

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[0438] 30

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[0633] 10

[0634] 20

[0635]

[0636] Example 2 - Preparation of the compounds of the present invention

[0637] General Procedures (GP)

[0638] GP 1 : Alkylation K2CO3 or CS2CO3

[0639] The corresponding phenol or aniline (1.0 eq) was dissolved in solvent (DMSO, ACN or DMF 0.13-1.1 M) and a base (K2CO3 or CS2CO32.0-4.5 eq) and the desired alkyl halide the corresponding p-toluene sulphonic ester (1.0-4.5 eq) were added. In 30

[0640] 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 overForeignfiling text P25-116-SEC-WO01

[0641] 87

[0642] anhydrous sodium sulphate 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.

[0643] 5

[0644] GP 2: Borylation

[0645] The desired aryl halide (1.0 eq), 1.0-4.0 eq bis(pinacolato)diboron, 3-28 % PdCI2(PPh3)2 or Pd(dppf)Ch and 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 10 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% NaHCCh and brine extraction occasionally. The combined organic phases were dried over sodium sulphate, filtered, concentrated and the residue was purified by silica gel column chromatography. In a few occasions, Pd(OAc)2 and XPhos were used instead.

[0646] GP 3: Michael addition I

[0647] 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 20 gel column chromatography to afford the desired product. Alternatively, the reaction mixture was concentrated, diluted with water and extracted with EtOAc or DCM three times. The combined organic phases were dried over sodium sulphate, filtered, concentrated and the obtained residue was purified by silica gel column chromatography.

[0648] GP 4: Alkylation with NaH

[0649] 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 30 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%Foreignfiling text P25-116-SEC-WO01

[0650] 88

[0651] NaHCOs aqueous solution and / or brine, dried over anhydrous sodium sulphate, filtered and evaporated. The residue was purified by Prep HPLC or silica gel column chromatography to afford the desired product.

[0652] GP 5: Boc protection NaHMDS

[0653] 5

[0654] The corresponding aniline (1.0 eq) was dissolved in 0.5 M THF and cooled to 0°C.

[0655] 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 10 dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the desired product.

[0656] GP 6: Boc deprotection HCI or TFA

[0657] 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.

[0658] 20 GP 7: Boc protection K2CO3

[0659] 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 diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography to afford the desired product.

[0660] 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 product in pure form.

[0661] 30 GP 8: Reductive amination

[0662] 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 reactionForeignfiling text P25-116-SEC-WO01

[0663] 89

[0664] 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 sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to 5

[0665] afford the desired product.

[0666] GP 9: Suzuki coupling

[0667] 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 10 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(ll) or SPhos Pd G2, or XPhos 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 sulphate, filtered and evaporated to dryness. It was purified by chromatography to afford the desired product.

[0668] GP 10: chiral separation

[0669] The racemic mixture was separated via chiral SFC (Column: ChiralPAK IC, Eluent: CO2:HO / 7with or without 0.5%DEA (e.g. 80:20, depending on polarity), wave 20 length: 220 nM, flow rate: 2-5 mL / min) to obtain both enantiomers with 95-99%ee.

[0670] GP 11 : Ester phosphonate formation

[0671] The iodobromophenyl or bromochlorophenyl derivative (1.0 eq) was dissolved in anhydrous 1,4-dioxane (0.20-0.4 M). Diethylphosphite (1.0 eq) was added at RT. The vial was purged with nitrogen and tris(dibenzylideneacetone)dipalladium(0) (0.03 eq), xantphos (0.05 eq) and triethylamine (8.4 eq) were added. The mixture was stirred for 6-18 h at room temperature. The reaction mixture was absorbed onto diatomaceous earth (Isolute HM-N) or directly and purified by flash chromatography (silica gel; n-heptane / EtOAc, 0-100%) to afford the desired product.

[0672] 30 GP 12: Phosphonate ester cleavage

[0673] Phosphonate ester (1.0 eq) was dissolved in anhydrous DMF (0.4-0.6 M). Then bromotrimethylsilane (1.0 eq) was added dropwise. The reaction mixture was stirredForeignfiling text P25-116-SEC-WO01

[0674] 90

[0675] at RT for 6-18 h. The reaction mixture was purified by prep. HPLC. The residue was obtained by evaporation to dryness or lyophilization to effort the desired product. Boc groups were also cleaved off under these conditions, no additional synthetic step was needed.

[0676] 5

[0677] GP 13: Preparation of the primary sulphonamide

[0678]

[0679] The sulphonyl chloride (1.0 eq) was suspended in a solution of ammonia in MeOH (7.0 M, 10 eq) and stirred at ambient temperature and under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated in vacuo to afford the desired product and carried forward into the next reaction without purification.

[0680] GP 14: Zinc chloride promoted acetylation

[0681] 15

[0682]

[0683] The primary sulphonamide (1.0 eq) and acetic anhydride (1.0-11.0 eq) were stirred 20

[0684] neat or suspended in DCM (0.2 M) under a nitrogen atmosphere. To the reaction mixture was added zinc chloride (30-50 mol%) and the mixture was stirred for 18 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3x). The combined organic phases were dried over magnesium sulphate, filtered, concentrated in vacuo and purified by silica column chromatography to afford the desired product or carried forward to the next reaction without purification.

[0685] GP 15: Base promoted acetylation

[0686]

[0687] Foreignfiling text P25-116-SEC-WO01

[0688] 91

[0689] To a solution of the primary sulphonamide (1.0 eq) in DCM or DMF (0.04-0.2 M) was added triethylamine (3.0-9.0 eq) and acetyl chloride (3-4 eq). The reaction mixture was stirred at ambient temperature and under a nitrogen atmosphere for 18 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3x). The combined organic phases were dried over magnesium sulphate, filtered,

[0690] 5

[0691] concentrated in vacuo and purified by silica column chromatography to afford the desired product.

[0692] GP 16: Bartoli indole synthesis

[0693]

[0694] The nitroarene (1.0 eq) was suspended in tetrahydrofuran (0.2 M) and cooled 15 to -50 °C under a nitrogen atmosphere. To the solution was added dropwise a separate solution of isopropenylmagnesium bromide in tetrahydrofuran (0.5 M, 3.0 eq) and the mixture was stirred at -50 °C for 3-4 h. The mixture was quenched with sat. aq. ammonium chloride solution and extracted ethyl acetate (3x). The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica column chromatography to 20

[0695] afford the desired product.

[0696] GP 17: Borane promoted amide reduction

[0697]

[0698] The aromatic amide (1.0 eq) was suspended in tetrahydrofuran (0.2-0.7 M) and stirred at 0 °C - 50 °C under a nitrogen atmosphere. A separate solution of borane«THF (1 M, 2.5 eq) was added dropwise and the reaction mixture was stirred 30 for 0.5-48 h. The reaction was brought to ambient temperature, and careful quenched with MeOH and stirred for 30 min. The reaction mixture was concentrated in vacuo and purified by chromatography to afford the desired product.Foreignfiling text P25-116-SEC-WO01

[0699] 92

[0700] Synthesis of A-ring derivatives, Tetrazoles

[0701] Synthesis of 7-chloro-2-methyl-4-[(1 R)-1-(1 H-1 ,2,3,4-tetrazol-5-yl)propyl]-1 H-indole

[0702] 5

[0703]

[0704] (2R)-2-(7-chloro-2-methyl-1H-indol-4-yl)butanamide: To a solution of (2R)-2-(7- 10

[0705] chloro-2-methyl-1H-indol-4-yl)butanoic acid (1.20 g, 4.62 mmol, 1.0 eq, synthesis described in the 1stpatent) in DMF (15 mL) was added 2-(1H-benzotriazole-1-yl)- 1,1,3,3-tetramethylaminium tetrafluoroborate (2.22 g, 6.92 mmol, 1.5 eq), ammonium chloride (617 mg, 11.5 mmol, 2.5 eq) and N-ethyldiisopropylamine (2.35 mL, 13.8 mmol, 3.0 eq). The mixture stirred for 2h at RT. The solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed twice with water then with brine. The organic layer was dried with sodium sulphate, filtered and evaporated. The residue was used for flash chromatography on silica gel. All good fractions were combined and evaporated to dryness to yield in 1.05 g (4.15 mmol, 90%) of the desired product as viscous orange oil.

[0706] (2R)-2-(7-chloro-2-methyl-1H-indol-4-yl)butanenitrile: To a solution of (2R)-2-(7- 20

[0707] chloro-2-methyl-1H-indol-4-yl)butanamide (1.05 g, 4.15 mmol, 1.0 eq) in DCM (20 mL) triethylamine (1.27 mL, 9.14 mmol, 2.2 eq) was added and the flask rinsed with Argon. The mixture was cooled to 0°C and a solution of trichloroacetyl chloride (0.93 mL, 8.31 mmol, 2.0 eq) in DCM (3 mL) was added dropwise via canula within 1 min.

[0708] After completed addition the mixture stirred for further 45 min at 0°C, then the mixture stirred for further 45 min at RT. The mixture was diluted with DCM and washed with water and NaHCOs-solution, then with brine. The organic layer was dried with sodium sulphate, filtered and evaporated to dryness to yield in 950 mg (4.06 mmol, 98%) of the desired product as dark oil.

[0709] 30

[0710] 7-chloro-2-methyl-4-[(1R)-1-(1 H-1, 2, 3, 4-tetrazol-5-yl)propyl]-1 H-indole: (2R)-2-(7- chloro-2-methyl-1H-indol-4-yl)butanenitrile (950 mg, 4.06 mmol, 1.0 eq) was dissolved in toluene (50 mL) followed by addition of trimethyltinazide (2.15 g, 10.4Foreignfiling text P25-116-SEC-WO01

[0711] 93

[0712] mmol, 2.6 eq). The mixture was stirred at 120°C for 18 h. Further trimethyltinazide

[0713] (1.25 g, 6.09 mmol, 1.5 eq) were added and the mixture was refluxed for further

[0714] 24h. The mixture was diluted with some EtOAc and water and the excess of trimethyltinazide destroyed with sodium thiosulphate and iodine. The mixture was then diluted with EtOAc and washed with water. The organic layer was then washed

[0715] 5

[0716] with 1N NaOH basified water and the product moved into the aq. layer. The aq.

[0717] layer was then acidified with 1N HCI and extracted twice with DCM. The combined organic layer was dried with sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography to yield 7-chloro-2-methyl-4-[(1R)-1-(1H- 1,2,3,4-tetrazol-5-yl)propyl]-1H-indole 980 mg (3.55 mmol, 88%) of a white

[0718] amorphous solid.

[0719] According to that procedure the following building blocks were synthesized, starting from the corresponding Bromo derivative (described in the 1stpatent).

[0720]

[0721] Alternative synthesis of 5-[(1R)-1-(4-bromo-3-methylphenyl)propyl]-1H-1 ,2,3,4- tetrazole

[0722] 20

[0723]

[0724] 2-(4-bromo-3-methylphenyl)butanenitrile: To a stirred solution of NaH (14.0 g, 350 mmol, 1.6 eq) in DMF (450 mL) was added 2-(4-bromo-3-methylphenyl)acetonitrile

[0725] (50.0 g, 226 mmol, 1.0 eq) at 0 °C. The resulting mixture was stirred for 1 h at 0°C.

[0726] To the mixture was added iodoethane (28.5 mL, 349 mmol, 1.5 eq) in small portions over 10 min at 0°C. The resulting mixture was stirred for 1 h at room temperature.

[0727] 30

[0728] The reaction mixture was poured into saturated aqueous NH4CI solution (1.5 L) and extracted with EtOAc three times (2 L). The combined organic layer was washed

[0729] with brine (500 mL), dried over anhydrous Na2SO4. The filtrate was concentratedForeignfiling text P25-116-SEC-WO01

[0730] 94

[0731] under reduced pressure to dryness. The residue was purified by silica gel column chromatography, eluted with PE:THF (95: 5) to afford 2-(4-bromo-3- methylphenyl)butanenitrile (43.8 g, 141 mmol, 62 %) of a yellow oil.

[0732] 5-[1-(4-bromo-3-methylphenyl)propyl]-1H-1,2,3,4-tetrazole: To a stirred solution of 2- 5

[0733] (4-bromo-3-methylphenyl)butanenitrile (43.8 g, 141 mmol, 1.0 eq) and dibutyltin oxide (3.69 g, 14.1 mmol, 0.10 eq) in toluene (500 mL) was added TMSN3 (19.5 mL, 141 mmol, 1.00 eq) at 0°C. The resulting mixture was stirred for 24 h at 100 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature was concentrated to dryness. The residue was recrystallized from 10 MeOH (60 mL) and filtered to afford 5-[1-(4-bromo-3-methylphenyl)propyl]-1H- 1,2,3,4-tetrazole (23.2 g, 82.1 mmol, 58%) of a white solid. The mother liquid was concentrated under reduced pressure. The residue was purified directly via reverse phase chromatography (Column: C18 silica gel, Mobile phase, water / ACN to afford additional 5-[1-(4-bromo-3-methylphenyl)propyl]-1H-1,2,3,4-tetrazole (3.60 g, 12.50 mmol, 9 %, white solid, Purified Product).

[0734] 5-[(1R)-1-(4-bromo-3-methylphenyl)propyl]-1H-1,2,3,4-tetrazole: A mixture of 5-[1 - (4-bromo-3-methylphenyl)propyl]-1H-1,2,3,4-tetrazole (23.20 g, 82.1 mmol) was separated by achiral-SFC with following conditions: Column: (S, S)-WHELK-O1- Kromasil, 5*25 cm, 10 pm, Mobile Phase A: CO2, Mobile Phase B: MEOH, Flow 20 rate: 180 mL / min, Gradient: isocratic 60% B, Back Pressure(bar): 100, Wave Length: 220 nm, RT1(min): 4.8, RT2(min): 6.3, Sample Solvent: MEOH to afford 5- [(1R)-1-(4-bromo-3-methylphenyl)propyl]-1H-1,2,3,4-tetrazole (15.6 g, 55.5 mmol, 47%) of a bluish oil and 5-[(1S)-1-(4-bromo-3-methylphenyl)propyl]-1H-1 ,2,3,4- tetrazole (16.7 g, 59.4 mmol, 50%) as a blueish oil.

[0735] hat procedure the following building blocks were synthesized:

[0736]

[0737]

[0738] Introducing protection groups at tetrazole moietyForeignfiling text P25-116-SEC-WO01

[0739] 95

[0740] Synthesis of a mixture of 7-chloro-4-[(1R)-1-{1-[(4-methoxyphenyl)methyl]-1H- 1 ,2,3,4-tetrazol-5-yl}propyl]-2-methyl-1 H-indole and 7-chloro-4-[(1 R)-1 -{2-[(4- methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl}propyl]-2-methyl-1H-indole

[0741]

[0742] To a solution of 7-chloro-2-methyl-4-[(1R)-1-(1H-1 ,2,3, 4-tetrazol-5-yl)propyl]-1 I - indole (2.17 g, 7.77 mmol, 1.0 eq) in DMF (40 mL) was added sodium hydrogen carbonate (1.96 g, 23.3 mmol, 3.0 eq) was added at RT a solution of 4- methoxybenzyl bromide (1.64 g, 8.16 mmol, 1.05 eq) in DMF (5 mL) dropwise via dropping funnel. The mixture stirred for 2h at RT. 'The mixture was diluted further with DMF (20 mL) and additional 4-methoxybenzyl bromide (782 mg, 3.89 mmol, 0.5 eq) in DMF (1 mL) were added. The mixture stirred for 18 h at RT. The solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried with sodium sulphate, 20 filtered and adsorbed on silica gel for flash chromatography to yield in a 2.89 g (6.90 mmol, 87%) of an orange oil as a 1:1 mixture of the desired compounds with a purity of 93%.

[0743]

[0744] Synthesis of 5-[(1R)-1-(4-bromo-3-methylphenyl)propyl]-1-(oxan-2-yl)-1H-1 ,2,3,4- tetrazole

[0745] 30

[0746] To a stirred mixture of 5-[(1R)-1-(4-bromo-3-methylphenyl)propyl]-1H-1 ,2,3,4- tetrazole (1.00 g, 2.79 mmol, 1.0 eq) and pyridinium p-toluenesulphonate (179 mg,Foreignfiling text P25-116-SEC-WO01

[0747] 96

[0748] 0.68 mmol, 0.24 eq) in DCM (10 mL) was added 3,4-dihydro-2H-pyran (663 mg, 7.49 mmol, 2.68 eq) at 0°C and stirring was continued at RT for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography with following conditions (water / ACN, Gradient: 5% to 100%) to yield in 5-[(1R)-1-(4-bromo-3-methylphenyl)propyl]-1-(oxan-2-yl)-1H- 5

[0749] 1.2.3.4-tetrazole (663 mg, 1.78 mmol, 64%) as an off-white solid.

