Substituted bicyclic heterocyclic YAP-TEAD and / or TAZ-TEAD inhibitors

Abstract

The present invention relates to heterocyclic compounds. These heterocyclic compounds are suitable for use as TEAD binding agents and / or inhibitors of YAP-TEAD and TAZ-TEAD protein-protein interactions or binding, and for use in the prevention and / or treatment of cancer and other severe disorders and diseases.

Description

Substituted bicyclic heterocyclic YAP-TEAD and / or TAZ-TEAD inhibitors Technical Field

[0001] This invention relates to bicyclic compounds. These bicyclic compounds are suitable as TEAD binding agents and / or inhibitors of YAP-TEAD and TAZ-TEAD protein-protein interactions or binding, and are suitable for the prevention and / or treatment of cancer and other serious disorders and diseases. Background Technology

[0002] In recent years, the Hippo pathway has become a target of interest in the treatment of hyperproliferative disorders and diseases, particularly cancer (SA Smith et al., J. Med. Chem. 2019, 62, 1291-1305; KC Lin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. Kim et al., Cells (2019), 8, 468; KF Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)). The Hippo pathway regulates cell growth, proliferation, and migration. It is speculated that the Hippo pathway acts as a tumor suppressor in mammals, and dysfunction of Hippo signaling is frequently observed in human cancers.

[0003] Furthermore, since the Hippo pathway plays a role in several biological processes, such as in the self-renewal and differentiation of stem cells and precursor cells, wound healing and tissue regeneration, and in its interactions 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; KF Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)).

[0004] While several aspects of pathway activity and regulation remain to be further investigated, it has been established that, in the "on" state, the Hippo pathway involves a cytoplasmic kinase cascade (including Mst 1 / 2 and Lats 1 / 2), leading to phosphorylation of two transcriptional coactivators, YAP (a Yes-associated protein) and TAZ (a transcriptional coactivator with a PDZ-binding motif). Phosphorylation of YAP / TAZ isolates them in the cytoplasm, ultimately leading to their degradation. In contrast, when the Hippo pathway is "off" or dysregulated, the unphosphorylated activated YAP / TAZ coactivators translocate to the nucleus. Their primary target transcription factors are four proteins (TEAD1-4) from the transcription enhancement-associated domain (TEAD) family of transcription factors. The binding and activation of TEAD (or other transcription factors) with YAP or TAZ has been shown to induce the expression of several genes, many of which mediate cell survival and proliferation. Therefore, activated, unphosphorylated YAP and TAZ can act as oncogenes, while activated, turned-on Hippo pathways can act as tumor suppressors by deactivating YAP and TAZ, i.e., phosphorylating them.

[0005] Furthermore, the Hippo pathway may also play a role in the mechanisms of cancer cell resistance to oncology and immuno-oncology therapies (R. Reggiani et al., BBA - Reviews on Cancer 1873 (2020) 188341, 1-11).

[0006] Recently, small molecule inhibitors have been described as pan-TEAD inhibitors, namely compounds that bind not only to one member of the TEAD family, but also to more than one, and in particular to all four human TEAD paralogs, thereby blocking YAP / TAZ binding (TJ Hagenbeek, et al., Nature Cancer, 4, 812-828 (2023); WO2021 / 108483 A1).

[0007] Therefore, the Hippo pathway, as a tumor suppressor, is generally considered to be an important event in the development of various types of cancer and diseases due to its dysfunction or abnormal regulation.

[0008] Therefore, pharmacological intervention to inhibit YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD protein-protein interactions appears to be a rational and valuable strategy for the prevention and / or treatment of cancer and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction. This also applies to inhibiting not only binding to a single member of the TEAD family, but also binding to two, three, and / or all four TEAD paralogs. Summary of the Invention

[0009] This invention provides compounds applicable to the prevention and / or treatment of medical conditions, disorders, and / or diseases, particularly hyperproliferative disorders or diseases, such compounds being TEAD binding agents and / or inhibitors of YAP-TEAD or TAZ-TEAD protein-protein interactions. Some of the compounds of this invention are applicable to the preparation of other compounds of this invention.

[0010] In one embodiment, the present invention relates to a heteroaromatic compound of formula I. Where X 1 Indicates N or CR X1 ;R X1 Represents H, halogen, and straight or branched C that is unsubstituted or independently substituted by one, two, or three halogens. 1-4 Alkyl groups, and / or OH groups; R 1 Represents straight-chain or branched C atoms containing halogens, -NH2, -CN, unsubstituted or independently substituted by one, two or three halogens. 1-4 Alkyl; R 2 Represents H, Alk 2 Ar 2 Hetar 2 Cyc 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f ;R 3 The symbol represents H, -CN, -C(=O)-NH2, or a halogen; A represents 1,3-phenylene or a monocyclic divalent heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the 1,3-phenylene or monocyclic heteroaryl group has the compound of formula I at position 1. The bicyclic system, and relative to the bicyclic system, the L of the compound of formula I is located at position 3. 1 -B group, wherein each of the 1,3-phenylene or monocyclic heteroaryl groups may be further unsubstituted or independently converted to halogen, straight-chain or branched C groups. 1-4 -alkyl, OC 1-4 -alkyl, SC 1-4 -alkyl, C 3-7 -cycloalkyl, OC 3-7 -cycloalkyl or SC 3-7 - Cycloalkyl substitution, where C 1-4 -alkyl, OC 1-4 -alkyl, SC 1-4 -alkyl, C 3-7 -cycloalkyl, OC3-7 -cycloalkyl or SC 3-7 -The cycloalkyl group is either unsubstituted or substituted with one, two, or three halogens; B represents Ar. 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 Represents -O-, -S-, -N(R) 4 -, -O-CH2-, -O-CH(R) 5 -, -O-SO2-, -N(R) 6 -CH2-, -N(R) 6 -C(=O)-, -CH2-, -CH(R) 7 -, -CH2CH2-, -CH2-O-; R 4 Indicates H, straight chain or branched chain C 1-6 -alkyl; R 5 R 6 R 7 Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; L 2 Indicates a divalent -S(=O)2- group; Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 R 2a2 and / or R 2a3 Replace; Ar 1 This indicates a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein the aryl group is independently separated from each other by R. C1 R C2 and / or R C3 Replace; Ar a Ar 2 Ar 2a Each of the following independently represents a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryl group may be unsubstituted or independently represented by R. B1 R B2 R B3 R B4 and / or R B5 Replace; Hetar 1 This refers to a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is independently separated from each other by R. C1R C2 and / or R C3 Replace; Hetar a Hetar 2 Hetar 2a Each of the following independently represents a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is unsubstituted or independently converted to R B1 R B2 R B3 R B4 and / or R B5 Replace; Cyc 1 This refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings may be unsubstituted or independently of each other by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Cyc a Cyc 2 Cyc 2a Independently representing monocyclic, bicyclic, or tricyclic carbon rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings are not substituted or are independently represented by R B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; Hetcyc 1 This refers to a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycles are independently separated by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Hetcyc a Hetcyc 2 Hetcyc 2aIndependently representing saturated or partially unsaturated monocyclic or bicyclic heterocycles having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycles are unsubstituted or independently combined. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R 2a1 R 2a2 R 2a3 The terms -CF3, -CN, -NH2, and -NHR represent halogens independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SH, -SR f -S(=O)R f -S(=O)2R f -S(=O)(=NR) g )R f -N=S(=O)R f R h -C(=O)NH2, -C(=O)NHR a -C(=O)NR a R b -C(=O)OH, -C(=O)OR c -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; and / or R attached to the same carbon atom 2a1 R 2a2 R 2a3 The two together form a divalent oxo (=O) group; R a R b Each of these terms independently represents a straight-chain or branched C that may be unsubstituted or substituted with one, two, or three halogens. 1-6 -alkyl; Ar a Cyc a Hetar a Hetcyc a ; or R a and R bTogether with the nitrogen atom to which it is attached, it forms a saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N, O, or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is independently modified by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R c C represents a straight chain or a branch chain. 1-4 -alkyl, C 2-4 -Alkenyl or C 2-4 -Alynyl groups, each of which may be unsubstituted or substituted with -OH; C groups that may be unsubstituted or substituted with -OH and / or halogens 3-7 -cycloalkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f R h Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R g Indicates H, straight chain or branched chain C 1-6 -alkyl; R i Indicates H, straight chain or branched chain C 1-6 -alkyl; R B1 R B2 R B3 R B4 R B5 Halogens are represented independently of each other; -OH; -OC 1-4 -alkyl; C14 that may be unsubstituted or substituted with 1, 2 or 3 halogens. 1-4 -alkyl; R B6 R B7 R B8 R B9 R B10 R B11 Halogens are represented independently of each other; OH; -OC 1-4 -alkyl; C10 unsubstituted or substituted with 1 or 2 OH radicals and / or 1, 2 or 3 halogens. 1-4 -alkyl; and / or R attached to the same carbon atom of the carbide ring or the heterocycle. B6 R B7 R B8 R B9 R B10 R B11 Both of them form a divalent oxo (=O) group; and / or an R atom attached to the same sulfur (S) atom of the heterocycle.B6 R B7 R B8 R B9 R B10 R B11 The two molecules form a divalent oxo (=O) group, which is simultaneously attached to the R atom of the same sulfur atom. B6 R B7 R B8 R B9 R B10 R B11 The other two in it form divalent oxygen or divalent =NH or =NC 1-4 -alkyl groups, thereby forming -S(=O)2, -S(=O)(=NH) or -S(=O)(=NC 1-4 -alkyl) moiety; R C1 R C2 R C3 Halogens are represented independently of each other; C 1-4 -alkyl, -SC 1-4 -alkyl or -OC 1-4 -alkyl groups, each of which may be unsubstituted or substituted with one, two, or three halogens; R C6 R C7 R C8 R C9 R C10 and / or R C11 Each group independently represents a halogen; C14 cells are either unsubstituted or substituted with one, two, or three substituents independently selected from the halogen group. 1-4 -alkyl; unsubstituted or substituted with one, two or three substituents independently selected from halogens -OC 1-4 -alkyl; halogen means F, Cl, Br, I; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of the foregoing, including mixtures thereof in all proportions.

[0011] In another embodiment, the present invention relates to a heteroaromatic compound of formula I. Where X 1 Indicates N or CR X1 ;R X1 Represents H, halogen, and straight or branched C that is unsubstituted or independently substituted by one, two, or three halogens. 1-4 Alkyl groups, and / or OH groups; R 1 Represents straight-chain or branched C atoms containing halogens, -NH2, -CN, unsubstituted or independently substituted by one, two or three halogens. 1-4 Alkyl; R 2 Represents H, Alk 2 Ar2 Hetar 2 Cyc 2 Hetcyc 2 -L 2 -Ar 2a ;R 3 The symbol represents H, -CN, or a halogen; A represents 1,3-phenylene or a monocyclic divalent heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the monocyclic heteroaryl group has the compound of formula I at position 1. The bicyclic system, and relative to the bicyclic system, the L of the compound of formula I is located at position 3. 1 -B group, wherein each of the 1,3-phenylene or monocyclic heteroaryl groups may be further unsubstituted or independently converted to halogen, straight-chain or branched C groups. 1-4 -alkyl mono- or di-substituted, wherein the straight-chain or branched C 1-4 - The alkyl group is either unsubstituted or substituted with one, two, or three halogens; B represents Ar. 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 Represents -O-, -N(R) 4 -, -O-CH2-, -O-CH(R) 5 -, -O-SO2-, -N(R) 6 -CH2-, -N(R) 6 -C(=O)-, -CH2-, -CH(R) 7 -, -CH2CH2-, -CH2-O-; R 4 Indicates H, straight chain or branched chain C 1-6 -alkyl; R 5 R 6 R 7 Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; L 2 Indicates a divalent -S(=O)2- group; Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 R 2a2 and / or R 2a3 Replace; Ar 1 This indicates a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein the aryl group is independently separated from each other by R. C1 RC2 and / or R C3 Replace; Ar a Ar 2 Ar 2a Each of the following independently represents a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryl group may be unsubstituted or independently represented by R. B1 R B2 R B3 R B4 and / or R B5 Replace; Hetar 1 This refers to a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms; wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is independently separated from each other by R C1 R C2 and / or R C3 Replace; Hetar a Hetar 2 Hetar 2a Each of the following independently represents a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is unsubstituted or independently converted to R B1 R B2 R B3 R B4 and / or R B5 Replace; Cyc 1 This refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings may be unsubstituted or independently of each other by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Cyc 2 This refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings are not substituted or are independently converted by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; Hetcyc1 This refers to a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycles are independently separated by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Hetcyc a Hetcyc 2 Hetcyc 2a Each of the above independently represents a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or independently substituted by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R 2a1 R 2a2 R 2a3 The terms -CN, -NH2, and -NHR represent halogens independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SH, -SR f -S(=O)R f -S(=O)2R f -S(=O)(=NR) g )R f -N=S(=O)R f R h -C(=O)NH2, -C(=O)NHR a -C(=O)NR a R b -C(=O)OH, -C(=O)OR c -NH-C(=O)-R i Hetar 2a Hetcyc 2a ;R a R b Each can be represented independently as a straight chain or a branch C.1-6 -alkyl, Ar a Hetar a Hetcyc a ; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N, O, or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is independently modified by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R c C represents a straight chain or a branch chain. 1-4 -alkyl, C 2-4 -Alkenyl or C 2-4 -Alynyl groups, each of which may be unsubstituted or substituted with -OH; C groups that may be unsubstituted or substituted with -OH and / or halogens 3-7 -cycloalkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f R h Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R g Indicates H, straight chain or branched chain C 1-6 -alkyl; R i Indicates H, straight chain or branched chain C 1-6 -alkyl; R B1 R B2 R B3 R B4 R B5 Halogens are represented independently of each other; -OH; -OC 1-4 -alkyl; C14 that may be unsubstituted or substituted with 1, 2 or 3 halogens. 1-4 -alkyl; R B6 R B7 R B8 R B9 R B10 R B11 Halogens are represented independently of each other; OH; -OC 1-4 -alkyl; C10 unsubstituted or substituted with 1 or 2 OH radicals and / or 1, 2 or 3 halogens. 1-4 -alkyl; and / or R attached to the same carbon atom of the carbide ring or the heterocycle. B6 R B7R B8 R B9 R B10 R B11 Both of them form a divalent oxo (=O) group; and / or an R atom attached to the same sulfur (S) atom of the heterocycle. B6 R B7 R B8 R B9 R B10 R B11 The two molecules form a divalent oxo (=O) group, which is simultaneously attached to the R atom of the same sulfur atom. B6 R B7 R B8 R B9 R B10 R B11 The other two in it form divalent oxygen or divalent =NH or =NC 1-4 -alkyl groups, thereby forming -S(=O)2, -S(=O)(=NH) or -S(=O)(=NC 1-4 -alkyl) moiety; R C1 R C2 R C3 Halogens are represented independently of each other; C 1-4 -alkyl or -OC 1-4 -alkyl groups, each of which may be unsubstituted or substituted with one, two, or three halogens; R C6 R C7 R C8 R C9 R C10 and / or R C11 Each group independently represents a halogen; C14 cells are either unsubstituted or substituted with one, two, or three substituents independently selected from the halogen group. 1-4 -alkyl; unsubstituted or substituted with one, two or three substituents independently selected from halogens -OC 1-4 -alkyl; halogen means F, Cl, Br, I; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of the foregoing, including mixtures thereof in all proportions.

[0012] Generally, all residues, radicals, substituents, groups, parts, etc., appearing more than once may be the same or different, i.e., independent of each other. Unless otherwise stated, residues and parameters in the foregoing and hereinafter have the meanings indicated with respect to Formula I. Therefore, the present invention particularly relates to compounds of Formula I, wherein at least one of said residues, radicals, substituents has one of the preferred meanings indicated below.

[0013] Unless otherwise stated, any of the specific or even preferred embodiments of the invention specified below and in the claims refer not only to the specified Formula I compound, but also to its N-oxide, solvate, tautomer or stereoisomer, and pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

[0014] In a specific embodiment PE1, the compound of the present invention is a bicyclic compound of formula I, wherein X 1 Indicates N or CR X1 ;R X1 H represents H; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0015] In other words, compounds of PE1 are compounds of formula IA or IB: .

[0016] In another specific embodiment PE1a of PE1, the compound of the present invention is a bicyclic compound of formula I, wherein X 1 CH represents; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below. PE1a may also be described as a compound of Formula IA (see above).

[0017] In another specific embodiment PE1b of PE1, the compound of the present invention is a bicyclic compound of formula I, wherein X 1 N represents N; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below. PE1b can also be described as a compound of Formula IB (see above). In another specific embodiment PE2 of the invention, the compound of the invention is a bicyclic compound of Formula I, wherein R 1 Indicates Cl, -CN, or -CF3; and R 3 H represents H; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below. PE2 can also be described as a compound of Formula I. Where R 1 It represents Cl, -CN, or -CF3; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0018] In another specific embodiment PE2a of PE2, the compound of the present invention is a bicyclic compound of formula I or formula I, wherein R 1 Represents Cl or -CF3; and R3 H represents H; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0019] In another specific embodiment of the invention, PE3 (which may also be described as a specific embodiment of PE1a or PE2), the compound of the invention is a bicyclic compound of formula I, wherein R 1 Indicates Cl, -CN, or -CF3; and R 3 H; X 1 CH represents; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below. Alternatively, this specific embodiment PE3 may also be described as a compound of Formula I-AC: Where R 1 The designation represents Cl, -CN, or -CF3; and particularly Cl or -CF3 (PE3a); and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below. Embodiments PE3 and PE3a are preferred embodiments of the invention.

[0020] In another specific embodiment of the invention, PE3-0 (which may also be described as a specific embodiment of PE1b or PE2), the compound of the invention is a bicyclic compound of formula I, wherein R 1 Indicates Cl, -CN, or -CF3; and R 3 H; X 1 N represents N; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below. Alternatively, this specific embodiment PE3-0 may also be described as a compound of Formula I-BC: Where R 1 It represents Cl, -CN, or -CF3; and in particular Cl or -CF3 (PE3-0a); and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0021] In yet another specific embodiment PE4 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein R 1 Represents Cl or -CF3; and R 3 H represents H; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0022] In another specific embodiment of the present invention, PE4-0, the compound of the present invention is a bicyclic compound of formula I, wherein R 1 Represents -CH3; and R 3 It represents F or -CN; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0023] In another specific embodiment PE5 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein R 2 Represents H, Alk 2 Cyc 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0024] It is another specific implementation of PE5, PE5a, wherein R in formula I 2 Represents H, Alk 2 Cyc 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl, C 1-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 R 2a2 and / or R 2a3 Replace; Cyc a Cyc 2 Cyc 2a Each of the above independently represents a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring is not substituted or is independently modified by R. B6 and / or R B7 Replace; Hetcyc a Hetcyc 2 Hetcyc 2aIndependently representing saturated or partially unsaturated monocyclic heterocycles having 3, 4, 5, or 6 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or independently converted to R B6 and / or R B7 and / or R B8 With R B9 Common substitution (i.e., if it exists, then R) B8 and R B9 Both exist simultaneously, or are R B6 and / or R B7 and / or R B8 With R B9 With R B10 With R B11 Common substitution (i.e., if it exists, then R) B8 R B9 R B10 and R B11 All of them exist simultaneously); L 2 Indicates a divalent -S(=O)2- group; Ar a Ar 2a Independently representing either not being replaced or independently represented by R B1 and / or R B2 Substituted phenyl; Hetar a Hetar 2 Hetar 2a This indicates a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is unsubstituted or independently converted to R. B1 and / or R B2 Replace; R 2a1 R 2a2 R 2a3 The terms -CF3, -CN, -NH2, and -NHR represent halogens independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SR f -S(=O)2R f -S(=O)(=NR) g )R f -N=S(=O)R f R h -C(=O)NH2, -C(=O)NHR a -C(=O)NRa R b -C(=O)OH, -C(=O)OR c -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; and / or R attached to the same carbon atom 2a1 R 2a2 R 2a3 The two together form a divalent oxo (=O) group; R a R b Each of these terms independently represents a straight-chain or branched C that may be unsubstituted or substituted with one, two, or three halogens. 1-6 -alkyl; Ar a Cyc a Hetar a Hetcyc a ; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or partially unsaturated heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N, O, or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is independently modified by R. B6 and / or R B7 and / or R B8 With R B9 Common substitution (i.e., if it exists, then R) B8 and R B9 Both exist simultaneously); R c This refers to straight-chain or branched carbon that is either unsubstituted or substituted with -OH. 1-4 -alkyl; straight-chain and unsubstituted C 2-4 -Alynyl group; C 3-5 -cycloalkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f R h Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R g Indicates H, straight chain or branched chain C 1-6 -alkyl; R i Indicates H, straight chain or branched chain C 1-6 -alkyl; R B1 R B2 Halogens can be represented independently of each other; C can be unsubstituted or substituted with 1, 2 or 3 halogens. 1-4 -alkyl; OH; RB6 R B7 Halogens are represented independently of each other; OH; -OC 1-4 -alkyl; C10 unsubstituted or substituted with 1 OH or 1, 2 or 3 halogens. 1-4 -alkyl; R attached to the same carbon atom of the heterocycle B8 and R B9 Forming a divalent oxo (=O) group; or an R atom attached to the same sulfur (S) atom in the heterocycle. B8 R B9 R B10 and R B11 A divalent oxo(=O) group is formed, thereby forming the -S(=O)2 moiety; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0025] In another specific embodiment, PE5b, of PE5 and PE5a, the compound of the present invention is a bicyclic compound of formula I, wherein R 2 Represents H, Alk 2 Cyc 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f Alk 2 C represents a straight chain or a branch chain. 1-4 -alkyl, C 1-4 -Alkenyl or C 2-4 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 and / or R 2a2 Replace; Cyc 2 Cyc 2a Each of these terms independently represents a saturated monocyclic carbon ring having 3, 4, or 5 ring carbon atoms, wherein the carbon ring is monosubstituted by OH or -CH2OH; Hetcyc 2 This indicates a saturated monocyclic heterocycle with 5 ring atoms, wherein one ring atom is a heteroatom selected from N and O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is monosubstituted with OH; or it indicates a saturated monocyclic heterocycle with 4 ring atoms, wherein one ring atom is a heteroatom selected from S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is substituted with two oxo (=O) groups at the S atom; Hetcyc 2a This refers to a saturated monocyclic heterocycle having four ring atoms, wherein one of the ring atoms is a heteroatom selected from N or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or halogenated, particularly F, -OH, or OC.1-4 -alkyl or C 1-4 -Alkyl monosubstituted, or halogenated and C 1-4 -alkyl disubstituted, wherein the C 1-4 -alkyl groups may be unsubstituted or replaced with -OH or -OC in various cases. 1-4 -alkyl monosubstituted; or represents a saturated monocyclic heterocycle having 5 ring atoms, wherein one ring atom is a heteroatom selected from N or O, or wherein two ring atoms are heteroatoms selected from N and / or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or substituted with -OH, C 1-4 - Alkyl or oxo (=O) group monosubstituted or C 1-4 - Disubstituted alkyl and oxo (=O) groups; or representing a saturated monocyclic heterocycle having 6 ring atoms, wherein one ring atom is a heteroatom selected from N or O, or wherein two ring atoms are heteroatoms selected from N and / or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or substituted with OH, C 1-4 - Alkyl or oxo (=O) group monosubstituted or disubstituted with halogen; or representing a partially unsaturated monocyclic heterocycle having 6 ring atoms, wherein one ring atom is a heteroatom selected from N, and the remaining ring atoms are carbon atoms, wherein the heterocycle is monosubstituted with an oxo (=O) group; L 2 Indicates a divalent -S(=O)2- group; Ar 2a Hetar represents a phenyl group monosubstituted with -CH3; 2 Hetar 2a Each of the above terms independently represents a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is not substituted or converted to carbon. 1-4 -Alkyl monosubstituted; R 2a1 R 2a2 -CF3, -CN, -NH2, and -NHR are represented independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SR f -S(=O)2R f -S(=O)(=NR) g )R f -C(=O)NH2, -C(=O)NHR a -C(=O)NR a R b -C(=O)ORc -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; and / or R attached to the same carbon atom 2a1 and R 2a2 Together they form a divalent oxo (=O) group; R a R b Each of the following can be independently represented as a straight or branched C that may be unsubstituted or substituted by 1, 2, or 3 Fs. 1-4 -alkyl; Ar a Hetar a ; or R a and R b Together with the nitrogen atom it is attached to, it forms a saturated heterocycle with 4, 5, or 6 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is converted to carbon. 1-4 -Alkyl monosubstituted or disubstituted by F; R c This refers to straight-chain or branched carbon that is either unsubstituted or substituted with -OH. 1-4 -alkyl; unsubstituted C 2-4 -Alynyl group; unsubstituted C 3-5 -cycloalkyl; R d ,R e Each can be represented independently as a straight chain or a branch C. 1-4 -alkyl; R f C represents a straight chain or a branch chain. 1-4 -alkyl; R g H; R i Indicates H, straight chain or branched chain C 1-4 -alkyl; Ar a Hetar represents phenyl; a It represents a pyridinyl group; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0026] This is another specific embodiment of the present invention, PE5c. It may also be a specific embodiment of any one of specific embodiments PE5, PE5a, or PE5b. The compound of the present invention is a bicyclic compound of formula I, wherein R 2Represents 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-(azacyclobutan-1-yl)ethyl, 2-(pyrrolidone-1-yl) Ethyl, 2-(piperidin-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, (N-methylmorpholin-3-yl)methyl, 2-(morpholin-1-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)-CH3, -CH(CH3)CH2-OH, , , -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; (1-hydroxycyclobutyl)methyl ), (1H-imidazol-2-yl)methyl, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1H-2-methylimidazol-4-yl)methyl, (1H-pyrazole-4-yl)methyl, (1H-pyrazole-5-yl)methyl, (1-methyl-1H-pyrazole-4-yl)methyl, 1,2-thiazol-3 -yl, 1,3-thiazolyl-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-fluoroazacyclobutane-3-yl)methyl, (1-methylazacyclobutane-3-yl)methyl, (oxacyclobutane-3-yl)methyl, (3-fluorooxacyclobutane-3-yl)methyl ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ), (1-methylazacyclobutane-3-yl)ethyl, 2-(oxacyclobutane-3-yl)ethyl, 1,1-dioxo-1-λ-6-thionecyclobutane-3-yl( ), (5-oxo-pyrrolidone-2-yl)methyl ( ), (5-oxo-pyrrolidone-3-yl)methyl ( ), oxacyclopentane-3-ylmethyl ( ), (3-hydroxyoxacyclopentan-3-yl)methyl ( ), (2-oxo-1,3-oxazolidin-4-yl)methyl ( ), (2-oxo-1,3-oxazolidine-5-yl)methyl ( ), (4-methyl-2-oxo-1,3-oxazolidine-4-yl)methyl ( ), (4-hydroxyoxacyclohexane-4-yl)methyl ( ), 2-(4-hydroxyoxacyclohexane-4-yl)ethyl ( ); 1-hydroxymethylcyclopropyl, 3-hydroxycyclobutyl, 2-hydroxycyclopentyl; , , , , , ; sulfonyl-4-methylphenyl; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0027] This is another specific embodiment of the invention, PE5d, and may also be a specific embodiment of any one of specific embodiments PE5, PE5a, PE5b, or PE5c, wherein the compound of the invention is a bicyclic compound of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, wherein R 2 Represents H; -CH3, -CH=CH-CF3, -CH2-CN, -(CH2)2-CN, -(CH2)3-CN, -CH2-CH(OH)-CH2-CN, -(CH2)2-N(CH3)2, -CH2-CF2-CH2-NH2, -CH(CF3)-CH2-N(CH3)2, (N-methylmorpholin-3-yl)methyl, 2-(morpholin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, -(CH2)2-OH, -(CH2)2-O-(CH2)2-OH, -(CH2)3-OH, -CH(CH3)CH2-OH, , , -CH2-C(CH3)2-OH, -CH(CH2OH)2, -CH2CH(CH2OH)2, -CH2-CH(OH)-CH2-OCH3, , -(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-C(=O)-NHCH3, -CH2-C(=O)-NHCH2CH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -CH(C(=O)OCH2CH3)2, (1-hydroxycyclobutyl)methyl -(CH2)2-NH-C(=O)-CH3; (1H-imidazol-2-yl)methyl, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1H-2-methylimidazol-4-yl)methyl, (1H-pyrazole-4-yl)methyl, (1H-pyrazole-5-yl)methyl, (1-methyl-1H-pyrazole-4-yl)methyl, 1,2-thiazolyl-3-yl, 1,3-thiazolyl-2-yl, (1H-1,2,3-triazol-4-yl)methyl, pyrazin-2-yl, 2-(2-oxopyridin-1-yl)ethyl, (1,2,4-oxadiazol-3-yl)methyl, (oxetane-3-yl)methyl, (3-fluorooxetane-3-yl)methyl ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ), 2-(oxetane-3-yl)ethyl, 1,1-dioxo-1-λ-6-thionecyclobutane-3-yl( ), (5-oxo-pyrrolidine-2-yl)methyl, (5-oxo-pyrrolidine-3-yl)methyl, oxepane-3-ylmethyl, (3-hydroxyoxepane-3-yl)methyl, (2-oxo-1,3-oxazolidine-4-yl)methyl, (2-oxo-1,3-oxazolidine-5-yl)methyl, (4-methyl-2-oxo-1,3-oxazolidine-4-yl)methyl, (4-hydroxyoxepane-4-yl)methyl, 2-(4-hydroxyoxepane-4-yl)ethyl; 3-hydroxycyclobutyl; , , , , The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0028] In another specific embodiment PE6 of the invention, the compound of the invention is a bicyclic compound of formula I, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, wherein A represents in This indicates that ring A and compound of formula I The connection point of the double-ring system, and The term indicates the connection point with the L¹-B group of the compound of Formula I; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0029] In another specific embodiment PE6a of PE6, the compound of the present invention is a bicyclic compound of formula I, wherein A represents The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0030] In another specific embodiment, PE6b, of PE6 or PE6a, the compound of the present invention is a bicyclic compound of formula I, wherein A represents The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0031] In another specific embodiment PE7 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein B represents Ar. 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 Represents -O-, -S-, -N(R) 4 -, -O-CH2-, -O-CH(R)5 )-、-N(R 6 -CH2-, -N(R) 6 )-C(=O)-, -CH2-, -CH2CH2-; R 4 Represents H or CH3; R 5 R 6 Indicates CH3; Ar 1 Represents a phenyl group, wherein the phenyl group is reacted with R. C1 Monosubstitution; Hetar 1 This indicates a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is R C1 Single substitution or R C1 and R C2 Bisubstitution; Cyc 1 This refers to a saturated monocyclic or bicyclic carbon ring having 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or substituted with R. C6 Single substitution or being replaced by other R C6 and R C7 Bisubstitution; Hetcyc 1 This refers to a saturated monocyclic or bicyclic heterocycle having 5, 6, or 7 ring atoms, wherein 1 or 2 of these ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is decoupled by R. C6 Single substitution or being replaced by other R C6 and R C7 Bisubstitution; R C1 Represents F, Cl, CHF2, CF3, CH2CF3, OCF3, or SCF3; R C2 Indicates CH3 or C2H5; R C6 Represents F, Cl; CH3, CHF2, CF3, -OCH3, -OCHF2, -OCF3; R C7 F represents F; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0032] In yet another specific embodiment PE8 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein L 1 It represents -O-, -NH- or -O-CH2-; and the remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0033] In even other specific embodiments PE9 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein B represents The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0034] In yet another specific embodiment PE10, the compound of the present invention is a bicyclic compound of formula I, wherein L 1 -O- indicates; B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0035] It is a specific embodiment of PE10, PE10a, wherein the compound of the present invention is a bicyclic compound of formula I, wherein L 1 -O- indicates; B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0036] Other specific embodiments of PE10aa, PE10aa, wherein the compound of the present invention is a bicyclic compound of formula I, wherein A represents L 1 -O- indicates; B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0037] In yet another specific implementation of PE10aaa, PE10aaa, A represents... ; and preferably (PE10aaaa)A represents ;and L 1 It indicates -O- and B as defined above for PE10aa, preferably , The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0038] In yet another specific embodiment PE11 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein L 1 -NH–B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0039] It is a specific embodiment of PE11, PE11a, wherein the compound of the present invention is a bicyclic compound of formula I, wherein L 1 -NH–B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0040] In yet another specific embodiment PE12 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein L 1 B represents -O-CH2-; The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0041] It is a specific embodiment of PE12, PE12a, wherein the compound of the present invention is a bicyclic compound of formula I, wherein L 1 B represents -O-CH2-; The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0042] This is another specific embodiment of PE12aa, PE12aa, wherein the compound of the present invention is a bicyclic compound of formula I, wherein A represents L 1B represents -O-CH2-; The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0043] In another specific embodiment PE13 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein AL 1 -B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0044] In a specific implementation scheme PE13a of PE13, AL 1 -B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0045] In another specific implementation of PE13, PE13aa, AL 1 -B indicates The remaining groups and residues are as defined above with respect to Formula I, or with respect to any of the other specific embodiments described above or below.

