Substituted bicyclic compounds

Abstract

The present invention relates to heterocyclic compound. These heterocyclic compounds are useful as TEAD binders and / or inhibitors of YAP-TEAD and TAZ-TEAD protein-protein interaction or binding and for the prevention and / or treatment of cancer and other severe disorders and diseases.

Description

[0001] Foreignfiling_text_P25-005-SEC-WO01

[0002] 1

[0003] Substituted bicyclic compounds

[0004] Field of the invention

[0005] The present invention relates to bicyclic compound. These bicyclic compounds are useful as TEAD binders and / or inhibitors of YAP-TEAD and 5 TAZ-TEAD protein-protein interaction or binding and for the prevention and / or treatment of cancer and other severe disorders and diseases.

[0006] Background of the invention

[0007] In recent years the Hippo pathway has become a target of interest for the 10 treatment of hyperproliferative disorders and diseases, in particular cancer (S. A. Smith et al., J. Med. Chem. 2019, 62, 1291-1305; K. C. Lin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. Kim et al., Cells (2019), 8, 468; K. F. Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)). The Hippo pathway regulates cell growth, proliferation, and migration. It is assumed that in mammals the Hippo pathway acts as a tumor suppressor, and dysfunction of Hippo signaling is frequently observed in human cancers.

[0008] Furthermore, as the Hippo pathway plays a role in several biological processes - like in self-renewal and differentiation of stem cells and 20 progenitor cells, wound healing and tissue regeneration, interaction with other signaling pathways such as Wnt - its dysfunction may also play a role in human diseases other than cancer (C.-L. Kim et al., Cells (2019), 8, 468; Y. Xiao et al., Genes & Development (2019) 33: 1491-1505; K. F. Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)).

[0009] While several aspects of the pathway activity and regulation are still subject to further research, it is already established that in its “switched-on”-state the Hippo pathway involves a cascade of kinases (including Mst 1 / 2 and Lats 1 / 2) in the cytoplasm which results in the phosphorylation of two transcriptional 30 co-activators, YAP (Yes-associated protein) and TAZ (Transcription coactivator with PDZ binding motif). Phosphorylation of YAP / TAZ leads to their sequestration in the cytoplasm and eventually to their degradation. InForeignfiling_text_P25-005-SEC-WO01

[0010] 2

[0011] contrast, when the Hippo pathway is “switched-off” or dysfunctions, the nonphosphorylated, activated YAP / TAZ co-activators are translocated into the cell nucleus. Their major target transcription factors are the four proteins of the Transcriptional enhanced associate domain (TEAD) transcription factor 5 family (TEAD1 -4). Binding of YAP or TAZ to and activation of TEAD (or other transcription factors) have shown to induce the expression of several genes many of which mediate cell survival and proliferation. Thus, activated, nonphosphorylated YAP and TAZ may act as oncogenes, while the activated, switched-on Hippo pathway may act as a tumor suppressor by deactivating, i.e. phosphorylating YAP and TAZ.

[0012] Furthermore, the Hippo pathway may also play a role in resistance mechanisms of cancer cells to oncology and immune-oncology therapy (R. Reggiani et al., BBA - Reviews on Cancer 1873 (2020) 188341, 1-11).

[0013] 15

[0014] Recently, small molecule inhibtors have been described as pan-TEAD inhibitors, i.e., as compounds which bind not only to one of the TEAD family members but to more than one and in particular to all four human TEAD paralogs and thereby block YAP / TAZ binding (T. J. Hagenbeek, et al., Nature 20 Cancer, 4, 812-828 (2023); WO 2021 / 108483 A1).

[0015] Consequently, the dysfunction or aberrant regulation of the Hippo pathway as a tumor suppressor is believed to be an important event in the development of a wide variety of cancer types and diseases.

[0016] Therefore, inhibition of YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD protein-protein interaction by pharmacological intervention appears to be a reasonable and valuable strategy to prevent and / or treat cancer and other hyperproliferative disorders and diseases associated with the dysfunction of 30 the Hippo pathway. It may further be useful to inhibit the binding not only to one family member of TEAD, but even to two, three and / or all four TEAD paralogs.Foreignfiling_text_P25-005-SEC-WO01

[0017] Description of the invention

[0018] The present invention provides compounds that may be useful in the prevention and / or treatment of medical conditions, disorders and / or diseases, 5 in particular of hyperproliferative disorders or diseases, which compounds are TEAD binders and / or inhibitors of YAP-TEAD or TAZ-TEAD proteinprotein interaction. Some of the compounds of the present invention may be useful for making other compounds of the present invention.

[0019] The present invention refers in one embodiment to a heteroaromatic compound of formula I

[0020] A

[0021]

[0022] wherein

[0023] X1denotes N or CRX1;

[0024] RX1denotes H, halogen, straight-chain or branched Ci-4-alkyl, which is unsubstituted or substituted with independently from each other 1, 2, or 3 halogen, and / or OH;

[0025] R1denotes halogen, -NH2, -CN, straight-chain or branched Ci -4-alkyl, which is unsubstituted or substituted with independently from each other 1, 2, or 3 halogen;

[0026] R2denotes H, Aik2, Ar2, Hetar2, Cyc2, Hetcyc2, -L2-Ar2a, -S(=O)2Rf; R3denotes H, -CN, -C(=O)-NH2 or halogen;

[0027] A denotesForeignfiling_text_P25-005-SEC-WO01

[0028] 4

[0029]

[0030] or

[0031] 5

[0032] A-1 A-2,

[0033] A-1 and A-2 bear the bicyclic ring system of the compound of formula I

[0034]

[0035] in 1-positon and that L1-B radical of the compound of formula I in 3-position relative to that bicyclic ring system B denotes Ar1, Hetar1, Cyc1, Hetcyc1;

[0036] 15

[0037] L1denotes -O-, -S-, -N(R4)-, -O-CH2-, -O-CH(R5)-, -O-SO2-, -N(R6)-CH2- - N(R6)-C(=O)-, -CH2-, -CH(R7)-, -CH2CH2-, -CH2-O-;

[0038] R4denotes H, straight-chain or branched Ci-6-alkyl;

[0039] R5, R6, R7denote independently from each other straight-chain or branched C1-6-alkyl;

[0040] 20

[0041] L2denotes a divalent -S(=O)2- group;

[0042] Aik2denotes straight-chain or branched Ci-6-alkyl, C2-6-alkenyl or C2-6- alkinyl, each of which may be unsubstituted or substituted with independently from each other R2a1, R2a2and / or R2a3;

[0043] Ar1denotes a mono- or bicyclic aryl with 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein that aryl is substituted with independently from each other RC1, RC2, and / or RC3;

[0044] Ar®, Ar2, Ar2adenote independently from each other a mono- or bicyclic aryl with 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with independently from each other RB1, RB2, 30

[0045] RB3, RB4, and / or RB5;

[0046] Hetar1denotes a mono- or bicyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is / are a hetero atom(s)Foreignfiling_text_P25-005-SEC-WO01

[0047] 5

[0048] selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is substituted with independently from each other RC1, RC2, and / or RC3;

[0049] Hetara, Hetar2, Hetar2adenote independently from each other a mono- or 5 bicyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2,

[0050] 3, 4, 5 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is unsubstituted or substituted with independently from each other RB1, RB2, RB3, RB4, and / or RB5;

[0051] Cyc1denotes a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein said carbocycle may be un-substituted or substituted with independently from each other RC6, RC7, RC8, RC9, RC1°, and / or RC11; Cyca, Cyc2, Cyc2adenote independently from each other a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein said carbocycle is unsubstituted or substituted with independently from each other RB6, RB7, RB8, RB9, RB1°, and / or RB11;

[0052] Hetcyc1denotes a saturated or partially unsaturated, mono- or bicylic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is / are a hetero atom(s) selected from N, O and / or S and the remaining are carbon atoms, wherein said heterocycle is substituted with independently from each other RC6, RC7, RC8, RC9, RC1°, and / or RC11;

[0053] Hetcyca, Hetcyc2, Hetcyc2adenote independently from each other a saturated or partially unsaturated, mono- or bicylic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is / are a hetero atom(s) selected from N, O and / or S and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or 30 substituted with independently from each other RB6, RB7, RB8, RB9, RB1°, and / or RB11;Foreignfiling_text_P25-005-SEC-WO01

[0054] 6

[0055] R2a1, R2a2, R2a3denote independently from each other halogen, -CF3, - CN, -NH2, -NHRa, -NRaRb, -OH, -ORC, -P(=O)RdRe, -SH, -SRf, -S(=O)Rf, -S(=O)2Rf, -S(=O)(=NRg)Rf, -N=S(=O)RfRh, -C(=O)NH2, -C(=O)NHRa, - C(=O)NRaRb, -C(=O)OH, -C(=O)ORC, -NH-C(=O)-Ri, Ar2a, Cyc2a, 5 Hetar2a, Hetcyc2a;

[0056] and / or

[0057] two of R2a1, R2a2, R2a3which are attached to the same carbon atom form together a divalent oxo (=0) group;

[0058] Ra, Rbdenote independently from each other straight-chain or branched C1- 6-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 halogen; Ara, Cyca, Hetara, Hetcyca;

[0059] or

[0060] Raand Rbform together with the nitrogen atom to which they are attached to a saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, 0 or S and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or substituted with independently from each other RB6, RB7, RB8, RB9, RB1°, and / or RB11;

[0061] Rcdenotes straight-chain or branched Ci -4-alkyl, C2-4-alkenyl or C2-4-alkinyl, each of which may be unsubstituted or substituted with -OH; C3-7- cycloalkyl which may be unsubstituted or substituted with -OH and / or halogen;

[0062] Rd, Redenote independently from each other straight-chain or branched C1- 6-alkyl;

[0063] Rf, Rhdenote independently from each other straight-chain or branched C1- 6-alkyl;

[0064] Rgdenotes H, straight-chain or branched Ci-6-alkyl;

[0065] R' denotes H, straight-chain or branched Ci-6-alkyl;

[0066] 30 RA1denotes straight-chain or branched Ci-4-alkyl, which is unsubstituted or substituted with independently from each other 1, 2, or 3 halogen;

[0067] RA2denotes straight-chain or branched Ci-4-alkyl;Foreignfiling_text_P25-005-SEC-WO01

[0068] 7

[0069] RA3denotes halogen;

[0070] RB1, RB2, RB3, RB4, RB5denote independently from each other halogen; - OH; -OCi-4-alkyl; Ci-4-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 halogen;

[0071] 5 RB6, RB7, RB8, RB9, RB1°, RB11denote independently from each other halogen; OH; -OCi-4-alkyl; Ci-4-alkyl, which is unsubstituted or substituted with 1 or 2 OH and / or 1, 2, or 3 halogen;

[0072] and / or

[0073] two of RB6, RB7, RB8, RB9, RB1°, RB11which are attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=0) group;

[0074] and / or

[0075] two of RB6, RB7, RB8, RB9, RB1°, RB11which are attached to the same sulfur (S) atom of said heterocycle form a divalent oxo (=0) group while at the same time two further of RB6, RB7, RB8, RB9, RB1°, RB11which are attached to the same sulfur atom form either a divalent oxo group or a divalent =N-H or =N-Ci-4-alkyl group, thereby forming an -S(=O)2, - S(=O)(=NH), or -S(=O)(=N-Ci-4-alkyl) moiety;

[0076] RC1, RC2, RC3denote independently from each other halogen; Ci-4-alkyl, - SCi-4-alkyl or -OCi-4-alkyl, each of which may be unsubstituted or substituted with 1, 2, or 3 halogen;

[0077] RC6, RC7, RC8, RC9, RC10, and / or RC11denote independently from each other halogen; C1-4-alkyl, which is unsubstituted or substituted with 1, 2, or 3 substituents independently from each other selected from halogen; -O-C1-4-alkyl, which is unsubstituted or substituted with 1, 2, or 3 substituents independently from each other selected from halogen; halogen denotes F, Cl, Br, I;

[0078] or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures 30 thereof in all ratios.Foreignfiling_text_P25-005-SEC-WO01

[0079] 8

[0080] In general, all residues, radicals, substituents, groups, moieties, etc. which occur more than once may be identical or different, i.e. are independent of one another. Above and below, the residues and parameters have the meanings indicated for formula I, unless expressly indicated otherwise.

[0081] 5 Accordingly, the invention relates, in particular, to the compounds of formula I in which at least one of the said residues, radicals, substituents has one of the preferred meanings indicated below.

[0082] Any of those particular or even preferred embodiments of the present 10 invention as specified below and in the claims do not only refer to the specified compounds of formula I but to N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, too, unless indicated otherwise.

[0083] In a particular embodiment, PE1, the compound of the present invention is a bicyclic compound of formula I, wherein

[0084] 20

[0085]

[0086] A denotes

[0087] A-2;

[0088] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0089] In another particular embodiment of the invention, PE2, the compound of the present invention is a bicyclic compound formula of formula I, wherein RA1denotes methyl;

[0090] 30

[0091] RA2denotes methyl;

[0092] RA3denotes F,Foreignfiling_text_P25-005-SEC-WO01

[0093] 9

[0094] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0095] 5 In another particular embodiment, PE2a, of PE2, the compound of the present invention is a bicyclic compound formula of formula I, wherein RA1

[0096] RA2 Y r

[0097] ........

[0098]

[0099] A denotes

[0100] A-2;

[0101] RA1denotes methyl;

[0102] RA2denotes methyl;

[0103] RA3denotes F,

[0104] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0105] In another particular embodiment, PE3, which may also be particular embodiment of PE1 or PE2, the compound of the present invention is a bicyclic heterocycle of formula I wherein

[0106] X1denotes N or CRX1:

[0107] RX1denotes H;

[0108] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0109] In other words, compounds of PE3 are compounds of formula l-A or l-B: 30Foreignfiling_text_P25-005-SEC-WO01

[0110] 10

[0111] 5

[0112]

[0113] l-A l-B.

[0114] In another particular embodiment, PE3a, of PE3, the compound of the present invention is a bicyclic compound of formula I, wherein

[0115] X1denotes CH;

[0116] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below. PE3a may also be described as a compound of formula l-A (see above).

[0117] In still another particular embodiment, PE3b, of PE3, the compound of the present invention is a bicyclic compound of formula I, wherein

[0118] X1denotes N;

[0119] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below. PE3b may also be described as a compound of formula l-B (see above).

[0120] In a further particular embodiment of the present invention, PE4, the compound of the present invention is a bicyclic compound of formula I, wherein

[0121] R1denotes Cl, CFH2, -CF2H, or -CF3; and

[0122] R3denotes H;

[0123] 30 and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below. PE4 may also be described as a compound of formula l-CForeignfiling_text_P25-005-SEC-WO01

[0124] 11

[0125] 5

[0126]

[0127] l-C

[0128] wherein

[0129] R1denotes Cl, CFH2, -CF2H, or -CF3; and

[0130] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0131] In another particular embodiment, PE4a, of PE4 the compound of the present invention is a bicyclic compound of formula I - or formula l-C -, wherein

[0132] R1denotes Cl or -CF3; and

[0133] R3denotes H;

[0134] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0135] In another particular embodiment of the present invention, PE5, which may also be described as a particular embodiment of either PE3a or PE4, the compound of the present invention is a bicyclic compound of formula I wherein

[0136] R1denotes Cl, -CFH2, -CF2H, or -CF3; and

[0137] R3denotes H;

[0138] X1denotes CH;

[0139] 30 and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above orForeignfiling_text_P25-005-SEC-WO01

[0140] below. Alternatively, this particular embodiment PE5 can also be described as a compound of formula l-AC:

[0141] A

[0142] 5

[0143]

[0144] wherein

[0145] R1denotes Cl, CFH2, -CF2H, or -CF3; and in particular Cl or -CF3(PE5a);

[0146] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below. Embodiments PE5 and PE5a are preferred embodiments of the invention.

[0147] In another particular embodiment of the present invention, PE6, which may also be described as a particular embodiment of either PE3b or PE4, the compound of the present invention is a bicyclic compound of formula I wherein

[0148] R1denotes Cl CFH2, -CF2H, or -CF3; and

[0149] R3denotes H;

[0150] X1denotes N;

[0151] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below. Alternatively, this particular embodiment PE6 can also be described as a compound of formula l-BC:

[0152] 30Foreignfiling_text_P25-005-SEC-WO01

[0153] 5

[0154]

[0155] l-BC

[0156] wherein

[0157] R1denotes Cl, CFH2, -CF2H, or -CF3; and in particular Cl or -CF3(PE6a);

[0158] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0159] In another particular embodiment of the present invention, PE7, the compound of the present invention is a bicyclic compound of formula I, wherein

[0160] R2denotes H, Aik2, Cyc2, Hetar2, Hetcyc2, -L2-Ar2a, -S(=O)2Rf; and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0161] It is a further particular embodiment, PE7a, of PE7 in which in formula I R2denotes H, Aik2, Cyc2, Hetar2, Hetcyc2, -L2-Ar2a, -S(=O)2Rf;

[0162] Aik2denotes straight-chain or branched Ci-6-alkyl, Ci-6-alkenyl or C2-6- alkinyl, each of which may be unsubstituted or substituted with independently from each other R2a1, R2a2and / or R2a3;

[0163] Cyca, Cyc2, Cyc2adenote independently from each other a saturated monocyclic carbocycle with 3, 4, 5, 6, or 7 ring carbon atoms, wherein 30 said carbocycle is unsubstituted or substituted with independently from each other RB6and / or RB7;Foreignfiling_text_P25-005-SEC-WO01

[0164] 14

[0165] Hetcyca, Hetcyc2, Hetcyc2adenote independently from each other a saturated or partially unsaturated monocylic heterocycle with 3, 4, 5, or 6 ring atoms wherein 1 or 2 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, 5 wherein said heterocycle is unsubstituted or substituted with independently from each other RB6and / or RB7and / or RB8and RB9together (i.e., if present both RB8and RB9are present at the same time) or RB6and / or RB7and / or RB8and RB9and RB10and RB11together (i.e., if present all for of RB8, RB9, RB10and RB11are present at the same time); L2denotes a divalent -S(=O)2- group;

[0166] Ara, Ar2adenote independently from each other phenyl which may be unsubstituted or substituted with independently from each other RB1and / or RB2;

[0167] Hetara, Hetar2, Hetar2adenotes a monocyclic heteroaryl with 5 or 6 ring atoms wherein 1, 2, or 3 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is unsubstituted or substituted with independently from each other RB1and / or RB2;

[0168] R2a1, R2a2, R2a3denote independently from each other halogen, -CF3, -CN, -NH2, -NHRa, -NRaRb, -OH, -ORc, -P(=O)RdRe, -SRf, -S(=O)2Rf, -S(=O)(=NRg)Rf, -N=S(=O)RfRh, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -C(=O)OH, -C(=O)ORc, -NH-C(=O)-Ri, Cyc2a, Hetar2a, Hetcyc2a; and / or

[0169] two of R2a1, R2a2, R2a3which are attached to the same carbon atom form together a divalent oxo (=0) group;

[0170] Ra, Rbdenote independently from each other straight-chain or branched C1- 6-alkyl which may be unsubstituted or substituted with 1, 2, or 3 halogen; Ara, Cyca, Hetara, Hetcyca;

[0171] or

[0172] 30 Raand Rbform together with the nitrogen atom to which they are attached to a saturated or partially unsaturated heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or oneForeignfiling_text_P25-005-SEC-WO01

[0173] 15

[0174] further ring atom is a hetero atom selected from N, 0 or S and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or substituted with independently from each other RB6and / or RB7and / or RB8and RB9(i.e., if present, both RB8and RB9are present at the same 5 time);

[0175] Rcdenotes straight-chain or branched Ci-4-alkyl which is unsubstituted or substituted with -OH; straight-chain and unsubstituted C2-4-alkinyl; C3-5- cycloalkyl;

[0176] Rd, Redenote independently from each other straight-chain or branched C1- 6-alkyl;

[0177] Rf, Rhdenote independently from each other straight-chain or branched C1- 6-alkyl;

[0178] Rgdenotes H, straight-chain or branched Ci-6-alkyl;

[0179] R' denotes H, straight-chain or branched Ci-6-alkyl;

[0180] 15 RB1, RB2denote independently from each other halogen; Ci -4-alky I, which may be unsubstituted or substituted with 1, 2, or 3 halogen; OH;

[0181] RB6, RB7denote independently from each other halogen; OH; -OC1-4- alkyl; Ci-4-alkyl, which is unsubstituted or substituted with 1 OH or 1, 2, or 3 halogen;

[0182] 20 RB8and RB9which are attached to the same carbon atom of said heterocycle form a divalent oxo (=0) group; or

[0183] RB8, RB9, RB10and RB11which are attached to the same sulfur (S) atom of said heterocycle form a divalent oxo (=O) group, thereby forming an -S(=O)2moiety;

[0184] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0185] In still a further particular embodiment, PE7b, of PE7 and PE7a, the 30 compound of the present invention is a bicyclic compound of formula I, wherein

[0186] R2denotes H, Aik2, Cyc2, Hetar2, Hetcyc2, -L2-Ar2a, -S(=O)2Rf;Foreignfiling_text_P25-005-SEC-WO01

[0187] 16

[0188] Aik2denotes straight-chain or branched Ci-4-alkyl, Ci-4-alkenyl or C2-4- alkinyl, each of which may be unsubstituted or substituted with independently from each other R2a1and / or R2a2;

[0189] Cyc2, Cyc2adenote independently from each other a saturated monocyclic 5 carbocycle with 3, 4, or 5 ring carbon atoms, wherein said carbocycle is mono-substituted with OH, -CH2OH;

[0190] Hetcyc2denotes a saturated monocylic heterocycle with 5 ring atoms wherein 1 of said ring atoms is a hetero atom(s) selected from N, and 0 and the remaining are carbon atoms, wherein said heterocycle is monosubstituted with OH, or denotes a saturated monocyclic heterocycle with 4 ring atoms wherein 1 of said ring atoms is a heteroatom(s) selected from S and the remaining are carbon atoms, wherein said heterocycle is substituted with two oxo (=0) groups at the S atom;

[0191] Hetcyc2adenotes a saturated monocylic heterocycle with 4 ring atoms wherein 1 of said ring atoms is a hetero atom(s) selected from N or 0 and the remaining are carbonatoms, wherein said heterocycle is unsubstituted or mono-substituted with halogen, in particular F, -OH, 0- Ci-4-alkyl or Ci-4-alkyl, or disubstituted with halogen and Ci-4-alkyl wherein said Ci-4-alkyl in each case may be unsubstituted or monosubstituted with -OH or -OCi-4-alkyl; or denotes a saturated moncyclic heterocycle with 5 ring atoms wherein 1 of said ring atoms is a hetero atom selected from N or 0 or wherein 2 of said ring atoms are hetero atoms selected from N and / or 0 and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or mono-substituted with -OH, Ci -4-alky I or an oxo (=0) group or disubstituted with Ci -4-alky I and an oxo (=0) group; or denotes a saturated monocyclic heterocycle with 6 ring atoms wherein 1 of said ring atoms is a hetero atom selected from N or 0 or wherein 2 of said ring atoms are hetero atoms selected from N and / or 0 and the remaining are carbon atoms, wherein said heterocycle 30 is unsubstituted or mono-substituted with OH, Ci-4-alkyl or an oxo (=0) group) or disubstituted with halogen; or denotes a partially unsaturated monocyclic heterocycle with 6 ring atoms wherein 1 of said ring atoms isForeignfiling_text_P25-005-SEC-WO01

[0192] 17

[0193] a hetero atom selected from N and the remaining are carbon atoms, wherein said heterocycle is mono-substituted with an oxo (=0) group); L2denotes a divalent -S(=O)2- group;

[0194] Ar2adenotes phenyl which is mono-substituted with -CH3;