[0750] Synthesis of 1-(4-bromo-3-methylphenyl)-1-{1-[(4-methoxyphenyl)methyl]-1H- 1.2.3.4-tetrazol-5-yl}propan-1-ol

[0751]

[0752] A solution of 1-[(4-methoxyphenyl)methyl]-1H-1,2,3,4-tetrazole (500 mg, 2.50 mmol, 1.0 eq) and N,N,N',N'-tetramethylethylenediamine (1.10 mL, 7.34 mmol, 3.0 eq) in THF (15 mL) was cooled down to -78°C. Then n-butyl lithium solution 1.6 M in hexane (1.72 mL, 2.75 mmol, 1.1 eq) was added dropwise. After 5 min a solution of 20

[0753] 1-(4-bromo-3-methylphenyl)propan-1-one (608 mg, 2.62 mmol, 1.05 eq) in THF (6 mL) was added dropwise via canula and after 5 min at -78°C the mixture was allowed to reach RT within 1h. To the reaction sat. NH4CI-solution was added and the THF evaporated to dryness. The residue was dissolved in DCM and washed with water and with brine. The organic layer was dried with sodium sulphate, filtered and adsorbed on silica gel for flash chromatography with heptane / EtOAc to yield in 370 mg (0.88 mmol, 35%) of the desired product as a colorless solid.

[0754] Synthesis of 5-[(4-bromo-3-methylphenyl)(methylsulfanyl)methyl]-1-(oxan-2-yl)-1 H- 1,2,3,4-tetrazole

[0755] 30Foreignfiling text P25-116-SEC-WO01

[0756] 97

[0757] 5

[0758]

[0759] 2-(4-bromo-3-methylphenyl)-2-(methylsulfanyl)acetonitrile: To a suspension of potassium hydroxide (2.09 g, 37.3 mmol, 4.0 eq) in THF (20 mL) was added 2-(4- bromo-3-methylphenyl)acetonitrile (2.00 g, 9.33 mmol, 1.0 eq). With vigorous stirring a solution of dimethyl disulfide (6.79 mL, 74.6 mmol, 8.0 eq) in THF (20) was slowly 10 added. The reaction suspension was stirred for 18 h at RT. The reaction mixture was concentrated (40 °C), The residue was acidified under ice cooling with ~ 20 mL 2 N HCI and extracted with diethyl ether. The organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated (careful! volatile). The resulting oil was purified by flash chromatography (cyclohexane / MTB-ether, 0 - 5%) to yield in 2-(4-bromo-3-methylphenyl)-2-(methylsulfanyl)acetonitrile (1.14 g, 4,08 mmol, 44%) of an orange oil.

[0760] 5-[(4-bromo-3-methylphenyl)(methylsulfanyl)methyl]-1 H-1 ,2,3,4-tetrazole: 2-(4- bromo-3-methylphenyl)-2-(methylsulfanyl)acetonitrile (1.00 g, 3.58 mmol, 1.0 eq) and trimethyltinazide (1.11 g, 5.37 mmol, 1.5 eq) were suspended in o-xylene (10 20 mL) under argon atmosphere and stirred at 140°C for 18 h. The reaction mixture was evaporated to dryness and absorbed on isolute. Purification by flash chromatography (DCM / MeOH, 0-10%) to yield in 5-[(4-bromo-3- methylphenyl)(methylsulfanyl)methyl]-1 H-1 ,2,3,4-tetrazole (796 mg, 2.60 mmol, 73%) as a beige solid.

[0761] 5-[(4-bromo-3-methylphenyl)(methylsulfanyl)methyl]-1-(oxan-2-yl)-1 H-1 ,2,3,4- tetrazole: 5-[(4-bromo-3-methylphenyl)(methylsulfanyl)methyl]-1 H-1 ,2,3,4-tetrazole (796 mg, 2.60 mmol, 1.0 eq) and pyridinium p-toluenesulphonate (0.20 g, 0.78 mmol, 0.3 eq) were dissolved in ACN (16 mL). 3,4-Dihydro-2H-pyran (0.45 mL, 5.21 mmol, 2.0 eq) was added and the reaction mixture was stirred at 80°C for 3 h. The 30 reaction mixture was evaporated to dryness and purified by flash chromatography (heptane(MTB-ether, 0-50%) to yield in 5-[(4-bromo-3-Foreignfiling text P25-116-SEC-WO01

[0762] 98

[0763] methylphenyl)(methylsulfanyl)methyl]-1-(oxan-2-yl)-1H-1,2,3,4-tetrazole (648 mg, 1,66 mmol, 64%) as a colorless oil as a mixture of regioisomers.

[0764] Synthesis of A-ring derivatives, Phosphonates

[0765] Synthesis of diethyl (4-bromo-3-methylphenyl)phosphonate

[0766] 5

[0767]

[0768] According to GP 11 2-bromo-5-iodotoluene (1.00 g, 3.30 mmol 1.0 eq) was 10

[0769] dissolved in anhydrous 1,4-dioxane (12 mL). Diethylphosphite (426 pL, 3.30 mmol, 1.0 eq) was added at RT. The vial was purged with nitrogen and tris(dibenzylideneacetone)dipalladium(0) (93.5 mg, 0.10 mmol, 0.03 eq), xantphos (98.4 mg, 0.17 mmol; 0.05 eq) and triethylamine (3.84 mL, 27.7 mmol; 8.4 eq) were added. The vial was closed with a septum and was stirred for 18 h at room temperature. The reaction mixture was absorbed onto diatomaceous earth (Isolute HM-N) and purified by flash chromatography (silica gel; n-heptane / EtOAc, 0-100%). Vials containing the product were combined and evaporated to dryness to result in diethyl (4-bromo-3-methylphenyl)phosphonate (950 mg, 3.09 mmol; 94 %) as a brownish oil.

[0770] 20

[0771] According to that procedure the following building blocks were synthesized:

[0772]

[0773] Synthesis of A-ring derivatives, Phosphonates

[0774] Synthesis of N-(4-bromo-3-nitro-phenyl)sulphonylacetamide

[0775]

[0776] Foreignfiling text P25-116-SEC-WO01

[0777] 99

[0778] According to GP 14, 4-bromo-3-nitrobenzene-1-sulphonamide (500 mg, 1.78 mmol, 1.0 eq), acetic anhydride (1.68 mL, 17.8 mmol, 10 eq) and zinc chloride (75.31 mg, 0.534 mmol, 30 mol%) were stirred neat for 2 h to afford N-(4-bromo-3-nitro- phenyl)sulphonylacetamide (560 mg, 97%) as a white solid. The product was carried forward to the next reaction without purification.

[0779] 5

[0780] Synthesis of N-[(7-bromo-2-methyl-1 H-indol-4-yl)sulphonyl]acetamide

[0781]

[0782] According to GP 16, to a solution of N-(4-bromo-3-nitro-phenyl)sulphonylacetamide (400 mg, 1.24 mmol, 1.0 eq) in tetrahydrofuran (8.00 mL) was added dropwise a 15 separate solution of isopropenylmagnesium bromide in THF (7.40 mL, 0.5 M,

[0783] 3.71 mmol, 3 eq) and stirred at -50 °C for 4 h. The reaction mixture was purified by silica column chromatography (0-100% EtOAc in cyclohexane) to afford N-[(7- bromo-2-methyl-1H-indol-4-yl)sulphonyl]acetamide (143 mg, 35%) as a white solid.

[0784] Synthesis of N-(4-chloro-3-nitro-phenyl)sulphonylacetamide

[0785]

[0786] According to GP 14, 4-chloro-3-nitrobenzene-1-sulphonamide (4.43 g, 18.7 mmol, 1.0 eq), acetic anhydride (20.0 mL, 0.212 mol, 11 eq) and zinc chloride (0.770 g, 5.62 mmol, 30 mol%) were stirred neat for 1 h to afford N-(4-chloro-3-nitro- phenyl)sulphonylacetamide (5.16 g, 95%) as a white solid. The product was carried forward to the next reaction without purification.

[0787] 30

[0788] Synthesis of N-[(7-chloro-2-methyl-1 H-indol-4-yl)sulphonyl]acetamideForeignfiling text P25-116-SEC-WO01

[0789] 100

[0790]

[0791] According to GP 16, to a solution of N-(4-chloro-3-nitro-phenyl)sulphonylacetamide (1.00 g, 3.59 mmol, 1.0 eq) in tetrahydrofuran (20.0 mL) was added dropwise a separate solution of isopropenylmagnesium bromide in THF (22.0 mL, 0.5 M, 11.0 mmol, 3.0 eq) and stirred at -50 °C for 3 h. The reaction mixture purified by silica column chromatography (0-10% MeOH in DCM) then reverse-phase chromatography (C18, 10-100% MeOH in water, 0.1% F.A.) to afford N-[(7-chloro-2- methyl-1H-indol-4-yl)sulphonyl]acetamide (1.10 g, 76%) as a white solid.

[0792] Synthesis of N-[(4-bromo-1-naphthyl)sulphonyl]acetamide

[0793]

[0794] According to GP 14, 4-bromonapthalene-1-sulphonamide (248 mg, 0.866 mmol, 1.0 eq), acetic anhydride (0.10 mL, 1.0 mmol, 1.2 eq) and zinc chloride (55 mg, 0.39 20

[0795] mmol, 45 mol%) were stirred in DCM (5 mL, 0.2 M) for 18 h. The reaction mixture was purified by silica column chromatography (0-10% MeOH in DCM) to afford N- [(4-bromo-1-naphthyl)sulphonyl]acetamide (116 mg, 39%) as a white solid.

[0796] Synthesis of N-[(8-bromo-5-quinolyl)sulphonyl]acetamide

[0797]

[0798] 30 According to GP 13, 8-bromoquinoline-5-sulphonyl chloride (530 mg, 1.73 mmol) was stirred in a solution of ammonia in MeOH (7.0 M, 2.5 mL) to afford 8- bromoquinoline-5-sulphonamide as a white solid. The product was carried forward into the next reaction without purification.Foreignfiling text P25-116-SEC-WO01

[0799] 101

[0800] According to GP 15, 8-bromoquinoline-5-sulphonamide, triethylamine (1.06 mL, 7.77 mmol, 4.5 eq) and acetyl chloride (0.56 mL, 7.7 mmol, 4.5 eq) were stirred in DCM (10 mL, 0.2 M) for 6 h. The reaction mixture was purified by reverse-phase chromatography (C18, 0-100% MeOH in water, 0.1% F.A.) to afford N-[(8-bromo-5- quinolyl)sulphonyl]acetamide (108 mg, 19% over two steps) as a white solid.

[0801] 5

[0802] Synthesis of 4-(acetamidosulphonyl)-5-fluoronaphthalen-1-yl trifluoromethanesulphonate

[0803]

[0804] To a stirred solution of 5-methoxynaphthalen-1 -amine (5.00 g, 28.9 mmol) in HCI (20.0 mL, 40.0 mmol) and water (20 mL) was added NaNC (2.19 g, 31.8 mmol) portion-wise at 0°C. The mixture was stirred for 1 h at 0°C, then pentafluoro- Iambda5-phosphane hydrofluoride in water (12.0 g, 57.7 mmol, 70%) was added dropwise at 0°C and stirring was continued for 30 min. The resulting mixture was filtered, the filter cake was washed with water (100 mL*2) and the solid was dried under reduced pressure. The solid was stirred in water at 130°C for 2 h, extracted 20

[0805] with DCM (100 mL*2), washed with water (100 mL*2) and the organic phase was concentrated to dryness. The residue was purified by silica gel column chromatography, eluted with PE to afford the desired product (1.50 g, 8.09 mmol, 28%) as a colorless solid with a purity of 95%.

[0806] To a stirred solution of 1-fluoro-5-methoxynaphthalene (1.50 g, 8.09 mmol, 95%) in DCM (10 mL) was added sulfurochloridic acid (2.97 g, 25.5 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred for 2 h at 0°C and NH3.H2O (14.5 g, 170 mmol) was added at 0°C. The solution was stirred for 2 h, concentrated and filtered to afford the desired crude product (1.40 g, 3.85 mmol) as a white solid with a purity of 70%, which was used without further purification in the next step.

[0807] 30

[0808] To a stirred solution of 8-fluoro-4-methoxynaphthalene-1 -sulphonamide (1.40 mg, 5.48 mmol, 70%) in acetyl acetate (5 mL) was added ZnCh (374 mg, 2.74 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred for 2 h at RT,Foreignfiling text P25-116-SEC-WO01

[0809] 102

[0810] poured into water (20 mL), filtered, washed with water (50 mL) and evaporated to dryness to yield in the desired crude product (1.20 g, 2.79 mmol, 51%) as a yellow solid with a purity of 69%, which was used without further purification in the next step.

[0811] 5

[0812] To a stirred solution of N-[(8-fluoro-4-methoxynaphthalen-1-yl)sulphonyl]acetamide (1.20 g, 4.04 mmol) in DCM (5 mL) was added tribromoborane in DCM (40.4 mL, 40.4 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred for 8 h at RT, poured into ice. The organic phase was separated, washed with water (20 mL) and evaporated to dryness to afford the desired crude product (1.20 g, 4.04 10 mmol, 74%) as brownish solid, which was used without further purification in the next step.

[0813] To a stirred solution of N-[(8-fluoro-4-hydroxynaphthalen-1-yl)sulphonyl]acetamide (500 mg, 1.77 mmol) in THF (5 mL) was added lithiobis(trimethylsilyl)amine (3.53 mL, 3.53 mmol) dropwise at -78°C under nitrogen atmosphere. The mixture was stirred for 30 min at -78° C, 1,1,1-trifluoro-N-phenyl-N- trifluoromethanesulphonylmethanesulphonamide (820 mg, 2.29 mmol) was added and the mixture was slowly warmed to RT and stirred for additional 5 h. The reaction was quenched by addition of NH4CI (30 mg), extracted with ethyl acetate (50 mL), washed with brine, dried with sodium sulphate, filtered and concentrated to dryness.

[0814] 20 The residue was purified by silica gel column chromatography, eluted with ethyl acetate / DCM (0-50%) to afford the desired product (150 mg, 0.35 mmol, 20%) as a colorless solid.

[0815] Synthesis of N-[4-chloro-3-(methylsulfanyl)benzenesulphonyl]acetamide

[0816]

[0817] To a solution of 3-amino-4-chlorobenzene-1-sulphonic acid (10.0 g, 48.2 mmol) and 30

[0818] (methyldisulfanyl)methane (23.0 g, 244 mmol) in DME (150 mL) was added 3- methylbutyl nitrite (9.00 g, 76.8 mmol) at RT. The mixture solution was stirred at 85°C under nitrogen atmosphere for 16 h. The reaction mixture was filtered andForeignfiling text P25-116-SEC-WO01

[0819] 103

[0820] evaporated to dryness. To yield in the desired product (5.00 g, 17.1 mmol, 35.4 %) as a yellow solid with a purity of 82%, which was used in the next step without

[0821] further purification.

[0822] To a solution of 4-chloro-3-(methylsulfanyl)benzene-1-sulphonic acid (5.00 g, 17.07 5

[0823] mmol, 82% purity) in DCE (30 mL) was added methanesulfinyl chloride (6.00 g, 50.4 mmol) at RT. The mixture was stirred at 80°C for 2 h. The mixture was concentrated and re-dissolved THF (30 mL), then a 30% solution of NH4OH (6.00 g, 51.4 mmol) in water was added slowly at 0°C and stirring was continued at RT for 1 h. The reaction mixture was concentrated and the residue washed with water (20 mL) three 10 times. After drying the desired product (5.00 g, 15.7 mmol, 92%) was obtained as a yellow solid with a purity of 75%, which was used in the next step without further purification.

[0824] To a solution of 4-chloro-3-(methylsulfanyl)benzene-1 -sulphonamide (5.00 g, 15.7 mmol) in acetyl acetate (10 mL) was added ZnCh (1.10 g, 8.07 mmol) at RT. The mixture solution was stirred at RT for 2 h. The reaction solution was concentrated to dryness. The residue was purified by preparative MPLC (5%-95% ACN / water) to result in 3.00 g (10.5 mmol, 67%) of a colorless solid with a purity of 98%.

[0825] Synthesis of the B ring

[0826] 20 Synthesis of tert-butyl N-ethyl-N-[2-ethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]carbamate

[0827]

[0828] Tert-butyl N-(4-bromo-2-ethylphenyl)carbamate: According to GP 7 to a solution of 4-bromo-2-ethylaniline (10.0 g, 48.0 mmol, 1.0 eq) in THF (200 mL) and

[0829] demineralized water (100 mL) was added potassium carbonate (20.0 g, 144 mmol, 3.0 eq) followed by addition of di-tert-butyl dicarbonate (22.0 mL, 96.0 mmol, 2.0 eq) 30 at RT. The reaction mixture was stirred at 50°C for 18 h. The mixture was diluted

[0830] with water, the organic phase separated and the aqueous phase was extracted with DCM. The combined org. phases were washed with water, dried over sodiumForeignfiling text P25-116-SEC-WO01

[0831] 104

[0832] sulphate, 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.