[0046] In a specific embodiment PE14 of the invention, the compound of the invention is a bicyclic compound of formula I, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, wherein X 1 Indicates CH; R 1 Represents Cl or -CF3; R 2Represents H; -CH3, -CH=CH-CF3, -CH2-CN, -(CH2)2-CN, -(CH2)3-CN, -CH2-CH(OH)-CH2-CN, -(CH2)2-N(CH3)2, -CH2-CF2-CH2-NH2, -CH(CF3)-CH2-N(CH3)2, (N-methylmorpholin-3-yl)methyl, 2-(morpholin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, -(CH2)2-OH, -(CH2)2-O-(CH2)2-OH, -(CH2)3-OH, -CH(CH3)CH2-OH, , , -CH2-C(CH3)2-OH, -CH(CH2OH)2, -CH2CH(CH2OH)2, CH2-CH(OH)-CH2-OCH3, , -(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-C(=O)-NHCH3, -CH2-C(=O)-NHCH2CH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, (1-hydroxycyclobutyl)methyl ), -(CH2)2-NH-C(=O)-CH3; (1H-imidazol-2-yl)methyl, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1H-2-methylimidazol-4-yl)methyl, (1H-pyrazole-4-yl)methyl, (1H-pyrazole-5-yl)methyl (1-Methyl-1H-pyrazol-4-yl)methyl, 1,2-thiazolyl-3-yl, 1,3-thiazolyl-2-yl, (1H-1,2,3-triazol-4-yl)methyl, pyrazin-2-yl, 2-(2-oxopyridin-1-yl)ethyl, (1,2,4-oxadiazol-3-yl)methyl, (oxetane-3-yl)methyl, (3-fluorooxetane-3-yl)methyl ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ), 2-(oxetane-3-yl)ethyl; 1,1-dioxo-1-λ-6-thionecyclobutane-3-yl( ), (5-oxo-pyrrolidine-2-yl)methyl, (5-oxo-pyrrolidine-3-yl)methyl, oxepane-3-ylmethyl, (3-hydroxyoxepane-3-yl)methyl, (2-oxo-1,3-oxazolidine-4-yl)methyl, (2-oxo-1,3-oxazolidine-5-yl)methyl, (4-methyl-2-oxo-1,3-oxazolidine-4-yl)methyl, (4-hydroxyoxepane-4-yl)methyl, 2-(4-hydroxyoxepane-4-yl)ethyl; 3-hydroxycyclobutyl; , , , ;R 3 H; AL 1 -B indicates .

[0047] In a specific embodiment PE14a of PE14, 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 thereof, including mixtures thereof in all proportions, wherein X 1 Indicates CH; R 1 Represents Cl or -CF3; R 2 Represents H, -CH3, -CH2-CN, -(CH2)2-OH, -CH2-C(CH3)2-OH, (1H-imidazol-4-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, (oxetane-3-yl)methyl, (3-hydroxyoxetane-3-yl)methyl; R 3 H; AL 1 -B indicates .

[0048] In a specific embodiment PE14-0 of the present invention, which is also a specific embodiment of PE3-0 above, 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 thereof, including mixtures thereof in all proportions, wherein X 1 Represents N; R1 Represents Cl or -CF3; R 2 H; CH3; -CH2-CN, -(CH2)2-OH, -CH(CH2OH)2; (1H-imidazol-4-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl; (3-hydroxyoxacyclopentan-3-yl)methyl ), (4-hydroxyoxacyclohexane-4-yl)methyl ( ); R 3 H; AL 1 -B Table .

[0049] This particular embodiment, PE14-0, can also be described as a compound of formula IB or I-BC as defined above, having the R defined above. 1 R 2 R 3 and AL 1 -B has a specific meaning.

[0050] In yet another specific embodiment, PE15, the compound of the present invention is a bicyclic compound selected from the compounds shown in Tables 1 and 1A below, or any N-oxide, solvate, tautomer, or stereoisomer thereof and / or any pharmaceutically acceptable salt of the foregoing, including mixtures thereof in all ratios. In yet another specific embodiment, PE15a, the compound is selected from Table 1 or Table 1A and is a Formula I compound described above and within the scope of the claims. It should be understood that each individual compound depicted in Tables 1 and 1A, and any N-oxide, solvate, tautomer, or stereoisomer thereof and / or any pharmaceutically acceptable salt of such compounds, represents a specific embodiment of the invention. In yet another specific embodiment, PE15b, of PE15 or PE15a, the compound is selected from Table 1 or Table 1A, is a Formula I compound described above and within the scope of the claims, and is in Group A of the SK-HEP-1 reporter gene assay and / or Group A of the H226 activity assay and / or Group A of the H292 activity assay, as provided in Table 2 below.

[0051] As used herein, unless otherwise specified in the specification and / or the scope of the claims or otherwise specifically defined elsewhere, the following limitations regarding specific substituents, groups, residues, groups or portions shall apply.

[0052] As used herein, the term “aliphatic” or “aliphatic group” means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain (also referred to as “acyclic”) that is fully saturated or contains one or more unsaturated units; or a monocyclic, bicyclic or tricyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, such as one or more C=C double bonds and / or C≡C triple bonds, but is not aromatic (also referred to herein as “carbocyclic”, “cycloaliphatic” or “cycloalkyl”), which typically has a single connection point to the rest of the molecule, and unless otherwise defined in this specification or the appended claims. Unless otherwise specified, the aliphatic group contains 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 (respectively "C"). 1-10 -Aliphatic", C 1-8 --Lipids and C 1-6 --Aliphatic". In some embodiments, the aliphatic group contains 1 to 5 (i.e., 1, 2, 3, 4 or 5) aliphatic carbon atoms ("C"). 1-5 -Aliphatic". In other embodiments, the aliphatic group contains 1 to 4 (i.e., 1, 2, 3 or 4) aliphatic carbon atoms ("C"). 1-4 -Aliphatic". In other embodiments, the aliphatic group contains 1 to 3 (i.e., 1, 2 or 3) aliphatic carbon atoms ("C"). 1-3 -Aliphatic), in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms ("C"). 1-2 -Aliphatic”).

[0053] In some implementations, "cycloaliphatic" ("cycloalkyl") refers to monocyclic C3-C7 hydrocarbons (i.e., monocyclic hydrocarbons having 3, 4, 5, 6, or 7 ring carbon atoms), or bicyclic C3-C7 hydrocarbons. 5-8Hydrocarbons (i.e., bicyclic hydrocarbons having 5, 6, 7, or 8 ring carbon atoms), which are fully saturated or contain one or more unsaturated units but are not aromatic, have a single connection point with the rest of the molecule. In another embodiment, the term "cycloaliphatic" or "carbocyclic" refers to a monocyclic or bicyclic cycloaliphatic ring system fused to an aromatic, heteroaromatic, or heterocyclic ring system via two adjacent ring atoms; in other words, such a carbocyclic ring shares two ring atoms with its fused ring system, thereby having two connection points with the rest of the molecule. In another embodiment, the term "carbocyclic" refers to a bicyclic spirocyclic ring, wherein two monocyclic carbocyclic rings are fused to each other via the same single carbon atom. Generally, unless defined differently in specific cases, the term "aliphatic" covers both straight-chain (i.e., unbranched) and branched hydrocarbon chains where chemically possible. Furthermore, generally, if defined differently in specific cases, this term covers both possible unsubstituted and substituted hydrocarbon portions. Typical substituents of aliphatic groups include, but are not limited to, halogens, particularly cyano, hydroxyl, alkoxy, unsubstituted or monosubstituted or disubstituted amino, aryl, particularly unsubstituted or substituted phenyl, heteroaryl, particularly unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclic, particularly unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. Suitable aliphatic groups include, but are not limited to, straight-chain or branched substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0054] The term "alkyl" generally refers to a saturated aliphatic and acyclic moiety, while the term "alkenyl" generally refers to an unsaturated aliphatic and acyclic moiety having one or more C=C double bonds, and the term "alkynyl" (or "alkynyl group") generally refers to an aliphatic and acyclic moiety having one or more C≡C triple bonds. It should be understood that the term "alkenyl" encompasses all forms of isomers, namely E-isomers, Z-isomers, and mixtures thereof (E / Z-isomers). Exemplary aliphatic groups are straight-chain or branched substituted or unsubstituted C=C groups. 1-10 -alkyl, C 1-8 -alkyl, C 1-6 -alkyl, C 1-4 -alkyl, C 1-3 -alkyl, C 1-2 -alkyl, C 2-8 -Alkenyl, C 2-6 -Alkenyl, C 2-4 -Alkenyl, C 2-8 - Acynyl (C 2-8 -alkynyl group), C 2-6 - Acynyl (C 2-6 -alkynyl group), C 2-4 - Acynyl (C2-4 -Alynyl) groups and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0055] Specifically, the term "C" 1-3 "-alkyl" refers to an alkyl group having 1, 2, or 3 carbon atoms, i.e., a saturated acyclic aliphatic group. Example C 1-3 -alkyl alkyl groups are methyl, ethyl, propyl, and isopropyl. The term "C" 1-4 "-alkyl" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Example C 1-4 -The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The term "C" is also used. 1-6 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Example C 1-6 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl. The term "C" is also used. 1-8 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Example C 1-8 -The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4-trimethylpentyl. The term "C" is used. 1-10 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Example C 1-10The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl, 2-octyl, 2,2,4-trimethylpentyl, and n-decyl. Each of these alkyl groups may be straight-chain or (except C1 and C2 alkyl groups) branched, and may be unsubstituted or substituted with one, two, or three substituents that may be the same or different and may (if not specified in this specification and / or the appended claims) be selected from the group consisting of: halogens, particularly F, cyano, hydroxyl, alkoxy, thiol, thioalkoxy, dialkylphosphoryl, particularly -P(=O)(CH3)2, unsubstituted or monosubstituted or disubstituted amino groups, sulfoxides, etc. Sulfons, iminoalkyl sulfones, especially -S(=O)(=NH)CH3, iminodialkyl sulfones, especially -N=S(=O)(CH3)2, carboxylic acids, carboxylic esters, carboxylic amides (primary, secondary, and tertiary), carbamates, aryl groups, especially unsubstituted or substituted phenyl groups, heteroaryl groups, especially unsubstituted or substituted pyridinyl or pyrimidinyl groups, saturated or partially unsaturated heterocyclic groups, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. Exemplary substituted alkyl groups are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl, difluoromethoxy, and trifluoromethoxy.

[0056] In some cases, C 1-3 -alkyl, C 1-4 -alkyl, C 1-6 -alkyl, C 1-8 -alkyl, C 1-10-alkyl groups may also include residues in which one or two uncapped and non-adjacent -CH2- (methylene) groups are replaced by -O-, -S-, and / or one or two uncapped and non-adjacent -CH2- or -CH- groups are replaced by -NH-, -N-. These substitutions yield, for example, (modified) alkyl groups such as –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-CH2-O-CH2-CH3, CH2-CH2-N(CH3)-CH2-CH3, etc. Other and / or different substitutions of -CH- and -CH2- groups may be defined to suit specific alkyl substituents or groups used elsewhere in the specification and / or within the scope of the claims. As described above for unmodified alkyl groups, these modified alkyl groups may optionally be substituted with one, two, or three substituents that may be the same or different and may (if not specified in the scope of this specification and / or the appended claims) be selected from the group consisting of: halogens, particularly F; hydroxyl groups; alkoxy groups; unsubstituted or monosubstituted or disubstituted amino groups; aryl groups, particularly unsubstituted or substituted phenyl groups; heteroaryl groups, particularly unsubstituted or substituted pyridyl or pyrimidinyl groups; heterocyclic groups, particularly unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl groups. Exemplary 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, and CHR-CH(OH)-CH2-CH2-O-CH2-CH2-O-CH2-CH2-NH2, where "R" represents another substituent.

[0057] Unless otherwise specified elsewhere, the term "carbocyclic ring" generally refers to a saturated or partially unsaturated but non-aromatic ring system having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 ring carbon atoms and acyclic heteroatoms; the carbocyclic ring may be a monocyclic ring (C 3-15 ) or double ring (C 5-15 ) or three rings (C 8-15It should be understood that a bicyclic carbon ring can be (a) a carbon ring in which two carbon ring portions are connected to each other by two different ring carbon atoms, such as in bicyclic [1.1.1]pentyl or bicyclic [3.1.0]hexyl; or (b) a carbon ring in which two carbon ring portions are connected to each other by the same ring carbon atoms, thereby forming a spirocyclic ring, such as in spiro[3.3]heptyl. With necessary modifications to the details, the same applies to tricyclic carbon rings. The carbon ring can be unsubstituted or substituted.

[0058] The term "cycloalkyl" refers to the cyclic aliphatic hydrocarbons or carbocyclic rings defined above. The term "C"... 3-7 "-Cycloalkyl" refers to cyclic aliphatic hydrocarbons having 3, 4, 5, 6, or 7 ring carbon atoms as defined above. Similarly, the term "C"... 3-6 "Cycloalkyl" refers to a cyclic aliphatic hydrocarbon or carbocyclic ring having 3, 4, 5, or 6 carbon atoms. As used herein, the terms "cycloalkyl" and "C" are used interchangeably. 3-7 -cycloalkyl" and "C 3-6 "-Cycloalkyl" comprises a cyclic hydrocarbon or carbocyclic ring that is saturated or contains one or more unsaturated units, such as a C=C double bond; such cyclic hydrocarbons having at least one unsaturated unit may also be called "cycloalkenyl" groups. 3-7 -The cycloalkyl group may be unsubstituted or substituted (unless otherwise specified in this specification) with 1, 2, or 3 substituents that may be the same or different and may be (unless otherwise specified in this specification) selected from the group consisting of: C 1-6 -alkyl, OC 1-6 -alkyl (alkoxy), halogen, hydroxyl, unsubstituted or monosubstituted or disubstituted amino, aryl, especially unsubstituted or substituted phenyl. If substituted, then C 3-7 -Cycloalkyl groups encompass all possible stereoisomers. Example C 3-7 -The cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl. The term "bicyclic C" is also used. 5-8 "-Cycloalkyl" refers to bicyclic aliphatic hydrocarbons having 5, 6, 7, or 8 ring carbon atoms as defined above; it includes spirocyclic systems, i.e., bicyclic C... 5-8 - A cycloalkyl group consists of two carbon rings linked together by the same carbon atom in a ring system. Bicyclic C 5-8 -The cycloalkyl group may be unsubstituted or substituted (unless otherwise specified in this specification) with 1, 2, or 3 substituents that may be the same or different and may be (unless otherwise specified in this specification) selected from the group consisting of: C 1-6 -alkyl group, which may be substituted with 1, 2 or 3 halogens; OC 1-6-alkyl (alkoxy) group, which may be substituted with 1, 2, or 3 halogens; hydroxyl, halogen, unsubstituted or mono- or disubstituted with an amino group. If substituted, the bicyclic C 5-8 -Cycloalkyl groups encompass all possible stereoisomers. Example bicyclic C 5-8 -The cycloalkyl group is spiro[3.3]heptyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.2]oct-2-yl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, bicyclo[3.1.1]hept-2-en-2-yl.

[0059] The term "aliphatic oxygen group" refers to a saturated or unsaturated aliphatic group or substituent as defined above, which is attached to another structural moiety via an oxygen atom (-O-). The term "C 1-6 "-Aliphatic oxygen group" refers to an aliphatic oxygen group having 1, 2, 3, 4, 5, or 6 carbon atoms within an aliphatic group. The term "alkoxy group" refers to a specific subgroup of saturated aliphatic oxygen groups, namely alkyl substituents and residues connected to another structural moiety via an oxygen atom (-O-). Sometimes, it is also called "O-alkyl," and more specifically, "OC." 1-2 -alkyl", "OC" 1-3 -alkyl", "OC" 1-4 -alkyl", "OC" 1-6 -alkyl", "OC" 1-8 -alkyl. Similar to alkyl groups, which may be straight-chain or (other than -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 may (if otherwise specified in this specification) be selected from the group consisting of: halogens, unsubstituted or monosubstituted or disubstituted amino groups. Exemplary alkoxy groups are methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and n-pentoxy.

[0060] The term "alkylene" refers to a divalent aliphatic group, and particularly a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). j -, where j is a positive integer, preferably 1, 2, 3, 4, 5, or 6. In the context of this invention, "C" 1-3 -alkylene refers to alkylene moieties having 1, 2, and 3 -CH2- groups, respectively; however, the term "alkylene" includes not only straight-chain alkylene, i.e., "alkylene chain," but also branched-chain alkylene. The term "C 1-3 -alkylene refers to a straight-chain (i.e., alkylene chain) or branched alkylene moiety having 1, 2, 3, 4, 5, or 6 carbon atoms. The term "C" 2-6-alkylene refers to an alkylene moiety having 2, 3, 4, 5, or 6 carbon atoms, while "C 3-4 -alkylene refers to an alkylene moiety having 3 or 4 carbon atoms, and "C 2-3 "-alkylene" refers to an alkylene moiety having 2 or 3 carbon atoms. A substituted alkylene chain is a group in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below with respect to the substituted alkyl group. In some cases, one or two methylene groups of the alkylene chain may be, for example, replaced by O, S and / or NH or NC. 1-4 - Alkyl substitution. 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-, –O–CH2–CH2–CH2-O-, –CH2-NH–CH2–CH2-, –CH2-N(CH3)–CH2–CH2-.

[0061] The term "alkenyl" refers to a divalent alkenyl group. The substituted alkenyl chain is a polymethylene containing at least one double bond and with one or more hydrogen atoms replaced by a substituent. Suitable substituents include those described herein with respect to the substituted aliphatic group. The term "alkenyl" refers not only to straight-chain divalent alkenyl groups, i.e., alkenyl chains, but also to branched alkenyl groups. The term "C..." 2-6 "-Alkenyl" refers to alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms.

[0062] The term "halogen" refers to F, Cl, Br, or I. In particular, "halogen" refers to F.

[0063] The term “heteroatom” refers to one or more of the following: oxygen (O), sulfur (S), or nitrogen (N), including any oxidized form of nitrogen or sulfur, such as N-oxides, sulfoxides, and sulfones; any quaternized form of basic nitrogen or a substituted nitrogen of a heterocyclic or heteroaromatic ring, such as N (e.g., in 3,4-dihydro-2H-pyrrole), NH (e.g., in pyrrolealkyl) or N-SUB, wherein SUB is a suitable substituent (e.g., in N-substituted pyrrolealkyl).

[0064] The term "aryl," used alone or as part of a larger portion (such as in "aralkyl," "ararylalkoxy," or "aryloxyalkyl"), refers to a monocyclic, bicyclic, or tricyclic ring system having a total of five to fourteen ring members, wherein these ring members are carbon atoms, and wherein at least one ring in the system is aromatic, i.e., it has (4n + 2)π electrons (where n is an integer selected from 0, 1, 2, 3, 4, 5), these electrons are non-localized in the system, and wherein each ring in the system contains three to seven ring members. Preferably, all rings or the entire ring system in the aryl system is aromatic. The term "aryl" may be used interchangeably with the term "aryl ring." In some embodiments of the invention, "aryl" refers to "aromatic ring system." More particularly, those aromatic ring systems may be monocyclic, bicyclic, or tricyclic with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms. More specifically, these aromatic ring systems can be monocyclic or bicyclic with 6, 7, 8, 9, or 10 ring carbon atoms. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracene, etc., which may be unsubstituted or substituted with one or more of the same or different substituents. As used herein, the term "aryl" or "aromatic ring system" also includes groups whose aromatic rings are fused to one or more non-aromatic rings, such as dihydroindenyl, phthalimide, naphthimide, phenanthridine, or tetrahydronaphthyl. In the latter case, the "aryl" group or substituent is attached to its side group via the aromatic portion of the ring system.

[0065] The term "benzo[a]" refers to a six-membered aromatic ring (having carbon ring atoms) fused to another ring via two adjacent carbon atoms. This six-membered aromatic ring is a cycloaliphatic ring, aromatic ring, heteroaromatic ring, or heterocyclic (heteroaliphatic) ring; thus, a ring system with at least two rings is formed, wherein the benzo[a] ring and the other ring fused to it share two common carbon atoms. For example, if the benzo[a] ring is fused to a benzene ring, a naphthalene ring system is formed; simultaneously, fusion of the benzo[a] ring to pyridine yields quinoline or isoquinoline; fusion of the benzo[a] ring to a cyclopentene ring yields an indene ring.

[0066] The terms "heteroaryl" and "heteroaryl-" used alone or as part of a larger portion of terms such as "heteroarylalkyl" or "heteroarylalkoxy" refer to a group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (these atoms are carbon atoms and heteroatoms), preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 cyclic arrays of shared π electrons; and having 1, 2, 3, 4, or 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur; and any quaternized form of basic nitrogen. In other words, a "heteroaryl" ring or ring system (or a heteroaryl ring or ring system) can also be described as an aromatic heterocycle. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, thiadiazolyl, furanyl, pyridinyl, pyrimidinyl, imidazolyl, thiazolyl, thiazolyl, pyridinyl, pyridinyl, imidazolyl, thiazolyl, and pyridinyl and pyridinyl, especially pyrido[2,3-b]pyridinyl. As used herein, the terms “heteroaryl” and “heteroaryl-” also include groups in which a heteroaryl ring is fused with one or more aryl rings, cycloaliphatic rings, or heterocyclic rings, wherein the linking group or linking point is preferably on the heteroaryl ring or (if present) the aryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl / benzothiophenyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, furanyl, quinoxalinyl, phthalazinyl, 4H-quinazinyl, carbazolyl, acridineyl, phenazinyl, phenthiazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one, etc. For example, the indolyl ring may be linked via a ring atom of a six-membered aryl ring or via a ring atom of a five-membered heteroaryl ring. The heteroaryl group is optionally monocyclic, bicyclic, or tricyclic. The term “heteroaryl” is used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaryl family,” any of which includes a ring that is unsubstituted or substituted with one or more identical or different substituents. The term “heteroarylalkyl” refers to a heteroaryl-substituted alkyl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0067] A heteroaryl ring can be attached to its side group at either a heterocyclic atom or a carbon ring atom, and this attachment produces a stable structure or molecule: either of the ring atoms may be unsubstituted or substituted.

[0068] As used herein, the terms “heterocyclic,” “heterocyclic group,” “heterocyclic radical,” and “heterocyclic” are used interchangeably and refer to a stable monocyclic, bicyclic, or tricyclic heterocyclic moiety having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of these ring atoms are heteroatoms and the heterocyclic moiety is saturated or partially unsaturated; the heterocyclic moiety as an aromatic ring or ring system is generally referred to as the “heteroaryl” moiety described above. Preferably, the heterocycle is a stable saturated or partially unsaturated 3-membered, 4-membered, 5-membered, 6-membered, or 7-membered monocyclic, or 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or 11-membered bicyclic, or 11-membered, 12-membered, 13-membered, or 14-membered tricyclic heterocyclic moiety.

[0069] When used with respect to the ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having one to three heteroatoms selected from nitrogen, oxygen, or sulfur, nitrogen is N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidinyl), or N-SUB, where SUB is a suitable substituent (as in N-substituted pyrrolidinyl).

[0070] In the context of the term "heterocycle," the term "saturated" refers to a fully saturated heterocyclic system, such as pyrrolidinyl, piperidinyl, morpholinyl, piperidinoneyl, tetrahydrofuranyl, thiohexacyclohexyl, and dioxothiohexacyclohexyl. Regarding the term "heterocycle," the term "partially unsaturated" refers to (i) a heterocyclic system containing one or more unsaturated units (e.g., C=C or C=heteroatomic bonds) but not aromatic, such as tetrahydropyridinyl; or (ii) a heterocyclic system fused with an aromatic or heteroaromatic ring system (either saturated or unsaturated, but non-aromatic), where the "partially unsaturated heterocycle" is connected to the remainder of the molecule (its side groups) via a ring atom of the "heterocyclic" portion of the system and not via the aromatic or heteroaromatic portion. This first type of "partially unsaturated" heterocycle may also be referred to as a "non-aromatic partially unsaturated" heterocycle. This type of second (ii) "partially unsaturated" heterocycle can also be called a (bicyclic or tricyclic) "partially aromatic" heterocycle, indicating that at least one ring of the heterocycle is a saturated or unsaturated, but non-aromatic, heterocycle fused with at least one aromatic ring system or heteroaromatic ring system. Typical examples of these "partially aromatic" heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl.

[0071] Heterocycles can be attached to their side groups at any heteroatom or carbon atom to produce a stable structure, and any ring atom may be unsubstituted or substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, thiohexaneyl, dioxothiohexaneyl, tetrahydrothiophenyl, pyrroliyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, thiazolyl, piperazine, dioxaneyl, dioxopentaneyl, diazaheptanyl, thiazoheptanyl, thiazohexaneyl, morpholinyl, and piperazine. The terms “heterocyclic,” “heterocyclic group,” “heterocyclic ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indololinyl, 3H-indolyl, dihydroindolyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl, wherein the linking group or linking point is on the heterocyclic ring. The heterocyclic group is optionally monocyclic, bicyclic, or tricyclic. The term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl group and the heterocyclic moiety are independently unsubstituted or substituted.

[0072] As used herein, the term "unsaturated" means that a part or group or substituent has one or more unsaturated units.

[0073] As used herein with respect to any ring, ring system, ring moiety, etc., the term "partially unsaturated" means that the ring moiety includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple unsaturated sites. Specifically, it encompasses (i) unsaturated (monocyclic, bicyclic, or tricyclic) ring systems without any aromatic or heteroaromatic moiety; and (ii) bicyclic or tricyclic ring systems in which one ring is an aromatic or heteroaromatic ring fused with another ring that is neither aromatic nor heteroaromatic, such as tetrahydronaphthyl or tetrahydroquinolinyl. Type I (i) "partially unsaturated" rings, ring systems, and ring moiety may also be referred to as "non-aromatic partially unsaturated" rings, ring systems, and ring moiety, while Type II (ii) may be referred to as "partially aromatic" rings, ring systems, and ring moiety.

[0074] As used herein, the terms “bicyclic,” “bicyclic,” or “bicyclic system” refer to any bicyclic system, i.e., a carbocyclic or heterocyclic system, saturated or having one or more unsaturated units, i.e., partially unsaturated or aromatic, having one or more common atoms between the two rings of the system. Thus, the term includes any permitted ring fusion, such as ortho-rings or spirocyclics. As used herein, the term “heterobicyclic” is a subset of “bicyclic” requiring the presence of one or more heteroatoms in one or both rings of the bicyclic system. Such heteroatoms may be present at ring junctions and optionally be substituted, and may be selected from nitrogen (including nitrogen oxides), oxygen, sulfur (including oxidized forms such as sulfoxides and sulfones), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Similarly, the terms "tricyclic," "tricyclic," or "tricyclic system" refer to any tricyclic system, i.e., a carbon ring or heterocyclic ring, saturated or having one or more unsaturated units, i.e., partially unsaturated or aromatic, wherein a bicyclic 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" rings requiring the presence of one or more heteroatoms in one or two of the rings. Such heteroatoms may be present at ring junctions and optionally substituted, and may be selected from nitrogen (including nitrogen oxides), oxygen, sulfur (including oxidized forms such as sulfoxides and sulfones), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, the tricyclic group has 10-14 ring members and 0 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0075] As described herein, certain compounds of the present invention contain a “substituted” or “optionally substituted” portion. Generally, the term “substituted” refers, whether or not preceded by the term “optionally,” to one or more hydrogens in the portion being replaced by a suitable substituent. “Substituted” applies to one or more hydrogens, whether structurally defined or implicit. Unless otherwise specified, a “substituted” or “optionally substituted” group has suitable substituents at each substituted position of the group, and when more than one position in any given structure is replaced by more than one substituent selected from a defined group, the substituents at each position are the same or different. If a group, substituent, portion, or group is “monosubstituted,” it carries (1) substituents. If it is “disubstituted,” it carries (2) the same or different substituents; if it is “trisubstituted,” it carries (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. The combinations of substituents contemplated in the present invention are preferably combinations that form stable or chemically viable compounds. As used herein, the term "stable" means a compound that is not substantially altered when subjected to conditions that allow it to be produced, detected, and in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0076] Unless otherwise specified in this specification or the appended claims, it should be understood that each optional substituent on the substituted carbon is independently selected from the following monovalent substituents: halogen; –(CH2). 0–4 R ○ ;–(CH2) 0–4 OR ○ ;-O(CH2) 0- 4R o –O–(CH2) 0–4 C(O)OR°;–(CH2) 0–4 CH(OR ○ )2;–(CH2) 0–4 SR ○ ;–(CH2) 0–4 Ph, which can be replaced by one or more R°; –(CH2) 0–4 O(CH2) 0–1 Ph, which can be substituted by one or more R°; –CH=CHPh, which can be substituted by one or more R°; –(CH2) 0–4 O(CH2) 0–1 -Pyridyl group, which may be substituted with one or more R°; –NO2; –CN; –N3; –(CH2) 0–4 N(R ○ )2;–(CH2) 0–4 N(R ○ )C(O)R ○;–N(R ○ )C(S)R ○ ;–(CH2) 0–4 N(R ○ )C(O)NR ○ 2;–N(R ○ )C(S)NR ○ 2;–(CH2) 0–4 N(R ○ )C(O)OR ○ ;–N(R ○ )N(R ○ )C(O)R ○ ;–N(R ○ )N(R ○ )C(O)NR ○ 2;–N(R ○ )N(R ○ )C(O)OR ○ ;–(CH2) 0–4 C(O)R ○ ;–C(S)R ○ ;–(CH2) 0–4 C(O)OR ○ ;–(CH2) 0–4 C(O)SR ○ ;–(CH2) 0–4 C(O)OSiR ○ 3;–(CH2) 0–4 OC(O)R ○ ;–OC(O)(CH2) 0–4 SR–、SC(S)SR°;–(CH2) 0–4 SC(O)R ○ ;–(CH2) 0–4 C(O)NR ○ 2;–C(S)NR ○ 2;–C(S)SR°;–SC(S)SR°、–(CH2) 0–4 OC(O)NR ○ 2;–C(O)N(OR ○ )R ○ ;–C(O)C(O)R ○ ;–C(O)CH2C(O)R ○ ;–C(NOR ○ )R ○ ;–(CH2) 0–4 SSR ○ ;–(CH2) 0–4 S(O)2R ○ ;–(CH2) 0–4 S(O)2OR○ ;–(CH2) 0–4 OS(O)2R ○ ;–S(O)2NR ○ 2; –S(O)(NR°)R°; –S(O)2N=C(NR°2)2; –(CH2) 0–4 S(O)R ○ ;–N(R ○ )S(O)2NR ○ 2; –N(R) ○ )S(O)2R ○ ; –N(OR) ○ )R ○ ;–C(NH)NR ○ 2; –P(O)2R ○ ;–P(O)R ○ 2; –OP(O)R ○ 2; –OP(O)(OR ○ )2; SiR ○ 3; –(C 1–4 (linear or branched alkylene) O–N(R ○ )2; or –(C 1–4 (straight-chain or branched alkylene)C(O)O–N(R) ○ 2. It should be understood that "Ph" refers to phenyl; and "–(CH2)" 0–4 "" indicates that if the subscript is "0" (zero), then there is no alkylene group, or there is an alkylene group with 1, 2, 3 or 4 CH2 units.

[0077] Each R° is independently hydrogen, halogen, C 1–6 Aliphatic groups, -CH2Ph, -O(CH2) 0–1 Ph, -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 foregoing, two independently occurring R° together with their inserted atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, the ring being substituted at the saturated carbon atom of R° by a divalent substituent selected from =O and =S; or each R° is optionally substituted by a monovalent substituent independently selected from: halogen, –(CH2). 0–2 R ● 、–(Halogenated R) ● ), –(CH2) 0-2 OH, –(CH2) 0-2 OR ● –(CH2) 0-2 CH(OR ● )2;O(halogenated R) ●–CN, –N3, –(CH2) 0-2 C(O)R ● –(CH2) 0-2 C(O)OH, –(CH2) 0–2 C(O)OR ● –(CH2) 0–2 SR ● –(CH2) 0-2 SH, –(CH2) 0- 2NH2、–(CH2) 0-2 NHR ● –(CH2) 0–2 NR ● 2. –NO2, –SiR ● 3. –OSiR ● 3. C(O)SR ● 、 –(C 1-4 (straight-chain or branched alkylene)C(O)OR ● Or –SSR ● It should be understood that "Ph" refers to phenyl; "halogen" refers to halogen; and "-(CH2)" 0-2 "" indicates that if the subscript is "0" (zero), then there is no alkylene group, or there is an alkylene group having one or two CH2 units.

[0078] Each R ● Selected independently from C 1–4 Aliphatic groups, -CH2Ph, -O(CH2) 0–1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R^λ is unsubstituted or, if present, substituted by one or more halogens; or wherein the optional substituents on the saturated carbon are independently selected from =O, =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R * =NR * =NOR * 、 –O(C(R) * 2)) 2–3 O – or –S(C(R) * 2)) 2–3 The divalent substituent of S–, or the divalent substituent of the ortho-substituted carbon attached to the "optionally substituted" group, is -–O(CR). * 2) 2– 3O–, where each independently occurring R is selected from hydrogen, C 1–6Aliphatic group or unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0079] When R * C 1–6 When the aliphatic group is present, R * Optional halogenated, –R ● 、(Halogenated R) ● ), OH, –OR ● –O(halogenated R) ● ), –CN, –C(O)OH, –C(O)OR ● –NH2, –NHR ● –NR ● 2 or –NO2 substitution, where each R ● Selected independently from C 1–4 Aliphatic groups, -CH2Ph, -O(CH2) 0–1 Ph or a 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R ● It is not replaced, or it is replaced by one or more halogens when there is a halogen in front of it.

[0080] The optional substituents on the substituted nitrogen are independently –R † –NR † 2. –C(O)R † –C(O)OR † –C(O)C(O)R † –C(O)CH2C(O)R † S(O)2R † S(O)2NR † 2. –C(S)NR † 2. –C(NH)NR † 2 or –N(R) † )S(O)2R † ; where each R † Independently hydrogen, C 1–6 An aliphatic group, an unsubstituted -OPh, or an unsubstituted 5-6 member saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independently occurring R† together with their inserted atoms to form an unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R † C 1–6 When the aliphatic group is present, R † Optional halogenated, –R ● -(halogenated R) ● ), OH, –OR● –O(halogenated R) ● ), –CN, –C(O)OH, –C(O)OR ● –NH2, –NHR ● –NR ● 2. Or –NO2 substitution, or having 5-6 membered saturated, partially unsaturated or aromatic rings with 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein each R ● It is either unsubstituted or, when a halogen is present before it, substituted by one or more halogens. It should be understood that "Ph" refers to phenyl, and "halogen" refers to a halogen.