[0195] 5 Hetar2, Hetar2adenote independently from each other a monocyclic heteroaryl with 5 or 6 ring atoms wherein 1, 2 or 3 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is unsubstituted or monosubstituted with Ci-4-alkyl;

[0196] R2a1, R2a2denote independently from each other -CF3, -CN, -NH2, -NHRa, -NRaRb, -OH, -ORc, -P(=O)RdRe, -SRf, -S(=O)2Rf, -S(=O)(=NRg)Rf, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -C(=O)ORc, -NH-C(=O)-Ri, Cyc2a, Hetar2a, Hetcyc2a;

[0197] and / or

[0198] 15 R2a1and R2a2which are attached to the same carbon atom form together a divalent oxo (=0) group;

[0199] Ra, Rbdenote independently from each other straight-chain or branched C1- 4-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 F; Ara, Hetara;

[0200] 20 or

[0201] Raand Rbform together with the nitrogen atom to which they are attached to a saturated heterocycle with 4, 5, or 6 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N or 0 and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or monosubstituted with C1-4- alkyl or di-substituted with F;

[0202] Rcdenotes straight-chain or branched Ci-4-alkyl which is unsubstituted or substituted with -OH; unsubstituted C2-4-alkinyl; unsubstituted C3-5- cycloalkyl;

[0203] 30 Rd, Redenote independently from each other straight-chain or branched C1- 4-alkyl;

[0204] Rfdenotes straight-chain or branched Ci-4-alkyl;Foreignfiling_text_P25-005-SEC-WO01

[0205] 18

[0206] Rgdenotes H;

[0207] Ridenotes H, straight-chain or branched Ci-4-alkyl;

[0208] Aradenotes phenyl;

[0209] Hetaradenotes pyridyl;

[0210] 5 and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0211] It is another particular embodiment of the present invention, PE7c, which may also be a particular embodiment of any one of particular embodiments PE7, PE7a or PE7b, the compound of the present invention is a bicyclic compound of formula I, wherein

[0212] R2denotes H; -CH3, -CH=CH-CF3, -C C-CH2-OH, -CH2-CN, -(CH2)2-CN, - (CH2)3-CN, -CH2-CH(OH)-CH2-CN, -(CH2)2-NH2, -(CH2)2-NHCH3, - (CH2)2-NHCH2CF3, -(CH2)2-NH-pyridin-2-yl, -(CH2)2-N(CH3)2, -(CH2)2- N(CF3)2, -CH2-CF2-CH2-NH2, -CH(CF3)-CH2-N(CH3)2, 2-(azetidin-1- yl)ethyl, 2-(pyrrolidin-1 -yl)ethyl, 2-(piperidin-1 -yl)ethyl, 2-(4,4- d if luoropiperid in-1 -y l)ethy I, (N-methylmorpholin-3-yl)methyl, 2- (morpholin-l-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, -(CH2)3-NH2, - (CH2)3-NHCH3, -(CH2)3-N(CH3)2, -(CH2)4-NH2, -(CH2)4-NHCH3, -(CH2)4- N(CH3)2, -(CH2)2-OH, -(CH2)2-O-(CH2)2-OH, -(CH2)3-OH, -CH2CH(OH)-

[0213] CH3, -CH(CH3)CH2-OH,, -CH2-C(CH3)2-OH, - CH(CH2OH)2, -CH2CH(CH2OH)2, -CH2-CH(OH)-CH2OH, -CH2-CH(OH)- OH OH

[0214] C

[0215]

[0216] H2-OCH3,,, -CH(CH2OCH3)2, - (CH2)2-O-CH2-C CH, 2-hydroxy-1-(pyrazin-2-yl)ethyl, -(CH2)2-S-CH3, - (CH2)2-S-CH2CH3, -(CH2)2-S(=O)2-CH3, -(CH2)2-S(=O)(=NH)CH3, - 30 (CH2)2-S(=O)(=NH)CH2CH3, -CH2-P(=O)(CH3)2, -CH2-C(=O)-NH2, -CH2- C(=O)-NHCH3, -CH2-C(=O)-NHCH2CH3, -CH2-C(=O)-N(CH3)2, -CH2- C(=O)-NH-phenyl, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-Foreignfiling_text_P25-005-SEC-WO01

[0217] C(=O)-N(CH3)2, -CH(C(=O)OCH2CH3)2,, -(CH2)2-NH-C(=O)-CH3, -C(=O)-CH3, -C(=O)-(CH2)2-CH3; (l-hydroxycyclobutyl)methyl (

[0218] 5

[0219]

[0220] ), (1 H-imidazol-2-yl)methyl, (1 H-imidazol-4-yl)methyl, (1- methyl-1 H-imidazol-4-yl)methyl, (1 -methyl-1 H-imidazol-5-yl)methyl, (1 H- 2-methylimidazol-4-yl)methyl, (1 H-pyrazol-4-yl)methyl, (1 H-pyrazol-5- yl)methyl, (1 -methyl-1 H-pyrazol-4-yl)methyl, 1,2-thiazol-3-yl, 1,3-thiazol- 2-yl, (1 H-1,2,3-triazol-4-yl)methyl, pyrazin-2-yl, (1,2,4-oxadiazol-3- yl)methyl, 2-(2-oxopyridin-1-yl)ethyl, (3-fluoroazetidin-3-yl)methyl, (1- methylazetidin-3-yl)methyl, (oxetan-3-yl)methyl, (3-fluorooxetan-3-

[0221]

[0222] yl)methyl ( ), (3-hydroxyoxetan-3-yl)methyl (

[0223]

[0224]

[0225] o

[0226] methoxyoxetan-3-yl)methyl ( ), methyl(oxetan-3-yl)methanol

[0227] ), (1-methylazetidin-3-yl)ethyl, 2-(oxetan-3-yl)ethyl, 1,1-

[0228] d

[0229]

[0230] ioxo-1-lambda-6-thietan-3-yl ( (5-oxo-pyrrolidin-2-yl)methyl (

[0231] 30

[0232]

[0233] ), (5-oxo-pyrrolidin-3-yl)methyl

[0234]

[0235] ( ), oxolan-3-ylmethyl (Foreignfiling_text_P25-005-SEC-WO01

[0236] 20

[0237] o' '

[0238] ), (3-hydroxyoxolan-3-yl)methyl ( ), (2-oxo-1,3-

[0239] 5

[0240] v

[0241]

[0242] H

[0243] oxazolidin-4-yl)methyl ( ), (2-oxo-1,3-oxazolidin-5-yl)methyl (

[0244] Y" ), (4-methyl-2 -oxo-1,3-oxazolidin-4-yl)methyl ( ), (4- \

[0245]

[0246] hydroxyoxan-4-yl)methyl ( ), 2-(4-hydroxyoxan-4-yl)ethyl (

[0247]

[0248] ); 1 -hydroxymethylcyclopropyl, 3-hydroxycyclobutyl, 2- OH OH

[0249]

[0250] hydroxycyclopentyl;

[0251] OH OH

[0252]

[0253] ,; sulfonyl-4-methylphenyl;

[0254] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or 30 below.Foreignfiling_text_P25-005-SEC-WO01

[0255] 21

[0256] It is still a further particular embodiment of the present invention, PE7d, which may also be a particular embodiment of any one of particular embodiments PE7, PE7a, PE7b or PE7c, in which the compound of the present invention is a bicyclic compound of formula I, or any N-oxide, solvate, tautomer or 5 stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein

[0257] R2denotes H; -CH3, -(CH2)2-OH, -CH2-C(CH3)2-OH;

[0258] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0259] In a further particular embodiment of the present invention, PE8, the compound of the present invention is a bicyclic compound of formula I, wherein

[0260] 15 B denotes Ar1, Hetar1, Cyc1, Hetcyc1;

[0261] L1denotes -O-, -S-, -N(R4)-, -O-CH2-, -O-CH(R5)-, -N(R6)-CH2-, -N(R6)-C(=O)-, -CH2-, -CH2CH2-;

[0262] R4denotes H or CH3;

[0263] R5, R6denote CH3;

[0264] 20 Ar1denotes a phenyl, wherein that phenyl is mono-substituted with RC1;

[0265] Hetar1denotes a mono-cyclic heteroaryl with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is monosubstituted with RC1or di-substituted with RC1and RC2;

[0266] Cyc1denotes a saturated, mono- or bi-cyclic carbocycle with 4, 5, 6, or 7 ring carbon atoms, wherein said carbocycle may be un-substituted or mono-substituted with RC6or di-substituted with other RC6and RC7; Hetcyc1denotes a saturated, mono- or bicylic heterocycle with 5, 6, or 7 ring atoms wherein 1 or 2 of said ring atoms is / are a hetero atom(s) 30 selected from N, 0 and / or S and the remaining are carbon atoms, wherein said heterocycle is substituted mono-substituted with RC6or di- substituted with other RC6and RC7;Foreignfiling_text_P25-005-SEC-WO01

[0267] 22

[0268] RC1denotes F, Cl, CHF2, CF3, CH2CF3, OCF3, or SCF3;

[0269] RC2denotes CH3or C2H5;

[0270] RC6denotes F, Cl; CH3, CHF2, CF3, -OCH3, -OCHF2, -OCF3;

[0271] RC7denotes F;

[0272] 5 and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0273] In still another particular embodiment of the present invention, PE9, the compound of the present invention is a bicyclic compound of formula I, wherein

[0274] L1denotes -O-, -NH- or -O-CH2-; and in particular -O- (PE9a); and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or 15 below.

[0275] In even a further particular embodiment of the present invention, PE10, which also a particular embodiment of PE8, PE9, and PE9a, the compound of the present invention is a bicyclic compound of formula I, wherein 20

[0276]

[0277]

[0278] 30Foreignfiling_text_P25-005-SEC-WO01

[0279] 23

[0280] 5

[0281]

[0282] 30Foreignfiling_text_P25-005-SEC-WO01

[0283] 5

[0284]

[0285] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0286] In still another particular embodiment, PE11, the compound of the present invention is a bicyclic compound of formula I, wherein

[0287] L1denotes -O-;

[0288]

[0289] 30

[0290]

[0291] Foreignfiling_text_P25-005-SEC-WO01

[0292] 5

[0293]

[0294] and the remaining radicals and residues are as defined for formula I above 15 or for any of the further particular embodiments described herein above or below.

[0295] It is a particular embodiment, PE11a, of PE11 in which the compound of the present invention is a bicyclic compound of formula I, wherein

[0296] 20 L1denotes -O-;

[0297]

[0298] B denotes,, or

[0299] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0300] It is a further particular embodiment, PE11aa, of PE11a in which the compound of the present invention is a bicyclic heterocycle of formula I, L1denotes -O-;

[0301] 30

[0302]

[0303] B denotesForeignfiling_text_P25-005-SEC-WO01

[0304] 26

[0305] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0306] 5 In another particular embodiment of the present invention, PE12, the compound of the present invention is a bicyclic compound of formula I, wherein

[0307]

[0308] A-L1-B denotes

[0309]

[0310] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0311] In a particular embodiment, PE12a, of PE12, A-L1-B denotes

[0312]

[0313] and the remaining radicals and residues are as defined for formula I above or for any of the further particular embodiments described herein above or below.

[0314] In a particular embodiment of the present invention, PE13, the compound of the present invention is a bicyclic compound of formula I, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all 30 ratios, wherein

[0315] X1denotes CH;

[0316] R1denotes Cl or -CF3;Foreignfiling_text_P25-005-SEC-WO01

[0317] R2denotes H; -CH3, -(CH2)2-OH, -CH2-C(CH3)2-OH,;

[0318] R3denotes H;

[0319] 5

[0320]

[0321] A-L1-B denotes

[0322] In still another particular embodiment, PE14, the compound of the present invention is a single atropisomer, or any N-oxide, solvate, or tautomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

[0323] It will be appreciated by a person skilled in the art that the term “atropisomer” 15

[0324] as used herein refers to a stereoisomer which arises due to a restricted rotation around a single bond that creates a chiral axis. It will be further appreciated that the rotation barrier around said single bond has to be sufficiently high to permit the isolation of a single atropisomer. Said rotation barrier can result, for example, from steric interactions with other residues of 20

[0325] the same molecule thereby restricting said rotation around said single bond. Both steric and electronic factors come into play and may reinforce or counteract one another (see, for instance, S. R LaPlante et al., ChemMedChem 2011, 6, 505-513; M. Basilaia et al., Acc. Chem. Res. 2022.

[0326] 55, 2904-2919).

[0327] The utilization of chiral compounds that contain an asymmetric center is well established in drug discovery, in principle. In particular, it is known in the art that racemic mixtures of two chiral compounds usually consist of one more active and one less active enantiomer as compared to the racemic mixture.

[0328] 30

[0329] Thus, the utilization of only one of the two enantiomers can be advantageous to improve the overall potency of the compound.Foreignfiling_text_P25-005-SEC-WO01

[0330] However, the utilization of atropisomers, which are stereoisomers that arise only due to a hindered rotation around an axis, i.e., a single bond, is generally seen as undesirable. In particular, atropisomers are commonly regarded as 5 a liability in drug discovery, since the stability of these isomers depends on energy differences resulting from steric strain or other factors that create a barrier to the rotation around said single bond. In contrast to chiral compounds resulting from asymmetric centers, atropisomerism cannot be readily predicted. In particular, it is generally not possible to readily predict 10 the stability of an atropisomer. In particular, the height of said energy barrier determines the time of the interconversion of two corresponding atropisomers. The interconversion of a biologically active atropisomer into its optical antipode, i.e., the corresponding other atropisomer can, thus, reduce its biological activity and introduce off-target or other unwanted effects. Therefore, only stable atropisomers that possess a sufficiently high energy barrier may be suitable in drug discovery.

[0331] It has been surprisingly found that compounds of the present invention can be separated into their respective atropisomers. The separated atropisomers 20 have been found to not easily convert into the respective other atropisomer.

[0332] It will be understood by those skilled in the art that the atropisomers of the compounds of the present invention can be separated due to the hindered rotation around the axis which is formed between the bicyclic ring system of

[0333] R1A

[0334] N

[0335] R

[0336]

[0337] the compound of formula I and the ring A as indicated 30 by the arrow in depicted formula I. Typically, for the compounds of the present invention which can be separated into their respective atropisomers the maximal energy value of the rotational barrier is in the range of about 20 toForeignfiling_text_P25-005-SEC-WO01

[0338] 29

[0339] about 50 kcal / mol, more specifically in the range of about 25 to 45 kcal / mol, even more specifically in the range of about 30 to 40 kcal / mol.

[0340] In still another particular embodiment, PE15, the compound of the present 5 invention is a bicyclic compound selected from the compounds shown in Table 1 below, or any N-oxide, solvate, tautomer or stereoisomer, in particular atropisomer, thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios. In yet another particular embodiment, PE15a, of PE15, the compound is selected from Table 1 and is a compound of formula I as described hereinabove. It is understood that each single compound depicted in Table 1 as well as any N- oxide, solvate, tautomer or stereoisomer, in particular atropisomer, thereof and / or any pharmaceutically acceptable salt of such compound represents a particular embodiment of the present invention. In yet a further particular 15 embodiment, PE15b, of PE15 or PE15a, the compound is selected from Table 1, is a compound of formula I as described hereinabove and in the claims, and is within Group A in the SK-HEP-1 reporter assay and / or within Group A in the H226 viability assay as provided in Table 2 below.

[0341] 20 As used herein, the following definitions shall apply unless otherwise indicated or defined specifically elsewhere in the description and / or the claims for specific substituents, radicals, residues, groups or moieties.

[0342] The term “aliphatic” or “aliphatic group”, as used herein, means a straightchain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain (also referred to as “acyclic”) that is completely saturated or that contains one or more units of unsaturation; or a monocyclic hydrocarbon or bicyclic hydrocarbon or tricyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, such 30 as one or more C=C double bond(s) and / or C=C triple bond(s), but which is not aromatic (also referred to herein as “carbocycle”, “cycloaliphatic” or “cycloalkyl”), that has - in general and if not defined otherwise in thisForeignfiling_text_P25-005-SEC-WO01

[0343] 30

[0344] specification or the accompanied claims - a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1 to 10 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) 1 to 8 (i.e., 1, 2, 3, 4, 5, 6, 7, or 8) or 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) aliphatic carbon atoms (“Ci-10-aliphatic”, “C1-8- 5 aliphatic” and “Ci-6-aliphatic”, respectively). In some embodiments, aliphatic groups contain 1-5 (i.e., 1, 2, 3, 4, or 5) aliphatic carbon atoms (“C1-5- aliphatic”). In other embodiments, aliphatic groups contain 1-4 (i.e., 1, 2, 3, or 4) aliphatic carbon atoms (“Ci-4-aliphatic”). In still other embodiments, aliphatic groups contain 1-3 (i.e., 1, 2, or 3) aliphatic carbon atoms (“C1-3- aliphatic”), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (“Ci-2-aliphatic”).

[0345] In some embodiments, “cycloaliphatic” (“cycloalkyl”) refers to a monocyclic C3-C7hydrocarbon (i.e., a monocyclic hydrocarbon with 3, 4, 5, 6, or 7 ring 15 carbon atoms) or to a bicyclic C5-8hydrocarbon (i.e. a bicyclic hydrocarbon with 5, 6, 7, or 8 ring carbon atoms) that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. In another embodiment the term “cycloaliphatic” or “carbocycle” refers to a monocyclic 20 or bicyclic cycloaliphatic ring system which is fused to an aromatic, heteroaromatic or heterocyclic ring or ring system via 2 adjacent ring atoms of that aromatic, heteroaromatic or heterocyclic ring or ring system; in other words, such carbocycle shares two ring atoms with the ring or ring system to which it is fused thereby having two points of attachment to the rest of the molecule. In another embodiment the term “carbocycle” refers to bicyclic spiro-cycles in which two monocyclic carbocycles are fused to each other via the same single carbon atom. In general, the term “aliphatic” encompasses, to the extent chemically possible, straight-chain, i.e. unbranched, as well as branched hydrocarbon chains, if not defined differently in a particular 30 instance. Also, in general this term encompasses, to the extent chemically possible, unsubstituted and substituted hydrocarbon moieties, if not defined differently in a particular instance. Typical substituents of an aliphatic groupForeignfiling_text_P25-005-SEC-WO01

[0346] 31

[0347] include, but are not limited to halogen, in particular F, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, in particular unsubstituted or 5 substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl (alkinyl), cycloalkyl, cycloalkenyl groups and hybrids thereof as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0348] 10

[0349] The term "alkyl" usually refers to a saturated aliphatic and acyclic moiety, while the term “alkenyl” usually refers to an unsaturated aliphatic and acyclic moiety with one or more C=C double bonds and the term “alkynyl” (or “alkinyl”) usually refers to an aliphatic and acyclic moiety with one or more C=C triple bonds. It is understood that the term “alkenyl” comprises all forms of isomers, i.e. E-isomers, Z-isomers as well as mixtures thereof (E / Z- isomers). Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C1-10-alkyl, Ci-8-alkyl, C1-6-alkyl, Ci-4-alkyl, Ci-3-alkyl, Ci-2-alkyl, C2-8-alkenyl, C2-6-alkenyl, C2-4-alkenyl, C2-8-alkynyl (C2-8-alkinyl), C2-6-alkynyl 20 (C2-6-alkinyl), C2-4-alkynyl (C2-4-alkinyl) groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0350] In particular, the term “Ci-3-alkyl” refers to alkyl groups, i.e. saturated acyclic aliphatic groups, having 1, 2 or 3 carbon atoms. Exemplary Ci-3-alkyl groups are methyl, ethyl, propyl and isopropyl. The term “Ci-4-alkyl” refers to alkyl groups having 1, 2, 3 or 4 carbon atoms. Exemplary Ci-4-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The term “C1-6- alkyl” refers to alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Exemplary C1-6-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 30 n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl. The term “Ci-8-alkyl” refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary C1-8-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl,Foreignfiling_text_P25-005-SEC-WO01

[0351] 32

[0352] 2-pentyl, n-hexyl, 2-hexyl n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4- trimethylpentyl. The term “Ci-10-alkyl” refers to alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Exemplary C1-10-alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 5 2-hexyl n-heptyl, 2-heptyl, n-octyl, 2-octyl, 2,2,4-trimethylpentyl, and n-decyl.

[0353] Each of these alkyl groups may be straight-chain or - except for Ci -alkyl and C2-alkyl - branched and may be unsubstituted or substituted with 1, 2 or 3 substituents that may be the same or different and may be, if not specified differently elsewhere in this specification and / or the accompanying claims, selected from the group comprising halogen, in particular F, cyano, hydroxy, alkoxy, thiol, thioalkoxy, dialkylphosphoryl, in particular, -P(=O)(CH3)2, unsubstituted or mono- or di-substituted amino, sulfoxide, sulfone, iminoalkylsulfone, in particular -S(=O)(=NH)CH3, iminodialkylsulfone, in particular -N=S(=O)(CH3)2, carboxylic acid, carboxylic acid ester, carboxylic acid amide (primary, secondary, tertiary), carbamate, aryl, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, saturated or partially unsaturated heterocyclyl, in particular unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Exemplary substituted alkyl groups are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2- hydroxyethyl, difluoromethoxy, trifluoromethoxy.

[0354] In some instances the Ci-3-alkyl, Ci-4-alkyl, Ci-6-alkyl, C1-8-alkyl, C1-10-alkyl groups - both unbranched and branched - may also comprise those residues in which 1 or 2 of non-terminal and non-adjacent -CH2- (methylene) groups are replaced by -O-, -S- and / or 1 or 2 non-terminal and non-adjacent -CH2- or -CH- groups are replaced by -NH- or -N-. These replacements yield, for instance, (modified) alkyl groups like -CH2-CH2-O-CH3, -CH2-CH2-CH2-S- CH3, CH2-CH2-NH-CH2-CH3, CH2-CH2-O-CH2-CH2-O-CH3, CH2-CH2-O-CH2- 30 CH2-O-CH2-CH3, CH2-CH2-N(CH3)-CH2-CH3, and the like. Further and / or different replacements of -CH- and -CH2- groups may be defined for specific alkyl substituents or radicals elsewhere in the description and / or theForeignfiling_text_P25-005-SEC-WO01

[0355] 33

[0356] claims. As described for “unmodified” alkyl groups hereinabove these “modified” alkyl groups may optionally be substituted with 1, 2 or 3 substituents that may be the same or different and may be, if not specified differently elsewhere in this specification and / or the accompanying claims, 5 selected from the group comprising halogen, in particular F, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, in particular unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Examplary modified alkyl groups are CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH2, CH2-CH2- O-CH2-CH2-O-CH2-CH2-NH-C(=O)-CH3, CH2-CH2-O-CH2-CH2-O-CH2-CH2- NH-C(=O)-OC(CH3)3CH2-CH2-CH2-CH2-CH2-O-CH2-CH2-NH2, CH2-CH2- CH2-CH2-CH2-O-CH2-CH2-NH-C(=O)-CH3, CH2-CH(OH)-CH2-CH2-O-CH2- CH2-O-CH2-CH2-NH2, CHR-CH(OH)-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH215 wherein “R” denotes another substituent.

[0357] The term “carbocycle” refers in general, if not defined differently elsewhere, to a saturated or partially unsaturated but not aromatic ring system with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms and non ring hetero 20 atoms; that carbocycle may be monocyclic (C3-15) or bicyclic (C5-15) or tricyclic (C8-15). It will be understood that a bicyclic carbocycle may be (a) a carbocycle in which the two carbocyclic moieties are attached to each other via two different ring carbon atoms, like in bicyclo[1.1,1]pentanyl or bicyclo[3.1.0]hexanyl; or (b) a carbocycle in which the two carbocyclic moieties are attached to each other via the same ring carbon atom, thereby forming a sprio ring, like in spiro[3.3]heptanyl. The same applies, mutatis mutandis, to tricyclic carbocycles. Carbocycles may be unsubstituted or substituted.