[0833] 5

[0834] Tert-butyl N-(4-bromo-2-ethylphenyl)-N-ethylcarbamate: According to GP 4 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 mg, 20.4 mmol, 1.2 eq) was added portion-wise and was stirring was continued for 15 10 min at 0°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 DCM and the combined organic layers were washed with brine, dried over sodium sulphate, 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.

[0835] Tert-butyl N-ethyl-N-[2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate, According to GP 2 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 20 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.

[0836] 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%.

[0837] 30 According to that procedure the following building blocks were synthesized:Foreignfiling text P25-116-SEC-WO01

[0838]

[0839] 10

[0840]

[0841] According to that procedure the following precursor were synthesized

[0842]

[0843] Synthesis of 4-bromo-N-ethyl-2,3-difluoroaniline:

[0844] 20

[0845]

[0846] According to GP 84-bromo-2,3-difluoroaniline (200 mg, 0.03 mmol, 1.0 eq) and

[0847] dissolved in DCM (5 mL). Acetaldehyde (0.16 mL, 2.80 mmol, 3.0 eq) and acetic

[0848] 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

[0849] mmol, 2.0 eq) was added and the mixture stirred for additional 2h at 50°C. The

[0850] mixture was diluted with DCM and washed with water, sat. NaHCO3-solution and

[0851] with brine. The organic layer was dried with sodium sulphate, filtered and

[0852] evaporated to dryness. The crude material was separated by preparative

[0853] 30

[0854] chromatography. The product-containing fractions were combined and adjusted to

[0855] pH = 8 by adding sat. NaHCO3-solution and extracted with DCM. The organic layer was dried with sodium sulphate, filtered and evaporated to dryness to yield in 4-Foreignfiling text P25-116-SEC-WO01

[0856] 106

[0857] bromo-N-ethyl-2,3-difluoroaniline (44.0 mg, 16.6 mmol, 16%) of a colorless oil with

[0858] purity of 82%.

[0859] In analogy these derivatives were synthesized:

[0860]

[0861] Synthesis of 2-bromo-N-(2-fluoroethyl)-4-iodoaniline

[0862] 20

[0863]

[0864] According to GP 1 to a solution of 2-bromo-4-iodoaniline (4.00 g, 13.4 mmol, 1.0 eq)

[0865] in THF (20 mL) at 0°C was added NaH (1.07 g, 26.9 mmol, 2.0 eq) and the mixture

[0866] stirred at 25°C for 2 h. Then 1-fluoro-2-iodoethane (4.67 g, 26.9 mmol, 2.0 eq) was

[0867] added and the mixture was stirred at 60°C for additional 4 h. Water (50 mL) was

[0868] added slowly and the mixture was extracted 3 times with EtOAc (50 mL) and the

[0869] combined organic phase was evaporated to dryness. The crude product was

[0870] 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.

[0871] In Analogy to the following intermediates were synthesized

[0872] 30Foreignfiling text P25-116-SEC-WO01

[0873] 107

[0874]

[0875] Followed by GP 2 to result in

[0876] 5

[0877]

[0878] Synthesis of tert-butyl N-(2-cyanoethyl)-N-[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- 10 dioxaborolan-2-yl)phenyl]carbamate

[0879]

[0880] Tert-butyl N-(4-bromo-2-methylphenyl)-N-(2-cyanoethyl)carbamate, According to GP 3 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).

[0881] 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 20

[0882] 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.

[0883] 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 2 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 pl, 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) 30

[0884] was added. The reaction mixture was stirred at 100°C for 5 h. 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 byForeignfiling text P25-116-SEC-WO01

[0885] 108

[0886] 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.

[0887] In analogy the following intermediated were synthesized

[0888] 5

[0889]

[0890] Or derivatives without borylation and / or BOC protection 10

[0891]

[0892] 2 also the phenol derivatives can be reacted under the same

[0893]

[0894] conons:

[0895]

[0896] According to GP 1 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 ethenEtOAc = 30

[0897] 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.Foreignfiling text P25-116-SEC-WO01

[0898] 109

[0899] Followed by GP 2 to result in

[0900] 5

[0901]

[0902] Synthesis of 2-[4-cyclopropanecarbonyl-3-(trifluoromethyl)phenyl]-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane

[0903] 10

[0904]

[0905] According to GP 2 [4-bromo-2-(trifluoromethyl)phenyl](cyclopropyl)methanone, 95%

[0906] (300 mg, 0.97 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL) and bis(pinacolato)diboron (299 mg, 1.17 mmol, 1.2 eq), potassium acetate (239 mg,

[0907] 2.43 mmol, 2.5 eq) and bis(triphenylphosphine)palladium(ll)dichloride (68.3 mg,

[0908] 0.10 mmol, 0.1 eq) was added. The reaction mixture was stirred at 105°C for 16 h.

[0909] 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

[0910] over sodium sulphate, filtered and evaporated to dryness to yield in 2-[4- 20

[0911] 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

[0912] crude product was used without purification in the next step.

[0913] Synthesis of 2-nitro-N-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenyl]-N-[4-(trimethylsilyl)but-3-yn-1-yl]benzene-1 -sulphonamide

[0914] 30

[0915]

[0916] N-[4-bromo-2-(trifluoromethyl)phenyl]-2-nitrobenzene-1-sulphonamide: To a solution of 4-bromo-2-(trifluoromethyl)aniline (10.0 g, 39.6 mmol, 1.0 eq) in pyridine (125 mL)Foreignfiling text P25-116-SEC-WO01

[0917] 110

[0918] was added 2-nitrobenzene-1 -sulphonyl chloride (18.5 g, 79.2 mmol, 2.0 eq) at 0°C. The resulting mixture was stirred for 1h at 80°C. The mixture was diluted with HCI (1 M aq, 100 mL) and extracted with ethyl acetate (150 mL) three times. The combined organic layer was washed with brine (25 x 2 mL), dried over anhydrous Na2SO4, filtered, the filtrate evaporated to dryness. The residue was purified by silica gel 5

[0919] column chromatography, eluted with PE:EtOAc (50:50) to afford N-[4-bromo-2- (trifluoromethyl)phenyl]-2-nitrobenzene-1 -sulphonamide (6.40 g, 13.7 mmol, 35%) as a brown yellow solid.

[0920] N-[4-bromo-2-(trifluoromethyl)phenyl]-2-nitro-N-[4-(trimethylsilyl)but-3-yn-1- 10 yl]benzene-1 -sulphonamide: To a stirred solution of N-[4-bromo-2- (trifluoromethyl)phenyl]-2-nitrobenzene-1-sulphonamide (2.20 g, 4.70 mmol, 1.0 eq), 4-(trimethylsilyl)but-3-yn-1-ol (1.65 mL, 9.39 mmol, 2.0 eq) and PPhs (1.94 g, 7.04 mmol, 1.5 eq) in THF (33 mL) was added DIAD (1.30 mL, 7.04 mmol, 1.5 eq) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 15 h at RT. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and the filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (45:55) to afford N-[4-bromo-2-(trifluoromethyl)phenyl]-2-nitro-N-[4-(trimethylsilyl)but-3-yn-1- yl]benzene-1 -sulphonamide (2.30 g, 3.97 mmol, 85%) as a brown oil.

[0921] 20

[0922] 2-Nitro-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]- N-[4-(trimethylsilyl)but-3-yn-1-yl]benzene-1-sulphonamide: According to GP 2, a mixture of bis(pinacolato)diboron (1.51 g, 5.95 mmol, 1.5 eq), N-[4-bromo-2- (trifluoromethyl)phenyl]-2-nitro-N-[4-(trimethylsilyl)but-3-yn-1-yl]benzene-1- sulphonamide (2.30 g, 3.97 mmol, 1.0 eq), Pd(dppf)Cl2 (0.32 g, 0.40 mmol, 0.1 eq) and KOAc (1.02 g, 9.91 mmol, 2.5 eq) in dioxane (29 mL) was stirred for 1.5 h at 100°C under nitrogen atmosphere. The mixture was filtered through a Celite pad, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (75:25) to afford 2-nitro-N-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]-N-[4- 30 (trimethylsilyl)but-3-yn-1-yl]benzene-1 -sulphonamide (2.40 g, 3.87 mmol, 98%) as a yellow oil.Foreignfiling text P25-116-SEC-WO01

[0923] 111

[0924] In analogy to these procedures the following derivatives were synthesized:

[0925] 5

[0926]

[0927] Synthesis of trimethyl({4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenoxy]but-1-yn-1-yl})silane

[0928] 10

[0929]

[0930] {4-[4-bromo-2-(trifluoromethyl)phenoxy]but-1-yn-1-yl}trimethylsilane: A mixture of 4- bromo-2-(trifluoromethyl)phenol (1.20 g, 4.73 mmol, 1.0 eq), 4-(trimethylsilyl)but-3- yn-1-ol (2.58 mL, 14.7 mmol, 3.1 eq) and PPhs (3.30 g, 12.0 mmol, 2.5 eq) in THF

[0931] (15 mL) was stirred under nitrogen atmosphere at room temperature for 30 min. To the above mixture was added DIAD (diisopropyl azodicarboxylate, 2.30 mL, 12.4

[0932] mmol, 2.6 eq) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture

[0933] was stirred under nitrogen atmosphere at 70 °C for 1 h. The mixture was cooled to room temperature and evaporated to dryness. The residue was purified by reverse phase chromatography (water / MeCN, 50 % to 100 %) to afford {4-[4-bromo-2- (trifluoromethyl)phenoxy]but-1-yn-1-yl}trimethylsilane (820 mg, 2.12 mmol, 45%) as

[0934] 20

[0935] a colorless oil.

[0936] Trimethyl({4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenoxy]but-1-yn-1-yl})silane: According to GP 2, a mixture of {4-[4- bromo-2-(trifluoromethyl)phenoxy]but-1-yn-1-yl}trimethylsilane (500 mg, 1.29 mmol,

[0937] 1.0 eq), bis(pinacolato)diboron (550 mg, 2.06 mmol, 1.6 eq), Pd(dppf)Cl2 (110 mg,

[0938] 0.14 mmol, 0.1 eq) and KOAc (350 mg, 3.39 mmol, 2.6 eq) in 1,4-dioxane (6 mL)

[0939] was stirred at 100°C under nitrogen atmosphere for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was evaporated to dryness. The residue was purified by silica gel column (PE / EtOAc, 0% to 30%) to afford trimethyl({4-[4- 30 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy]but-1-yn-1- yl})silane (410 mg, 0.96 mmol, 74%) as a colorless solid.Foreignfiling text P25-116-SEC-WO01

[0940] 112

[0941] Synthesis of 4-bromo-2-chloro-N-ethyl-aniline

[0942] 5

[0943]

[0944] According to GP 17, N-(4-bromo-2-chlorophenyl)acetamide (503 mg, 2.02 mmol, 1.0 eq) was suspended in tetrahydrofuran (10.0 mL, 0.2 M) and stirred at 0 °C. A separate solution of borane tetrahydrofuran complex (1 M, 5.06 mL, 5.06 mmol, 2.5 eq) was added dropwise to the reaction mixture and stirred for 2 days. The reaction was quenched with MeOH (20 mL) and purified by silica column

[0945] 10

[0946] chromatography (0-80% EtOAc in cyclohexane) to give 4-bromo-2-chloro-N-ethyl- aniline (344 mg, 66%) as a colorless oil.

[0947] Synthesis of 4-bromo-N,2-diethyl-aniline

[0948]

[0949] According to GP 17, 4-bromo-2'-ethylacetamide (2.67 g, 11.0 mmol, 1.eq) was suspended in tetrahydrofuran (15.0 mL, 0.7 M) and stirred at 50 °C. A separate solution of borane tetrahydrofuran complex (1 M, 27.6 mL, 27.6 mmol, 2.5 eq) was 20 added dropwise to the reaction mixture and stirred for 30 min. The reaction was cooled to ambient temperature, quenched with MeOH (15 mL) and concentrated in vacuo to give 4-bromo-N,2-diethyl-aniline (2.36 g, 83%) as a white solid. The product was carried forward to the next reaction without purification.

[0950] Synthesis of 4-bromo-N-ethyl-2-(trifluoromethyl)aniline

[0951]

[0952] To a solution of 4-bromo-2-(trifluoromethyl)aniline (0.58 mL, 4.2 mmol, 1.0 eq) and triethylamine (0.68 mL, 5.0 mmol, 1.2 eq) in DCM (15 mL, 0.3 M) was added acetyl 30

[0953] chloride (0.36 mL, 5.0 mmol, 1.2 eq) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by silica columnForeignfiling text P25-116-SEC-WO01

[0954] 113

[0955] chromatography (0-20% MeOH in DCM) to afford N-[4-bromo-2- (trifluoromethyl)phenyl]acetamide (414 mg, 35%) as an off-white solid.

[0956] According to GP 17, N-[4-bromo-2-(trifluoromethyl)phenyl]acetamide (1.025 g, 3.634 mmol, 1.0 eq) was suspended in tetrahydrofuran (5.0 mL, 0.7 M) and stirred at 50 °C. A separate solution of borane tetrahydrofuran complex (1 M, 9.1 mL, 5

[0957] 9.1 mmol, 2.5 eq) was added dropwise to the reaction mixture and stirred for 80 min. The reaction was cooled to ambient temperature, quenched with MeOH (10 mL) and purified by silica column chromatography (0-100% EtOAc in cyclohexane) to give 4-bromo-N-ethyl-2-(trifluoromethyl)aniline (502 mg, 52%) as a white solid.

[0958] Synthesis of 2-chloro-N-ethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline

[0959]

[0960] 15

[0961] According to GP 2, 4-bromo-2-chloro-N-ethyl-aniline (84.0 mg, 0.358 mmol, 1.0 eq), bis(pinacolato)diboron (91.0 mg, 0.358 mmol, 1.0 eq) and potassium acetate (106.54 mg, 1.0745 mmol, 3.0 eq) were suspended in 1,4-dioxane (3.5 mL, 0.1 M).

[0962] To the reaction mixture was added [1 ,1 ’-Bis(di-tert- 20 butylphosphino)ferrocene]dichlorpalladium(ll) (7.7 mg, 9.0 pmol, 8 mol%) and heated to 100 °C under a nitrogen atmosphere for 18 h. The mixture was quenched with sat. aq. ammonium chloride (5 mL), extracted with ethyl acetate (3x5 mL). The combined organic phases were washed with brine (5 mL), concentrated in vacuo and then purified by silica chromatography (0-50% EtOAc in cyclohexane) to afford 2-chloro-N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (53 mg, 53%) as a colorless oil.

[0963] Synthesis of N,2-diethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline

[0964] 30Foreignfiling text P25-116-SEC-WO01

[0965] 114

[0966] 5

[0967]

[0968] According to GP 2, 4-bromo-N,2-diethyl-aniline (2.36 g, 9.22 mmol, 1.0 eq), bis(pinacolato)diboron (2.36 g, 9.29 mmol, 1.0 eq) and potassium pivalate (3.82 g, 27.3 mmol, 3.0 eq) were suspended in 1,4-dioxane (30 mL, 0.3 M). To the reaction mixture was added [1,T-Bis(di-tert-butylphosphino)ferrocene]dichlorpalladium(ll) (0.190 g, 0.225 mmol, 2 mol%) and heated to 85 °C under a nitrogen atmosphere for 18 h. The mixture was filtered through celite and then purified by silica chromatography (0-90% EtOAc in cyclohexane) to afford N, 2-diethyl-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.73 g, 68%) as a pale yellow solid.

[0969] Synthesis of N-ethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- 15

[0970] (trifluoromethyl)aniline

[0971]

[0972] According to GP 2, 4-bromo-N-ethyl-2-(trifluoromethyl)aniline (502.0 mg, 1.873 mmol, 1.0 eq), bis(pinacolato)diboron (543.7 mg, 2.141 mmol, 1.1 eq) and potassium pivalate (802.7 mg, 5.724 mmol, 3.0 eq) were suspended in 1,4-dioxane (10 mL, 0.2 M). To the reaction mixture was added [1 ,1 ’-Bis(di-tert- butylphosphino)ferrocene]dichlorpalladium(ll) (79.4 mg, 92.4 pmol, 9 mol%) and heated to 90 °C under a nitrogen atmosphere for 24 h. The mixture was filtered through celite and then purified by silica chromatography (0-100% EtOAc in cyclohexane) to afford N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)aniline (430 mg, 73%) as a pale yellow oil.

[0973] 30

[0974] Synthesis of 3-[2-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)anilino]propanenitrileForeignfiling text P25-116-SEC-WO01

[0975] 115

[0976]

[0977] To a solution of 4-bromo-2-chloroaniline (773.0 mg, 3.744 mmol, 1.0 eq) and acrylonitrile (0.25 mL, 3.8 mmol, 1.0 eq) in 1,4-dioxane (4.0 mL, 0.9 M) was added dropwise benzyltrimethylammonium hydroxide (40% in MeOH, 0.17 mL, 0.37 mmol, 10 10 mol%) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated in vacuo and purified by silica column chromatography (0-50% EtOAc in cyclohexane) to afford 3-(4-bromo-2-chloro-anilino)propanenitrile (255 mg, 26%) as a white solid.