[0081] The term "solvent" refers to the addition form of the compound of the present invention with a solvent (preferably a pharmaceutically acceptable solvent), containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to retain solvent molecules in a fixed molar ratio in a crystalline solid state, thereby forming a solvate. If the solvent is water, the formed solvate is a hydrate, such as a hemihydrate, monohydrate, or dihydrate. If the solvent is an alcohol, the formed solvate is an alcohol, such as a methanol or ethanol. If the solvent is an ether, the formed solvate is an ether compound, such as a diethyl ether compound.

[0082] The term "N-oxide" refers to such compounds of the present invention containing an amine oxide moiety (i.e., an oxide of a tertiary amine group).

[0083] Compounds of Formula I may also have one or more chiral centers, depending on the nature of the substituents they can carry. They can therefore exist in various enantiomeric and diastereomeric forms, and, depending on the specific circumstances, in racemic or optically active forms. Therefore, this invention also refers to the optically active forms, enantiomers, racemates, diastereomerics, and mixtures thereof in all proportions of these compounds, collectively referred to for the purposes of this invention as “stereoisomers.” Since the medicinal activities of the racemates or stereoisomers of the compounds of this invention may differ, it may be necessary to use a specific stereoisomer, such as a specific enantiomer or diastereomeric isomer. In these cases, the compounds of this invention obtained in racemic or even intermediate form can be isolated into stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical methods known to those skilled in the art. Another approach to obtaining one or more specific stereoisomers of the compounds of the present invention in concentrated or pure form utilizes stereoselective synthetic procedures, such as using starting materials in concentrated or pure stereoisomeric form (e.g., using pure or concentrated (R)- or (S)-enantiomers of a specific starting material carrying a chiral center) or utilizing chiral reagents or catalysts, specifically enzymes. In the context of the present invention, the term "pure enantiomer" generally refers to an enantiomer with a relative purity of 95% or greater than that of another (its enantiomer), preferably ≥98%, more preferably ≥98.5%, and even more preferably ≥99%.

[0084] Therefore, compounds of the present invention, for example having one or more chiral centers and existing in racemic form or as a mixture of enantiomers or diastereomers, can be fractionated or resolved by methods known to themselves to their optically pure or concentrated isomers, i.e., enantiomers or diastereomers. The separation of compounds of the present invention can be carried out by chromatographic methods, such as column separation on a chiral or achiral phase, or by recrystallization with an optionally selected optically active solvent, or by using an optically active acid or base, or by derivatization with an optically active reagent such as an optically active alcohol followed by elimination of groups.

[0085] In the context of this invention, the term "tautomer" refers to the compounds of this invention that can exist in tautomeric forms and exhibit tautomerism; for example, carbonyl compounds can exist in their ketone and / or enol forms and exhibit keto-enol tautomerism. Those tautomers can exist in their individual forms (e.g., ketone or enol forms) or in mixtures thereof, and are claimed individually and together in any ratio of mixtures. The same applies to cis / trans isomers, E / Z isomers, conformational isomers, etc.

[0086] In one embodiment, depending on the specific circumstances, the compounds of the present invention are in the form of a free acid or base, 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 pharmaceutically acceptable salt.

[0087] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable acid or base (including inorganic acids or bases and organic acids or bases). Where the compounds of this invention contain one or more acidic or basic groups, this invention also includes their corresponding pharmaceutically acceptable salts. Thus, compounds of this invention containing acidic groups (such as carboxyl groups) can exist in salt form and can be used according to this invention, for example, as alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. More precise examples of such salts include lithium salts, sodium salts, potassium salts, ammonium salts, magnesium salts, barium salts, or salts formed from ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine, pyridine, N-methylglutamylamine, or amino acids. These salts can be readily obtained, for example, by reacting a compound having an acidic group with a suitable base such as lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide. Other basic salts of the compounds of this invention include, but are not limited to, copper (I), copper (II), iron (II), iron (III), manganese (II), and zinc salts. Compounds of the present invention containing one or more basic groups (e.g., protonable groups) may exist in salt form and may be used according to the invention in the form of addition salts with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pentylene acid, diethylacetic acid, malonic acid, succinic acid, pimecrolic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, aminosulfonic 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 those skilled in the art. The salts formed are, in particular, hydrochlorides, chlorides, hydrobromates, bromides, iodides, sulfates, phosphates, methanesulfonates, toluenesulfonates, carbonates, bicarbonates, formates, acetates, sulfoacetates, trifluoromethanesulfonates, oxalates, malonates, maleates, succinates, tartrates, malates, embosylates, mandelates, fumarates, lactates, citrates, glutarate esters, stearates, aspartate salts, and glutamates. The stoichiometry of the salts formed from the compounds of this invention may also be an integer or a non-integer multiple of one.

[0088] The compounds of the present invention containing basic nitrogen-containing groups can be quaternized using the following reagents: (C1-C4) alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, isopropyl, and tert-butyl groups; di(C1-C4) alkyl sulfates, such as dimethyl, diethyl, and dipentyl sulfates; (C1-C4) alkyl halides. 10 -C 18 Alkyl halides, such as chlorides, bromides, and iodides of decyl, dodecyl, lauryl, myristyl, and stearyl groups; and aryl (C1-C4) alkyl halides, such as benzyl chloride and phenethyl bromide. Water-soluble and oil-soluble compounds according to the invention can be prepared using such salts.

[0089] If the compounds of the present invention contain both acid and base groups in their molecules, the present invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned. The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example by contacting them in a solvent or dispersant with an organic or inorganic acid or base, or by anion or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention that are unsuitable for direct use in pharmaceuticals due to low physiological compatibility, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0090] Therefore, the following items are also applicable according to the invention: (a) all stereoisomers or tautomers of the compound, including mixtures thereof in all ratios; (b) pharmaceutically acceptable salts of the compound and the items mentioned in (a); (c) pharmaceutically acceptable solvates of the compound and the items mentioned in (a) and (b); and (d) N-oxides of the compound and the items mentioned in (a), (b), and (c).

[0091] It should be understood that all references to the compounds above and below are intended to include, in particular, pharmaceutically acceptable solvates of the compounds or pharmaceutically acceptable salts thereof.

[0092] Furthermore, the compounds of the present invention are intended to include their isotopic notation forms. The isotopic notation forms of the compounds of Formula I are identical to those of this compound, except that one or more atoms of the compound have been replaced by one or more atoms whose atomic mass or mass number differs from that of naturally occurring atoms. Examples of readily available isotopes that can be incorporated into the compounds of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example… 2 H (D), 3 H, 13 C 14 C 15 N、 18 O、 17O、 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F and 36 CI. Compounds of Formula I containing one or more of the isotopes mentioned above and / or other isotopes of other atoms, or pharmaceutically acceptable salts thereof, are intended to be part of this invention. Compounds labeled with the isotopes of Formula I can be used in many advantageous ways. For example, those already incorporated as... 3 H or 14 The isotope-labeled compounds of the present invention, containing radioactive isotopes of C, are suitable for pharmaceutical and / or tissue distribution analysis. These radioactive isotopes are xenon (³H) and carbon-14 (³H). 14 C) is particularly preferred due to its simple preparation and excellent detectability. This isotope-labeled compound also exhibits high metabolic stability, for example, deuterium (…). 2 Compounds of Formula I with heavier isotopes incorporated into them (H) have therapeutic advantages. Higher metabolic stability directly translates to prolonged in vivo half-life or reduced dosage, which in most cases represents a preferred embodiment of the invention. Isotope-labeled Formula I compounds and salts can generally be prepared by replacing non-isotope-labeled reactants with readily available isotope-labeled reactants, following the synthetic diagrams and related descriptions disclosed in the Examples and Preparation sections of this invention.

[0093] deuterium( 2 H; D) can also be incorporated into compounds of Formula I to achieve the goal of controlling the oxidative metabolism of compounds by means of first-order kinetic isotope effects. First-order kinetic isotope effects are changes in the rate of chemical reactions caused by isotopic nuclear exchange, which in turn causes a change in the ground-state energy required for the formation of covalent bonds after the exchange. Exchange of heavier isotopes typically leads to a decrease in the ground-state energy of chemical bonds, thus causing a reduction in the rate of rate-limiting bond breaking. If bond breaking occurs in or near a saddle point region along the multi-product reaction coordinate system, the product distribution ratio can be substantially altered. For explanation: if deuterium binds to a carbon atom at a non-exchangeable position, a rate difference of k_M / k_D = 2-7 ​​is typical. If this rate difference is successfully applied to easily oxidized Formula I compounds, the in vivo form of the compound can be significantly altered, leading to improvements in pharmacokinetic properties.

[0094] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while preserving the desired in vitro properties. It is reasonable to assume that many compounds with unfavorable pharmacokinetic patterns are readily metabolized by oxidation. Currently available in vitro liver microsomal analysis provides valuable information on this type of oxidative metabolism, which in turn allows for the rational design of deuterated Formula I compounds with improved stability through resistance to these oxidative processes. This results in a significant improvement in the pharmacokinetic profile of Formula I compounds, and in terms of in vivo half-life (t... 1 / 2 ), concentration at maximum therapeutic effect (C) max The increase can be quantified in terms of the area under the dose-response curve (AUC) and F; as well as in terms of reduced clearance, dose, and material cost.

[0095] The following aims to illustrate the above: Compounds of Formula I, possessing multiple potential sites of attack for oxidative metabolism, such as benzyl hydrogen atoms bonded to nitrogen atoms and nitrogen atoms, are prepared as a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms, such that some, most, or all of these hydrogen atoms are replaced by deuterium atoms. Determination of half-life can advantageously and accurately determine the extent to which resistance to oxidative metabolism has been improved. In this way, it can be determined that the half-life of the philic compound can be extended by up to 100% due to this type of hydrogen-deuterium exchange.

[0096] The hydrogen-deuterium exchange in the compounds of the present invention can also be used to achieve a favorable alteration of the metabolite profile of the starting compound, thereby mitigating or eliminating undesirable toxic metabolites. For example, if toxic metabolites emerge via the cleavage of oxidative carbon-hydrogen (CH) bonds, it is reasonable to assume that deuteration analogs will greatly reduce or eliminate the production of unwanted metabolites, even if the specific oxidation is not a rate-determining step. Further information on current advanced technologies for hydrogen-deuterium exchange can be found in, for example, Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al., Carcinogenesis 16(4), 683-688, 1995.

[0097] Furthermore, the present invention relates to a pharmaceutical composition comprising: at least one compound of formula I as an active ingredient, or an N-oxide, solvate, tautomer or stereoisomer thereof, and a pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, and a pharmaceutically acceptable carrier.

[0098] For the purposes of this invention, the term "pharmaceutical composition" (or "pharmaceutical formulation") refers to a composition or product comprising one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product produced directly or indirectly by a combination, compounding, or aggregation of any two or more of the aforementioned ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions of this invention encompass any composition prepared by mixing at least one compound of this invention with a pharmaceutically acceptable carrier. It may additionally contain physiologically acceptable excipients, adjuvants, auxiliaries, diluents, and / or additional pharmaceutically active substances besides the compounds of this invention.

[0099] Pharmaceutical compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (for ophthalmic use), pulmonary (nasal or buccal inhalation), or nasal administration, but the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They can be conveniently presented in unit dosage forms and prepared by any method well known in pharmaceutical technology.

[0100] The pharmaceutical compositions of the present invention may additionally comprise one or more other compounds as active ingredients (pharmaceuticals), 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-oxide, solvate, tautomer, or stereoisomer, and pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions, wherein the second active ingredient is different from the compound of formula I; preferably, the second active ingredient is suitable for treating, preventing, inhibiting, and / or improving medical conditions or lesions for which the compounds of the present invention are also applicable and listed elsewhere above or below. Such combinations of two or more active ingredients or pharmaceuticals may be safer or more effective than individual pharmaceuticals or active ingredients, or the combination may be safer or more effective than would be expected based on the additive properties of the individual pharmaceuticals. Such other pharmaceuticals may be administered concurrently or sequentially with the compounds of the present invention via the usual route and at the usual amount. When the compounds of the present invention are used concurrently with one or more other pharmaceuticals or active ingredients, combination products containing such other pharmaceuticals and the compounds of the present invention (also referred to as “fixed-dose combinations”) are preferred. However, combination therapies also include therapies in which the compounds of the present invention and one or more other pharmaceuticals are administered at different weight intervals. Considering that when used in combination with other active ingredients, the compounds of the present invention or another active ingredient, or both, can be used at lower doses than when each is used alone, the pharmaceutical compositions of the present invention include pharmaceutical compositions containing one or more other active ingredients besides the compounds of the present invention.

[0101] The compounds of the present invention, or their N-oxides, solvates, tautomers, or stereoisomers, and / or pharmaceutically acceptable salts thereof, including mixtures thereof in all proportions, can be used as pharmaceutical agents. 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 interactions. Notably, some compounds of the present invention bind not only to one member of the TEAD family (TEAD 1, 2, 3, or 4) but also 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 hypothesized that through this activity, the compounds of the present invention can prevent or reverse dysfunction of the Hippo pathway. By preventing its dysfunction, the Hippo pathway may be able to exert its role as a tumor suppressor. In addition to preventing or reversing dysfunction of the Hippo pathway without relying on upstream Hippo regulation, the pharmacological activity of the compounds of the present invention can also be applied to other pathophysiological conditions in which inhibiting or disrupting TEAD binding and / or abnormal YAP-TEAD and / or abnormal TAZ-TEAD communication would be beneficial.

[0102] Therefore, the compounds of the present invention, as TEAD binding agents and / or YAP-TEAD and / or TAZ-TEAD interaction inhibitors, are particularly suitable for treating, preventing, inhibiting, and / or alleviating hyperproliferative disorders and cancers, especially including solid tumors, breast cancer, lung cancer, mesothelioma, epithelioid angioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, neuroblastoma, colorectal cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma. Without wishing to be bound by any particular theory or interpretation, it may be assumed that the compounds may achieve this purpose through direct effects on cancer cells and / or indirectly by modulating the immune system's response to tumors. Furthermore, the compounds of the present invention are also suitable for treating, preventing, inhibiting, and / or improving non-cancerous disorders and diseases, such as cardiovascular diseases and fibrosis (e.g., liver fibrosis).

[0103] In certain embodiments, the compounds of the present invention are suitable for prevention and / or treatment, particularly for treating any of the disorders or diseases listed above, preferably cancer, especially tumors, including solid tumors, the specific types of cancer disclosed in the preceding paragraphs; or any of the non-cancerous disorders or diseases disclosed in the preceding paragraphs.

[0104] Another specific embodiment of the invention is a method for preventing and / or treating, preferably treating, a disorder or disease selected from the group consisting of: hyperproliferative disorders and cancer, particularly tumors, including solid tumors, the specific types of cancer disclosed in the preceding paragraph; or any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0105] Another specific embodiment of the invention is the use of the compound of the invention or its N-oxide, prodrug, solvate, tautomer or stereoisomer, and / or pharmaceutically acceptable salts thereof, including mixtures thereof in all ratios, for the preparation, particularly for the prevention and / or treatment, preferably for the treatment of disorders or diseases selected from the group consisting of: hyperproliferative disorders and cancer, especially tumors, including solid tumors, the specific types of cancer disclosed in the preceding paragraph; or any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0106] Preferably, the invention relates to a compound of the invention suitable for the prevention and / or treatment of a disease; or alternatively, to a method for preventing and / or treating a disease by administering an effective amount of the compound of the invention; or in another alternative, to the use of a compound of the invention in the preparation of an agent for the prevention and / or treatment of a disease, wherein the disease is cancer, particularly a tumor, including solid tumors, the specific types of cancer disclosed in the preceding paragraphs; and more preferably, wherein the administration of the compound is performed simultaneously, sequentially, or alternately with the administration of at least one other active pharmaceutical agent.

[0107] The compounds of the present invention disclosed herein, and particularly the compounds of Formula I, can be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anticancer agent" refers to any agent administered to a patient with cancer for the purpose of treating cancer. The anticancer therapeutic agents defined above can be administered as monotherapy or may involve conventional surgical or radiation therapy or medical therapies other than the compounds of the present invention disclosed herein. Such medical therapies, such as chemotherapy or targeted therapy, may include one or more of the following antitumor agents, but preferably one of them: Alkylating agentsExamples include altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactalol, and nimustine. ), ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipebroman, trofosfamide, uramustine, evofosfamide, VAL-083 (dianhydrogalactitol); platinum compounds Such as carboplatin, cisplatin, eptaplatin, miriplatin hydroate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, and satraplatin. DNA alteration agent Such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, and clofarabine. topoisomerase inhibitorsExamples include etoposide, irinotecan, razoxane, sobuzoxane, teniposide, and topotecan; amonafide, belotecan, elliptinium acetate, and voreloxin. Microtubule regulator Examples include cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel; Antimetabolites Examples include asparaginase, pegaspargase, azacitidine, calcium levonorgestrel, capecitabine, cladribine, cytarabine, enocitabine, fluxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur, and trimetrexate. anticancer antibioticsExamples include bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin; aclarubicin, peplomycin, and pirarubicin. Hormones / Antagonists Examples include abalelix, abiraterone, bicalutamide, buserelin, calusterone, trichlorotriarylene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, and thyrotropin alpha. alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide; Aromatase inhibitorsExamples include aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, and formestane. Small molecule kinase inhibitorsExamples of remedies include crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, and dovitinib. Inib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, ratotinib, rigosertib, tepotinib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib (rivoceranib), cabozantinib S-malate, ibrutinib, icotinib, buparlisib, cipatinib, cobimetinib, idelalisib, fedratinib, tesevatinib; photosensitizerExamples include methoxsalen, porfimer sodium, talaporfin, and temoporfin. Antibody Examples include alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab; catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, and nimotuzumab. otuzumab), obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, racotumomab, tabalumab, abituzumab, atezolizumab, durvalumab, pembrolizumab, nivolumab; Cytokines Examples include aldesleukin, interferon α2, interferon α2a, and interferon α2b; celmoleukin, tasonermin, teceleukin, oprelvekin, and recombinant interferon β-1a. Drug conjugatesExamples include denileukin diftitox, ibritumomab tiuxetan, iobenguane I 123, prednimustine, trastuzumab bemtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomabestafenatox, oportunumab monatox, arcitumomab (99mTc), and vintafolide. PARP inhibitors Such as olaparib, veliparib, niraparib, rucaparib, talazoparib, pamiparib; KRAS inhibitors Such as sotorasib and adagrasib. Other medicinesExamples include alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel-T, sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, and zoledronic acid. acid), vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide lidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine, picibanil, reolysin, retaspimycin hydrochloride, trebananib, virulizin, carfilzomib, endostatin, immucothel, belinostat.

[0108] In a particular embodiment of the invention, the medical therapy includes a combination of the compound of the invention that inhibits TEAD activity with a KRAS inhibitor.

[0109] 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 other pharmacologically active substance other than the compound of the invention. This set or kit preferably comprises separately packaged: a) an effective amount of a compound of formula I or any of its N-oxide, solvate, tautomer, or stereoisomer, and a pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, and b) an effective amount of another active ingredient, which is not a compound of formula I.

[0110] Another embodiment of the present invention is a method for manufacturing the pharmaceutical composition of the present invention, characterized in that one or more of the compounds of the present invention and one or more compounds selected from the group consisting of solid, liquid or semi-liquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds of the present invention are converted into a suitable dosage form.

[0111] The pharmaceutical compositions (formulations) of the present invention can be administered by any means to achieve their intended purpose. For example, they can be administered orally, parenterally, topically, intravenously, intramuscularly, by inhalation, nasally, intra-articularly, intraspinally, via the trachea, via the eye, subcutaneously, intraperitoneally, percutaneously, or buccally. Alternatively, they can be administered orally simultaneously. The dosage administered will depend on the recipient's age, health condition, and weight, the type of concurrent treatment (if present), the frequency of treatment, and the nature of the desired effect. Parenterally administration is preferred. Oral administration is particularly preferred.

[0112] Suitable dosage forms include, but are not limited to, capsules, tablets, pills, sugar-coated pills, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, gel patches, gels, patches, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be produced according to methods known in the art.

[0113] Generally, non-chemical pathways for producing pharmaceutical compositions and / or pharmaceutical formulations involve processing steps, known in the art, on suitable mechanical tools to transfer one or more of the compounds of the invention into a dosage form suitable for administration to a patient requiring such treatment. Typically, converting one or more of the compounds of the invention into such dosage forms involves adding one or more compounds selected from the group consisting of: carriers, excipients, adjuvants, and pharmaceutically active ingredients other than the compounds of the invention. Suitable processing steps include, but are not limited to, combining, grinding, mixing, granulating, dissolving, dispensing, homogenizing, casting, and / or pressing the corresponding active and inactive ingredients. Mechanical tools for performing these processing steps are known in the art. In this regard, the active ingredient is preferably at least one compound of the invention and optionally one or more additional compounds other than the compounds of the invention, which exhibit valuable pharmaceutical properties and are preferably pharmaceutically active agents other than the compounds of the invention, as disclosed herein.

[0114] Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices, or drops; suitable for rectal use are suppositories; suitable for parenteral use are solutions, preferably oil-based solutions or aqueous solutions, as well as suspensions, emulsions, or implants; and suitable for topical use are ointments, creams, or powders. The compounds of the present invention can also be lyophilized, and the resulting lyophilized products are used, for example, in the preparation of injectable formulations. The indicated formulations may be sterilized and / or contain adjuvants such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for adjusting osmotic pressure, buffering substances, dyes, flavoring agents, and / or several other active ingredients (e.g., one or more vitamins).

[0115] Suitable excipients are organic or inorganic substances suitable for enteral (e.g., oral), parenteral, or topical application and that do not react with the compounds of the present invention, such as water, vegetable oil, benzyl alcohol, alkyl glycol, polyethylene glycol, triacetin, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol, or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations, and / or calcium phosphate, such as tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or petrolatum.

[0116] If necessary, disintegrants may be added, such as starch as mentioned above, as well as carboxymethyl starch, croscarmellose, agar, or alginate or its salts, such as sodium alginate. Adjuvants include, but are not limited to, flow regulators and lubricants, such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. The core of the sugar-coated pill has a suitable coating, which may be gastric acid resistant. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, varnish, and suitable organic solvents or solvent mixtures. To produce a gastric acid resistant coating or to provide a dosage form that imparts a prolonged effect, tablets, sugar-coated pills, or pellets may contain an internal dose component and an external dose component, the latter being an encapsulation above the former. The two components may be separated by an enteric coating to prevent disintegration in the stomach and allow the internal component to enter the duodenum intact or delay release. Various materials can be used for such enteric coatings or coatings, including solutions of various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, or cellulose acetate phthalate, cellulose acetate, or hydroxypropyl methylcellulose phthalate suitable for cellulose formulations. Dyes or pigments can be added to the coating of tablets or sugar-coated pills, for example, to use for identification or to characterize the dosage of the active compound.

[0117] Suitable carrier materials are organic or inorganic substances suitable for enteral (e.g., oral) or parenteral or topical application and that do not react with the novel compound, such as water, vegetable oil, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, and petroleum jelly. Specifically, tablets, coated tablets, capsules, syrups, suspensions, drops, or suppositories are used for enteral application; solutions (preferably oil solutions or aqueous solutions), suspensions, emulsions, or implants are used for parenteral application; and ointments, creams, or powders are used for topical application. The compounds of the present invention can also be lyophilized, and the resulting lyophilized products can, for example, be used to produce injectable formulations.

[0118] Other orally administered pharmaceutical formulations include incorporation capsules made of gelatin and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Incorporation capsules may contain an active compound in particulate form, which can be mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid (such as fatty oil or liquid paraffin). Additionally, stabilizers may be added.

[0119] Novel compositions that can be incorporated into this invention in liquid form for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical carriers. Dispersants or suspending agents suitable for aqueous suspensions include synthetic and natural gums such as gum arabic, gum arabic, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0120] Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form (e.g., water-soluble salts and alkaline solutions). Alternatively, suspensions of the active compound, optionally oil-based injectable suspensions, may be used. Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or polyethylene glycol-400 (the compound is soluble in PEG-400).

[0121] Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran; optionally, the suspension may also contain stabilizers.

[0122] Possible pharmaceutical formulations that can be used rectally include, for example, suppositories, in which one or more active compounds are combined with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons. Alternatively, gelatin rectal capsules may also be used, which consist of a combination of active compounds and a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycol, or paraffin hydrocarbons.

[0123] Pharmaceutical formulations may be used as human and veterinary medicines. As used herein, the term "effective amount" means an amount of drug or pharmaceutical agent that will elicit a biological or medical response in a tissue, system, animal, or human, as sought by, for example, an investigator or clinician. Furthermore, the term also includes, within its scope, "therapeutic effective amount," which means any amount that causes improved treatment, cure, prevention, or improvement of a disease, disorder, or side effect, or a reduced rate of progression of a disease or disorder or symptoms associated with such disease or disorder, compared to a corresponding subject who did not receive this amount; it may also refer to prevention or provision of prevention of a disease or disorder in a subject who has or is at risk of developing a disease or disorder disclosed herein. The term also includes, within its scope, amounts that effectively enhance normal physiological function. Such therapeutically effective amounts of one or more compounds of the invention are known to those skilled in the art or can be readily determined by standard methods known in the art.

[0124] As used in this article, “treating” or “treatment” means the complete or partial relief of symptoms associated with a disorder or disease, or the slowing or prevention of the further progression or worsening of those symptoms, or the prevention or treatment of a disease or disorder in an individual at risk of developing the disorder or disease.

[0125] The compounds of the present invention and optional additional active substances are generally administered in a manner similar to commercially available formulations. Typically, suitable therapeutically effective doses are in the range of 0.0005 mg to 1000 mg per dose unit, preferably 0.005 mg to 500 mg, and particularly 0.5 mg to 100 mg. The daily dose is preferably between about 0.001 mg / kg and 10 mg / kg body weight.

[0126] Those skilled in the art should readily understand that dosage can vary depending on the specific compound, the severity of symptoms, and individual susceptibility to side effects. Some specific compounds are more effective than others. The preferred dosage of a given compound can be readily determined by those skilled in the art through various means. A preferred means is to measure the physiological potency of the given compound.

[0127] However, the specific dosage for an individual patient (especially a specific human patient) depends on numerous factors, such as the efficacy of the particular compound used, age, weight, general health condition, sex, diet, timing and route of administration, excretion rate, type of drug and dosage form to be administered, drug combination, and the severity of the specific disorder involved in the therapy. The specific therapeutically effective dosage for an individual patient can be readily determined, for example, by the physician or doctor advising or involved in the therapeutic treatment through routine experiments.

[0128] The compounds of the present invention can be prepared using suitable materials according to the procedures described in the following figures and examples, and are further illustrated by the following specific examples. They can also be prepared by methods known per se as described in the literature, specifically under reaction conditions known and suitable for the reactions. Variations known per se but not mentioned in more detail herein can also be used.

[0129] Similarly, starting materials used in the preparation of the compounds of the present invention can be prepared by methods as described in the examples or by methods known to those skilled in the art as described in the synthetic organic chemistry literature, or may be commercially available. The starting materials of the claimed and / or methods employed may, if necessary, be formed in situ by immediately further converting them into the compounds or intermediates of the present invention without separating them from the reaction mixture. Alternatively, the reaction can generally be carried out stepwise.

[0130] Those skilled in the art will recognize that some Formula I compounds can serve as starting materials for the preparation of other Formula I compounds. For example, Formula I compounds with carboxylic acid functional groups can be readily converted into related Formula I compounds with amide functional groups using appropriate synthetic methods.

[0131] Preferably, the reaction of the compound is carried out in the presence of a suitable solvent, which is preferably inert under the corresponding reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 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 ether or monoethyl ether or ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidone (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 these solvents or mixtures of these solvents with water.

[0132] The reaction temperature is between approximately -100°C and 300°C, depending on the reaction steps and conditions used.

[0133] Reaction times typically range from minutes to several days, depending on the reactivity of the compound and the reaction conditions. Suitable reaction times can be readily determined using methods known in the art, such as monitoring the reaction. Based on the reaction temperatures given above, suitable reaction times are generally between 10 minutes and 48 hours.

[0134] Furthermore, the extra-class compounds of the invention claimed herein can be readily prepared using the procedures described herein in conjunction with general techniques in the art. However, the compounds illustrated in the examples should not be construed as forming the only genus considered to be of the invention. The examples further illustrate the details of preparing the compounds of the invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds.

[0135] This invention also relates to a method for preparing a compound of formula I, or its N-oxide, solvate, tautomer or stereoisomer, and pharmaceutically acceptable salt thereof, of any one of PE1, PE1a, PE1b, PE2, PE2a, PE3, PE3a, PE3-0, PE3-0a, PE4, PE4-0, PE5, PE5a, PE5b, PE5c, PE5d, PE6, PE6a, PE6b, PE7, PE8, PE9, PE10, PE10a, PE10aa, PE10aaa, PE11, PE11a, PE12, PE12a, PE12aa, PE13, PE13a, PE13aa, PE14, PE14a, PE14-0, PE15, PE15a and PE15b, in its most general form and embodiments as well as the specific embodiments described herein, characterized in that (A) in a first reaction step, the compound of formula II is... Where R 1 R 3 and X 1 As defined above or by Formula I of any one of claims 1 to 28; Y 1 Indicates H or suitable protecting group PG 1 Hal 1 Y represents Cl, Br, or I; reacts with compound III under suitable C / C coupling reaction conditions. 2 -AL 1 -BIII where A, L 1 B is as defined above or as Formula I of any one of claims 1 to 28; Y 2 Indicate the suitable borate ester functional group; to obtain compound of formula IV. Or (B) in the first reaction step, make compound V... Where R 1 R 3 and X 1 As defined above or by Formula I of any one of claims 1 to 28; Y 1 Indicates H or suitable protecting group PG 1 ;Y 3 Indicates a suitable borate ester functional group; reacts with compound VI under suitable C / C coupling reaction conditions. 2 -AL 1 -BVI where A and L 1 And B as defined above or as Formula I of any one of claims 1 to 28; Hal 2Representing Cl, Br, or I; yielding a compound of formula IV; and optionally; (C) (1) if in formula IV above, Y 1 PG 1 In the second reaction step, PG is removed under suitable reaction conditions. 1 , to obtain Y 1 A compound of formula IV with H, which can also be described as having R 2 Compound of formula I for H; and / or (C) (2) If Y is in formula IV above 1 If H represents the compound, then in another reaction step, compound IV reacts with compound VII under suitable reaction conditions. 2 -LG 1 VII where R 2 As defined above or as any one of claims 1 to 28, but not H; and LG 1 Represents a suitable leaving group; to obtain a compound of formula I as defined above or as claimed in any one of claims 1 to 28.

[0136] As will be understood by those skilled in the art, the compounds of the present invention, especially those of Formula I, can be readily obtained by various synthetic routes, some of which are illustrated in the accompanying experimental section. Those skilled in the art will readily recognize what reagents and reaction conditions will be used and how they will be applied and modified (where necessary or useful) in any particular instance to obtain the compounds of the present invention. Furthermore, some compounds of the present invention can be readily synthesized by reacting other compounds of the present invention under suitable conditions, for example by converting a particular functional group present in a compound of the present invention or a suitable precursor molecule into another functional group by applying standard synthetic methods (such as reduction, oxidation, addition, or substitution reactions); those methods are well known to those skilled in the art. Similarly, those skilled in the art will apply (where necessary or applicable) synthetic protecting (or protective) groups; suitable protecting groups and methods for their introduction and removal are well known to those skilled in the art of chemical synthesis.

[0137] In the following text, the general synthetic routes that can be used to prepare the compounds of the present invention are described in more detail in the following figures A to E.

[0138] Diagram A The above diagram A depicts a general synthetic route for the preparation of compounds of formula I (described here as formula H). Unless specifically defined differently, R... 1 R 2 R 3 A, L 1 B and X 1As defined above or in the claims, compounds of formula I. Substituted 5-azaindole (or 1H-pyrrolo[3,2-c]pyridine) of formula A (= formula A, wherein X...) 1 For CR X1 In particular, CH; compounds of formula IA) or substituted 1H-pyrazolo[4,3-c]pyridine of formula A (= formula A, where X 1 The compound of formula A (N; compound IB) is commercially available or readily obtained using synthetic methods and procedures well known to those skilled in the art. In reaction step (a), the bicyclic compound of formula A is reacted under suitable reaction conditions with an iodinizing agent, such as iodosuccinimide (NIS; 1-iodopyrrolidone-2,5-dione) in DMF, to give the iodinated compound of formula B. Subsequently, in reaction step (b), the compound of formula B is reacted under suitable reaction conditions with a suitable protecting group Y for introducing a suitable protecting group Y onto the nitrogen ring atom at position 5 of the bicyclic system. 1 The reaction with a suitable reagent yields a compound of formula C. A suitable protecting group Y... 1 Any protecting group PG that substantially protects the nitrogen ring atom at position 5 from reacting with any of the reagents and substances used in step (c) below. 1 Examples of suitable protecting groups include tert-butyl formate (-C(=O)-O-tert-butyl), which can be introduced by reacting compound B with, for example, di-tert-butyl formate in the presence of a catalytic amount of DMAP (4-dimethylaminopyridine); or (trimethylsilyl)ethoxy-methyl (-CH2-O-(CH2)2-Si(CH3)3), which can be introduced by reacting compound B with, for example, [2-(chloromethoxy)ethyl]trimethylsilane in the presence of sodium hydride (NaH); or toluenesulfonate (p-methylbenzenesulfonyl), which can be introduced by reacting compound B with, for example, toluenesulfonyl chloride in the presence of NaH. In reaction (c), the compound of formula C is reacted with the compound of formula D in a C-C cross-coupling reaction (e.g., Suzuki coupling), wherein A, L 1 B has the same meaning as the compound of formula I, and Y 2 The functional group is a boronic acid ester (e.g., -B(OH)2 or a suitable ester thereof). Boric acid or boronic acid ester derivatives of formula D can be, for example, by compounds with corresponding chlorine substitutions of the self-contained formula D well known in the art (Y). 2 Boric acid (Y) is readily obtained from (Cl); for example, by subsequent hydrolysis of trimethyl borate and borate ester in the presence of a strong base such as lithium phenyl, to obtain boric acid (Y). 1= -B(OH)2), or by using 4,4,5,5-tetramethyl-1,3,2-dioxaborane in the presence of potassium acetate and chloro(2-bicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XphosPd G2) as a palladium(II)-catalyst, to obtain compounds of formula D, where Y²= Reaction step (c) is carried out under typical reaction conditions for a CC cross-coupling reaction such as Suzuki coupling, for example by reacting the compound of formula C with the compound of formula D in the presence of potassium carbonate and 1,1'-bis(diphenylphosphino)ferrocene palladium or 4-[bis(2-methyl-2-propyl)phosphino]-N,N-dimethylaniline-dichloropalladium (Pd(amphos)2Cl2). In reaction step (d), depending on the nature of the specific protecting group, protecting group Y is removed from the compound of formula E under acidic conditions (e.g., trifluoroacetic acid, TFA) or basic conditions (e.g., sodium hydroxide). 1 This yields a compound of formula F, which can also be described as a compound of formula I in which R² is H. Finally, a substituent R with a value different from H... 2 Compounds of formula I, i.e., compounds of formula H in diagram A, can be obtained by reacting compounds of formula F with appropriate compounds of formula G, LG. 1 -R 2 The reaction was obtained, in which LG 1 For a suitable leaving base, and R 2 As defined by equation I (but not H) (reaction step (e)). For example, if LG 1 If the halogen is selected from Cl, Br, or I, then reaction step (e) can be the reaction of a compound of formula F with LG. 1 -R 2 The nucleophilic substitution reaction. Depends on LG. 1 -R 2 Due to its specific properties, this reaction step (e) can be carried out by deprotonating the NH group using a suitable base (such as sodium hydride or cesium carbonate), followed by reacting the intermediate with a suitable compound of formula G, such as an alkyl iodide (e.g., CH3-I), a bromide (e.g., Br-CH2CN), or a chlorinating compound (e.g., chloromethylimidazolium hydrochloride). The substituent R of the compound of formula H... 2 It can be further modified to obtain other compounds of formula H.