[0358] 30 The term “cycloalkyl” refers to a cycloaliphatic hydrocarbon, or carbocycle, as defined above. The term “C3-7-cycloalkyl” refers to a cycloaliphatic hydrocarbon, or carbocycle, as defined above, with 3, 4, 5, 6 or 7 ring carbonForeignfiling_text_P25-005-SEC-WO01

[0359] 34

[0360] atoms. Likewise, the term “C3-6-cycloalkyl” refers to a cycloaliphatic hydrocarbon, or carbocycle, with 3, 4, 5, or 6 ring carbon atoms. The terms “cycloalkyl”, “C3-7-cycloalkyl” and “C3-6-cycloalkyl” as used herein comprise cyclic hydrocarbons, or carbocycles, which are saturated or contain one or 5 more units of unsaturation, such as a C=C double bond; such cyclic hydrocarbons having at least one unit of unsaturation may also referred to as “cycloalkenyl” group. C3-7-cycloalkyl groups may be unsubstituted or substituted with - unless specified differently elsewhere in this specification - 1, 2 or 3 substituents that may be the same of different and are - unless specified differently elsewhere in this specification - selected from the group comprising C1-6-alkyl, O-C1-6-alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl. If substituted, C3-7-cycloalkyl comprises all possible stereoisomers. Exemplary C3-7-cycloalkyl groups are cyclopropyl, 2-methyl- 15 cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl. The term “bicyclic Cs-s-cycloalkyl” refers to a bicyclic cycloaliphatic hydrocarbon, as defined above, with 5, 6, 7, or 8 ring carbon atoms; it includes spirocyclic ring systems, i.e. ring systems in which the two carbocycles of the bicyclic Cs- 20 s-cycloalkyl are attached to each other via the same carbon atom. Bicylic Cs- s-cycloalkyl groups may be unsubstituted or substituted with - unless specified differently elsewhere in this specification - 1, 2 or 3 substituents that may be the same of different and are - unless specified differently elsewhere in this specification - selected from the group comprising C1-6-alkyl, which may be substituted with 1, 2, or 3 halogen, O-C1-6-alkyl (alkoxy), which may be substituted with 1, 2, or 3 halogen, hydroxy, halogen, unsubstituted or mono- or di-substituted amino. If substituted, bicyclic Cs-s- cycloalkyl comprises all possible stereoisomers. Exemplary bicyclic Cs-s- cycloalkyls are spiro[3.3]heptanyl, bicyclo[1.1,1]pentanyl, 30 bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, bicyclo[3.1.1]hept-2-en-2-yl.Foreignfiling_text_P25-005-SEC-WO01

[0361] 35

[0362] The term “aliphatoxy” refers to saturated or unsaturated aliphatic groups or substituents as defined above that are connected to another structural moiety via an oxygen atom (-O-). The term “Ci-6-aliphatoxy” refers to an aliphatoxy radical with 1, 2, 3, 4, 5, or 6 carbon atoms within the aliphatic group. The 5 term “alkoxy” refers to a particular subgroup of saturated aliphatoxy, i.e. to alkyl substituents and residues that are connected to another structural moiety via an oxygen atom (-O-). Sometimes, it is also referred to as “O-alkyl” and more specifically as “O-Ci-2-alkyl”, “O-Ci-3-alkyl”, “O-Ci-4-alkyl”, “O-C1-6- alkyl”, “O-Ci-8-alkyl”. Like the similar alkyl groups, it may be straight-chain or 10 - except for -O-C1 -alkyl and -O-C2-alkyl - branched and may be unsubstituted or substituted with 1, 2 or 3 substituents that may be the same or different and are, if not specified differently elsewhere in this specification, selected from the group comprising halogen, unsubstituted or mono- or disubstituted amino. Exemplary alkoxy groups are methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.

[0363] The term “alkylene” refers to a divalent aliphatic group and in particular a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., - 20 (CH2)j-, wherein j is a positive integer, preferably 1, 2, 3, 4, 5 or 6. In the context of the present invention“" Ci-3-alkylene”" refers to an alkylene moiety with 1, 2 and 3, respectively, -CH2- groups; the term“"alkylene”", however, not only comprises linear alkylene groups, i.e. “"alkylene chains", but branched alkylene groups as well. The term " Ci-6-alkylene" refers to an alkylene moiety that is either linear, i.e. an alkylene chain, or branched and has 1, 2, 3, 4, 5 or 6 carbon atoms. The term " C2-6-alkylene" refers to an alkylene moiety with 2, 3, 4, 5, or 6 carbon atoms, while a " C3-4-alkylene" refers to an alkylene moiety with 3 or 4 carbon atoms and" C2-3-alkylene" refers to an alkylene moiety with 2 or 3 carbon atoms. A substituted alkylene 30 is a group in which one or more methylene hydrogen atoms are replaced by (or with) a substituent. Suitable substituents include those described herein for a substituted alkyl group. In some instances 1 or 2 methylene groups ofForeignfiling_text_P25-005-SEC-WO01

[0364] 36

[0365] the alkylene chain may be replaced by, for instance, 0, S and / or NH or N-Ci- 4-alkyl. Exemplary alkylene groups are -CH2-, -CH2-CH2-, -CH2-CH2-CH2- CH2-, -O-CH2-CH2-, -O-CH2-CH2-CH2-, -CH2-O-CH2-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -CH2-NH-CH2-CH2-, -CH2- 5 N(CH3)-CH2-CH2-.

[0366] The term “alkenylene” refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group. The term “alkenylene” not only refers to straight-chain divalent alkenylene radicals, i.e. an alkenylene chain, but to branched alkenylene groups as well. The term “C2-6-alkenylene” refers to an alkenylene radical having 2, 3, 4, 5, or 6 carbon atoms.

[0367] The term “halogen” means F, Cl, Br, or I. In particular, “halogen” refers to F.

[0368] The term “heteroatom” means one or more of oxygen (O), sulfur (S), or nitrogen (N), including any oxidized form of nitrogen or sulfur, e.g. N-oxides, sulfoxides and sulfones; the quaternized form of any basic nitrogen or a substitutable nitrogen of a heterocyclic or heteroaromatic ring, for example N (as in 3,4-dihydro-2 / - / -pyrrolyl), NH (as in pyrrolidinyl) or N-SUB with SUB being a suitable substituent (as in N-substituted pyrrolidinyl).

[0369] The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, that ring members being carbon atoms, wherein at least one ring in the system is aromatic, i.e., it has (4n+2) π (pi) electrons (with n being an integer selected from 0, 1, 2, 3, 30 4, 5), which electrons are delocalized over the system, and wherein each ring in the system contains three to seven ring members. Preferably, all rings in the aryl system or the entire ring system are aromatic. The term “aryl” is usedForeignfiling_text_P25-005-SEC-WO01

[0370] 37

[0371] interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an “aromatic ring system”. More specifically, those aromatic ring systems may be mono-, bi- or tricyclic with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms. Even more specifically, those aromatic 5 ring systems may be mono- or bicyclic with 6, 7, 8, 9, 10 ring carbon atoms.

[0372] Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which may be unsubstituted or substituted with one or more identical or different substituents. Also included within the scope of the terms “aryl” or “aromatic ring system”, as they are used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. In the latter case the "aryl" group or substituent is attached to its pendant group via the aromatic part of the ring system.

[0373] 15 The term “benzo” refers to a six-membered aromatic ring (with carbon ring atoms) that is fused via two adjacent carbon atoms to another ring, being it a cycloaliphatic, aromatic, heteroaromatic or heterocyclic (heteroaliphatic) ring; as a result a ring system with at least two rings is formed in which the benzo ring shares two common carbon atoms with the other ring to which it is fused.

[0374] 20 For example, if a benzo ring is fused to a phenyl ring, a napthaline ring system is formed, while fusing a benzo ring to a pyridine provides for either a quinoline or an isoquinoline; fusing a benzo ring to a cyclopentene ring provides an indene ring.

[0375] The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms (which atoms are carbon and hetero atoms), preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 π (pi) electrons shared in a cyclic array; and having, in addition to carbon atoms, 1, 2, 3, 4 or 30 5 heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. In other words, a “heteroaryl” ring or ring system (orForeignfiling_text_P25-005-SEC-WO01

[0376] 38

[0377] a heteroaromatic ring or ring system) may also be described as an aromatic heterocycle. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl (pyridinyl), 5 pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, in particular pyrrolo[2, 3-b]pyridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on 10 the heteroaromatic or, if present, the aryl ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. For example, an indolyl ring may be attached via one of the ring atoms of the six-membered aryl ring or via one of the ring atoms of the five-membered heteroaryl ring. A heteroaryl group is optionally mono-, bi- or tricyclic. The term “heteroaryl” is used 20 interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are unsubstituted or substituted with one or more identical or different substituents. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0378] A heteroaryl ring can be attached to its pendant group at any of its hetero or carbon ring atoms which attachment results in a stable structure or molecule: any of the ring atoms may be unsubstituted or substituted.

[0379] 30 As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable mono- bi- or tricyclic heterocyclic moiety with 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ringForeignfiling_text_P25-005-SEC-WO01

[0380] 39

[0381] atoms wherein 1, 2, 3, 4, 5 of said ring atoms are hetero atoms and wherein that heterocyclic moiety is either saturated or partially unsaturated; heterocyclic moieties that are aromatic rings or ring systems are usually referred to as “heteroaryl” moieties as described hereinabove. Preferably, the 5 heterocycle is a stable saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7- membered monocyclic or 6- 7- 8-, 9-, 10- or 11 -membered bicyclic or 11- 12- 13- or 14-membered tricyclic heterocyclic moiety.

[0382] When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB with SUB being a suitable substituent (as in N- substituted pyrrolidinyl).

[0383] 15

[0384] In the context of the term "heterocycle" the term "saturated" refers to a completely saturated heterocyclic system, like pyrrolidinyl, piperidinyl, morpholinyl, piperidinonyl, tetrahydrofuranyl, thianyl, and dioxothianyl. With regard to the term "heterocycle" the term "partially unsaturated" refers to 20 heterocyclic systems (i) that contain one or more units of unsaturation, e.g. a C=C or a C=Heteroatom bond, but that are not aromatic, for instance, tetrahydropyridinyl; or (ii) in which a (saturated or unsaturated but nonaromatic) heterocyclic ring is fused with an aromatic or heteroaromatic ring system, wherein, however, the "partially unsaturated heterocycle" is attached to the rest of the molecule (its pendant group) via one of the ring atoms of the "heterocyclic" part of the system and not via the aromatic or heteroaromatic part. This first class (i) of "partially unsaturated" heterocycles may also be referred to as "non-aromatic partially unsaturated" heterocycles. This second class (ii) of "partially unsaturated" heterocycles may also be referred to as 30 (bicyclic or tricyclic) "partially aromatic" heterocycles indicating that at least one of the rings of that heterocycle is a saturated or unsaturated but non- aromatic heterocycle that is fused with at least one aromatic orForeignfiling_text_P25-005-SEC-WO01

[0385] 40

[0386] heteroaromatic ring system. Typical examples of these "partially aromatic" heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4- tetrahydroisoquinolinyl.

[0387] 5 A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms may be unsubstituted or substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, thianyl, dioxothianyl, 10 tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group is optionally 20 mono-, bi- or tricyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are unsubstituted or substituted.

[0388] The term “unsaturated”, as used herein, means that a moiety or group or substituent has one or more units of unsaturation.

[0389] As used herein with reference to any rings, ring systems, ring moieties, and the like, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended 30 to encompass rings having multiple sites of unsaturation. In particular, it encompasses (i) non-saturated (mono-, bi- or tricyclic) ring systems without any aromatic or heteroaromatic moiety or part; and (ii) bi- or tricyclic ringForeignfiling_text_P25-005-SEC-WO01

[0390] 41

[0391] systems in which one of the rings of that system is an aromatic or heteroaromatic ring which is fused with another ring that is neither an aromatic nor a heteroaromatic ring, e.g. tetrahydronaphthyl or tetrahydroquinolinyl. The first class (i) of "partially unsaturated" rings, ring 5 systems, ring moieties may also be referred to as "non-aromatic partially unsaturated" rings, ring systems, ring moieties, while the second class (ii) may be referred to as "partially aromatic" rings, ring systems, ring moieties.

[0392] As used herein, the term “bicyclic”, “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e. being partially unsaturated or aromatic, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a 15 subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as 20 phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Likewise, the term “tricyclic”, “tricyclic ring” or “tricyclic ring system” refers to any tricyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, i.e. being partially unsaturated or aromatic, in which a bicyclic ring system (as defined above) is fused with another, third ring. Thus, the term includes any permissible ring fusion. As used herein, the term “heterotricyclic” is a subset of “tricyclic” that requires that one or more heteroatoms are present in one or both rings of the tricycle. Such heteroatoms may be present at ring junctions and are optionally 30 substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. InForeignfiling_text_P25-005-SEC-WO01

[0393] 42

[0394] some embodiments, a tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0395] As described herein, certain compounds of the invention contain “substituted” 5 or “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that are either explicit or implicit from the structure. Unless otherwise indicated, a “substituted” or “optionally substituted” group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent is either the same or different at every position. If a certain group, substituent, moiety or radical is "mono-substituted", it bears one (1) 15 substituent. If it is "di-substituted", it bears two (2) substituents, being either the same or different; if it is "tri-substituted", it bears three (3) substituents, wherein all three are the same or two are the same and the third is different or all three are different from each other. Combinations of substituents envisioned by this invention are preferably those that result in the formation 20 of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0396] If not specified otherwise elsewhere in the specification or the accompanying claims it is understood that each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; - (CH2)O-4R°; -(CH2)O-4OR°; -0(CH2)O-4R°, -0-(CH2)O-4C(0)OR°; -(CH2)O- 30 4CH(0RO)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with one or more R°; -(CH2)O-40(CH2)O-I Ph which may be substituted with one or more R°; -CH=CHPh, which may be substituted with one or more R°; -(CH2)o-Foreignfiling_text_P25-005-SEC-WO01

[0397] 43

[0398] 40(CH2)O-I -pyridyl which may be substituted with one or more R°; -NO2; - CN; -N3; -(CH2)O-4N(R0)2; -(CH2)O-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)O- 4N(RO)C(0)NRO2; -N(RO)C(S)NR°2; -(CH2)O-4N(R°)C(0)OR°;

[0399] N(R°)N(R°)C(O)R°; -N(Ro)N(Ro)C(0)NRo2; -N(R°)N(R°)C(O)OR°; -(CH2)o- 54C(O)R°; -C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)O-4C(0)SR°; -(CH2)O-4C(0)0SiRo3; -(CH2)O-40C(0)R°; -OC(0)(CH2)O-4SR- SC(S)SR°; -(CH2)O-4SC(O)R°; -(CH2)O-4C(0)NR°2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O- 4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)20R°; -(CH2)O- 10

[0400] 40S(0)2RO; -S(0)2NRO2; -S(O)(NR°)R°; -S(0)2N=C(NRO2)2; -(CH2)O-4S(O)R°; -N(RO)S(0)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; - P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C1-4 straight or branched alkylene)O-N(R°)2; or-(Ci-4 straight or branched alkylene)C(O)O- N(R°)2. It is understood that “Ph” means phenyl; and that “-(CH2)o-4” means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1, 2, 3 or 4 CH2 units.

[0401] Each R° is independently hydrogen, halogen, C1-6 aliphatic, -CH2Ph, - 20 0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2)o-2R*, - 30 (haloR*), -(CH2)O-2OH, -(CH2)O-20R*, -(CH2)O-2CH(OR*)2; O(haloR’), -CN,

[0402] -N3, -(CH2)O-2C(0)R*, -(CH2)O-2C(0)OH, -(CH2)O-2C(0)OR*, -(CH2)O-2SR*, -(CH2)O-2SH, - (CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -Foreignfiling_text_P25-005-SEC-WO01

[0403] 44

[0404] OSiR*3, C(O)SR* -(C1-4 straight or branched alkylene)C(O)OR*, or-SSR*. It is understood that “Ph” means phenyl; “halo” means halogen; and “-(CH2)o- 2 means that there is either no alkylene group if the subscript is “0” (zero) or an alkylene group with 1 or 2 CH2 units.

[0405] 5

[0406] Each R* is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o- 1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is 10 substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =0, =S, =NNR*2, =NNHC(O)R‘, =NNHC(O)OR‘, =NNHS(O)2R‘, =

[0407]

[0408] NR‘, =NOR‘, - O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, or a divalent substituent bound to vicinal substitutable carbons of an “optionally substituted” group is - O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0409] 20 When R* is C1-6 aliphatic, R* is optionally substituted with halogen, -R*,

[0410] (haloR*), OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is independently selected from C1- 4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0411] An optional substituent on a substitutable nitrogen is independently -Rt, - NRt2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, 30 C(O)CH2C(O)Rf, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, -C(NH)NRt2, or - N(R1’)S(O)2Rt; wherein each Rt is independently hydrogen, C1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partiallyForeignfiling_text_P25-005-SEC-WO01

[0412] 45

[0413] unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of Rt, taken together with their intervening atom(s) form an unsubstituted 3-12- membered saturated, partially unsaturated, or aryl mono- or bicyclic ring 5 having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when Rt is C1-6 aliphatic, Rt is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, - C(O)OR*, — NH2, -NHR*, -NR*2, or-NO2, wherein each R* is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered 10 saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens. It is understood that “Ph” means phenyl; and “halo” means halogen.

[0414] The term “solvates” means addition forms of the compounds of the present invention with solvents, preferably pharmaceutically acceptable solvents that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules 20 in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, e.g. a hemi-, mono- or dihydrate. If the solvent is alcohol, the solvate formed is an alcoholate, e.g., a methanolate or ethanolate. If the solvent is an ether, the solvate formed is an etherate, e.g., diethyl etherate.

[0415] The term " N-oxides" means such compounds of the present invention that contain an amine oxide moiety, i.e. the oxide of a tertiary amine group.

[0416] The compounds of formula I may - also depending on the nature of 30 substituents they may bear - have one or more centers of chirality. They may accordingly occur in various enantiomeric and diastereomeric forms, as the case may be, and be in racemic or optically active form. The invention,Foreignfiling_text_P25-005-SEC-WO01

[0417] 46

[0418] therefore, also relates to the optically active forms, enantiomers, racemates, diastereomers, mixtures thereof in all ratios, collectively: “stereoisomers” for the purpose of the present invention, of these compounds. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds 5 according to the invention may differ, it may be desirable to use a specific stereoisomer, e.g. one specific enantiomer or diastereomer. In these cases, a compound according to the present invention obtained as a racemate or even intermediates thereof - may be separated into the stereoisomeric (enantiomeric, diastereoisomeric) compounds by chemical or physical measures known to the person skilled in the art. Another approach that may be applied to obtain one or more specific stereoisomers of a compound of the present invention in an enriched or pure form makes use of stereoselective synthetic procedures, e.g. applying starting material in a stereoisomerically enriched or pure form (for instance using the pure or enriched (R)- or (S)- 15 enantiomer of a particular starting material bearing a chiral center) or utilizing chiral reagents or catalysts, in particular enzymes. In the context of the present invention the term "pure enantiomer" usually refers to a relative purity of one enantiomer over the other (its antipode) of equal to or greater than 95%, preferably > 98 %, more preferably > 98.5%, still more preferably > 99%.

[0419] 20

[0420] Thus, for example, the compounds of the invention which have one or more centers of chirality and which occur as racemates or as mixtures of enantiomers or diastereoisomers can be fractionated or resolved by methods known per se into their optically pure or enriched isomers, i.e. enantiomers or diastereomers. The separation of the compounds of the invention can take place by chromatographic methods, e.g. column separation on chiral or nonchiral phases, or by recrystallization from an optionally optically active solvent or by use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, 30 and subsequent elimination of the radical.Foreignfiling_text_P25-005-SEC-WO01

[0421] 47

[0422] In the context of the present invention the term “tautomer” refers to compounds of the present invention that may exist in tautomeric forms and show tautomerism; for instance, carbonyl compounds may be present in their keto and / or their enol form and show keto-enol tautomerism. Those 5 tautomers may occur in their individual forms, e.g., the keto or the enol form, or as mixtures thereof and are claimed separately and together as mixtures in any ratio. The same applies for cis / trans isomers, E / Z isomers, conformers and the like.

[0423] In one embodiment the compounds of the present invention are in the form of free base or acid - as the case may be -, i.e. in their non-salt (or salt-free) form. In another embodiment the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a 15 pharmaceutically acceptable salt.

[0424] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. In cases where the compounds of the 20 present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically acceptable salts. Thus, the compounds of the present invention which contain acidic groups, such as carboxyl groups, can be present in salt form, and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts, aluminium salts or as ammonium salts. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, diethanolamine, triethanolamine, piperdine, N-methylglutamine or amino acids. These salts are readily 30 available, for instance, by reacting the compound having an acidic group with a suitable base, e.g. lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calciumForeignfiling_text_P25-005-SEC-WO01

[0425] 48

[0426] hydroxide or barium hydroxide. Other base salts of compounds of the present invention include but are not limited to copper(l), copper(ll), iron(ll), iron (III), manganese(ll) and zinc salts. Compounds of the present invention which contain one or more basic groups, e.g. groups which can be protonated, can 5 be present in salt form, and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, 10 trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonicacid, mandelic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid, and other acids known to the person skilled in the art. The salts which are formed are, inter alia, hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), tosylates, carbonates, bicarbonates, formates, acetates, 20 sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates. The stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or nonintegral multiple of one.

[0427] Compounds of the present invention which contain basic nitrogen-containing groups can be quaternized using agents such as (Ci-C4)alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; di(Ci-C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10- 30 Cis)alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl(Ci-C4)alkyl halides, for example benzylForeignfiling_text_P25-005-SEC-WO01

[0428] 49

[0429] chloride and phenethyl bromide. Both water- and oil-soluble compounds according to the invention can be prepared using such salts.

[0430] If the compounds of the present invention simultaneously contain acidic and 5 basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to a person skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation 10 exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0431] Therefore, the following items are also in accordance with the invention: (a) all stereoisomers or tautomers of the compounds, including mixtures thereof in all ratios;

[0432] (b) pharmaceutically acceptable salts of the compounds and of the items 20 mentioned under (a);

[0433] (c) pharmaceutically acceptable solvates of the compounds and of the items mentioned under (a) and (b);

[0434] (d) N-oxides of the compounds and of the items mentioned under (a), (b), and (c).

[0435] It will be understood that all references to compounds above and below are meant to include these items, in particular pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable solvates of their pharmaceutically acceptable salts.

[0436] 30

[0437] There is furthermore intended that a compound of the present invention includes isotope-labelled forms thereof. An isotope-labelled form of aForeignfiling_text_P25-005-SEC-WO01

[0438] 50

[0439] compound of the formula I is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally. Examples 5 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, phosphorus, sulfur, fluorine and chlorine, for example2H (D),3H,13C,14C,15N,18O,17O,31P,32P,33S,34S,35S,36S,18F and36CI, respectively. A 10 compound of formula I or a pharmaceutically acceptable salt thereof 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 isotopelabelled compound of formula I 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 simple preparation and excellent detectability. Incorporation of heavier isotopes, for example deuterium (2H), into a compound of formula I 20 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 formula I 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 by a readily available isotope-labelled reactant.

[0440] 30 Deuterium (2H; D) can also be incorporated into a compound of formula I for the purpose of manipulating the oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect isForeignfiling_text_P25-005-SEC-WO01

[0441] 51

[0442] a change of the rate for 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 exchange. Exchange of a heavier isotope usually results in a lowering of the ground 5 state energy for a chemical bond and thus cause 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 at a non-exchangeable position, rate differences of kM / kD= 2-7 are typical. If this rate difference is successfully applied to a compound of the formula I that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties.