[0978] According to GP 2, 3-(4-bromo-2-chloro-anilino)propanenitrile (133 mg, 0.513 mmol, 1.0 eq), bis(pinacolato)diboron (130 mg, 0.513 mmol, 1.0 eq) and potassium acetate (152.4 mg, 1.537 mmol, 3.0 eq) were suspended in 1,4-dioxane (3.0 mL, 0.2 M). To the reaction mixture was added [1 ,1 ’-Bis(di-tert- butylphosphino)ferrocene]dichlorpalladium(ll) (22.0 mg, 25.6 pmol, 2.5 mol%) and heated to reflux under a nitrogen atmosphere for 18 h. The mixture was filtered 20 through celite and then purified by silica chromatography (0-100% EtOAc in cyclohexane) to afford 3-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)anilino]propanenitrile (91 mg, 58%) as a white solid.

[0979] Synthesis of N-ethyl-2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline

[0980]

[0981] 30 According to GP 2, 4-bromo-N-ethyl-2-methyl-aniline (446.9 mg, 2.087 mmol,

[0982] 1.0 eq), bis(pinacolato)diboron (1.189 g, 4.682 mmol, 2.2 eq) and potassium acetate (1.285 mg, 12.96 mmol, 6.0 eq) were suspended in 1,4-dioxane (10.0 mL, 0.2 M).Foreignfiling text P25-116-SEC-WO01

[0983] 116

[0984] To the reaction mixture was added [1 ,1 ’-Bis(di-tert- butylphosphino)ferrocene]dichlorpalladium(ll) (217.1 mg, 0.253 mmol, 10 mol%) and heated to 90 °C under a nitrogen atmosphere for 18 h. The mixture was filtered through celite and then purified by silica chromatography (0-100% EtOAc in cyclohexane) to afford N-ethyl-2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- 5

[0985] yl)aniline (171.8 mg, 26%) as a pale brown solid.

[0986] Synthesis of 3-[2-ethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy]propanenitrile

[0987]

[0988] To a neat mixture of 4-bromo-2-ethylphenol (224.0 mg, 1.114 mmol, 1.0 eq), potassium carbonate (7.7 mg, 56 pmol, 5 mol%) and acrylonitrile (0.73 mL, 11 mmol, 10 eq) was added anhydrous 2-Methyl-2-propanol (10 pL, 0.11 mmol, 10 mol%) and heated to 160 °C in a microwave reactor for 15 min. The reaction mixture was then cooled to ambient temperature and stirred for 18 h. The mixture was concentrated in vacuo, re-dissolved with ethyl acetate (5 mL) and washed with water (5 mL). The organic portion was washed with brine (5 mL), dried over magnesium 20

[0989] sulphate, concentrated in vacuo and then purified by silica column chromatography (0-80% EtOAc in cyclohexane) to afford 3-(4-bromo-2-ethyl-phenoxy)propanenitrile (78 mg, 28%).

[0990] According to GP 2, 3-(4-bromo-2-ethyl-phenoxy)propanenitrile (70.0 mg, 0.270 mmol, 1.0 eq), bis(pinacolato)diboron (68.6 mg, 0.270 mmol, 1.0 eq) and potassium acetate (89.22 mg, 0.8908 mmol, 3.3 eq) were suspended in 1,4-dioxane (2.0 mL, 0.1 M). To the reaction mixture was added [1 ,1 ’-Bis(di-tert- butylphosphino)ferrocene]dichlorpalladium(ll) (11.6 mg, 13.5 pmol, 5 mol%) and heated in a microwave reactor to 120 °C for 1 h. The mixture was filtered through celite and then purified by silica chromatography (0-100% EtOAc in cyclohexane) to 30

[0991] afford 3-[2-ethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy]propanenitrile (32 mg, 30%) as a pale brown solid.Foreignfiling text P25-116-SEC-WO01

[0992] 117

[0993] Synthesis of 3-[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy]propanenitrile

[0994]

[0995] To a neat mixture of 4-Bromo-2-methylphenol (2.00 g, 10.7 mmol, 1.0 eq) in 10 acrylonitrile (3.50 mL, 53.4 mmol, 5.0 eq) was added benzyltrimethylammonium hydroxide (40% in MeOH, 0.20 mL, 0.44 mmol, 4 mol%) and stirred at ambient temperature for 30 min then heated to 80 °C for 5 days. The reaction mixture was concentrated in vacuo and purified by silica column chromatography (0-100% EtOAc in cyclohexane) to afford 3-(4-bromo-2-methyl-phenoxy)propanenitrile (1.48 g, 58%) as a colorless oil.

[0996] According to GP 2, 3-(4-bromo-2-methyl-phenoxy)propanenitrile (579.0 mg, 2.412 mmol, 1.0 eq), bis(pinacolato)diboron (612.4 mg, 2.412 mmol, 1.0 eq) and potassium acetate (717.3 mg, 7.235 mmol, 3.0 eq) were suspended in 1,4-dioxane (12 mL, 0.2 M). To the reaction mixture was added [1 ,1 ’-Bis(di-tert- 20 butylphosphino)ferrocene]dichlorpalladium(ll) (51.8 mg, 60.3 pmol, 6 mol%) and heated in a microwave reactor to 120 °C for 1 h. The mixture was quenched with sat. aq. ammonium chloride (5 mL) and extracted with ethyl acetate (3x5 mL). The combined organic phases were washed with brine (5 mL), concentrated in vacuo and then purified by silica chromatography (0-50% EtOAc in cyclohexane) to afford 3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propanenitrile (706 mg, quant.) as a colorless oil.

[0997] Synthesis of 3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenoxy]propanenitrile

[0998] 30Foreignfiling text P25-116-SEC-WO01

[0999] 118

[1000]

[1001] To a neat mixture of 4-bromo-2-(trifluoromethyl)phenol (938.0 mg, 3.892 mmol, 1.0 eq), potassium carbonate (53.79 mg, 0.3892 mmol, 10 mol%) and acrylonitrile (2.55 mL, 38.9 mmol, 10 eq) was added anhydrous 2-Methyl-2-propanol (37 pL, 0.389 mmol, 10 mol%) and heated to 165 °C in a microwave reactor for 30 min. The 10

[1002] mixture was concentrated in vacuo, re-dissolved with ethyl acetate (5 mL) and washed with water (5 mL). The organic portion was washed with brine (5 mL), dried over magnesium sulphate, concentrated in vacuo and then purified by silica column chromatography (0-70% EtOAc in cyclohexane) to afford 3-[4-bromo-2- (trifluoromethyl)phenoxy]propanenitrile (14 mg, 1%).

[1003] According to GP 2, 3-[4-bromo-2-(trifluoromethyl)phenoxy]propanenitrile (21.0 mg, 62.1 pmol, 1.0 eq), bis(pinacolato)diboron (15.8 mg, 62.1 pmol, 1.0 eq) and potassium acetate (20.5 mg, 0.205 mmol, 3.3 eq) were suspended in 1,4-dioxane (2.0 mL, 31 mM). To the reaction mixture was added [1 ,1 ’-Bis(di-tert- butylphosphino)ferrocene]dichlorpalladium(ll) (2.7 mg, 3.1 pmol, 5 mol%) and 20

[1004] heated in a microwave reactor to 120 °C for 1 h. The mixture was filtered through celite and then purified by silica chromatography (0-100% EtOAc in cyclohexane) to afford 3-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenoxy]propanenitrile (15 mg, 46%) as a pale brown solid.

[1005] Synthesis of final derivatives, Tetrazoles

[1006] Synthesis of N,2-diethyl-4-{2-methyl-4-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-1H- indol-7-yl}aniline

[1007] 30Foreignfiling text P25-116-SEC-WO01

[1008] 119

[1009]

[1010] tert-butyl N-ethyl-N-(2-ethyl-4-{2-methyl-4-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]- 1H-indol-7-yl}phenyl)carbamate: According to GP 9, to a solution of 7-chloro-2- 10 methyl-4-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-1H-indole (70.0 mg, 0.25 mmol, 1.0 eq) in 1,4-dioxane (4 mL) was added tert-butyl N-ethyl-N-[2-ethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (111 mg, 0.28 mmol, 1.1 eq), potassium carbonate (70.0 mg, 0.51 mmol, 2.0 eq) and XPhos Pd G3 (21.5 mg, 0.025 mmol, 0.1 eq) and water (1 mL). Additional tert-butyl N-ethyl-N-[2-ethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (65.0 mg, 016 mmol, 0.6 eq), potassium carbonate (70.0 mg, 0.51 mmol, 2.0 eq) and XPhos Pd G3 (10.0 mg, 0.012 mmol, 0.05 mol%) were added and the mixture stirred for further additional 6 h at 110°C. The solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water then with brine. The organic layer was dried with sodium sulphate, filtered and evaporated. The obtained residue 20 was used for flash chromatography on silica gel to yield in 54.0 mg (0..10 mmol, 39%) of the desired product as white solid with purity of 90%.

[1011] N,2-diethyl-4-{2-methyl-4-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-1H-indol-7- yljaniline: According to GP 6, to a solution of tert-butyl N-ethyl-N-(2-ethyl-4-{2- methyl-4-[(1 R)-1-(1 H-1 ,2,3,4-tetrazol-5-yl)propyl]-1 H-indol-7-yl}phenyl)carbamate (54.0 mg, 0.10 mmol, 1.0 eq) in DCM (4 mL) was added HCI, 4 M solution 1,4- dioxane (1 mL) and the mixture stirred for 2h at RT. The mixture was diluted with DCM and washed with water then with brine. The organic layer was dried with sodium sulphate, filtered and evaporated to dryness. The residue was purified by preparative chromatography. The combined fractions were extracted with DCM. The 30 organic layer was washed with brine, dried with sodium sulphate, filtered and evaporated to dryness to yield in 25.0 mg (0.06 mmol, 63%) of the desired product as white solid with purity of 98%.Foreignfiling text P25-116-SEC-WO01

[1012] 120

[1013] In analogy the following intermediated were synthesized. Sometimes racemic

[1014] mixtures was synthesized and separated to the enantiomers at the last step:

[1015]

[1016] In analogy the following cpds without BOC-protection group following GP 9 were synthesized:

[1017]

[1018] Synthesis of N,3-diethyl-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-[1,T- 30 biphenyl]-4-amineForeignfiling text P25-116-SEC-WO01

[1019] 121

[1020]

[1021] Tert-butyl N-[4'-(1-cyanopropyl)-3-ethyl-2'-methyl-[1,T-biphenyl]-4-yl]-N- ethylcarbamate: According to GP 9 tert-butyl N-ethyl-N-[2-ethyl-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (150 mg, 0.32 mmol, 1.0 eq), 2-(4-bromo-3-methylphenyl)butanenitrile (106 mg, 0.39 mmol, 1.2 eq) and

[1022] potassium carbonate (36.7 pl, 065 mmol, 2.0 eq) were suspended in AON (1.4 mL)

[1023] 20 and water (1.4 mL). The vial was spilled with argon followed by the addition of [1,1’- bis(di-tert-butylphosphino)ferrocen]dichlorpalladium(ll) (10.5 mg, 0.02 mmol, 0.05 eq) and the mixture was stirred at 80°C for 1.5 h. The reaction mixture was filtered through celite and concentrated to dryness. The residue was dissolved in DCM, absorbed onto diatomaceous earth and purified by flash chromatography (heptane / EtOAc) to yield in tert-butyl N-[4'-(1-cyanopropyl)-3-ethyl-2'-methyl-[1,1'- biphenyl]-4-yl]-N-ethylcarbamate (103 mg, 0.24 mmol, 75%) as a colorless solid.

[1024] Tert-butyl N-ethyl-N-fS-ethyl^'-methyM'-II^IH-I^.S^-tetrazol-S-yOpropylHI,!'- biphenyl]-4-yl}carbamate: tert-butyl N-[4'-(1-cyanopropyl)-3-ethyl-2'-methyl-[1,1'- biphenyl]-4-yl]-N-ethylcarbamate (103 mg, 0.24 mmol, 1.0 eq ) , zinc chloride

[1025] (132 mg, 0.96 mmol, 4.0 eq) and sodium azide (75.9 mg, 1.16 mmol, 4.8 eq) were

[1026] 30 suspended in 1-propanol (5 mL). The mixture stirred at 100°C (heating block temperature) 18h. LC-MS showed product and starting material.Foreignfiling text P25-116-SEC-WO01

[1027] 122

[1028] Sodium azide extra pure (38.0 mg, 0,578 mmol, 2.4 eq) and zinc chloride anhydrous (65.7 mg, 0.48 mmol, 2.0 eq) were added again and the reaction mixture was stirred for 12 h at 100°C. Sodium azide (38.0 mg, 0,58 mmol, 2.4 eq) and zinc chloride (65.7 mg, 0,48 mmol, 2.0 eq) were added again and the reaction mixture was stirred foe additional 19 h at 100°C.The reaction mixture was diluted with water and 5

[1029] extracted twice with DCM. The pooled organic phases were dried with Na2SO4, filtered and evaporated to dryness to yield in tert-butyl N-ethyl-N-{3-ethyl-2'-methyl- 4'-[1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-[1,1'-biphenyl]-4-yl}carbamate (108 mg, 0.11 mmol, 47%) of a beige solid with a purity of 48%. The residue was used in the next step without further purification.

[1030] 10

[1031] N,3-diethyl-2'-methyl-4'-[1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-[1,T-biphenyl]-4-amine: According to GP 6 tert-butyl N-ethyl-N-{3-ethyl-2'-methyl-4'-[1-(1H-1,2,3,4-tetrazol-5- yl)propyl]-[1,1'-biphenyl]-4-yl}carbamate (108 mg, 0.11 mmol, 1.0 eq, 48% purity) was dissolved in DCM (20 mL) and trifluoroacetic acid (87.5 pl, 1.14 mmol, 1.0 eq) was added at RT and the reaction mixture was stirred at RT for 18 h. The reaction solution was evaporated to dryness and the residue was purified by flash chromatography. The product containing fractions were treated with saturated Na2COs solution and extracted twice with ethyl acetate. The combined layer were dried with Na2SO4, filtered and evaporated to dryness to yield in N,3-diethyl-2'- methyl-4'-[1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-[1,T-biphenyl]-4-amine (35.3 mg, 0.10 20 mmol, 88%) as a yellow solid.

[1032] N,3-diethyl-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-[1,T-biphenyl]-4- amine: N,3-diethyl-2'-methyl-4'-[1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-[1,T-biphenyl]-4- amine (33.4 mg, 0,10 mmol, 1.0 eq) was separated via chiral SFC (Column:

[1033] ChiralPAK IC, Eluent: CO .EtOH (80:20), wave length: 220 nM, flow rate: 2-5 mL / min) to give N,3-diethyl-2'-methyl-4'-[(1S)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]- [1,1'-biphenyl]-4-amine (14.4 mg, 0.04 mmol, 43%) as a yellow solid and N,3- diethyl-2'-methyl-4'-[(1 R)-1 -(1 H-1 ,2,3,4-tetrazol-5-yl)propyl]-[1 ,1 '-biphenyl]-4-amine (14.6 mg, 0.041 mmol, 43%) as a yellow solid with an ee of 99.5%.

[1034] In analogy the following intermediated were synthesized:

[1035] 30Foreignfiling text P25-116-SEC-WO01

[1036] 123

[1037] 5

[1038]

[1039] In analogy the following intermediated were synthesized without having a BOC- protection:

[1040] 10

[1041]

[1042] Synthesis of N-(but-3-yn-1-yl)-2-ethyl-4-{2-methyl-4-[(1 R)-1-(2H-1 ,2,3,4-tetrazol-5- yl)propyl]-1H-indol-7-yl}aniline

[1043]

[1044] 2-ethyl-4-{4-[(1R)-1-{2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl}propyl]-2- methyl-1H-indol-7-yl}aniline: According to GP 97-chloro-4-[(1 R)-1 -{2-[(4- methoxyphenyl)methyl]-2H-1 ,2,3,4-tetrazol-5-yl}propyl]-2-methyl-1 H-indole (101 mg,

[1045] 30

[1046] 0.25 mmol, 1.0 eq), 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[1047] (70.7 mg, 0.28 mmol, 1.1 eq), potassium carbonate (70.3 mg, 0.50 mmol, 2.0 eq)

[1048] and XPhos Pd G3, 95% (22.4 mg, 0.03 mmol, 0.1eq were dissolved I 1,4-dioxaneForeignfiling text P25-116-SEC-WO01

[1049] 124

[1050] (10 mL) and deionized water (2 mL). The bottle was sealed, evacuated and backfilled with Ar. The mixture was stirred at 100°C for 1h. The mixture was evaporated to dryness. The black residue was sonicated with ACN (1 mL) nonsoluble parts were filtered off via silica gel. The filtrate was evaporated to dryness and the residue purified by preparative chromatography. Product containing 5

[1051] fractions were combined and diluted with water, and extracted with DCM. The organic layer was dried with sodium sulphate, filtered and evaporated to yield in 74.0 mg (0.15 mmol, 61%) of a colorless solid.