[0139] Schematic B The above diagram B depicts the synthesis of a substance with substituent R. 2An alternative route for compounds of formula I, where the substituent remains unaffected by the Suzuki CC cross-coupling reaction or a similar cross-coupling reaction: The compound of formula B is reacted with a suitable compound of formula G under conditions similar to those described above for reaction step (e) in formula A (step (f)) to obtain the corresponding compound of formula J. Subsequently, the compound of formula J is further reacted with the compound of formula D under reaction conditions similar to those described above for reaction step (c) in formula A (step (g)).

[0140] Schematic C Figure C depicts the compound used to synthesize formula E (where L...). 1 An alternative route for representing the divalent -O-CH2- linker group (the compound of formula E-1 in diagram C) is as follows: the compound of formula C (obtainable via the synthetic route outlined in diagram A above) can be reacted with the compound of formula K in a C-C cross-coupling reaction (reaction step (g)), where A is as defined in formula I, and Y 2 As defined by compound D in Figure A above, a hydroxyl-substituted compound of formula L is obtained. The reaction conditions for step (g) can be the same as or similar to those for step (c) in Figure A. Subsequently, the compound of formula L can be reacted with a compound of formula M under suitable reaction conditions (using, for example, DMF containing cesium carbonate), wherein B is as defined in formula I, and Y... 3 LG 3 -CH2-, where LG 2 For a suitable leaving group, such as an alkyl-SO3 group (alkyl sulfonate), a compound of formula E-1 is obtained, wherein L¹ represents a divalent -O-CH2- group. The compound of formula E-1 can then be subjected to reaction step (d) as described above with respect to formula A and optionally to reaction step (c) to obtain compounds of formulas F and H, respectively, wherein L¹ represents a divalent -O-CH2- group.

[0141] Schematic D Figure D outlines the compounds used to prepare formula I, and especially formula IC (where R...). 1One potential synthetic route for N-CF3 is as follows: a 1-chloro-substituted compound of formula A (A-Cl) is tosylsulfonated, wherein a strong base, such as NaH, is first added, followed by p-tolylsulfonyl chloride, to provide a compound of formula N-Cl (reaction step (j)) (where Ts represents the tosylate group), which is then reacted with hydroiodic acid (HI) in the presence of sodium iodide (NaI) to give a compound of formula NI (reaction step (k)). In a subsequent reaction step (m), compound NI is reacted with methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (compound O) in the presence of copper iodide (I) to give a compound of formula N-CF3. After (optionally) removal of the tosylate protecting group under alkaline conditions (e.g., sodium hydroxide), a compound of formula A-CF3 is obtained, which can be further used to prepare compounds of formula I, particularly IC, of ​​the present invention, wherein R 1 This indicates CF3.

[0142] Schematic E The above figure E describes an alternative scheme for preparing compounds of formula E, which can then be converted into compounds of formula I (described in figure A above): this alternative scheme begins with compounds of formula P, wherein R 1 R 3 and X 1 As defined in Equation I, Y 1 As defined by compounds of formulas C and E in diagram A above, and Y 4 The functional group is a boronic ester (e.g., -B(OH)2 or a suitable ester thereof). Boric acid or boronic ester derivatives of formula P can be derived, for example, from the corresponding chlorine-substituted compound of formula P (Y) by methods well known in the art. 4 Boric acid (Y) is readily obtained from (Cl); for example, by subsequent hydrolysis of trimethyl borate and borate ester in the presence of a strong base such as lithium phenyl, to obtain boric acid (Y). 4 = -B(OH)2), or by using 4,4,5,5-tetramethyl-1,3,2-dioxaborane in the presence of potassium acetate and chloro(2-bicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XphosPd G2) as a palladium(II)-catalyst, to obtain compounds of formula P, wherein Y 4 = The compound of formula P reacts with the compound of formula Q in reaction step (o) (where A, L¹ and B are as defined in formula I, and Y...). 5This indicates that Br or I) reacts under typical reaction conditions such as the Suzuki coupling CC cross-coupling reaction, for example by reacting a compound of formula P with a compound of formula Q in the presence of sodium carbonate and Pd(dppf)Cl2-CH2Cl2 (dichloride [1,1'-bis(diphenylphosphino)ferrocene]palladium(II)).

[0143] It should be noted that, except where the specific statement or context provides a different meaning, terms are generally used in number, that is, their singular and plural forms, and are read interchangeably. For example, the singular term "compound" may also include or refer to a plural number of compounds, while the plural term "compound" may include or refer to a singular number of compounds.

[0144] Examples and Experiments The compounds of the present invention can be prepared using suitable materials according to the procedures of the following figures and examples, and are further illustrated by the following specific examples. The compounds are shown in Tables 1 and 1A. Analytical data of the compounds prepared according to the following examples are also shown in Tables 1 and 1A.

[0145] The present invention will be described with reference to specific embodiments as illustrated in the following examples, but is not limited thereto. Unless otherwise specified in the drawings, variables have the same meaning as described above and within the scope of the claims.

[0146] Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification or by synthetic methods similar to those specifically described herein. Unless otherwise stated, all temperatures are expressed in °C and all reactions were carried out at room temperature (RT). Compounds were purified by silica gel chromatography or preparative HPLC. The purity of reaction products (intermediates) used in subsequent reaction steps was generally confirmed by GC-MS (without further characterization of intermediates).

[0147] 1H NMR: 1 H-NMR data are provided in Tables 1 and 1A below. Unless otherwise reported, 1 ¹H NMR spectra are typically obtained on 300 MHz, 400 MHz, 500 MHz, or 700 MHz NMR spectrometers, such as the Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300, or Bruker Avance III 700 MHz NMR spectrometer, under standard conditions using TMS (tetramethylsilane) as an internal reference and DMSO-d6 as a standard solvent. NS (number of scans): 32, SF (spectrometer frequency): as indicated. TE (temperature): 297 K. Chemical shifts (δ) relative to the TMS signal are reported in ppm. 11H NMR data are reported as follows: chemical shifts (multiplicity, coupling constant, and number of hydrogen atoms). Multiplicity is abbreviated as: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), dd (double doublet), tt (triple triplet), td (triple doublet), br (broad peak). Coupling constants (J) are reported in Hz.

[0148] LC-MS: The LC-MS data provided in Tables 1 and 1A are given in m / z. The results can be obtained by one of the methods described below.

[0149] synthesis Example 1: 4-Chloro-3-{3-[(4-fluorophenyl)methoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine 1.1: 4-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine A single addition of 1-iodopyrrolidine-2,5-dione (1.4 g; 6.19 mmol) was made to a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (900 mg; 5.90 mmol) in anhydrous DMF (6 ml). The yellow clear solution turned into a dark brown clear solution. The reaction mixture was stirred at 25 °C for 3 hours. Subsequently, 21 ml of water was added, and the brown precipitate was filtered off, washed with water, and azeotropically reacted with toluene to give the desired compound (1.45 g) as a brown solid, which was used without further purification.

[0150] 1.2: 4-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester Di-tert-butyl dicarbonate (669 mg; 3.06 mmol) was added in a single addition to a solution of 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (843 mg; 2.79 mmol) (step 1.1) in anhydrous DCM (18 ml), followed by the addition of DMAP (34 mg; 0.28 mmol). The clear solution was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water and diluted with DCM; the organic layer was separated and concentrated. The residue was purified by chromatography to give the product as a yellow solid (950 mg; 87%).

[0151] 1.3: 4-Chloro-3-{3-[(4-fluorophenyl)methoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert- Butyl acetate Under argon atmosphere, commercially available (3-((4-fluorobenzyl)oxy)phenyl)boronic acid (99 mg; 0.40 mmol), K₂CO₃ (107 mg; 0.77 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (23 mg; 0.03 mmol) were added to a solution of 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid (120 mg; 0.31 mmol) (step 1.2) in dioxane (5 ml) / water (0.4 ml). The reaction mixture was stirred at 80 °C for 3 h. The mixture was diluted with EtOAc and extracted with H₂O, dried over Na₂SO₄ and evaporated to dryness. The residue was purified by chromatography to give the product (61 mg, 42%) as a colorless oil.

[0152] 1.4: 4-Chloro-3-{3-[(4-fluorophenyl)methoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine (Compound No.). 1) TFA (1 ml) was added to a solution of tert-butyl 4-chloro-3-{3-[(4-fluorophenyl)methoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (61 mg; 0.13 mmol) (step 1.3) in DCM (10 ml), and the mixture was stirred at room temperature for 16 hours. The reactants were alkalized with NaOH-2N and diluted with DCM, extracted with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by chromatography to give the product as a white solid (48 mg; 100%).

[0153] Example 2: 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine 2.1: 4-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine NaH (1.14 g; 28.61 mmol) was added to a suspension of 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (8 g; 23.84 mmol) (step 1.1) in DMF (160 ml) at 0 °C under a nitrogen atmosphere for 1 h. [2-(chloromethoxy)ethyl]trimethylsilane (4.77 g; 28.61 mmol) was added to the mixture, and the mixture was stirred at 0 °C for 4 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum and purified by chromatography to give a pure product as a yellow solid (8.10 g; 37%).

[0154] 2.2: 3-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine-3- Benzyl)phenol To a solution of 4-chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine (1.50 g; 1.65 mmol) (step 2.1) in 1,4-dioxane (30 ml) / water (3 ml), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)phenol (0.39 ml; 1.57 mmol), Pd(dppf)Cl2 (120.72 mg; 0.17 mmol) and K2CO3 (571 mg; 4.13 mmol) were added. The resulting reaction mixture was stirred at 90 °C under a N2 atmosphere for 6 h. The mixture was filtered, the filtrate was concentrated under vacuum, and the residue was diluted with EtOAc, washed with water and brine, dried over Na2SO4, concentrated, and purified by chromatography to give the product as a grayish-white solid (560 mg; 73%).

[0155] 2.3: Methyl 4,4-difluorocyclohexyl methanesulfonate (4,4-Difluorocyclohexyl)methanol (500 mg; 3.33 mmol) was dissolved in DCM (10 ml). The solution was cooled to 0 °C, and methanesulfonyl chloride (572 mg; 4.99 mmol) was added, followed by triethylamine (842.32 mg; 8.32 mmol). The mixture was stirred at room temperature for 3 h. The crude reaction mixture was diluted with H2O and DCM, the organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product as a grayish-white solid, which was used without further purification (800 mg; 84%).

[0156] 2.4: 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1-{[2-(trimethylsilyl)ethoxy] [methyl]-1H-pyrrolo[3,2-c]pyridine A suspension of 3-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridin-3-yl)phenol (300 mg; 0.65 mmol) (step 2.2), methyl (4,4-difluorocyclohexyl)methanesulfonate (370 mg; 1.30 mmol) (step 2.3), and K₂CO₃ (448 mg; 3.24 mmol) in DMF (3 ml) was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was filtered, the filtrate was concentrated under vacuum, and the residue was diluted with EtOAc, washed with H₂O and brine, dried over Na₂SO₄, concentrated, and purified by chromatography to give the product as a grayish-white solid (340 mg; 97%).

[0157] 2.5: 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine (chemical) Compound No. 4) TFA (3 ml) was slowly added to a solution of 4-chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine (300 mg; 0.56 mmol) (step 2.4) in anhydrous DCM (3 ml). The mixture was then stirred at 15 °C for 16 h. After removing the volatiles, the residue was dissolved in MeOH (3 ml) and ammonia solution (3 ml) was added. The final mixture was stirred at 35 °C for 3 h. After removing the methanol, the precipitate was collected and purified by chromatography to give the product as a white solid (130 mg; 62%).

[0158] Example 3: 3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-4-(trifluoromethyl)-1H-pyrrolo[3, 2-c]pyridine 3.1: 4-Chloro-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine A solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine (1.5 g; 9.83 mmol) in THF (10 ml) was cooled to 0 °C under N2. NaH (433 mg; 10.81 mmol) was added to the solution for 1 h. 4-Methylbenzene-1-sulfonyl chloride (2.2 g; 11.80 mmol) was added, and the mixture was stirred at 25 °C for 15 h. H2O was added. The mixture was extracted with EtOAc, and the organic phase was dried over Na2SO4, concentrated, and purified by chromatography to give the product as a yellow solid (2.2 g; 72%).

[0159] 3.2: 4-Iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine HI (8695 mg; 3.87 mmol) was added to a mixture of 4-chloro-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (1 g; 3.23 mmol) (step 3.1), NaI (1.3 g; 8.39 mmol), and butane-2-one (15 ml). The mixture was stirred at 85 °C under N2 for 16 h. H2O (30 ml) was added, and the mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography to give the desired product (930 mg; 72%) as a brown solid.

[0160] 3.3: 1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine Add [bis(dimethylamino)phosphoryl]dimethylamine (1.6 g; 8.84 mmol) to a solution of 4-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (880 mg; 2.21 mmol) (step 3.2), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.3 g; 6.63 mmol), and CuI (168 mg; 0.88 mmol) in DMF (100 ml). Stir the mixture in a sealed tube at 80 °C under N2 for 16 h. Add H2O, and extract the mixture with EtOAc. Dry the organic phase in Na2SO4 and concentrate. Purify the residue by chromatography to give the product as a white solid (410 mg; 50%).

[0161] 3.4: 4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine Add 5 ml of H₂O containing NaOH (443 mg; 11.08 mmol) to a solution of 1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (410 mg; 1.11 mmol) (step 3.3) in EtOH (10 ml). Stir the resulting mixture at 30 °C for 2 h. Concentrate the mixture, and dilute the residue with H₂O. After extraction with EtOAc (50 ml), the organic phase is dried over anhydrous Na₂SO₄ and concentrated. The residue (206 mg; 1.11 mmol; off-white solid) is used in the next step without further purification.

[0162] 3.5: 3-Iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine Add 1-iodopyrrolidine-2,5-dione (242 mg; 1.07 mmol) to a solution of 4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (200 mg; 1.07 mmol) (step 3.4) in DMF (3 mL). Stir the reaction mixture at 25 °C under a nitrogen atmosphere for 2 h, followed by the addition of H₂O. After extraction with EtOAc, the organic phase was dried over anhydrous Na₂SO₄ and concentrated. The residue (300 mg; 0.96 mmol; pale yellow solid) was used without further purification.

[0163] 3.6: 2-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaboron Pentocyclohexane 4-(bromomethyl)-1,1-difluorocyclohexane (250 mg; 1.17 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentane-2-yl)phenol (0.29 ml; 1.17 mmol), and Cs₂CO₃ (765 mg; 2.35 mmol) were suspended in DMF (5 ml). The reaction mixture was heated to 70 °C for 16 h under a nitrogen atmosphere. H₂O was then added, and the mixture was extracted with EtOAc. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated. The crude product was purified by chromatography to give the product as a white solid (380 mg, 64%).

[0164] 3.7: 3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-4-(trifluoromethyl)-1H-pyrrolo[3,2-c] Pyridine (Compound No. 15) Add 1,1'-bis(diphenylphosphino)ferro[3,2-c]pyridine (220 mg; 0.66 mmol) (step 3.5), 2-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxabortylcyclopentane (335 mg; 0.66 mmol) (step 3.6), and K₂CO₃ (275 mg; 1.99 mmol) to a solution of 3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (220 mg; 0.66 mmol) in water (20 ml) / dioxane (2 ml) to palladium ferrocene (49 mg; 0.07 mmol). Stir the mixture at 70 °C under N₂ for 16 h. Add H₂O to the reaction mixture and extract with EtOAc. Dry the organic phase over anhydrous Na₂SO₄ and concentrate. Purify the residue by chromatography to give the product as a white solid (110 mg; 40%).

[0165] Example 4: 4-[(3-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}phenoxy)methyl]-1-(trifluoromethyl) 1H-pyrazole 4.1: Ethyl 1-(bromodifluoromethyl)-1H-pyrazole-4-carboxylate Ethyl 1H-pyrazole-4-carboxylate (10 g; 71 mmol) was added to a suspension of NaH (4.3 g; 107 mmol, 60% in paraffin oil) in anhydrous DMF (50 ml) at 0 °C. The mixture was stirred at 25 °C under N2 for 1 h. Dibromodifluoromethane (22.5 g; 107 mmol) was then added for 2 h. H2O was added, and the mixture was extracted with DCM. The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography to give the product as a clear, colorless oil (5.35 g; 28%).

[0166] 4.2: Ethyl 1-(trifluoromethyl)-1H-pyrazole-4-carboxylate Silver tetrafluoroborate (I) (3.73 g; 19.18 mmol) was added to a solution of ethyl 1-(bromodifluoromethyl)-1H-pyrazole-4-carboxylate (2 g; 6.39 mmol) (step 4.1) in anhydrous DCM (30 ml) at -60 °C. The mixture was stirred at 20 °C under N2 for 2 h. H2O was then added, and the mixture was extracted with DCM. The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude product (1.46 g; 6.03 mmol; clear, colorless liquid) was used without further purification.

[0167] 4.3: 1-(trifluoromethyl)-1H-pyrazole-4-yl]methanol A solution of LiAlH4 in THF (5.78 ml; 5.78 mmol) was added to a solution of ethyl 1-(trifluoromethyl)-1H-pyrazole-4-carboxylate (700 mg; 2.89 mmol) (step 4.2) in anhydrous THF (10 ml) at 0 °C. The mixture was stirred at 25 °C under N2 for 2 h. H2O was then added, and after extraction with EtOAc, the organic phase was dried over Na2SO4 and concentrated. The crude product (490 mg; 2.54 mmol; clear, colorless liquid) was used without further purification.

[0168] 4.4: [1-(trifluoromethyl)-1H-pyrazole-4-yl]methyl methanesulfonate e TEA (684 mg; 6.76 mmol) and methanesulfonyl chloride (387 mg; 3.38 mmol) were added to a solution of [1-(trifluoromethyl)-1H-pyrazol-4-yl]methanol (390 mg; 2.25 mmol) (step 4.3) in anhydrous DCM (5 ml) at 0 °C. The mixture was stirred at 25 °C under N2 for 1 h. After adding H2O and extracting with DCM, the organic phase was dried over Na2SO4 and concentrated. The crude product (490 mg; 0.46 mmol; clear, colorless oil) was used without further purification.

[0169] 4.5: 4-{[3-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine- 3-yl)phenoxy]methyl}-1-(trifluoromethyl)-1H-pyrazole A solution of methyl [1-(trifluoromethyl)-1H-pyrazole-4-yl]methanesulfonate (490 mg; 0.46 mmol) (step 4.4) in DMF was supplemented with 3-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridin-3-yl)phenol (200 mg; 0.43 mmol) (step 2.2) and K₂CO₃ (191 mg; 1.38 mmol). The mixture was stirred at 80 °C under N₂ for 16 h. After adding H₂O and extracting with EtOAc, the organic phase was dried over Na₂SO₄ and concentrated. The residue was purified by chromatography to give the product (100 mg; 41%) as a clear, colorless oil.

[0170] 4.6: 4-[(3-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}phenoxy)methyl]-1-(trifluoromethyl)- 1H-pyrazole (Compound No. 7) TFA (3 ml) was added to a solution of 4-{[3-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridin-3-yl)phenoxy]methyl}-1-(trifluoromethyl)-1H-pyrazole (100 mg; 0.15 mmol) (step 4.5) in DCM (3 ml) for 1 h under N2. After removing all volatiles under vacuum, NH3·H2O (3 ml) and MeOH (3 ml) were added. The mixture was stirred at 35 °C under N2 for 2 h and then concentrated. The residue was purified by chromatography to give the product as a white solid (40 mg; 65%).

[0171] Example 5: 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1H-pyrazolo[4,3-c]pyridine 5.1: 2-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaboron Pentocyclohexane Methyl (4,4-difluorocyclohexyl) methanesulfonate (265 mg; 0.93 mmol) (step 2.3), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenol (0.23 ml; 0.93 mmol), and Cs₂CO₃ (605 mg; 1.86 mmol) were suspended in DMF (5 ml). The reaction mixture was heated to 70 °C for 16 h under a nitrogen atmosphere. H₂O was added, and after phase separation, the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na₂SO₄. After filtration and evaporation, the residue was purified by chromatography to give the product as a grayish-white solid (340 mg; 96%).

[0172] 5.2: 4-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine 4-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (299 mg; 1 mmol) (step 1.1) and NaH (48 mg; 1.20 mmol) were suspended in THF (3 ml) for 1 h at 0 °C and then at 25 °C for 1 h. Subsequently, [2-(chloromethoxy)ethyl]trimethylsilane (200 mg; 1.20 mmol) was added at 25 °C for 3 h. H₂O and brine were added to the reaction mixture. After the addition of EtOAc, the organic layer was concentrated. The residue was purified by chromatography to give the product as a grayish-white solid (420 mg; 99%).

[0173] 5.3: 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1-{[2-(trimethylsilyl)ethoxy] [methyl]-1H-pyrazolo[4,3-c]pyridine 4-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine (349 mg; 0.82 mmol) (step 5.2), 2-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (315 mg; 0.82 mmol) (step 5.1), Pd(amphos)Cl2 (117 mg; 0.16 mmol), and Cs2CO3 (805 mg; 2.47 mmol) were combined in a dioxane (6 ml) / H2O (0.60 ml). The reaction mixture was stirred at 50 °C for 16 h under a N2 atmosphere. H2O and brine were added to the reaction mixture. After the addition of EtOAc, the organic layer was concentrated. The residue was purified by chromatography to give the product as a grayish-white solid (240 mg; 50%).

[0174] 5.4: 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1H-pyrazolo[4,3-c]pyridine (chemical) Compound No. 13) 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]pyridine (140 mg; 0.24 mmol) (step 5.3) was dissolved in DCM (1 ml), followed by the addition of TFA (0.50 ml) at 0 °C, and the reaction mixture was slowly heated to 25 °C for 1 h. The DCM was removed under vacuum, followed by the addition of NH3 (4 M in methanol) (2 ml; 8 mmol) at 25 °C for 1 h. The solvent was removed, and the residue was purified by chromatography to give the product as a grayish-white solid (44 mg; 47%).

[0175] Example 6: 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]-4-fluorophenyl}-1H-pyrrolo[3,2- c] Pyridine (Compound No. 14) 4-Chloro-3-{3-[(4,4-difluorocyclohexyl)methoxy]-4-fluorophenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine (200 mg; 0.35 mmol) (obtainable via a synthetic procedure similar to that used to prepare the compound in step 2.4) was dissolved in DCM (2 ml), followed by the addition of TFA (1 ml) at 0 °C, and the reaction mixture was slowly heated to 25 °C for 1 h. The DCM was removed under vacuum, and NH3 (4 M in methanol; 3 ml) was added at 25 °C for 1 h. The solvent was removed, and the residue was purified by chromatography to give the product as a grayish-white solid (44.60 mg; 32%).

[0176] Example 7: 4-Chloro-3-(3-{[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methoxy}phenyl)- 1H-pyrrolo[3,2-c]pyridine 7.1: Methyl methanesulfonate [3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl] ester [3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methanol (100 mg; 0.54 mmol) was dissolved in DCM (2 ml). The solution was cooled to 0 °C, and methanesulfonyl chloride (93 mg; 0.81 mmol) was added, followed by TEA (137 mg; 1.35 mmol). After 3 h at room temperature, the crude reaction mixture was filtered, and the organic layer was concentrated under reduced pressure to give a crude product as a grayish-white solid (100 mg; 68%).

[0177] 7.2: 4-Chloro-3-(3-{[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methoxy}phenyl)-1-{[2- [(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine A suspension of 3-(4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridin-3-yl)phenol (113 mg; 0.24 mmol) (step 2.2), methyl [3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methanesulfonate (100 mg; 0.37 mmol) (step 7.1), and K₂CO₃ (169 mg; 1.22 mmol) in DMF (1.13 ml) was stirred overnight at room temperature under a nitrogen atmosphere. The crude reaction mixture was filtered, and the organic layer was concentrated under reduced pressure to give a crude product (130 mg; 92%) as a grayish-white solid, which was used in the next step without further purification.

[0178] 7.3: 4-Chloro-3-(3-{[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methoxy}phenyl)-1H-pyridine Pyrro[3,2-c]pyridine (Compound No. 21) TFA (1 ml) was slowly added to a solution of 4-chloro-3-(3-{[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]methoxy}phenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine (120 mg; 0.21 mmol) (step 7.2) in anhydrous DCM (1 ml). The mixture was stirred at 15 °C for 16 h. After removing all volatiles, the residue was dissolved in MeOH (1 ml) and ammonia solution (1 ml) was added. The mixture was stirred at 35 °C for 3 h, quenched with H2O, and purified by chromatography to give the desired compound (60 mg; 74%) as a white solid.

[0179] Example 8: 2-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-5-[4-(trifluoromethyl)phenoxy]-1, 3,4-Thiadiazole 8.1: 2-Bromo-5-[4-(trifluoromethyl)phenoxy]-1,3,4-thiadiazole K₂CO₃ (1.30 g; 8.94 mmol) was added to a stirred solution of dibromo-1,3,4-thiadiazole (1.50 g; 5.84 mmol) and 4-(trifluoromethyl)phenol (1.00 g; 5.86 mmol) in DMF (20 ml). The resulting mixture was stirred at 90 °C for 2 h and then diluted with H₂O. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a white solid (1.20 g; 52%).

[0180] 8.2: 4-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester Under argon atmosphere, tert-butyl 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (5.84 g; 15.43 mmol) (step 1.2) and tetrakis(triphenylphosphine)palladium(0) (1.78 g; 1.54 mmol) in a solution of TEA (43 ml) and dioxane (88 ml) were added to form 4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (6.92 ml; 46.29 mmol). A strong gas was formed. The reactants were stirred at 90 °C for 2 h and then at 100 °C for 2 h. At room temperature, the reaction mixture was diluted with EtOAc and H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and aspirated. The filtrate was evaporated to dryness and purified by chromatography to give the product as a yellow oil (4.43 g; 76%).

[0181] 8.3: 2-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-5-[4-(trifluoromethyl)phenoxy]-1,3,4- Thiadiazole (Compound No. 30) To a solution of 2-bromo-5-[4-(trifluoromethyl)phenoxy]-1,3,4-thiadiazole (150 mg; 0.38 mmol) (step 8.1) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (160 mg; 0.41 mmol) (step 8.2) in dioxane (5 ml) and H2O (1 ml), Na2CO3 (150 mg; 1.34 mmol) and Pd(dppf)Cl2·CH2Cl2 (50 mg; 0.06 mmol) were added. After stirring at 90 °C for 16 h under a N2 atmosphere, the reaction mixture was diluted with H2O. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography to obtain the product as a white solid (15.40 mg; 10%).

[0182] Example 9: 2-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-5-{[4-(trifluoromethyl)phenyl]methyl 1,3,4-thiadiazole 9.1: 5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-thiadiazole-2-amine Aminothiourea (2.70 g; 28.14 mmol) was added to a solution of 2-[4-(trifluoromethyl)phenyl]acetonitrile (5 g; 25.66 mmol) in TFA (50 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 3 h and then concentrated under reduced pressure. The residue was diluted with EtOAc and neutralized to pH 7 with saturated NaHCO3 (aqueous solution). The mixture was extracted with EtOAc, and the combined organic layers were washed with H2O and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a grayish-white solid (6 g; 79%).

[0183] 9.2: 2-Bromo-5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-thiadiazole Copper bromide (4.60 g; 19.57 mmol) and t-BuONO (2.10 g; 19.35 mmol) were added to a solution of 5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-thiadiazol-2-amine (2.90 g; 9.84 mmol) (step 9.1) in 50 mL of ACN at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C for 3 h and then concentrated under reduced pressure. The residue was purified by chromatography to give the product (2.90 g; 85%) as a pale yellow solid.

[0184] 9.3: 2-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-5-{[4-(trifluoromethyl)phenyl]methyl}-1, 3,4-Thiadiazole (Compound No. 31) Pd(dppf)Cl2 (20 mg; 0.03 mmol) and Na2CO3 (50 mg; 0.45 mmol) were added to a solution of 2-bromo-5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-thiadiazole (80 mg; 0.23 mmol) (step 9.2) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (95 mg; 0.24 mmol) (step 8.2) in dioxane (5 ml) / H2O (1 ml) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C and then concentrated under reduced pressure. The residue was purified by chromatography to give the product as a pale yellow solid (58.10 mg; 63%).

[0185] Example 10: 3-Methyl-5-[4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-N ... [Fluoromethyl]phenyl]aniline 10.1: 3-Chloro-5-methyl-N-[4-(trifluoromethyl)phenyl]aniline XPhos Pd G3 (824 mg; 0.97 mmol) was added to a suspension of 1-bromo-3-chloro-5-methylbenzene (2 g; 9.73 mmol), 4-(trifluoromethyl)aniline (1.9 g; 11.68 mmol), and Cs₂CO₃ (9.5 g; 29.20 mmol) in dioxane (40 ml). The mixture was stirred at 50 °C under N₂ for 16 h, followed by the addition of H₂O. The mixture was extracted with EtOAc, and the combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified by chromatography to give the product as a yellow oil (2.1 g; 69%).

[0186] 10.2: 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)-N-[4-(trimethylolprop ... [Fluoromethyl]phenyl]aniline XphosPd G2 (245 mg; 0.31 mmol) was added to a solution of 3-chloro-5-methyl-N-[4-(trifluoromethyl)phenyl]aniline (1 g; 3.12 mmol) (step 10.1), bis(pinacolyl)diboron (BPD) (1.2 g; 4.67 mmol), and KOAc (0.9 g; 9.35 mmol) in dioxane (10 ml). The mixture was stirred at 80 °C under N2 for 16 h, followed by the addition of H2O. The mixture was extracted with EtOAc, and the combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by chromatography to give the product as a colorless oil (1.32 g; 83%).

[0187] 10.3: 3-Methyl-5-[4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-N-[4-(trifluoromethyl) [B-phenyl]aniline (Compound No. 37) Pd(amphos)₂Cl₂ (23.15 mg; 0.03 mmol) was added to a solution of 3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (120 mg; 0.33 mmol) (step 3.5), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-N-[4-(trifluoromethyl)phenyl]aniline (200 mg; 0.39 mmol) (step 10.2), and K₂CO₃ (136 mg; 0.98 mmol) in dioxane (4 ml) / H₂O (0.4 ml). The mixture was stirred at 100 °C under N₂ for 16 h. For treatment, H₂O was added and the mixture was extracted with EtOAc. The combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified by chromatography to give the product as a white solid (57.70 mg; 40%).

[0188] Example 11: 2-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-4-{2-[4-(trifluoromethyl)phenyl] Ethyl-1,3-thiazole 11.1: N-{4-[(1E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-thiazolyl}tert-carbamate Butyl acetate To a 100 ml round-bottom flask, add chlorotriphenyl{[4-(trifluoromethyl)phenyl]methyl}-5-phosphine (1.9 g; 4.16 mmol) and THF (10 ml). Add NaOtBu (450 mg; 4.45 mmol) and stir the reaction mixture at room temperature for 15 minutes. Add N-(4-formyl-1,3-thiazolyl-2-yl)tert-butyl carbamate (500 mg; 2.08 mmol) and stir the reaction mixture at room temperature overnight. The next morning, remove the solvent under vacuum and dissolve the residue in DCM. Wash the organic layer with saturated NH4Cl, dry to Na2SO4, filter, and concentrate under vacuum. The resulting crude material is purified by chromatography to give the product as a pale yellow oil (450 mg; 58%).

[0189] 11.2: N-(4-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-thiazolyl)tert-butyl carbamate Pd / C (29 mg; 0.03 mmol) was added to a stirred solution of N-{4-[(1E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-thiazolyl-2-yl}carbamate (100 mg; 0.27 mmol) (step 11.1) in MeOH (3 ml) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure to give a crude product (80 mg; 75%) as a pale yellow oil, which was used without further purification.