[0443] 15 When discovering and developing therapeutic agents, the person skilled in the art attempts to optimize pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. In vitro liver microsomal assays currently available provide valuable 20 information on the course of oxidative metabolism of this type, which in turn permits the rational design of deuterated compounds of the formula I with improved stability through resistance to such oxidative meta-bolism. Significant improvements in the pharmacokinetic profiles of compounds of the formula I 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 materials costs.

[0444] The following is intended to illustrate the above: a compound of formula I 30 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 ofForeignfiling_text_P25-005-SEC-WO01

[0445] 52

[0446] hydrogen atoms are replaced by deuterium atoms, so that some, most or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favourable and accurate determination of the extent of the extent to which the improvement in resistance to oxidative metabolism 5 has improved. In this way, it is deter-mined that the half-life of the parent compound can be extended by up to 100% as the result of deuteriumhydrogen exchange of this type.

[0447] Deuterium-hydrogen exchange in a compound of the present invention can 10 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 carbon-hydrogen (C-H) bond cleavage, it can reasonably be assumed that the deuterated analogue will greatly diminish or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate-determining step. Further information on the state of the art with respect to deuteriumhydrogen exchange may be found, for 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 20 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688,

[0448] 1995.

[0449] Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound of formula I, or its N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, as active ingredient, together with a pharmaceutically acceptable carrier.

[0450] 30 For the purpose of the present invention the term “pharmaceutical composition” (or “pharmaceutical formulation”) refers to a composition or product comprising one or more active ingredients, and one or more inertForeignfiling_text_P25-005-SEC-WO01

[0451] 53

[0452] ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of 5 the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing at least one compound of the present invention and a pharmaceutically acceptable carrier. It may further comprise physiologically acceptable excipients, auxiliaries, adjuvants, diluents and / or additional pharmaceutically active substance other than the compounds of the invention.

[0453] The pharmaceutical compositions include compositions and pharmaceutical formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

[0454] A pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention. In a particular embodiment the pharmaceutical composition further comprises a second active ingredient or its N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, wherein that second active ingredient is other than a compound of formula I; preferably, that second active ingredient is a compound that is useful in the treatment, prevention, 30 suppression and / or amelioration of medicinal conditions or pathologies for which the compounds of the present invention are useful as well and which are listed elsewhere hereinbefore or hereinafter. Such combination of two orForeignfiling_text_P25-005-SEC-WO01

[0455] 54

[0456] more active ingredients or drugs may be safer or more effective than either drug or active ingredient alone, or the combination is safer or more effective than it would be expected based on the additive properties of the individual drugs. Such other drug(s) may be administered, by a route and in an amount 5 commonly used contemporaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs or active ingredients, a combination product containing such other drug(s) and the compound of the invention - also referred to as “fixed dose combination” - is preferred. However, combination therapy also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is contemplated that when used in combination with other active ingredients, the compound of the present invention or the other active ingredient or both may be used effectively in lower doses than when 15 each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.

[0457] The compounds of the present invention - or N-oxides, solvates, tautomers 20 or stereoisomers thereof and / or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios - can be used as medicaments. They have been found to exhibit pharmacological activity by binding to TEAD and / or disrupting and / or inhibiting YAP-TEAD and / or TAZ-TEAD protein-protein interaction. It is worth mentioning that some of the compounds of the present invention may not only bind to one of the TEAD family members (TEAD 1, 2, 3, or 4) but to more than one TEAD paralog, i.e., to two, three or even all four TEAD paralogs, thereby exhibiting activity as pan-TEAD inhibitors. It is assumed that by this activity the compounds of the present invention may prevent or reverse dysfunction of the Hippo pathway.

[0458] 30 By preventing its dysfunction, the Hippo pathway may be capable of playing its role as a tumor suppressor. Apart from preventing or reversing dysfunction of the Hippo pathway and independent of upstream Hippo regulation, theForeignfiling_text_P25-005-SEC-WO01

[0459] 55

[0460] pharmacological activity of the compounds of the present invention may also be useful in other pathophysiological scenarios where inhibition or disruption of TEAD binding and / or aberrant YAP-TEAD and / or aberrant TAZ-TEAD signaling would be beneficial.

[0461] 5

[0462] Thus, the compounds of the present invention being TEAD binders and / or inhibitors of YAP-TEAD and / or TAZ-TEAD interaction are useful in particular in the treatment, prevention, suppression and / or amelioration of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cancer, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, basal cell carcinoma. Without wishing to commit to any specific theory or explanation it 15 may be assumed that the compounds might be able to achieve this by direct effects on the cancer cells and / or indirectly by modulating the response of the immune system against the tumor. Furthermore, the compounds of the present invention may also be useful in the treatment, prevention, suppression and / or amelioration of non-cancerous disorders and diseases, 20 e.g. cardiovascular diseases and fibrosis (like liver fibrosis).

[0463] In a particular embodiment the compounds of the present invention are for use in the prevention and / or treatment, especially in the treatment of any of the disorders or diseases listed above, preferably of cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraph; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraph.

[0464] Another particular embodiment of the present invention is a method for 30 preventing and / or treating, preferably treating a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of the specific types of cancerForeignfiling_text_P25-005-SEC-WO01

[0465] 56

[0466] disclosed in the previous paragraphs; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraphs.

[0467] Still another particular embodiment of the invention is the use of a compound 5 of the present invention - or N-oxides, prodrugs, solvates, tautomers or stereoisomers thereof and / or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios - for the manufacturing of a medicament, in particular for preventing and / or treating, preferably treating a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; or of any of the non-cancerous disorders or diseases disclosed in the previous paragraphs.

[0468] 15 Preferably, the present invention relates to a compound of the present invention for use in the prevention and / or treatment of a disease - or, alternatively, a method for preventing and / or treating a disease by administering an effective amount of a compound of the present invention; or, in another alternative, a use of a compound of the present invention for 20 the manufacturing of a medicament for the prevention and / or treatment of a disease - wherein that disease is a cancer, in particular tumors including solid tumors, of the specific types of cancer disclosed in the previous paragraphs; and more preferably, wherein administration of the compound is simultaneous, sequential or in alternation with administration of at least one other active drug agent.

[0469] The disclosed compounds of the present invention and in particular of formula I can be administered in combination with other known therapeutic agents, including anticancer agents. As used here, the term "anticancer agent" 30 relates to any agent which is administered to a patient with cancer for the purposes of treating the cancer. The anti-cancer treatment defined above may be applied as a monotherapy or may involve, in addition to the hereinForeignfiling_text_P25-005-SEC-WO01

[0470] 57

[0471] disclosed compounds of the present invention, conventional surgery or radiotherapy or medicinal therapy. Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, may include one or more, but preferably one, of the following anti-tumor agents:

[0472] 5 Alkylating agents

[0473] such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboguone; apaziguone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, evofosfamide, VAL- 083(dianhydrogalactitol);

[0474] Platinum Compounds

[0475] such as carboplatin, cisplatin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

[0476] DNA altering agents

[0477] such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine;

[0478] Topoisomerase Inhibitors

[0479] such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;

[0480] Microtubule modifiers

[0481] such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel;

[0482] Antimetabolites

[0483] such as asparaginase, pegaaspargase, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, 30 elacytarabine, raltitrexed, sapacitabine, tegafur, trimetrexate;Foreignfiling_text_P25-005-SEC-WO01

[0484] 58

[0485] Anticancer antibiotics

[0486] such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, 5 pirarubicin;

[0487] Hormones / Antagonists

[0488] such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide;

[0489] Aromatase inhibitors

[0490] such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

[0491] Small molecule kinase inhibitors

[0492] such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tepotinib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib (rivoceranib), cabozantinib S-malate, ibrutinib, icotinib, buparlisib, cipatinib, cobimetinib, idelalisib, fedratinib, tesevatinib;

[0493] Photosensitizers

[0494] such as methoxsalen; porfimer sodium, talaporfin, temoporfin;

[0495] Antibodies

[0496] 30 such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab; catumaxomab,Foreignfiling_text_P25-005-SEC-WO01

[0497] 59

[0498] elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, racotumomab, tabalumab, 5 abituzumab, atezolizumab, durvalumab, pembrolizumab, nivolumab;

[0499]

[0500] such as aldesleukin, interferon alfa2, interferon alfa2a, interferon alfa2b; celmoleukin, tasonermin, teceleukin, oprelvekin, recombinant interferon betala;

[0501]

[0502] such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I 123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab, vintafolide;

[0503] PARP inhibitors

[0504] such as olaparib, veliparib, niraparib, rucaparib, talzaoparib, pamiparib; KRAS inhibitors

[0505] such as sotorasib, adagrasib;

[0506] Miscellaneous

[0507] such as alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel, sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine, picibanil, reolysin, retaspimycin hydrochloride, trebananib, virulizin, carfilzomib, endostatin, 30 immucothel, belinostat;Foreignfiling_text_P25-005-SEC-WO01

[0508] 60

[0509] In a particular embodiment of the present invention, the medical therapy includes a combination of a compound of the present invention, which inhibits the activity of TEAD, with a KRAS inhibitor.

[0510] 5 In another aspect of the invention, a set or kit is provided comprising a therapeutically effective amount of at least one compound of the invention and / or at least one pharmaceutical composition as described herein and a therapeutically effective amount of at least one further pharmacologically active substance other than the compounds of the invention. It is preferred that this set or kit comprises separate packs of

[0511] a) an effective amount of a compound of formula I, or any of its N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, and

[0512] 15 b) an effective amount of a further active ingredient that further active ingredient not being a compound of formula I.

[0513] A further embodiment of the present invention is a process for the manufacture of the pharmaceutical compositions of the present invention, 20 characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semiliquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the invention, are converted in a suitable dosage form.

[0514] The pharmaceutical compositions (formulations) of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, 30 transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively, or concurrently, administration may be via the oral route. The dosage administered will be dependent upon the age, health,Foreignfiling_text_P25-005-SEC-WO01

[0515] 61

[0516] and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is especially preferred.

[0517] 5 Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, which can be produced according to methods known in the art.

[0518] In general, non-chemical routes for the production of pharmaceutical compositions and / or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds of the invention into a dosage form suitable for administration to 15 a patient in need of such a treatment. Usually, the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries, and pharmaceutical active ingredients other than the compounds of the invention. Suitable processing steps include, but are not 20 limited to combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and / or compressing the respective active and nonactive ingredients. Mechanical means for performing said processing steps are known in the art. In this respect, active ingredients are preferably at least one compound of the invention and optionally one or more additional compounds other than the compounds of the invention, which show valuable pharmaceutical properties, preferably those pharmaceutical active agents other than the compounds of the invention, which are disclosed herein.

[0519] Particularly suitable for oral use are tablets, pills, coated tablets, capsules, 30 powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, andForeignfiling_text_P25-005-SEC-WO01

[0520] 62

[0521] suitable for topical use are ointments, creams or powders. The compounds of the invention may also be lyophilized and the resultant lyophilizates used, for example, for the preparation of injection preparations. The preparations indicated may be sterilized and / or comprise assistants, such as lubricants, 5 preservatives, stabilizers and / or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavors and / or a plurality of further active ingredients, for example one or more vitamins.

[0522] Suitable excipients are organic or inorganic substances, which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose 15 preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone and / or vaseline.

[0523] 20 If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or 30 solvent mixtures. In order to produce coatings resistant to gastric juices or to provide a dosage form affording the advantage of prolonged action, the tablet, dragee or pill can comprise an inner dosage and an outer dosageForeignfiling_text_P25-005-SEC-WO01

[0524] 63

[0525] component the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be 5 used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethylcellulose phthalate, are used. Dye stuffs or pigments may be added to the 10 tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0526] Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or 20 aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injection preparations.

[0527] Other pharmaceutical preparations, which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules, which may be mixed 30 with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are preferably dissolved or suspended in suitableForeignfiling_text_P25-005-SEC-WO01

[0528] 64

[0529] liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[0530] The liquid forms in which the novel compositions of the present invention may 5 be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

[0531] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble 15 salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).

[0532] 20

[0533] Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran, optionally, the suspension may also contain stabilizers.

[0534] Possible pharmaceutical preparations, which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In 30 addition, it is also possible to use gelatin rectal capsules, which consist of a combination of the active compounds with a base. Possible base materialsForeignfiling_text_P25-005-SEC-WO01

[0535] 65

[0536] include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0537] The pharmaceutical preparations can be employed as medicaments in 5 human and veterinary medicine. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term also includes within its scope a "therapeutically effective amount" which means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, or of symptoms associated with such disease or disorder; it may also refer to preventing or providing 15 prophylaxis for the disease or disorder in a subject having or at risk for developing a disease disclosed herein. The term also includes within its scope amounts effective to enhance normal physiological function. Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by 20 standard methods known in the art.

[0538] " Treating" or “treatment” as used herein, means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing, or halting of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder in a subject at risk for developing the disease or disorder.

[0539] The compounds of the present invention and the optional additional active substances are generally administered analogously to commercial 30 preparations. Usually, suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and especially between 0.5 mg and 100 mg per dose unit. TheForeignfiling_text_P25-005-SEC-WO01

[0540] 66

[0541] daily dose is preferably between about 0.001 mg / kg and 10 mg / kg of body weight.

[0542] Those of skill will readily appreciate that dose levels can vary as a function of 5 the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[0543] The specific dose for the individual patient, in particular for the individual human patient, depends, however, on the multitude of factors, for example on the efficacy of the specific compounds employed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of 15 administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy relates. The specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which 20 advises or attends the therapeutic treatment.

[0544] The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials, and as further exemplified by the following specific examples. They may also be prepared by methods known per se, as described in the literature, to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made of variants which are known per se, but are not mentioned here in greater detail.

[0545] 30 Likewise, the starting materials for the preparation of compounds of the present invention can be prepared by methods as described in the examples or by methods known per se, as described in the literature of syntheticForeignfiling_text_P25-005-SEC-WO01

[0546] 67

[0547] organic chemistry and known to the skilled person, or can be obtained commercially. The starting materials for the processes claimed and / or utilized may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds 5 of the invention or intermediate compounds. On the other hand, in general it is possible to carry out the reaction stepwise.

[0548] It will be recognized by those skilled in the art that some of the compounds of formula I may serve as starting material for making other compounds of formula I. For instance, a compound of formula I bearing a carboxylic functional group may readily be converted into a related compound of formula I bearing an amide functional group by utilizing appropriate synthetic methods.

[0549] Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents or mixtures with water.

[0550] 30

[0551] The reaction temperature is between about -100°C and 300°C, depending on the reaction step and the conditions used.Foreignfiling_text_P25-005-SEC-WO01

[0552] 68

[0553] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily 5 determinable by methods known in the art, for example reaction monitoring.

[0554] Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0555] Moreover, by utilizing the procedures described herein, in conjunction with 10 ordinary skills in the art, additional compounds of the present invention described and claimed herein can be readily prepared. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0556] The present invention also refers to a process for manufacturing a compound 20 of formula I in its most general form and embodiments as well as any of the particular embodiments, PE1, PE2, PE2a, PE3, PE3a, PE3b, PE4, PE4a, PE5, PE5a, PE6, PE6a, PE7, PE7a, PE7b, PE7c, PE7d, PE8, PE9, PE9a, PE10, PE11, PE11a, PE11aa, PE12, PE12a, PE13, PE14, PE15. PE15a, and PE15b described herein, or N-oxides, solvates, tautomers or stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, the process being characterized in that

[0557] (A) in a first reaction step a compound of formula II

[0558] 30Foreignfiling_text_P25-005-SEC-WO01

[0559] 5

[0560]

[0561] wherein

[0562] R1, R3, and X1are defined as for formula I hereinabove or below;

[0563] Y1denotes H or a suitable protecting group, PG1;

[0564] Hal1denotes Cl, Br, or I;

[0565] is reacted under suitable C-C coupling reaction conditions with a compound of formula III

[0566] Y2-A-L1-B

[0567]

[0568] wherein

[0569] A, L1, and B are defined as for formula I hereinabove or below;

[0570] Y2denotes a suitable boronate functional group;

[0571] to provide a compound of formula IV

[0572] A

[0573] IV;

[0574]

[0575] (B) in a first reaction step a compound of formula V

[0576] 30Foreignfiling_text_P25-005-SEC-WO01

[0577] 70

[0578] 5

[0579]

[0580] V

[0581] wherein

[0582] R1, R3, and X1are defined as for formula I hereinabove or below; Y1denotes H or a suitable protecting group, PG1;

[0583] 10

[0584] Y3denotes a suitable boronate functional group;

[0585] is reacted under suitable C-C coupling reaction conditions with a compound of formula VI

[0586] Hal2-A-L1-B

[0587] VI

[0588] wherein

[0589] A, L1, and B are defined as for formula I hereinabove or below;

[0590] Hal2denotes Cl, Br, or I;

[0591] to provide a compound of formula IV;

[0592] and, optionally,

[0593] 20

[0594] (C) (1) if in formula IV above Y1denotes PG1, in a second reaction step PG1is removed under suitable reaction conditions to provide a compound of formula IV with Y1being H, which can also be described as a compound of formula I with R2being H; and / or

[0595] (C) (2) if in formula IV above Y1denotes H, in another reaction step that compound of formula IV is reactied under suitable reaction conditions with a compound of formula VII

[0596] R2-LG1

[0597] VII

[0598] wherein

[0599] 30

[0600] R2is defined as hereinabove or belowwith the exception of H; and LG1denotes a suitable leaving group;Foreignfiling_text_P25-005-SEC-WO01

[0601] 71

[0602] to provide a compound of formula I as defined hereinabove or below; and, optionally, and, optionally, after step (C),

[0603] the compound of formula I is separated into its individual atropisomers.

[0604] 5 As will be understood by the person skilled in the art of organic synthesis compounds of the present invention, in particular compounds of formula I, are readily accessible by various synthetic routes, some of which are exemplified in the accompanying Experimental Part. The skilled artisan will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance - wherever necessary or useful - in order to obtain the compounds of the present invention. Furthermore, some of the compounds of the present invention can readily be synthesized by reacting other compounds of the present invention under suitable conditions, for instance, by converting one 15 particular functional group being present in a compound of the present invention, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilled artisan will apply - whenever necessary or useful - 20 synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well-known to the person skilled in the art of chemical synthesis.

[0605] In the following general synthetic routes that may be utilized to prepare compounds of the present invention are described in more detail in Schemes A to F below

[0606] 30Foreignfiling_text_P25-005-SEC-WO01

[0607] 72

[0608] 5

[0609]

[0610] Scheme A

[0611] Scheme A above depicts a general route of synthesis for preparing compounds of formula I (here depicted as formula H). Unless specifically defined in a different manner, R1, R2, R3, A, L1, B, and X1are defined as for the compounds of formula I hereinabove or hereinbelow. The substituted 5- azaindole (or 1 H-pyrrolo[3,2-c]pyridine) (= formula A with X1being CRX1, in particular CH; compound of formula l-A) of formula A or substituted 1H- pyrazolo[4,3-c]pyridine (= formula A with X1being N; compound of formula I- B) of formula A is either available from a commercial source or readibly available by utilizing synthetic methods and procedures well-known to the skilled person. In reaction step (a) the bicyclic compound of formula A is reacted with an iodination reagent under suitable reaction condition, for instance, iodo-succinimide (NIS; 1-iodopyrrolidinone-2, 5-dione) in DMF, to provide the iodinated compound of formula B. Subsequently, in reaction step (b) the compound of formula B is reacted under appropriate reaction conditions with a suitable reagent for introducing a suitable protecting group, 30

[0612] Y1, on the nitrogen ring atom in position 5 of the bicyclic ring system, to yield the compound of formula C. A suitable protecting group Y1may be anyForeignfiling_text_P25-005-SEC-WO01

[0613] 73

[0614] protecting group, PG1, that substantially protects this nitrogen ring atom in 5- position from reacting with any of the reagents and substances utilized in the following reaction step (c). Examples for such suitable protecting groups are tert.-butyl carboxylate (-C(=O)-O-tert.-butyl), which may be introduced by 5 reacting the compound of formula B with, e.g., di-tert.-butyl carbonate in the presence of catalytic amounts of DMAP (4-dimethylaminopyridine); or (trimethylsilyl)ethoxy-methyl (-CH2-O-(CH2)2-Si(CH3)3), which may be introduced by reacting the compound of formula B with, e.g., [2- (chloromethoxy)ethyl]trimethylsilane in the presence of sodium hydride (NaH); or tosylate (p-methylphenylsulfonyl) which may be introduced by reacting the compound of formula B with, e.g., tosylchloride in the presence of NaH. In reaction (c) the compound of formula C is reacted in a C-C crosscoupling reaction, for instance a Suzuki coupling, with the compound of formula D, wherein A, L1, and B have the same meaning as for compounds 15 of formula I and Y2is a boronate functional group (e.g., -B(OH)2 or a suitable ester thereof). The boronic acid or boronic acid ester derivative of formula D is readily available, e.g., from the respective chloro-substituted compound of formula D (Y2= Cl) by methods well-known in the art; for instance, by utilizing trimethyl borate in the presence of a strong base like phenyl lithium and 20 subsequent hydrolysis of the boronic acid ester to yield the boronic acid (Y2

[0615] = -B(OH)2) or by utilizing 4,4,5,5-tetramethyl-1,3,2-dioxaborolan in the presensence of potassium acetate and chloro(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-1, T-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ll) (XphosPd G2) as a palladium(ll)-catalyst to provide the compound of formula

[0616]

[0617] D with Y2= Reaction step (c) is performed under typical reaction conditions of C-C cross-coupling reactions like the Suzuki coupling, for instance by reacting compound of formula C with compound of formula D 30 in the presence of potassium carbonate and 1,1'- bis(diphenylphosphino)ferrocene palladium or 4-[bis(2-methyl-2- propanyl)phosphino]-N, N-dimethylaniline-dichloropalladiumForeignfiling_text_P25-005-SEC-WO01

[0618] 74

[0619] (Pd(amphos)2Cl2). Removing the protecting group, Y1, from the compound of formula E in reaction step (d) under either acidic (e.g., trifluoro acetic acid, TFA) or basic conditions (e.g., sodium hydroxide) depending on the nature of the specific protecting group yields the compound of formula F, which can 5 also be described as a compound of formula I with R2being H. Finally, compounds of formula I with a substituent R2other than H, i.e., compounds of formula H in Scheme A are available by reacting a compound of formula F with an appropriate compound of formula G, LG1-R2with LG1being a suitable leaving group and R2being as defined for formula I (except for H) (reaction 10 step (e)). For instance, if LG1is a halogen selected from Cl, Br or I, then reaction step (e) may be nucleophilic substitution reaction of the compound of formula F with LG1-R2. Depending on the specific nature of LG1-R2this reaction step (e) may be performed by deprotonating the NH group utilizing a suitable base such as sodium hydride or cesium carbonate and subsequent reaction of the intermediate with a suitable compound of formula G, e.g., a alkyliodide like CH3-I, a brominated compound like Br-CH2CN, or a chlorinated compound like chloromethylimidazole hydrochloride. Substituent R2of the compound of formula H may further be modified to obtain further compounds of formula H.