[1052] N-(but-3-yn-1-yl)-2-ethyl-4-{4-[(1R)-1-{2-[(4-methoxyphenyl)methyl]-2H-1, 2,3,4- 10 tetrazol-5-yl}propyl]-2-methyl-1H-indol-7-yl}aniline: According to GP 5, to a solution of 2-ethyl-4-{4-[(1R)-1-{2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl}propyl]- 2-methyl-1H-indol-7-yl}aniline (74.0 mg, 0.15 mmol, 1.0 eq) in anhydrous DMF (4 mL) was added potassium iodide (19.00 mg, 0.11 mmol, 7.5 eq), potassium carbonate (84.0 mg, 0.61 mmol, 4.0 eq) and 4-bromo-1 -butyne (104 mg, 0.76 mmol, 5.0 eq). The mixture stirred for at 100°C for 2 h. Additional 4-bromo-1 -butyne (52.1 mg, 0.38 mmol, 2.5 eq%) and potassium carbonate (63.0 mg, 0.46 mmol, 3.0 eq) were added and the mixture was stirred for additional 18 h at 120°C. The solvent was evaporated to dryness. The residue was dissolved in DCM and washed with water. The organic layer was evaporated to dryness and the residue was used for preparative chromatography. Product containing fractions were combined and 20 diluted with water, then extracted with DCM. The organic layer was dried with sodium sulphate, filtered and evaporated to yield in 16.0 mg (0.03 mmol, 20%) of the desired as a colorless solid.

[1053] N-(but-3-yn-1-yl)-2-ethyl-4-{2-methyl-4-[(1 R)-1-(2H-1 ,2,3,4-tetrazol-5-yl)propyl]-1 H- indol-7-yl}aniline: To a solution of N-(but-3-yn-1-yl)-2-ethyl-4-{4-[(1R)-1-{2-[(4- methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5-yl}propyl]-2-methyl-1H-indol-7- yljaniline (16.0 mg, 0.03 mmol, 1.0 eq) in DCM (0.50 mL) was added trifluoroacetic acid (0.50 mL) and the mixture was stirred for 18 h at 40°C. Additional trifluoroacetic acid (0.5) were added and the mixture stirred over weekend at 40°C. The mixture was diluted with DCM and washed with water to remove the TFA. The organic layer 30 was evaporated to dryness and the residue was used for preparative chromatography. Product containing fractions were combined and diluted with DCM and then washed with water and with brine. The organic layer was dried with sodiumForeignfiling text P25-116-SEC-WO01

[1054] 125

[1055] sulphate, filtered and evaporated to dryness. The product was freeze-dried to get

[1056] finally 5.60 mg (0.01 mmol, 41%) of a beige solid.

[1057] In analogy the following intermediated were synthesized.

[1058]

[1059] Synthesis of N-(but-3-yn-1-yl)-4-{2-methyl-4-[(1R)-1-(1H-1,2,3,4-tetrazol-5- yl)propyl]phenyl}-2,3-dihydro-1-benzofuran-7-amine

[1060]

[1061] 20 4-{2-methyl-4-[(1 R)-1-[1-(oxan-2-yl)-1 H-1 ,2,3,4-tetrazol-5-yl]propyl]phenyl}-2,3- dihydro-1-benzofuran-7-amine: According to GP 9 a mixture of 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-7-amine (300 mg,

[1062] 1.11 mmol, 1.0 eq), 5-[(1R)-1-(4-bromo-3-methylphenyl)propyl]-1-(oxan-2-yl)-1H- 1,2,3,4-tetrazole (400 mg, 1.07 mmol, 0.96 eq), K2CO3 (630 mg, 4.34 mmol, 3.9 eq)

[1063] in dioxane (6 mL) and water (2 mL) was stirred at 90 °C under nitrogen atmosphere

[1064] for 40 min. The resulting mixture was filtered and the filtrate concentrated to

[1065] dryness. The residue was purified by silica gel chromatography (THF / EtOAc, 0% to

[1066] 50%) to afford 4-{2-methyl-4-[(1R)-1-[1-(oxan-2-yl)-1H-1,2,3,4-tetrazol-5- yl]propyl]phenyl}-2,3-dihydro-1-benzofuran-7-amine (470 mg, 0.97 mmol, 87 %) of a

[1067] reddish oil.

[1068] 30

[1069] N-(but-3-yn-1-yl)-4-{2-methyl-4-[(1R)-1-[1-(oxan-2-yl)-1H-1,2,3,4-tetrazol-5- yl]propyl]phenyl}-2,3-dihydro-1-benzofuran-7-amine: According to GP 1 a mixture ofForeignfiling text P25-116-SEC-WO01

[1070] 126

[1071] 4-{2-methyl-4-[(1 R)-1-[1-(oxan-2-yl)-1 H-1 ,2,3,4-tetrazol-5-yl]propyl]phenyl}-2,3- dihydro-1-benzofuran-7-amine (200 mg, 0.41 mmol, 1.0 eq), 4-bromobut-1-yne (900 mg, 6.56 mmol, 16 eq), K2CO3 (200 mg, 1.38 mmol, 3.4 eq) and KI (10.0 mg, 0.06 mmol, 0.14 eq) in DMF (5 mL) was stirred at 100 °C under nitrogen atmosphere for

[1072] 3 h. The mixture was filtered, evaporated to dryness and the residue was purified by

[1073] 5

[1074] reverse phase chromatography (water / MeCN, 30% to 60%) to afford N-(but-3-yn-1- yl)-4-{2-methyl-4-[(1R)-1-[1-(oxan-2-yl)-1H-1,2,3,4-tetrazol-5-yl]propyl]phenyl}-2,3- dihydro-1-benzofuran-7-amine (135 mg, 0.24 mmol, 60%) of a yellow oil.

[1075] N-(but-3-yn-1-yl)-4-{2-methyl-4-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]phenyl}-2,3- 10 dihydro-1-benzofuran-7-amine: To a stirred mixture of N-(but-3-yn-1-yl)-4-{2-methyl- 4-[(1R)-1-[1-(oxan-2-yl)-1H-1,2,3,4-tetrazol-5-yl]propyl]phenyl}-2,3-dihydro-1- benzofuran-7-amine (130 mg, 0.23 mmol, 1.0 eq) in DCM (3 mL) was added TFA

[1076] (0.70 mL, 8.59 mmol, 36.7 eq) at 0 °C. The mixture was stirred at room temperature for 1 h and then partitioned between sat. aq. NH4HCO3 (50 mL) and DCM (50 mL).

[1077] The organic layer was separated and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to dryness. The residue was purified by reverse phase chromatography (water / MeCN, 20% to 60%) to afford N-(but-3-yn-1-yl)-4-{2-methyl- 4-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]phenyl}-2,3-dihydro-1-benzofuran-7-amine

[1078] (35.2 mg, 0.09 mmol, 38%) of a colorless solid.

[1079] 20 In analog to these procedures the following cpds were synthesized:

[1080]

[1081] Synthesis of N-(but-3-yn-1-yl)-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]- 3-(trifluoromethyl)-[1 , 1 '-biphenyl]-4-amine

[1082] 30Foreignfiling text P25-116-SEC-WO01

[1083] 127

[1084]

[1085] 3-Ethyl-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-N-(1,1,1-trifluoropropan- 2-yl)-[1,1'-biphenyl]-4-amine: A mixture of 5-[(1R)-1-(4-bromo-3- 10

[1086] methylphenyl)propyl]-1H-1,2,3,4-tetrazole (242 mg, 0.86 mmol, 0.9 eq), 2-nitro-N-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl]-N-[4- (trimethylsilyl)but-3-yn-1-yl]benzene-1 -sulphonamide (590 mg, 0.95 mmol, 1.0 eq), Pd(dtbpf)Cl2 (66.0 mg, 0.10 mmol, 0.10 eq), K2CO3 (555 mg, 3.81 mmol, 4.0 eq) in

[1087] water (1.40 mL) and dioxane (5.80 mL) was stirred for 6 h at 100°C under nitrogen atmosphere. The mixture was diluted with water (20 mL) and extracted with EtOAc

[1088] (30 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced

[1089] pressure. The mixture was purified directly via reverse phase chromatography (water / ACN, 5% to 100%) to afford 3-ethyl-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol- 5-yl)propyl]-N-(1,1,1-trifluoropropan-2-yl)-[1,T-biphenyl]-4-amine (283 mg, 0.42

[1090] 20

[1091] mmol, 44%) of a yellow oil.

[1092] 2'-methyl-4'-[(1 R)-1-(1 H-1 ,2,3,4-tetrazol-5-yl)propyl]-3-(trifluoromethyl)-N-[4- (trimethylsilyl)but-3-yn-1-yl]-[1,1'-biphenyl]-4-amine: A mixture of 3-ethyl-2'-methyl- 4'-[(1 R)-1-(1 H-1 ,2,3,4-tetrazol-5-yl)propyl]-N-(1 ,1 ,1-trifluoropropan-2-yl)-[1 ,T- biphenyl]-4-amine (260 mg, 0.39 mmol, 1.0 eq) , CS2CO3 (255 mg, 0.74 mmol, 1.9

[1093] eq) and 4-methylbenzene-1 -thiol (39.0 mg, 0.31 mmol, 0.8 eq) in DMF (5.20 mL)

[1094] was stirred for 5h at 30°C. The mixture was filtered through a Celite pad, and the

[1095] filtrate was concentrated to dryness. The mixture was purified via reverse phase chromatography (water / ACN, 5% to 100%) to afford 2'-methyl-4'-[(1R)-1-(1H- 30 1, 2,3, 4-tetrazol-5-yl)propyl]-3-( trifluoromethyl )-N-[4-(trimethylsilyl)but-3-yn-1 -yl]-[1 ,1 '- biphenyl]-4-amine (73.0 mg, 0.15 mmol, 39%) as a yellow oil.Foreignfiling text P25-116-SEC-WO01

[1096] 128

[1097] N-(but-3-yn-1-yl)-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-3- (trifluoromethyl)-[1,T-biphenyl]-4-amine: A mixture of 2'-methyl-4'-[(1R)-1-(1H- 1, 2,3, 4-tetrazol-5-yl)propyl]-3-( trifluoromethyl )-N-[4-(trimethylsilyl)but-3-yn-1 -yl]-[1 ,1 biphenyl]-4-amine (50.0 mg, 0.10 mmol, 1.0 eq) and K2CO3 (36.0 mg, 0.25 mmol,

[1098] 2.4 eq) in MeOH (1.5 mL) was stirred for 1h at RT. The mixture was filtered through

[1099] 5

[1100] a Celite pad, and the filtrate was concentrated to dryness. The mixture was purified via reverse phase chromatography (water / ACN, 5% to 100%) to afford N-(but-3-yn- 1-yl)-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-3-(trifluoromethyl)-[1,T- biphenyl]-4-amine (23.5 mg, 0.06 mmol, 55%) as a colorless solid.

[1101]

[1102] In analogy also the allene was introduced, without the TMS-protecting group:

[1103]

[1104] Synthesis of 5-[(1R)-1-[4'-(but-3-yn-1-yloxy)-2-methyl-3'-(trifluoromethyl)-[1,T- biphenyl]-4-yl]propyl]-1 H-1 ,2,3,4-tetrazole

[1105] 30Foreignfiling text P25-116-SEC-WO01

[1106] 129

[1107]

[1108] 5-[(1R)-1-[2-methyl-3'-(trifluoromethyl)-4'-{[4-(trimethylsilyl)but-3-yn-1-yl]oxy}-[1,T- biphenyl]-4-yl]propyl]-1H-1,2,3,4-tetrazole: According to GP 9, a mixture of 10

[1109] trimethyl({4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenoxy]but-1-yn-1-yl})silane (390 mg, 0.91 mmol, 1.0 eq), 5-[(1 R)- 1-(4-bromo-3-methylphenyl)propyl]-1H-1,2,3,4-tetrazole (250 mg, 0.88 mmol, 1.0 eq), K2CO3 (450 mg, 3.10 mmol, 3.4 eq) and Pd(dtbpf)Cl2 (80.0 mg, 0.12 mmol, 0.1 eq) in MeCN (6 mL) and water (2 mL) was stirred at 90 °C under nitrogen atmosphere for 40 min. The mixture was cooled to room temperature and filtered.

[1110] After evaporation to dryness the filtrate was purified by reverse phase chromatography (water / MeCN, 20% to 60%) to afford 5-[(1R)-1-[2-methyl-3'- (trifluoromethyl)-4'-{[4-(trimethylsilyl)but-3-yn-1-yl]oxy}-[1,T-biphenyl]-4-yl]propyl]- 1H-1,2,3,4-tetrazole (330 mg, 0.68 mmol, 75%) as a colorless solid.

[1111] 20

[1112] 5-[(1R)-1-[4'-(but-3-yn-1-yloxy)-2-methyl-3'-(trifluoromethyl)-[1,T-biphenyl]-4- yl]propyl]-1H-1,2,3,4-tetrazole: A mixture of 5-[(1R)-1-[2-methyl-3’-(trifluoromethyl)- 4'-{[4-(trimethylsilyl)but-3-yn-1-yl]oxy}-[1,1'-biphenyl]-4-yl]propyl]-1H-1 ,2,3,4- tetrazole (150 mg, 0.31 mmol, 1.0 eq) and K2CO3 (90.0 mg, 0.62 mmol, 2.0 eq) in MeOH (4 mL) was stirred at RT for 40 min. The mixture was evaporated to dryness. The residue was purified by reverse phase chromatography (water / MeCN, 0 % to 50 %) to afford 5-[(1R)-1-[4'-(but-3-yn-1-yloxy)-2-methyl-3'-(trifluoromethyl)-[1,T- biphenyl]-4-yl]propyl]-1H-1,2,3,4-tetrazole (63.3 mg, 0.15 mmol, 50%) as a colorless solid.

[1113] 30Foreignfiling text P25-116-SEC-WO01

[1114] 130

[1115] Synthesis of 3-bromo-N-(but-3-yn-1-yl)-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5- yl )propy l]-[ 1 , 1 '-biphenyl]-4-amine

[1116]

[1117] 10

[1118] 3-bromo-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-N-[4-(trimethylsilyl)but- 3-yn-1-yl]-[1,1'-biphenyl]-4-amine: According to GP 9, a mixture of 2-bromo-4-iodo- N-[4-(trimethylsilyl)but-3-yn-1-yl]aniline (150 mg, 0.35 mmol, 1.0 eq), 5-[(1 R)-1 -[3- methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]propyl]-1 H-1 ,2,3,4- tetrazole (100 mg, 0.30 mmol, 0.9 eq), K2CO3 (150 mg, 1.03 mmol, 3.0 eq) and Pd(dppf)Cl2.CH2Cl2 (30.0 mg, 0.04 mmol, 0.1 eq) in 1,4-dioxane (3 mL) and water (1 mL) was stirred at 90 °C under nitrogen atmosphere for 40 min. The mixture was cooled to room temperature and filtered. The filtrate was purified by reverse phase chromatography (water / MeCN, 20% to 60%) to afford 3-bromo-2'-methyl-4’-[(1R)-1- (1H-1,2,3,4-tetrazol-5-yl)propyl]-N-[4-(trimethylsilyl)but-3-yn-1-yl]-[1,1'-biphenyl]-4- amine (80.0 mg, 0.13 mmol, 39%) as a colorless solid.

[1119] 20

[1120] 3-bromo-N-(but-3-yn-1-yl)-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5-yl)propyl]-[1,T- biphenyl]-4-amine: A mixture of 3-bromo-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5- yl)propyl]-N-[4-(trimethylsilyl)but-3-yn-1-yl]-[1,1'-biphenyl]-4-amine (70.0 mg, 0.12 mmol, 1.0 eq) and K2CO3 (35.0 mg, 0.24 mmol, 2.0 eq) in MeOH (2.00 mL) was stirred at room temperature for 40 min. The mixture was evaporated to dryness. The residue was purified by reverse phase chromatography (water / MeCN, 0% to 40%) to afford 3-bromo-N-(but-3-yn-1-yl)-2'-methyl-4'-[(1R)-1-(1H-1,2,3,4-tetrazol-5- yl)propyl]-[1,1'-biphenyl]-4-amine (24.2 mg, 0.06 mmol, 48%) as a brownish solid. Synthesis of 1-[3'-ethyl-4'-(ethylamino)-2-methyl-[1 ,1 '-biphenyl]-4-yl]-1 -( 1 H-1 ,2,3,4- 30 tetrazol-5-yl)propan-1 -olForeignfiling text P25-116-SEC-WO01

[1121] 131

[1122]

[1123] 10

[1124] Tert-butyl N-ethyl-N-[3-ethyl-4'-(1 -hydroxy-1 -{1-[(4-methoxyphenyl)methyl]-1H- 1 ,2,3,4-tetrazol-5-yl}propyl)-2'-methyl-[1 ,1'-biphenyl]-4-yl]carbamate: According to

[1125] GP 9 1-(4-bromo-3-methylphenyl)-1-{1-[(4-methoxyphenyl)methyl]-1H-1 ,2,3,4- tetrazol-5-yl}propan-1-ol (67.5 mg, 0.16 mmol, 1.0 eq), tert-butyl N-ethyl-N-[2-ethyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (70.2 mg, 0.18

[1126] mmol, 1.1 eq), potassium carbonate (49.2 mg, 0.36 mmol, 2.2 eq) and dichloro[1,1'- bis-(diphenylphosphino)-ferrocen]palladium(ll) dichlormethan-complex (dppf) (13.2

[1127] mg, 0.02 mmol, 0.11 eq) were dissolved in 1,4-doxane (10 mL) and water (2 mL).