[0190] 11.3: 4-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-thiazolyl-2-amine TFA (2 ml) was added dropwise to a stirred solution of N-(4-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-thiazolyl-2-yl)carbamate (380 mg; 1 mmol) (step 11.2) in DCM (6 ml). The resulting mixture was stirred overnight at room temperature. After adjusting the pH to 8 with saturated NaHCO3 (aqueous solution) at 0 °C, the resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (280 mg, 98%) was used in the next step without further purification.

[0191] 11.4: 2-Bromo-4-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-thiazole CuBr (113 mg; 0.75 mmol) was added to a stirred solution of 4-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-thiazol-2-amine (210 mg; 0.75 mmol) and tBuONO (162 mg; 1.49 mmol) (step 11.3) in ACN (1 ml). The resulting mixture was stirred at 85 °C for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a pale yellow oil (130 mg; 49%).

[0192] 11.5: 2-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-4-{2-[4-(trifluoromethyl)phenyl]ethyl β-1,3-thiazole (Compound No. 105) To a solution of 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (127 mg; 0.34 mmol) (step 8.2) and 2-bromo-4-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3-thiazole (80 mg; 0.22 mmol) (step 11.4) in dioxane (3 ml) and H2O (0.5 ml), Na2CO3 (63 mg; 0.56 mmol) and Pd(dppf)Cl2·CH2Cl2 (19 mg; 0.02 mmol) were added. After stirring at 90 °C for 16 h under a N2 atmosphere, the resulting mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography to obtain the product as a white solid (39.50 mg; 43%).

[0193] Example 12: 2-[3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine-4- [3,2-c]pyridin-1-yl]ethyl-1-ol (Compound No. 342) 12.1: 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine Cs₂CO₃ (3.76 g; 11.54 mmol) was added to a solution of 3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (2 g; 5.77 mmol) (step 3.5) and (2-bromoethoxy)(tert-butyl)dimethylsilane (2.76 g; 11.54 mmol) in DMSO (30 ml). The mixture was stirred at 40 °C for 6 h. After the addition of H₂O, the mixture was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and filtered. The filtrate was concentrated to give a crude product (3 g; 95%) as a brown gel, which was used in the next step without further purification.

[0194] 12.2: 2-[3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethanol Dioxane-hydrochloride (10 ml) was added to a solution of 1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (3 g; 5.49 mmol) (step 12.1) in dioxane (40 ml) at 0 °C. The mixture was stirred at 25 °C for 2 h, and then diluted with H2O and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated to give the desired product (2 g; 96%) as a grayish-white solid, which was used in the next step without further purification.

[0195] 12.3: 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-4-(trifluoromethyl)- 1H-pyrrolo[3,2-c]pyridin-1-yl]ethyl-1-ol Under argon atmosphere, 4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (355 µl; 2.38 mmol), TEA (2.2 ml), and tetra(triphenylphosphine)palladium(0) (91.5 mg; 0.08 mmol) were added to a solution of 2-[3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethane (6 ml) in dioxane (6 ml). The reaction mixture was stirred at 100 °C for 2 h, filtered at room temperature, and evaporated to dryness. The residue was purified by chromatography to give the product (235 mg, 74%) as a brown oil.

[0196] 12.4 4-Bromo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine NaH (68 mg; 1.7 mmol) was added to a solution of trans-4-(trifluoromethyl)cyclohexanol (196 mg; 1.13 mmol) in THF (10 ml) at 0 °C for 30 min. Then, 4,6-dibromo-2-methylpyrimidine (300 mg; 1.1 mmol) dissolved in THF (1 ml) was added dropwise. The mixture was stirred at 0 °C for 1 h and then overnight at room temperature. For treatment, the reaction mixture was cooled to 0 °C and H₂O was added dropwise. After extraction with EtOAc, the organic phase was dried over Na₂SO₄, filtered, and evaporated. The residue was purified by chromatography to give the product as a colorless resin (227 mg; 57%).

[0197] 12.5: 2-[3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-4- (trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethanol-1-ol Under argon atmosphere at 60 °C, 4-bromo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethane-1-ol (205 mg; 0.51 mmol) (step 12.3) in a solution of 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexyl]oxy}pyrimidine (227 mg; 0.67 mmol) (step 12.4), K2CO3 (355 mg; 2.57 mmol), and tetra(triphenylphosphine)palladium(0) (89 mg; 0.08 mmol) were added to a solution of 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethane-1-ol (205 mg; 0.51 mmol) in dioxane (4 ml) / H2O (400 µl) for 16 h. The reaction mixture was diluted with EtOAc and extracted with H2O, dried over Na2SO4, and evaporated to dryness. The residue was purified by chromatography to give the product as a white solid (86 mg, 34%).

[0198] Example 13: {4-chloro-3-[2-methyl-6-(4-trifluoromethyl-phenoxy)-pyrimidin-4-yl]-pyrazolo[4, [3-c]pyridin-1-yl}-acetonitrile (Compound No. 385) 2-Bromoacetonitrile (26 mg; 0.21 mmol) and Cs₂CO₃ (145 mg; 0.44 mmol) were added to a stirred solution of 4-{4-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (60 mg; 0.13 mmol) (Example 22, step 22.4) in ACN (1 ml) for 2 h at 90 °C. The reaction mixture was directly purified by chromatography to give the product (12 mg, 22%) as a pale yellow solid.

[0199] Example 14: 4-{4-chloro-1-[(1H-imidazol-4-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}- 2-Methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyridine (Compound No. 365) NaH (440 mg; 11 mmol) was added to a stirred solution of 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyridine (1.20 g; 2.73 mmol) (Example 23, step 23.5) in DMF (30 ml) for 30 min at 0 °C. 4-(chloromethyl)-1H-imidazolium hydrochloride (880 mg; 5.46 mmol) was added at the given temperature, and the resulting mixture was stirred for another 16 h at room temperature. After removing all volatiles, the residue was purified by chromatography to give the product as a white solid (522 mg; 38%).

[0200] Example 15: 2-[4-chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} Pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethane-1-ol (Compound No. 346) 15.1: 4-Chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine-4- tert-butyl 1-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid Tetra(triphenylphosphine)palladium(O) (187 mg; 0.16 mmol) was added to a stirred solution of 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (420 mg; 1.08 mmol) (step 8.2) and 4-chloro-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (381 mg; 1.19 mmol) (step 21.4) degassed with argon in dioxane (8 ml) / H2O (3 ml) and Na2CO3 (572 mg; 5.40 mmol). The resulting mixture was stirred at 40 °C for 3 h under an argon atmosphere. A further portion of tetra(triphenylphosphine)palladium(0) (94 mg; 0.08 mmol) was added overnight at 40 °C. For further treatment, the reaction mixture was diluted with H₂O and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered, and evaporated. The residue was purified by chromatography to give the product as a yellow resin (105 mg; 17%).

[0201] 15.2: 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-5-fluoro-2-methyl-6-{[(1r,4r)-4- [(trifluoromethyl)cyclohexyl]oxypyrimidine 4-Chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (105 mg; 0.18 mmol) (step 15.1) was dissolved in DCM (15 ml) and TFA (140 µl) was added overnight at room temperature. Subsequently, the reaction mixture was diluted in H2O with saturated NaHCO3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by chromatography to give the product as a white solid (103 mg; 100%).

[0202] 15.3: 2-[4-chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethyl acetate 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (750 mg; 1.75 mmol) (step 15.2) and ethyl bromoacetate (374 µl; 3.30 mmol) were dissolved in ACN (40 ml). K₂CO₃ (913 mg; 6.61 mmol) was added overnight at room temperature. For treatment, the reaction mixture was diluted with H₂O and extracted with DCM. The organic layer was washed with H₂O, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by chromatography to give the product as a pale brown solid (1.1 g; 97%).

[0203] 15.4: 2-[4-chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethanol-1-ol Ethyl 2-[4-chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethyl acetate (1.1 g; 2.14 mmol) (step 15.3) was dissolved in MeOH (60 ml) and sodium borohydride (404 mg; 10.68 mmol) was added fractionally. The mixture was stirred overnight at room temperature, diluted with H2O, and extracted with EtOAc. The combined organic layers were extracted with H2O, dried over Na2SO4, filtered, and evaporated. The crude product (1.15 g) was crystallized from ACN and heptane to give the product as a white solid (950 mg, 94%).

[0204] Example 16: 3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2-c]pyridine- 4-Carbonitrile (Compound No. 219) 16.1: 3-Bromo-1H-pyrrolo[3,2-c]pyridine-4-carboxylonitrile NBS (2.72 g; 14.82 mmol) was added to a commercially available solution of 1H-pyrrolo[3,2-c]pyridine-4-carboxynitrile (2 g; 13.27 mmol) in DCM (100 ml) under stirring. The reaction mixture was stirred at room temperature for 2 h. It was then filtered, and the filter cake was washed with DCM to give the desired crude product as a white solid (2.30 g; 78%), which was used without further purification.

[0205] 16.2: 1-Bromo-3-{[4-(trifluoromethyl)phenyl]methoxy}benzene K₂CO₃ (13 g; 89.55 mmol) was added to a stirred solution of 3-bromophenol (3 ml; 28.61 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (8 g; 30.12 mmol) in acetone (30 ml) for 2 h at 60 °C. The mixture was concentrated, and the residue was purified by chromatography to give a product (7.6 g; 80%) as a colorless oil.

[0206] 16.3: 4,4,5,5-Tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2-dioxane Boron pentane Pd(dppf)Cl2·CH2Cl2 (25 mg; 0.03 mmol) and AcOK (90 mg; 0.91 mmol) were added to a stirred solution of 1-bromo-3-{[4-(trifluoromethyl)phenyl]methoxy}benzene (100 mg; 0.30 mmol) (step 16.2) and bis(pinacolyl)diboron (BPD) (400 mg; 1.42 mmol) in dioxane (10 ml). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. After evaporation, the residue was purified by chromatography to give the product as a colorless oil (104 mg; 91%).

[0207] 16.4: 3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2-c]pyridine-4-methyl nitrile Under a nitrogen atmosphere, Pd(dppf)Cl2·CH2Cl2 (50 mg; 0.06 mmol) and Na2CO3 (150 mg; 1.34 mmol) were added to a stirred solution of 4,4,5,5-tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2-dioxaborhexacyclopentane (100 mg; 0.26 mmol) (step 16.3) and 3-bromo-1H-pyrrolo[3,2-c]pyridine-4-carboxynitrile (70 mg; 0.32 mmol) (step 16.1) in dioxane (10 ml) / H2O (2 ml). The reaction mixture was stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was purified by chromatography to give the product as a yellow solid (14.60 mg; 14%).

[0208] Example 17: 3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2-c]pyridine- 4-Formamide (Compound No. 224) K₂CO₃ (60 mg; 0.41 mmol) and H₂O₂ (2 ml) were added to a stirred solution of 3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2-c]pyridine-4-carboxynitrile (200 mg; 0.41 mmol) (step 16.4) in DMSO (6 ml) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After evaporation, the residue was purified by chromatography to give the product as a white solid (22.8 mg; 14%).

[0209] Example 18: 7-Fluoro-4-methyl-3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo [3,2-c]pyridine (Compound No. 222) 18.1: 3-Bromo-5-fluoro-2-methylpyridin-4-amine NBS (3.3 g; 18.08 mmol) was added to a commercially available 5-fluoro-2-methylpyridin-4-amine (2 g; 15.06 mmol) in a stirred solution of ACN (30 ml) at 25 °C for 2 h. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (2.90 g; 94%) as a yellow solid. 18.2: 3-[(1E)-2-ethoxyvinyl]-5-fluoro-2-methylpyridine-4-amine Pd(dppf)Cl2 (1.1 g; 1.37 mmol) and K2CO3 (3.9 g; 27.31 mmol) were added to a stirred solution of 3-bromo-5-fluoro-2-methylpyridin-4-amine (2.8 g; 13.66 mmol) (step 18.1) and 2-[(1E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (3.4 g; 16.39 mmol) in dioxane (40 ml) / H2O (8 ml). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (2.80 g; 99%) as a yellow oil.

[0210] 18.3: 7-Fluoro-4-methyl-1H-pyrrolo[3,2-c]pyridine An aqueous solution of HCl (3 ml) was added to a stirred solution of 3-[(1E)-2-ethoxyvinyl]-5-fluoro-2-methylpyridin-4-amine (1.50 g; 7.31 mmol) (step 18.2) in isopropanol (30 ml). The resulting mixture was stirred at 80 °C for 2 h and then concentrated under vacuum. The residue was neutralized to pH 8 with NaHCO3 (aqueous solution) and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (950 mg; 87%) as a yellow solid, which was used without further purification.

[0211] 18.4: 3-Bromo-7-fluoro-4-methyl-1H-pyrrolo[3,2-c]pyridine NBS (653 mg; 3.56 mmol) was added to a stirred solution of 7-fluoro-4-methyl-1H-pyrrolo[3,2-c]pyridine (500 mg; 3.33 mmol) (step 18.3) in DCM (14 ml) at 0 °C for 30 min. The resulting mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was purified by chromatography to give the product as a yellow solid (380 mg; 50%).

[0212] 18.5: 7-Fluoro-4-methyl-3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2- c) Pyridine Pd(dppf)Cl2·CH2Cl2 (50 mg; 0.06 mmol) and K2CO3 (250 mg; 1.7 mmol) were added to a stirred solution of 3-bromo-7-fluoro-4-methyl-1H-pyrrolo[3,2-c]pyridine (140 mg; 0.58 mmol) (step 18.4) and 4,4,5,5-tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2-dioxaborhecyclopentane (260 mg; 0.69 mmol) (step 16.3) in dioxane (10 ml) / H2O (1 ml). The resulting mixture was stirred overnight at 80 °C under a N2 atmosphere. After evaporation, the residue was purified by chromatography to give the product as a white solid (39 mg; 16%).

[0213] Example 19: 4-Methyl-3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2- c] Pyridine-7-carboxynitrile (Compound No. 231) 19.1: 4-Amino-6-methylpyridine-3-carboxynitrile Pd(PPh3)4 (1.2 g; 1.02 mmol) was added to a stirred solution of 5-bromo-2-methylpyridin-4-amine (2 g; 10.16 mmol) and Zn(CN)2 (753 mg; 6.10 mmol) in DMF (20 ml). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give 4-amino-6-methylpyridin-3-carboxynitrile (850 mg; 63%) as a yellow solid.

[0214] 19.2: 4-Amino-5-bromo-6-methylpyridine-3-carboxynitrile NBS (1.4 g; 7.48 mmol) was added to a stirred solution of 4-amino-6-methylpyridin-3-carboxynitrile (830 mg; 6.23 mmol) (step 19.1) in ACN (20 ml). The resulting mixture was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was purified by chromatography to give the product as a yellow solid (1.20 g; 91%).

[0215] 19.3: 4-Amino-5-[(1E)-2-ethoxyvinyl]-6-methylpyridine-3-carboxynitrile Pd(dppf)Cl2 (418 mg; 0.54 mmol) and K2CO3 (1.6 g; 10.85 mmol) were added to a stirred solution of 4-amino-5-bromo-6-methylpyridin-3-carboxynitrile (1.15 g; 5.42 mmol) in dioxane (20 ml) / H2O (3 ml). The resulting mixture was stirred at 90 °C under a N2 atmosphere for 2 h and then concentrated under vacuum. The residue was purified by chromatography to give the product (550 mg; 50%) as a brown-orange solid.

[0216] 19.4: 4-Methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxynitrile An aqueous solution of HCl (1 ml) was added to a stirred solution of 4-amino-5-[(1E)-2-ethoxyvinyl]-6-methylpyridine-3-carboxynitrile (530 mg; 2.61 mmol) (step 19.3) in isopropanol (10 ml). The resulting mixture was stirred at 70 °C for 1 h. After concentration under vacuum and neutralization to pH 8 with NaHCO3 (aqueous solution), the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (340 mg; 83%) as a brown-orange solid, which was used in the next step without further purification.

[0217] 19.5: 3-Bromo-4-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxynitrile NBS (340 mg; 1.81 mmol) was added to a stirred solution of 4-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxynitrile (300 mg; 1.91 mmol) (step 19.4) in DCM (10 ml) at 0 °C for 30 min. The resulting mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was purified by chromatography to give the product (340 mg; 69%) as a white solid.

[0218] 19.6: 4-Methyl-3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2-c] ... Pyridine-7-carboxynitrile Pd(dppf)Cl2·CH2Cl2 (52 mg; 0.06 mmol) and K2CO3 (263 mg; 1.81 mmol) were added to a stirred solution of 3-bromo-4-methyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylonitrile (150 mg; 0.45 mmol) (step 19.5) and 4,4,5,5-tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2-dioxaborhecyclopentane (360 mg; 0.95 mmol) (step 16.3) in dioxane (10 ml) / H2O (1 ml). The resulting mixture was stirred at 80 °C for 2 h under a N2 atmosphere. After evaporation, the residue was purified by chromatography to give the product as a white solid (33 mg; 18%).

[0219] Example 20: 3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2-c]pyridine- 4-Amine (Compound No. 211) 20.1: 3-Iodo-1H-pyrrolo[3,2-c]pyridine-4-amine At 0 °C, a solution of commercially available 1H-pyrrolo[3,2-c]pyridine-4-amine (1 g; 7.51 mmol) in ACN (40 ml) was added to ACN (10 ml) containing 1-iodopyrrolidin-2,5-dione (2.03 g; 9.01 mmol). The mixture was stirred at 30 °C for 1 h. The reaction mixture was concentrated, and the residue was purified by chromatography to give the desired product (970 mg; 48%) as a brownish-yellow powder.

[0220] 20.2: 3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H-pyrrolo[3,2-c]pyridine-4-amine To a mixture of 3-iodo-1H-pyrrolo[3,2-c]pyridine-4-amine (220 mg; 0.82 mmol) (step 20.1), 4,4,5,5-tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2-dioxaborhecyclopentane (446 mg; 0.98 mmol) (step 16.3), and K₂CO₃ (338 mg; 2.45 mmol) in H₂O (2 ml) / dioxane (20 ml), bis(4-(di-tert-butylphosphino)-N,N-dimethylaniline)dichloropalladium (58 mg; 0.08 mmol) was added. The mixture was stirred at 50 °C under N₂ for 16 h. The reaction mixture was concentrated, and the residue was purified by chromatography to give the desired product (71 mg; 22%) as a white solid.

[0221] Example 21: 2-[4-chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} Pyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl]acetonitrile (Compound No. 382) 21.1: 4-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine A solution of commercially available 4-chloro-1H-pyrazolo[4,3-c]pyridine (2 g; 12.37 mmol) and NIS (3 g; 12.67 mmol) in DMF (20 ml) was stirred at 100 °C for 4 h. The mixture was extracted with EtOAc, and the combined organic layers were washed with H2O and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a yellow solid (2 g; 54%).

[0222] 21.2: 4-Chloro-3-iodo-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridine NaH (305 mg; 7.63 mmol, 60% in oil) was added to a solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.90 g; 6.36 mmol) (step 21.1) in DMF (20 ml) for 30 min at 0 °C. (Chlorodiphenylmethyl)benzene (2 g; 6.82 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H₂O and extracted with DCM. The combined organic layers were washed with H₂O and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a yellow solid (3 g; 86%).

[0223] 21.3: 4-Chloro-3-(trimethyltinyl)-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridine A solution of 4-chloro-3-iodo-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridine (400 mg; 0.73 mmol) (step 21.2), hexamethyldistannane (724 mg; 2.19 mmol), and Pd(amphos)Cl2 (109 mg; 0.15 mmol) in toluene (4 ml) was stirred in a microwave at 140 °C for 2 h. The mixture was then extracted with EtOAc, and the combined organic layers were washed with H2O, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product as a white solid (300 mg; 67%).

[0224] 21.4: 4-Chloro-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine KHMDS (6.60 ml; 6.60 mmol; 1 M in toluene) was added to a stirred solution of 4,6-dichloro-5-fluoro-2-methylpyrimidine (1 g; 5.25 mmol) and (1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (0.92 g; 5.36 mmol) in THF (20 ml). After 1 h at room temperature, the mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a colorless oil (950 mg; 51%).

[0225] 21.5: 5-Fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine NaI (700 mg; 4.44 mmol) was added to a stirred mixture of 4-chloro-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (1.40 g; 3.95 mmol) (step 21.4) in HI (57% in H2O, 20.00 ml) for 2 h. The mixture was extracted with DCM, and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a brown oil (1.65 g; 47%).

[0226] 21.6: 4-[4-chloro-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-2-methyl- 6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine Pd(PPh3)4 (225 mg; 0.18 mmol) and CuI (372 mg; 1.86 mmol) were added to a stirred solution of 4-chloro-3-(trimethyltinyl)-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridine (1.13 g; 1.85 mmol) (step 21.3) and 5-fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (1.64 g; 1.84 mmol) (step 21.5) in DMF (40 ml). The resulting mixture was stirred overnight at 100 °C under a N2 atmosphere. After evaporation, the residue was purified by chromatography to give the product as a brown oil (840 mg; 65%).

[0227] 21.7: 4-{4-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl}-5-fluoro-2-methyl-6-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxypyrimidine (compound No. 373) Et3SiH (2.50 ml) and TFA (5 ml) were added to a stirred solution of 4-[4-chloro-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (840 mg; 1.20 mmol) (step 21.6) in DCM (50 ml) for 2 h. After evaporation, the residue was purified by chromatography to give the product as a white solid (410 mg; 79%).

[0228] 21.8: 2-[4-chloro-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl]acetonitrile Cs₂CO₃ (113 mg; 0.33 mmol) was added to a stirred solution of 4-{4-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl}-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (50 mg; 0.12 mmol) (step 21.7) and 2-bromoacetonitrile (21 mg; 0.17 mmol) in ACN (5 ml). The resulting mixture was then stirred at 90 °C for 2 h. The crude substance was purified by chromatography to give the product as a white solid (23 mg; 42%).

[0229] Example 22: 4-{4-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-methyl-6-[4-(trifluoromethyl)benzene [Oxyptiidine] (Compound No. 378) 22.1: 4-Chloro-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine At room temperature, K₂CO₃ (12.70 g; 87.30 mmol) was added to a stirred solution of 4,6-dichloro-2-methylpyrimidine (5 g; 29.75 mmol) and 4-(trifluoromethyl)phenol (4.9 g; 28.72 mmol) in DMSO (150 ml), and the resulting mixture was stirred at 50 °C for 2 h. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (8.6 g; 82%) as a yellow oil, which was used in the next step without further purification.

[0230] 22.2: 4-Iodo-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine NaI (50 mg; 0.32 mmol) was added to a stirred solution of 4-chloro-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (500 mg; 1.42 mmol) (step 22.1) in HI (57% in H2O, 25 ml) for 2 h. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure to give a crude product (580 mg; 90%) as a brown oil, which was used in the next step without further purification.

[0231] 22.3: 4-[4-chloro-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-methyl-6-[4- [(trifluoromethyl)phenoxy]pyrimidine Pd(PPh3)4 (170 mg; 0.14 mmol) and CuI (50 mg; 0.25 mmol) were added to a stirred solution of 4-iodo-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (560 mg; 1.24 mmol) (step 22.2) and 4-chloro-3-(trimethyltinyl)-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyrimidine (820 mg; 1.37 mmol) (step 21.3) in DMF (15 ml) for 3 h. The mixture was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a yellow oil (490 mg; 55.0%).

[0232] 22.4: 4-{4-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl}-2-methyl-6-[4-(trifluoromethyl)phenoxy [Base]pyrimidine Et3SiH (0.88 ml; 5.37 mmol) and TFA (1.75 ml; 21.71 mmol) were added to a stirred solution of 4-[4-chloro-1-(triphenylmethyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (350 mg; 0.49 mmol) (step 22.3) in DCM (10 ml) for 15 min. The resulting mixture was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (60 mg; 29%) as a white solid.

[0233] Example 23: 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[6-(trifluoromethyl)} Pyridine-3-yl]oxy}pyridine (Compound No. 354) 23.1: 4-Chloro-3-iodo-1-(triphenylmethyl)-1H-pyrrolo[3,2-c]pyridine NaH (60% in oil, 1 g; 25 mmol) was added to a solution of 4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (5 g; 17.95 mmol) (step 1.1) in DMF (50 ml) at 0 °C. The mixture was stirred for 30 min, followed by the addition of (chlorodiphenylmethyl)benzene (6 g; 20.45 mmol). The mixture was stirred at room temperature for 2 h, followed by quenching with H2O. After extraction with DCM, the combined organic layers were washed with H2O and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a yellow solid (6.50 g; 68%).

[0234] 23.2: 4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-(triphenylmethyl) 1H-pyrrolo[3,2-c]pyridine A solution of 4-chloro-3-iodo-1-(triphenylmethyl)-1H-pyrrolo[3,2-c]pyridine (25.5 g; 47.45 mmol) (step 23.1), 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (13 g; 99.55 mmol), and Pd(PPh3)4 (6 g; 4.93 mmol) in TEA (90 ml) and dioxane (260 ml) was stirred at 80 °C under a N2 atmosphere for 4 h. The mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (14 g; 51%) as a yellow solid.

[0235] 23.3: 4-Iodo-2-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyridine K₂CO₃ (5.40 g; 37.21 mmol) was added to a stirred solution of 2-fluoro-4-iodo-6-methylpyridine (3 g; 12.40 mmol) and 6-(trifluoromethyl)pyridin-3-ol (2.06 g; 12.40 mmol) in DMF (60 ml). The resulting mixture was stirred overnight at 120 °C. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product as a colorless oil (2.8 g; 42%).

[0236] 23.4: 4-[4-chloro-1-(triphenylmethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[6- (trifluoromethyl)pyridin-3-yl]oxypyridine Pd(PPh3)4 (650 mg; 0.53 mmol) and Na2CO3 (1.75 g; 15.66 mmol) were added to a stirred solution of 4-iodo-2-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyridine (2.80 g; 5.22 mmol) (step 23.3) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-(triphenylmethyl)-1H-pyrrolo[3,2-c]pyridine (3.30 g; 5.73 mmol) (step 23.2) in dioxane (100 ml) / H2O (10 ml) for 6 h. After evaporation, the residue was purified by chromatography to give the product as a yellow solid (2.4 g; 65%).

[0237] 23.5: 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[6-(trifluoromethyl)pyridine- 3-yl]oxypyridine TFA (6 ml) and Et3SiH (3 ml) were added to a stirred solution of 4-[4-chloro-1-(triphenylmethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyridine (2.40 g; 3.37 mmol) (step 23.4) in DCM (50 ml) for 4 h. After evaporation, the residue was purified by chromatography to give the product as a white solid (1.20 g; 81.2%).

[0238] Example 24: 2-[3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine- 4-yl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]ethyl-1-ol (Compound No. 350) Under argon atmosphere at 60 °C, 4-bromo-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl] ethanol-1-ol (100 mg; 0.23 mmol) (step 12.3) in a solution of dioxane (7 ml) / H2O (2 ml) was added to a solution of pyrimidine (97 mg; 0.26 mmol) (similar to the preparation of the compound in step 12.4), K2CO3 (160 mg; 1.16 mmol), and tetra(triphenylphosphine)palladium (0) (40 mg; 0.03 mmol) for 6 h. The reactants were diluted with EtOAc and extracted with H2O, dried over Na2SO4, filtered, and then evaporated to dryness. The residue was purified by chromatography to give the product as a white solid (36 mg, 31%).

[0239] Example 25: 2-Methyl-4-{1-[(oxecyclobutane-3-yl)methyl]-4-(trifluoromethyl)-1H-pyrrolo} [3,2-c]pyridin-3-yl}-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 359) 25.1: 2-Methyl-4-[1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine- 3-yl]-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine Tetra(triphenylphosphine)palladium(O) (95 mg; 0.08 mmol) was added to a stirred solution of 1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (Examples 35, 35.2, and 35.3) (343 mg; 0.66 mmol) and 4-chloro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (167 mg; 0.55 mmol) in dioxane (7 ml) / H2O (1 ml) and K2CO3 (380 mg; 2.75 mmol). The resulting mixture was stirred overnight at 60 °C under an argon atmosphere. For treatment, the reaction mixture was diluted with H2O and extracted with DCM. The combined organic phases were dried over Na2SO4, filtered, and evaporated. The residue was purified by chromatography to give the product as a colorless solid (222 mg; 67%).

[0240] 25.2: 2-Methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-[4-(trifluoromethyl)-1H- Pyrrolo[3,2-c]pyridin-3-yl]pyrimidine (Compound No. 340) Tetramethylammonium fluoride (178 mg; 1.85 mmol) was added to a solution of 2-methyl-4-[1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (222 mg; 0.37 mmol) in DMF (5 mL) for 2 h at 60 °C. For the treatment, the reaction mixture was diluted with H₂O and extracted with DCM. The combined organic phases were dried over Na₂SO₄, filtered, and evaporated. The residue was purified by chromatography to give the product as a colorless solid (167 mg, 99%).

[0241] 25.3: 2-Methyl-4-{1-[(oxecyclobutane-3-yl)methyl]-4-(trifluoromethyl)-1H-pyrrolo[3,2- c]pyridin-3-yl}-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 359) 2-Methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-[4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]pyrimidine (60 mg; 0.14 mmol) was dissolved in THF (2 ml). NaH (16.20 mg; 0.41 mmol, a 60% suspension in paraffin oil) was added dropwise at 0 °C for 2 h. 3-(bromomethyl)oxetane (44.86 mg; 0.3 mmol) was dissolved in THF (0.2 ml) and added dropwise to the reaction mixture at 0 °C with stirring under argon for 18 h. The reaction mixture was quenched by adding H2O and brine, and then extracted with THF. The organic layer was washed with H2O, dried over Na2SO4, filtered, and evaporated. The residue was purified by chromatography to give the product as a colorless solid (30.70 mg; 44%).

[0242] Example 26: 5-Fluoro-2-methyl-4-{1-[(1-methyl-1H-pyrazol-4-yl)methyl]-4-(trifluoromethyl)- 1H-pyrrolo[3,2-c]pyridin-3-yl}-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No.). 358) A solution of 5-fluoro-2-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-[4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]pyrimidine (27 mg; 0.05 mmol) (similar to the compound synthesis described in step 25.2) in DMF (5 ml) was added to a suspension of NaH (6.4 mg; 0.16 mmol) in DMF (5 ml) for 2 h at 0 °C. 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (46 mg; 0.16 mmol) was dissolved in DMF (1 ml) and added dropwise to the reaction mixture at 0 °C with stirring under argon for 2 h. The reaction mixture was quenched by adding H₂O at 0 °C and subsequently extracted twice with EtOAc. The organic layer was washed three times with H2O, dried over Na2SO4, filtered, and evaporated. The residue was purified by chromatography to give the product as a light brown solid (10 mg; 34%).

[0243] Example 27: [4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyridine [3,2-c]pyridin-1-yl]-N,N-dimethylpropionamide (Compound No. 296) 27.1: 3-{3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl}-N,N-dimethylpropionamide 3-Bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine (250 mg; 1.1 mmol) (which can be obtained using NBS instead of NIS, similar to the compound described in step 1.1) was dissolved in THF (10 ml). Methanol (40 µl; 0.22 mmol) containing 40 wt% benzyltrimethylammonium hydroxide solution and N,N-dimethylacrylamide (334 µl; 3.24 mmol) were added. The mixture was stirred overnight at 50 °C and evaporated to dryness. The residue was purified by chromatography to give the product (327 mg, 92%) as a colorless resin.

[0244] 27.2: 2-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2-yl)phenoxy] 5-(trifluoromethyl)pyrazine 2-(3-bromo-5-methylphenoxy)-5-(trifluoromethyl)pyrazine (1.49 g; 4.35 mmol), bis(triphenylphosphine)palladium(II) dichloride (96 mg; 0.13 mmol), and KOAc (1.28 g; 13.05 mmol) were suspended in dioxane (30 ml). The vial was then screwed shut, placed under vacuum, sonicated for 1 min, and refilled with argon. This procedure was repeated three times, followed by the addition of bis(pinacolyl)diboron (BPD) (1.24 g; 4.79 mmol) at 100 °C for 3 h. For further treatment, the reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The residue was purified by chromatography to give the product as a colorless oil (1.34 g; 69%).

[0245] 27.3: 4-Chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo [3,2-c]pyridin-1-yl]-N,N-dimethylpropionamide To a stirred solution of 3-{3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl}-N,N-dimethylpropionamide (100 mg; 0.3 mmol) (step 27.1) and 2-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]-5-(trifluoromethyl)pyrazine (126.49 mg; 0.33 mmol) in dioxane (4 ml) (step 27.2), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (21.42 mg; 0.03 mmol) and tripotassium phosphate monohydrate (139 mg; 0.6 mmol) were added. The mixture was stirred at 60 °C under an argon atmosphere for 1 h, then diluted with H2O and extracted twice with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered, and evaporated. The residue was purified by chromatography to give the product as a colorless resin (72 mg; 47%).

[0246] Example 28: 4-(4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3, 2-c]pyridin-1-yl)but-1-amine (Compound No. 153) 28.1: 4-Chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine (Compound No. 5) TFA (557 mg; 4.89 mmol) was added to a solution of 4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-c]pyridine (140 mg; 0.24 mmol) (obtainable by a synthetic method similar to that used to prepare the compound described in step 5.2 above) in DCM (0.5 ml). The mixture was stirred at 25 °C for 2 h and then concentrated under vacuum. MeOH (1 ml) and NH3·H2O (332 mg; 4.89 mmol) were added. The mixture was stirred at 25 °C for 1 h and then concentrated. The residue was purified by chromatography to give the product as a white solid (68 mg; 69%).

[0247] 28.2: 1-{4-[(tert-butyldimethylsilyl)oxy]butyl}-4-chloro-3-{3-methyl-5-[4-(trifluoromethyl) [Phenoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine NaH (in a 60% suspension in paraffin oil, 90.56 mg; 2.26 mmol) was added to a solution of 4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine (800 mg; 1.51 mmol) in DMF (8 ml) at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. Subsequently, (4-bromobutoxy)(tert-butyl)dimethylsilane (807 mg; 3.02 mmol) was added at 0 °C, followed by stirring at 25 °C for 12 h. The reaction mixture was diluted with cooled H2O and extracted with diethyl ether. The combined organic phases were dried over Na2SO4 and concentrated to give a crude product (1.50 g) as a yellow oil, which was used in the next step without further purification.