[0620] 20

[0621]

[0622] Scheme B

[0623] Scheme B above depicts an alternative route of synthesis of compounds of formula I which bear a substituent R2that remains unaffected under C-C 30 cross coupling reactions of a Suzuki or similar cross-coupling reaction: A compound of formula B is subjected to a reaction (step (f)) with a suitable compound of formula G under conditions which are similar to those describedForeignfiling_text_P25-005-SEC-WO01

[0624] 75

[0625] above for reaction step (e) in Scheme A to provide the respective compound of formula J. The compound of formula J then in turn is subjected to a reaction with a compound of formula D (step (g)) under reaction conditions which are similar to those described above for reaction step (c) in Scheme A. 5

[0626]

[0627] Scheme C

[0628] Scheme C depicts an alternative route for synthesizing a compound of formula E wherein L1denotes a divalent -O-CH2- linker group (compounds of formula E-1 in Scheme C): A compound of formula C (available via the 15

[0629] synthetic route outlined in Scheme A above) may be reacted in a C-C crosscoupling reaction with a compound of formula K (reaction step (g)), wherein A is as defined for formula I and Y2is as defined for compound D in Scheme A above to yield the hydroxy-substituted compound of formula L. Reaction conditions of step (g) may be the same or similar to the reaction conditions 20

[0630] of step (c) in Scheme A. The compound of formula L may then be reacted under appropriate reaction conditions (utilizing, e.g., cesium carbonate in DMF) with a compound of formula M, wherein B is as defined for formula I and Y3denotes LG2-CH2- with LG2being a suitable leaving group, such as a alkyl-SO3group (alkylsulfonate), which provides a compound of formula E-1 with L1denoting a divalent -O-CH2- radical. The compound of formula E-1 may then be subjected to the reactions steps (d) and optionally (c) as described for Scheme A above to provide compounds of formula F and H, respectively, with L1denoting a divalent -O-CH2-radical.

[0631] 30Foreignfiling_text_P25-005-SEC-WO01

[0632] 5

[0633]

[0634] 10

[0635]

[0636] A’CF3N-CF3

[0637] Scheme D

[0638] Scheme D summarizes one of the potential synthetic routes for making compounds of formula I, and in particular of formula l-C, in which R1denotes CF3: The 1-chloro-substituted compound of formula A (A-CI) is subjected to 20

[0639] a tosylation reaction, in which first a strong base, like NaH is added and then p-tolylsulfonylchloride to provide the compound of formula N-CI (reaction step (j)) (with Ts representing a tosylate group), which in turn is reacted with hydriotic acid (HI) in the presence of sodium iodide (Nal) to yield the compound of formula N-l (reaction step (k)). In subsequent reaction step (m) compound N-l is reacted with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (compound 0) in the presence of copper(l)-iodide to provide the compound of formula N-CF3. After the (optional) removal of the tosylate protecting group under basic conditions (e.g., sodium hydroxide) the compound of formula A- CF3 is obtained which may further be used to prepare compounds of the 30

[0640] present invention according to formula I, in particular l-C, in which R1denotes CF3.Foreignfiling_text_P25-005-SEC-WO01

[0641] 77

[0642] 5

[0643]

[0644] PE

[0645] Scheme E

[0646] A further alternative to prepare compounds of formula E, which in turn may then be converted into compounds of formula I (as described in Scheme A 10 above) is depicted in Scheme E above: It starts with a compound of formula P, in which R1, R3, and X1are as defined for formula I, Y1is as defined for compounds of formulas C and E in Scheme A above, and Y4is a boronate functional group (e.g., -B(OH)2 or a suitable ester thereof). The boronic acid or boronic acid ester derivative of formula P is readily available, e.g., from the respective chloro-substituted compound of formula P (Y4= Cl) by methods well-known in the art; for instance, by utilizing trimethyl borate in the presence of a strong base like phenyl lithium and subsequent hydrolysis of the boronic acid ester to yield the boronic acid (Y4= -B(OH)2) or by utilizing 4, 4,5,5- tetramethyl-1,3,2-dioxaborolan in the presence of potassium acetate and 20 chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1, 1 '-biphenyl)[2-(2'- amino-1,1'-biphenyl)]palladium(ll) (XphosPd G2) as a palladium(ll)-catalyst

[0647]

[0648] to provide the compound of formula P with Y4=. The compound of formula P is reacted in reaction step (o) with a compound of formula Q, in which A, L1, and B are as defined for formula I and Y5denotes Br or I, under typical reaction conditions of C-C cross-coupling reactions like the Suzuki coupling, for instance by reacting a compound of formula P with compound of formula Q in the presence of sodium carbonate and Pd(dppf)Cl2-CH2Cl2 30

[0649] ([1, T-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride).Foreignfiling_text_P25-005-SEC-WO01

[0650] 5

[0651]

[0652] F-I-Ring-A2 -I-Ring-A2 Scheme F

[0653] Racemic compounds of formula I, such as rac-l-Ring-A2 depicted in Scheme F above, can be separated into their respective P- and / W-atropisomers (e.g., P-I-Ring-A2 and / W-I-Ring-A2 in Scheme F) using chiral chromatography (step p in Scheme F), including supercritical fluid chromatography (SFC). The respective undesired atropisomer can be subjected to racemization, e.g., thermal reacemization, to yield the racemic compound as new starting material for the separation.

[0654] It is to be noted that - except for instances where it is specifically stated or the context provides for a different meaning - in general the number of a term, i.e. its singular and plural form, is used and can be read interchangeably. For example, the term “compound” in its singular form may also comprise or refer to a plurality of compounds, while the term “compounds” in its plural form may also comprise or refer to a singular compound.

[0655] Examples and Experimental Part

[0656] The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. The compounds are shown in Table 1. Analytical data of compounds made 30

[0657] according to the following examples are shown in Table 1, too.Foreignfiling_text_P25-005-SEC-WO01

[0658] 79

[0659] The invention will be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Unless otherwise indicated in the schemes, the variables have the same meaning as described above, below and in the claims.

[0660] 5

[0661] Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purifications or are available by synthetic methods similar to those specifically described herein. Unless otherwise specified, all temperatures are expressed in °C and all reactions are conducted at room temperature (RT). Compounds are purified by either silica chromatography or preparative HPLC. Purity of reaction products which were used in subsequent reaction steps (intermediates) were usually confirmed by GC-MS (without further characterizing the intermediates).

[0662] 151H NMR:

[0663] 1H-NMR data is provided in Table 1 below.1H NMR spectra were usually acquired on a 300 MHz, 400 MHz, 500 MHz, or 700 MHz NMR spectrometers such as a Bruker Avance DRX 500, a Bruker Avance 400, a Bruker DPX 300 or a Bruker Avance III 700 MHz NMR spectrometer under standard conditions 20 using TMS (tetramethylsilane) as internal reference and DMSO-d6 as standard solvents, if not reported otherwise. NS (Number of Scans): 32, SF (Spectrometer Frequency) as indicated. TE (Temperature): 297 K. Chemical shifts (5) are reported in ppm relative to the TMS signal.1H NMR data are reported as follows: chemical shift (multiplicity, coupling constants and number of hydrogens). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets) br (broad) and coupling constants (J) are reported in Hz.

[0664] 30 LC-MS:

[0665] LC-MS data provided in Table 1 are given with mass in m / z. The results can be obtained by one of the methods described below.Foreignfiling_text_P25-005-SEC-WO01

[0666] Syntheses

[0667] Example 1: rel-2-[4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoro- methyl)cyclohexyl]oxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridin-1 -yllethan-1 -ol 5 Ex1.1: 4-chloro-3-iodo-1 H-pyrrolo[3,2-c]pyridine

[0668]

[0669] To a solution of 4-chloro-1 H-pyrrolo[3,2-c]pyridine (900 mg; 5.90 mmol) in dry DMF (6 mL) was added 1-iodopyrrolidine-2, 5-dione (1.4 g; 6.19 mmol) in one portion. The yellow clear solution became dark brown clear solution. The reaction mixture was stirred at 25 °C for 3 h. Then 21 mL water was added and the brown preciptiated was filtered, washed with water and azeotroped with toluene, to afford the desired compound (1.45 g) as brown solid which 15

[0670] was used without further purification.

[0671] Ex1.2: tert-butyl 4-chloro-3-iodo-1 H-pyrrolo[3,2-c]pyridine-1 -carboxylate

[0672] 20

[0673]

[0674] To a solution of 4-chloro-3-iodo-1 H-pyrrolo[3,2-c]pyridine (843 mg; 2.79 mmol) (Ex1.1) in dry DCM (18 ml) was added di-tert-butyl dicarbonate (669 mg; 3.06 mmol) in one portion followed by DMAP (34 mg; 0.28 mmol). The clear solution was stirred at 25 °C for 16 h. The reaction was quenched with water and diluted with DCM; the organic layer was separated and concentrated. The residue was purified by chromatography to afford the product (950 mg; 87 %) as yellow solid.

[0675] 30Foreignfiling_text_P25-005-SEC-WO01

[0676] Ex1.3: tert-butyl 4-chloro-3-iodo-1 H-pyrrolo[3,2-clpyridine-1 -carboxylate

[0677] 5

[0678]

[0679] To tert-butyl 4-chloro-3-iodo-1 H-pyrrolo[3,2-c]pyridine-1 -carboxylate (5.84 g; 15.43 mmol) (Ex1.2) and Tetrakis(triphenylphosphine)palladium(0) (1.78 g; 1.54 mmol) in TEA (43 mL) and dioxane (88 mL) was added unter argon 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.92 mL; 46.29 mmol). Strong gas formation. The reaction was stirred for 2 h at 90 °C and 2 h at 100 °C. At RT the reaction mixture was diluted with EtOAc and H₂O and extracted with EtOAc. The combined organic layers were washed with brine, dried over 15 Na₂SO₄ and sucked off. The filtrate was evaporated to dryness and purified by chromatography to afford the product (4.43 g; 76 %) as yellow oil.

[0680] Ex1.4: rel-3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}- pyridine

[0681] 20

[0682]

[0683] A mixture of 2-chloro-3-fluoro-5,6-dimethylpyridine (300 mg; 1.86 mmol), rel- (1r,4r)-4-(trifluoromethyl)cyclohexan-1-ol (661 mg; 3.73 mmol), Pd2(dba)3 (190 mg; 0.19 mmol), (S)-BINAP (122 mg; 0.19 mmol) and CS2CO3 (1.30 g; 3.59 mmol) in toluene (5 mL) was stirred overnight at 110 °C. Then the 30

[0684] mixture was concentrated under reduced pressure and the residue wasForeignfiling_text_P25-005-SEC-WO01

[0685] 82

[0686] purified by chromatography to afford the product (220 mg; 37 %) as colorless oil.

[0687] Ex1.5: rel-3-fluoro-4-iodo-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclo- 5 hexylloxyjpyridine

[0688]

[0689] To a stirred solution of rel-3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine (Ex1.4) (500 mg; 1.61 mmol) in THF (5 mL) was added n-BuLi (2.5 M in hexane, 0.84 mL;2.09 mmol) dropwise at -78 °C under N₂ for 30 min. Then another batch of n-BuLi, (2.5 M in hexane, 0.84 mL; 2.09 mmol) was added for additional 20 min at the same temperature. To this mixture was added iodine (103 mg; 0.39 mmol) in THF for 1 h at -78 °C. The resulting mixture was quenched with saturated aqueous NH₄Cl solution and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and after filtration the solution was concentrated under reduced pressure. The residue was purified by chromatography to afford the product (220 mg; 33 %) as white solid.

[0690] Ex1.6: rel-tert-butyl 4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridine-1 -carboxylate

[0691] 30

[0692]

[0693] Foreignfiling_text_P25-005-SEC-WO01

[0694] 83

[0695] A mixture of rel-3-fluoro-4-iodo-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridine (Ex1.5) (180 mg; 0.42 mmol), tert-butyl 4-chloro-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[3,2-c]pyridine-1 - carboxylate (Ex1.3) (340 mg; 0.85 mmol), K₃PO₄ (190 mg; 0.85 mmol) and 5 SPhos Pd G3 (58.12 mg; 0.06 mmol) in CPME (5 mL) and H2O (0.5 mL) was stirred for 1 h at 80 °C under N₂. The mixture was diluted with water and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na₂SO₄. After filtration and evaporation under reduced pressure the residue was purified by chromatography to afford 10 rel-4-{4-chloro-1 H-pyrrolo[3,2-c]pyridin-3-yl}-3-fluoro-5,6-dimethyl-2- {[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (25 mg; 26 %) as white solid and rel-tert-butyl 4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridine-1- carboxylate (55 mg; 46 %) also as colorless oil.

[0696] Ex1.7: rel-4-{4-chloro-1 H-pyrrolo[3,2-clpyridin-3-yl}-3-fluoro-5,6-dimethyl-2- {r(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine

[0697] 20

[0698]

[0699] rel-tert-butyl 4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoro- methyl)cyclohexyl]oxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridine-1 -carboxylate (Ex1.6) (50 mg; 0.09 mmol) was treated with TFA (1 mL) in DCM (3 mL) for 30 1 h at RT. After concentration under reduced pressure the residue was purified by chromatography to afford the product (23.10 mg; 58 %) as white solid.Foreignfiling_text_P25-005-SEC-WO01

[0700] Ex1.8: rel-2-[4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)- cyclohexylloxy}pyridin-4-yl)-1 H-pyrrolo[3,2-clpyridin-1 -yllethan-1 -ol

[0701] 5

[0702]

[0703] To a stirred solution of rel-4-{4-chloro-1 H-pyrrolo[3,2-c]pyridin-3-yl}-3-fluoro- 5,6-dimethyl-2-{[(1 r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (Ex1.7) (70 mg; 0.15 mmol) in DMF (2 mL) was added 1,3-dioxolan-2-one (70 mg; 0.79 mmol) and DBU (0.1 mL; 0.44 mmol) for 2 h at 100 °C. After dilution with H₂O and extraction with EtOAc the combined organic layers were washed with brine and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (70 mg; 85 %) as yellow solid.

[0704] Ex1.9: rel-2-[(2P)-4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoro- methyl)cyclohexylloxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridin-1 -yllethan-1 -ol (Compound No. 5)

[0705] and

[0706] rel-2-[(2M)-4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)- cyclohexylloxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridin-1 -yllethan-1 -ol (Compound No. 8)

[0707] 30Foreignfiling_text_P25-005-SEC-WO01

[0708] 5

[0709]

[0710] rel-2-[4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclo- hexyl]oxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridin-1 -yl]ethan-1 -ol (Ex1.8) (60 mg; 0.12 mmol) was purified by chromatography to obtain the two atropoisomers. Column: CHIRALPAK IK 2*25 cm, 5 pm; Mobile Phase A: Hexane (0.5 % 2M NH3-MeOH), Mobile Phase B: EtOH: DCM = 1 / 1; Flow rate: 20 mL / min; Gradient: isocratic; Sample Solvent: EtOH; Injection Volume: 0.3 mL; Number Of Runs: 10; Detector: UV 254 nm.

[0711] 15

[0712] rel-2-[(2P)-4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridin-1- yl]ethan-1 -ol:

[0713] Rt: 12.99 min; 19 mg; 32 %; white solid.

[0714] rel-2-[(2M)-4-chloro-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- 20

[0715] (trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1 H-pyrrolo[3,2-c]pyridin-1- yl]ethan-1 -ol:

[0716] Rt: 16.75 min; 21 mg; 36 %; white solid

[0717] The P / M descriptors were assigned arbitrarily.

[0718] 2 rel-1-[3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclo- idin-4-yl)-4-(trifluoromethyl)-1 H-i,2-c]pyridin-1-yl]-2-

[0719]

[0720] i-2-ol

[0721] 30

[0722] Ex2.1: 3-iodo-1 -(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1 H-

[0723]

[0724] ,2-iForeignfiling_text_P25-005-SEC-WO01

[0725]

[0726] 5 To a stirred solution of 4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridine (3.50 g;

[0727] 16.92 mmol) in DMF (80 mL) was added NIS (4.41 g; 18.62 mmol). The mixture was stirred for 2 h at RT and then diluted with EtOAc. The organic phase was washed with brine and dried over Na₂SO₄. After filtration the solvent was removed under reduced pressure and the residue was purified by chromatography to afford 3-iodo-4-(trifluoromethyl)-1 H-pyrrolo[3,2- c]pyridine (6.20 g; 96 %) as yellow solid.

[0728] To a stirred solution of 3-iodo-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridine (6.20 g; 16.20 mmol) in DCM (150 mL) was added TsCI (3.58 g; 17.82 mmol), 15 DMAP (420.00 mg; 3.27 mmol) and TEA (5.18 g; 48.59 mmol). The mixture was stirred for 4 h at RT and then concentrated under reduced pressure. The residue was purified by chromatography to afford 3-iodo-1-(4- methylbenzenesulfonyl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridine (8.30 g; 94 %) as white solid.

[0729] 20

[0730] Ex2.2: 1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxa- borolan-2-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridine

[0731]

[0732] To a stirred solution of 3-iodo-1-(4-methylbenzenesulfonyl)-4-(trifluoro- methyl)-1 H-pyrrolo[3,2-c]pyridine (Ex2.1) (4.70 g; 8.65 mmol) and 4, 4,5,5- 30 tetramethyl-1,3,2-dioxaborolane (2.90 mL; 18.99 mmol) in dioxane (84 mL) was added Pd(PPh₃)₄ (1.17 g; 0.96 mmol) and TEA (28 mL). The mixture was stirred for 2 h at 90 °C. Then the mixture was concentrated under reducedForeignfiling_text_P25-005-SEC-WO01

[0733] 87

[0734] pressure and the residue was purified by chromatography to afford 1-(4- methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (4.10 g; 62 %) as yellow solid.

[0735] 5 Ex2.3: rel-3-fluoro-5,6-dimethyl-4-[1-(4-methylbenzenesulfonyl)-4-(trifluoro- methyl)-1 H-pyrrolo[3,2-c]pyridin-3-yl]-2-{((1 r,4r)-4-(trifluoromethyl)- cyclohexylloxyjpyridine

[0736] 10

[0737]

[0738] A mixture of rel-3-fluoro-4-iodo-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridine (Ex1.5) (400 mg; 0.94 mmol), 1-(4-methyl- benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoro- methyl)-1 H-pyrrolo[3,2-c]pyridine (Ex2.2) (705 mg; 1.41 mmol), K₃PO₄ (420 20 mg; 1.88 mmol) and SPhos Pd G3 (86 mg; 0.09 mmol) in CPME (8 mL) and H₂O (0.8 mL) was stirred for 4 h at 110 °C under N₂ atmosphere. For work up the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na₂SO₄. After filtration the solvent phase was concentrated under reduced pressure and the residue was purified by chromatography to afford rel-3-fluoro-5,6- dimethyl-4-[1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2- c]pyrid in-3-y l]-2-{[(1 r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (550 mg; 54 %) as yellow oil.

[0739] 30 Ex2.4: rel-3-fluoro-5,6-dimethyl-2-{r(1r,4r)-4-(trifluoromethyl)cyclohexyl1oxy}- 4-[4-(trifluoromethyl)-1H-pyrrolo[3,2-clpyridin-3-yllpyridineForeignfiling_text_P25-005-SEC-WO01

[0740] 5

[0741]

[0742] To rel-3-fluoro-5,6-dimethyl-4-[1-(4-methylbenzenesulfonyl)-4-(trifluoro- methyl)-1 H-pyrrolo[3,2-c]pyridin-3-yl]-2-{[(1r,4r)-4-(trifluoromethyl)cyclo- hexyl]oxy}pyridine (Ex2.3) (540 mg; 0.50 mmol) in EtOH (10 mL) was added NaOMe (30 wt% in MeOH, 0.37 mL; 2.00 mmol) at RT. The mixture was stirred for 2 h and then diluted with water. After extraction with EtOAc the combined organic layers were dried over Na₂SO₄, and after filtration, the solution was concentrated under reduced pressure. The residue was purified 15

[0743] by chromatography to afford rel-3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}-4-[4-(trifluoromethyl)-1 H-pyrrolo[3,2- c]pyridin-3-yl]pyridine (480 mg; 99 %) as white solid.

[0744] Ex2.5: rel-(3P)-3-fluoro-5,6-dimethyl-2-{r(1r,4r)-4-(trifluoromethyl)cyclo- 20

[0745] hexyl]oxy}-4-[4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-3-yllpyridine (Compound No. 6)

[0746] and

[0747] rel-(3M)-3-fluoro-5,6-dimethyl-2-{r(1r,4r)-4-(trifluoromethyl)cyclohexylloxy}- 4-[4-(trifluoromethyl)-1H-pyrrolo[3,2-clpyridin-3-yl]pyridine (Compound No. 6)

[0748] 30

[0749]

[0750] Foreignfiling_text_P25-005-SEC-WO01

[0751] 89

[0752] rel-3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-4-[4- (trifluoromethyl)-l H-pyrrolo[3,2-c]pyridin-3-yl]pyridine (60.00 mg; 0.12 mmol; 1.00 eq.) was purified by Prep-Chiral HPLC to afford rel-(3P)-3-fluoro-5,6- dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-4-[4-(trifluoromethyl)- 5 1 H-pyrrolo[3,2-c]pyridin-3-yl]pyridine (19.10 mg; 65 %) as white solid Column: CHIRALPAK IJ-3, 4.6*50 mm, 3 pm; Mobile Phase A: Hex(0.1%DEA):(EtOH: DCM=1:1)=90:10; Flow rate: 1 mL / min; 1.52 min and

[0753] rel-(3M)-3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}- 4-[4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]pyridine (15.30 mg; 51 %) as white solid.

[0754] Column: CHIRALPAK IJ-3, 4.6*50 mm, 3 pm; Mobile Phase A: Hex(0.1%DEA):(EtOH: DCM=1:1)=90:10; Flow rate: 1 mL / min; 2.81 min

[0755] 15 The P / M descriptors were assigned arbitrarily.

[0756] Example 3: rel-1-[3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclo- hexyl]oxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yll-2- methylpropan-2-ol

[0757] 20 Ex3.1: rel-1-[3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclo- hexyl]oxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yll-2- methylpropan-2-ol

[0758] 30

[0759]

[0760] To a stirred suspension of rel-3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}-4-[4-(trifluoromethyl)-1 H-pyrrolo[3,2-Foreignfiling_text_P25-005-SEC-WO01

[0761] 90

[0762] c]pyridin-3-yl]pyridine (Ex2.4) (90 mg; 0.18 mmol) and Cs₂CO₃ (236 mg; 0.72 mmol) in ACN (2 mL) was added 2,2-dimethyloxirane (200 mg; 2.64 mmol) dropwise. The resulting mixture was stirred for 3 h at 80 °C and then diluted with water. After extraction with EtOAc the combined organic layers were 5 dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography to afford rel-1 -[3-(3-fluoro-5,6-dimethyl-2-{[(1 r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}- pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yl]-2-methyl- propan-2-ol (39 mg; 40 %) as white solid.

[0763] Ex3.2: rel-1 -[(2P)-3-(3-fluoro-5,6-dimethyl-2-{[(1 r,4r)-4-(trifluoromethyl)cyclo- hexylloxy)pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yll-2- methylpropan-2-ol (Compound No. 22)

[0764] and

[0765] rel-1 -[(2M)-3-(3-fluoro-5,6-dimethyl-2-{[(1 r,4r)-4-(trifluoromethyl)cyclohexyll- oxy)pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yll-2-methyl- propan-2-ol (Compound No. 20)

[0766]

[0767] The atropoisomer mixture of Ex3.1 was purified by chiral-Prep-HPLC with the following conditions:

[0768] Column: CHIRALPAK IB, 2*25 cm, 5 pm; Mobile Phase A: HEX (0.5 % 2M NH₃-MeOH), Mobile Phase B: EtOH: DCM=1: 1 -HPLC; Flow rate: 20 mL / min; Gradient: isocratic 8; Wave Length: 220 / 254 nm; Sample Solvent: EtOH; 30 Injection Volume: 0.5 mL; Number Of Runs: 5; to affordForeignfiling_text_P25-005-SEC-WO01

[0769] 91

[0770] rel-1-[(2P)-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]- oxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yl]-2-methyl- propan-2-ol (12.90 mg; 31 %; white solid; Purified Product) RT1(min): 13.74 and

[0771] 5 rel-1-[(2M)-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]- oxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yl]-2-methyl- propan-2-ol (15.20 mg; 36 %; white solid; Purified Product). RT2(min): 19.66

[0772] The P / M descriptors were assigned arbitrarily.