[1128] The bottle was sealed, evacuated and backfilled with Ar. The mixture stirred for 1h

[1129] at 100°C. The residue was evaporated to dryness, re-dissolved in DCM and washed

[1130] 20 with water and then with brine. The organic layer was dried with sodium sulphate,

[1131] filtered and evaporated to dryness. The residue was used for preparative chromatography. Product containing fractions were combined and diluted with

[1132] further water and then extracted with DCM. The organic layer was washed with

[1133] brine, dried with sodium sulphate, filtered and evaporated to dryness to result in

[1134] 66.0 mg (0.11 mmol, 69%) as a colorless oil with about 99% purity

[1135] tert-butyl N-ethyl-N-{3-ethyl-4'-[1 -hydroxy-1 -(1H-1, 2,3, 4-tetrazol-5-yl)propyl]-2'- methyl-[1,T-biphenyl]-4-yl}carbamate: tert-butyl N-ethyl-N-[3-ethyl-4'-(1-hydroxy-1- {1-[(4-methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl}propyl)-2'-methyl-[1,T- biphenyl]-4-yl]carbamate (34.0 mg, 0.06 mmol, 1.0 ) was dissolved in THF (10 mL),

[1136] 30 Pd / C (100 mg) were added and the solution was stirred at RT for 18 under H2 atmosphere. The catalyst was filtered off and the filtrate was evaporated to drynessForeignfiling text P25-116-SEC-WO01

[1137] 132

[1138] to yield in 42.0 mg (0.04 mmol, 75%) of a brownish residue with a purity of 48%,

[1139] which was used for the next step without further purification.

[1140] 1 -[3'-ethyl-4'-(ethylamino)-2-methyl-[1 , 1 '-bipheny l]-4-yl]- 1 -(1 H-1 ,2,3,4-tetrazol-5- yl)propan-1-ol: To a solution of tert-butyl N-ethyl-N-{3-ethyl-4'-[1-hydroxy-1-(1H- 1,2,3,4-tetrazol-5-yl)propyl]-2'-methyl-[1,1'-biphenyl]-4-yl}carbamate (42.0 mg, 0.04

[1141] 5

[1142] mmol, 1.0eq, 48% purity) in DCM (4 mL) was added trifluoroacetic acid (0.3 mL) and stirring was continued for 1h at RT. The mixture was further diluted with DCM and washed with water and brine. The organic layer was evaporated to dryness and the residue was used for preparative chromatography. The product containing fractions were combined and diluted with further water, then extracted with DCM. The organic layer was dried with sodium sulphate, filtered and evaporated to yield in 3.70 mg

[1143] (0.01 mmol, 24%) of a colorless solid.

[1144] In analogy the following intermediated were synthesized. Sometimes racemic

[1145] mixtures was synthesized and separated to the enantiomers at the last step:

[1146] 15

[1147] 20

[1148]

[1149] Synthesis of final derivatives, Phosphonates

[1150] Synthesis of (4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- methylphenyl)phosphonic acid

[1151]

[1152] Foreignfiling text P25-116-SEC-WO01

[1153] 133

[1154] Diethyl [4-(7-amino-2,3-dihydro-1-benzofuran-4-yl)-3-methylphenyl]phosphonate: According to GP 9 diethyl (4-bromo-3-methylphenyl)phosphonate (160 mg, 0.52 mmol, 1.0 eq), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1- benzofuran-7-amine (150 mg, 0.52 mmol, 1.0) and potassium carbonate (288 mg, 2.08 mmol, 4.0 eq) were dissolved in ACN / water (5 mL, 1:1). The suspension was 5

[1155] flushed with nitrogen and [1 ,1 '-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(ll) (65.2 mg, 0.10 mmol, 0.19 eq) was added and the mixture heated in a microwave at 120°C for 2 h. The reaction mixture was absorbed onto diatomaceous earth (Isolute HM-N) and purified by flash chromatography (silica gel, n-heptane / EtOAc, 0 - 100%). The product containing 10 vials were combined and evaporated to dryness to yield in diethyl [4-(7-amino-2,3- dihydro-1-benzofuran-4-yl)-3-methylphenyl]phosphonate (110 mg, 0.29 mmol, 56 %) of a yellow oil.

[1156] Diethyl (4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- methylphenyl)phosphonate: According to GP 1 diethyl [4-(7-amino-2,3-dihydro-1- benzofuran-4-yl)-3-methylphenyl]phosphonate (110 mg, 0.29 mmol, 1.0 eq), potassium iodide (9.60 mg, 0.06 mmol, 0.2 eq) and potassium carbonate (160 mg, 1.16 mmol, 4.0 eq) were dissolved in anhydrous DMF (2 mL). To this mixture 4- bromo-1 -butyne (109 mg, 1.45 mmol, 5.0 eq) was added and stirred at 100°C for 18 h. The reaction mixture was absorbed onto diatomaceous earth (Isolute HM-N) and 20 purified by flash chromatography (silica gel, n-heptane / EtOAc, 0-70%). The productcontaining vials were combined and evaporated to dryness to yield in diethyl (4-{7- [(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3-methylphenyl)phosphonate (65.0 mg, 0.10 mmol, 36%) as a yellow oil.

[1157] (4-{7-[(but-3-yn-1-yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3- methylphenyl)phosphonic acid: According to GP 12 diethyl (4-{7-[(but-3-yn-1- yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3-methylphenyl)phosphonate (65.0 mg, 0.10 mmol, 1.0 eq) was dissolved in anhydrous DMF (2 mL). Then bromotrimethylsilane (137 pL, 1.04 mmol, 1.0 eq) was added dropwise over a period of 2 min. The reaction mixture was stirred at RT for 18 h. The reaction mixture was 30 purified by prep. HPLC (C18, water / ACN, gradient). The product-containing vials were combined and the solvent evaporated to dryness. Diluted hydrochloric acid was added and the aqueous solution was lyophilized to yield in (4-{7-[(but-3-yn-1-Foreignfiling text P25-116-SEC-WO01

[1158] 134

[1159] yl)amino]-2,3-dihydro-1-benzofuran-4-yl}-3-methylphenyl)phosphonic acid (11.4 mg,

[1160] 0.03 mmol, 30%) of a brownish solid).

[1161] According to that procedure the following products were synthesized:

[1162] 5

[1163] 10

[1164]

[1165] Synthesis of diethyl {4-[7-(ethylamino)-2,3-dihydro-1-benzofuran-4-yl]-3- methylphenyljphosphonate

[1166]

[1167] According to GP 9 diethyl (4-bromo-3-methylphenyl)phosphonate (100 mg, 0.32

[1168] 20 mmol, 1.eq), N-ethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1- benzofuran-7-amine (116 mg, 0.39 mmol, 1.2 eq) and potassium carbonate (134

[1169] mg, 0.97 mmol, 3.0 eq) were suspended in 1,4-dioxane (4.50 mL) and deionized

[1170] water (0.50 mL). The suspension was flushed with nitrogen and XPhos Pd G3 (28.9

[1171] mg, 0.03 mmol, 0.1 eq) was added and heated in a microwave oven to 120°C for 2

[1172] h. The reaction mixture was filtered over celite. The filtrate was absorbed onto

[1173] diatomaceous earth (Isolute HM-N) and purified by flash chromatography (silica gel,

[1174] n-heptane / EtOAc, 0-100%). The product-containing vials were combined and

[1175] evaporated to dryness to yield in diethyl {4-[7-(ethylamino)-2,3-dihydro-1- benzofuran-4-yl]-3-methylphenyl}phosphonate (96.0 mg, 0.25 mmol, 76 %) of a

[1176] colorless oil.

[1177] 30 According to that procedure the following products were synthesized:Foreignfiling text P25-116-SEC-WO01

[1178] 135

[1179]

[1180] Under the phosphonate cleavage conditions also the BOC-protected Amins were deprotected to yield in the following products

[1181]

[1182] 15

[1183] Synthesis of final derivatives, Acylsulphonamides

[1184] Synthesis of N-[[4-[3-ethyl-4-(ethylamino)phenyl]-1 -naphthyl]sulphonyl]acetamide

[1185]

[1186] According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (116 mg,

[1187] 0.334 mmol, 1.0 eq), N,2-diethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (103 mg, 0.374 mmol, 1.1 eq) and triethylamine (50.0 pL, 0.40 mmol, 1.2

[1188] 30 eq) were suspended in 1,4-dioxane:water (1:1, 4 mL, 84 mM). To the reaction

[1189] mixture was added [1,T-Bis(di-tert-butylphosphino)ferrocene]dichlorpalladium(ll)

[1190] (17.0 mg, 20.0 pmol, 6 mol%) and stirred at 70 °C for 18 h. The mixture was purifiedForeignfiling text P25-116-SEC-WO01

[1191] 136

[1192] by silica chromatography (0-10% MeOH in DCM) to afford N-[[4-[3-ethyl-4- (ethylamino)phenyl]-1-naphthyl]sulphonyl]acetamide (23.8 mg, 17%) as a bright yellow solid.

[1193] Synthesis of N-[[4-[3-chloro-4-(ethylamino)phenyl]-1 -naphthyl]sulphonyl]acetamide 5

[1194]

[1195] According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (65.0 mg, 0.198 mmol, 1.0 eq), 2-chloro-N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (62.0 mg, 0.220 mmol, 1.1 eq) and cesium fluoride (60.2 mg, 0.396 mmol, 2.0 eq) were suspended in 1 ,4-dioxane:water (3:1, 4.0 mL, 0.1 M). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy- 1,1'biphenyl)palladium(ll) (6.00 mg, 9.90 pmol, 5 mol%) and stirred at 100 °C for 5 20 h. The mixture was purified by silica chromatography (0-10% MeOH in DCM) then reverse-phase chromatography (C18, 0-100% MeOH in water, 0.1% F.A.) to afford N-[[4-[3-chloro-4-(ethylamino)phenyl]-1-naphthyl]sulphonyl]acetamide (10.2 mg, 13%) as a white solid.

[1196] Synthesis of N-[[7-(4-ethoxy-3-ethyl-phenyl)-2-methyl-1 H-indol-4- yl]sulphonyl]acetamide

[1197] 30Foreignfiling text P25-116-SEC-WO01

[1198] 137

[1199]

[1200] 10 According to GP 9, N-[(7-bromo-2-methyl-1H-indol-4-yl)sulphonyl]acetamide (60.0 mg, 0.181 mmol, 1.0 eq), 2-(4-ethoxy-3-ethyl-phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (70.1 mg, 0.254 mmol, 1.4 eq) and triethylamine (50.0 pL, 0.36 mmol, 3.0 eq) were suspended in 1 ,4-dioxane:water (1:1, 4 mL, 45 mM). To the reaction mixture was added [1,T-Bis(di-tert-butylphosphino)ferrocene]dichlorpalladium(ll) (15.5 mg, 18.1 pmol, 10 mol%) and stirred at 70 °C for 18 h. The mixture was purified by reverse-phase chromatography (C18, 0-100% MeOH in water, 0.1% F.A.) to afford N-[[7-(4-ethoxy-3-ethyl-phenyl)-2-methyl-1H-indol-4- yl]sulphonyl]acetamide (3.00 mg, 4%) as a pale-yellow solid.

[1201] Synthesis of N-[[8-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-5- 20 quinolyl]sulphonyl]acetamide

[1202]

[1203] According to GP 9, N-[(8-bromo-5-quinolyl)sulphonyl]acetamide (82.8 mg,

[1204] 30

[1205] 0.204 mmol, 1.0 eq), N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)aniline (74.7 mg, 0.237 mmol, 1.2 eq) and cesium fluoride (92.3 mg, 0.60 mmol, 3.0 eq) were suspended in DMSO:water (2:1, 1 mL, 0.2 M). To theForeignfiling text P25-116-SEC-WO01

[1206] 138

[1207] reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy- 1,1'biphenyl)palladium(ll) (7.90 mg, 13.0 pmol, 6 mol%) and stirred at 70 °C for 18 h. The mixture was purified by HPLC (Agilent 6125 MS-Prep2, 10-00% MeOH in water, 0.1% F.A) to afford N-[[8-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-5- 5 quinolyl]sulfonyl]acetamide (66.1 mg, 70%) as a white solid.

[1208] Synthesis of N-[[4-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-1- naphthyl]sulphonyl]acetamide

[1209]

[1210] According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (34.3 mg, 61.7 pmol, 1.0 eq), N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)aniline (21.7 mg, 68.9 pmol, 1.0 eq) and triethylamine (10 pL, 20 62 pmol, 1.0 eq) were suspended in 1 ,4-dioxane:water (1:1, 4.0 mL, 15 mM). To the reaction mixture was added [1 ,1 ’-Bis(di-tert- butylphosphino)ferrocene]dichlorpalladium(ll) (3.9 mg, 4.5 pmol, 7 mol%) and stirred at 70 °C for 18 h. The mixture was purified by reverse-phase chromatography (C18, 0-100% MeOH in water, 0.1% F.A.) to afford as N-[[4-[4-(ethylamino)-3- (trifluoromethyl)phenyl]-1-naphthyl]sulfonyl]acetamide (7.1 mg, 26%) as a paleyellow solid.

[1211] Synthesis of N-[[4-(4-ethoxy-3-ethyl-phenyl)-1-naphthyl]sulphonyl]acetamide

[1212] 30Foreignfiling text P25-116-SEC-WO01

[1213] 139

[1214]

[1215] 10 According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (34.2 mg, 61.5 pmol, 1.0 eq), 4-ethoxy-3-ethylphenylboronic acid pinacol ester (17.6 mg, 63.7 pmol, 1.0 eq) and triethylamine (10 pL, 62 pmol, 1.0 eq) were suspended in

[1216] 1 ,4-dioxane:water (1:1, 4.0 mL, 15 mM). To the reaction mixture was added [1,1’- Bis(di-tert-butylphosphino)ferrocene]dichlorpalladium(ll) (4.30 mg, 5.00 pmol, 8 mol%) and stirred at 70 °C for 18 h. The mixture was purified by HPLC (Agilent 6125 MS-Prep2, 10-100% MeOH in water, 0.1% F.A) to afford N-[[4-(4-ethoxy-3-ethyl- phenyl)-1-naphthyl]sulphonyl]acetamide (6.2 mg, 24%) as a white solid.

[1217] Synthesis of N-[[7-[4-(ethylamino)-3-(trifluoromethyl)phenyl]-2-methyl-1 H-indol-4- yl]sulphonyl]acetamide

[1218]

[1219] According to GP 9, of N-[(7-bromo-2-methyl-1H-indol-4-yl)sulphonyl]acetamide (60.0 mg, 0.181 mmol, 1.0 eq), N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 30

[1220] yl)-2-(trifluoromethyl)aniline (79.9 mg, 0.254 mmol, 1.4 eq) and triethylamine (50.0 pL, 0.36 mmol, 2.0 eq) were suspended in 1 ,4-dioxane:water (1:1, 4.0 mL, 45 mM). To the reaction mixture was added [1 ,1 ’-Bis(di-tert-Foreignfiling text P25-116-SEC-WO01

[1221] 140 butylphosphino)ferrocene]dichlorpalladium(ll) (15.6 mg, 18.1 pmol, 10 mol%) and stirred at 70 °C for 18 h. The mixture was purified by reverse-phase chromatography (C18, 0-100% MeOH in water, 0.1% F.A.) to afford N-[[7-[4-(ethylamino)-3- (trifluoromethyl)phenyl]-2-methyl-1H-indol-4-yl]sulphonyl]acetamide (11.0 mg, 13%) as a white solid.

[1222] 5

[1223] Synthesis of N-[[7-[3-chloro-4-(2-fluoroethylamino)phenyl]-2-methyl-1 H-indol-4- yl]sulphonyl]acetamide

[1224]

[1225] According to GP 9, N-[(7-chloro-2-methyl-1H-indol-4-yl)sulphonyl]acetamide (26.0 mg, 64.4 pmol, 1.0 eq), 2-chloro-N-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (33.0 mg, 0.110 mmol, 1.7 eq) and cesium fluoride 20 (19.7 mg, 0.129 mmol, 2.0 eq) were suspended in 1 ,4-dioxane:water (2:1, 0.6 mL, 0.1 M). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'biphenyl)palladium(ll) (3.90 mg, 6.40 pmol, 10 mol%) and stirred at 100 °C for 18 h. The mixture was purified by silica column chromatography (0- 10% MeOH in DCM) then reverse-phase column chromatography (C18, 0-100% MeOH in water, 0.1% F.A) to afford N-[[7-[3-chloro-4-(2-fluoroethylamino)phenyl]-2- methyl-1H-indol-4-yl]sulphonyl]acetamide (3.2 mg, 12%) as a white solid.