[0248] 28.3: 4-(4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c] (pyridin-1-yl)but-1-ol At 0 °C, dioxane (10 ml) containing HCl was added dropwise to a solution of 1-{4-[(tert-butyldimethylsilyl)oxy]butyl}-4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c]pyridine (1.45 g; 1.92 mmol) (step 28.2) in dioxane (10 ml). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated, and the brown oily residue was diluted with H2O. The aqueous solution was repeatedly extracted with diethyl ether, and the combined organic phases were washed with a saturated aqueous solution of Na2CO3, dried over Na2SO4, and concentrated to give a crude product (1.50 g) as a yellow oil, which was used in the next step without further purification.

[0249] 28.4: Methanesulfonic acid 4-(4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3, 2-C]pyridin-1-yl)butyl ester TEA (0.52 g; 5.12 mmol) and methanesulfonyl chloride (0.58 g; 5.12 mmol) were added to a solution of 4-(4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c]pyridin-1-yl)but-1-ol (1 g; 1.71 mmol) (step 28.3) in DCM (10 ml) at 0 °C. The mixture was stirred at 25 °C for 1 h and then H2O (100 ml) was added. After extraction with DCM, the combined organic phases were dried over Na2SO4 and concentrated to give a crude product (1.20 g) as a yellow oil, which was used in the next step without further purification.

[0250] 28.5: 4-(4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c] pyridin-1-yl)but-1-amine To a solution of 4-(4-chloro-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H-pyrrolo[3,2-c]pyridin-1-yl)butyl methanesulfonate (350 mg; 0.51 mmol) (step 28.4) and tetrabutylammonium iodide (18.70 mg; 0.05 mmol) in EtOH (3.50 ml), NH3·H2O (3.50 ml) was added. The mixture was stirred at 80 °C under N2 for 16 h. The mixture was quenched with 2 mol / L HCl (5 ml) and neutralized with 28% NH3·H2O (8 ml). The mixture was extracted with EtOAc, the organic layer was washed with H2O, dried over Na2SO4, and concentrated. The residue was purified by chromatography to give the product as a colorless gel (106 mg; 42%).

[0251] Example 29: 3-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H- Pyrrolo[3,2-c]pyridin-1-yl]acrylamide (Compound No. 291) 29.1: 3-{3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl}propionamide 3-Bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine (200 mg; 0.86 mmol) (which may be obtained using NBS instead of NIS, similar to the compound described in step 1.1) was dissolved in dioxane (20 ml). KOH (48 mg; 0.86 mmol) and acrylamide (92 mg; 1.3 mmol) were added at 0 °C, and the mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with H₂O and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The residue was purified by chromatography to give the product (41 mg; 16%) as a pale brown resin.

[0252] 29.2: 3-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrole [3,2-c]pyridin-1-yl]acrylamide Add bis(di-tert-butyl(4-dimethylaminophenyl)phosphine dichloropalladium(II)) (9.6 mg; 0.014 mmol) and an aqueous solution of tripotassium phosphate monohydrate (271 µl; 0.27 mmol) to a stirred solution of 3-{3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl}propionamide (41 mg; 0.14 mmol) (step 29.1) and 2-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenoxy]-5-(trifluoromethyl)pyrazine (57 mg; 0.15 mmol) (step 27.2) in dioxane (3 ml) / H2O (1.5 ml) to a stirred solution. Heat the resulting mixture at 60 °C under an argon atmosphere for 1 minute. h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered, and evaporated. The residue was purified by chromatography to give the product as a pale brown solid (28 mg; 43%).

[0253] Example 30: 30.1: (3R, 4S)-4-{3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl}oxacyclopentane-3- Alcohol & (3S, 4R)-4-{3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl}oxacyclopentan-3-ol ("trans" isomer) (a mixture of substances) Add 3,6-dioxabicyclo[3.1.0]hexane (2.58 g; 28.51 mmol) and Cs₂CO₃ (19.56 g; 57.03 mmol) to a stirred solution of 3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine (4.40 g; 19.01 mmol) in DMF (80 ml). Stir the resulting mixture at 120 °C for 2 h. For further treatment, add H₂O and extract the mixture with EtOAc. Wash the combined organic layers with brine and dry with Na₂SO₄. After filtration, concentrate the filtrate under reduced pressure, and purify the residue by chromatography to give a mixture of the “trans” product as a yellow oil (3.80 g; 31.2%).

[0254] 30.2: (3R,4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)- 1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol &(3S,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(tri- (Fluoromethyl)pyrazin-2-yl]oxyphenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol Pd(dppf)Cl2·CH2Cl2 (170 mg; 0.20 mmol) and Na2CO3 (670 mg; 6.01 mmol) were added to a stirred solution of (3R,4S)- and (3S,4R)-4-{3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl}oxepentan-3-ol (1.25 g; 2 mmol) (step 30.1) and 2-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenoxy]-5-(trifluoromethyl)pyrazine (940 mg; 2.39 mmol) in dioxane (20 ml) / H2O (2 ml). The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 2 h. After conventional aqueous solution treatment, the residue was purified by chromatography to give a mixture of the “trans” products as yellow oil (300 mg; 24%).

[0255] 30.3: (3S,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)- 1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol (Compound No. 282); and (3R,4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrazinyl [3,2-c]pyridin-1-yl]oxacyclopentan-3-ol (Compound No. 281) Isomers (3R,4S)- and (3S,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol (300 mg; 0.49 mmol) (step 30.2) were subjected to chromatography [CHIRALPAK IC-3, 4.6*50 mm, 3 μm; mobile phase A: Hex (0.1% DEA): EtOH = 80:20; flow rate: 1 Purification at [mL / min] yielded (3S,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxepane-3-ol (29.20 mg; 12%) as a white solid and (3R,4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxepane-3-ol (24.2 mg; 10%) as a white solid (absolute configuration is arbitrarily specified).

[0256] 30.4: (4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H- Pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-one &(4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)] [Pyrazin-2-yl]oxyphenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-one Dess-Martin periodane (360 mg; 0.81 mmol) was added to a stirred solution of (3R,4S)- and (3S,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol (400 mg; 0.66 mmol) in DCM (15 ml). The resulting mixture was stirred at room temperature for 6 h. After filtration, the DCM was removed under vacuum, and the residue was purified by chromatography to give a mixture of isomers as a yellow oil (350 mg; 75%).

[0257] 30.5: (3S,4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)- 1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol &(3R,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(tri- (Fluoromethyl)pyrazin-2-yl]oxyphenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol Trisec-butylborohydride (L-selectride) (2.47 ml; 2.47 mmol) was added to a stirred solution of (4S)- and (4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-one (430 mg; 0.6 mmol) (step 30.4) in THF (10 ml) for 2 h. After conventional aqueous treatment, the residue was purified by chromatography to give a mixture of “cis” products (50 mg; 16%) as a white solid.

[0258] 30.6 (3S,4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)- 1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol (Compound No. 284); (3S,4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrazinyl [3,2-c]pyridin-1-yl]oxacyclopentan-3-ol (Compound No. 283) A mixture of isomers (3S,4S)- and (3R,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxacyclopentan-3-ol (50 mg; 0.10 mmol) (step 30.5) was subjected to chromatography [CHIRALPAK IG-3, 4.6*50 mm, 3 μm; mobile phase A: Hex (0.1% DEA): EtOH = 75:25; flow rate: 1] Purification at [mL / min] yielded (3R,4R)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxepane-3-ol (20.50 mg; 41%) as a white solid; and (3S,4S)-4-[4-chloro-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]oxepane-3-ol (19.70 mg; 39%) as a white solid (absolute configuration is arbitrarily specified).

[0259] Example 31: 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(tri- Fluoromethylcyclohexyloxypyrimidine (Compound No. 333) 31.1: 4-Chloro-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrrolo [3,2-c]pyridine-1-carboxylic acid tert-butyl ester Under argon atmosphere at -78 °C, tert-butyl 3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (2 g; 6.03 mmol) was added dropwise to a solution of tert-butyl 3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (5.28 ml; 8.44 mmol) in THF (50 mL). The reaction mixture was stirred at -78 °C for 30 min, followed by slow addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (1.38 ml; 6.63 mmol) dissolved in THF (5 ml). The mixture was stirred at -78 °C for 3 h. The mixture was poured into H2O and extracted twice with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to give the residue. The resulting 2.9 g light brown solid was purified by chromatography to give tert-butyl 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1.7 g; 73%) as a colorless resin.

[0260] 31.2: 4-Chloro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine A sodium hydride suspension (60% suspension in paraffin oil, 173 mg; 4.33 mmol) was added dropwise to a solution of trans-4-(trifluoromethyl)cyclohexanol (500 mg; 2.88 mmol) in THF (20 mL) for 30 min at 0 °C. Then, 4,6-dichloro-2-methylpyrimidine (470 mg; 2.88 mmol) dissolved in THF (5 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h and then overnight at room temperature. The reaction mixture was cooled to 0 °C, and H₂O was added dropwise. After extraction with DCM, the organic phase was dried over sodium sulfate, filtered, and evaporated. The crude product (934 mg; light brown solid) was purified by chromatography to give 4-chloro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (592 mg) as a white solid.

[0261] 31.3: 4-Chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)- 1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester Tetra(triphenylphosphine)palladium(O) (46 mg; 0.04 mmol) was added to a stirred and degassed solution of 4-chloro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (92 mg; 0.31 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (100 mg; 0.26 mmol) and potassium carbonate (180 mg; 1.32 mmol) in dioxane (3 mL) / H2O (1 mL). The resulting mixture was stirred overnight at 60 °C under an argon atmosphere. The reaction mixture was diluted with H2O and extracted twice with DCM. The organic phase was dried over sodium sulfate, filtered, and evaporated. The crude substance (344 mg; brown solid) was purified by chromatography to obtain tert-butyl 4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid (34 mg; 25%) as a colorless resin.

[0262] 31.4: 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl) Cyclohexyloxypyrimidine (Compound No. 333) 4-Chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (40 mg; 0.08 mmol) was dissolved in DCM (10 ml). TFA (60 µL; 0.79 mmol) was added, and the mixture was stirred at room temperature for one weekend. The reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and evaporated. The crude substance (32 mg; white solid) was purified by chromatography to give 4-{4-chloro-1H-pyrrolo[3,2-c]pyrimidin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin (23 mg) as a white solid.

[0263] Example 32: 1-[4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine- 4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]-2-methylprop-2-ol (Compound No. 596) Cesium carbonate (211 mg; 0.65 mmol) and 2,2-dimethyl-ethylene oxide (31 mg; 0.43 mmol) were added to a stirred solution of 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (90 mg; 0.22 mmol) (Examples 31, 31.4) in acetonitrile (3 mL) and incubated overnight. The reaction mixture was concentrated under reduced pressure, and the crude substance was purified by chromatography to give 1-[4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]-2-methylpropane-2-ol (93 mg; 90%) as a colorless solid.

[0264] Example 33: (3S)-3-{[4-chloro-3-(2-methyl-6-{[(1r*,4r*)-4-(trifluoromethyl)cyclohexyl]oxy Pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl]oxacyclopentan-3-ol (Compound No. 531) (3R)-3-{[4-chloro-3-(2-methyl-6-{[(1r*,4r*)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine-4- 1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}oxacyclopentan-3-ol (Compound No. 533) 33.1: Under argon atmosphere and at 110 °C, 3-(hydroxymethyl)oxacyclopentan-3-ol (45 mg; 0.36 mmol) and cyanomethylene-(tributyl)phosphine (266 mg; 1.08 mmol) were added to toluene (3 mL) at 3 mL in 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Examples 31, 31.4) (80 mg; 0.18 mmol) for 16 h. The reactants were diluted with EtOAc and extracted with H2O, dried over Na2SO4 and evaporated to dryness to give the product as a beige solid (35 mg; 38%).

[0265] 33.2: Isomers were separated by SFC: ChiralCell OD-H; CO2: isopropanol 85:15. 29 mg of racemic starting material (33.1) yielded the first isomer (compound number 531) (Rt: 9.21 min; 12 mg; 40%) and the second isomer (compound number 533) (Rt: 11.18 min; 13 mg; 43%), both as white solids.

[0266] Example 34: rel-4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-(methylthio)-6- {[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 643) 34.1:rel-4-chloro-2-(methylthio)-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine A sodium hydride suspension (60% suspension in paraffin oil; 308 mg; 7.69 mmol) was added to a solution of trans-4-(trifluoromethyl)cyclohexanol (889 mg; 5.13 mmol) in THF (100 mL) for 30 min at room temperature. Subsequently, 4,6-dichloro-2-(methylthio)pyrimidine (1 g; 5.13 mmol) was added for 16 h at room temperature. The reactants were diluted with EtOAc and extracted with H2O, dried over Na2SO4, and evaporated to dryness. The residue was purified by chromatography to give rel-4-chloro-2-(methylthio)-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (1.3 g; 69%) as a pale yellow solid.

[0267] 34.2: rel-4-chloro-3-[2-(methylthio)-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine [Pyridine-4-yl]-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester Under argon atmosphere at 60 °C, rel-4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (31.1) (400 mg; 1.05 mmol) in a solution of dioxane (10 mL) / H₂O (1 mL) was added to pyrimidine (34.1) (463 mg; 1.26 mmol), sodium carbonate (558 mg; 5.27 mmol), and tetra(triphenylphosphine)palladium (0) (243 mg; 0.21 mmol) for 16 h. The reactants were drawn through diatomaceous earth and evaporated to dryness. The residue was purified by chromatography to give rel-4-chloro-3-[2-(methylthio)-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl]-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (173 mg; 26%) as a yellow solid.

[0268] 34.3: rel-4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-(methylthio)-6-{[(1r, 4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 643) TFA (2 mL) was added to a solution of rel-4-chloro-3-[2-(methylthio)-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl]-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (34.2) (173 mg; 0.27 mmol) in DCM (5 mL) for 16 h. The reactants were evaporated to dryness and the residue was purified by chromatography to give rel-4-{4-chloro-1H-pyrrolo[3,2-c]pyrimidin-3-yl}-2-(methylthio)-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin (112 mg; 92%) as a pale yellow solid.

[0269] Example 35: 4-{[3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-(tri... Fluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}-1H-imidazolium (Compound No. 457) 35.1: 1-Bromo-3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}benzene NaH (0.40 g; 9.98 mmol) was added to a stirred solution of (1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (1.61 g; 9.07 mmol) in DMA (40 mL) at 0 °C for 20 min. Then, 1-bromo-3-chloro-5-fluorobenzene (2 g; 9.07 mmol) was added, and the mixture was stirred at 60 °C for 3 h. The mixture was extracted with EtOAc, and the organic layer was washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give 1-bromo-3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}benzene (2.60 g; 76%) as a clear, colorless oil.

[0270] 35.2: 3-Iodo-1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine NaH (1.38 g; 34.61 mmol) was added fractionally to a solution of 3-iodo-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (Examples 3, 3.5) (10 g; 28.84 mmol) cooled to 0°C in THF (100 mL) under N2. The mixture was stirred at 25°C for 0.5 h. 4-Methylbenzene-1-sulfonyl chloride (6.60 g; 34.61 mmol) was added continuously for 12 h. The reaction mixture was poured into cooled H2O, and the precipitate was collected by filtration. The filter cake was washed with H2O to give the desired compound (15 g, 97%) as a yellow solid, which was used in the next step without further purification.

[0271] 35.3: 1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane-2- 4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine A solution of 3-iodo-1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (2 g; 4.29 mmol), TEA (11.89 ml), and tetra(triphenylphosphine)palladium(0) (496 mg; 0.43 mmol) in dioxane (100 mL) was added for 4 hours at 100 °C. The reaction mixture was aspirated with diatomaceous earth and washed with EtOAc. The solution was evaporated and the residue was purified by chromatography to give the product (1.74 g; 85%) as a brown resin.

[0272] 35.4: 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-1-(4-methylbenzenesulfonate) Acyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine Pd(PPh3)4 (130 mg; 0.11 mmol) and Na2CO3 (235 mg; 2.11 mmol) were added to a stirred mixture of 1-bromo-3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}benzene (400 mg; 1.05 mmol) and 1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (600 mg; 1.10 mmol) in dioxane (10 mL) / H2O (2 mL) for 3 h at 90 °C under a N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was purified by chromatography to give 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (700 mg; 70%) as a yellow solid.

[0273] 35.5: 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-(trifluoromethyl)- 1H-pyrrolo[3,2-c]pyridine EtONa / EtOH (w / w 21%; 409 mg; 1.26 mmol) was added to a stirred mixture of 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-1-(4-methylbenzenesulfonyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (600 mg; 0.63 mmol) in EtOH (10 mL) for 1 h. The mixture was extracted with DCM, and the combined organic layers were washed with brine and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to obtain 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (300 mg; 91%) as a yellow solid.

[0274] 35.6: 4-{[3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-(trifluoromethyl) 1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}-1H-imidazolium (Compound No. 457) NaH (38 mg; 0.95 mmol) was added to a stirred solution of 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridine (100 mg; 0.19 mmol) in 10 mL of DMF at 0 °C for 30 min. Subsequently, 4-(chloromethyl)-1H-imidazolium hydrochloride (62 mg; 0.38 mmol) was added at room temperature for 5 h. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the crude substance was purified by chromatography to obtain 4-{[3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}-1H-imidazole (25 mg; 24%) as a white solid.

[0275] Example 36: 3-{[4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Pinidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}oxetane-3-ol (Compound No. 507) 36.1: Cesium carbonate (2 g; 6.14 mmol) was added to a stirred solution of 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Examples 31, 31.4) (850 mg; 2.05 mmol) in ACN (40 mL). 1,5-dioxaspiro[2.3]hexane (223 mg; 2.47 mmol) dissolved in ACN (2 mL) was added dropwise to this mixture at 0 °C. The resulting mixture was stirred overnight at room temperature and subsequently diluted with H2O and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography to give 3-{[4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}oxetane-3-ol (400 mg) as a brown solid.

[0276] Example 37: (5S)-5-{[3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Pyridine-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}-1,3-oxazolidine-2-one (compound) No. 465) 37.1: 4-Methylbenzene-1-sulfonic acid [(5S)-2-oxo-1,3-oxazolidine-5-yl]methyl 4-methyl ester TsCl (194 mg; 0.97 mmol) and DMAP (21 mg; 0.16 mmol) were added to a stirred solution of (5S)-5-(hydroxymethyl)-1,3-oxazolidin-2-one (100 mg; 0.81 mmol) and TEA (0.35 mL; 2.42 mmol) in DCM (10 mL) for 1 h at room temperature. After treatment with aqueous solution, the residue was purified by chromatography to give methyl 4-methylbenzene-1-sulfonic acid [(5S)-2-oxo-1,3-oxazolidin-5-yl] ester (200 mg; 86%) as a yellow oil.

[0277] 37.2: (5S)-5-{[3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine-4- )-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}-1,3-oxazolidin-2-one (Compound No.). 465) K₂CO₃ (93 mg; 0.64 mmol) was added to a stirred solution of 4-methylbenzene-1-sulfonic acid [(5S)-2-oxo-1,3-oxazolidine-5-yl]methyl ester (61 mg; 0.21 mmol) and 2-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-[4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]pyrimidine (Examples 25, 25.2) (100 mg; 0.21 mmol) in DMF (5 mL) for 2 h. After treatment with aqueous solution, the crude substance was purified by chromatography to obtain (5S)-5-{[3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-4-(trifluoromethyl)-1H-pyrrolo[3,2-c]pyridin-1-yl]methyl}-1,3-oxazolidin-2-one (37 mg; 32%) as a white solid.

[0278] Example 38: rel-3-[4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyr (Pyridine-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]-1λ6-thionecyclobutane-1,1-dione 38.1: 4-Iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine NaH (330 mg; 8.25 mmol) was added to a stirred solution of (1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (730 mg; 4.12 mmol) in DMF (50 mL) at 0 °C for 30 min. Subsequently, 2-fluoro-4-iodo-6-methylpyridine (1 g; 4.13 mmol) was added at 80 °C for 2 h. After aqueous treatment, the mixture was extracted with EtOAc, the combined organic layers were washed with brine, and dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give 4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (1.04 g; 46%) as a yellow oil.

[0279] 38.2: rel-4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine-4- tert-butyl 1-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid Tetra(triphenylphosphine)palladium(O) (387 mg; 0.33 mmol) was added overnight to a stirred solution of rel-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (1.5 g; 3.31 mmol) and 4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (Examples 31, 31.1) (1.40 g; 3.31 mmol) in dioxane (75 mL) / H2O (7.5 mL) and cesium carbonate (2.18 g; 6.62 mmol). After aqueous treatment, the mixture was concentrated under vacuum and partitioned between EtOAc and concentrated NaHCO3 solution. The aqueous layer was extracted with EtOAc, and the combined organic layer was extracted with brine. After drying with Na2SO4, the mixture was filtered, concentrated under vacuum, and purified by chromatography to obtain rel-4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.15 g; 64%) as a yellow powder.

[0280] 38.3: rel-4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(tri- Fluoromethyl)cyclohexyl]oxypyridine 1.15 g; 2.12 mmol of rel-4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester was dissolved in DCM (230 ml). TFA (33 ml; 42.39 mmol) was added at room temperature for 4 h. The reaction mixture was concentrated, and the residue was partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The aqueous layer was then extracted with EtOAc, the combined organic matter was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by chromatography to give rel-4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (726 mg; 75%) as a white solid.

[0281] 38.4: rel-3-[4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine- 4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]-1λ6-thione-1,1-dione (Compound No. 697) rel-4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (50 mg; 0.11 mmol) was dissolved in THF (1 ml) and a sodium hydride suspension (60% suspension in paraffin oil; 13 mg; 0.33 mmol) and 3-bromothionecyclobutane-1,1-dioxide (42 mg; 0.22 mmol) were added at 0 °C for 1 h. The reaction mixture was concentrated under vacuum and partitioned between EtOAc and H2O. The aqueous layer was then extracted with EtOAc, and the combined organic layers were extracted with brine, dried over Na2SO4, filtered, and concentrated. The crude substance was purified by chromatography to obtain rel-3-[4-chloro-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl]-1λ@6-thionecyclobutane-1,1-dione (42 mg; 73%) as a white powder.

[0282] Example 39: 4-[4-chloro-1-(pyrazin-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6- {[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 511) 4-{4-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl}-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Examples 31, 31.4) (50 mg; 0.12 mmol) was dissolved in dioxane (3 ml) and CuI (2.32 mg; 0.01 mmol), and N,N'-dimethylethylenediamine (3.27 µL; 0.03 mmol), potassium carbonate (100 mg; 0.73 mmol), and 2-iodopyrazine (51 mg; 0.24 mmol) were added overnight at 100 °C. The reaction mixture was then diluted with H₂O and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography to give 4-[4-chloro-1-(pyrazin-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (22 mg; 37%) as colorless crystals.

[0283] Example 40: rel-4-[4-(fluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6- {[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 672) 40.1: 2-Methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-(trimethyltinyl)pyrimidine pyridine A solution of 4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (620 mg; 1.59 mmol), hexamethyldistannane (0.50 mL; 2.39 mmol), and Pd(PPh3)4 (193 mg; 0.16 mmol) in dioxane (15 mL) was stirred at 100 °C for 1 h. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give 2-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-(trimethylstannyl)pyrimidine (1.15 g; 65%) as a yellow oil.

[0284] 40.2: 4-Vinyl-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine A mixture of 4-chloro-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (1 g; 2.93 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxabortane (950 mg; 5.86 mmol), Pd(dppf)Cl2·CH2Cl2 (242 mg; 0.29 mmol), and potassium carbonate (817 mg; 5.86 mmol) in dioxane (16 mL) / H2O (4 mL) was stirred at 90 °C for 2 h. The mixture was then concentrated under reduced pressure, and the residue was purified by chromatography to give 4-vinyl-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (850 mg; 93%) as a yellow solid.

[0285] 40.3: 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine-4-carboxaldehyde A solution of NaIO4 (1.79 g; 7.96 mmol) in H2O (5.50 mL) and potassium osmium tetroxide dihydrate (VI) (74 mg; 0.19 mmol) was added to a stirred solution of 4-vinyl-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (500 mg; 1.59 mmol) in THF (27 mL) and incubated overnight at 0 °C. The reaction mixture was quenched by adding 10% Na2SO3 (35 mL) at 0 °C, and the mixture was extracted with DCM. 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 give 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine-4-carboxaldehyde (220 mg; 43%) as a grayish-white solid.

[0286] 40.4: [1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]methanol NaBH4 (706 mg; 16.80 mmol) was added fractionally to a stirred solution of 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-carboxaldehyde (1.80 g; 5.60 mmol) in MeOH (22 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by adding saturated NaHCO3 at 0 °C. The mixture 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 give [1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]methanol (1.50 g; 87%) as a white solid.

[0287] 40.5: 4-(fluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine DAST (0.14 ml; 1.28 mmol) was added dropwise to a stirred solution of [1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]methanol (300 mg; 0.98 mmol) in DCM (10 mL) at 0 °C, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHCO3 solution, and the aqueous phase was extracted with DCM. The combined organic layers were dried over Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give 4-(fluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (130 mg; 43%) as a beige solid.

[0288] 40.6: 4-(fluoromethyl)-1H-pyrrolo[3,2-c]pyridine EtONa / EtOH (w / w 21%; 0.77 mL; 3.58 mmol) was added dropwise to a stirred solution of 4-(fluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (550 mg; 1.79 mmol) in 10 mL of EtOH at 0 °C. The resulting mixture was stirred at room temperature for 2 h and then diluted with H2O. The mixture was extracted with EtOAc, and the combined organic layers were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 4-(fluoromethyl)-1H-pyrrolo[3,2-c]pyridine (270 mg; 83%) as a pale yellow oil.

[0289] 40.7: 4-(fluoromethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine NIS (498 mg; 2.10 mmol) was added fractionally to a stirred solution of 4-(fluoromethyl)-1H-pyrrolo[3,2-c]pyridine (255 mg; 1.40 mmol) in DMF (5 mL) for 2 h at room temperature. The reactants were diluted with H2O, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give 4-(fluoromethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (300 mg; 74%) as a pale yellow oil.

[0290] 40.8: 4-(fluoromethyl)-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine TsCl (296 mg; 1.47 mmol) was added fractionally to a stirred solution of 4-(fluoromethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine (285 mg; 0.98 mmol) and TEA (0.43 mL; 2.94 mmol) in DCM (10 mL) for 2 h at room temperature. The reactants were diluted with saturated NaHCO3 solution, and the resulting mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give 4-(fluoromethyl)-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (400 mg; 87%) as a pale yellow oil.

[0291] 40.9: 4-[4-(fluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2- Methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine Pd(PPh3)4 (98 mg; 0.08 mmol) and CuI (161 mg; 0.80 mmol) were added to a stirred solution of 2-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-(trimethyltinyl)pyrimidine (1.07 g; 0.96 mmol) and 4-(fluoromethyl)-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (375 mg; 0.80 mmol) in DMF (1 mL). The resulting mixture was stirred at 100 °C for 3 h. For further treatment, the mixture was diluted with H2O and extracted with EtOAc. 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 obtain 4-[4-(fluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (220 mg; 48%) as a pale yellow oil.

[0292] 40.10.: rel-4-[4-(fluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r, 4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 672) EtONa / EtOH (w / w 21%; 0.15 ml; 0.71 mmol) was added dropwise to a stirred solution of rel-4-[4-(fluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (200 mg; 0.35 mmol) in EtOH (4 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. For treatment, the reactants were diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The crude substance was purified by chromatography to give rel-4-[4-(fluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (33 mg; 23%) as a white solid.

[0293] Example 41: 4-[4-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r, 4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Compound No. 662) 41.1: 4-(difluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine DAST (diethylaminotrifluoride) (0.22 ml; 2.02 mmol) was added dropwise to a stirred solution of 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine-4-carboxaldehyde (Examples 40, 40.3) (500 mg; 1.52 mmol) in DCM (15 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was quenched by adding saturated NaHCO3 solution at 0 °C. The mixture was extracted with DCM, and the combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give 4-(difluoromethoxy)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (430 mg; 87%) as a grayish-white solid.

[0294] 41.2: 4-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridine EtONa / EtOH (w / w 21%; 0.54 mL; 2.52 mmol) was added dropwise to a stirred solution of 4-(difluoromethoxy)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (410 mg; 1.26 mmol) in EtOH (6 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. For treatment, the reactants were diluted with H2O and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give 4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine (220 mg; 88%) as a pale yellow solid.

[0295] 41.3: 4-(difluoromethyl)-3-iodo-1H-pyrrolo[3,2-c]pyridine NIS (359 mg; 1.52 mmol) was added fractionally to a stirred solution of 4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridine (200 mg; 1.01 mmol) in DMF (5 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. For treatment, the reactants were diluted with H₂O and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give 4-(difluoromethoxy)-3-iodo-1H-pyrrolo[3,2-c]pyridine (290 mg; 96%) as a beige solid.

[0296] 41.4: 4-(difluoromethyl)-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine TsCl (232 mg; 1.16 mmol) was added fractionally to a stirred solution of 4-(difluoromethoxy)-3-iodo-1H-pyrrolo[3,2-c]pyridine (270 mg; 0.90 mmol) and TEA (0.33 ml; 2.25 mmol) in DCM (8 mL) at 0 °C. The resulting mixture was stirred at room temperature for 2 h and then diluted with saturated NaHCO3 solution. The resulting mixture was extracted with DCM, 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 give 4-(difluoromethoxy)-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (300 mg; 73%) as a grayish-white solid.

[0297] 41.5: 4-[4-(difluoromethyl)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]- 2-Methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine Pd(PPh3)4 (69 mg; 0.06 mmol) was added to a stirred solution of 4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (360 mg; 0.89 mmol) and hexamethyldistannane (244 mg; 0.74 mmol) in dioxane (9 mL), followed by addition at 100 °C for 2 h. The resulting mixture was filtered through diatomaceous earth, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to give the intermediate rel-2-methyl-4-(((1r,4r)-4-(trifluoromethyl)cyclohexyl)oxy)-6-(trimethylstannyl)pyrimidine, which was used directly in the next step without further purification. Pd(PPh3)4 (69 mg; 0.06 mmol) and CuI (114 mg; 0.57 mmol) were added to a stirred solution of the intermediate and 4-(difluoromethoxy)-3-iodo-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridine (260 mg; 0.57 mmol) in DMF (6 mL), followed by addition at 100 °C for 3 h. The reactants were diluted with H2O, and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give 4-[4-(difluoromethoxy)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (130 mg; 39%) as a pale yellow oil.

[0298] 41.6: 4-[4-(difluoromethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)- 4-(trifluoromethyl)cyclohexyl]oxypyrimidine (Compound No. 662) EtONa / EtOH (w / w 21%; 0.09 ml; 0.43 mmol) was added dropwise to a stirred solution of 4-[4-(difluoromethoxy)-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (125 mg; 0.21 mmol) in EtOH (4 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h and then diluted with H2O. After extraction with EtOAc, the combined organic layers were dried over Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The crude substance was purified by chromatography to give 4-[4-(difluoromethoxy)-1H-pyrrolo[3,2-c]pyridin-3-yl]-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (21 mg; 23%) as a white solid.

[0299] Table 1 and Table 1A Tables 1 and 1A below show exemplary compounds of the present invention. They have been synthesized as described in or similarly described in the examples above.

[0300] Table 1 and Table 1A Note: Unless otherwise specified for a particular compound and its structure (e.g., by assigning “absolute” to the structure), any absolute configuration described for the structures of the compounds in Table 1 below may be arbitrarily assigned.