[0773] Example 4: rel-2-[3-(3-fluoro-5,6-dimethyl-2-{((1r,4r)-4-(trifluoromethyl)cvclo- hexylloxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yll- ethan-1-ol

[0774] Ex4.1: rel-2-[3-(3-fluoro-5,6-dimethyl-2-n(1r,4r)-4-(trifluoromethyl)cyclo- hexylloxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yll- ethan-1-ol

[0775]

[0776] To a stirred solution of rel-3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoro- methyl)cyclohexyl]oxy}-4-[4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-3- yl]pyridine (90 mg; 0.18 mmol) and 1,3-dioxolan-2-one (43 mg; 0.48 mmol) in DMF (2 mL) was added DBU (86 mg; 0.54 mmol) dropwise. The reaction mixture was stirred for 3 h at 95 °C and then diluted with water. The mixture 30

[0777] was extracted with EtOAc and the combined organic layers were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography to afford rel-2-[3-(3-fluoro-Foreignfiling_text_P25-005-SEC-WO01

[0778] 92

[0779] 5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-4- (trifluoromethyl)-l H-pyrrolo[3,2-c]pyridin-1-yl]ethan-1-ol (65 mg; 68 %) as white solid.

[0780] 5 Ex4.2: rel-2-[(2P)-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclo- hexyl]oxy)pyridin-4-yl)-4-(trifluoromethyl)-1 H-pyrrolo[3,2-c]pyridin-1-yll- ethan-1-ol (Compound No. 16)

[0781] and

[0782] rel-2-[(2M)-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl1oxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H- pyrrolo[3,2-c]pyridin-1-yllethan-1-ol (Compound No. 18)

[0783]

[0784] The mixture of the atropoisomers (64 mg) was separated by Prep-Chiral- HPLC with the following conditions:

[0785] Column: chiralpak IJ 2*25 cm, 5 pm; Mobile Phase A: hexane (0.5% 2M NH3- MeOH), Mobile Phase B: EtOH: DCM = 1:1; Flow rate: 20 mL / min; Gradient: isocratic 10; Wave Length: 220 / 254 nm; Sample Solvent: EtOH; Injection Volume: 0.6 mL; Number Of Runs: 9.

[0786] The chromatography afforded rel-2-[(2P)-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)- 4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-4-(trifluoromethyl)-1H- pyrrolo[3,2-c]pyridin-1 -yl]ethan-1 -ol (19.30 mg; 30 %) as white solid Rt: 2.71 min

[0787] 30 andForeignfiling_text_P25-005-SEC-WO01

[0788] 93

[0789] rel-2-[(2M)-3-(3-fluoro-5,6-dimethyl-2-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-4-(trifluoromethyl)-1 H- pyrrolo[3,2-c]pyridin-1-yl]ethan-1-ol (22 mg; 34 %) as white solid.

[0790] Rt: 3.87 min

[0791] 5

[0792] The P / M descriptors were assigned arbitrarily.

[0793] Example 5: Molecular mechanics calculations of rotational barriers 3D structures of all input molecules have been generated using LigPrep (release 14.1.138, Schrodinger, LLC, New York, NY). The LigPrep process involved adding hydrogen atoms, generation of ionization states, tautomers and 3D conformations and their minimization. All structures were subsequently docked into the crystal structure of TEAD3 to produce an approximation to the bound conformation of the molecules using Glide 15 (release 14.1.138, Schrodinger, LLC, New York, NY). Based on these input structures and their bound conformations rotational energy barriers were calculated from relaxed dihedral angle scans using the program MacroModel (release 14.1.138, Schrodinger, LLC, New York, NY) employing the PLS4 force field, water as solvent and with a torsion angle increment of 1°. The 20 structures were optimized after each increment using the same level of theory.

[0794] Default parameters have been used for the optimization step. The torsion profile has been obtained by plotting the torsion angle values to the calculated energies. The lowest energy barrier for each compound has been determined that allows for interconversion between both isomers.

[0795] Calculations for the atropisomers described in Ex4.2 (compounds nos. 16 and 18) revealed a high predicted rotational barrier of 32 kcal / mol that translates into highly stable atropisomers.

[0796] 30 Table 1Foreignfiling_text_P25-005-SEC-WO01

[0797] 94

[0798] Table 1 below shows exemplary compounds of the present invention. They have been synthesized as described in the Examples above or similar thereto.

[0799] 5 Note: Unless indicated otherwise for a specific compound and its structure (e.g., by assigning “Absolute” to a structure), the absolute configuration as depicted for the structures of the compounds in Table 1 below is assigned arbitrarily.

[0800] Table 1

[0801] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min] LCMS method 1 F 1H NMR (300 MHz, 442,1

[0802] VF DMSO) 12.24 (s, 1H),

[0803] F8.02 (d, J = 5.6 Hz, 1H),

[0804] 15 7.62 (s, 1H), 7.51 (d, J = 1,12

[0805] 5.7 Hz, 1H), 5.04 (s, lH),

[0806] 2.39 (s, 4H), 2.20 (s, 2H),

[0807] 1.94 (s, 5H), 1.50 (d, J = LCMS method 3 F \C

[0808] 1l

[0809] 10.0 Hz, 4H).

[0810] 4-{4-chloro-lH-pyrrolo[3,2-c]pyridin-3- 20

[0811] yl}-3-fluoro-5,6-dimethyl-2-{[( lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0812] 2 F 1H NMR (300 MHz, 442,15

[0813] V-F DMSO) 12.26 (s, 1H),

[0814] F8.02 (d, J = 5.6 Hz, 1H),

[0815] 7.62 (s, 1H), 7.51 (d, J = 1,34

[0816] 5.7 Hz, 1H), 5.06 (d, J =

[0817] 10.4 Hz, 1H), 2.39 (s,

[0818] 'I 3— ci 4H), 2.20 (s, 2H), 1.94 (s, LCMS method 4 F \ /

[0819] 5H), 1.50 (d, J = 10.6 Hz,

[0820] Z" T| N

[0821] 4H).

[0822] HN'' ^^

[0823] (4P)-4-{4-chloro-lH-pyrrolo[3,2- c]pyridin-3-yl}-3-fluoro-5,6-dimethyl-2- 30 {[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridine

[0824]

[0825] Foreignfiling_text_P25-005-SEC-WO01

[0826] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[0827] LCMS method 3 F 1H NMR (300 MHz, 442,15

[0828] V-F DMSO) 12.26 (s, 1H),

[0829] F8.02 (d, J = 5.6 Hz, 1H),

[0830] 5 7.62 (s, 1H), 7.51 (d, J = 1,73

[0831] \. N=sZ 5.7 Hz, 1H), 5.06 (d, J =

[0832] 10.4 Hz, 1H), 2.39 (s,

[0833] Cl 4H), 2.20 (s, 2H), 1.94 (s, LCMS method 4

[0834] 5H), 1.50 (d, J = 10.6 Hz,

[0835] Z" T| N

[0836] 4H).

[0837] HN'' ^^

[0838] (4M)-4-{4-chloro-lH-pyrrolo[3,2- c]pyridin-3-yl}-3-fluoro-5,6-dimethyl-2- {[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridine

[0839] 4 F 1H NMR (300 MHz, 456,15

[0840] UF

[0841] F" V DMSO) 8.08 (d, J = 5.7

[0842] Hz, 1H), 7.69-7.60 (m,

[0843] 2H), 5.04 (q, J=6.1 Hz, 3,52 KN^Z 1H), 3.91 (s, 3H), 2.40 (s,

[0844] °"1\ 4H), 2.20 (s, 2H), 1.95 (s,

[0845] Kf ci LCMS method 4 F \ T 5H), 1.52 (p, J = 12.4 Hz, 0 7 4H).

[0846] /

[0847] (4M)-4-{4-chloro-l-methyl-lH- pyrrolo[3,2-c]pyridin-3-yl}-3-fluoro-5,6- dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0848] 5 F 1H NMR (300 MHz, 486,15

[0849] •F

[0850] F \ DMSO) 8.05 (d, J = 5.7

[0851] Hz, 1H), 7.68 (d, J = 5.8

[0852] Hz, 1H), 7.62 (s, 1H), 1,94

[0853] V- 5.01 (dt, J = 19.9, 5.2 Hz, W ci 2H), 4.42 - 4.27 (m, 2H),

[0854] 3.76 (q, J = 5.2 Hz, 2H), LCMS method 4 2.39 (s, 4H), 2.20 (s, 2H),

[0855] 1.96 (s, 5H), 1.50 (q, J =

[0856] HO

[0857] 12.1 Hz, 4H).

[0858] 2-[(2P)-4-chloro-3-(3-fluoro-5,6- dimethyl-2-{[(lr,4r)-4-(trifluoro- 30 methyl)cyclohexyl]oxy}pyridin-4-yl)-lH-

[0859]

[0860] pyrrolo[3,2-c]pyridin-l-yl]ethan-l-olForeignfiling_text_P25-005-SEC-W001

[0861] 96

[0862] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[0863] LCMS method 6 F 1H NMR (300 MHz, 476,15

[0864] DMSO) 12.48 (s, 1H),

[0865] 8.36 (d, J = 5.6 Hz, 1H),

[0866] 7.81 (d, J = 5.6 Hz, 1H), 1,52

[0867] X-N 7.73 (s, 1H), 5.11-4.98

[0868] F J V° (m, 1H), 2.39 (s, 3H),

[0869] 2.35 (s, 1H), 2.20 (s, 2H), LCMS method 4 1 J F 2.0 -1.91 (m, 2H), 1.85

[0870] NiT v (s, 3H), 1.50 (m, J = 10.7 XV'NH

[0871] Hz, 4H).

[0872] (3P)-3-fluoro-5,6-dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}-4-[4- (trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-3-yl] pyridine

[0873] 7 F 1H NMR (300 MHz, 456,12

[0874] VF

[0875] F " V DMSO) 8.08 (d, J = 5.7

[0876] Hz, 1H), 7.69-7.60 (m,

[0877] 2H), 5.04 (q, J=6.1 Hz, 1,12

[0878] 1H), 3.91 (s, 3H), 2.40 (s,

[0879] 4H), 2.20 (s, 2H), 1.95 (s,

[0880] Cl LCMS method 4 F \ 1 5H), 1.52 (p, J = 12.4 Hz,

[0881] < ]l ] 4H).

[0882] /

[0883] (4P)-4-{4-chloro-l-methyl-lH- pyrrolo[3,2-c]pyridin-3-yl}-3-fluoro-5,6- 20 dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0884] 8 F 1H NMR (300 MHz, 486,2

[0885] •F

[0886] F \ DMSO) 8.05 (d, J = 5.8

[0887] Hz, 1H), 7.68 (d, J = 5.8

[0888] Hz, 1H), 7.62 (s, 1H),

[0889] 5.01 (dt, J = 19.9, 5.2 Hz, 2,37

[0890] 25 °~1 yjjrn,,. Z / V QI 2H), 4.33 (t, J = 5.3 Hz,

[0891] O JN 2H), 3.76 (q, J = 5.3 Hz,

[0892] 2H), 2.39 (s, 4H), 2.20 (s, LCMS method 4 2H), 1.95 (s, 5H), 1.50

[0893] HO

[0894] (q, J = 12.1 Hz, 4H).

[0895] 2-[(2M)-4-chloro-3-(3-fluoro-5,6- dimethyl-2-{[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridin-4-yl)-lH- pyrrolo[3,2-c]pyridin-l-yl]ethan-l-ol

[0896]

[0897] Foreignfiling_text_P25-005-SEC-WO01

[0898] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[0899] LCMS method 9 F 1H NMR (300 MHz, 476,1

[0900] DMSO) 12.48 (s, 1H),

[0901] 8.36 (d, J = 5.6 Hz, 1H),

[0902] 5 7.81 (d, J = 5.6 Hz, 1H), 2,81

[0903] N 4 7.73 (s, 1H), 5.11-4.98

[0904] u y° (m, 1H), 2.39 (s, 3H),

[0905] FT~F V=A 2.35 (s, 1H), 2.20 (s, 2H), LCMS method 2 1 J F 2.0 -1.91 (m, 2H), 1.85

[0906] NiT v (s, 3H), 1.50 (m, J = 10.7

[0907] Hz, 4H).

[0908] (3M)-3-fluoro-5,6-dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}-4-[4- (trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-3-yl] pyridine

[0909] 10 F 1H NMR (300 MHz, 490,1

[0910] DMSO) 8.42 (d, J = 5.7

[0911] Hz, 1H), 7.95 (d, J = 5.7

[0912] Hz, 1H), 7.73 (s, 1H), 0,93

[0913] 5.05 (s, 1H), 3.97 (s, 3H),

[0914] F J yo

[0915] 2.39 (s, 4H), 2.20 (s, 2H),

[0916] 1.96 (s, 2H), 1.86 (s, 3H), LCMS method 4 A / F

[0917] 1.50 (d, J = 9.5 Hz, 4H).

[0918] I! O>

[0919] (3P)-3-fluoro-5,6-dimethyl-4-[l-methyl-4- (trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-3-yl]-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0920] 11 F 1H NMR (300 MHz, 458,3

[0921] FDMSO) 12.26 (s, 1H),

[0922] ' P

[0923] 8.30 (d, J = 5.6 Hz, 1H),

[0924] 7.71 - 7.60 (m, 2H), 6.60 2,28

[0925] (t, J = 54.5 Hz, 1H), 5.04

[0926] (s, 1H), 2.38 (s, 4H), 2.20 A A (s, 2H), 2.00 - 1.91 (m, LCMS method 4

[0927] 2H), 1.86 (s, 3H), 1.49

[0928] L JO (q, J = 11.4 Hz, 4H).

[0929] (4P)-4-[4-(difluoromethyl)-lH- pyrrolo[3,2-c]pyridin-3-yl]-3-fluoro-5,6- 30 dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0930]

[0931] Foreignfiling_text_P25-005-SEC-W001

[0932] 98

[0933] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[0934] LCMS method 12 F 1H NMR (300 MHz, 472,1

[0935] DMSO) 8.36 (d, J = 5.7

[0936] Hz, 1H), 7.80 (d, J = 5.7

[0937] 5 Hz, 1H), 7.63 (s, 1H), 2,03

[0938] 6.61 (t, J = 54.4 Hz, 1H),

[0939] F J VO

[0940] F-y 5.06 (d, J = 9.4 Hz, 1H),

[0941] X J F 3.93 (s, 3H), 2.38 (s, 4H), LCMS method 4

[0942] 2.19 (s, 2H), 2.00 - 1.90

[0943] t o

[0944] (m, 2H), 1.86 (s, 3H),

[0945] \

[0946] 1.48 (t, J = 10.5 Hz, 4H).

[0947] (3P)-4-[4-(difluoromethyl)-l-methyl-lH- pyrrolo[3,2-c]pyridin-3-yl]-3-fluoro-5,6- dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0948] 13 F 1H NMR (300 MHz, 490,15

[0949] DMSO) 8.42 (d, J = 5.7

[0950] Hz, 1H), 7.95 (d, J = 5.7

[0951] C^F Hz, 1H), 7.73 (s, 1H), 1,1

[0952] 5.05 (s, 1H), 3.97 (s, 3H),

[0953] M— FF)" Vi 2.39 (s, 4H), 2.20 (s, 2H),

[0954] 1.96 LCMS method 4 f A J F (s, 2H), 1.86 (s, 3H),

[0955] n 1.50 (d, J = 9.5 Hz, 4H).

[0956] (3M)-3-fluoro-5,6-dimethyl-4-[l-methyl- 20 4-(trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-3-yl]-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0957] 14 F 1H NMR (300 MHz, 458,3

[0958] DMSO) 12.26 (s, 1H),

[0959] - F

[0960] 8.30 (d, J = 5.6 Hz, 1H),

[0961] 7.71 - 7.60 (m, 2H), 6.60 4,21

[0962] (s, 1H), 5.03 (dd, J =

[0963] 25 VN.

[0964] 10.6, 5.9 Hz, 1H), 2.38

[0965] 1 (s, 4H), 2.20 (s, 2H), 2.01 LCMS method 4 7 F

[0966] 03 - 1.91 (m, 2H), 1.86 (s,

[0967] 3H), 1.50 (td, J = 12.2,

[0968] x^ ^NH

[0969] 6.4 Hz, 4H).

[0970] (4M)-4-[4-(difluoromethyl)-lH- pyrrolo[3,2-c]pyridin-3-yl]-3-fluoro-5,6- dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine

[0971]

[0972] Foreignfiling_text_P25-005-SEC-WO01

[0973] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[0974] LCMS method 15 F 1H NMR (300 MHz, 472,1 DMSO) 8.36 (d, J = 5.7 Hz, 1H), 7.80 (d, J = 5.8 5 Hz, 1H), 7.63 (s, 1H), 2,8

[0975] 6.61 (t, J = 54.4 Hz, 1H), F 5.04 (dt, J = 10.6, 5.6 Hz,

[0976] LCMS method 4 X J F 1H), 3.93 (s, 3H), 2.38 (s,

[0977] 4H), 2.23 - 2.16 (m, 2H), 2.04 - 1.92 (m, 2H), 1.87 \

[0978] (s, 3H), 1.48 (t, J = 10.6 (3M)-4-[4-(difluoromethyl)-l-methyl-lH- Hz, 4H). pyrrolo[3,2-c]pyridin-3-yl]-3-fluoro-5,6- dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridine 16 F 1H NMR (300 MHz, 520,25 DMSO) 8.39 (d, J = 5.7 Hz, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.71 (s, 1H), 2,71FF V / NVx Or5.09 - 4.95 (m, 2H), 4.40 VF(t, J = 5.2 Hz, 2H), 3.78 L 15 (q, J = 5.2 Hz, 2H), 2.38 LCMS method 5

[0979] (s, 4H), 2.19 (s, 2H), 1.96 (s, 2H), 1.86 (s, 3H), 1.58 OH - 1.44 (m, 4H).

[0980] 2-[(2P)-3-(3-fluoro-5,6-dimethyl-2- {[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridin- 4-yl)-4-(trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-l-yl]ethan-l-ol 17 F 1H NMR (400 MHz, 502,3 DMSO-d6) 8.33 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 5.8 Hz, 1H), 7.63 (s, 1H), 1,48FF jT V-o' 6.61 (t, J = 54.5 Hz, 1H),

[0981] 5.04 (dt, J = 10.7, 5.7 Hz,

[0982] LCMS method 1 liF1H), 4.99 (t, J = 5.2 Hz,

[0983] 1H), 4.39 -4.33 (m, 2H), 3.77 (q, J = 5.3 Hz, 2H), OH 2.41 - 2.31 (m, 4H), 2.26 2-[(2P)-4-(difluoromethyl)-3-(3-fluoro- - 2.14 (m, 2H), 1.99 - 30 5,6-dimethyl-2-{[(lr,4r)-4-(trifluoro- 1.91 (m, 2H), 1.87 (s, methyl)cyclohexyl]oxy}pyridin-4-yl)-lH- pyrrolo[3,2-c]pyridin-l-yl]ethan-l-ol 3H), 1.59 - 1.38 (m, 4H).

[0984]

[0985] Foreignfiling_text_P25-005-SEC-WO01

[0986] 100

[0987] Cpd. Structure & Name LCMS [M+H] No. LCMS Rt [min]

[0988] LCMS method 18 1H NMR (300 MHz, 520,15 DMSO) 8.39 (d, J = 5.7 Hz, 1H), 7.98 (d, J = 5.7 5 Hz, 1H), 7.71 (s, 1H), 3,87

[0989] 5.01 (q, J = 6.2 Hz, 2H), 4.40 (t, J = 5.2 Hz, 2H), 3.78 (q, J = 5.2 Hz, 2H), LCMS method 6 2.38 (s, 4H), 2.19 (s, 2H), 1.96 (s, 2H), 1.85 (s, 3H), 1.56 - 1.37 (m, 4H).

[0990] 2-[(2M)-3-(3-fluoro-5,6-dimethyl-2- {[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridin-4-yl)-4- (trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-l-yl]ethan-l-ol 1H NMR (400 MHz, 502,3 DMSO-d6) 8.33 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 5.8 Hz, 1H), 7.63 (s, 1H), 1,95 6.61 (t, J = 54.5 Hz, 1H), 5.08 - 5.01 (m, 1H), 4.99 (t, J = 5.2 Hz, 1H), 4.36 LCMS method 1 (t, J = 5.3 Hz, 2H), 3.77 (q, J = 5.3 Hz, 2H), 2.41 - 2.35 (m, 4H), 2.26- 2.17 2-[(2M)-4-(difluoromethyl)-3-(3-fluoro- (m, 2H), 2.00 - 1.93 (m, 5,6-dimethyl-2-{[(lr,4r)-4-(trifluoro- 2H), 1.87 (s, 3H), 1.59 - methyl)cyclohexyl]oxy}pyridin-4-yl)-lH- pyrrolo[3,2-c]pyridin-l-yl]ethan-l-ol 1.40 (m, 1H).

[0991] F 1H NMR (300 MHz, 548,35

[0992] DMSO) 8.37 (d, J = 5.7 Hz, 1H), 8.03 (d, J = 5.8 Hz, 1H), 7.64 (s, 1H), 2,709 5.07 - 5.00 (m, 1H), 4.80 (s, 1H), 4.26 (q, J = 14.3 Hz, 2H), 2.38 (s, 4H), LCMS method 5 2.19 (s, 2H), 1.95 (s, 2H), 1.86 (s, 3H), 1.49 (d, J = OH

[0993] 10.3 Hz, 4H), 1.12 (d, J = l-[(2M)-3-(3-fluoro-5,6-dimethyl-2- 4.9 Hz, 6H). {[(lr,4r)-4-(trifluoromethyl)- 30 cyclohexyl]oxy}pyridin-4-yl)-4- (trifluoromethyl)-lH-pyrrolo[3,2-

[0994]

[0995] c]pyridin-l-yl]-2-methylpropan-2-olForeignfiling_text_P25-005-SEC-WO01

[0996] 101

[0997] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[0998] LCMS method 21 F 1H NMR (400 MHz, 530,3

[0999] VF DMSO) 8.31 (d, J = 5.8

[1000] Hz, 1H), 7.89 (d, J = 5.8

[1001] 5 1,2

[1002] V O Hz, 1H), 7.56 (s, 1H), 9

[1003] FF VO 6.61 (s, 1H), 5.04 (dt, J =

[1004] 10.3, 5.4 Hz, 1H), 4.78

[1005] X J F

[1006] (s, 1H), 4.30 - 4.12 (m, LCMS method 1 2H), 2.38 (s, 4H), 2.20

[1007] (s,2H), 1.96 (d, J = 9.3

[1008] OH Hz, 2H), 1.87 (s, 3H),

[1009] l-[(2P)-4-(difluoromethyl)-3-(3-fluoro- 1.60 - 1.44 (m, 4H), 1.11

[1010] 5,6-dimethyl-2-{[(lr,4r)-4- (d, J = 7.9 Hz, 6H).

[1011] (trifluoromethyl)cyclohexyl]oxy}pyridin- 4-yl)-lH-pyrrolo[3,2-c]pyridin-l-yl]-2- methylpropan-2-ol

[1012] 22 F 1H NMR (300 MHz, 548,25

[1013] DMSO) 8.37 (d, J = 5.7

[1014] Hz, 1H), 8.03 (d, J = 5.7

[1015] Hz, 1H), 7.64 (s, 1H), 2119

[1016] 5.04 (s, 1H), 4.80 (s, 1H),

[1017] 4.26 (q, J = 14.3 Hz, 2H),

[1018] 2.38 (s, 4H), 2.19 (s, 2H), LCMS method 6

[1019] 1.95 (s, 2H), 1.86 (s, 3H),

[1020] V- 1.49 (d, J = 9.5 Hz, 4H),

[1021] OH

[1022] 1.12 (d, J = 4.9 Hz, 6H).