[1226] The following analogs were synthesized according to GP 9:

[1227] 30Foreignfiling text P25-116-SEC-WO01

[1228] 141

[1229]

[1230] Synthesis of N-[[4-[3-chloro-4-(2-fluoroethylamino)phenyl]-1- naphthyl]sulphonyl]acetamide

[1231]

[1232] According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (131 mg, 20 0.40 mmol, 1.0 eq), 2-chloro-N-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (132 mg, 0.440 mmol, 1.1 eq) and cesium fluoride (91.1 mg, 0.60 mmol, 1.5 eq) were suspended in 1 ,4-dioxane:water (2:1, 9 mL, 44 mM). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'biphenyl)palladium(ll) (12.2 mg, 20.0 pmol, 5 mol%) and stirred at 130 °C for 2 h in a microwave reactor. The mixture was purified by silica column chromatography (0-100% EtOAc in cyclohexane) then HPLC (Agilent 6125 MS- Prep2, 10-100% MeOH in water, 0.1% F.A) to afford N-[[4-[3-chloro-4-(2- fluoroethylamino)phenyl]-1-naphthyl]sulphonyl]acetamide (9.0 mg, 5%) as a white solid.

[1233] 30

[1234] Synthesis of N-[[4-[4-(ethylamino)-3-methyl-phenyl]-1 -naphthyl]sulphonyl]acetamideForeignfiling text P25-116-SEC-WO01

[1235] 142

[1236]

[1237] 10 According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (42.7 mg,

[1238] 76.8 pmol, 1.1 eq), N-ethyl-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)aniline (21.6 mg, 67.8 pmol, 1.0 eq) and cesium fluoride (30.7 mg, 0.201 mmol, 3.0 eq) were suspended in 1 ,4-dioxane:water (2:1, 1.0 mL, 68 mM). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy- 1,1'biphenyl)palladium(ll) (3.60 mg, 5.90 pmol, 9 mol%) and stirred at 70 °C for 18 h. The reaction mixture was cooled to ambient temperature and excess palladium was scavenged out by addition of Si-TMT (98.0 mg, 29 pM) and agitated for 45 min. The reaction mixture was filtered through celite, concentrated in vacuo and purified by HPLC (Agilent 6125 MS-Prep2, 10-100% MeOH in water, 0.1% F.A) to afford N- [[4-[4-(ethylamino)-3-methyl-phenyl]-1-naphthyl]sulphonyl]acetamide (1.12 mg, 4%) 20 as a yellow solid.

[1239] Synthesis of N-[[4-[4-(2-cyanoethoxy)-3-methyl-phenyl]-1- naphthyl]sulphonyl]acetamide

[1240]

[1241] Foreignfiling text P25-116-SEC-WO01

[1242] 143

[1243] According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (33.7 mg, 0.103 mmol, 1.0 eq), 3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]propanenitrile (326 mg, 0.114 mmol, 1.1 eq) and cesium fluoride (44.6 mg, 0.292 mmol, 3.0 eq) were suspended in 1 ,4-dioxane:water (2:1, 1 mL, 0.1 M). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'- 5

[1244] dimethoxy-1,1'biphenyl)palladium(ll) (5.4 mg, 8.9 pmol, 1 mol%) and stirred at 70 °C for 18 h. The reaction mixture was cooled to ambient temperature and excess palladium was scavenged out by addition of Si-TMT (124 mg, 37.3 pM) and agitated for 45 min. The reaction mixture was filtered through celite, concentrated in vacuo and purified by HPLC (Agilent 6125 MS-Prep2, 10-100% MeOH in water, 0.1% F.A) to afford N-[[4-[4-(2-cyanoethoxy)-3-methyl-phenyl]-1 -naphthyl]sulphonyl]acetamide (4.40 mg, 10%) as a white solid.

[1245] Synthesis of N-[[4-[3-chloro-4-(2-cyanoethylamino)phenyl]-1- naphthyl]sulphonyl]acetamide

[1246]

[1247] . , . , ,,,,,- yl)anilino]propanenitrile (9.2 mg, 30 pmol, 1.0 eq) and cesium fluoride (10.2 mg, 66.7 pmol, 2.0 eq) were suspended in 1 ,4-dioxane:water (2:1, 1 mL, 30 mM). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy- 1,1'biphenyl)palladium(ll) (4.2 mg, 6.9 pmol, 1 mol%) and stirred at 50 °C for 18 h. The reaction mixture was cooled to ambient temperature and excess palladium was 30

[1248] scavenged out by addition of Si-TMT (134 mg, 40.0 pM) and agitated for 45 min. The reaction mixture was filtered through celite, concentrated in vacuo and purified by HPLC (Agilent 6125 MS-Prep2, 10-100% MeOH in water, 0.1% F.A) to afford asForeignfiling text P25-116-SEC-WO01

[1249] 144

[1250] N-[[4-[3-chloro-4-(2-cyanoethylamino)phenyl]-1-naphthyl]sulphonyl]acetamide (80 pg, 1%) as a white solid.

[1251] Synthesis of N-[[4-[4-(2-cyanoethoxy)-3-ethyl-phenyl]-1 -naphthyl]sulfonyl]acetamide

[1252]

[1253] yl)phenoxy]propanenitrile (22.0 mg, 54.8 pmol, 1.0 eq) and cesium fluoride (8.32 mg, 54.8 pmol, 1.0 eq) were suspended in 1 ,4-dioxane:water (5:1, 1.5 mL, 37 mM). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino- 2',6'-dimethoxy-1,1'biphenyl)palladium(ll) (1.70 mg, 2.7 pmol, 5 mol%) and stirred at 120 °C for 1 h in a microwave reactor. The reaction mixture was purified by reverse20

[1254] phase column chromatography (C18, 0-1-00% MeOH in water, 0.1% F.A.) to afford as N-[[4-[4-(2-cyanoethoxy)-3-ethyl-phenyl]-1-naphthyl]sulfonyl]acetamide (1.00 mg, 4%) as a white solid.

[1255] Synthesis of N-[[4-[4-(2-cyanoethoxy)-3-(trifluoromethyl)phenyl]-1- naphthyl]sulfonyl]acetamide

[1256] 30Foreignfiling text P25-116-SEC-WO01

[1257] 145

[1258]

[1259] 10

[1260] According to GP 9, N-[(4-bromo-1-naphthyl)sulphonyl]acetamide (8.13 mg, 24.8 pmol, 1.0 eq), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)phenoxy]propanenitrile (13.0 mg, 24.8 pmol, 1.0 eq) and cesium fluoride (3.76 mg, 24.8 pmol, 1.0 eq) were suspended in 1 ,4-dioxane:water (2:1, 0.75 mL, 33 mM). To the reaction mixture was added chloro(crotyl)(2- dicyclohexylphosphino-2',6'-dimethoxy-1,1'biphenyl)palladium(ll) (75.0 pg, 1.20 pmol, 5 mol%) and stirred at 120 °C for 1 h in a microwave reactor. The reaction mixture was purified by silica column chromatography (0-100% EtOAc in cyclohexane) then HPLC (Agilent 6125 MS-Prep2, 40-100% MeOH in water, 0.1% F.A) to afford as N-[[4-[4-(2-cyanoethoxy)-3-(trifluoromethyl)phenyl]-1- naphthyl]sulfonyl]acetamide (1.30 mg, 10%) as a white solid.

[1261] 20

[1262] The following analogs were synthesized according to GP7

[1263]

[1264] 30

[1265] Synthesis of N-({4-[3-ethyl-4-(ethylamino)phenyl]-8-fluoronaphthalen-1 - yl}sulphonyl)acetamideForeignfiling text P25-116-SEC-WO01

[1266] 146

[1267]

[1268] According to GP 9, to a solution of 4-(acetamidosulphonyl)-5-fluoronaphthalen-1-yl 10 trifluoromethanesulphonate (150 mg, 0.36 mmol) and N, 2-diethyl-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (119 mg, 0.43 mmol) Pd(amphos)2Cl2 (25.6 mg, 0.04 mmol) in dioxane (2 mL) and water (0.50 mL) was added K3PO4 (230 mg, 1.08 mmol) in small portions at RT under nitrogen atmosphere. The mixture was degassed for 15 min and stirred for 4 h at 80°C. The re-cooled mixture was extracted with ethyl acetate (20 mL*2), washed with brine (20 mL*2), dried over Na2SO4, filtered, evaporated to dryness and purified by silica gel column chromatography with MeOH / DCM (0-15%) to afford the desired product (14.0 mg, 0.03 mmol, 9%) as a colorless solid.

[1269] Synthesis of N-{4-[7-(ethylamino)-2,3-dihydro-1 -benzofuran-4-yl]-3- 20 (methylsulfanyl)benzenesulphonyl}acetamide

[1270]

[1271] According to GP 9, to a solution of N-[4-chloro-3- (methylsulfanyl)benzenesulphonyl]acetamide (115 mg, 0.40 mmol) in dioxane (3 30

[1272] mL) and water (0.30 mL) was added N-ethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-7-amine (135 mg, 0.44 mmol), Amphos-Pd (28.5 mg, 0.04 mmol) and K3PO4 (256 mg, 1.21 mmol) and the mixtureForeignfiling text P25-116-SEC-WO01

[1273] 147

[1274] was stirred for 6 h at 80°C. The mixture was filtered and purified by column chromatography to yield in the desired product (30.0 mg, 0.07 mmol, 18%) as a colorless solid.

[1275] The following analogs were synthesized following GP 9:

[1276] 5

[1277]

[1278] Synthesis of 4,7-dibromo-1 ,2-dimethyl-benzimidazole

[1279]

[1280] To a solution of 4,7-dibromo-2-methyl-1H-benzimidazole (593 mg, 2.04 mmol, 1.0 eq) in tetrahydrofuran (8 mL, 0.3 M) was added sodium hydride (60% in mineral oil, 161 mg, 4.03 mmol, 1.9 eq) and stirred at ambient temperature and under a 20 nitrogen atmosphere for 10 min. To the reaction mixture was then added iodomethane (0.15 mL, 2.453 mmol. 1.2 eq) and heated to 50 °C for 1 h. The mixture was cooled to ambient temperature and was quenched with water (25 mL) and extracted with ethyl acetate (3x25 mL). The combined organic phases were washed with brine (25 mL), dried over magnesium sulphate and concentrated in vacuo to afford 4, 7-dibromo-1 ,2-dimethyl-benzimidazole (579 mg, 93%) as a yellow solid. The product was carried forward into the next reaction without purification. Synthesis of 4-benzylsulfanyl-7-bromo-1 ,2-dimethyl-benzimidazole

[1281]

[1282] Foreignfiling text P25-116-SEC-WO01

[1283] 148

[1284] To a solution of 4,7-dibromo-1,2-dimethyl-benzimidazole (579 mg, 1.90 mmol, 1.0 eq) in 1,4-dioxane (15.0 mL, 0.10 M) was added triethylamine (1.04 mL, 7.61 mmol, 4.0 eq), phenylmethanethiol (0.89 mL, 7.6 mmol, 4.0 eq) and allyl[4,5- bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(ll) chloride (1.40 mg, 1.90 pmol, 1 mol%) and stirred at 100 °C under a nitrogen atmosphere for 18 h. The 5

[1285] mixture was cooled to ambient temperature, diluted with ethyl acetate (10 mL) and filtered through a pad of celite. The mixture was concentrated in vacuo and purified by silica column chromatography (0-100% EtOAc in cyclohexane) to afford 4- benzylsulfanyl-7-bromo-1,2-dimethyl-benzimidazole (472 mg, 53%) as a yellow oil.

[1286] Synthesis of 7-benzylsulfanyl-4-(4-ethoxy-3-ethyl-phenyl)-1 ,2-dimethyl- benzimidazole

[1287]

[1288] According to GP 9, 7-benzylsulfanyl-4-bromo-1,2-dimethyl-benzimidazole (71.3 mg, 0.21 mmol, 1.0 eq), 4-ethoxy-3-ethylphenylboronic acid pinacol ester (68.1 mg, 0.25 mmol, 1.2 eq) and cesium fluoride (58.9 mg, 0.385 mmol, 1.9 eq) were suspended in 1 ,4-dioxane:water (2:1, 2 mL, 0.1 M). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,Tbiphenyl)palladium(ll) (4.20 mg, 6.90 pmol, 7 mol%) and stirred at 70 °C for 3 days. The mixture was purified by reverse-phase column chromatography (C18, 0-100% MeOH in water, 0.1% F.A) to afford as 7-benzylsulfanyl-4-(4-ethoxy-3-ethyl-phenyl)-1,2-dimethyl- benzimidazole (21.2 mg, 22%) as a pale yellow solid.

[1289] 30

[1290] Synthesis of 7-(4-ethoxy-3-ethyl-phenyl)-2,3-dimethyl-benzimidazole-4- sulphonamideForeignfiling text P25-116-SEC-WO01

[1291] 149

[1292]

[1293] To a solution 7-benzylsulfanyl-4-(4-ethoxy-3-ethyl-phenyl)-1,2-dimethyl- benzimidazole (21.2 mg, 45.8 pmol, 1.0 eq) in anhydrous tetrahydrofuran (5.0 mL, 10

[1294] 0.1 M) was added aq. hydrogen chloride (32%, 0.10 mL, 1.0 mmol, 22 eq) and then 1,3-dichloro-5,5-dimethylhydantoin (24.1 mg, 0.122 mmol, 2.7 eq) and stirred at ambient temperature under a nitrogen atmosphere for 18 h. The mixture was quenched by addition of sat. aq. sodium hydrogen carbonate solution (5 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to afford the sulphonyl chloride intermediate as a brown solid.

[1295] The sulphonyl chloride was resuspended in a solution of ammonia in MeOH (7.0 M, 2.0 mL) and stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo and purified by silica column chromatography (0-20% MeOH in DCM) to 20

[1296] afford 7-(4-ethoxy-3-ethyl-phenyl)-2,3-dimethyl-benzimidazole-4-sulphonamide (6.30 mg, 30%) as a pale-brown solid.

[1297] #Synthesis of N-[7-(4-ethoxy-3-ethyl-phenyl)-2,3-dimethyl-benzimidazol-4- yl]sulphonylacetamide

[1298]

[1299] According to GP 15, 7-(4-ethoxy-3-ethyl-phenyl)-2,3-dimethyl-benzimidazole-4- sulphonamide (6.30 mg, 16.9 pmol, 1.0 eq), triethylamine (8.0 pL, 60 pmol, 3.5 eq)Foreignfiling text P25-116-SEC-WO01

[1300] 150

[1301] and acetyl chloride (4.0 pL, 60 pmol, 3.5 eq) were stirred in DCM (2.0 mL, 10 mM) at ambient temperature for 18 h. The reaction mixture was purified by silica chromatography (0-20% MeOH in DCM) then HPLC (Agilent 6125 MS-Prep2, 10-100% MeOH in water, 0.1% F.A) to afford N-[7-(4-ethoxy-3-ethyl-phenyl)-2,3- dimethyl-benzimidazol-4-yl]sulphonylacetamide (4.69 mg, 64%) as a white solid.

[1302] 5

[1303] The following analog was synthesized according to GP 9:

[1304]

[1305] ,8-dibromo-2,3-dimethyl-quinoxaline

[1306]

[1307] 20

[1308] To a solution of 3,6-dibromobenzene-1,2-diamine (593 mg, 2.23 mmol, 1.0 eq) and triethylamine (610 uL, 4.47 mmol, 2 eq) in dry ethanol (8.00 mL, 0.3 M) was added 2,3-butanedione (196 uL, 2.23 mmol, 1.0 eq). The reaction mixture was stirred at ambient temperature for 24 h. The reaction mixture was concentrated in vacuo and purified by silica column chromatography (0-100% EtOAc in cyclohexane) to afford 5,8-dibromo-2,3-dimethyl-quinoxaline (452 mg, 64%) as a pale-yellow solid. Synthesis of 5-benzylsulfanyl-8-bromo-2,3-dimethyl-quinoxaline

[1309]

[1310] Foreignfiling text P25-116-SEC-WO01

[1311] 151

[1312] To a solution of 5,8-dibromo-2,3-dimethyl-quinoxaline (453 mg, 1.43 mmol, 1.0 eq) in 1,4-dioxane (15.0 mL, 0.10 M) was added triethylamine (590 uL, 4.33 mmol, 3.0 eq), phenylmethanethiol (0.25 mL, 2.2 mmol, 1.5 eq) and allyl[4,5- bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(ll) chloride (276 mg, 0.362 mmol, 26 mol%) and stirred at 100 °C under a nitrogen atmosphere for 18 h.