[0301] LCMS methods / conditions (as shown in Table 1):AA: H2O + 0.1% TFA | B: MeCN + 0.1% TFA T: 40℃ | Flow rate: 3.3 ml / min | MS: 85-800 μm Positive ion column: Chromolith SpeedRod RP-18e 5.0 µm 50-4.6 mm 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min) Agilent HPH 50 mm x 3.0 mm; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10) Mobile phase B: Acetonitrile Chromolith HR C18 5.0 µm 50-4.6 mm; A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH; 1% -> 99% B: 0 ->1,0 min | 99% B: 1,0 ->1,3 min; DAD: 220nmD Chromolith HR C18 5,0 ìm 50-4,6 mm; A: H2O + 0,1% TFA | ->2,5 min; T: 40℃ | Flow rate: 3,3ml / min | MS: 61-1000 amu positive ion; DAD: 220 nmE Chromolith HR RP-18e 50-4,6 mm; A: H2O + 0,05% HCOOH | B: MeCN + 0,04% HCOOH + 1% H2O; 1% ->99% B: 0 ->2,0 min | 99% B: 2.0 -> 2.5 min; DAD: 220nmF Chromolith® HR RP-18 5.0µm 50-4.6mm; A: H2O + 0.1% TFA; B: MeCN + 0.1% TFA; 1%->99% B: 0->2.0 min; 99% B: 2.0->2.5 min; T: 40℃; Flow rate: 3.3 ml / min; MS: 85-1000 amu; Positive ion G column: HALO C18, 2.0 µm, 3.0 x 30 mm; Mobile phase A: H2O / 0.05% TFA; Mobile phase B: Acetonitrile / 0.05% TFA; H column: Shim-Pack C18, 3 μm, 3.0 x 33 mm; Solvent A: H2O / 5mM NH4HCO3; Solvent B: Acetonitrile; Column: Waters XBridge C18 3.5µm, 50*4.6mm; LCMS28, 100-1000; Mobile phase A: 0.02% NH4OAc / H2O (NH4Oac in H2O); Mobile phase B: Acetonitrile; Gradient: 5-95% within 3.0 min; Column: XBridge C8, 3.5 µm, 4.6 x 50 mm; LCMS11: Flow rate: 2.0 ml / min; Analysis time: 3.0 min; MS scan range: 61-800; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.1 min: 5% B, 1.5 min: 95% B, 2.5 min: 95% B, 2.6 min: 5% B, 3.0 min: 5% B; K column: XBridge C8, 3.5 µm, 4.6 x 50 mm; Solvent A: H2O + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow rate: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B; BL column: HALO C18, 3.0*30 mm, 2.0 µm particles; Column oven: 40°C; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; M column: HALO C18 column, 3.0*30mm, 2.0 μm particles; Column oven: 40°C; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.5 ml / min; Gradient: 5% B to 95% B in 1-2 min, hold for 0-6 min; PDA: 254 nm; N column: HALO C18, 3.0*30mm, 2.0 μm particles; Column oven: 40°C; Mobile phase A: H2O / 6.5 mMNH4HCO3 + ammonia (pH=10), Mobile phase B: acetonitrile; O column: HALO C18, 3.0*30mm, 2.0 μm particles; Column oven: 40°C; Mobile phase A: H2O / 0.1% FA, Mobile phase B: acetonitrile / 0.1% FA; 254nm P column: Halo C18, 100 mm, 4.6 mm; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.0.05% TFAQ column: HALO C18, 3.0*30mm, 2.0um; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFAR column: HALO, 3.0*30mm, 2um; Column oven: 40°C; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; S column: HALO, 3.0*30mm, 2um; Column oven: 40°C; Mobile phase A: H2O / 5 mM NH4HCO3; Mobile phase B: Acetonitrile; Flow rate: 1.2 ml / min; Gradient: 10% B to 100% B within 1.2 min, hold for 0.6 min; 254nm T column: HALO, 3.0*30mm, 2um; Column oven: 40°C; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2 ml / min; Gradient: 5% B to 100% B within 1.2 min, hold for 0.6 min; 254 nm U column: HALO, 3.0*30 mm, 2 μm; Column oven: 40°C; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; W column: Poroshell HPH C18, 3.0*50 mm, 2.7 μm; Column oven: 40°C; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10), Mobile phase B: Acetonitrile; X column: Poroshell HPH C18, 3.0*50 mm, 2.7 μm; Column oven: 40°C; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10), Mobile phase B: Acetonitrile; Y column: Poroshell HPH C18, 3.0*50 mm, 2.7 μm; Column oven: 40°C; Flow rate: 1.2 ml / min; Gradient: 10% B to 95% B in 1.8 min, hold for 0.9 min; 254 nm Z HALO C18, 30 mm, 3.0 mm, 2 μm particles; Solvent A: H2O + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow rate: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B. 8.5 min: 5% B, 10 min 5% B.AA HALO C18; 30 mm, 3.0 mm; Mobile phase A: H2O / O.1% FA; Mobile phase B: Acetonitrile / 0.1% FABB HALO C18; Mobile phase A: H2O / 0.1% FA; Mobile phase B: Acetonitrile / 0.1% FACC HALO, 3.0*30mm, 2um; Column oven: 40°C; Mobile phase A: 6.5mM NH4HCO3+NH4OH (pH=10), Mobile phase B: Acetonitrile; Flow rate: 1.2 ml / min; Gradient: 10% B to 95% B within 1.9 min, hold for 0.8 min; 254nm DD HALO, 3.0*30mm, 2um; Column oven: 40°C; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2 ml / min; Gradient: 5% B to 100% B within 1.2 min, hold for 0.6 min; 254nm FF HALO, 3.0*30mm, 2µm; Column oven: 40°C; Mobile phase A: H2O / 5mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.2 ml / min; Gradient: 10% B to 95% B in 2.1 min, hold for 0.6 min; 254nm GG HPLC_MS 24; Column: Waters XBridge C18 3.5µm, 50*4.6mm; 10-95%: Analysis time: 6.5 min; Mobile phase A: 0.02 NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; HH HPLC_MS 24; Column: H2Os XBridge C18 3.5um, 50*4.6mm; 5-95%; Analysis time: 6.5 min; Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; II HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 5-95% B within 3.0 min; HPLC_MS 3; Column 1: Waters XBridge C18 5um, 50*4.6mm; 10-95%; Analysis time: 6.5 min; Mobile phase A: 0.02 NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; KK HPLC_MS 3; Column 1: Waters XBridge C18 5um, 50*4.6mm; 5-95%: Analysis time: 6.5 min; Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; LL Kinetex EVO C18 5,0µm 50-4.6mm; A: H2O+0.1% TFA B: MeCN+0.1% TFA ;1%->99% B: 0->1.8 min ; 99% B: 1.8->2.1 min ; T: 40℃ ; Flow rate: 3.3 ml / min ;MM Kinetex EVO C18 5,0µm 50-4.6mm; A: H2O+0.1% TFA B: MeCN+0.1% TFA ;1%->99% B: 0->1.8 min ; 99% B: 1.8->2.1 min ; T: 40℃; Flow rate: 3.3 ml / min ;NN Kinetex EVO-C18 1,7µm 50-2.1mm; A: H2O+0.05% HCOOH B: MeCN + 0.04% HCOOH; T: 40℃; Flow rate: 0.9 ml / min; 1% -> 99% B: 0 -> 1.0 min; 99% B: 1.0 -> 1.3 min. Kinetex EVO-C18 1.7µm 50-2.1mm; A: H2O + 0.05% HCOOH; B: MeCN + 0.04% HCOOH; T: 40℃; Flow rate: 0.9 ml / min; 1% -> 99% B: 0 -> 1.0 min; 99% B: 1.0 -> 1.3 min. / (Kinetex UPLC)PP LC-MS Agilent 1200 Series Chromolith RP-18e 50-4.6mm; 3.3 ml / min Solvent A: H2O + 0.05% HCOOH Solvent B: Acetonitrile + 0.0.04% HCOOH 220 nm 0 to 2.0 min: 1% B to 99% B 2.0 to 2.5 min: 99% QQ LC-MS Agilent 1200 Series Chromolith RP-18e 50-4.6 mm; 3.3 ml / min Solvent A: H2O + 0.05% HCOOH Solvent B: Acetonitrile + 0.04% HCOOH 220 nm 0 to 2.0 min: 0% B to 100% B 2.0 to 2.5 min: 100% BRR LC-MS Agilent 1200 Series Chromolith RP-18e 50-4.6 mm; 3.3 ml / min Solvent A: H2O + 0.05% HCOOH Solvent B: Acetonitrile + 0.04% HCOOH 220 nm 0 to 2.0 min: 0% B to 100% B; 2.0 to 2.5 min: 100% BSS; LCMS basic; Column: Waters Xbridge C18, 3.5 μm, 3.0*30 mm; 0-98%; Flow rate: 1.5 ml / min; Analysis time: 1.8 min; MS scan range: 61-800; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.1 min: 5% B, 1.55 min: 98% B, 1.56 min: 5% B, 1.8 min: 5% B; TT LCMS basic; Column: Waters Xbridge C18, 3.5 μm, 3.0*30 mm; 10-95%; Flow rate: 1.5 ml / min; Analysis time: 6.5 min; MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; UU LCMS basic; Column: Waters Xbridge C18, 3.5 μm, 3.0*30 mm; LCMS 5-95%: Flow rate: 1.5 ml / min; Analysis time: 2.5 min; MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.1 min: 5% B, 1.0 min: 95% B, 2 ...1 min: 95% B, 2.2 min: 5% B, 2.5 min: 5% B; VV LCMS-14; Chromolith HR RP-18e 50-4, 6 mm.; LCMS14: 0-100%; Flow rate: 3.3 ml / min; Analysis time: 2.5 min; MS scan range: 61-800; Mobile phase A: 0.05% HCOOH / H2O; Mobile phase B: 0.04% HCOOH and 1% H2O / acetonitrile; Gradient: 0 min: 0% B, 2.0 min: 100% B, 2.5 min: 100% B; WW LCMS-20; basic; Column: Waters Xbridge C18, 3.5 μm, 3.0*30 mm; LCMS20; 30-98%; Flow rate: 2.0 ml / min; Analysis time: 2.5 min; MS scan range: 100-1500; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.1 min; 30% B, 1.0 min; 98% B, 2.0 min; 98% B; XX LCMS-20; basic; Column: Waters Xbridge C18, 3.5um, 3.0*30mm; LCMS20: 0-100%: Flow rate: 2.0 ml / min; Analysis time: 3.0 min; MS scan range: 61-800; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.1 min; 5% B, 1.5 min; 95% B, 2.5 min; 95% B, 2.6 min: 5% B, 3.0 min: 5% B; YY QC: Column: Agilent EC-C18; column size: 4.6*50mm, 4.0um; NHA: 40-85%; flow rate: 1.5 ml / min; analysis time: 6.5 min; MS scan range: 100-1000; mobile phase A: 0.02NH4OAc / H2O; mobile phase B: acetonitrile. ZZ QC: Column: Agilent EC-C18; column size: 4.6*50mm, 4.0um; NHA: 5-95%; flow rate: 1.5 ml / min; analysis time: 6.5 min; MS scan range: 100-1000; mobile phase A: 0.02 NH4OAc / H2O; mobile phase B: acetonitrile.AAA QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; 10-95%: Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; BBB QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; 10-95%: Mobile phase A: 0.02 NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B B, 6.1 min: 5% B, 6.5 min: 5% B; CCC QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; LCMS20; 30-98%; Flow rate: 2.0 ml / min; Analysis time: 2.5 min; MS scan range: 100-1500; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient; 0.1 min; 30% B, 1.0 min; 98% B, 2.0 min; 98% B; DDD QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; LCMS20; 5-98%; Flow rate: 2.0 ml / min; Analysis time: 2.5 min; MS scan range: 100-1500; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.1 min; 5% B, 1.0 min; 98% B, 2.0 min; 98% B; EEE QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; LCMS28, 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 5-95% FFF within 3.0 min; QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; NH4AC; MS scan range: 100-1000; Mobile phase A: 0.0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 5-95% within 3.0 min; QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; NHA: 5-95%; Flow rate: 1.5 ml / min; Analysis time: 6.5 min; MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; TFA; MS scan range: 100-1000; Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile; Gradient: 5-95% within 3.0 min; III QC: HPLC_MS 24; Column: Waters XBridge C18 3.5um, 50*4.6mm; TFA: 20-70%; Flow rate: 1.5 ml / min; Analysis time: 6.5 min; MS scan range: 100-1000; Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile. QC: HPLC_MS 3; Column 1: Waters XBridge C18 5um, 50*4.6mm; 10-95%; Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; KKK QC: HPLC_MS 3; Column 1: Waters XBridge C18 5um, 50*4.6mm; 10-95%; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; LC-MS11: Flow rate: 2.0 ml / min; Analysis time: 3.0 min; MS scan range: 61-800; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.1 min: 5% B, 1.5 min: 95% B, 2.5 min: 95% B, 2.6 min: 5% B, 3.0 min: 5% B; MMM QC: HPLC_MS 3; Column 1: Waters XBridge C18 5um, 50*4.6mm; NH4AC, MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 5-95% B within 3.0 min. MMM QC: HPLC_MS 3; Column 1: Waters XBridge C18 5um, 50*4.6mm; TFA, MS scan range: 100-1000; Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile; Gradient: 5-95% B within 3.0 min. MMM QC: HPLC_MS 5; Column 1: Waters XBridge C18 5µm, 50*4.6mm; NH4AC, MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 5-95% PPP within 3.0 min. Shim-Pack C18, 3µm, 3.0 mm x 33 mm; Solvent A: H2O + 0.1% FA; Solvent B: ACN + 0.1% FAQQQ Waters XBridge C18 5µm, 50*4.6mm; 10-80%; Flow rate: 1.5 ml / min; Analysis time: 6.5 min; MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 80% B, 4.6 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; RRR Waters XBridge C18 5um, 50*4.6mm; 10-95%: Flow rate: 1.5 ml / min; Analysis time: 6.5 min; MS scan range: 100-1000; Mobile phase A: 0.02 NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; SSS Waters XBridge C18 5um, 50*4.6mm; 10-95%: Flow rate: 1.5 ml / min; Analysis time: 6.5 min; MS scan range: 100-1000; Mobile phase A: 0.02 NH4OAc / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; SSS Waters XBridge C18 5um, 50*4.6mm; 10-95%: Flow rate: 1.5 ml / min;5 ml / min; Analysis time: 6.5 min; MS scan range: 100-1000; Mobile phase A: 0.1% TFA / H2O; Mobile phase B: Acetonitrile; Gradient: 0.15 min: 10% B, 4.5 min: 95% B, 6.0 min: 95% B, 6.1 min: 5% B, 6.5 min: 5% B; TTT column: PC18, 2.0 µm, 3.0 x 30 mm; Mobile phase A: H2O / 0.1% FA; Mobile phase B: Acetonitrile / 0.1% FAUUU Kinetex EV O-C 18 1,7 µm 5 0-2,1 mm; A: H2O + 0,1% TFA | B: MeCN + 0,1% TFA; 1% -> 99% B: 0 ->1.8 min | 99% B: 1.8 ->2.1 min; T: 40℃ | Flow rate: 3.3 ml / min | MS: 61-1000 amu positive ions; DAD: 220 nm VVV HALO 90A C18, 3.0*30mm, 2.0um; Column temperature: 40℃; Mobile phase A: H2O / 0.1%FA; Mobile phase B: Acetonitrile / 0.1%FA; 254nm WWW HALO C18, 3.0*30mm, 2um; Column temperature: 40℃; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2 ml / min; Gradient: 5% B to 100% B within 1.2 min, hold for 0.6 min; 254nm XXX column: HALO; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: 5% B to 100% B over 0.7 min, hold for 0.4 min; 254 nm YYY column: Poroshell HPH C18, 3.0*50 mm, 2.7 μm; Column oven: 40°C; Mobile phase A: H2O / 5 mM NH4HCO3; Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 100% B over 1.2 min, hold for 0.4 min.6 min; 254nm ZZZ Chromolith HR C18 5.0 μm 50-4.6 mm; A: H2O + 0.1% TFA | B: MeCN +0.1% TFA; 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min; T: 40℃ | Flow rate: 3.3 ml / min | MS: 61-1000 amu positive ions; DAD: 220 nm AAAA Column: Poroshell HPH C18, 3.0*50 mm, 2.7 μm; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10) Mobile phase B: Acetonitrile BBBB Column HALO 90A C 18, 2 μm, 3.0 mm x 30 mm; Solvent A: H2O + 0.1% FA; Solvent B: ACN + 0.1% FACCCC; Column: Poroshell HPH C18, 3.0*50 mm, 2.7µm; Column oven: 40°C; Mobile phase A: 6.5mM NH4HCO3+NH4OH (pH=10), Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B within 1.8 min, hold for 0.9 min; 254nm HALO C18, 3.0*30 mm, 2µm; Column oven: 40°C; Mobile phase A: H2O / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: 5% B to 100% B within 1.2 min, hold for 0.6 min; 254nm Column: Poroshell HPH-C18; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10); Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B in 1.0 min, hold for 0.7 min; 254 nm.

[0302] LCMS Method / Conditions (as given in Table 1A): LCMS Method 0 (D1): UPLC; Kinetex EV O-C 18 1.7 µm 50-2.1 mm; (D1)UPLC: Kinetex (HCOOH); A: H2O+0.05% HCOOH; B: CH3CN + 0.04% HCOOH + 1% water; T: 40℃; Flow rate: 0.9 ml / min; 1% --> 99% B; 0 --> 1.0 min; 99% B 1.0 --> 1.3 min; WL: 220 nm LCMS Method 1 1H NMR (300 MHz, DMSO-d6) 12.09 (s, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.60 (s, 1H), 7.47 (d, J = ... 5.6 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.04 (dd, J = 8.1, 1.6 Hz, 2H), 6.94–6.84 (m, 1H), 3.85 (d, J = 6.3 Hz, 2H), 2.30–2.17 (m, 1H), 2.00–1.85 (m, 4H), 1.82–1.71 (m, 1H), 1.36–1.09 (m, 4H). LCMS Method 2 A: H₂O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH + 1% H₂O OT: 40℃ | Flow rate: 3.3 ml / min | MS: 61–800 amu Positive ion column: Chromolith HR RP-18e 50-4.6 mm 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min LCMS Method 3 A: H2O + 0.1% TFA | B: MeCN + 0.1% TFAT: 40℃ | Flow rate: 3.3 ml / min | MS: 85-800 amu Positive ion column: Chromolith SpeedRod RP-18e 5.0 mm 50-4.6 mm 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min LCMS Method 4 CORTECS T3 1.6 µm 30-2.1 mm; A: H2O + 0.1% HCOOH | B: MeCN + 0.1% HCOOH;1% -> 99% B: 0 -> 2.5 min | 99% B: 2.5 -> 2.9 min; T: 40℃ | Flow rate: 3.5 ml / min | MS: 61-1000 amu positive ions; DAD: 220 nm LCMS Method 5 Chromolith HR C18 5.0 μm 50-4.6 mm; A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH; T: 45℃ | Flow rate: 0.9 ml / min | 2% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.31 min LCMS Method 6 Chromolith HR C18 5.0 μm 50-4.6 mm; A: H2O + 0.1% HCOOH | B: MeCN + 0.1% HCOOH; 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min; T: 40℃ | Flow rate: 3.3 ml / min | MS: 61-1000 amu positive ions; DAD: 220 nm LCMS Method 7 Chromolith HR C18 5.0 μm 50-4.6 mm; A: H2O + 0.1% HCOOH | B: MeCN + 0.1% HCOOH; 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.7 min; T: 40℃ | Flow rate: 1.4 ml / min | MS: 61-1000 amu positive ions; DAD: 220 nm LCMS Method 8 Chromolith HR C18 5.0 μm 50-4.6 mm mm; A: H2O + 0.1% TFA | B: MeCN + 0.1% TFA; 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min; T: 40℃ | Flow rate: 3.3 ml / min | MS: 61-1000 amu positive ions; DAD: 220 nm LCMS method 9 Chromolith HR RP-18e 50-4.6 mm; A: H2O + 0.1% HCOOH | B: MeCN + 0.1% HCOOH; 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min;T: 40℃ | Flow rate: 3.3 ml / min | LCMS Method 10 Chromolith HR RP-18e 50-4.6 mm; CHROMOLITH: eluent A: Water + 0.05% formic acid; eluent B: Acetonitrile + 0.04% formic acid + 1% H2O; WL: 220 nm; Flow rate: 3.3 ml / min; Gradient: 0% -> 100% B: 0.0 -> 2.0 min / 100% B: 2.0 -> 2.5 min LCMS Method 11 Chromolith SpeedROD RP-18e 50-4.6 mm; A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH + 1% H2O; 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0->2.5 min; T: 40℃ | Flow rate: 3.3 ml / min | MS: 61-800 amu positive ions; DAD: 220 nm LCMS Method 12 Chromolith® HighResolution RP18e 50-4.6nm; (A1): Chromolith (HCOOH): A: H2O+0.05% HCOOH; B: CH3CN + 0.04 % HCOOH + 1% water; T: 40℃; Flow rate: 3.3 ml / min; MS: 61-1000 amu positive ions; 1% --> 99% B; 0 --> 2.0 min; 99% B: 2.0 --> 2.5 min; WL 220 / 254nm LCMS Method 13 Column: CORTECS C18, 2.1*30mm, 2.7um; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; LCMS Method 14; Column: CORTECS C18, 2.1*30mm, 2.7µm; Column oven: 40°C;Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA LCMS Method 15 Column: Chromolith HR RP-18e 50-4.6 mm 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH + 1% H2O O: 40℃ | Flow rate: 3.3 ml / min | MS: 61-800 amu Positive ion LCMS Method 16 Column: Chromolith HR RP-18e 50-4.6 mm A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH + 1% H2O O: 40℃ | Flow rate: 3.3 ml / min | MS: 61-800 amu positive ions 1% -> 99% B: 0 -> 2.0 min | 99% B: 2.0 -> 2.5 min LCMS Method 17 Column: Chromolith HR RP-18e 50-4.6 mm; Chromolith MethodInfo: A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH + 1% H2O | T: 40℃ | Flow rate: 3.3 ml / min | MS: 61-800 amu positive ions | 0% -> 100% B: 0 -> 2.0 min | 100% B: 2.0 -> 2.5 min LCMS Method 18 Column: HALO 90A C18, 2 μm, 3 x 30 mm; Mobile phase A: Water / 0.1% FA; Mobile phase B: Acetonitrile / 0.1% TFA LCMS Method 19 Column: HALO 90A C18, 2.2 μm, 3 x 30 mm; Mobile phase A: Water / 0.05% TFA; Mobile phase B: Acetonitrile / 0.05% TFA LCMS Method 20 Column: HALO 90A C18, 3.0*30 mm, 2.0 μm; Column oven: 40°C; Mobile phase A: Water / 0.1% FA; Mobile phase B: Acetonitrile / 0.1% FA; LCMS Method 21 Column: HALO C18, 2.0 µm, 3.0 x 30 mm; Mobile phase A: Water / 0.05% TFA; Mobile phase B: Acetonitrile / 0.05% TFA LCMS Method 22 Column: HALO C18, 2.7 µm, 4.6 x 100 mm; Mobile phase A: Water / 0.05% TFA;Mobile phase B: Acetonitrile / 0.05% TFA LCMS Method 23 Column: Shim-pack Scepter C18-120, 3µm, 3.0*33 mm; Column oven: 40°C; Mobile phase A: 6.5mM NH4HCO3+NH4OH (pH=10) Mobile phase B: Acetonitrile LCMS Method 24 Column: XBridge C8, 3.5 µm, 4.6 x 50 mm; Solvent A: Water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow rate: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B. LCMS Method 25 Column: HALO 90A C18, 3.0*30mm, 2.0um; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA LCMS Method 26 Column: HALO 90A C18, 3.0*30mm, 2.0um; Column oven: 40°C; Mobile phase A: Water / 0.1% FA; Mobile phase B: Acetonitrile / 0.1% FA LCMS Method 27 Column: HALO C18, 3.0*30mm, 2um; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; LCMS Method 28 Column: Halo C18 4.6*100 mm, 2.7um; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA LCMS Method 29 Column: Poroshell HPH C18, 3.0*50 mm, 2.7 μm; Column oven: 40°C; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10), Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B within 1.8 min, hold for 0.9 min; 254 nm LCMS Method 30 Column: Poroshell HPH C18, 3.0*50 mm, 2.7 μm; Column oven: 40°C; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10), Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B within 1.0 min, hold for 0.7 min; 254 nm LCMS Method 31 Column: Poroshell HPH C18, 3.0*50 mm, 2.7um;Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10); Mobile phase B: Acetonitrile; LCMS Method 32; Column: Shim-pack Scepter C18-120; Column oven: 40°C; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10), Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B within 1.0 min, hold for 0.7 min; 254 nm LCMS Method 33; Column: Shim-pack Scepter C18-120; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5% B to 100% B within 0.7 min, hold for 0.4 min; 254nm LCMS Method 34: Column: Shim-pack Scepter C18-120; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: Acetonitrile / 0.05% TFA; Flow rate: 1.0 mL / min; Gradient: 5% B to 100% B in 0.7 min, hold for 0.4 min; 254nm LCMS Method 35: HALO C18, 3.0*30 mm, 2 μm; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; LCMS Method 36: HALO C18, 3.0*30 mm, 2 μm; Column oven: 40°C; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2 mL / min; Gradient: 5% B to 100% B within 1.2 min, hold for 0.6 min; 254nm LCMS Method 37 HALO C18, 3.0*30mm, 2µm; Column oven: 40°C; Mobile phase A: Water / 0.1% FA, Mobile phase B: ACN / 0.1% FA; Flow rate: 1.5 mL / min; Gradient: 5% B to 100% B within 1.2 min, hold for 0.6 min; 254nm LCMS Method 38 HALO, 3.0*30mm, 2µm; Column oven: 40°C; Mobile phase A: 6.5mM NH4HCO3+NH4OH (pH=10), Mobile phase B: Acetonitrile; Flow rate: 1.2 mL / min; Gradient: 10% B to 95% B within 1.9 min, hold for 0.8 min; 254nm LCMS Method 39 LC-MS Agilent 1200 Series Chromolith RP-18e 50-4,6mm;3.3 ml / min Solvent A: Water + 0.05% HCOOH Solvent B: Acetonitrile + 0.04% HCOOH 220 nm 0 to 2.0 min: 1% B to 99% B 2.0 to 2.5 min: 99% B LCMS Method 40 LC-MS chromolith 254 nm; Water + 0.1% TFA / ACN + 0.1% TFA 1:99, 2.0 min, flow rate 3.3 ml / min LCMS Method 41 LCMS (Agilent) Chromolith HR-RP 18e 50-4.6 mm; chromolith .m, 3.3 ml / min, T: 45℃; 220 nm, Buffer A 0.05% HCOOH / H2O, Buffer B 0.04% HCOOH / ACN, 0.0-2.0 min 0%-99% Buffer B; 2.0-2.5 min 99% LCMS Method 42 Poroshell HPH C18, 2.7 μm, 100 mm x 4.6 mm; Mobile phase A: water / 5 mM NH4HCO3, Mobile phase B: acetonitrile LCMS Method 43 Shim-pack Scepter C18-120 33 mm x 3 mm 3.0 μm; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10), Mobile phase B: acetonitrile LCMS Method 44 Shim-pack Scepter C18-120 33 mm x 3 mm 3.0 μm; Mobile phase A: 6.5 mM NH4HCO3 + NH4OH (pH=10), Mobile phase B: acetonitrile LCMS Method 45 Shim-pack Scepter C18-120 33 mm x 3 mm 3.0µm; Solvent A: Water + 10Mm NH4HCO3; Solvent B: ACN; Flow rate: 1 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B. LCMS method 46 Sunfire C18 5.0µm 100-3mm; (A1): Chromolith (HCOOH): A: H2O + 0.05% HCOOH; B: CH3CN + 0.04% HCOOH + 1% water; T: 40℃; Flow rate: 3.3ml / min; MS: 61-1000 amu positive ions; 1% --> 99% B; 0 --> 2.0 min;99%B: 2.0 --> 2.5 min; WL220 / 254nmLCMS Method 47 Sunfire C18 5.0µm 100-3mm; (C1): Sunfire (HCOOH): A: H2O + 0.05% HCOOH; B: CH3CN + 0.04% HCOOH + 1% water; T: 40℃; Flow rate: 1.4ml / min; MS: 61-1000 amu positive ions; 1% --> 99% B; 0 --> 2.0 min; 99%B: 2.0 --> 2.7 min; WL 220nmLCMS Method 48 UPLC-MS Waters A cquity UP LC (BSM + SM + CMA + PDA + SQ D2); A: H2O + 0.05% HC OOH | B: MeCN + 0.04% HC OO HT: 40℃ | Flow rate: 0.9 ml / min | Column: Kinetex EV O-C 18 1.7; m 5 0-2 ,1mm 1% ->9 9% B: 0 ->1 ,0 min | 99% B: 1 ,0 ->1,3 min LCMS Method 49 UPLC; Kinetex EVO-C18 1,7 µm 50-2,1 mm; UPLC: Kinetex(HCOOH); A: H2O+0.05% HCOOH; B: CH3CN + 0.04% HCOOH + 1% water; T:40℃; Flow rate:0.9ml / min; 1% -->99% B; 0 -->1.0min; 99% B 1.0 -->1.3min; WL:220nm LCMS Method 50 UPLC; Kinetex EVO-C18 1.7 µm 50-2.1 mm; (D1) UPLC(Kinetex): A: H2O + 0.05% HCOOH; B: MeCN + 0.04% HCOOH + 1% H2O; T: 40℃; Flow rate: 0.9 ml / min; 1% ->99% B: 0 ->1.0 min | 99% B: 1.0 ->1.3 min; WL: 220 nm.

[0303] The following compounds (provided as enantiomers in Table 1A) have been isolated from stereochemical mixtures containing these compounds under the following chromatographic (HPLC or SFC) separation conditions (Rt = retention time): .

[0304] Biological data SK-HEP-1 reporter assay To identify inhibitors of YAP-TEAD interaction, an 8xTEAD response element driving the NanoLuc® luciferase gene was stably integrated into SK-HEP-1 cells (ECACC #: 91091816). For the assay, cells were treated in duplicate with 10-point doses of the test compound, with the highest concentration starting at 30 µM (the final concentration in the assay). After culturing at 37°C, 95% rH, and 5% CO2 for 24 hours, the luciferase substrate / lysis reagent mixture (NanoLuc®) was used. TM Promega is added to cells, thereby allowing for the quantification of cytoluciferase activity.

[0305] Cell culture medium: Cells were cultured in the following medium: MEM, +10% FBS, +1×GlutaMAX, +1 mM sodium pyruvate, +100 µM non-essential amino acids, +0.1 mg / ml hygromycin. The medium used for analysis was: MEM (phenol red-free), +10% FBS, +1×GlutaMAX, +1 mM sodium pyruvate, +100 µM non-essential amino acids, +0.5% penicillin / streptomycin.

[0306] Reagents: The reagents used are listed below: .

[0307] Cell culture: Use an inverted microscope to examine the cells to assess their health and density. To separate the adherent cells, wash the monolayer once with preheated PBS. After removing the PBS, add 3 ml of preheated Accutase® to the F75 culture flask, disperse evenly, and allow the flask to stand in the incubator for approximately 4–5 minutes.

[0308] Once a single-cell suspension is obtained, add 7 ml of preheated growth medium and resuspend the cells together. Transfer the cell suspension to a sterile 15 ml conical centrifuge tube and centrifuge at 300 × g for 5 min at room temperature. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[0309] Determine the total cell count and add 20 µl of the desired cell count to each well of a 384-well plate using Multidrop Combi. The plate is then incubated at 37°C, 95% rH, and 5% CO2 for 24 hours.

[0310] Compound treatment: 24 hours after inoculation, the cells were treated with a compound.

[0311] Prepare a 1:333 dilution of the compound in DMSO to obtain a final concentration of 0.3% DMSO per well. To transfer the compound to the analytical plate, inject 120 nl from a Labcyte low-volume dish into a cell plate containing 20 µl of culture medium per well using an ECHO 555 liquid handling system.

[0312] After treatment, 20 µl of fresh, preheated analytical medium was fed into the cells using a Multidrop combi.

[0313] The analytical plate was then incubated at 37°C, 95% rH and 5% CO2 for another 24 hours.

[0314] Luciferase reading: 24 h after treatment, remove the plate from the incubator and allow it to equilibrate to room temperature. Add 30 µl of NanoGlo® reagent to the plate in the dark. Shake the plate on a Teleshake (approximately 1500 rpm) for 20 min in the dark. Then measure the temperature using an EnVision multi-plate reader. Genedata Screener® is used to generate IC50 values. 50 value.

[0315] Viability analysis of H226 (YAP-dependent) and SW620 YAP KO (non-YAP-dependent) cells The ability of the YAP-TEAD inhibitor to inhibit tumor cell growth was evaluated using two different cell lines: NCI-H226, a YAP-dependent cell line; and SW620 cells, in which YAP and TAZ were knocked out using CRISPR to generate a YAP-independent cell line.

[0316] For the analysis, cells were treated in duplicate with 10 doses of the test compound using a 1:3 dilution procedure, with the highest concentration starting at 30 µM (the final concentration in the analysis). After culturing for 96 hours at 37°C, 95% rH, and 5% CO2, a cell-permeable DNA-binding dye (CyQUANT®, Promega) that stains only healthy cells was added to the cells, allowing for the quantification of cell viability.

[0317] Cell culture medium: NCI-H226 cells were cultured in the following medium: RPMI 1640, +10% FBS, +1×GlutaMAX, +10 mM HEPES, +0.5% penicillin / streptomycin. SW620-KO cells were cultured in the following medium: DMEM / F-12, +10% FBS, +1×GlutaMAX, +10 mM HEPES, +0.5% penicillin / streptomycin.

[0318] Reagents: The reagents used are listed below: .

[0319] Cell culture: Use an inverted microscope to examine the cells to check their health status and cell density. To detach the adherent cells, wash the monolayer of cells once with preheated PBS. After removing the PBS, add 3 ml of preheated Accutase to the F75 culture flask, disperse it evenly, and let the flask stand in the incubator for about 4-5 minutes.

[0320] Once a single-cell suspension is obtained, add 7 ml of preheated growth medium and resuspend the cells together. Transfer the cell suspension to a sterile 15 ml conical centrifuge tube and centrifuge at 300 × g for 5 min at room temperature. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[0321] Determine the total cell count and add 20 µl of the desired cell count to each well of a 384-well plate using Multidrop Combi. The plate is then incubated at 37°C, 95% rH, and 5% CO2 for 24 hours.

[0322] Compound treatment: 24 hours after inoculation, the cells were treated with a compound.

[0323] Prepare a 1:333 dilution of the compound in DMSO to obtain a final concentration of 0.3% DMSO per well. To transfer the compound to the analytical plate, inject 120 nl from a Labcyte low-volume dish into a cell plate containing 20 µl of culture medium per well using an ECHO 555 liquid handling system.

[0324] After treatment, 20 µl of fresh, preheated analytical medium was fed into the cells using a Multidrop combi.

[0325] The analytical plate was then incubated at 37°C, 95% rH, and 5% CO2 for 96 h.

[0326] CyQuant® Measurement 96 h after treatment, 30 µl of CyQuant® reagent was added to the analysis plate in the dark using a Multidrop combo. The plate was then incubated at 37 °C, 95% rH, and 5% CO2 for 1 h. Afterward, the analysis plate was removed from the incubator and allowed to equilibrate to room temperature in the dark for 30 minutes without a lid. Finally, measurements were taken using an EnVision multi-plate reader with a FITC bottom readout program.

[0327] Viability analysis of H292 cells ("H292 viability analysis") This analysis was used to identify compounds that inhibit the growth of YAP-dependent cells. For the analysis, cells were treated in duplicate with 10-point doses of the test compound, with the highest concentration starting at 30 µM (the final concentration in the analysis). After culturing for 96 hours at 37°C, 95% rH, and 5% CO2, a cell-permeable DNA-binding dye (CyQUANT®) was added to the cells to allow for the quantification of cell viability.