[1023] l-[(2P)-3-(3-fluoro-5,6-dimethyl-2- {[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridin-4-yl)-4- (trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-l-yl]-2-methylpropan-2-ol

[1024] 23 F 1H NMR (400 MHz, 530,3

[1025] FVF DMSO) 8.31 (d, J = 5.8

[1026] Hz, 1H), 7.89 (d, J = 5.8

[1027] 1,52

[1028] X \rN O i Hz, 1H), 7.56 (s, 1H),

[1029] F VO 6.61 (t, J = 54.5 Hz, 1H),

[1030] 5.04 (dt, J = 10.6, 5.6 Hz,

[1031] X J F

[1032] 1H), 4.78 (s, 1H), 4.30 - LCMS method 1 4.12 (m, 2H), 2.38 (s,

[1033] 4H), 2.20 (s, 2H), 1.96

[1034] OH (d, J = 8.3 Hz, 2H), 1.87

[1035] l-[(2M)-4-(difluoromethyl)-3-(3-fluoro- (s, 3H), 1.50 (q, J = 12.5

[1036] 5,6-dimethyl-2-{[(lr,4r)-4- 30 Hz, 4H), 1.11 (d, J = 7.9

[1037] (trifluoromethyl)cyclohexyl]oxy}pyridin- 4-yl)-lH-pyrrolo[3,2-c]pyridin-l-yl]-2- Hz, 6H).

[1038]

[1039] methylpropan-2-olForeignfiling_text_P25-005-SEC-WO01

[1040] 102

[1041] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[1042] LCMS method 24 F 1H NMR (300 MHz, 440,2

[1043] DMSO) 12.08 (d, J = 2.4

[1044] Hz, 1H), 8.26 (d, J = 5.7

[1045] 5 Hz, 1H), 7.61 - 7.50 (m, 1,3

[1046] 2H), 5.25 (s, 1H), 5.09 (s,

[1047] # \\-o 2H), 2.40 (d, J = 1.2 Hz,

[1048] F-^

[1049] X J 4H), 2.21 (s, 2H), 2.02 - LCMS method 5

[1050] F

[1051] 03 1.93 (m, 2H), 1.90 (s,

[1052] 3H), 1.64 - 1.37 (m, 4H).

[1053] (3P)-3-fluoro-4-[4-(fluoromethyl)-lH- pyrrolo[3,2-c]pyridin-3-yl]-5,6-dimethyl- 2-{[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridine

[1054] 25 F 1H NMR (300 MHz, 440,2

[1055] DMSO) 12.09 (d, J = 2.5

[1056] Hz, 1H), 8.26 (d, J = 5.7

[1057] 1,94 Hz, 1H), 7.62 - 7.51 (m,

[1058] \..-N -T 2H), 5.25 (s, 1H), 5.08

[1059] (d, J = 11.4 Hz, 2H), 2.40

[1060] F y jy °

[1061] X J (d, J = 1.2 Hz, 4H), 2.21 LCMS method 5

[1062] F

[1063] 03 (s, 2H), 2.02 - 1.92 (m,

[1064] 2H), 1.90 (s, 3H), 1.51

[1065] (qd, J = 10.3, 3.3 Hz, 4H).

[1066] (3M)-3-fluoro-4-[4-(fluoromethyl)-lH- pyrrolo[3,2-c]pyridin-3-yl]-5,6-dimethyl- 2-{[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridine

[1067] 26 1H NMR (300 MHz, 454,1 F

[1068] DMSO) 8.31 (d, J = 5.8

[1069] Hz, 1H), 7.75 - 7.21 (m,

[1070] C^F 2H), 5.25 (s, 1H), 5.07 1,09

[1071] (d, J = 10.0 Hz, 2H), 3.91 J / V-o

[1072] (s, 3H), 2.48 - 2.26 (m,

[1073] X J LCMS method 0

[1074] F 4H), 2.30 - 2.08 (m, 2H),

[1075] I.91 (s, 5H), 1.50 (q, J =

[1076] II.8 Hz, 4H). \

[1077] 3-fluoro-4-[4-(fluoromethyl)-l-methyl- lH-pyrrolo[3,2-c] pyridin-3-yl]-5,6- dimethyl-2-{[(lr,4r)-4-(trifluoromethyl)- cyclohexyl]oxy}pyridine

[1078]

[1079] 30Foreignfiling_text_P25-005-SEC-WO01

[1080] 103

[1081] Cpd. Structure & Name NMR LCMS [M+H] No. LCMS Rt [min]

[1082] LCMS method 27 F 1H NMR (300 MHz, 512,2 F^-F DMSO) 8.27 (d, J = 5.8

[1083] Hz, 1H), 7.75 (d, J = 5.8, 5 1,

[1084] VN C' 1.8 Hz, 1H), 7.51 (s, 1H), 1FJ / y-o 5.43 - 4.93 (m, 3H), 4.76 X J F (s, 1H), 4.30 - 4.11 (m,

[1085] 2H), 2.31 (d, J = 57.2 Hz, LCMS method 0 I

[1086] 6H), 1.92 (s, 5H), 1.50 (d, J = 10.2 Hz, 4H), 1.12 OH (d, J = 6.8 Hz, 6H). l-[3-(3-fluoro-5,6-dimethyl-2-{[(lr,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyridin- 4-yl)-4-(fluoromethyl)-lH-pyrrolo[3,2-

[1087]

[1088] c]pyridin-l-yl]-2-methylpropan-2-ol

[1089] LCMS Method No. LCMS Method Conditions

[1090] LCMS method 0 HALO C18 2 μm 3.0-30 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 100 % B in 2.0 min.

[1091] LCMS method 1 HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 0 % B – 100 % B in 2.0 min.

[1092] LCMS method 2 HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 30 % B – 95 % B in 3.0 min.

[1093] LCMS method 3 HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 95 % B in 1.5 min.

[1094] LCMS method 4 HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B – 95 % B in 2.0 min.

[1095] LCMS method 5 Shim-Pack Scepter C18-1203.0 pm 3.0-33 mm; flow: 1.5 mL / min; T: 40 °C;

[1096] buffer A: 5 mM NH4HCO3 in water; buffer B: Acetonitrile; gradient: 10 % B - 95 % B in 2.0 min.

[1097] LCMS method 6 Shim-Pack Scepter C18-1203.0 pm 3.0-33 mm; flow: 1.5 mL / min; T: 40 °C;

[1098] buffer A: 5 mM NH4HCO3 in water; buffer B: Acetonitrile; gradient: 30 % B -

[1099]

[1100] 95 % B in 3.0 min.

[1101] The following compounds provided in Table 1 and being atriopisomers have been separated from stereochemical mixtures containing these compounds under the following chromatographical (HPLC) separation conditions (RT: 30

[1102] retention time in min)Foreignfiling_text_P25-005-SEC-W001

[1103] 104

[1104] Cpd. Conditions

[1105] No.

[1106] 2 CHIRAL ART Cellulose-SB; Mobile Phase: Hex (0.5% 2M NH3- MeOH):(EtOH: DCM=l:l)=90:10; Flow rate: 20 mL / min; Rt: 1.34 min.

[1107] 3 CHIRAL ART Cellulose-SB; Mobile Phase: Hex (0.5% 2M NH3- 5 MeOH);(EtOH: DCM=l:l)=90:10; Flow rate: 20 mL / min; Rt: 1.73 min.

[1108] 4 CHIRAL ART Cellulose-SB; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Flow rate: 1 mL / min; Rt: 3.52 min.

[1109] 5 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=80:20; Flow rate: 1 mL / min; Rt: 1.94 min.

[1110] 6 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Flow 10 rate: 1 mL / min; Rt: 1.52 min.

[1111] 7 Column: CHIRALART Cellulose-SB; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Flow rate: 1 mL / min; Rt: 1.12 min.

[1112] 8 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=1: l)=80: 20; Flow rate: 1 mL / min; Rt: 2.37 min.

[1113] 9 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Flow 15 rate: 1 mL / min; Rt: 2.81 min.

[1114] 10 CHIRALPAK IF-3; Mobile Phase: Hex (0.1%DEA): EtOH=70:30; Flow rate: 1 mL / min; Rt: 0.93 min.

[1115] 11 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Flow rate: 1 mL / min; Rt: 2.28 min.

[1116] 12 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=85:15; Flow 20 rate: 1 mL / min; Rt: 2.03 min.

[1117] 13 CHIRALPAK IF-3; Mobile Phase: Hex (0.1%DEA): EtOH=70:30; Flow rate: 1 mL / min; Rt: 1.10 min.

[1118] 14 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10;

[1119] Flow rate: 1 mL / min; Rt: 4.21 min.

[1120] 15 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=80:20; 25 Flow rate: 1 mL / min; Rt: 2.80 min.

[1121] 16 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Rt:

[1122] 2.71 min.

[1123] 17 CHIRALPAK IE-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=80:20;

[1124] Flow rate: 1 mL / min; Rt: 1.48 min.

[1125] 18 CHIRALPAK IJ-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Rt: 30 3.87 min.

[1126] 19 CHIRALPAK IE-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=80:20;

[1127] Flow rate: 1 mL / min; Rt: 1.95 min.

[1128]

[1129] Foreignfiling_text_P25-005-SEC-WO01

[1130] 105

[1131] Cpd. Conditions

[1132] No.

[1133] 20 CHIRALART Cellulose SB;; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Flow: 1 mL / min; Rt: 2.71 min.

[1134] 21 CHIRALPAK IE-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=80:20; 5

[1135] Flow rate: 1 mL / min; Rt: 1.29 min.

[1136] 22 CHIRALART Cellulose SB; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=90:10; Flow: 1 mL / min; Rt: 2.12 min.

[1137] 23 CHIRALPAK IE 3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=80:20;

[1138] Flow rate: 1 mL / min; Rt: 1.52 min.

[1139] 24 CHIRALPAK IK-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=1:1)=85:15;

[1140] Flow rate: 1 mL / min; Rt: 1.30 min.

[1141] 25 CHIRALPAK IK-3; Mobile Phase: Hex (0.1%DEA):(EtOH: DCM=l:l)=85:15Flow rate: 1 mL / min; Rt: 1.94 min.

[1142]

[1143] Biological Data

[1144] SK-HEP-1 reporter assay (“reporter assay”)

[1145] To identify inhibitors of YAP-TEAD interaction, 8x TEAD responsive elements driving the NanoLuc® luciferase gene were stably integrated into SK-HEP-1 cells (ECACC #: 91091816).

[1146] For the assay, cells were treated in duplicates with the test compounds in a 10-point dose, with the top concentration starting at 30 pM (final concentration in assay). After a 24 hour incubation at 37 °C, 95% rH, and 5% CO2, a luciferase substrate / lysis reagent mix (NanoGio™, Promega) was added to the cells, allowing the quantification of cellular luciferase activity.

[1147] Cell Media: The cells were cultured in the following media: MEM, +10 % FBS, +1x GlutaMAX, +1 mM Sodium-Pyruvate, + 100 pM Non-essential amino 30

[1148] acids, +0.1 mg / ml Hygromycin. The media used for the assay was: MEM (w / o Phenol Red), +10 % FBS, +1x GlutaMAX, +1 mM Sodium-Pyruvate, + 100 pM Non-essential amino acids, +0.5 % Pen / Strep.Foreignfiling_text_P25-005-SEC-WO01

[1149] 106

[1150] Reagents: The reagents used are listed below:

[1151] Reagent Manufacturer Order No.

[1152] 5 MEM Sigma 2279-500ml MEM (w / o Phenol Red) Gibco 51200-046

[1153] FBS PAN Biotech P30-1502 GlutaMAX Gibco 35050-038 Sodium Pyruvate Gibco 11360

[1154] NEAA Gibco 11140 Hygromycin Sigma 10687-010 NanoGio® Luciferase Assay System Promega N1150

[1155] Penicillin / Streptomycin Invitrogen 15140

[1156] DPBS (1x) Gibco 14190

[1157] Accutase PAN Biotech P10-21500

[1158]

[1159] Cell culture: The cells were examined using an inverted microscope to check for health and cell density. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3 mL pre-warmed Accutase® was added to a F75 flask, dispersed evenly and the flask was allowed to sit in incubator for ~4-5 minutes.

[1160] When a single cell suspension was obtained, 7 ml of prewarmed growth media was added and resuspended with the cells. The cell suspension was transferred to a sterile 15 mL conical centrifuge tube, and spun for 5 min at 300xg, RT. The supernatant was discarded and the pellet was resuspended in 10 mL of pre-warmed growth media.

[1161] The total cell count was determined, and 20 pL of the desired cell number was added to each well of a 384 well plate using a Multidrop Combi. The plates were then incubated for 24 hours at 37 °C, 95 % rH, and 5 % CO2.

[1162] 30 Compound treatment: 24 hours after seeding, the cells were treated with compounds.Foreignfiling_text_P25-005-SEC-WO01

[1163] 107

[1164] A 1:333 dilution of compounds, diluted in DMSO, was made to get a final concentration of 0.3 % DMSO per well. To transfer the compounds to the assay plate, 120 nL was shot from Labcyte low dead volume plates to the cell plates containing 20 pL media / well with the ECHO 555 liquid handling 5 system.

[1165] After treatment, the cells were fed with 20 pL fresh pre-warmed assay media using a Multidrop combi.

[1166] The assay plates were then incubated for another 24 h at 37 °C, 95 % rH, and 5 % CO2.

[1167] Luciferase readout: 24 h after treatment, the plates were taken out of the incubator and were allowed to equilibrate to RT. 30 pL of NanoGio® reagent was added to the plates in the dark. Plates were shaken for 20 min on a Teleshake (~1500 rpm) in the dark. The luminescence was then measured using an EnVision microplate reader. The IC50 values were generated using Genedata Screener®.

[1168] Viability assay in H226 (Yap-dependent) and SW620 Yap KO (Yap independent) cells

[1169] The ability of YAP-TEAD inhibitors to inhibit tumor cell growth was evaluated using two different cell lines: NCI-H226, which is a YAP dependent cell line, and SW620 cells, where YAP and TAZ were knocked out using CRISPR to generate a YAP independent cell line.

[1170] For the assay, cells were treated in duplicates with the test compounds in a 10-point dose, 1:3 dilution steps, with the top concentration starting at 30 pM (final concentration in assay). After a 96 hour incubation at 37 °C, 95 % rH, and 5 % CO2, a cell-permeant DNA-binding dye that stains only healthy cells 30 (CyQUANT®, Promega) was added to the cells, allowing the quantification of cell viability.Foreignfiling_text_P25-005-SEC-WO01

[1171] 108

[1172] Cell Media: The NCI-H226 cells were cultured in the following media: RPMI 1640, +10 % FBS, +1x GlutaMAX, +10 mM HEPES, + 0.5 % Pen / Strep. The SW620-KO cells were cultured in the following media: DMEM / F-12, +10 % FBS, +1x GlutaMAX, +10 mM HEPES, +0.5 % Pen / Strep.

[1173] 5

[1174] Reagents: The reagents used are listed below:

[1175] Reagent Manufacturer Order No.

[1176] DMEM / F12 Gibco 21331

[1177] RPMI 1640 Gibco 31870

[1178] FBS PAN Biotech P30-1502 GlutaMAX Gibco 35050-038

[1179] HEPES Gibco 15630

[1180] CyQuant® Promega C35012

[1181] Penicillin / Streptomycin Invitrogen 15140

[1182] DPBS (1x) Gibco 14190

[1183] Accutase PAN Biotech P10-21500

[1184]

[1185] Cell culture: The cells were examined using an inverted microscope to check for health, cell density, etc. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3 mL pre-warmed Accutase was added to a F75 flask, dispersed evenly and the flask was allowed to sit in incubator for ~4-5 minutes.

[1186] When a single cell suspension was obtained, 7 mL of prewarmed growth media was added and resuspended with the cells. The cell suspension was transferred to a sterile 15 mL conical centrifuge tube, and spun for 5 min at 300xg, RT. The supernatant was discarded and the pellet was resuspended in 10 mL of pre-warmed growth media.

[1187] The total cell count was determined, and 20 pL of the desired cell number was added to each well of a 384 well plate using a Multidrop Combi. The 30 plates were then incubated for 24 hours at 37 °C, 95 % rH, and 5 % CO2.Foreignfiling_text_P25-005-SEC-WO01

[1188] 109

[1189] Compound treatment: 24 hours after seeding, the cells were treated with compounds.

[1190] A 1:333 dilution of compounds, diluted in DMSO, was made to get a final concentration of 0.3 % DMSO per well. To transfer the compounds to the 5 assay plate, 120 nL was shot from Labcyte low dead volume plates to the cell plates containing 20 pL media / well with the ECHO 555 liquid handling system.

[1191] After treatment, the cells were fed with 20 pL fresh pre-warmed assay media using a Multidrop combi.

[1192] The assay plates were then incubated for 96 h at 37 °C, 95 % rH, and 5 % CO2.

[1193] CyQuant® Measurement

[1194] 96h after treatment 30 pL of CyQuant® reagent was added to the assay plates using a Multidrop combi in the dark. The plates were then incubated for 1 hour at 37 °C, 95 % rH and 5 % CO2. Thereafter, the assay plates were removed from the incubator and allowed to equilibrate to RT for 30 min in the dark without lid. Finally, they were measured using an EnVision microplate reader with a FITC bottom read program.

[1195] Experimental data in SK-HEP-1 reporter assay of the compounds shown in Table 1 are shown in Table 2 below and classified in the following groups:

[1196] Group A IC50 is in the range of 1 nM to 100 nM

[1197] Group B IC50 is in the range of >100 nM to 1000 nM

[1198] Group C IC50 is in the range of >1000 nM to 10000 nM

[1199] Group D IC50 is in the range >10000 to 30000 nM

[1200] n.d. Not detectable below threshold given in parantheses

[1201] 30 Experimental data in the viability assays of the compounds shown in Table 1 are shown in Table 2 below and classified in the following groups:Foreignfiling_text_P25-005-SEC-WO01

[1202] 110

[1203] Group A IC50 is in the range of 1 nM to 100 nM

[1204] Group B IC50 is in the range of >100 nM to 1000 nM Group C IC50 is in the range of >1000 nM to 10000 nM Group D IC50 is in the range >10000 to 30000 nM

[1205] 5 n.d. Not detectable below threshold given in parantheses

[1206] Table 2

[1207] Cpd. No. SW620 KO H226 Reporter

[1208] viability

[1209] 1 n.d. (>=3000) B B

[1210] 2 n.d. (>=3000) C B

[1211] 3 n.d. (>=3000) B A

[1212] 4 n.d. (>=3000) B A

[1213] 5 n.d. (>=3000) B B

[1214] 6 n.d. (>=3000) C C

[1215] 7 n.d. (>=3000) C B

[1216] 8 n.d. (>=3000) A A

[1217] 9 n.d. (>=3000) B A

[1218] 10 n.d. (>=3000) B A

[1219] 11 n.d. (>=3000) B A

[1220] 12 n.d. (>=3000) B A

[1221] 13 n.d. (>=3000) C C

[1222] 14 n.d. (>=3000) B A

[1223] 15 n.d. (>=3000) B A

[1224] 16 n.d. (>=3000) C B

[1225] 17 n.d. (>=3000) A A

[1226] 18 n.d. (>=3000) B A

[1227] 19 n.d. (>=3000) B A

[1228] 20 n.d. (>=3000) B B

[1229] 21 n.d. (>=3000) B A

[1230] 22 n.d. (>=3000) C C

[1231] 23 n.d. (>=3000) B B

[1232] 24 n.d. (>=3000) B A

[1233] 25 n.d. (>=3000) B A

[1234] 26 n.d. (>=30000 ) B A

[1235] 27 n.d. (>=3000) B B

[1236] 30

[1237]

[1238] Thermal shift assayForeignfiling_text_P25-005-SEC-WO01

[1239] 111

[1240] Nano Differential Scanning Fluorimetry. NanoDSF was performed on a Prometheus NT.48 instrument (NanoTemper Technologies GmbH). Protein sample was briefly centrifuged before preparation. The final reaction mixture contained 11.8 pM of hsTEADI (209-426), 7.3 pM of hsTEAD2 (217-447)- 5 His, 7.9 pM of hsTEAD3 (216-435) or 11.7 pM of hsTEAD4 (217-434)-Thrb- His diluted in 20 mM Tris pH 8.0, 150 mM NaCI, 0.5 mM TCEP to which 1 pL DMSO 100% (apo) or 100 pM of each compound were added. This incubation was performed at 4 °C for 2 h. High sensitivity capillaries (NanoTemper Technologies) were filled with 10 pL of sample and placed on the Prometheus NT.48 sample holder. A temperature gradient of 1 °C / min was applied from 25 °C to 90 °C. The intrinsic protein fluorescence at 330 and 350 nm and light scattering were recorded. Data were analysed with respect to the fluorescence (330 nm) and / or aggregation values. The melting temperatures (Tm) were obtained by calculating the midpoint of each transition, using the PR. ThermControl Software™ version 2.16 and Stability Analysis Software™ version 1.1. The thermal stability and aggregation effect of each compound was calculated by subtracting the Tm values in the presence of each compound to those obtained in the presence of DMSO. A change in the Tm was considered significant when the |ATm| > 2 °C. Samples were tested in duplicates or triplicates.