[1313] 5

[1314] The mixture was cooled to ambient temperature, diluted with ethyl acetate (10 mL) and filtered through a pad of celite. The mixture was concentrated in vacuo and purified by silica column chromatography (0100% EtOAc in cyclohexane) to afford 5- benzylsulfanyl-8-bromo-2,3-dimethyl-quinoxaline (140 mg, 19%) as a brown solid.

[1315] 10 Synthesis of 8-bromo-2,3-dimethyl-quinoxaline-5-sulphonamide

[1316]

[1317] To a solution of 5-benzylsulfanyl-8-bromo-2,3-dimethyl-quinoxaline (140 mg, 0.39 mmol, 1.0 eq) in anhydrous tetrahydrofuran (5.0 mL, 0.1 M) was added aq. hydrogen chloride (32%, 54 uL, 0.47 mmol, 1.2 eq) and 1,3-dichloro-5,5- dimethylhydantoin (173 mg, 0.880 mmol, 2.3 eq) and stirred at ambient temperature 20 under a nitrogen atmosphere for 2 h. The mixture was quenched by addition of sat.

[1318] aq. sodium hydrogen carbonate solution (25 mL) and extracted ethyl acetate (3x25 mL). The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to afford the sulphonyl chloride intermediate as a brown solid.

[1319] The sulphonyl chloride was resuspended in a solution of ammonia in MeOH (7.0 M, 2.5 mL) and stirred at ambient temperature for 18 h. The mixture was concentrated in vacuo and purified by reverse-phase column chromatography (C18, 0-100% MeOH in water, 0.1% F.A) to afford 8-bromo-2,3-dimethyl-quinoxaline-5- sulphonamide (23.0 mg, 18%) as an off-white solid.

[1320] Synthesis of N-(8-bromo-2,3-dimethyl-quinoxalin-5-yl)sulphonylacetamide

[1321] 30Foreignfiling text P25-116-SEC-WO01

[1322] 152

[1323] 5

[1324]

[1325] According to GP 15, 8-bromo-2,3-dimethyl-quinoxaline-5-sulphonamide (23.0 mg, 72.0 pmol, 1.0 eq), triethylamine (90.0 uL, 0.66 mmol, 9.0 eq) and acetyl chloride (48.0 uL, 0.67 mmol, 9.0 eq) were stirred in DMF (2 mL, 40 mM) for 18 h. The reaction mixture was purified by reverse-phase chromatography (C18, 0-100% MeOH in water, 0.1% F.A.) to afford N-(8-bromo-2,3-dimethyl-quinoxalin-5- yl)sulphonylacetamide (28.0 mg, 89%) as a white solid.

[1326] Synthesis of N-[8-(4-ethoxy-3-ethyl-phenyl)-2,3-dimethyl-quinoxalin-5-

[1327]

[1328]

[1329] According to GP 9, N-(8-bromo-2,3-dimethyl-quinoxalin-5-yl)sulphonylacetamide (28.1 mg, 54.1 pmol, 1.0 eq), 4-Ethoxy-3-ethylphenylboronic acid pinacol ester (15.1 mg, 54.7 pmol, 1.0 eq) and cesium fluoride (19 mg, 0.12 mmol, 2.0 eq) were suspended in 1,4-dioxane:water (2:1, 1.0 mL, 54 mM). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy- 1,1'biphenyl)palladium(ll) (2.00 mg, 3.30 pmol, 6 mol%) and stirred at 75 °C for 18 h. The mixture was purified by then reverse-phase column chromatography (C18, 0-100% MeOH in water, 0.1% F.A) to afford as N-[8-(4-ethoxy-3-ethyl-phenyl)-2,3- 30

[1330] dimethyl-quinoxalin-5-yl]sulphonylacetamide (500 pg, 2%) as a pale yellow solid.

[1331] Synthesis of 4-bromo-7-chloro-1-methyl-benzimidazoleForeignfiling text P25-116-SEC-WO01

[1332] 153

[1333]

[1334] 5 To a solution of 4-bromo-7-chloro-1 H-benzimidazole (1.00 g, 4.32 mmol, 1.0 eq) in tetrahydrofuran (10 mL, 0.40 M) at 0 °C and under a nitrogen atmosphere was added sodium hydride (60% in mineral oil, 207.3 mg, 5.184 mmol, 1.2 eq) and stirred for 30 min. To the reaction mixture was then added iodomethane (70.0 pL, 1.08 mmol. 1.0 eq) and the suspension was warmed to ambient temperature over 3 h. The reaction mixture was quenched with water (25 mL) and extracted with ethyl 10

[1335] acetate (3x25 mL). The combined organic phases were washed with brine (25 mL), dried over magnesium sulphate and concentrated in vacuo to afford 4-bromo-7- chloro-1-methyl-benzimidazole (1.10 g, quant.) as a mixture of regioisomers (1.6:1). The product mixture was carried forward into the next reaction without purification. Synthesis of 4-benzylsulfanyl-7-chloro-1 -methyl-benzimidazole

[1336]

[1337] To a solution of 4-bromo-7-chloro-1 -methyl-benzimidazole ( 502.0 mg, 2.045 mmol, 1.0 eq) in 1,4-dioxane (5 mL, 0.40 M) was added N,N-Diisopropylethylamine (0.72 mL, 4.1 mmol, 2.0 eq), phenylmethanethiol (0.26 mL, 2.2493 mmol, 4.0 eq) and allyl[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(ll) chloride (155.9 mg, 0.2045 mmol, 10 mol%) and stirred at 100 °C under a nitrogen atmosphere for 3 h. The mixture was cooled to ambient temperature and excess palladium was scavenged out by addition of Si-TMT (1.5 g, 0.13 mmol) and agitated for 2 h. The reaction mixture was filtered through celite, concentrated in vacuo and purified by silica column chromatography (0-60% EtOAc in cyclohexane) to afford 4- benzylsulfanyl-7-chloro-1-methyl-benzimidazole (142 mg, 18%) as a mixture of 30 regioisomers (1.6:1).

[1338] Synthesis of 7-chloro-3-methyl-benzimidazole-4-sulfonamideForeignfiling text P25-116-SEC-WO01

[1339] 154

[1340]

[1341] To a solution 4-benzylsulfanyl-7-chloro-1-methyl-benzimidazole ( 294.0 mg, 1.018 mmol, 1.0 eq) in anhydrous tetrahydrofuran (1.0 mL, 0.2 M) and at 0 °C was added aq. hydrogen chloride (32%, 0.12 mL, 1.2 mmol, 1.2 eq) and then 1,3-dichloro-5,5- dimethylhydantoin (401.1 mg, 2.036 mmol, 2.0 eq) and stirred at 0 °C under a 10

[1342] nitrogen atmosphere for 1 h. The mixture was quenched by addition of sat. aq. sodium hydrogen carbonate solution (5 mL), warmed to ambient temperature and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (5 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to afford the sulphonyl chloride intermediate as a mixture of regioisomers (1.6:1.0).

[1343] The sulphonyl chloride was resuspended in a solution of ammonia in MeOH (7.0 M, 13.0 mL) and stirred at ambient temperature for 1.5 h. The mixture was quenched by addition of water (5 mL), warmed to ambient temperature and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (5 mL), 20

[1344] dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (0-1-0% MeOH in DCM) resulting in successful separation of the regioisomers to afford the desired product 7-chloro-3- methyl-benzimidazole-4-sulfonamide (53 mg, 21%) and the undesired regioisomer 7-chloro-1-methyl-benzimidazole-4-sulfonamide (45 mg, 18%).

[1345] Synthesis of N-(7-chloro-3-methyl-benzimidazol-4-yl)sulfonylacetamide

[1346]

[1347] Foreignfiling text P25-116-SEC-WO01

[1348] 155

[1349] To a solution of 7-chloro-3-methyl-benzimidazole-4-sulfonamide (196 mg, 0.798 mmol, 1.0 eq), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (252.7 mg, 1.596 mmol, 2.0 eq) and 4-dimethylaminopyridine (292.4 mg, 2.393 mmol, 3.0 eq) in dichloromethane (3.0 mL, 0.3 M) was added acetic acid (50 pL, 0.96 mmol, 1.2 eq). The reaction mixture was stirred at ambient temperature for 18 h, concentrated in 5

[1350] vacuo and then purified by reverse-phase column chromatography (C18, 0-100% MeOH in water, 0.1% F.A) to afford N-(7-chloro-3-methyl-benzimidazol-4- yl)sulfonylacetamide (48 mg, 21%) as a white solid.

[1351] Synthesis of N-[7-(4-ethoxy-3-ethyl-phenyl)-3-methyl-benzimidazol-4-

[1352]

[1353] 20 According to GP 9, N-(7-chloro-3-methyl-benzimidazol-4-yl)sulfonylacetamide (46.0 mg, 0.160 mmol, 1.0 eq), 4-ethoxy-3-ethylphenylboronic acid pinacol ester (48.57 mg, 0.1759 mmol, 1.1 eq) and cesium fluoride (48.89 mg, 0.3198 mmol, 2.0 eq) were suspended in 1,4-dioxane:water (1.4:1.0, 1.2 mL, 0.1 M). To the reaction mixture was added chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'- biphenyl)palladium(ll) (4.9 mg, 8.0 pmol, 5 mol%) and stirred at 100 °C for 18 h. The mixture was cooled to ambient temperature and excess palladium was scavenged out by addition of Si-TMT (80 mg, 24 pmol) and agitated for 1 h. The reaction mixture was filtered through celite, concentrated in vacuo and purified by silica column chromatography (0-5% MeOH in DCM) and then reverse-phase column chromatography (C18, 0-100% MeOH in water, 0.1% F.A.) to afford N-[7-(4-ethoxy- 30 3-ethyl-phenyl)-3-methyl-benzimidazol-4-yl]sulfonylacetamide (10.5 mg, 216%) as a pale yellow solid.Foreignfiling text P25-116-SEC-WO01

[1354] 156

[1355] Example 3 - ATPase and splicing assay

[1356] 5 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 when DHX8 processes an RNA oligo. Inhibiting compounds can compete with this. A commercial luminescence-based ADP-GLO kit is applied.

[1357] 10 Assay procedure: Compounds are serial diluted from 10mM to 320 nM (final start concentration in assay of DRC 37 pM) in DMSO.

[1358] - 2 pl DHX8 / RNA work solution is plated into the wells

[1359] - 15 nl compound solution is added

[1360] - 20 min incubation at RT

[1361] - 2 pl ATP work solution is added

[1362] - 120 min incubation at RT

[1363] - 4 pl ADP-GLO reagent (kit) is added

[1364] - 40 min incubation at RT

[1365] - 8 pl kinase detection reagent (kit) is added

[1366] - 40 min incubation at RT

[1367] 20

[1368] Readout: Read luminescence with Envision Plate Reader.

[1369] 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).

[1370] Final concentrations in the assay

[1371] 50 mM HEPES pH 7.4, 1 mM MgCI2, 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

[1372] Splicing assay ROP9674 is intended to characterize compounds that influence 30 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 mRNA is spliced into the two different splice isoform transcripts MCL1-L or MCL1-S,Foreignfiling text P25-116-SEC-WO01

[1373] 157

[1374] 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 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 5

[1375] mRNA transcripts.

[1376] Assay Procedure:

[1377] Day 1: Cell Seeding:

[1378] • Seed cells 25 pl cell suspension at a final concentration of 2500 cells / well into a 10 384-well plate and incubate at 37°C with 5% CO2 overnight.

[1379] Day 2: Incubation with Compounds and qPCR Assay:

[1380] • Compounds are serial diluted from 10 mM to 320 nM (final start concentration in assay of DRC 30 pM) in DMSO.

[1381] • Dispense 75 nl of compound (or DMSO) using Echo555, incubate for 4 hours at 37°C with 5% CO2.

[1382] • Remove medium and wash with ice-cold PBS. Remove PBS again.

[1383] • Thaw lysis buffer from Cells-to-cDNAII Kit, add 12.5 pl / well, mix, and transfer 8pl to a PCR plate.

[1384] • Seal the plate and incubate at 75°C for 15 minutes, then hold at 10°C.

[1385] 20

[1386] One-Step qPCR Assay:

[1387] • Prepare the TaqPath™ 1-Step RT-qPCR Master Mix.

[1388] • Transfer 98pl of nuclease-free water to a fresh 384-well plate and add 2 pl of lysate.

[1389] • Transfer 4 pl diluted lysate from Greiner 384 well plate to Endura optical 384 qPCR plate.

[1390] • Prepare master mix (TaqPath™ 1-Step RT-qPCR Kit) and transfer 6pl to each well, seal the plate, and mix.

[1391] • Spin the plate to eliminate air bubbles and analyze using the Viia7 device. • Run measurement of biological duplicates and technical replicates.

[1392] 30

[1393] Readout: qPCR analysis device Viia7 (life technologies) + QuantStudio softwareViia7 qPCR.Foreignfiling text P25-116-SEC-WO01

[1394] 158

[1395] Final value is the calculated ratio (RQ vic,MCL1s / RQ fam,MCL1l).

[1396] The table below illustrates the Helicase activity of the described entities, represented by IC50 values, which effectively translate into their activity in splicing, demonstrated 5

[1397] by EC50 values. These properties make these compounds suitable for treating the specified diseases.

[1398] Table 3: Biochemical and cellular potencies

[1399] 10

[1400] 20

[1401] 30

[1402]

[1403] Foreignfiling text P25-116-SEC-WO01

[1404] 159

[1405] 5

[1406] 15

[1407] 20

[1408] 30

[1409]

[1410] Foreignfiling text P25-116-SEC-WO01

[1411] 160

[1412] 5

[1413]

[1414] Example 4 - CellTiter-Glo® Luminescent Cell Viability Assay

[1415] 10

[1416] 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.

[1417] 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 DM EM 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 20

[1418] 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.

[1419] Data analysis involved normalizing the raw luminescence data to the average control values obtained from 0.3% DMSO. Subsequently, the IC50 value was 30

[1420] determined from the DMSO control-normalized relative data using a 4-parameter logistic nonlinear regression model implemented in GraphPad Prism.Foreignfiling text P25-116-SEC-WO01

[1421] 161

[1422] In the following table the activity of the described entities is shown for their effect on viability as IC50 values in HCT116 cells as indicators for treatment of the claimed diseases.

[1423] The obtained good biochemical and cellular splicing inhibition translated also nicely 5

[1424] into the cell viability in human HCT116 cells.

[1425] 15

[1426]

[1427] 20

[1428] 30

Claims

Foreignfiling text P25-116-SEC-WO01162Claims1. Compound of the general formula I,5R1 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,30Z is O, N or C=O,R8 is F,Foreignfiling text P25-116-SEC-WO01163R9 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 OCF3and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

52. Compound according claim 1, whereinR2 is methyl, ethyl isopropyl, cyclopropyl, cyclobutyl, tertbutyl, OCH3, SCH3, CH2OCH3, CH2CHCH3OCH3or (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 according claim 1 or 2, wherein Z is C=O, then R8 and R9 form a cyclopropyl, and R1, R2, R3, R4, R5, R6, R7, B and R10 are as defined above and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

4. Compound selected from the group consisting of:Foreignfiling_text P25-116-SEC-WO01164Foreignfiling_text P25-116-SEC-WO01165Foreignfiling_text P25-116-SEC-WO01166Foreignfiling_text P25-116-SEC-WO01167Foreignfiling text P25-116-SEC-WO01168530Foreignfiling_text P25-116-SEC-WO01169Foreignfiling_text P25-116-SEC-WO01170Foreignfiling text P25-116-SEC-WO011715and physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.

5. Process for the preparation of a compound according to one or more of claims 1 to 4 and / 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.

6. Pharmaceutical preparation comprising at least one compound according to one or more of claims 1 to 4 and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios.30 7. Pharmaceutical preparation according to claim 6 comprising further excipients and / or adjuvants.Foreignfiling text P25-116-SEC-WO011728. Pharmaceutical preparation comprising comprising at least one compound according to one or more of claims 1 to 4 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.

59. Process for the preparation of a pharmaceutical preparation, characterised in that at least one compound according to one or more of claims 1 to 4 and / or one of its physiologically acceptable salts, derivatives, solvates, prodrugs 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.

10. Medicament comprising comprising at least one compound according to one or more of claims 1 to 4 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.

11. Medicament for use according to claim 10, 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 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 inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), vascular hyperproliferation secondary to retinal hypoxia and vasculitis.3012. Medicament for use according to claim 10, wherein the physiological and / or pathophysiological state is cancer.Foreignfiling text P25-116-SEC-WO0117313. Medicament for use according to claim 12, 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 5granulocytic 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.

14. Set (kit) consisting of separate packs ofa) an effective amount of at least one compound according to one or more of claims 1 to 4 and / or physiologically acceptable salts, derivatives, solvates, prodrugs and stereoisomers thereof, including mixtures thereof in all ratios, andb) an effective amount of a further medicament active compound.30

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