[0328] Cell culture medium: Cells were cultured in the following medium: RPMI 1640, +10% FBS, +1×GlutaMAX, +1 mM sodium pyruvate, +10 mM HEPES, +1% penicillin / streptomycin.

[0329] Reagents: The reagents used are listed below: .

[0330] Cell culture: Examine the cells using an inverted microscope to check their health and density. To separate the adherent cells, wash the monolayer once with preheated PBS. After removing the PBS, add 3 ml of preheated Accutase® to the F75 culture flask, disperse evenly, and allow the flask to stand in the incubator for approximately 4–5 minutes.

[0331] Once a single-cell suspension is obtained, add 7 ml of preheated growth medium and resuspend the cells. Transfer the cell suspension to a sterile 15 ml conical centrifuge tube and centrifuge at 300 × g for 5 min at room temperature. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[0332] Determine the total cell count and add 20 µl of the desired cell count to each well of a 384-well plate using Multidrop Combi. The plate is then incubated at 37°C, 95% rH, and 5% CO2 for 24 hours.

[0333] Compound treatment: Twenty-four hours after inoculation, the cells were treated with a compound.

[0334] The compounds diluted in DMSO were diluted 1:333 to obtain a final concentration of 0.3% DMSO per well. To transfer the compounds to the analytical plate, 120 nl was injected from the Labcyte low-volume tray into a cell plate containing 20 µl of culture medium per well using an ECHO 555 liquid handling system.

[0335] After treatment, 20 µl of fresh, preheated analytical medium was fed into the cells using a Multidrop combi.

[0336] The analytical plate was then incubated at 37°C, 95% rH and 5% CO2 for another 24 h.

[0337] CyQuant® Measurement: 96 h after treatment, 30 µl of 2x CyQuant® staining solution (inhibitor to staining agent ratio of 1:5) was added to the plate in the dark. The plate was incubated at 37 °C, 95% rH, and 5% CO2 for 1 h. The plate was then equilibrated to room temperature in the dark for 30 min. Fluorescence was then measured using an EnVision multi-plate reader with a FITC filter. IC50 was generated using Genedata Screener®. 50 value.

[0338] Th...

Claims

1. A compound of formula I Where X 1 Indicates N or CR X1 ;R X1 Represents H, halogen, and straight or branched C that is unsubstituted or independently substituted by one, two, or three halogens. 1-4 Alkyl groups, and / or OH groups; R 1 Represents straight-chain or branched C atoms containing halogens, -NH2, -CN, unsubstituted or independently substituted by one, two or three halogens. 1-4 Alkyl; R 2 Represents H, Alk 2 Ar 2 Hetar 2 Cyc 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f ;R 3 The symbol represents H, -CN, -C(=O)-NH2, or a halogen; A represents 1,3-phenylene or a monocyclic divalent heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the 1,3-phenylene or monocyclic heteroaryl group has the compound of formula I at position 1. The bicyclic system, and relative to the bicyclic system, the L of the compound of formula I is located at position 3. 1 -B group, wherein each of the 1,3-phenylene or monocyclic heteroaryl groups may be further unsubstituted or independently converted to halogen, straight-chain or branched C groups. 1-4 -alkyl, OC 1-4 -alkyl, SC 1-4 -alkyl, C 3-7 -cycloalkyl, OC 3-7 -cycloalkyl or SC 3-7 - Cycloalkyl mono- or di-substituted, wherein C 1-4 -alkyl, OC 1-4 -alkyl, SC 1-4 -alkyl, C 3-7 -cycloalkyl, OC 3-7 -cycloalkyl or SC 3-7 -The cycloalkyl group is either unsubstituted or substituted with one, two, or three halogens; B represents Ar. 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 Represents -O-, -S-, -N(R) 4 -, -O-CH2-, -O-CH(R) 5 -, -O-SO2-, -N(R) 6 -CH2-, -N(R) 6 -C(=O)-, -CH2-, -CH(R) 7 -, -CH2CH2-, -CH2-O-; R 4 Indicates H, straight chain or branched chain C 1-6 -alkyl; R 5 R 6 R 7 Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; L 2 Indicates a divalent -S(=O)2- group; Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 R 2a2 and / or R 2a3 Replace; Ar 1 This indicates a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein the aryl group is independently separated from each other by R. C1 R C2 and / or R C3 Replace; Ar a Ar 2 Ar 2a Each of the following independently represents a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryl group may be unsubstituted or independently represented by R. B1 R B2 R B3 R B4 and / or R B5 Replace; Hetar 1 This refers to a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is independently separated from each other by R. C1 R C2 and / or R C3 Replace; Hetar a Hetar 2 Hetar 2a Each of the following independently represents a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is unsubstituted or independently converted to R B1 R B2 R B3 R B4 and / or R B5 Replace; Cyc 1 This refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings may be unsubstituted or independently of each other by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Cyc a Cyc 2 Cyc 2a Independently representing monocyclic, bicyclic, or tricyclic carbon rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings are not substituted or are independently represented by R B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; Hetcyc 1 This refers to a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycles are independently separated by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Hetcyc a Hetcyc 2 Hetcyc 2a Each of the above independently represents a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or independently substituted by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R 2a1 R 2a2 R 2a3 The terms -CF3, -CN, -NH2, and -NHR represent halogens independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SH, -SR f -S(=O)R f -S(=O)2R f -S(=O)(=NR) g )R f -N=S(=O)R f R h -C(=O)NH2, -C(=O)NHR a -C(=O)NR a R b -C(=O)OH, -C(=O)OR c -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; and / or R attached to the same carbon atom 2a1 R 2a2 R 2a3 The two together form a divalent oxo (=O) group; R a R b Each of these terms independently represents a straight-chain or branched C that may be unsubstituted or substituted with one, two, or three halogens. 1-6 -alkyl; Ar a Cyc a Hetar a Hetcyc a ; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N, O, or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is independently modified by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R c C represents a straight chain or a branch chain. 1-4 -alkyl, C 2-4 -Alkenyl or C 2-4 -Alynyl groups, each of which may be unsubstituted or substituted with -OH; C groups that may be unsubstituted or substituted with -OH and / or halogens 3-7 -cycloalkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f R h Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R g Indicates H, straight chain or branched chain C 1-6 -alkyl; R i Indicates H, straight chain or branched chain C 1-6 -alkyl; R B1 R B2 R B3 R B4 R B5 Halogens are represented independently of each other; -OH; -OC 1-4 -alkyl; C14 that may be unsubstituted or substituted with 1, 2 or 3 halogens. 1-4 -alkyl; R B6 R B7 R B8 R B9 R B10 R B11 Halogens are represented independently of each other; OH; -OC 1-4 -alkyl; C10 unsubstituted or substituted with 1 or 2 OH radicals and / or 1, 2 or 3 halogens. 1-4 -alkyl; and / or R attached to the same carbon atom of the carbide ring or the heterocycle. B6 R B7 R B8 R B9 R B10 R B11 Both of them form a divalent oxo (=O) group; and / or an R atom attached to the same sulfur (S) atom of the heterocycle. B6 R B7 R B8 R B9 R B10 R B11 The two molecules form a divalent oxo (=O) group, which is simultaneously attached to the R atom of the same sulfur atom. B6 R B7 R B8 R B9 R B10 R B11 The other two in it form divalent oxygen or divalent =NH or =NC 1-4 -alkyl groups, thereby forming -S(=O)2, -S(=O)(=NH) or -S(=O)(=NC 1-4 -alkyl) moiety; R C1 R C2 R C3 Halogens are represented independently of each other; C 1-4 -alkyl, -SC 1-4 -alkyl or -OC 1-4 -alkyl groups, each of which may be unsubstituted or substituted with one, two, or three halogens; R C6 R C7 R C8 R C9 R C10 and / or R C11 Each group independently represents a halogen; C14 cells are either unsubstituted or substituted with one, two, or three substituents independently selected from the halogen group. 1-4 -alkyl; unsubstituted or substituted with one, two or three substituents independently selected from halogens -OC 1-4 -alkyl; halogen means F, Cl, Br, I; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions.

2. A compound of formula I Where X 1 Indicates N or CR X1 ;R X1 Represents H, halogen, and straight or branched C that is unsubstituted or independently substituted by one, two, or three halogens. 1-4 Alkyl groups, and / or OH groups; R 1 Represents straight-chain or branched C atoms containing halogens, -NH2, -CN, unsubstituted or independently substituted by one, two or three halogens. 1-4 Alkyl; R 2 Represents H, Alk 2 Ar 2 Hetar 2 Cyc 2 Hetcyc 2 -L 2 -Ar 2a ;R 3 The symbol represents H, -CN, or a halogen; A represents 1,3-phenylene or a monocyclic divalent heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the 1,3-phenylene or monocyclic heteroaryl group has the compound of formula I at position 1. The bicyclic system, and relative to the bicyclic system, the L of the compound of formula I is located at position 3. 1 -B group, wherein each of the 1,3-phenylene or monocyclic heteroaryl groups may be further unsubstituted or independently converted to halogen, straight-chain or branched C groups. 1-4 -alkyl substitution, wherein the straight-chain or branched C 1-4 - The alkyl group is either unsubstituted or substituted with one, two, or three halogens; B represents Ar. 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 Represents -O-, -N(R) 4 -, -O-CH2-, -O-CH(R) 5 -, -O-SO2-, -N(R) 6 -CH2-, -N(R) 6 -C(=O)-, -CH2-, -CH(R) 7 -, -CH2CH2-, -CH2-O-; R 4 Indicates H, straight chain or branched chain C 1-6 -alkyl; R 5 R 6 R 7 Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; L 2 Indicates a divalent -S(=O)2- group; Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 R 2a2 and / or R 2a3 Replace; Ar 1 This indicates a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein the aryl group is independently separated from each other by R. C1 R C2 and / or R C3 Replace; Ar a Ar 2 Ar 2a Each of the following independently represents a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 cyclic carbon atoms, wherein the aryl group may be unsubstituted or independently represented by R. B1 R B2 R B3 R B4 and / or R B5 Replace; Hetar 1 This refers to a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is independently separated from each other by R. C1 R C2 and / or R C3 Replace; Hetar a Hetar 2 Hetar 2a Each of the following independently represents a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is unsubstituted or independently converted to R B1 R B2 R B3 R B4 and / or R B5 Replace; Cyc 1 This refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings may be unsubstituted or independently of each other by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Cyc 2 This refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic carbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, wherein the carbon rings are not substituted or are independently converted by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; Hetcyc 1 This refers to a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycles are independently separated by R. C6 R C7 R C8 R C9 R C10 and / or R C11 Replace; Hetcyc a Hetcyc 2 Hetcyc 2a Each of the above independently represents a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or independently substituted by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R 2a1 R 2a2 R 2a3 The terms -CN, -NH2, and -NHR represent halogens independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SH, -SR f -S(=O)R f -S(=O)2R f -S(=O)(=NR) g )R f -N=S(=O)R f R h -C(=O)NH2, -C(=O)NHR a -C(=O)NR a R b -C(=O)OH, -C(=O)OR c -NH-C(=O)-R i Hetar 2a Hetcyc 2a ;R a R b Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl, Ar a Hetar a Hetcyc a ; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N, O, or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is independently modified by R. B6 R B7 R B8 R B9 R B10 and / or R B11 Replace; R c C represents a straight chain or a branch chain. 1-4 -alkyl, C 2-4 -Alkenyl or C 2-4 -Alynyl groups, each of which may be unsubstituted or substituted with -OH; C groups that may be unsubstituted or substituted with -OH and / or halogens 3-7 -cycloalkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f R h Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R g Indicates H, straight chain or branched chain C 1-6 -alkyl; R i Indicates H, straight chain or branched chain C 1-6 -alkyl; R B1 R B2 R B3 R B4 R B5 Halogens are represented independently of each other; -OH; -OC 1-4 -alkyl; C14 that may be unsubstituted or substituted with 1, 2 or 3 halogens. 1-4 -alkyl; R B6 R B7 R B8 R B9 R B10 R B11 Halogens are represented independently of each other; OH; -OC 1-4 -alkyl; C10 unsubstituted or substituted with 1 or 2 OH radicals and / or 1, 2 or 3 halogens. 1-4 -alkyl; and / or R attached to the same carbon atom of the carbide ring or the heterocycle. B6 R B7 R B8 R B9 R B10 R B11 Both of them form a divalent oxo (=O) group; and / or an R atom attached to the same sulfur (S) atom of the heterocycle. B6 R B7 R B8 R B9 R B10 R B11 The two molecules form a divalent oxo (=O) group, which is simultaneously attached to the R atom of the same sulfur atom. B6 R B7 R B8 R B9 R B10 R B11 The other two in it form divalent oxygen or divalent =NH or =NC 1-4 -alkyl groups, thereby forming -S(=O)2, -S(=O)(=NH) or -S(=O)(=NC 1-4 -alkyl) moiety; R C1 R C2 R C3 Halogens are represented independently of each other; C 1-4 -alkyl or -OC 1-4 -alkyl groups, each of which may be unsubstituted or substituted with one, two, or three halogens; R C6 R C7 R C8 R C9 R C10 and / or R C11 Each group independently represents a halogen; C14 cells are either unsubstituted or substituted with one, two, or three substituents independently selected from the halogen group. 1-4 -alkyl; unsubstituted or substituted with one, two or three substituents independently selected from halogens -OC 1-4 -alkyl; halogen means F, Cl, Br, I; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions.

3. The compound according to claim 1 or 2, wherein X 1 Indicates N or CR X1 ;R X1 Represents H; or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

4. The compound according to any one of the preceding claims, wherein X 1 It represents CH; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of the foregoing, including mixtures thereof in all proportions.

5. The compound according to any one of the preceding claims, wherein R 1 Indicates Cl, -CN, or -CF3; and R 3 Represents H; or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

6. The compound according to any one of the preceding claims, wherein R 1 Represents Cl or -CF3; and R 3 Represents H; or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

7. The compound according to any one of claims 1 to 4, wherein R 1 Represents -CH3; and R 3 It represents F or -CN; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of the foregoing, including mixtures thereof in all ratios.

8. The compound according to any one of the preceding claims, wherein R 2 Represents H, Alk 2 Cyc 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f ; or any N-oxide, solvate, tautomer or stereoisomer or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions.

9. The compound according to any one of the preceding claims, wherein R 2 Represents H, Alk 2 Cyc 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl, C 1-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 R 2a2 and / or R 2a3 Replace; Cyc a Cyc 2 Cyc 2a Each of the above independently represents a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring is not substituted or is independently modified by R. B6 and / or R B7 Replace; Hetcyc a Hetcyc 2 Hetcyc 2a Independently representing saturated or partially unsaturated monocyclic heterocycles having 3, 4, 5, or 6 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or independently converted to R B6 and / or R B7 and / or R B8 With R B9 Jointly replace, or be replaced by R B6 and / or R B7 and / or R B8 With R B9 With R B10 With R B11 Common replacement; L 2 Indicates a divalent -S(=O)2- group; Ar a Ar 2a They can be expressed independently of each other and not be replaced or can be expressed independently of R. B1 and / or R B2 Substituted phenyl; Hetar a Hetar 2 Hetar 2a This indicates a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is unsubstituted or independently converted to R. B1 and / or R B2 Replace; R 2a1 R 2a2 R 2a3 The terms -CF3, -CN, -NH2, and -NHR represent halogens independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SR f -S(=O)2R f -S(=O)(=NR) g )R f -N=S(=O)R f R h -C(=O)NH2, -C(=O)NHR a -C(=O)NR a R b -C(=O)OH, -C(=O)OR c -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; and / or R attached to the same carbon atom 2a1 R 2a2 R 2a3 The two together form a divalent oxo (=O) group; R a R b Each of these terms independently represents a straight-chain or branched C that may be unsubstituted or substituted with one, two, or three halogens. 1-6 -alkyl; Ar a Cyc a Hetar a Hetcyc a ; or R a and R b Together with the nitrogen atom to which it is attached, it forms a saturated or partially unsaturated heterocycle with 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N, O, or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is independently modified by R. B6 and / or R B7 and / or R B8 With R B9 Co-substitution; R c This refers to straight-chain or branched carbon that is either unsubstituted or substituted with -OH. 1-4 -alkyl; straight-chain and unsubstituted C 2-4 -Alynyl group; C 3-5 -cycloalkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f R h Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R g Indicates H, straight chain or branched chain C 1-6 -alkyl; R i Indicates H, straight chain or branched chain C 1-6 -alkyl; R B1 R B2 Halogens can be represented independently of each other; C can be unsubstituted or substituted with 1, 2 or 3 halogens. 1-4 -alkyl; OH; R B6 R B7 Halogens are represented independently of each other; OH; -OC 1-4 -alkyl; C10 unsubstituted or substituted with 1 OH or 1, 2 or 3 halogens. 1-4 -alkyl; R attached to the same carbon atom of the heterocycle B8 and R B9 Forming a divalent oxo (=O) group; or an R atom attached to the same sulfur (S) atom in the heterocycle. B8 R B9 R B10 and R B11 Forming a divalent oxo(=O) group, thereby forming a -S(=O)2 moiety; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios.

10. The compound according to any one of the preceding claims, wherein R 2 Represents H, Alk 2 Cyc 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a -S(=O)2R f Alk 2 C represents a straight chain or a branch chain. 1-4 -alkyl, C 1-4 -Alkenyl or C 2-4 -Alynyl groups, each of which may be unsubstituted or independently converted to R 2a1 and / or R 2a2 Replace; Cyc 2 Cyc 2a Each of these terms independently represents a saturated monocyclic carbon ring having 3, 4, or 5 ring carbon atoms, wherein the carbon ring is monosubstituted by OH or -CH2OH; Hetcyc 2 This indicates a saturated monocyclic heterocycle with 5 ring atoms, wherein one ring atom is a heteroatom selected from N and O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is monosubstituted with OH; or it indicates a saturated monocyclic heterocycle with 4 ring atoms, wherein one ring atom is a heteroatom selected from S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is substituted with two oxo (=O) groups at the S atom; Hetcyc 2a This refers to a saturated monocyclic heterocycle having four ring atoms, wherein one ring atom is a heteroatom selected from N or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or converted by halogens, -OH, or OC. 1-4 -alkyl or C 1-4 -Alkyl monosubstituted, or halogenated and C 1-4 -alkyl disubstituted, wherein the C 1-4 -alkyl groups may be unsubstituted or replaced with -OH or -OC in various cases. 1-4 -alkyl monosubstituted; or represents a saturated monocyclic heterocycle having 5 ring atoms, wherein one ring atom is a heteroatom selected from N or O, or wherein two ring atoms are heteroatoms selected from N and / or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or substituted with -OH, C 1-4 - Alkyl or oxo (=O) group monosubstituted or C 1-4 - Disubstituted alkyl and oxo (=O) groups; or representing a saturated monocyclic heterocycle having 6 ring atoms, wherein one ring atom is a heteroatom selected from N or O, or wherein two ring atoms are heteroatoms selected from N and / or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or substituted with OH, C 1-4 - Alkyl or oxo (=O) group monosubstituted or disubstituted with halogen; or representing a partially unsaturated monocyclic heterocycle having 6 ring atoms, wherein one ring atom is a heteroatom selected from N, and the remaining ring atoms are carbon atoms, wherein the heterocycle is monosubstituted with an oxo (=O) group; L 2 Indicates a divalent -S(=O)2- group; Ar 2a Hetar represents a phenyl group monosubstituted with -CH3; 2 Hetar 2a Each of the above terms independently represents a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is not substituted or converted to carbon. 1-4 -Alkyl monosubstituted; R 2a1 R 2a2 -CF3, -CN, -NH2, and -NHR are represented independently of each other. a -NR a R b -OH, -OR c -P(=O)R d R e -SR f -S(=O)2R f -S(=O)(=NR) g )R f -C(=O)NH2, -C(=O)NHR a -C(=O)NR a R b -C(=O)OR c -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; and / or R attached to the same carbon atom 2a1 and R 2a2 Together they form a divalent oxo (=O) group; R a R b Each of the above terms represents a straight or branched C that can be either unsubstituted or substituted by 1, 2, or 3 Fs. 1-4 -alkyl; Ar a Hetar a ; or R a and R b Together with the nitrogen atom it is attached to, it forms a saturated heterocycle with 4, 5, or 6 ring atoms, wherein one of the ring atoms is the nitrogen atom, and another ring atom is absent or present and is a heteroatom selected from N or O, and the remaining ring atoms are carbon atoms, wherein the heterocycle is not substituted or is converted to carbon. 1-4 -Alkyl monosubstituted or disubstituted by F; R c This refers to straight-chain or branched carbon that is either unsubstituted or substituted with -OH. 1-4 -alkyl; unsubstituted C 2-4 -Alynyl group; unsubstituted C 3-5 -cycloalkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-4 -alkyl; R f C represents a straight chain or a branch chain. 1-4 -alkyl; R g H; R i Indicates H, straight chain or branched chain C 1-4 -alkyl; Ar a Hetar represents phenyl; a It represents pyridyl; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions.

11. The compound according to any one of the preceding claims, wherein R 2 Represents 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-(azacyclobutane-1-yl)ethyl, 2-(pyrrolidine-1-yl)ethyl, (N-methylmorpholin-3-yl)methyl, 2-(piperidin-1-yl)ethyl, 2-(4,4-difluoropiperidin-1-yl)ethyl, (N-methylmorpholin-3-yl)methyl, 2-(morpholin-1-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)-CH3, -CH(CH3)CH2-OH, 、 、-CH2-C(CH3)2-OH、-CH(CH2OH) 2、-CH2 CH(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; (1-hydroxycyclobutyl)methyl ), (1H-imidazol-2-yl)methyl, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1H-2-methylimidazol-4-yl)methyl, (1H-pyrazole-4-yl)methyl, (1H-pyrazole-5-yl)methyl, (1-methyl-1H-pyrazole-4-yl)methyl, 1,2-thiazol-3 -yl, 1,3-thiazolyl-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-fluoroazacyclobutane-3-yl)methyl, (1-methylazacyclobutane-3-yl)methyl, (oxacyclobutane-3-yl)methyl, (3-fluorooxacyclobutane-3-yl)methyl ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ), (1-methylazacyclobutane-3-yl)ethyl, 2-(oxacyclobutane-3-yl)ethyl, 1,1-dioxo-1-λ-6-thionecyclobutane-3-yl( ), (5-oxo-pyrrolidone-2-yl)methyl ( ), (5-oxo-pyrrolidone-3-yl)methyl ( ), oxacyclopentane-3-ylmethyl ( ), (3-hydroxyoxacyclopentan-3-yl)methyl ( ), (2-oxo-1,3-oxazolidin-4-yl)methyl ( ), (2-oxo-1,3-oxazolidine-5-yl)methyl ( ), (4-methyl-2-oxo-1,3-oxazolidine-4-yl)methyl ( ), (4-hydroxyoxacyclohexane-4-yl)methyl ( ), 2-(4-hydroxyoxacyclohexane-4-yl)ethyl ( ); 1-hydroxymethylcyclopropyl, 3-hydroxycyclobutyl, 2-hydroxycyclopentyl; 、 、 、 、 、 ; sulfonyl-4-methylphenyl; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions.

12. The compound according to any one of the preceding claims, wherein R 2 Represents H; -CH3, -CH=CH-CF3, -CH2-CN, -(CH2)2-CN, -(CH2)3-CN, -CH2-CH(OH)-CH2-CN, -(CH2)2-N(CH3)2, -CH2-CF2-CH2-NH2, -CH(CF3)-CH2-N(CH3)2, (N-methylmorpholin-3-yl)methyl, 2-(morpholin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, -(CH2)2-OH, -(CH2)2-O-(CH2)2-OH, -(CH2)3-OH, -CH(CH3)CH2-OH, 、 、-CH2-C(CH3)2-OH、-CH(CH2OH)2、-CH2CH(CH2OH)2、-CH2-CH(OH)-CH2-OCH3、 、 -(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-C(=O)-NHCH3, -CH2-C(=O)-NHCH2CH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -CH(C(=O)OCH2CH3)2, (1-hydroxycyclobutyl)methyl ), -(CH2)2-NH-C(=O)-CH3; (1H-imidazol-2-yl)methyl, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1H-2-methylimidazol-4-yl)methyl, (1H-pyrazole-4-yl)methyl, (1H-pyrazole-5-yl)methyl (1-Methyl-1H-pyrazol-4-yl)methyl, 1,2-thiazolyl-3-yl, 1,3-thiazolyl-2-yl, (1H-1,2,3-triazol-4-yl)methyl, pyrazin-2-yl, 2-(2-oxopyridin-1-yl)ethyl, (1,2,4-oxadiazol-3-yl)methyl, (oxetane-3-yl)methyl, (3-fluorooxetane-3-yl)methyl ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ), 2-(oxetane-3-yl)ethyl, 1,1-dioxo-1-λ-6-thionecyclobutane-3-yl( ), (5-oxo-pyrrolidine-2-yl)methyl, (5-oxo-pyrrolidine-3-yl)methyl, oxepane-3-ylmethyl, (3-hydroxyoxepane-3-yl)methyl, (2-oxo-1,3-oxazolidine-4-yl)methyl, (2-oxo-1,3-oxazolidine-5-yl)methyl, (4-methyl-2-oxo-1,3-oxazolidine-4-yl)methyl, (4-hydroxyoxepane-4-yl)methyl, 2-(4-hydroxyoxepane-4-yl)ethyl; 3-hydroxycyclobutyl; 、 、 、 、 ; or any N-oxide, solvate, tautomer or stereoisomer or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions.

13. Compound A according to any one of the preceding claims represents in This indicates that ring A and compound of formula I The connection point of the double-ring system, and The term indicates the point of connection with the L¹-B group of a compound of Formula I; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions.

14. The compound according to any one of the preceding claims, wherein A represents Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

15. The compound according to any one of the preceding claims, wherein A represents Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

16. The compound according to any one of the preceding claims, wherein B represents Ar. 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 Represents -O-, -S-, -N(R) 4 -, -O-CH2-, -O-CH(R) 5 )-、-N(R 6 -CH2-, -N(R) 6 )-C(=O)-, -CH2-, -CH2CH2-; R 4 Represents H or CH3; R 5 R 6 Represents CH3; Hetar 1 This indicates a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S, and the remaining ring atoms are carbon atoms, wherein the heteroaryl group is R C1 Single substitution or R C1 and R C2 Bisubstitution; Cyc 1 This refers to a saturated monocyclic or bicyclic carbon ring having 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or substituted with R. C6 Single substitution or R C6 and R C7 Bisubstitution; Hetcyc 1 This refers to a saturated monocyclic or bicyclic heterocycle having 5, 6, or 7 ring atoms, wherein 1 or 2 of these ring atoms are heteroatoms selected from N, O, and / or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is decoupled by R. C6 Single substitution or R C6 and R C7 Bisubstitution; R C1 Represents F, Cl, CHF2, CF3, CH2CF3, OCF3, or SCF3; R C2 Indicates CH3 or C2H5; R C6 Represents F, Cl; CH3, CHF2, CF3, -OCH3, -OCHF2, -OCF3; R C7 It represents F; or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

17. The compound according to any one of the preceding claims, wherein L 1 Represents -O-, -NH- or -O-CH2-; or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of the foregoing, including mixtures thereof in all ratios.

18. The compound according to any one of the preceding claims, wherein B represents Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

19. The compound according to any one of the preceding claims, wherein L 1 -O- indicates; B indicates Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

20. The compound according to any one of the preceding claims, wherein L 1 -O- indicates; B indicates Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

21. The compound according to any one of claims 1 to 18, wherein L 1 -NH--B indicates Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

22. The compound according to any one of claims 1 to 18 or 21, wherein L 1 -NH--B indicates Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

23. The compound according to any one of claims 1 to 18, wherein L 1 B represents -O-CH2-; Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

24. The compound according to any one of claims 1 to 18 or 23, wherein L 1 B represents -O-CH2-; Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

25. The compound according to any one of the preceding claims, wherein AL 1 -B indicates Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

26. The compound of formula I according to any one of the preceding claims, wherein X 1 Indicates CH; R 1 Represents Cl or -CF3; R 2 Represents H; -CH3, -CH=CH-CF3, -CH2-CN, -(CH2)2-CN, -(CH2)3-CN, -CH2-CH(OH)-CH2-CN, -(CH2)2-N(CH3)2, -CH2-CF2-CH2-NH2, -CH(CF3)-CH2-N(CH3)2, (N-methylmorpholin-3-yl)methyl, 2-(morpholin-1-yl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, -(CH2)2-OH, -(CH2)2-O-(CH2)2-OH, -(CH2)3-OH, -CH(CH3)CH2-OH, 、 、-CH2-C(CH3)2-OH、-CH(CH2OH)2、-CH2CH(CH2OH)2、CH2-CH(OH)-CH2-OCH3、 、 -(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-C(=O)-NHCH3, -CH2-C(=O)-NHCH2CH 3、-( CH2)2-C(=O)-NH2、-(CH2)2-C(=O)-NHCH3、(1-hydroxycyclobutyl)methyl ), -(CH2)2-NH-C(=O)-CH3; (1H-imidazol-2-yl)methyl, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1H-2-methylimidazol-4-yl)methyl, (1H-pyrazole-4-yl)methyl, (1H-pyrazole-5-yl)methyl (1-Methyl-1H-pyrazol-4-yl)methyl, 1,2-thiazolyl-3-yl, 1,3-thiazolyl-2-yl, (1H-1,2,3-triazol-4-yl)methyl, pyrazin-2-yl, 2-(2-oxopyridin-1-yl)ethyl, (1,2,4-oxadiazol-3-yl)methyl, (oxetane-3-yl)methyl, (3-fluorooxetane-3-yl)methyl ), (3-hydroxyoxetane-3-yl)methyl ( ), (3-methoxyoxetane-3-yl)methyl ( ), methyl(oxetane-3-yl)methanol ), 2-(oxetane-3-yl)ethyl; 1,1-dioxo-1-λ-6-thionecyclobutane-3-yl( ), (5-oxo-pyrrolidine-2-yl)methyl, (5-oxo-pyrrolidine-3-yl)methyl, oxepane-3-ylmethyl, (3-hydroxyoxepane-3-yl)methyl, (2-oxo-1,3-oxazolidine-4-yl)methyl, (2-oxo-1,3-oxazolidine-5-yl)methyl, (4-methyl-2-oxo-1,3-oxazolidine-4-yl)methyl, (4-hydroxyoxepane-4-yl)methyl, 2-(4-hydroxyoxepane-4-yl)ethyl; 3-hydroxycyclobutyl; , , , , ;R 3 H; AL 1 -B indicates Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

27. The compound according to any one of claims 1 to 3 or 5 to 26, wherein X 1 Represents N; R 1 Represents Cl or -CF3; R 2 Represents H; CH3; -CH2-CN, -(CH2)2-OH, -CH(CH2OH)2; (1H-imidazol-4-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl; (3-hydroxyoxacyclopentan-3-yl)methyl ), (4-hydroxyoxacyclohexane-4-yl)methyl ( ); R 3 H; AL 1 -B indicates Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions.

28. The compound of claim 1 or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, wherein the compound is selected from the compounds depicted in Tables 1 and 1A.

29. A compound according to any one of the preceding claims, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, used as a pharmaceutical agent.

30. The compound of any one of claims 1 to 28, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, for the prevention and / or treatment of medical conditions or diseases affected by inhibition of the interaction between YAP-TEAD and / or TAZ-TEAD.

31. The compound of any one of claims 1 to 28, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, for the prevention and / or treatment of medical conditions or diseases comprising the group consisting of: cancer, particularly tumors, including solid tumors, breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colorectal cancer, pancreatic cancer; cardiovascular diseases and fibrosis, particularly liver fibrosis.

32. A pharmaceutical composition comprising at least one compound as an active ingredient, any N-oxide, solvate, tautomer or stereoisomer of the compound or any of the foregoing, including mixtures thereof in all proportions, and a pharmaceutically acceptable carrier.

33. A pharmaceutical composition comprising (a) a compound of any one of claims 1 to 28 or any N-oxide, solvate, tautomer or stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, as a first active ingredient; and (b) a second active ingredient, wherein the second active ingredient is different from the compound of formula I as defined in any one of claims 1 to 28.

34. A method for preparing a compound according to any one of claims 1 to 28, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, comprising mixtures thereof in all proportions, characterized in that (A) in a first reaction step, the compound of formula II is subjected to... Where R 1 R 3 and X 1 As defined in any one of claims 1 to 28 with respect to formula I; Y 1 Indicates H or suitable protecting group PG 1 Hal 1 Y represents Cl, Br, or I; reacts with compound III under suitable C / C coupling reaction conditions. 2 -AL 1 -BIII where A, L 1 B is defined as described in any one of claims 1 to 28 with respect to formula I; Y 2 Indicate the suitable borate ester functional group; to obtain compound of formula IV. Or (B) in the first reaction step, make compound V... Where R 1 R 3 and X 1 As defined by Formula I of any one of claims 1 to 28; Y 1 Indicates H or suitable protecting group PG 1 ;Y 3 Indicates a suitable borate ester functional group; reacts with compound VI under suitable C / C coupling reaction conditions. 2 -AL 1 -BVI where A and L 1 And B as defined in any one of claims 1 to 28 with respect to formula I; Hal 2 Representing Cl, Br, or I; yielding a compound of formula IV; and optionally, after step (A) or (B) (C) (1) if in formula IV above, Y 1 PG 1 In the second reaction step, PG is removed under suitable reaction conditions. 1 , to obtain Y 1 A compound of formula IV with H, which can also be described as having R 2 Compound of formula I for H; and / or (C) (2) If Y is in formula IV above 1 If H represents the compound, then in another reaction step, compound IV reacts with compound VII under suitable reaction conditions. 2 -LG 1 VII where R 2 As defined in any one of claims 1 to 26, but not H; and LG 1 Represents a suitable leaving group; to obtain a compound of formula I as defined in any one of claims 1 to 28.

Images