[1241] Table 3

[1242] Cpd. No. abs TEAD1 abs TEAD2 abs TEAD3 abs TEAD4

[1243] delta T (° C) delta T (° C) delta T (° C) delta T (° C)

[1244] 2 7 5 1 4

[1245] 3 11 14 5 20

[1246] 5 9 10 1 6

[1247] 8 14 13 5 18

[1248] 18 13 11 6 17

[1249] 30 19 12 10 4 15

[1250]

Claims

Foreignfiling_text_P25-005-SEC-WO01112Claims1. Compound of formula I5whereinX1denotes N or CRX1;RX1denotes H, halogen, straight-chain or branched Ci-4-alkyl, which is unsubstituted or substituted with independently from each other 1, 2, or 3 halogen, and / or OH;R1denotes halogen, -NH2, -CN, straight-chain or branched Ci-4-alkyl, which is unsubstituted or substituted with independently from each other 1, 2, or 3 halogen;R2denotes H, Aik2, Ar2, Hetar2, Cyc2, Hetcyc2, -L2-Ar2a, -S(=O)2Rf; R3denotes H, -CN, -C(=O)-NH2 or halogen;A denotesA-1Foreignfiling_text_P25-005-SEC-WO01113wherein A-1 and A-2 bear the bicyclic ring system of the compound5of formula I in 1-positon and that L1-B radical of the compound of formula I in 3-position relative to that bicyclic ring system;B denotes Ar1, Hetar1, Cyc1, Hetcyc1;L1denotes -O-, -S-, -N(R4)-, -O-CH2-, -O-CH(R5)-, -O-SO2-, -N(R6)-CH2-, -N(R6)-C(=O)-, -CH2-, -CH(R7)-, -CH2CH2-, -CH2-O-;R4denotes H, straight-chain or branched Ci-6-alkyl;R5, R6, R7denote independently from each other straight-chain or branched Ci-6-alkyl;L2denotes a divalent -S(=O)2- group;Aik2denotes straight-chain or branched Ci-6-alkyl, C2-6-alkenyl or C2-6- alkinyl, each of which may be unsubstituted or substituted with independently from each other R2a1, R2a2and / or R2a3;Ar1denotes a mono- or bicyclic aryl with 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein that aryl is substituted with independently from each other RC1, RC2, and / or RC3;Ara, Ar2, Ar2adenote independently from each other a mono- or bicyclic aryl with 5, 6, 7, 8, 9, 10 ring carbon atoms, wherein that aryl may be unsubstituted or substituted with independently from each other RB1, RB2, RB3, RB4, and / or RB5;Hetar1denotes a mono- or bicyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon 30 atoms, wherein that heteroaryl is substituted with independently from each other RC1, RC2, and / or RC3;Foreignfiling_text_P25-005-SEC-WO01114Hetara, Hetar2, Hetar2adenote independently from each other a mono- or bicyclic heteroaryl with 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that 5 heteroaryl is unsubstituted or substituted with independently from each other RB1, RB2, RB3, RB4, and / or RB5;Cyc1denotes a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein said carbocycle may be un-substituted or substituted with independently from each other RC6, RC7, RC8, RC9, RC1°, and / or RC11;Cyca, Cyc2, Cyc2adenote independently from each other a saturated or partially unsaturated, mono-, bi- or tricyclic carbocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms, wherein said carbocycle is unsubstituted or substituted with independently from each other RB6, RB7, RB8, RB9, RB1°, and / or RB11;Hetcyc1denotes a saturated or partially unsaturated, mono- or bicylic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is / are a hetero atom(s) selected from N, O and / or S and the remaining are carbon atoms, wherein said heterocycle is substituted with independently from each other RC6, RC7, RC8, RC9, RC1°, and / or RC11;Hetcyca, Hetcyc2, Hetcyc2adenote independently from each other a saturated or partially unsaturated, mono- or bicylic heterocycle with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ring atoms wherein 1, 2, 3, 4, 5 of said ring atoms is / are a hetero atom(s) selected from N, O and / or S and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or substituted with independently from each other RB6, RB7, RB8, RB9, RB1°, and / or RB11;30 R2a1, R2a2, R2a3denote independently from each other halogen, -CF3, - CN, -NH2, -NHRa, -NRaRb, -OH, -ORC, -P(=O)RdRe, -SH, -SRf, - S(=O)Rf, -S(=O)2Rf, -S(=O)(=NRg)Rf, -N=S(=O)RfRh, -C(=O)NH2, -Foreignfiling_text_P25-005-SEC-WO01115C(=O)NHRa, -C(=O)NRaRb, -C(=O)OH, -C(=O)ORC, -NH-C(=O)-Ri, Ar2a, Cyc2a, Hetar2a, Hetcyc2a;and / ortwo of R2a1, R2a2, R2a3which are attached to the same carbon atom form 5 together a divalent oxo (=0) group;Ra, Rbdenote independently from each other straight-chain or branched Ci-6-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 halogen; Ara, Cyca, Hetara, Hetcyca;orRaand Rbform together with the nitrogen atom to which they are attached to a saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, 0 or S and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or substituted with independently from each other RB6, RB7, RB8, RB9, RB1°, and / or RB11;Rcdenotes straight-chain or branched Ci-4-alkyl, C2-4-alkenyl or C2-4- alkinyl, each of which may be unsubstituted or substituted with -OH; C3-7-cycloalkyl which may be unsubstituted or substituted with -OH and / or halogen;Rd, Redenote independently from each other straight-chain or branched C1- 6-alkyl;Rf, Rhdenote independently from each other straight-chain or branched C1- 6-alkyl;Rgdenotes H, straight-chain or branched Ci-6-alkyl;R' denotes H, straight-chain or branched Ci-6-alkyl;RA1denotes straight-chain or branched Ci-4-alkyl, which is unsubstituted or substituted with independently from each other 1, 2, or 3 halogen; RA2denotes straight-chain or branched Ci-4-alkyl;30 RA3denotes halogen;Foreignfiling_text_P25-005-SEC-WO01116RB1, RB2, RB3, RB4, RB5denote independently from each other halogen; - OH; -OCi-4-alkyl; Ci-4-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 halogen;RB6, RB7, RB8, RB9, RB1°, RB11denote independently from each other 5 halogen; OH; -OCi-4-alkyl; Ci-4-alkyl, which is unsubstituted or substituted with 1 or 2 OH and / or 1, 2, or 3 halogen;and / ortwo of RB6, RB7, RB8, RB9, RB1°, RB11which are attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=0) group;and / ortwo of RB6, RB7, RB8, RB9, RB1°, RB11which are attached to the same sulfur (S) atom of said heterocycle form a divalent oxo (=0) group while at the same time two further of RB6, RB7, RB8, RB9, RB1°, RB11which are attached to the same sulfur atom form either a divalent oxo group or a divalent =N-H or =N-Ci-4-alkyl group, thereby forming an - S(=0)2, -S(=O)(=NH), or -S(=O)(=N-Ci-4-alkyl) moiety;RC1, RC2, RC3denote independently from each other halogen; Ci-4-alkyl, - SCi-4-alkyl or -OCi-4-alkyl, each of which may be unsubstituted or substituted with 1, 2, or 3 halogen;RC6, RC7, RC8, RC9, RC10, and / or RC11denote independently from each other halogen; C1-4-alkyl, which is unsubstituted or substituted with 1, 2, or 3 substituents independently from each other selected from halogen; -O-C1-4-alkyl, which is unsubstituted or substituted with 1, 2, or 3 substituents independently from each other selected from halogen; halogen denotes F, Cl, Br, I;or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.30Foreignfiling_text_P25-005-SEC-WO011172. Compound according to claim 1, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein5A denotes3. Compound according to claim 1 or 2, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein RA1denotes methyl;RA2denotes methyl;RA3denotes F.

4. Compound according to any one of the preceding claimswhereinX1denotes CH;or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

5. Compound according to any one of the preceding claimswhereinR1denotes Cl, -CFH2, -CF2H or -CF3; andR3denotes H;or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including 30mixtures thereof in all ratios.Foreignfiling_text_P25-005-SEC-WO011186. Compound according to any one of the preceding claims whereinR2denotes H, Aik2, Cyc2, Hetar2, Hetcyc2, -L2-Ar2a, -S(=O)2Rf; Aik2denotes straight-chain or branched Ci-6-alkyl, Ci-6-alkenyl or C2-6- 5 alkinyl, each of which may be unsubstituted or substituted with independently from each other R2a1, R2a2and / or R2a3;Cyca, Cyc2, Cyc2adenote independently from each other a saturated monocyclic carbocycle with 3, 4, 5, 6, or 7 ring carbon atoms, wherein said carbocycle is unsubstituted or substituted with independently from each other RB6and / or RB7;Hetcyca, Hetcyc2, Hetcyc2adenote independently from each other a saturated or partially unsaturated monocylic heterocycle with 3, 4, 5, or 6 ring atoms wherein 1 or 2 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or substituted with independently from each other RB6and / or RB7and / or RB8and RB9together or RB6and / or RB7and / or RB8and RB9and RB1° and RB11together;L2denotes a divalent -S(=O)2- group;Ara, Ar2adenote independently from each other phenyl which may be unsubstituted or substituted with independently from each other RB1and / or RB2;Hetara, Hetar2, Hetar2adenotes a monocyclic heteroaryl with 5 or 6 ring atoms wherein 1, 2, or 3 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is unsubstituted or substituted with independently from each other RB1and / or RB2;R2a1, R2a2, R2a3denote independently from each other halogen, -CF3, -CN, -NH2, -NHRa, -NRaRb, -OH, -ORc, -P(=O)RdRe, -SRf, -S(=O)2Rf, -S(=O)(=NRg)Rf, -N=S(=O)RfRh, -C(=O)NH2, -C(=O)NHRa, -C(=O)NRaRb, -C(=O)OH, -C(=O)ORc, -NH-C(=O)-Ri, Cyc2a, Hetar2a, Hetcyc2a;Foreignfiling_text_P25-005-SEC-WO01119and / ortwo of R2a1, R2a2, R2a3which are attached to the same carbon atom form together a divalent oxo (=0) group;Ra, Rbdenote independently from each other straight-chain or branched 5 Ci-6-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 halogen; Ara, Cyca, Hetara, Hetcyca;orRaand Rbform together with the nitrogen atom to which they are attached to a saturated or partially unsaturated heterocycle with 3, 4, 5, 6, 7 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N, 0 or S and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or substituted with independently from each other RB6and / or RB7and / or RB8and RB9together;Rcdenotes straight-chain or branched Ci-4-alkyl which is unsubstituted or substituted with -OH; straight-chain and unsubstituted C2-4-alkinyl; Cs-s-cycloalkyl;Rd, Redenote independently from each other straight-chain or branched Ci-6-alkyl;Rf, Rhdenote independently from each other straight-chain or branched Ci- 6-alkyl;Rgdenotes H, straight-chain or branched Ci-6-alkyl;R' denotes H, straight-chain or branched Ci-6-alkyl;RB1, RB2denote independently from each other halogen; C1-4-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 halogen; OH; RB6, RB7denote independently from each other halogen; OH; -OC1-4-alkyl;Ci-4-alkyl, which is unsubstituted or substituted with 1 OH or 1, 2, or 3 halogen;RB8and RB9which are attached to the same carbon atom of said 30 heterocycle form a divalent oxo (=0) group; orForeignfiling_text_P25-005-SEC-WO01120RB8, RB9, RB1° and RB11which are attached to the same sulfur (S) atom of said heterocycle form a divalent oxo (=0) group, thereby forming an -S(=O)2moiety;or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any 5 pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

7. Compound according to any one of the preceding claimswhereinR2denotes H, Aik2, Cyc2, Hetar2, Hetcyc2, -L2-Ar2a, -S(=O)2Rf; Aik2denotes straight-chain or branched Ci-4-alkyl, Ci-4-alkenyl or C2-4- alkinyl, each of which may be unsubstituted or substituted with independently from each other R2a1and / or R2a2;Cyc2, Cyc2adenote independently from each other a saturated monocyclic carbocycle with 3, 4, or 5 ring carbon atoms, wherein said carbocycle is mono-substituted with OH, -CH2OH;Hetcyc2denotes a saturated monocylic heterocycle with 5 ring atoms wherein 1 of said ring atoms is a hetero atom(s) selected from N, and 0 and the remaining are carbon atoms, wherein said heterocycle is mono-substituted with OH, or denotes a saturated monocyclic heterocycle with 4 ring atoms wherein 1 of said ring atoms is a heteroatom(s) selected from S and the remaining are carbon atoms, wherein said heterocycle is substituted with two oxo (=0) groups at the S atom;Hetcyc2adenotes a saturated monocylic heterocycle with 4 ring atoms wherein 1 of said ring atoms is a hetero atom(s) selected from N or 0 and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or mono-substituted with halogen, -OH, -O-Ci-4-alkyl or Ci-4-alkyl or disubstituted with halogen and Ci-4-alkyl, wherein said 30 Ci-4-alkyl in each case may be unsubstituted or mono-substituted with -OH or -OCi-4-alkyl; or denotes a saturated moncyclic heterocycle with 5 ring atoms wherein 1 of said ring atoms is a heteroForeignfiling_text_P25-005-SEC-WO01121atom selected from N or 0 or wherein 2 of said ring atoms are hetero atoms selected from N and / or 0 and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or mono-substituted with - OH, Ci-4-alkyl or an oxo (=0) group or disubstituted with Ci-4-alkyl 5 and an oxo (=0) group; or denotes a saturated monocyclic heterocycle with 6 ring atoms wherein 1 of said ring atoms is a hetero atom selected from N or 0 or wherein 2 of said ring atoms are hetero atoms selected from N and / or 0 and the remaining are carbon atoms, wherein said heterocycle is unsubstituted or mono-substituted with OH, Ci -4-alkyl or an oxo (=0) group) or disubstituted with halogen; or denotes a partially unsaturated monocyclic heterocycle with 6 ring atoms wherein 1 of said ring atoms is a hetero atom selected from N and the remaining are carbon atoms, wherein said heterocycle is mono-substituted with an oxo (=0) group);L2denotes a divalent -S(=0)2- group;Ar2adenotes phenyl which is mono-substituted with -CH3;Hetar2, Hetar2adenote independently from each other a monocyclic heteroaryl with 5 or 6 ring atoms wherein 1, 2, or 3 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is unsubstituted or monosubstituted with Ci-4-alkyl;R2a1, R2a2denote independently from each other -CF3, -CN, -NH2, -NHRa, - NRaRb, -OH, -ORC, -P(=0)RdRe, -SRf, -S(=O)2Rf, -S(=O)(=NRg)Rf, - C(=O)NH2, -C(=0)NHRa, -C(=0)NRaRb, -C(=0)0Rc, -NH-C(=0)-Ri, Cyc2a, Hetar2a, Hetcyc2a;and / orR2a1and R2a2which are attached to the same carbon atom form together a divalent oxo (=0) group;Ra, Rbdenote independently from each other straight-chain or branched 30 Ci -4-alkyl, which may be unsubstituted or substituted with 1, 2, or 3 F;Ara, Hetara;orForeignfiling_text_P25-005-SEC-WO01122Raand Rbform together with the nitrogen atom to which they are attached to a saturated heterocycle with 4, 5, or 6 ring atoms wherein 1 of said ring atoms is said nitrogen atom and no or one further ring atom is a hetero atom selected from N or 0 and the remaining are 5 carbon atoms, wherein said heterocycle is unsubstituted or monosubstituted with Ci -4-alkyl or di-substituted with F;Rcdenotes straight-chain or branched Ci-4-alkyl which is unsubstituted or substituted with -OH; unsubstituted C2-4-alkinyl; unsubstituted C3- 5-cycloalkyl;Rd, Redenote independently from each other straight-chain or branched Ci-4-alkyl;Rfdenotes straight-chain or branched Ci-4-alkyl;Rgdenotes H;R' denotes H, straight-chain or branched Ci-4-alkyl;Aradenotes phenyl;Hetaradenotes pyridyl;or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

8. Compound according to any one of the preceding claimswhereinR2denotes H; -CH3, -CH=CH-CF3, -C≡C-CH2-OH, -CH2-CN, -(CH2)2- CN, -(CH2)3-CN, -CH2-CH(OH)-CH2-CN, -(CH2)2-NH2, -(CH2)2- NHCH3, -(CH2)2-NHCH2CF3, -(CH2)2-NH-pyridin-2-yl, -(CH2)2- N(CH3)2, -(CH2)2-N(CF3)2, -CH2-CF2-CH2-NH2, -CH(CF3)-CH2- N(CH3)2, 2-(azetidin-1-yl)ethyl, 2-(pyrrolidin-1 -yl)ethyl, 2-(piperidin-1 - y l)ethy 1, 2-(4,4-d if luoropiperid in-1 -y l)ethy I, (N-methylmorpholin-3- yl)methyl, 2-(morpholin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, - 30 (CH2)3-NH2, -(CH2)3-NHCH3, -(CH2)3-N(CH3)2, -(CH2)4-NH2, -(CH2)4- NHCH3, -(CH2)4-N(CH3)2, -(CH2)2-OH, -(CH2)2-O-(CH2)2-OH, -(CH2)3-Foreignfiling_text_P25-005-SEC-WO01OH, -CH2CH(OH)-CH3, -CH(CH3)CH2-OH,5, -CH2-C(CH3)2-OH, -CH(CH2OH)2, -CH2CH(CH2OH)2, -CH2-CH(OH)-CH2OH, -CH2-CH(OH)-CH2-OCH3,, -CH(CH2OCH3)2, -(CH2)2-O-CH2-C≡CH, 2-hydroxy- 1-(pyrazin-2-yl)ethyl, -(CH2)2-S-CH3, -(CH2)2-S-CH2CH3, -(CH2)2- S(=O)2-CH3, -(CH2)2-S(=O)(=NH)CH3, -(CH2)2-S(=O)(=NH)CH2CH3, -CH2-P(=O)(CH3)2, -CH2-C(=O)-NH2, -CH2-C(=O)-NHCH3, -CH2- C(=O)-NHCH2CH3, -CH2-C(=O)-N(CH3)2, -CH2-C(=O)-NH-phenyl, - (CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-C(=O)-N(CH3)2, - CH(C(=O)OCH2CH3)2, -(CH2)2-NH-C(=O)-CH3, -C(=O)-CH3, -C(=O)-(CH2)2-CH3; (l-hydroxycyclobutyl)methyl ( ), (1 H-imidazol- 2-yl)methyl, (1 H-imidazol-4-yl)methyl, (1-methyl-1 H-imidazol-4- yl)methyl, (1 -methyl-1 H-imidazol-5-yl)methyl, (1 H-2-methylimidazol- 4-yl)methyl, (1 H-pyrazol-4-yl)methyl, (1 H-pyrazol-5-yl)methyl, (1- methyl-1H-pyrazol-4-yl)methyl, 1,2-thiazol-3-yl, 1,3-thiazol-2-yl, (1H- 1,2,3-triazol-4-yl)methyl, pyrazin-2-yl, (1,2,4-oxadiazol-3-yl)methyl, 2-(2-oxopyridin-1-yl)ethyl, (3-fluoroazetidin-3-yl)methyl, (1- methylazetidin-3-yl)methyl, (oxetan-3-yl)methyl, (3-fluorooxetan-3-30yl)methyl ( ), (3-hydroxyoxetan-3-yl)methyl ( ), (3-Foreignfiling_text_P25-005-SEC-WO01124methoxyoxetan-3-yl)methyl), methyl(oxetan-3- 5yl)methanol ( ), (1-methylazetidin-3-yl)ethyl, 2-(oxetan-3-yl)ethyl, 1,1-dioxo-1-lambda-6-thietan-3-yl ), (5-oxo-pyrrolidin-2-yl)methyl ( ° (5-oxo-pyrrolidin-3-yl)methyl (ooxolan-3-ylmethyl ), (3-hydroxyoxolan-3-OH C> J'lHyl)methyl ( ), (2-oxo-1,3-oxazolidin-4-yl)methyl (0(2-oxo-1,3-oxazolidin-5-yl)methyl), (4-methyl-2-oxo-1,3-30YHoxazolidin-4-yl)methyl ), (4-hydroxyoxan-4-yl)methyl (Foreignfiling_text_P25-005-SEC-WO011252-(4-hydroxyoxan-4-yl)ethyl 5 hydroxymethylcyclopropyl, 3-hydroxycyclobutyl, 2-hydroxycyclopentyl;sulfonyl-4-methylphenyl; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including 15mixtures thereof in all ratios.

9. Compound according to any one of the preceding claims whereinR2denotes H; -CH3, -(CH2)2-OH, -CH2-C(CH3)2-OH;20or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

10. Compound according to any one of the preceding claims whereinB denotes Ar1, Hetar1, Cyc1, Hetcyc1;L1denotes -O-, -S-, -N(R4)-, -O-CH2-, -O-CH(R5)-, -N(R6)-CH2-, -N(R6)-C(=O)-, -CH2-, -CH2CH2-;R4denotes H or CH3;30R5, R6denote CH3;Ar1denotes a phenyl, wherein that phenyl is mono-substituted with RC1;Foreignfiling_text_P25-005-SEC-WO01126Hetar1denotes a mono-cyclic heteroaryl with 5 or 6 ring atoms wherein 1 or 2 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein that heteroaryl is monosubstituted with RC1or di-substituted with RC1and RC2;5 Cyc1denotes a saturated, mono- or bi-cyclic carbocycle with 4, 5, 6, or 7 ring carbon atoms, wherein said carbocycle may be un-substituted or mono-substituted with RC6or di-substituted with RC6and RC7;Hetcyc1denotes a saturated, mono- or bicylic heterocycle with 5, 6, or 7 ring atoms wherein 1 or 2 of said ring atoms is / are a hetero atom(s) selected from N, 0 and / or S and the remaining are carbon atoms, wherein said heterocycle is substituted mono-substituted with RC6or di-substituted with RC6and RC7;RC1denotes F, Cl, CHF2, CF3, CH2CF3, OCF3, or SCF3;RC2denotes CH3or C2H5;RC6denotes F, Cl; CH3, CHF2, CF3, -OCH3, -OCHF2, -OCF3;RC7denotes F;or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

11. Compound according to any one of the preceding claims wherein30Foreignfiling_text_P25-005-SEC-WO01127530Foreignfiling_text_P25-005-SEC-WO011285or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

12. Compound according to any one of the preceding claims whereinL1denotes -O-;B denotes30Foreignfiling_text_P25-005-SEC-WO011295or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

13. Compound according to any one of the preceding claimswhereinL1denotes -O-;B denotes,, or; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

14. Compound according to any one of the preceding claims wherein30Foreignfiling_text_P25-005-SEC-WO011305or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

15. Compound of formula I according to any one of the preceding claims 15 whereinX1denotes CH;R1denotes Cl or -CF3;R2denotes H; -CH3, -(CH2)2-OH, -CH2-C(CH3)2-OH;R3denotes H;20A-L1-B denotesor any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.

16. Compound of formula I according to any one of the preceding claims, wherein the compound is a single atropisomer, or any N-oxide, solvate, or 30tautomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios.Foreignfiling_text_P25-005-SEC-WO0113117. Compound according to claim 1, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein the 5 compound is selected from the compounds depicted in Table 1.

18. Compound according to any of the proceeding claims, or any N- oxide, solvate, tautomer or stereoisomer thereof and / or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, for use as a medicament.

19. Compound according to any of claims 1 to 17, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, for use in the prevention and / or treatment of a medical condition or disease that is affected by inhibiting YAP-TEAD and / or TAZ-TEAD interaction.

20. Compound according to any of claims 1 to 17, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, for use in the prevention and / or treatment of a medical condition or disease selected from the group consisting of: cancer, in particular tumors including solid tumors, of breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cancer, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer; cardiovascular diseases and fibrosis, in particular, liver fibrosis.

21. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 17, or any N-oxide, solvate, tautomer or 30 stereoisomer thereof and / or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, as active ingredient, together with a pharmaceutically acceptable carrier.Foreignfiling_text_P25-005-SEC-WO0113222. A pharmaceutical composition comprising (a) as a first active ingredient a compound according to any one of claims 1 to 17, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or the pharmaceutically acceptable 5 salts of each of the foregoing, including mixtures thereof in all ratios; and (b) a second active ingredient, wherein that second active ingredient is other than a compound of formula I as defined in any one of claims 1 to 17.

23. Process for manufacturing a compound according to any one of claims 1 to 17, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, the process being characterized in that either(A) in a first reaction step a compound of formula IIIIwhereinR1, R3, and X1are defined as for formula I in any one of claims 1 to 17; Y1denotes H or a suitable protecting group, PG1;Hal1denotes Cl, Br, or I;is reacted under suitable C-C coupling reaction conditions with a compound of formula IIIY2-A-L1-BIIIwherein30A, L1, and B are defined as for formula I in any one of claims 1 to 17; Y2denotes a suitable boronate functional group;Foreignfiling_text_P25-005-SEC-WO01133to provide a compound of formula IVB5IV;or(B) in a first reaction step a compound of formula VVwhereinR1, R3, and X1are defined as for formula I in any one of claims 1 to 17; Y1denotes H or a suitable protecting group, PG1;Y3denotes a suitable boronate functional group;is reacted under suitable C-C coupling reaction conditions with a compound of formula VIHal2-A-L1-BVIwhereinA, L1, and B are defined as for formula I in any one of claims 1 to 17; Hal2denotes Cl, Br, or I;to provide a compound of formula IV;and, optionally, after step (A) or (B)30(C) (1) if in formula IV above Y1denotes PG1, in a second reaction step PG1is removed under suitable reaction conditions to provide a compoundForeignfiling_text_P25-005-SEC-WO01134of formula IV with Y1being H, which can also be described as a compound of formula I with R2being H; and / or(C) (2) if in formula IV above Y1denotes H, in another reaction step that compound of formula IV is reactied under suitable reaction conditions with 5 a compound of formula VIIR2-LG1VIIwhereinR2is defined as in any one of claims 1 to 17 with the exception of H; andLG1denotes a suitable leaving group;to provide a compound of formula I as defined in any one of claims 1 to 17; and, optionally, after step (C),the compound of formula I is separated into its individual atropisomers.30

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